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TRANSCRIBER NOTES:

    Words in italics are indicated with an underscore (_) at the begining
    and end. Words in bold are indicated with an equal sign (=) at the
    begining and end. Subscripts contained in chemical notations are
    indicated as _{ }.

    The table on page 32 has been modified to fit by the use of
    keys to replace some of the information.




  U. S. DEPARTMENT OF AGRICULTURE.

  BUREAU OF PLANT INDUSTRY--BULLETIN NO. 129.

  B. T. GALLOWAY, _Chief of Bureau_.


  BARIUM, A CAUSE OF THE
  LOCO-WEED DISEASE.


  BY

  ALBERT C. CRAWFORD,

  PHARMACOLOGIST, POISONOUS-PLANT INVESTIGATIONS.


  ISSUED AUGUST 22, 1908.

  [Illustration]


  WASHINGTON:
  GOVERNMENT PRINTING OFFICE.
  1908.




BUREAU OF PLANT INDUSTRY.


  _Physiologist and Pathologist, and Chief of Bureau_,
      Beverly T. Galloway.
  _Physiologist and Pathologist, and Assistant Chief of Bureau_,
      Albert F. Woods.
  _Laboratory of Plant Pathology_,
      Erwin F. Smith, Pathologist in Charge.
  _Investigations of Diseases of Fruits_,
      Merton B. Waite, Pathologist in Charge.
  _Laboratory of Forest Pathology_,
      Haven Metcalf, Pathologist in Charge.
  _Cotton and Truck Diseases and Plant Disease Survey_,
      William A. Orton, Pathologist in Charge.
  _Plant Life History Investigations_,
      Walter T. Swingle, Physiologist in Charge.
  _Cotton Breeding Investigations_,
      Archibald D. Shamel and Daniel N. Shoemaker, Physiologists in
      Charge.
  _Tobacco Investigations_,
      Archibald D. Shamel, Wightman W. Garner, and Ernest H. Mathewson,
      in Charge.
  _Corn Investigations_,
      Charles P. Hartley, Physiologist in Charge.
  _Alkali and Drought Resistant Plant Breeding Investigations_,
      Thomas H. Kearney, Physiologist in Charge.
  _Soil Bacteriology and Water Purification Investigations_,
      Karl F. Kellerman, Physiologist in Charge.
  _Bionomic Investigations of Tropical and Subtropical Plants_,
      Orator F. Cook, Bionomist in Charge.
  _Drug and Poisonous Plant Investigations and Tea Culture
      Investigations_, Rodney H. True, Physiologist in Charge.
  _Physical Laboratory_,
      Lyman J. Briggs, Physicist in Charge.
  _Crop Technology and Fiber Plant Investigations_,
      Nathan A. Cobb, Crop Technologist in Charge.
  _Taxonomic and Range Investigations_,
      Frederick V. Coville, Botanist in Charge.
  _Farm Management Investigations_,
      William J. Spillman, Agriculturist in Charge.
  _Grain Investigations_,
      Mark Alfred Carleton, Cerealist in Charge.
  _Arlington Experimental Farm_,
      Lee C. Corbett, Horticulturist in Charge.
  _Vegetable Testing Gardens_,
      William W. Tracy, sr., Superintendent.
  _Sugar-Beet Investigations_,
      Charles O. Townsend, Pathologist in Charge.
  _Western Agricultural Extension Investigations_,
      Carl S. Scofield, Agriculturist in Charge.
  _Dry-Land Agriculture Investigations_,
      E. Channing Chilcott, Agriculturist in Charge.
  _Pomological Collections_,
      Gustavus B. Brackett, Pomologist in Charge.
  _Field Investigations in Pomology_,
      William A. Taylor and G. Harold Powell, Pomologists in Charge.
  _Experimental Gardens and Grounds_,
      Edward N. Byrnes, Superintendent.
  _Foreign Seed and Plant Introduction_,
      David Fairchild, Agricultural Explorer in Charge.
  _Forage Crop Investigations_,
      Charles V. Piper, Agrostologist in Charge.
  _Seed Laboratory_,
      Edgar Brown, Botanist in Charge.
  _Grain Standardization_,
      John D. Shanahan, Crop Technologist in Charge.
  _Subtropical Laboratory and Garden, Miami, Fla._,
      Ernst A. Bessey, Pathologist in Charge.
  _Plant Introduction Garden, Chico, Cal._,
      W. W. Tracy, jr., Assistant Botanist in Charge.
  _South Texas Garden, Brownsville, Tex._,
      Edward C. Green, Pomologist in Charge.
  _Farmers' Cooperative Demonstration Work_,
      Seaman A. Knapp, Special Agent in Charge.
  _Seed Distribution_ (Directed by Chief of Bureau),
      Lisle Morrison, Assistant in General Charge.


  _Editor_, J. E. Rockwell.
  _Chief Clerk_, James E. Jones.




POISONOUS-PLANT INVESTIGATIONS.

SCIENTIFIC STAFF.


Rodney H. True, _Physiologist in Charge_.

  C. Dwight Marsh, _Expert in Charge of Field Investigations_.
  Albert C. Crawford, _Pharmacologist_.
  Arthur B. Clawson, _Expert in Field Investigations_.
  Ivar Tidestrom, _Assistant Botanist, in Cooperation with Forest
    Service_.




LETTER OF TRANSMITTAL.


  U. S. DEPARTMENT OF AGRICULTURE,
  BUREAU OF PLANT INDUSTRY,
  OFFICE OF THE CHIEF,
  _Washington, D. C., April 10, 1908_.


SIR: I have the honor to transmit herewith the manuscript of a technical
bulletin entitled "Barium, a Cause of the Loco-Weed Disease," prepared
by Dr. A. C. Crawford, Pharmacologist, under the direction of Dr. Rodney
H. True, Physiologist in Charge of Poisonous-Plant Investigations, and
to recommend that it be published as Bulletin No. 129 of the series of
this Bureau.

For many years the stockmen in many parts of the West have reported
disastrous consequences following the eating of so-called loco weeds
characteristic of the regions involved. While many have doubted any
causal relation between the plants in question and the stock losses, the
reality of the damage has remained and has seemed to require a
thoroughgoing sifting of the evidence concerning the part played by the
plants. Accordingly, in the spring of 1905 a station for the
experimental study of the problem was established at Hugo, Colo., in
charge of Dr. C. Dwight Marsh, Expert, in cooperation with the Colorado
Agricultural Experiment Station. Later a further feeding experiment was
undertaken at Imperial, Nebr., in cooperation with the Nebraska
Agricultural Experiment Station. Parallel with the feeding work in the
field, laboratory work, designed to test under laboratory conditions the
poisonous action of the plants from given areas, was undertaken at
Washington by Dr. A. C. Crawford, Pharmacologist. A further phase of his
part of the work was an attempt to ascertain the nature of such
poisonous substance or substances as might occur in the loco plants.

In both of these lines of work Doctor Crawford has been successful, and
the technical results of his work are here collected.

Respectfully,

                                                        B. T. GALLOWAY,
                                                     _Chief of Bureau_.

  Hon. JAMES WILSON,
  _Secretary of Agriculture_.




INTRODUCTORY STATEMENT.


A scientific understanding of the so-called loco-weed disease has been
demanded and sought after for several decades for most practical
purposes, but, in spite of the great amount of attention which this
problem has received, no general agreement has been found among the
results obtained. The field investigations have given such contradictory
evidence that until the Bureau of Plant Industry of the Department of
Agriculture turned its attention to the matter the whole subject of the
loco disease was regarded by many as a kind of delusion and the
existence of a distinct entity was freely doubted. Not only did this
confusion characterize the field aspect of the matter, but the situation
viewed from the standpoint of laboratory study was also much obscured.
Some investigators claimed to have separated poisonous substances of
various sorts from the loco weeds, while others of equal scientific
standing denied the presence of any poisonous substance in the plants
under general suspicion--the so-called loco weeds.

In view of the great seriousness of the loco situation from the
standpoint of the stock interests, an active campaign both in the line
of feeding experiments in the field and laboratory study at Washington
was undertaken by the Office of Poisonous-Plant Investigations of the
Bureau of Plant Industry.

The feeding experiments carried out at Hugo, Colo., in cooperation with
the Colorado Agricultural Experiment Station, before the close of the
first season developed evidence that there was in reality such a thing
as a loco disease. The investigator in charge was enabled to describe
the disease in its most important manifestations and made it possible to
sift the facts from the large number of contradictory statements in the
literature.

The laboratory work, undertaken and carried on simultaneously, consisted
of a pharmacological study, under laboratory conditions and with the
usual laboratory subjects, of the action of plant material sent in from
the field. The acute phase of loco-weed poisoning, as well as a more
prolonged type of the disease, was studied. In plants found in this
preliminary feeding to be harmful, the poisonous principle was sought,
with the very striking results fully described in this paper. The
demonstration of the presence of barium in the plants was followed by
barium feeding, with the production of symptoms which agreed with those
produced in the laboratory with loco extracts and in the field
experiments with the loco plants as seen growing on the range. By
comparing these laboratory results with those produced in connection
with the field work, it became possible to sift the wheat from the chaff
in the mass of contradictory evidence detailed in the literature of this
subject.

The practical importance of the discovery of the true nature of the
active poisonous principle of the loco weeds is very great. It not only
sheds light on the loco situation and enables one to explain many
hitherto inexplicable things, but it also adds much to our knowledge of
barium in its medical bearings. It opens up most important problems
concerning the soils and the relation of the flora to them. It should be
borne in mind that although barium is shown to be chiefly responsible
for the poisonous properties of loco weeds in eastern Colorado, it is
entirely possible that in other regions other substances may be equally
or even more significant. This discovery also seems likely to provide a
basis for a rational treatment of locoed stock. Unfortunately, the
discovery of the fact that barium is the poisonous constituent of loco
weeds came too late to aid in the search for remedial measures on the
range during the period covered by this report, but those empirically
arrived at have received additional support from these laboratory
results.

Thus the work in field and laboratory, undertaken after repeated
attempts and discouraging failures by others, has yielded results to
persistent scientific research and promises practical aid to the now
suffering live-stock interests. The results of the laboratory work are
presented in this bulletin.


  RODNEY H. TRUE,
  _Physiologist in Charge_.




CONTENTS.

                                                                   Page.

  Geographical distribution of the loco-weed disease and
      allied conditions                                               9

  Plants associated with the locoed condition                        10

  Clinical symptoms of locoed animals as described in literature     12

  Conditions similar to loco-weed poisoning in other parts
      of the world                                                   16

  Pathological conditions in locoed animals as described on
      the range                                                      18

  Historical sketch of loco investigations from a pharmacological
      standpoint                                                     19

  Notes on various members of the loco-weed family                   35

  Laboratory experiments--physiological                              36

  Experiments on rabbits                                             36

  Acute cases                                                        36

  Chronic cases                                                      38

  Pregnant animals                                                   42

  Subcutaneous injections                                            43

  Summary of feeding experiments on rabbits                          44

  Experiments on sheep                                               44

  Laboratory experiments--chemical                                   46

  Effect of the aqueous extract of ashed loco plants                 49

  Total ash determinations of loco plants                            54

  Barium determinations in the ash of loco plants                    55

  Analysis of soils                                                  57

  Feeding experiments with barium salts on animals in the
      laboratory                                                     57

  Barium poisoning in man                                            62

  Pathological lesions in experimental barium poisoning              65

  Toxicity of various aqueous extracts of loco plants                66

  Theoretical antidote for loco-weed poisoning                       71

  Action of barium on domestic and farm animals                      72

  Application of the results of these investigations to
      the range                                                      74

  Conclusions                                                        75

  Index                                                              77




  BARIUM, A CAUSE OF THE LOCO-WEED
  DISEASE.




=GEOGRAPHICAL DISTRIBUTION OF THE LOCO-WEED DISEASE AND ALLIED
CONDITIONS.=


In our Western States there is a marked annual loss of stock due to
various causes. Some of these animals die in a condition known as
"locoed," a term derived from the Spanish word "loco," meaning foolish
or crazy.

This disorder extends from Montana to Texas and Mexico, and from Kansas
and Nebraska to California.[1]

In 1898 the United States Department of Agriculture sent out, under the
immediate direction of Mr. V. K. Chesnut, a request for information
concerning the ravages of the loco disease. It was found that in the ten
States of California, Colorado, Kansas, Montana, Nebraska, New Mexico,
North Dakota, Oklahoma, Texas, and Wyoming the loss in 1898 was
$144,850. Of this amount, $117,300 was attributed to Colorado alone; in
fact, the disorder spread so that this State expended more than $200,000
in two years and over $425,000 in a period of nine years in attempts to
eradicate the loco plants, the supposed cause of the trouble.[2]

The loss in one area of 35 by 120 miles in southwestern Kansas amounted
to 25,000 cattle in 1883.[3] This loss in stock has been so great that
the raising of horses has of necessity been abandoned in certain areas
on account of the prevalence of these loco weeds.

It is difficult to obtain accurate data, as the ranchmen believe that
any information as to the prevalence of the disorder would interfere
with the value of their stock.[4]

Dr. James Fletcher, of the Central Experimental Farm, Ottawa, Canada,
testified before the Select Standing Committee on Agriculture and
Colonization that he had never seen a case in the North-west of a
Canadian bred animal being locoed, although the loco plants were
prevalent. He explained this absence of loco disease by the abundance of
grass on the range, because of which the animals do not acquire the
habit of eating loco plants.[5] Cases have been reported, however, in
Manitoba.[6]

       *       *       *       *       *

FOOTNOTES:

    [1] Stalker, M. The "Loco" Plant and Its Effect on Animals.
    Bur. Animal Industry, 3d Ann. Rept. (1886), p. 271. 1887.

    [2] Bur. Animal Industry, 6th and 7th Ann. Repts. (1889 and
    1890), p. 272. 1891.

    [3] Day, M. G. Loco-Weed. In F. P. Foster's Reference-Book of
    Practical Therapeutics, vol. 1, p. 587. 1896.

    [4] O'Brine, D. Progress Bulletin on the Loco and Larkspur.
    Colo. State Agric. Coll. Bul. 25, p. 18. 1893.

    [5] Fletcher, J. Evidence Before the Select Standing
    Comminttee on Agriculture and Colonization. Ottawas, 1905, p.
    53.

    [6] Fletcher, J. Experimental Farms Reports for 1892, p. 148.
    1893.




=PLANTS ASSOCIATED WITH THE LOCOED CONDITION.=


The condition known as "locoed" is popularly believed to be due to
eating various plants, especially the members of the Astragalus and
Aragallus genera of the Leguminosæ, or pea family, but particularly to
_Astragalus mollissimus_ and _Aragallus lamberti_. These plants have
therefore received the name "loco plants,"[7] or crazy weed. But others,
as _Astragalus mortoni_,[8] _A. hornii_, _A. lentiginosus_, _A.
pattersoni_,[9] _A. nuttallianus_, _A. missouriensis_, _A. lotifloras_,
_A. bisulcatus_, _A. haydenianus_,[10] _A. tridactylicus_,[11]
_Crotalaria sagittalis_, _Lotus americanus_,[12] _Sophora sericea_,
_Caprioides aureum_, _Aragallus deflexa_,[13] _A. campestris_,[14] _A.
lagopus_,[15] _Malvastrum coccineum_, _Amaranthus graecizans_, and
_Rhamnus lanceolata_, are considered by some as loco plants.[16] In
other places _Stipa vaseyi_, _Leucocrinum montanum_, _Fritillaria
pudica_, _Zygadenus elegans_,[17] and even species of Delphinium are
considered loco plants, so widely has this name been used.

In Mexico the term "locoed" embraces a condition due to the action of
_Cannabis sativa_ and various members of the nightshade family. This
term has been much abused and has been made to embrace many groups of
symptoms. In fact, if an animal dies while showing more or less stupor
it is said to be locoed.[18] The early Spanish settlers seemed to be
unfamiliar with the disease, or at least of any causative relation
between the plant and the disease. The Spanish name for _Astragalus
mollissimus_ was "Garbanzillo," from its resemblance to Garbanzo (_Cicer
arietinum_), which is used in Spain as a food.[19] The term as applied
to this condition seems to be of comparatively recent origin.[20]

A somewhat similar condition to the loco in stock is sometimes
attributed by the ranchmen of our Western States to eating various
sages.[21] In Texas the loco disease is known as "grass staggers."[22]

Hayes[23] has described as follows a condition known as grass staggers,
which apparently has little resemblance to loco and is supposed to be
due to eating overripe grass, especially rye.

     The symptoms, generally, take two or three days to become
     developed. The animal gradually becomes more or less unconscious
     and paralyzed and staggers if forced to walk. Although he may have
     great difficulty in keeping on his legs, he is extremely averse
     from going down and leans for support against any convenient
     object. He breathes in a snoring manner. The mucous membranes are
     tinged with yellow. Convulsions, or spasms, like those of tetanus,
     may come on.

     Recovery may be expected in cases which are not marked by extreme
     symptoms.

If animals are not regularly salted, they visit salt deposits and eat
the alkalis. This some sheepmen believe to be the cause of the locoed
condition, but this is disproved by the occurrence of locoed animals in
ranges without salt. Others modify this view by claiming that the
vitiation in taste from eating these alkalis leads to a desire for the
loco weeds and thus to the locoed condition.[24]

       *       *       *       *       *

FOOTNOTES:

    [5] Fletcher, J. Evidence Before the Select Standing
    Committee on Agriculture and Colonization. Ottawa, 1905, p.
    53.

    [7] Sayre, L. E. Loco Weed. Amer. Vet. Rev., vol. 11, p. 555.
    1887.--Stalker, M. The "Loco" Plant and Its Effect on
    Animals. Bur. Animal Industry, 3d Ann. Report. (1886), p.
    271. 1887.

    [8] Eastwood, A. The Loco Weeds. Zoe, vol. 3, p. 53. 1892.

    [9] Chesnut, V. K. Preliminary Catalogue of Plants Poisonous
    to Stock. Bur. Animal Industry, 15th Ann. Rept. (1898), p.
    404.

    [10] Williams, T. A. Some Plants Injurious to Stock. S. Dak.
    Agric. Coll. and Exper. Sta. Bul. 33, p. 21. 1893.

    [11] Givens, A. J. Loco or Crazy Weed. Med. Century, vol. 1,
    p. 22. 1893.

    [12] Eastwood, A., l. c. 1892.

    [13] Sayre, L. E. Loco Weed. Amer. Vet. Rev., vol. 11, p.
    555. 1887.

    [14] Amer. Pharm. Assoc. Proc. for 1879, vol. 27, p. 611.
    1880.

    [15] Kelsey, F. D. Another Loco Plant. Bot. Gaz., vol. 14, p.
    20. 1889.

    [16] Sayre, L. E. Loco Weed. Kans. State Board Agric., 5th
    Bienn. Rept., p. 209. 1887.

    [17] Anderson, F. W. Poisonous Plants and the Symptoms They
    Produce. Bot. Gaz., vol. 14, p. 180. 1889.--Pammel, L. H.
    Loco Weeds. Vis Medicatrix, vol. 1, p. 44. 1891.

    [18] Stalker, M. The "Loco" Plant and Its Effect on Animals.
    Bur. Animal Industry, 3d Ann. Rept. (1886), p. 275.
    1887.--Anderson, F. W. Poisonous Plants and the Symptoms They
    Produce. Bot. Gaz., vol. 14, p. 180. 1889.

    NOTE.--The symptoms described in Janvier's interesting story,
    "In Old Mexico" (Scribner's Magazine, vol. 1, p. 67, 1887),
    would coincide with those due to some member of the
    nightshade family (probably _Datura stramonium_). See also
    Pilgrim, C. W., Does the Loco Weed Produce Insanity? in Proc.
    Amer. Medico-Psycholog. Assoc., vol. 5, p. 167. 1898.

    [19] Sayre, L. E. Loco Weed. Kans. State Board Agric., 5th
    Bienn. Rept., p. 209. 1887.

    [20] Stalker, M. The "Loco" Plant and Its Effect on Animals.
    Bur. Animal Industry, 3d Ann. Rept. (1886), p. 272. 1887.

    [21] Mayo, N. S. Loco. The Industrialist, vol. 30, p. 473.
    1904.

    [22] Science, vol. 9, p. 32. 1887.

    [23] Hayes, M. H. Veterinary Notes for Horse Owners, London,
    1903, p. 425.--Compare Woronin, M. Ueber die Taumelgetreide
    in Süd-Ussurien. Bot. Zeit., vol. 49, p. 80. 1891.

    [24] Chesnut, V. K., and Wilcox, E. V. Stock-Poisoning Plants
    of Montana. U. S. Dept. Agric., Div. Bot., Bul. 26, p. 88.
    1901.

    NOTE.--The wide distribution of these plants is claimed to be
    partly due to the buffalo. See Blankinship, J. W., The Loco
    and Some Other Poisonous Plants in Montana, in Mont. Agric.
    Exper. Sta. Bul. 45, p. 79. 1903.




=CLINICAL SYMPTOMS OF LOCOED ANIMALS AS DESCRIBED IN LITERATURE.=


The animals usually affected are sheep, horses, cattle, mules,[25]
donkeys,[26] and goats. It is claimed that practically all herbivorous
animals are liable to the disease, even antelopes being affected.[27]
Hogs are said to be unaffected,[28] but definite information is lacking.
Cows seem to be less sensitive to this form of intoxication.[29] The
condition is usually a chronic one, although acute cases are said to
occur at times. The symptoms consist of digestive disturbances,
associated with emaciation and various symptoms suggesting lesions in
the nervous system, central or peripheral. The animals lose their
appetite from the first, begin to emaciate, and show symptoms of
malnutrition and starvation. The head trembles, the gait becomes feeble
and uncertain, the eyes become sunken and have a "flat, glassy
look."[30] There is a general sluggishness, muscular incoordination, and
difficulty in motion; finally all control of the limbs is lost and the
animal is unable to stand; the coat becomes rough and loses its luster,
and, in fact, all the typical symptoms of starvation appear. In some
cases diarrhea is also present.

All of Nockolds's animals, however, were constipated and the stools were
covered with mucus.[31] The dependent portions of the body may swell,
simply as an expression of the anæmia.[32] Sometimes there are symptoms
indicating acute pain,[33] the animals running about as if affected with
colic. They may belch and their abdomens swell. Some claim that the
animals are markedly salivated so that the saliva trickles from their
mouths. In other cases the mouth may be dry.[34] The eyes may be rolled
up so that the whites alone show. In some cases the pupil has been noted
to be dilated, as in atropine poisoning,[35] but Wilcox states that
they are contracted as after the use of eserine.[36] The temperature of
the animal falls from 1/2 degree to 1-1/2 degrees F. below normal.[37]
Tetanic symptoms may occur,[38] or the muscles of the mouth and tongue
becoming paralyzed may interfere with mastication. When water is offered
to the animal, it gazes stupidly at it and may not drink for days. One
of the symptoms noted is the loss of power to back properly.[39] Cows
during the first two or three months of gestation are almost sure to
abort.[40] This is claimed by Knowles, however, to be due to
malnutrition. As a result of these observations, suggesting some uterine
action, the drug has been proposed as an emmenagogue.[41]

The psychical symptoms are shown by errors of judgment. The animal
becomes dull and spiritless and wanders about half dazed. The mental
dullness passes into stupor. This dull, stupid condition has been
compared to intoxication with opium. If the locoed horse is led across a
stick lying on the ground he often jumps high as if it were a great
obstacle. The animal may now have maniacal attacks, during which he
rears and may fall backward,[42] and makes unreasonable jumps and other
unexpected movements, thus rendering himself dangerous to man.[43] Other
symptoms due to disturbances of the central nervous system are
hallucinations of various sorts. Though the optic nerve itself is
apparently not affected, the animal will stare at an object for a long
time without any apparent comprehension of its nature. This disturbance
in the visual function McCullaugh claims to be one of the first symptoms
of this disease. The animal seems to lose all idea of distance, as he
will butt against an obstruction as if oblivious of its presence. Any
sudden or violent motion made before him may cause him to fall.
According to some, the animal loses the sense which guides him in
finding water. A cow may fail to recognize her calf.[44] There is more
or less loss of control of the limbs[45] and tremors;[46] the feet are
lifted abnormally high when trotting, and, if crowded, the animal falls
headlong and will jump over little hollows as if they were wide
ditches.[47] The horse may shy without apparent cause and kick at
imaginary objects,[48] and, in fact, the reasoning powers seem to be
lost. These attacks are brought on by sudden excitement or when crossing
water.[49] There may be cutaneous hyperæsthesia.

The animals may remain with the herd, but they often wander away.
Stalker records the following observations:

     I have seen a single animal miles away from any other individual of
     the herd, carefully searching as if for some lost object, and when
     a loco plant is found he would devour every morsel of it with the
     greatest relish. As soon as one plant was eaten he would
     immediately go in search of more, apparently oblivious to
     everything but the intoxication afforded by his one favorite
     article of food.[50]

All of Nockolds's animals which were locoed were mares more than 6 years
of age.[51]

According to Stalker there is a passive type in which the animal shows
symptoms only on being disturbed; the animal then becomes unmanageable.
This happens even with old, well-broken saddle horses.[52]

There are few published reports as to the symptoms occurring in sheep
which are locoed. Stalker[53] says sheep "become loco-eaters, grow
stupid, emaciated, and eventually die." One of the few descriptions of
the symptoms is that of Ruedi,[54] in which he claims that the symptoms
in sheep are those comparable to the symptoms of cerebro-spinal
meningitis except that there is an absence of fever. Ruedi speaks of
sheep "lying flat on the ground, not able to stand, and not able even to
lift their heads to drink the offered water; the head and the vertebra
in opisthotonus position; the four legs stretched out and stiff;
breathing was stertorous, pulse slow, abdomen much distended, diarrhea
present. * * * The heart * * * was very slow and insufficient." The
teeth (in sheep) may blacken and fall out.[55]

It is mainly the young animals, such as lambs and colts, that are
affected, probably due to the fact that their attention is more easily
directed to the flower of the loco[56] plants. It is claimed (on slight
evidence) that men have become locoed. The symptoms in them are nausea
and headache.[57]

Schuchardt[58] has called attention to the resemblance of the symptoms
in locoed animals to those which occur in so-called lathyrism, but most
observers in this country have especially marked the resemblance of the
symptoms to those induced by the habitual use of narcotic drugs.[59]

As a rule the loco plants are refused by animals save when there is lack
of other food, although at times animals have shown the keenest relish
for these plants, rejected all other forage, and devoted their whole
attention to searching for the loco plants.[60]

Stalker says that animals not too long addicted to the use of these
plants, if confined, soon lose their taste for them (after two or three
months),[61] although old loco eaters do not readily lose the habit.
Stalker also says that "it is to be presumed that the plant is possessed
of some toxic property that has a specific effect on the nervous
centers, and that these effects have a marked tendency to remain
permanent."[62]

The fundamental character of the disorder seems to be a progressing
anæmia. The interpretation of psychical symptoms in herbivora, and
especially on the range, must often be fallacious.

       *       *       *       *       *

FOOTNOTES:

    [25] Kingsley, B. F. The Loco Plant. Daniel's Texas Medical
    Journal, vol. 3, p. 522. 1888.

    [26] Schwartzkopff, O. The Effects of "Loco-Weed." Amer. Vet.
    Rev., vol. 12, p. 162. 1888.

    [27] McCullaugh, F. A. Locoed Horses. Journ. Comp. Med. &
    Vet. Archives, vol. 13, p. 435. 1892.

    [28] Eastwood, A. The Loco Weeds. Zoe, vol. 3, p. 57. 1892.

    [29] Vasey, G. Plants Poisonous to Cattle in California.
    Report of Commissioner of Agriculture for 1874, p. 159. 1875.

    [30] Vasey, G., l. c., p. 159.

    [31] Nockolds, C. Poisoning by Loco Weed. Amer. Vet. Rev.,
    vol. 20, p. 570. 1896-7.

    [32] Patterson, A. H. Starvation OEdema. Med. Rev., vol.
    56, p. 715, 1899.

    [33] Vasey, G. Botanical Notes, Monthly Reports of Dept.
    Agriculture for 1873, p. 504. 1874.

    [34] Anderson, F. W. Poisonous Plants and the Symptoms They
    Produce. Bot. Gaz., vol. 14, p. 180. 1889.

    [35] Schwartzkopff, O. The Effects of "Loco-Weed." Amer. Vet.
    Rev., vol. 12, p. 161. 1888.

    [36] Wilcox, T. E. Treatment of "Loco" Poisoning in Idaho
    Territory. Med. Rec., vol. 31, p. 268. 1887.

    [37] Mayo, N. S. Some Observations Upon Loco. Kans. State
    Agric. Coll. Bul. 35, p. 118. 1893.

    [38] McCullaugh, F. A. Locoed Horses. Journ. Comp. Med. and
    Vet. Archives, vol. 13, p. 436. 1892.

    [39] O'Brine, D. Progress Bulletin on the Loco and Larkspur.
    Colo. State Agric. Coll. Bul. 25, p. 12. 1893.

    [40] Knowles, M. E. Loco Poisoning. Breeders' Gaz., vol. 39,
    p. 973. 1901.--Sayre, L. E. Loco Weed. Kans. State Board of
    Agric., 5th Bienn. Rept., p. 211. 1887.--Ruedi, C. Loco Weed.
    Trans. Colo. State Med. Soc., p. 422. 1895.

    [41] Miller, C. H. The Loco Weed: Its Probable Usefulness as
    an Emmenagogue. Southern Clinic, vol. 11, p. 269. 1888.

    [42] Vasey, G. Botanical Notes. Monthly Reports of Dept.
    Agriculture for 1873, p. 504. 1874.

    [43] Parker, W. T. The Loco-Weed. Science, vol. 23, p. 101.
    1894.

    [44] Vasey, G. Botanical Notes. Monthly Reports of Dept.
    Agriculture for 1874, p. 513. 1875.

    [45] Anderson, F. W. Poisonous Plants and the Symptoms They
    Produce. Bot. Gaz., vol. 14, p. 180. 1889.

    [46] Sayre, L. E. Loco Weed. Proc. Amer. Pharm. Assoc., vol.
    36, p. 111. 1888.

    [47] Nockolds, C. Poisoning by Loco Weed. Amer. Vet. Rev.,
    vol. 20, p. 570. 1896-7.

    [48] Knowles, M. E. Loco Poisoning. Breeders' Gaz., vol. 39,
    p. 972. 1901.

    [49] Vasey, G. Botanical Notes. Monthly Reports of Dept.
    Agriculture for 1873, p. 504. 1874.

    [50] Stalker, M. The "Loco" Plant and Its Effect on Animals.
    Bur. Animal Industry, 3d Ann. Rept. (1886), p. 272.
    1887.--Nockolds, C. Poisoning by Loco Weed. Amer. Vet. Rev.,
    vol. 20, p. 570. 1896-7.--Maisch, J. M. Poisonous Species of
    Astragalus. Amer. Journ. Pharm., vol. 51, p. 239. 1879.

    [51] Nockolds, C. Poisoning by Loco Weed. Amer. Vet. Rev.,
    vol. 20, p. 570. 1896-7.

    [52] Stalker, M., l. c., p. 273.

    [53] Stalker, M., l. c., p. 274.

    [54] Ruedi, C. Loco Weed (Astragalus Mollissimus): A
    Toxico-Chemical Study. Trans. Colo. State Med. Soc., 1895, p.
    417.

    [55] Blankinship, J. W. Loco and Some Other Poisonous Plants
    in Montana. Mont. Agric. Exper. Sta. Bul. 45, p. 81. 1903.

    [56] Blankinship, J. W., l. c.

    [57] Day, M. G. Loco-Weed. In F. P. Foster's Reference Book
    of Practical Therapeutics, vol. 1, p. 588. 1896.--Pilgrim, C.
    W. Does the Loco-Weed Produce Insanity? Proc. Amer.
    Medico-Psycholog. Assoc., vol. 5, p. 167. 1898.

    [58] Schuchardt, B. Die Loco-Krankheit der Pferde und des
    Rindviehs. Deutsch. Zeits. f. Thiermed., vol. 18, p. 405.
    1892.--Parker, W. T. Loco-Weed. Science, vol. 23, p. 101.
    1894.

    [59] McCullaugh, F. A. Locoed Horses. Journ. Comp. Med. and
    Vet. Archives, vol. 13, p. 435. 1892.

    [60] Stalker, M. The "Loco" Plant and Its Effect on Animals.
    Bur. Animal Industry, 3d Ann. Rept. (1886), p. 272. 1887.

    [61] Stalker, M. The "Loco" Plant and Its Effect on Animals.
    Bur. Animal Industry, 3d Ann. Rept. (1886), p. 272.
    1887.--See also Linfield, F. B. Sheep Feeding, in Mont.
    Agric. Coll. Exper. Sta. Bul., 59. 1905.--Special Report on
    Diseases of Cattle. Bur. Animal Industry, 1904, p.
    66.--Wilcox, E. V. Plant Poisoning of Stock in Montana. Bur.
    Animal Industry, 17th Ann. Rept., p. 115. 1900.

    [62] Stalker, M., l. c., p. 275.




=CONDITIONS SIMILAR TO LOCO-WEED POISONING IN OTHER PARTS OF THE WORLD.=


According to Maiden[63] a condition similar to loco is met with among
animals in Australia and is there believed to be due to eating various
species of Swainsona.[64] As Maiden says, "Its effect on sheep is well
known; they separate from the flock, wander about listlessly, and are
known to the shepherds as 'pea-eaters' or 'indigo-eaters.' When once a
sheep takes to eating this plant it seldom or never fattens, and may be
said to be lost to its owner." Horses, after eating this herb, "were
exceptionally difficult to catch, and it was observed how strange they
appeared. Their eyes were staring out of their heads and they were
prancing against trees and stumps. The second day two out of nine died,
and five others had to be left at the camp."

Martin[65] experimentally studied these cases of intoxication and sums
up his work as follows:

     1. That one can by feeding sheep upon Darling pea reproduce all the
     symptoms which are attributed by pastoralists to this cause.
     Briefly stated these symptoms are: Stupidity, loss of alertness and
     an agonized expression, followed by stiffness and slight staggering
     and frequently trembling of the head or limbs. Later, clumsiness
     and unsteadiness ensue, which slowly advance until the animal often
     falls down. In this stage, the action of the animal in running over
     small obstacles is characteristic. It jumps over a twig as if it
     were a foot in height. When first it commences to tumble about, it
     is able more or less readily to regain its feet, but in the
     advanced stage of the disease this is impossible and, after
     exhausting itself in efforts to do so, it remains lying down until
     it dies. During the whole time the sheep become progressively more
     bloodless, and in advanced cases the blood when shed appears to the
     naked eye lighter in color. It contains fewer red blood-cells
     (about two-thirds to one-half the usual number). (The corpuscles
     were estimated in several cases by means of a hæmocytometer.) All
     these symptoms are much aggravated by driving. Thus, an animal in
     which the symptoms are little marked may exhibit them in a striking
     degree after being driven. In addition to the above the teeth
     (especially in young sheep) frequently become loose, and
     consequently displaced or even dislodged.

     2. That the time which elapses before the onset of definite
     symptoms is three to four weeks in sheep of 2 to 3 years old. (It
     is probable, however, that with younger animals the time is
     shorter.)

     3. That under the conditions of the experiment, the animals
     survived about three months. They lived, however, an invalid's
     life. Everything was brought to them, and it is improbable that if
     feeding exclusively upon the pea, and left to shift for themselves
     in the paddocks, they would survive more than two months.

     4. That if a sheep be returned to proper fodder after one month to
     six weeks feeding upon the pea, and before the symptoms are fully
     established, it may recover completely.

     5. That when once the paralytic symptoms are established it will
     not recover; but if returned to proper food, will remain in much
     the same condition, becoming neither better nor worse.

     6. That Darling pea contains a very fair amount of nourishing
     material so that animals may, provided they eat it readily, retain
     their condition on it for some weeks, until the poisonous principle
     contained has had time to exert its effects.

These plants, if fed with other herbage, do not seem to be injurious and
apparently lose their harmful action upon being cultivated.[66] As long
as salt is properly fed the animals will not eat this plant[67] and are
said to suffer no effects from it. Physiological study has shown the
presence of a body with marked sudorific power which causes rapid
emaciation in frogs.[68]

It has been claimed that these symptoms are due to the presence of a
narcotic poison in the plant.[69] Post-mortem examinations were negative
save for the presence of a peripheral neuritis.[70]

       *       *       *       *       *

FOOTNOTES:

    [63] Maiden, J. H. Plants Reputed to be Poisonous to Stock in
    Australia. Dept. Agric., New South Wales, Misc. Pub. No. 477,
    pp. 15, 16. 1901.

    [64] Notes on Some American and Australian Plants Injurious
    to Stock. Agric. Gaz., New South Wales, vol. 4, p. 677.
    1894.--Notes on Weeds. The Darling Pea. Agric. Gaz., New
    South Wales, vol. 3, p. 330. 1893.

    [65] Martin, C. J. Report on an Investigation into the
    Effects of Darling Pea (Swainsona Galegifolia) upon Sheep.
    Agric. Gaz., New South Wales, vol. 8, p. 366. 1898.

    [66] Woolls, W. On the Forage-Plants Indigenous in New South
    Wales. Linn. Soc., New South Wales, Proc., vol. 7, pp.
    315-316. 1882.

    [67] Guthrie, F. B., and Turner, F. Supposed Poisonous Plant.
    Agric. Gaz., New South Wales, vol. 4, p. 86. 1894.

    [68] Bailey, F. M., and Gordon, P. R. Plants Reputed
    Poisonous and Injurious to Stock, Brisbane, 1887, p. 25.

    [69] Guthrie, F. B., and Turner, F. Supposed Poisonous Plant.
    Agric. Gaz., New South Wales, vol. 4, p. 87. 1894.

    [70] Martin, C. J. Report on the Investigation into the
    Effects of Darling Pea (Swainsona Galegifolia) upon Sheep.
    Agric. Gaz., New South Wales, vol. 8, p. 367. 1898. (Further
    literature on the indigo disease will be found in Bailey, F.
    M., and Gordon, P. R. Plants Reputed Poisonous and Injurious
    to Stock, Brisbane, 1887, p. 25).

    NOTE.--In Canada a chronic disease associated with cirrhosis
    of the liver results from eating ragwort, or _Senecio
    jacobaea_. See Dept. of Agriculture, Canada, Rept. of
    Veterinary Director General, 1905, Ottawa, 1906, p. 31.--In
    South Africa a disorder known as nenta appears in goats after
    eating certain plants, especially _Cotyledon ventricosa_. See
    Hutcheon, D., Nenta, in Agric. Journ. Cape of Good Hope, vol.
    14, p. 862. 1899.




=PATHOLOGICAL CONDITIONS IN LOCOED ANIMALS AS DESCRIBED ON THE RANGE.=


The pathological features as described by previous writers are a
softening and ulceration of the stomach walls[71] and a degeneration of
the walls of the intestines with or without perforations. The peritoneum
may be found inflamed.[72] The peritoneum and omentum in one case (cow),
reported by Sayre, were covered with small nodules. These were probably
tubercular in origin. The colon in one horse was found enormously
distended, while the coecum and small intestines were normal,[73] save
that the walls appeared thin.

Ulcers have been found at times in the kidneys, but were probably
secondary in origin, as other cases are reported with normal kidneys.
Faville has found in some cases amyloid degeneration. The pancreas and
spleen are reported normal. The abdominal cavity may contain a slight
effusion.[74] The liver has been found cirrhotic, and at times shows
tubercular lesions of a secondary nature. The inner coat of the bladder
has been found softened, and in sheep the bladder may be markedly
distended at the autopsy. The cerebral membranes are congested and
perhaps adherent,[75] and there may be blood clots over the longitudinal
sinus or at the base of the brain. Effusions have been especially noted
around the medulla. The arachnoid has also shown slight congestion, and
in other cases the membranes showed a slight thickening. The middle
ventricle was found filled with yellow serum, while the fourth ventricle
contained a hemorrhagic effusion,[76] and the base of the brain was
covered by a clot. The hemorrhage may become organized and the brain be
held to the membranes by tough organized fibers. In many cases serous
effusion is present in the lateral ventricles. The arachnoid space is
also in some cases similarly filled. Microscopic examination of the
brain in the case of a steer showed atrophy of Purkinjie's cells.[77]

In sheep the post-mortem examination showed paleness, anæmia of the
muscles, and great distention of the abdomen. The intestines were found
filled with gases, and the mesenteric blood vessels filled with blood.
No peritonitis, or ascites, or ecchymoses in the mucous membranes were
noted in the autopsies made on sheep by Ruedi. The liver has been seen
enlarged. In sheep the brain was anæmic. Microscopically the brain
showed atrophy and the Purkinjie's cells disappeared or their processes
atrophied. In these sheep the brain was so anæmic that the distinction
between the gray and the white matter was hard to define.[78] The
membranes of the cord have been found inflamed and adherent, but the
spinal cord was usually normal.[79] In some cases, however, the spinal
cord has been found softened[80] and oedematous. The arteries of the
limbs were gorged with blood,[81] and at the same time there was a
collection of serum in the abdominal cavity. Death is thought to be due
to starvation.[82] In other words, the pathological condition, according
to published accounts, shows little that is characteristic save some
action on the gastro-intestinal tract.

       *       *       *       *       *

FOOTNOTES:

    [71] Anderson, F. W. Poisonous Plants and the Symptoms They
    Produce. Bot. Gaz., vol. 14, p. 180. 1889.

    [72] Sayre, L. E. Loco Weed. Amer. Vet. Rev., vol. 11, p.
    558. 1887.

    [73] O'Brine, D. Progress Bulletin on the Loco and Larkspur.
    Colo. State Agric. Coll. Bul. 25, p. 12. 1893.

    [74] Faville, in O'Brine, D. Progress Bulletin on the Loco
    and Larkspur. Colo. State Agric. Coll. Bul. 25, p. 11. 1893.

    [75] Sayre, L. E. Loco Weed. Amer. Vet. Rev., vol. 11, p.
    559. 1887.

    [76] Stalker, M. The "Loco" Plant and Its Effect on Animals.
    Bur. Animal Industry, 3d Ann. Rept. (1886), p. 274.
    1887--Sayre, L. E. Loco-Weed. Amer. Pharm. Assoc. Proc., vol.
    38, p. 108. 1890.--O'Brine, D. Progress Bulletin on the Loco
    and Larkspur. Colo. State Agric. Coll. Bul. 25, pp. 16, 17.
    1893.

    [77] Mayo, N. S., l. c., p. 118.

    [78] Ruedi, C. Loco Weed (Astragalus Mollissimus): A
    Toxico-Chemical Study. Trans. Colo. State Med. Soc., 1895, p.
    418.

    [79] Sayre, L. E. Loco Weed. Amer. Vet. Rev., vol. 11, p.
    559. 1887.

    [80] O'Brine, D. Progress Bulletin on the Loco and Larkspur.
    Colo. State Agric. Coll. Bul. 25, p. 12. 1893.--Klench, J. P.
    Rattleweed or Loco Disease. Amer. Vet. Rev., vol 12, p. 399.
    1888.

    [81] Anderson, F. W. Poisonous Plants and the Symptoms They
    Produce. Bot. Gaz., vol. 14, p. 180. 1889.

    [82] McCullaugh, F. A. Locoed Horses. Journ. Comp. Med. and
    Vet. Archives, vol. 13, p. 436. 1892.




=HISTORICAL SKETCH OF LOCO INVESTIGATIONS FROM A PHARMACOLOGICAL
STANDPOINT.=


During the western immigration of 1849 the Indians along the Missouri
River described to the immigrants a plant (_Astragalus mollissimus_)
producing death in horses and cattle, which was preceded by various
forms of excitement.[83]

The attention of the United States Department of Agriculture was first
called to the toxic action of the loco plants in 1873, when specimens of
the plants, which were identified as _Astragalus hornii_ and _A.
lentiginosus_,[84] were sent from California by Mr. O. B. Ormsby, with
the statement that they were poisonous to stock, especially to horses.
Mrs. J. S. Whipple also corroborated this information. The botanist of
the Department, Dr. George Vasey,[85] published a note and requested
further information concerning the plants. These notes were enlarged by
a similar contribution by Dr. P. Moffat on _Aragallus lamberti_.[86] The
following year Vasey reported with more fullness, and his description of
the action of the plants is substantially what we find in most of the
books of to-day.

In 1876 Lemmon[87] noted that _Astragalus mortoni_ was "a deadly sheep
poison." At the same time Rothrock,[88] botanist of the United States
Geographical Survey under Lieutenant Wheeler, described these plants,
and Kellogg,[89] a botanist in California, reported that _Astragalus
menziesii_ was causing great losses in horses, sheep, and cattle and
claimed that the stockmen had been familiar with this disorder for at
least ten or fifteen years. This report of Kellogg was followed by that
of Rothrock[90] in 1877.

In 1876 a specimen of _Aragallus lamberti_ was sent from Colorado to
Professor Prescott, of the University of Michigan, under the name of
"crazy weed," with the statement that it was poisonous to horses and
cattle and that, while the Mexicans often used it in making beer, it
sometimes caused symptoms in men. His pupil, Miss Watson, undertook a
study of its chemical properties. She failed to isolate any pure
chemical compound, but claimed that in the root there was a body giving
alkaloidal reactions and that there was also a resinous body present.
Another of his pupils, W. R. Birdsall, took the ground-up root himself
in doses of 20 grains at various intervals for several days and later
40-grain doses in one and a half hours, but without experiencing any
marked symptoms except colicky pains. A kitten also was given about one
and a half ounces of the fluid extract without effect. Prescott[91] sums
up by saying that "it would seem that the dried ground root possesses no
poisonous properties." The work of Miss Watson was considered of
sufficient importance to be abstracted in the Annual Report of the
Commissioner of Agriculture for 1878 (1879), page 134.

Gradually the Department of Agriculture became more and more interested
in this subject, and Peter Collier, chief chemist, in 1878, examined the
roots and leaves of _Aragallus lamberti_ for alkaloids, but found
none.[92]

In 1880 Peter Collier published a proximate analysis of _Astragalus
mollissimus_ made by Francis A. Wentz, of Kansas. His investigations
showed it to have an ash content of 6.76 per cent, while the _Aragallus
lamberti_, analyzed by L. F. Dyrenforth, of Chicago, showed an ash
content of 4.32 per cent. Collier[93] sums up by saying:

     From the additional work done at this Department it seems probable
     that the deleterious effects observed from animals eating this
     plant may be due principally to the fact that the sweet taste
     causes cattle to reject more nutritious food and strive to subsist
     upon the Oxytropis only. This plant is mechanically a very unfit
     substance for food, being of a tough, fibrous, and indigestible
     character. It is possible that, when the animal becomes somewhat
     enfeebled by lack of proper nourishment, the small amount of
     alkaloid may have a direct poisonous action. Again, it seems
     probable that the plant may contain much larger proportions of
     alkaloid at certain stages in its development than at others, or
     the seeds may prove to be the most injurious portion.

The departmental work was continued by further short notices by
Vasey[94] in 1884, 1886, and 1887, and by the report of Stalker in 1887.
This report by Stalker is still the best description on the clinical
side of the question.

Rothrock,[95] meeting the loco plants in his survey work, describes
their effects on animals as follows:

     Certain it is, however, that, once commenced, they continue it,
     passing through temporary intoxication to a complete nervous and
     muscular wreck in the later stages, when it has developed into a
     fully marked disease which terminates in death from starvation or
     inability to digest a more nourishing food. The animal toward the
     last becomes stupid or wild, or even vicious, or, again, acting as
     though attacked with "blind staggers."

Under the name of Crotalaria, H. Gibbons,[96] in 1879, refers to a plant
growing in California which it was claimed was producing characteristic
symptoms of poisoning in horses and sheep. This plant Professor Maisch
afterwards identified as _Aragallus lamberti_.

Dr. Isaac Ott[97] undertook the physiological study of the question and
used an alcoholic extract of _Astragalus mollissimus_. He found from its
action on frogs, rabbits, and cats that the plant had decided
physiological action, as follows:

     (1) It decreases the irritability of the motor nerves.

     (2) Greatly affects the sensory ganglia of the central nervous
         system, preventing them from readily receiving impressions.

     (3) Has a spinal tetanic action.

     (4) Kills mainly by arrest of the heart.

     (5) Increases the salivary secretion.

     (6) Has a stupefying action on the brain.

     (7) Reduces the cardiac force and frequency.

     (8) Temporarily increases arterial tension, but finally decreases
         it.

     (9) It greatly dilates the pupil.

Doctor Stockman, in England, about this time tried the action of the
aqueous and alcoholic extracts of the dried _Astragalus mollissimus_
sent from Texas. He experimented with frogs and rabbits in increasing
doses, but without result.[98]

In 1888 Hill reported that a species of Astragalus was acting
detrimentally on cattle, goats, and sheep in Cyprus and that these
animals fell down as if intoxicated, and also that the natives in time
of great drought feed their cattle with this plant mixed with straw, but
that they were always made sick until they became used to it.

In 1885 Professor Sayre, of the University of Kansas, undertook the
investigation of the loco question. His first report was made in the
Transactions of the Kansas Academy of Sciences for 1885, and his reports
have been continued at various periods up to 1904. The results of his
experiments on various animals--dogs, cats, and frogs[99]--have been
entirely negative. He administered alcoholic preparations to himself and
took them until they became too nauseous to continue, and found they
produced absolutely no symptoms besides the nausea. He suggests,
however, that if the plant really is poisonous it is due to its fine
hairs, which might mechanically cause death. Sayre has stated that he
has sent thousands of pounds of the dried loco plants to various
investigators in America and Europe, but all reports were negative as to
pharmacological activity. He has, however, done some work on the pure
chemistry of the plant and found that the plant contained 10 per cent of
moisture and yielded 12.01 per cent of ash. Of this ash, 25 per cent was
soluble in water, while 50.6 per cent was soluble in HCl. The insoluble
portion consisted largely of silica. He found CaO, K_{2}O, MgO,
Al_{2}O_{3}, and Fe_{2}O_{3}, with the acid radicals SO_{3}, Cl,
P_{2}O_{5}, CO_{2}, and SiO_{2}.[100] Although Sayre claims that the
plant is physiologically inactive, he tried by chemical means to isolate
a physiologically active body and, naturally enough under the
circumstances, failed to find one. He claims that while the plant might
give alkaloid reactions, he was unable to isolate this body in a pure
state, and that alfalfa reacted similarly.

The investigation on animals was continued by Kennedy.[101] He
administered an infusion of 1/2 ounce of green _Astragalus mollissimus_
to a fasting dog weighing 23 pounds, but there were no symptoms after 12
hours. A decoction of 1 ounce of the green plant and one of 4 ounces of
the dried plant were likewise without action. Extracts with hydrochloric
acid were also inactive. When 400 grams of the dried and powdered plant
were fed in substance the result was merely to increase the appetite.
The organic acid obtained from 4 ounces of the plant was also found to
be inert.

Kennedy did not state in what season the plant was collected and from
what locality it was obtained, but says simply that the plant extract
was inactive to a dog, a carnivorous animal, and that therefore the
plant is nonpoisonous. He adds that death might be due to the tough
fibers and indigestible character of the plant. He overlooks, however,
the fact that the plant might vary in its toxicity, and he infers from
the experiments on carnivorous animals that these results would hold
good for herbivora, yet he does not claim that carnivora become locoed
in nature.

Kennedy found that the plant lost 80 per cent in weight on drying and
that the water extract which represented 30.6 per cent of the powdered
and dried plant contained magnesium sulphate and sodium chlorid, tannic
acid, gum, coloring matter, an extractive, and a "peculiar organic
acid." The ashed plant yielded 20 per cent of ash, consisting of
magnesium sulphate, sodium chlorid, alumina, silica, and a trace of
iron. "The abundant precipitate produced by the alkaline hydrates,
potassium, sodium, and ammonium was found to consist of magnesium
hydrate, an abundance of this base being present in the plant." Kennedy
also obtained alkaloidal reactions, but failed to isolate the body
giving these reactions.

In 1889 the investigations were greatly stimulated by the report of
Doctor Day,[102] then of the University of Michigan. She claimed that
she was able to produce marked physiological symptoms, using both
_Astragalus mollissimus_ and _Aragallus lamberti_ in her work. She
administered daily 60 to 70 c.c. of a decoction[103] of the plants to
kittens, together with abundant milk and other food. She states that in
two days--

     The kittens became less active, the coat grew rough, appetite for
     ordinary food diminished and fondness for the "loco" increased,
     diarrhea came on, and retching and vomiting occasionally occurred.
     The expression became peculiar and characteristic. Emaciation and
     the above symptoms progressively increased until the eighteenth
     day, when periods of convulsive excitement supervened. At times the
     convulsions were tetanic in character; frothing at the mouth and
     throwing the head backward as in opisthotonus were marked. At other
     times the kitten would stand on its hind legs and strike the air
     with its forepaws, then fall backward and throw itself from side to
     side. These periods of excitement were followed by perfect quiet,
     the only apparent sign of life being the respiratory movements.
     After a short interval of quiet the convulsive movements would
     recur. These alternate periods of excitement and quiet lasted
     thirty-six hours, when the posterior extremities became paralyzed,
     and the kitten died about two hours afterward. There was no
     apparent loss of consciousness before death.

     The post-mortem examination revealed the presence of ulcers in the
     stomach and duodenum. Some of the ulcers had nearly perforated the
     walls of the stomach and duodenum. The heart was in diastole; brain
     and myel appeared normal. As might be expected from the emaciated
     condition, the entire body was anæmic.

     In a second case 60 to 70 cubic centimeters of a more concentrated
     decoction were fed daily, with other food as before, to a vigorous
     adult cat. The symptoms of inactivity, loss of appetite, rough
     coat, diarrhea, and the peculiar expression of countenance were as
     in the first case. By the twelfth day the cat was wasted almost to
     a skeleton, and was correspondingly weak. Paralysis of the hind
     limbs came on, and the cat died on the thirteenth day. There were
     no periods of excitement in this case.

These cats developed a craving for the decoction and "would beg for it
as an ordinary kitten does for milk, and when supplied would lie down
contented."

Doctor Day made controls with healthy animals under the same conditions,
with the exception that they received no loco plant. She also fed a
young wild jack rabbit on milk and grass for a few days and then
substituted fresh loco plants for grass.

     At first the "loco" was refused, but after two or three days the
     "loco" was eaten with as much relish as the grass had been. After
     ten days of the milk and "loco" diet the rabbit was found dead,
     with the head thrown back and the stomach ruptured.

     Subcutaneous injections of the concentrated decoction caused
     nervous twitchings in frogs and kittens, and if large amounts were
     used death followed in from one to two hours from paralysis of the
     heart. The same symptoms were produced in frogs by the injection of
     an alcoholic extract of the residue left after the evaporation to
     dryness of the decoction.

In other words, Doctor Day was able to produce a chronic form of loco
poisoning with the characteristic symptoms so often described save in
the occurrence of diarrhea. Diarrhea is not usually noted on the range.
Sayre had already reported an ulcerated condition of the intestines of a
locoed cow similar to that described by Doctor Day as occurring in cats.
Doctor Day urged that the reason previous experimenters failed to
produce symptoms was that they had used too small an amount of the plant
and that by systematic feeding to healthy cats cases of loco disease may
be produced.

Storke states that "Dr. V. C. Vaughan, of the University of Michigan,
has since fully corroborated Dr. Day's views."[104]

In her experiments Doctor Day used the leaves, roots, and stems of the
plants gathered in September. She believed that the greatest amount of
poison is present in autumn and winter. She later undertook the
isolation of the active principle, and proceeded as follows:[105]

     The roots, stems, and leaves were boiled ten hours, strained, and
     the decoction concentrated to a sirup, poured, while hot, into a
     hot flask, corked and set away. At the end of ten days the sirup
     had separated into two layers--the upper a blackish liquid, the
     lower a brownish sediment. The liquid was poured into a flask and
     covered with six times its volume of very dilute alcohol, 30 per
     cent (the sediment also was washed with dilute alcohol, to insure a
     complete removal of the liquid), corked, and let stand three days;
     agitated occasionally, then filtered, and the filtrate slowly
     evaporated in the air, when crystals were formed. It was found
     important not to hurry the evaporation, for when this took place
     too rapidly the crystals did not form.

     These crystals are microscopic in size, blue-white in color, and of
     a variety of forms. The most characteristic are slender and
     pointed, arranged in rosettes or grouped in various ways. They are
     soluble in distilled water and very dilute alcohol, very sparingly
     soluble in strong alcohol, not soluble in chloroform or ether.

     The evaporated mass containing the crystals, when dissolved in
     distilled water, is slightly acid in reaction. A small amount of
     this fed to a kitten produced the train of characteristic toxic
     symptoms--sleepiness, loss of appetite, retching, and
     diarrhea--that is produced by quite large amounts of the decoction.

The crystals Sayre[106] claims to have already seen. He says that they
gave no precipitate with Mayer's reagent, platinum chlorid, or with
ammonia, but that barium chlorid and ammonium oxalate gave a
precipitate, and he believes that they were in reality an inorganic
combination of calcium, so that while Doctor Day may have obtained an
extract which produced characteristic symptoms she certainly has not
isolated any pure active principle. Later she admitted that it was not
possible "to make positive statements as to the chemical character of
the active principle."[107]

In 1884 there was a fatal outbreak of a disorder in horses in portions
of the Missouri Valley in Iowa, Nebraska, and Dakota. This was almost
uniformly fatal in a few weeks or months. The animals lost strength and
became emaciated, although they were kept in pasture where there was
abundant grass. There was marked stupor, the animals falling asleep
while eating, and they "would remain standing for a whole week, sleeping
much of the time, with the head resting upon some object." The
post-mortem examination showed that "in every instance there was marked
hemorrhagic effusion into the fourth ventricle, the liver and spleen
were abnormally dense, the walls of the intestines were almost destitute
of blood, and the stomach enormously distended with undigested food."
The post-mortem find and clinical symptoms suggested to Stalker[108]
that this disorder was due to some plant analogous to _Astragalus
mollissimus_. He found abundant in these regions _Crotalaria
sagittalis_, or rattle-box, one of the so-called loco weeds, and by the
administration per os to a young horse of an infusion of 15 pounds of
the plant, given in two days, produced the clinical symptoms and the
post-mortem condition of the brain which he previously observed on the
range.

Power and Cambier[109] undertook the chemical study and the isolation of
the active principle of this plant, together with that of _Astragalus
mollissimus_. They found that the _Astragalus mollissimus_ if distilled
with water yielded a distillate which possessed a peculiar odor, which
they thought due to a trace of volatile oil. On distilling with alkali
they obtained ammonia and a trace of trimethylamine. In the case of
Crotalaria only ammonia was found.[110] They argued that because
trimethylamine was not obtained in this case choline was not present. On
distilling the _Astragalus mollissimus_ with acidulated water
(H_{2}SO_{4}) the distillate was found to contain acetic acid--settling
the nature of the "peculiar organic acid" described by Kennedy. From
this plant they obtained a resin or mixture of resinous bodies by
extracting the plant with alcohol, and after concentration precipitating
with acid water. These resins in doses of from 2 to 5 grains failed to
produce any symptoms in kittens.

An albuminoid which was obtained by precipitating a concentrated aqueous
extract of _Astragalus mollissimus_ by means of alcohol likewise was
found to be inactive to a kitten in doses corresponding to 50 grams of
the crude plant. A globulin which was isolated by precipitation from a
10 per cent sodium chlorid solution proved also to be inactive in doses
of 0.2 gram. They then extracted 3 kilograms of these plants with 1/2
per cent sulphuric acid, and after evaporation to a thick gum the mass
was extracted with strong alcohol, the alcoholic solution was
evaporated, and the alcoholic residue taken up in water and precipitated
by neutral and basic lead acetates, and after removing the lead with
sulphureted hydrogen the filtrate gave precipitates with various
alkaloidal reagents. The sirupy residue which they obtained from
_Astragalus mollissimus_ by decomposing the precipitate with Mayer's
solution administered to kittens in doses of 0.1 gram produced merely
frothing at the mouth with profuse flow of saliva, but the animals soon
recovered. The presence of a large amount of calcium was shown but not
estimated quantitatively.

Power and Cambier summed up their conclusions by stating that both the
Astragalus and the Crotalaria contain very small amounts of toxic
alkaloids, to which they believe the symptoms of poisoning produced were
due. Their work from a chemical standpoint is excellent, but from a
pharmacological point of view seems to be deficient; in fact, Power does
not claim to be a pharmacologist. What would seem to be the proper
course would have been to test for themselves the action of the plant
on various animals and, after deciding which reacted most
characteristically, test, after various precipitations, both the
precipitates and filtrates on various animals to see whether the
original symptoms and pathological lesions could be produced. They
failed, however, to test their mother substance. It is well recognized
that plants grown under varying conditions and on different soils vary
in the amount of the physiologically active principle they contain.

In the case of Crotalaria, Power and Cambier had before them the
experiment of Stalker, in which he reproduced the disorder by feeding
the plant extract to horses, yet they claimed that the body which they
administered was the active principle, merely because it produced some
frothing at the mouth and salivation in a kitten. The percentage of
active principle they found would be too small to account for the
symptoms, except in the case of a very active compound.

Certain of these precipitates were also later examined physiologically
by O'Brine.[111] He also found the resin precipitated from an alcoholic
extract of the plant and also the alcoholic extract from 2.2 pounds of
the dried _Astragalus mollissimus_ to be physiologically inactive.

Oatman,[112] using Power and Cambier's method with alfalfa (_Medicago
sativa_), obtained a noncrystalline mass which when given in 0.1 gram
dose caused frothing at the mouth in a kitten, but no serious symptoms.
This 0.1 gram represented about 5 pounds of powdered leaves and tops of
the plants.

Since the appearance of Power and Cambier's work Sayre has published
various papers on the loco weeds in the Transactions of the Kansas
Academy of Sciences for 1903-4, vol. 19, p. 194, 1905; 1901-2, vol. 18,
p. 141; Seventh Biennial Report of the State Board of Agriculture of
Kansas, vol. 12, p. 97, 1891; Journal of the Kansas Medical Society,
vol. 4, pp. 222 and 241, 1904, etc. He has contributed nothing
especially new, but says that "the old theory that an alkaloidal poison
is secreted in the plant causing the loco trouble has not been found
tenable," but wishes to be understood that he does not discredit the
ground for the opinion that in some mysterious way certain disorders
occur in cattle in connection with what is commonly called loco-weed. He
suggests that this connection might be somewhat similar to the
relationship between the disorder caused by over-feeding half-starved
animals on clover or alfalfa[113] and has had the plant analyzed as to
its nutritive value, giving the table in the Transactions of the Kansas
Academy of Sciences, vol. 19, p. 194. He makes the suggestion that any
injurious action the plants may have might be due to the fine, hair-like
projections on the plant which mechanically set up irritation. This
supposition can be thrown out at once by the experiment of Day and
others, who induced symptoms in animals by extracts of the plant, and by
the fact that other coarse plants do not act similarly. This fine,
hair-like material was found to constitute about 33 per cent of the
plant on grinding. But Sayre himself does not seem to be positive as to
any conclusion. He, like O'Brine and others, has obtained alkaloidal
reactions from the plant, but states he has obtained similar ones from
alfalfa.[114] At one time he said:

     I do not consider loco directly or indirectly the cause of the
     condition, but am of the opinion that what is called "locoed" is,
     first, congestion of the brain and spinal marrow (causing blindness
     and first symptoms), and, second, softening to a greater or less
     extent.[115] These terms describing the alleged symptoms of
     "locoism" might occur in well recognized diseases resulting from
     brain lesions, which latter occur in so-called forage poisoning and
     poisoning from foul drinking water, etc.

     We are not prepared to affirm or deny that the loco-weed produces a
     train of symptoms characteristic of the plant.[116]

Again Sayre states:

     It seems not unreasonable to suppose that the peculiar condition of
     the animals of the plains, when they gorge themselves with this
     highly nitrogenous weed, has something to do with the disease. A
     condition of malnutrition may set in and give rise to the rapid
     growth of a toxic-producing micro-organism or an irritating
     principle. This principle may be capable of cultivation and of
     producing disease artificially. Be this as it may, we feel
     warranted in saying that the so-called poison is a development
     within the animal, not a product preexisting in the weed itself.

Sayre also suggests the possibility of the plants producing hydro-cyanic
acid, which, it is well known, occurs in sorghum.[117] In the Journal of
the Kansas Medical Society (vol. 4, p. 243), he claims to have isolated
a crystalline body, but this he has not tested physiologically. Sayre
especially deserves credit for keeping the loco investigation alive, and
no doubt his change in position is due to his lack of facilities for
pharmacological testing.

Carl Ruedi[11] fed rabbits daily by a stomach tube with 10 c.c. of an
extract (unstated strength) of _Astragalus mollissimus_ and recorded the
following results:

     After only five injections one of the rabbits died, and the
     post-mortem showed to a nicety the congestion of the whole tract of
     the vena portæ and the anæmia of the brain. I put six rabbits under
     the influence of loco, and the effect was marked, but not rapid, if
     not given in very concentrated solutions. The solutions were
     prepared differently, and each of the rabbits had its own
     preparation, but the effect was nearly the same. In the beginning
     loco acts as a stimulant; the animals get lively, hilarious,
     running about; cleaning themselves, etc. This lasts about eight
     hours, then they become very quiet, sit in a corner of a box, and
     one can do with them pretty nearly what one likes; they do not move
     from the place, or just run into another corner, to fall back into
     the same complacent reverie. One can leave the door open and hammer
     away at the box, but they do not show any inclination to run away.
     During the excitement, however, they become fierce, and I had once
     the opportunity to watch one of the drollest things possible: One
     of the rabbits, two hours after dosing it, got loose and ran under
     a porch. A heavy tomcat came near this hole, and commenced sniffing
     about; this offended the rabbit highly, and it jumped on the neck
     of the cat, bit it through the skin, and the cat ran screaming
     away. When the animals are first under the influence of moderate
     doses of loco, they suffer greatly from hyperæsthesia of the
     cutaneous nerves; when one touches them with a stick while lying in
     a corner, without hurting them, one sees the platysma working away
     very forcibly, and sometimes they utter sounds of pain. According
     to my experiments the loco-weed works slowly but surely; as soon as
     the anæmia of the brain sets in, the animals act in every respect
     mad like; one hour they are excitable, and then again dull and
     languid as can be. The rabbits eat, when well, very quickly, and
     whenever they have opportunity; not so the locoed rabbit; he eats
     slowly for a minute or two, then he goes into a corner and
     meditates, comes forward to nibble at a carrot or a piece of
     cabbage, but he never eats greedily, and does not steal it from the
     mouth of his neighbor, or only very exceptionally. I observed these
     rabbits for ten days; they did not die, because I gave them weaker
     solutions; but they all became very ill, and as I had to leave the
     park I killed them with the needle inserted into the medulla
     oblongata, and made the post-mortem. In all of these cases I found
     great congestion in the abdomen, and marked anæmia of the brain.
     The congestion of the vena portæ commences certainly very early,
     but still the first symptoms are the nervous symptoms, first as
     excitants, then depressing or sedative, with a marked hyperæsthesia
     of the cutaneous nerves.

Ruedi made an attempt to isolate the active principle and separated a
base, which he calls "locoin," from an ether shaking. This base,
however, he found to be physiologically inactive, but believes the
activity to be due to a body which he calls "loco-acid," which is
present in the mother liquid after the shaking with ether. He, however,
has not obtained this in any degree of purity and gives no chemical data
to substantiate this statement save that the fluid was acid.

Experiments made at the University of Pennsylvania with certain loco
plants on cats, dogs, and rabbits proved negative.[119]

Other experiments on rabbits have been made by Doctor Lewis. These
rabbits were fed on the leaves, stem, and whole plant, and also extracts
of one of the loco plants (presumably _Astragalus mollissimus_) for one
or two months, without producing any noticeable effect.[120]

This uncertainty in the results of the investigation as to the cause of
the loco disease turned the attention of observers into other lines.
President Ingersoll,[121] of the State Agricultural College of Colorado,
in his autopsies on sheep was struck by the presence of tapeworms
(_Taenia expansa_) in the gall duct and small intestines. He apparently
tried to prove a relationship between the tapeworms and the locoed
condition by feeding the extract of a loco plant to sheep, and thus
showing its harmlessness. He prepared a decoction from 20 pounds of loco
plant (the species was not stated) and boiled this down from 12 gallons
to 1 quart. This concentrated extract was fed in three days to a
bottle-fed lamb; this lamb showed no symptoms, although kept under
observation for two weeks. This theory of the causation of loco by worms
was also considered by Curtice,[122] and later brought forward by
Steele[123] and Marshall.[124] This idea is very suggestive when
considered in relation to the etiology of bothriocephalous anæmia.[125]

Others, again, have claimed that the disease is due to a parasite found
upon the loco plants, but all specimens examined by entomologists proved
to be harmless.[126]

Lloyd, from his study of the subject, says:

     From first to last I have failed in obtaining a characteristic
     proximate principle, either from the fresh or dried plant. The
     disease called loco was as murky as the milk sickness so prevalent
     in the new settlements of Indiana and Kentucky in early days, and,
     like the numberless herbs that have been presumed to produce that
     obscure peculiar disease, milk sickness, loco was unresponsive to
     my chemistry.[127]

     It may be safely said that if a specimen of the plant were to be
     examined in the ordinary manner by a chemist who had no idea of its
     importance he would report that it did not contain a characteristic
     proximate constituent.[128]

     Can it be that an admixture of loco and some undetermined plant or
     earth infected with bacteria taken with the roots, each innocuous
     under other conditions, can by digestion together in the stomach
     and intestines result in the production of a poison?[129]

     To sum up, it seems to the writer that the poison of loco is a
     product, and not an educt.[130]

But Lloyd adds, in speaking of the reports of various experts and
ranchmen:

     Their description concerning its toxic action on animals agreed,
     and it was folly to argue that so many observers from so many
     sections of the country could be misled. There must be an
     undetermined something behind the loco-weed.[131]

In 1893 O'Brine, from Colorado, and Mayo, from Kansas, reported on their
work with the loco plants. O'Brine failed to isolate any alkaloidal or
other poisonous body, and his feeding experiments on himself and on
rabbits having failed, he sums up in despair: "The more I examine the
loco question, the more I am persuaded that we must look for some other
cause besides the loco-weed."[132] At the end of his report he gives
some ash analyses but fails to interpret them. He also fails to give
details as to the method of obtaining and estimating his ash. O'Brine's
ash analyses are as follows:

  KEY TO ASH ANALYSIS:
   A = SiO_{2}.
   B = Fe_{2}O_{3} and Al_{2}O_{3}.
   C = CaO.
   D = MgO.
   E = K_{2}O.
   F = Na_{2}O.
   G = H_{2}SO_{4}
   H = Cl.
   I = P_{2}O_{5}.
   J = CO_{2}

  ------+-----+-----+-----+-----+----+-----+----+----+----+----+-----+
  Plant.|Total|     |     |     |    |     |    |    |    |    |     |
        |ash. |  A  |  B  |  C  |  D |  E  |  F |  G |  H | I  |  J  |
  ------+-----+-----+-----+-----+----+-----+----+----+----+----+-----+
    AM  |12.15|32.77|16.26| 6.05|3.11|13.30|3.21|3.9 |0.47|6.12|10.55|
        |     |     |     |     |    |     |    |    |    |    |     |
    AL  |13.52|17.08|12.21|14.27|2.62|17.26|5.75|3.22|3.87|3.30|17.37|
        |     |     |     |     |    |     |    |    |    |    |     |
    AC  |12.36| 7.82| 5.97|12.10|3.55|23.35|3.38|5.56|9.0 |4.67|20.62|
        |     |     |     |     |    |     |    |    |    |    |     |
  ------+-----+-----+-----+-----+----+-----+----+----+----+----+-----+
  KEY TO PLANTS:
   AM = _Astragalus mollissimus_ (whole plant)
   AL = _Aragallus lamberti_ (whole plant)
   AS = _Astragalus caryocarpus_

These analyses are evidently incorrect, as O'Brine estimates a carbon
content of 4.13 per cent for the first, and for the second 2.22 per
cent, showing incomplete combustion.

Mayo[133] experimented with alcoholic and aqueous extracts of dried
_Astragalus mollissimus_ on guinea pigs, with negative results, and was
first led to deny a relationship between the disease and the plants.
Later, as a result of the post-mortem findings, he was convinced that
his first conclusion was wrong and that "the disease is certainly the
result of animals feeding upon the loco-weed." Mayo says:

     A careful survey of the experiments performed and observations
     noted leads me to the opinion that the disease known as "loco" is
     the result of malnutrition, or a gradual starvation, caused by the
     animals eating the plants known as "loco weeds," either _Astragalus
     mollissimus_ or _Aragallus lamberti_. If there is a narcotic
     principle in the plant, chemists have failed to find it and a fluid
     extract does not possess it, and a ton of the plant eaten by an
     animal ought to contain enough of the poisonous properties to
     destroy an animal.

Kobert[134] has also tested the activity of _Astragalus mollissimus_ and
says, "Ich fand _Astragalus mollissimus_ ziemlich unwirksam."

Doctor McEackran[135] fed dried _Astragalus mollissimus_ and _Aragallus
lamberti_ mixed with feed to a stabled animal for two months without
result. (Animal not stated).[136] Similar negative experiments are
reported from the State of Washington, but the amounts used were too
small to form any conclusions.[137]

Mr. V. K. Chesnut[138] has busied himself with the loco problem, but
mainly in an executive capacity, his own efforts being directed to the
study of the relation of the loco plants to the disease on the range. He
has done no laboratory work. Chesnut and Wilcox made numerous autopsies
on sheep and experiments on animals. They claimed that an extract of
_Aragallus spicatus_ produced some slight narcotic action in rabbits.
Their pathological examinations failed to show any characteristic
lesion, but they state that the cerebral membranes were in all cases
slightly congested. They deny any causative relationship to the presence
of worms or with feeding upon alkalis. They believe that sheep are more
likely to become locoed if not salted regularly. Chesnut describes one
case in which a lamb became locoed by nursing from a locoed mother.

In 1901 Reid Hunt, at that time a special agent of the United States
Department of Agriculture, studied the loco question in Montana, working
mainly with _Aragallus spicatus_. He moistened the ground-up plant with
93 per cent ethyl alcohol and then percolated it until exhausted. This
extract was evaporated and taken up with water so that 1 c.c. of the
solution corresponded to 10 grams of the plant. This was fed to an
active young rabbit weighing 490 grams, 6 c.c. being fed by the mouth
and followed in about an hour by 10 c.c. more, and two hours after this
by 15 c.c. This rabbit showed no symptoms during the following day. The
next day it was very dull and there was marked muscular weakness, as the
rabbit's legs were spread wide apart and his nose rested on the ground.
Later respiration became very slow and the pupils were dilated. The
paralytic symptoms increased and finally, after a convulsive movement,
the animal died, thirty-six hours after the first feeding. Hunt merely
states of the post-mortem examination that the stomach was well filled
and that the "walls seem normal."

Hunt tried to isolate an active principle by the Dragendorff method, but
failed to obtain any physiologically active shakings. He tried
hypodermic injections of 80 per cent alcohol extractions of the fresh
green plant, and after the injection of an extract corresponding to 60
grams of the fresh plant there was no effect produced. He tried to
induce symptoms by feeding the plant itself to rabbits, but was
unsuccessful, as the rabbits refused to eat the plant. He was not able
to induce symptoms with the extracts of the dried plant.[139]

Marshall[140] studied the loco question with regard to sheep and
practically denies the existence of a locoed condition due to eating the
loco plants, but believes the condition due to bad feeding, parasitism,
etc. He lays great stress upon the presence of worms, but fails to see
that they may be merely a secondary infection superimposed upon an
already morbid condition produced by eating the plants. Others have
claimed that the cause is an insect living upon the loco plants. Others,
again, have suggested an analogy with trypanosome disorders.

Chesnut has held the view that many of the cases of so-called locoed
sheep were really due to parasites, but that there was a true locoed
condition due to eating the loco weeds.

The lack of agreement in the results of the investigators has caused
many to doubt any positive relation between the plant and the disease,
and even as late as 1904 Payne[141] practically says these diseases are
due to lack of nutrition and not to the loco plant. The matter has been
summed up in a recent work as follows:

     Though many chemists have sought for the constituents, none have
     been able to locate the active properties, the trace of alkaloids,
     resins, volatile and fixed oils having each in turn been found
     destitute of it. Yet the poisonous properties are fully established
     by field observations. The destructiveness of these plants to stock
     is so great as to have probably caused upward of a million dollars
     loss in the aggregate, and large bounties have been offered by
     State governments for an effective method of avoiding such losses.
     It is considered very probable that the poisonous constituent is
     albuminoidal.[142]

       *       *       *       *       *

FOOTNOTES:

    [83] Storke, B. F. The Loco Weed. Med. Current, vol. 8, p.
    155. 1892.--Kellogg, A. California and Colorado "Loco"
    Poisons. Cal. Acad. Sci. Proc. for 1875, vol. 6, p. 3. 1876.

    NOTE.--The very early reports of these loco plants were
    purely botanical. See Torrey, J., Botany, in Report on the
    United States and Mexican Boundary Survey, by W. H. Emory,
    vol. 2, p. 56, 1859; also Botanical Register, London, vol.
    13, pl. 1054, 1827.

    [84] Vasey, G. Plants Poisonous to Cattle in California.
    Rept. of Commissioner of Agriculture for 1874, p. 159. 1875.

    [85] Vasey, G. Botanical Notes. Monthly Reports of Dept.
    Agriculture for 1873, p. 503. 1874.

    [86] Vasey, G. Botanical Notes. Monthly Reports of Dept.
    Agriculture for 1874, p. 513. 1875.

    [87] Brewer, W. H., and Watson, S. Geological Survey of
    California, Botany, vol. 1, p. 155. 1876.

    [88] Rothrock, J. T. Notes on Economic Botany, in G. M.
    Wheeler's Report upon U. S. Geographical Surveys West of the
    One Hundredth Meridian, vol. 6, p. 43. 1878.

    [89] Kellogg, A. California and Colorado Loco Poisons. Cal.
    Academy of Sciences, Proc., 1875, vol. 6, p. 3. 1876.

    [90] Rothrock, J. T. Poisonous Properties of the Leguminosæ.
    Acad. of Nat. Sci., Phila., Proc., vol. 29, p. 274. 1877.

    [91] Prescott, A. B. Laboratory Notes--A Partial Analysis of
    the Oxytropis Lamberti. Amer. Journ. Pharm., vol. 50, p. 564.
    1878.

    [92] Rept. of Commissioner of Agriculture for 1878, p. 134.
    1879.

    [93] Rept. of Commissioner of Agriculture for 1879, pp. 89,
    90. 1880.

    [94] Rept. of Commissioner of Agriculture for 1886, p. 75.
    1887. Rept. of Commissioner of Agriculture for 1884, p. 123.
    1884.

    [95] Rothrock, J. T. Notes on Economic Botany, in G. M.
    Wheeler's Report upon U. S. Geographical Surveys West of the
    One Hundredth Meridian, vol. 6, p. 43. 1878.

    [96] Gibbons, H. Poisonous Effects of Crotalaria--Vulgo
    Rattle Weed, Loco Weed. Pacific Med. and Surg. Journ., vol.
    21, p. 496. 1878-79.

    [97] Ott, I. Physiological Action of Astragalus Mollissimus.
    New Remedies, vol. 11, p. 227. 1882.

    [98] Hill, J. R. Note on a Species of Astragalus from Cyprus.
    Pharm. Journ. and Trans., 3 s., vol. 18, p. 712. 1887-88.

    [99] Sayre, L. E. Loco-Weed. Proc. Amer. Pharm. Assoc., vol.
    36, p. 112. 1888.

    [100] Sayre, L. E. Loco Weed. Amer. Vet. Rev., vol. 11, p.
    556. 1887.

    [101] Kennedy, J. Loco Weed (Crazy Weed). Pharm. Rec., vol.
    8, p. 197. 1888.

    [102] Day, M. G. Experimental Demonstrations of the Toxicity
    of the "Loco Weed." N. Y. Med. Journ., vol. 49, p. 237. 1889.

    [103] Presumably a 10 per cent decoction, U. S. P.

    [104] Storke, R. F. The Loco Weed. Med. Current, vol. 8, p.
    157. 1892.

    [105] Day, M. G. The Separation of the Poison of the "Loco
    Weed." N. Y. Med. Journ., vol. 50, p. 604. 1889.

    [106] Sayre, L. E. Active Principle of Loco Weed. Notes on
    New Remedies, vol. 2, No. 12, p. 1.

    [107] Day, M. G. Loco Weed, in F. P. Foster's Reference-Book
    of Practical Therapeutics, vol. 1, p. 588. 1896.

    [108] Stalker, M. 1st Ann. Rept. State Vet. Surg. Iowa, p.
    16. 1885.

    [109] Power, F. B., and Cambier, J. Chemical Examination of
    Some Loco-Weeds. Pharm. Rundschau, vol. 9, p. 8.
    1891.--Power, F. B. Notes on the So-called Loco Weeds. Pharm.
    Rundschau, vol. 7, p. 134, 1889.--See also Hoffmann, F.,
    Loco-Weeds, in Pharm. Rundschau, vol. 7, p. 168. 1889.

    [110] Kennedy, J. Pharm. Rec., vol. 8, p. 197. 1888. Kennedy
    also obtained ammonia from _Astragalus mollissimus_.

    [111] O'Brine, D. Progress Bulletin on the Loco and Larkspur.
    Colo. State Agric. Coll. Bul. 25, p. 18. 1893.

    [112] Oatman, H. C. The Poisonous Principle of Loco Weed.
    Notes on New Remedies, vol. 4, p. 14. 1891-92.

    [113] Sayre, L. E. Loco Weed. Kans. Acad. Sci. Trans., vol.
    18, p. 141. 1903.

    [114] Sayre, L. E. Loco Weeds. 7th Bienn. Rept. Kans. State
    Board Agric. for 1889-90, vol. 12, pt. 2, p. 99. 1891.

    [115] Sayre, L. E. Further Report on Loco Weeds. Notes on New
    Remedies, vol. 4, p. 80. 1891-92.

    [116] Sayre, L. E. The Loco Disease. Journ. Kans. Med. Soc.,
    vol. 4, pp. 241-243. 1904.--What is Insanity in Lower
    Animals? Journ. Kans. Med. Soc., vol. 4, p. 222. 1904.

    [117] Sayre, L. E. Loco Weed. Kans. Acad. Sci. Trans., vol.
    18, p. 144. 1903.

    [118] Ruedi, C. Loco Weed (Astragalus Mollissimus): A
    Toxico-Chemical Study. Trans. Colo. State Med. Soc., p. 418.
    1895.--Also Treatment of Animals Poisoned by Loco Weed
    (unpublished article).

    [119] The "Loco Disease." Therap. Gaz., vol. 12, p. 30. 1888.

    [120] Sayre, L. E. Loco Weed. Kans. Acad. Sci. Trans., vol.
    18, p. 142. 1903.

    [121] Sayre, L. E. Loco Weeds. 7th Bien. Rept. Kansas State
    Board Agric. for 1889-1890, pt. 2, p. 98. 1891.

    [122] Curtice, C. Tape-Worm Disease of Sheep of the Western
    Plains. Bur. Animal Industry, 4th and 5th Ann. Rept., p. 167.
    1889.

    [123] Steele, C. D. New Theory about Loco. Farm and Ranch,
    vol. 20, No. 35, p. 1. 1901.

    [124] Marshall, H. T. Loco Weed Disease of Sheep. Johns
    Hopkins Hospital Bul., vol. 15, p. 181. 1904.--Data as to
    these parasites of sheep may be found in Curtice, C., The
    Animal Parasites of Sheep, Bur. Animal Industry, Rept., 1890.

    [125] Faust, E. S., and Tallquist, T. W. Ueber d. Ursachen
    der Bothriocephalus-anämie. Arch. f. Exp. Path., vol. 57, p.
    367. 1907.

    [126] Walshia Amorphella and the Loco Weed. Insect Life, vol.
    2, p. 50. 1889-90. Snow, F. H. Loco-Weed. Science, vol. 9, p.
    92. 1887.

    [127] Lloyd, J. U. Loco, or Crazy Weed. Eclectic Med. Journ.,
    vol. 53, p. 482. 1893.

    [128] Lloyd, J. U., l. c., p. 483.

    [129] Lloyd, J. U., l. c., p. 484.

    NOTE.--Eccles had previously announced a somewhat similar
    idea. Sayre, L. E. Loco Weed. Proc. Amer. Pharm. Assoc., vol.
    36, p. 115. 1889.

    [130] Lloyd, J. U., l. c., p. 486.

    [131] Lloyd, J. U., l. c., p. 483.

    [132] O'Brine, D. Progress Bulletin on the Loco and Larkspur.
    Colo. State Agric. Coll. Bul. 25, p. 17. 1893.

    [133] Mayo, N. S. Some Observations on Loco. Kans. State
    Agric. Coll. Bul. 35, p. 116. 1893.

    [134] Kobert, R. Lehrb. d. Intoxikationen, p. 615. 1893.

    [135] O'Brine, D. Progress Bulletin on Loco and Larkspur.
    Colo. State Agric. Coll. Bul. 25, p. 13. 1893.

    [136] After the manuscript of this bulletin was sent to the
    printer it was learned through Professor Carpenter that the
    animal was a horse.

    [137] Nelson, S. B. Feeding Wild Plants to Sheep. Bur. Animal
    Industry, Bul. 22, p. 12. 1898.

    [138] Chesnut, V. K., and Wilcox, E. V. Stock-Poisoning
    Plants of Montana. U. S. Dept. Agric., Div. Bot., Bul. 26, p.
    95. 1901.--Wilcox, E. V. Plant Poisoning of Stock in Montana.
    Bur. Animal Industry, 17th Ann. Rept., p. 111. 1900.

    NOTE.--The writer wishes to acknowledge the great literary
    help Mr. Chesnut's card catalogue has been to him in the
    preparation of this paper.

    [139] Unpublished report.

    [140] Marshall, H. T. Loco Weed Disease of Sheep. Johns
    Hopkins Hospital Bul., vol. 15, p. 182. 1904.

    [141] Payne, J. E. Cattle Raising on the Plains. Colo. Agric.
    Expt. Sta. Bul. 87, p. 16. 1904.

    [142] National Standard Dispensatory, p. 868. 1905.

    NOTE.--The field experiments of Harding and Tudor are rather
    conclusive as to the relation of these plants to this
    disorder. Sayre, L. E., Loco Weed, Amer. Vet. Rev., vol. 11,
    pp. 553-554, 1887--Blankinship, J. W., Loco and Some Other
    Poisonous Plants in Montana, Mont. Agric. Exper. Sta. Bul.
    45, pp. 83-84, 1903--Loco Disease, Therap. Gaz., vol. 12, p.
    30. 1898.




=NOTES ON VARIOUS MEMBERS OF THE LOCO-WEED FAMILY.=


_Astragalus caryocarpus_ is at times eaten in some of the Western
States, but is claimed by some at certain stages of its growth to
contain a poisonous principle. Frankforter,[143] from experiments on
himself, however, denies this.

_Astragalus glycophyllus_ has been used as a diuretic and _Astragalus
exscapus_ in the treatment of syphilis.[144] "The seed of _A. boeticus_,
planted in Germany and England, are found to be the very best substitute
for coffee yet tried, and so used--roasted, parched, and mixed with
coffee."[145] _Astragalus nuttallianus_, according to Smith,[146] is a
highly nutritious forage plant in spring. _Astragalus crassicarpus_ has
been prophesied by him to be a valuable addition to early spring soiling
crops. _Astragalus adsurgens_ (_nitidus_) and one or two other species
of Astragalus are still used in Chinese medicine.[147] The Indians of
the Southwest are familiar with certain loco plants.[148] The Tewans of
Hano are said to eat the root of _Aragallus lamberti_, and _Astragalus
mollissimus_ is applied locally for headaches by some of the Arizona
Indians. One of these species is used as a flavoring material by the
Coahuillas and is mixed with other plants as spices.[149] _Astragalus
kentrophyta_ had a reputation among the Navajos for the treatment of
rabies.[150] The use of certain loco plants--_Astragalus
mollissimus_--has been advocated on theoretical grounds in the treatment
of certain forms of insanity, but without favorable results.[151] In
Peru and Chile _Astragalus garbancillo_, _A. unifultus_, and _A.
ochroleucus_ have been considered injurious to animals.[152] _Astragalus
glyciphyllus_ and _A. alpinus_ have been used in Europe as food for
stock.[153]

Details as to the use of other Astragali can be found in Planchon, G.,
Sur les Astragales, in Journal de Pharmacie et de Chimie, 5th series,
vol 24, p. 473, 1891; 5th series, vol. 25, pp. 169, 233, 1892.

       *       *       *       *       *

FOOTNOTES:

    [143] Frankforter, G. B. A Chemical Study of Astragalus
    Caryocarpus. Amer. Journ. Pharm., vol. 72, p. 320. 1900.

    [144] Maisch, J. M. Poisonous Species of Astragalus. Amer.
    Journ. Pharm., vol. 51, p. 240. 1879.--Fleurot. Chimiques et
    Pharmaceutiques sur la Racines d'Astragale sans Tiges. Journ.
    de Chim. Med., vol. 10, p. 656. 1834.

    [145] Porcher, F. P. Resources of the Southern Fields and
    Forests, p. 204. 1869.

    [146] Smith, J. G. Fodder and Forage Plants. U. S. Dept.
    Agric., Div. Agrost., Bul. 2 (rev. ed.), p. 12. 1900.

    [147] Holmes, E. M. Notes on Chinese Drugs. Pharm. Journ. and
    Trans., vol. 21, 3 s., p. 1149. 1891.

    [148] Hough, W. Environmental Interrelations in Arizona.
    Amer. Anthropologist, vol. 11, pp. 143, 147. 1898.

    [149] Barrows, D. P. Ethno-Botany of the Coahuilla Indians of
    Southern California, p. 67. 1900.

    [150] Matthews, W. Navajo Names for Plants. Amer. Nat., vol.
    20, p. 772. 1886.

    [151] Givens, A. J. Loco or Crazy Weed. Med. Century, vol. 1.
    p. 21. 1893.--Compare Hurd, H. M. Amer. Journ. Insanity, vol.
    42, p. 178. 1885-86.

    [152] Rosenthal, D. A. Synopsis Plantarum Diaphoricarum,
    Erlangen, 1861, p. 1004. Greshoff, M. Beschrijving d. Giftige
    en Bedwelmeude Planten bij de Vischvangst in Gebrulk, p. 51.
    1900.

    [153] Pott, E. Handb. d. tierisch. Ernährung, vol. 2, p. 113.
    1907.




=LABORATORY EXPERIMENTS--PHYSIOLOGICAL.=


The first point in our investigations was to determine whether the plant
exerted any poisonous action and to find some animal which responded
regularly to it; then to ascertain if the lack of results of previous
investigators was not due to insufficient doses, and later to see if by
feeding smaller amounts at repeated intervals symptoms comparable to
those described as occurring on the range could not be produced. The
animal finally selected was the rabbit.




=EXPERIMENTS ON RABBITS.=


=ACUTE CASES.=

_Experiment No. 1._--On September 8, 1905, an aqueous extract of 333
grams of fresh _Astragalus mollissimus_, made in Hugo, Colo., and
shipped preserved in chloroform,[154] killed a rabbit weighing 1,616
grams in one hour and thirty-five minutes, while an extract
corresponding to 167 grams merely caused drowsiness and loss of appetite
in a rabbit weighing 765 grams.

_Experiment No. 2._--On November 29, 1905, a rabbit weighing 1,162.3
grams was fed with a concentrated aqueous extract of 500 grams of fresh
_Astragalus mollissimus_, which had been shipped from Hugo, Colo.,
preserved in chloroform in sealed vessels. This animal died in one hour
and ten minutes. The symptoms consisted in dullness, rapid respiration,
and signs of pain. At autopsy the stomach and upper part of the small
intestines showed hemorrhagic ecchymoses, with dilation of the dural
vessels of the brain and cord, with a clot over a portion of the spinal
cord.

_Experiment No. 3._--On February 13, 1906, a rabbit weighing 992 grams
was fed with a concentrated aqueous extract of 500 grams of the fresh
_Astragalus mollissimus_, collected in September and preserved in
chloroform water. Before feeding, the rabbit's ears were warm and the
rabbit struggled when any attempt was made to turn him on his back. The
temperature at 10.50 a.m., the time of feeding, was 103.5°F.; at 11.15
a.m., 102.5°F. At 11.30 a.m. the rabbit was breathing very rapidly
and would stay on his back for some time if placed so. The temperature
at this time was 102.6°F. Both pupils, the one exposed to the light and
the one protected, were contracted. At 12.02 p.m. convulsive movements
of the legs appeared. The rabbit made one leap, the temperature rose to
103.6°F., and after a few convulsive movements of the limbs the anus
relaxed and a small stool appeared, the pupils dilated, and the animal
died at 12.06 p.m.

_Experiment No. 4._--The feeding of the extract of 464 grams induced a
fall in temperature of 2.4°F. in three hours, and the rabbit died
several hours later (at night).

_Experiment No. 5._--March 2, 1906, a rabbit weighing 928 grams was fed
with a concentrated extract of 500 grams of the fresh seeds and pods of
_Astragalus mollissimus_, made in September, 1905, and preserved with
chloroform water. This animal died in one hour and seven minutes. The
animal showed the usual post-mortem conditions.

It was thus found that the aqueous extract of 500 grams of the fresh
_Astragalus mollissimus_ would cause death in about one hour in rabbits
weighing about 2 pounds (907 grams), these rabbits showing constant
clinical symptoms--urination, paralysis, more or less convulsive
muscular twitchings, often terminating in general convulsions,
drowsiness, and stupor, with more or less anesthesia. The pupils at the
time of death were often unequal. At first there was usually a slight
rise in temperature, but this was soon succeeded by a fall. Often there
were soft stools. The post-mortem lesions in these cases were marked
congestion, with hemorrhages in the stomach walls and a secretion of
thick mucus. The portions of the stomach walls most affected were the
dependent portions near the cardiac end. The intestines showed
dilatation of the blood vessels. The mesenteric vessels and also the
vessels in the cerebral portions of the dura were markedly dilated; in
some cases there were clots, especially at the posterior portion of the
brain, between the cerebrum and the cerebellum. At times there were
clots over the dorsal portion of the cord. On cutting into the brain the
brain substance itself did not appear to be congested. The cord seemed
about normal, but the vessels of its membranes were well marked. The
other organs showed nothing characteristic macroscopically. These
experiments were repeated many times and found to be constant.

These acute symptoms were likewise produced by an extract of 500 grams
of the fresh _Aragallus lamberti_ from Arizona preserved in chloroform
water (rabbit weighing 1,998 grams). An aqueous extract of 150 grams of
the dried _Astragalus mollissimus_[155] from Imperial, Nebr. (1906),
caused death in one hour and fifty-eight minutes in a rabbit weighing
1,530 grams, and an extract of 100 grams killed in one hour and
twenty-two minutes a rabbit weighing 736 grams.

An aqueous extract of 100 grams of the dried _Astragalus bigelowii_
induced death in one hour and thirty-eight minutes, the rabbit weighing
1,502 grams.

An aqueous extract of 150 grams of _Astragalus nitidus_ collected at
Woodland Park, Colo., in 1906 induced death in three hours and five
minutes, the rabbit weighing 1,672 grams.

An aqueous extract of 200 grams of the dried _Astragalus bisulcatus_
caused death after several hours (at night), the rabbit weighing 2,423
grams.

In certain cases this production of acute symptoms was not entirely a
question of salt action, as was shown by certain other experiments. In
other cases salt action seems to be the important factor, so that the
production of these acute symptoms can not always be considered
characteristic.

       *       *       *       *       *

FOOTNOTES:

    [154] In all cases in which the plants were preserved with
    chloroform sealed vessels were used for shipping. The
    chloroform was carefully evaporated off in vacuo before
    feeding the extract, the evaporation requiring several hours.
    The plants were collected by Dr. C. Dwight Marsh, in charge
    of the field investigations at Hugo, Colo.

    [155] All extracts from dried material were made at
    Washington.


=CHRONIC CASES.=

_Experiment No. 6._--February 19, 1906, a large gray rabbit weighing
2,055.3 grams was fed with 60 c.c. of fluid representing the
concentrated aqueous extract of 250 grams of the fresh _Astragalus
mollissimus_, collected September 18, 1905, and preserved in chloroform.
This rabbit was very hard to hold. The ears rested on the body. The
temperature at the time of feeding, 1.30 p.m., was 102.3°F. At 2.57 p.
m. the animal looked dull but resisted handling. At 3.30 p.m. it
urinated. At 4.15 p.m. the temperature was 98.5°F., the pupils were
about the same size as before feeding, and the animal became much
duller. The next day at 12.50 p.m. the temperature was 102.4°F., and
at this time the animal could be handled with greater ease. The animal
ate in the morning. The same amount of extract was again fed at 1.24 p.
m. At 1.35 p.m. the animal was much duller and could be turned on his
back with ease. If disturbed he ran against the wall as if utterly
unconscious of the obstruction. The animal had soft, liquid, brown
stools and tried to lie down as much as possible. If turned on its back
with the feet up it would stay so almost indefinitely. Temperature,
103.8°F.; respiration very rapid. At 2.40 p.m. the temperature was
99.8°F., and the animal died a few minutes later. After death the
pupils were much contracted. The vessels of the dura covering the brain
were much dilated, but the vessels inside the brain were not dilated.
The stomach walls were congested and marked with numerous petechiæ and
covered with mucus.

_Experiment No. 7._--On February 19, 1906, a white and brown rabbit
whose temperature was 103.2°F. was fed 30 c.c. of aqueous fluid
representing the concentrated extract of 125 grams of the fresh
_Astragalus mollissimus_, collected September, 1905, and preserved with
chloroform. The rabbit weighed 1,502.5 grams. This extract was fed at
1.45 p.m., and at 4.15 p.m. the temperature was 102.6°F., but there
were no marked symptoms. The following day at 2.04 p.m. the temperature
registered 102.5°F. The same amount of extract was given at 2.09 p.m.
The temperature at 4 p.m. was 99.8°F., the animal was dull, and the
pupils were perhaps a little smaller. The animal could not be turned
over without resistance. The following day, February 21, at 1.30 p.m.
the temperature was 102.6°F., and at 1.45 the same amount of extract
was given. At 1.54 p.m. the animal was much duller and the breathing
was very rapid. At 4.10 p.m. the temperature was 101.3°F. The animal
had been dull ever since the feeding was begun. It nibbled food shortly
before the last feeding. On February 23 the same amount of extract was
given at 2.16 p.m., temperature 99°F. The breathing was very rapid,
the ears shaking, and there was a sleepy, dull look about the animal. At
3.30 p.m. the animal was dull, but would still walk about if disturbed.
At this time the animal weighed 1,445.8 grams. At 4.30 p.m. the
temperature was 102°F. and the pupils were about normal size. There was
a marked sleepy look about the animal, which sat quietly in its cage.

February 24, at 1 p.m., the animal was very dull and could with ease be
turned on its back with its feet in the air. It would sit in its cage
perfectly quiet. The weight at this time was 1,417.5 grams, the
temperature 96.6°F. On February 26 the animal weighed 1,360.8 grams. It
was dull and refused to eat. The abdomen felt very distended and
tympanitic. February 27 the weight was still 1,360.8 grams, and the
animal sat in its cage as if asleep, with eyes half closed. There was no
diarrhea and the abdomen was very distended. At 11.15 a.m. there was a
general convulsion and the animal fell over. At 12 m. the abdomen seemed
even more swollen, the animal was hardly able to walk, and it fell over,
uttering a cry. Pupils were about normal--perhaps a little smaller. The
animal died at 12.10 p.m.

The post-mortem, made immediately after death, showed the abdomen
markedly tympanitic, and the large intestines could be outlined through
the abdominal walls with ease. The large intestines were of a chocolate
color, intensely congested, and marked with hemorrhages. On opening the
abdomen there was a decided putrefactive odor, and about an ounce of
bloody fluid was found in the peritoneal cavity, together with fibrin
flakes. The stomach was pale, the first three inches of the small
intestine up to where it turned sharply were pale, and below this the
intestines were injected and full of gas and of a dark red color. The
kidneys were 3-1/2 centimeters long and were pale, capsules easily
peeled off; cortex pale. Liver pale and infected with some coccideæ. The
gall bladder was one-quarter inch wide and one inch long. Spleen a
trifle pale; lungs pale, nothing abnormal; heart relaxed. On opening the
stomach gas and fluid, with some food, exuded. The walls were pale, but
pink in some places. There was no marked congestion or hemorrhage or
perforation. The mesenteric vessels were dilated. The upper portion of
the intestines contained a little mucus-like fluid, but lower down
became bloody, and still lower contained pus-like fluid. The walls were
hemorrhagic. The large intestine contained a soft, fecal-like fluid,
very foul. Its walls were much congested and full of hemorrhagic points.
The cortex of the suprarenal bodies was sharply defined, the medullæ
brownish. Brain pale, some dural vessels well marked, no clots or
hemorrhages. Base of brain pale. No congestion seen on cutting into the
brain. Spinal cord showed no hemorrhages or lymph effusions.

_Experiment No. 8._--On February 18, 1906, at 2 p.m., a rabbit whose
temperature was 102.2°F. was fed with the aqueous extract of 125 grams
of fresh _Astragalus mollissimus_, collected in September, 1905, and
preserved in chloroform, 30 c.c. of the fluid being used. At 4.25 p.m.
the temperature was 102.4°F. No symptoms were noted. This rabbit
weighed 1,644.3 grams. On February 20 at 2.09 p.m. the temperature was
102.2°F. and the rabbit showed no symptoms. The same dose was repeated
at 2.15 p.m. At 4 p.m. the temperature was 100.3°F. The rabbit was
dull but could not be turned over without a struggle. February 21 at
1.30 p.m. the temperature was 101.4°F. The same amount of extract was
fed at 1.45 p.m. At this time the animal was dull and breathed more
rapidly. At 4.10 p.m. the temperature was 97.3°F. Next day the same
amount of extract was again given at 2 p.m. At 2.16 p.m. the breathing
became rapid and the animal duller. The ears were directed forward. At
4.15 p.m. the temperature was 101.6°F.; weight 1,757.7 grams; animal
slightly dull. February 24, temperature 102°F., weight 1,786 grams.
March 5, weight 1,729.3 grams. The animal was fed at 3.20 p.m. with a
concentrated extract of 125 grams of _Astragalus mollissimus_, collected
in September. Temperature at time of feeding 100.4°F.; 3.40 p.m., no
symptoms; 4 p.m., temperature 102°F. March 7, weight 1,644.3 grams;
March 8, weight 1,672.6 grams; March 10, weight 1,701 grams; March 12,
weight 1,658.4 grams; March 14, weight 1,701 grams.

In this case, where the same dose was given in a period of five days,
very little effect on the rabbit was noted.

_Experiment No. 9._--On March 1, 1906, a black rabbit weighing 2,664.8
grams was fed with a concentrated aqueous extract of 250 grams of fresh
_Astragalus mollissimus_, collected in the fall of 1905.

On March 5 the weight was 2,296.3 grams. The animal was then given the
same amount of extract. During the afternoon it passed mucus and thick
pieces of feces and was dull; respiration very rapid. March 6, weight
2,282 grams; March 7, 3 p.m., animal very dull and would not eat; sat
hunched up, but resisted being disturbed: weight 2,310.5 grams. March 8,
weight 2,183 grams; March 9, weight 2,069.5 grams. Pupils dilated;
finger could be run almost against the eye, provided the lashes were not
touched, without the animal winking or paying any attention. Rabbit ate
very little and had not urinated since the preceding day. Left ear had
fallen to the side as if the animal were unable to support it. Weight,
1,912.8 grams. From March 9 to March 11, 67 c.c. of cloudy urine were
voided. This did not clear with acetic acid. Left eye tearing. March 10,
head held to right side. March 12, weight 1,786 grams. Left pupil
smaller than right, neither responding to light. Rabbit very weak. March
14, weight 1,729.3 grams. Would not eat. March 16, weight 1,644.3 grams.
Right pupil larger than left, neither responding to light. Diarrhea
present. Breathing noisy. In sitting down she raised herself on her
forelegs, evidently to take the pressure off her abdomen, which was
distended. If disturbed, she would butt against the side of the cage,
apparently oblivious of its presence. Knee jerks were very active,
almost a clonus. Reflex from tendo Achillis active. March 17, forelegs
spread out, head falling to left side. The temperature had fallen below
94°F. and would not register on the ordinary clinical thermometer. The
ears twitched, the head was thrown back, the abdomen was distended, and
the rabbit gritted its teeth. Died. Weight, 1,559.2 grams.

Brain and spinal cord pale. Dural vessels plainly seen but not marked.
Intestinal vessels congested. Stomach pale; nothing apparent
macroscopically save a small pin-point ulcer.[156] Heart relaxed.
Post-mortem examination otherwise negative macroscopically.

_Experiment No. 10._--A mouse-colored rabbit weighing 1,927.8 grams was
fed February 18, 1906, at 2.26 p.m., with a concentrated aqueous
extract of 250 grams of fresh _Astragalus mollissimus_ collected in
September, 1905, and preserved in chloroform water. The temperature of
this rabbit was 102.6°F. The fluid given was 40 c.c. At 2.45 p.m. the
rabbit urinated and at 2.57 p.m. was dull and the respiration became
rapid. The animal then aborted and had three young, two of which showed
some movement after birth, but were apparently premature.

On February 23 the temperature of this rabbit was 102.9°F. at 1.40 p.
m. She was then fed with the same amount of the extract as before. At
2.16 p.m. she lay down and became much duller; left ear fallen to side.
At 3.30 p.m. the rabbit was unable to stand. The pupil of the eye
exposed to the light was dilated. The animal died without a struggle.
The stomach contained much bloody mucus. In the dependent portion of the
stomach near the cardiac end were marked petechiæ in the walls, with
bright-red blood in the stomach itself. The heart was relaxed. The
intestines showed nothing abnormal. The dural vessels of the brain were
dilated; there was a clot on the dura over the fourth ventricle. Spinal
cord and kidneys normal, the capsules not adhering. Weight, 1,786 grams
at death.

_Experiment No. 11._--On March 1, 1906, a rabbit weighing 2,126.2 grams
was fed with a concentrated aqueous extract of 250 grams of the fresh
_Aragallus lamberti_ preserved in chloroform water. On March 5 this dose
was repeated, 37.5 c.c. of the fluid being used. March 6 the rabbit
weighed 1,956 grams; March 7, 1,913.6 grams; March 8, 1,828.5 grams;
March 9, 1,701 grams; March 12, 1,672.6 grams; March 14, 1,644.3 grams.

_Experiment No. 12._ January 19, 1906, a concentrated aqueous extract of
500 grams of the fresh _Aragallus lamberti_ preserved with chloroform
water was fed to a rabbit weighing 785 grams. The temperature at 12.10
p.m., the time of feeding, was 101.6°F. The temperature 1 hour and 43
minutes later was 94.6°F., and the animal died shortly after, showing
the same condition as occurred after feeding extracts of _Astragalus
mollissimus_.

       *       *       *       *       *

FOOTNOTES:

    [156] Compare Plönius, W., Beziehungen d. Geschwürs u. d.
    Erosionen d. Magens z. d. funktionell. Störungen u. Krankh.
    d. Darmes, Arch. f. Verdauungsk., vol. 13, pp. 180, 270,
    1907, and Tixier, L., Anémies Exper. Conséc. aux Ulcér. du
    Pylore, Comp. Rend. Hebd. Soc. de Biol., vol. 62, p. 1041,
    1907.


=PREGNANT ANIMALS.=

_Experiment No. 13._--A large, gray, pregnant rabbit weighing 2,891.6
grams was fed on February 22, 1906, with 42 c.c. of fluid,
corresponding to the aqueous extract of 250 grams of _Astragalus
mollissimus_ collected in September and October, 1905, and preserved
with chloroform. At 4 p.m. the animal was dull, but still resisted
efforts to handle. On February 24 this animal weighed 2,778.2 grams, and
on February 26 it bore a litter of seven young rabbits. One or two of
these showed movements of the limbs, but were apparently immature. This
rabbit on March 10 weighed 2,537.3 grams; March 12, 2,438 grams; March
14, 2,508.9 grams; March 22, 2,494.7 grams.

_Experiment No. 14._--On March 1, 1906, a black rabbit weighing 2,721.6
grams was fed at 12.15 p.m. with a concentrated aqueous extract of 250
grams of the fresh _Astragalus mollissimus_ collected in September,
1905. On March 2 it weighed 2,438 grams; at 2.58 p.m. it still resisted
efforts to turn it on its back; at 3.15 p.m. it could be turned on its
back with ease. March 6 the weight was 2,338.8 grams; March 7 the
animal was very dull, would not eat, pupils dilated, hind legs
paralyzed; died during the night; weight, 2,267.9 grams.

The stomach walls were pale save at the dependent portion near the
cardiac end, where there was a hemorrhagic, ulcerated area about 1-1/2
by 1-1/2 inches. The intestines were full of gas, but not hemorrhagic.
The uterus contained eight immature foeti. The uterine walls were
hemorrhagic. The kidneys weighed 9-1/2 grams; their medullæ were dark
and the straight tubules well defined. The cerebral dural vessels were
congested and the spinal dural vessels were well defined. The bladder
was found contracted. The blood gave no bands for methæmoglobin, but
showed merely those of oxyhæmoglobin on spectroscopic examination.

_Experiment No. 15._--Control experiments made by feeding water were
negative, except when a large quantity (150 c.c.) of water was given to
a rabbit weighing 1,020.5 grams. The animal died in 12 hours with marked
pallor of the tissues (hydræmia), a pathological condition quite
different from that obtained by feeding extracts of the loco plants, and
no such results were secured with the amount of water used in our
feeding experiments, 50 to 70 c.c.


=SUBCUTANEOUS INJECTIONS.=

_Experiment No. 16._--On February 28, 1906, a white rabbit weighing
581.2 grams was injected subcutaneously at 10.35 a.m. with a
concentrated aqueous extract of 83 grams of fresh _Astragalus
mollissimus_ collected in September, 1905, and preserved with
chloroform. The temperature before injection was 102.1°F. At 1.40 p.m.
the animal was dull; at 3.12 p.m. the temperature registered 99.8°F.
The animal died during the night. The post-mortem examination was
negative. Stomach pale; heart relaxed save left ventricle, which seemed
contracted; dural vessels of the brain dilated; kidneys perhaps normal.
No microscopical examination.

_Experiment No. 17._--February 28, 1906, at 10.25 a.m., a guinea pig
weighing 496 grams was injected subcutaneously with a concentrated
aqueous extract of 83 grams of the fresh _Astragalus mollissimus_
preserved in chloroform water. At 1.40 p.m. there was muscular
twitching. The animal was dull and could be easily turned on his back.
The hind legs began to show weakness. At 1.50 p.m. the hind legs were
almost completely paralyzed and the animal could be easily turned on his
back. Muscles of the limbs twitched and semen was expelled. Animal died
at 2.15 p.m.

Post-mortem showed dural vessels of cord and brain full of blood.
Stomach pinker than normal: mesenteric vessels dilated. Heart almost
empty of blood. Kidneys congested.


=SUMMARY OF FEEDING EXPERIMENTS ON RABBITS.=

These experiments indicate that an acute form of poisoning may be
induced by feeding concentrated aqueous extracts of _Astragalus
mollissimus_ and _Aragallus lamberti_ from Hugo, Colo., and Imperial,
Nebr., to rabbits, and that if the extract is given in smaller and
repeated doses a more prolonged or chronic condition may follow.

The rabbits showing the chronic effects of these plants exhibit symptoms
which have a marked parallelism with those reported as occurring in
larger herbivora (horses and cattle) on the range when locoed; that is,
the loss of appetite (Experiment No. 9), the emaciation and loss in
weight (Experiment No. 9), the dullness and stupor, with more or less
anesthesia (Experiment No. 7), the disturbance in the visual function
(Experiment No. 9), and the mental symptoms (Experiment No. 6). The
occasional abortion compares with what has been observed in larger
animals. The dried _Astragalus mollissimus_ and _Aragallus lamberti_
still retained their poisonous properties, as we were able to kill with
aqueous extracts of the dried plants made in the laboratory under the
proper conditions.


=EXPERIMENTS ON SHEEP.=

_Experiment No. 1._--On May 31, 1906, a sheep weighing 32.2 kilos was
fed with a concentrated aqueous extract of 1,000 grams of the fresh
_Astragalus mollissimus_ preserved in chloroform water. The temperature
at 11 o'clock, the time of feeding, was 103.4°F. At 11.45 a.m. this
dose was repeated. At 12 o'clock the temperature was 104.1°F. At 12.45
the animal urinated. At 1.10 p.m. a similar extract of 2,000 grams was
fed. The total liquid used was 1,500 c.c. On June 1 no symptoms were
noted. On June 5 an extract of 3,000 grams of fresh _Aragallus lamberti_
and 3,000 grams of _Astragalus mollissimus_ was fed. After feeding this
the animal could be easily turned over on its back and its ear pricked
with impunity. The animal at this time weighed 30.8 kilos. On June 6, at
11 a.m., the temperature was 104°F. The sheep had numerous soft
stools, and was very dull, and would not eat. On June 7 the temperature
was 103.7°F. and the sheep still refused to eat. On the 8th the
temperature was 103.2°F. at 10.40 a.m., and the stools were still
numerous and soft.

There were then fed 640 c.c., representing the aqueous extract of 4,000
grams of the fresh _Aragallus lamberti_. The animal could be easily
turned on its back. It weighed at this time 28.57 kilos. On June 9, at
10.47 a.m., the temperature was 103.4°F. The sheep still did not eat,
but had no diarrhea. It now weighed 27.9 kilos, and the temperature was
103°F. at 10.45 a.m.

On June 13 the animal began to eat, and 1,700 c.c. of fluid,
representing 5,500 grams of the fresh _Aragallus lamberti_, were fed.
The temperature at 12.30 p.m. was 103°F. On June 14 the temperature
was 103.4°F., the animal weighed 28.3 kilos, and refused food. On June
16 the weight was 28.3 kilos; the temperature at 2 p.m. was 103.5°F.
There was no diarrhea.

On June 19 the aqueous extract of 1,000 grams of the dried _Astragalus
mollissimus_ was fed with 420 c.c. of water. The temperature was 102.6°
F. On June 20 the temperature was 102.9°F. at 10.45 a.m.

On June 21 500 c.c., representing the aqueous extract of 1,000 grams of
the dried _Astragalus mollissimus_, were again fed. The animal now
weighed 26.9 kilos. On June 26 the animal weighed 26 kilos, and its gait
was very uncertain. The temperature was 104.2°F. It was fed 300 c.c.
of fluid, representing the extract of 400 grams of the dried _Astragalus
mollissimus_. On June 29 the animal weighed 26.8 kilos and the
temperature was 102.8°F. It was fed the extract of 1,000 grams of dried
_Astragalus mollissimus_ in 500 c.c. of water. On June 30, at 10.45 a.
m., the temperature was 104.2°F. The animal was very dull and died at
night.

At autopsy the intestines and stomach merely appeared pale. There were
no worms, and the lungs and other organs appeared normal.

_Experiment No. 2._--A lamb weighing 15.4 kilos was fed on July 6, at
1.10 p.m., with 640 c.c. of fluid, representing the extract of 2,000
grams of _Astragalus mollissimus_. At 1.17 p.m. the animal could be
turned on its back, and it regained its feet with difficulty. At 1.24 p.
m. it urinated and had a stool. The lamb died during the night.

The autopsy the following morning showed the heart filled with clots;
lungs normal save for hypostatic congestion. The cerebral and dural
vessels were dilated. About 1-1/2 teaspoonfuls of bloody serum were
found at the base of the brain. There was none in the lateral
ventricles, and no clots. The kidneys exhibited no marked congestion.
There was no fluid found in the peritoneal or the pleural or pericardial
cavities. The first stomach, however, contained small hemorrhagic spots,
and the second was black. There were small hemorrhages in the
intestines.

_Experiment No. 3._--July 13, 1906, a sheep weighing 19.5 kilos was fed
with 640 c.c. of fluid, representing the extract of 2,000 grams of
_Aragallus lamberti_. The temperature at the time of feeding, 1.10 p.
m., was 105.3°F. At 1.49 p.m. the sheep could be easily turned on its
back. At 2.23 p.m. the temperature was 103.6°F. At 3.42 p.m. the
temperature was 103.5°F. At 4.20 p.m. the respiration was fairly
rapid. On July 14, at 11.15 a.m., the temperature was 103.6°F. The
sheep would run about but could easily be turned over. It had not eaten,
but there was diarrhea present. July 15, at 3.30 p.m., the temperature
was 104°F. The animal had eaten. On July 17 the temperature was 104°F.
and the animal weighed 18.8 kilos. On the 27th it weighed 17.2 kilos; on
August 29, 20.8 kilos.

_Experiment No. 4._--A lamb weighing 19 kilos was fed August 21, 1906,
with 740 c.c., representing the aqueous extract of 2,500 grams of the
fresh _Astragalus mollissimus_, shipped to Washington in September,
1905. This animal ate at night, but the following day was dull. When
seen on August 27 there was diarrhea present and the animal was still
dull. On the 28th the animal died, weighing 16.7 kilos. There was no
autopsy on account of decomposition.

_Experiment No. 5._--A lamb weighing 15.6 kilos was fed on September 4,
1906, with an aqueous extract representing 3,500 grams of the dried
_Aragallus lamberti_, 1,000 c.c. of water being used. The temperature
at the time of feeding was 104.3°F. At 2.48 p.m. the animal on rising
to its feet developed a slight tremor of the fore legs and showed marked
disinclination to stand on its feet. The temperature was 104°F. The
animal died at 4.25 p.m. The post-mortem was negative, save for some
reddening of the second stomach.[157]

These feeding experiments in sheep can not be considered quantitative,
because, as is shown later, aqueous extracts of dried plants are often
inactive, yet poisonous principles may be obtained from the plants by
treatment with digestive fluids.

Extracts of dried loco plants vary much in their toxicity; with some the
writer was unable to kill rabbits, even when an extract of 300 grams of
the dried plant was used. It is interesting to note that when the field
station was established at Hugo, Colo., in 1905, almost all the aqueous
extracts of dried specimens sent to Washington would produce the acute
symptoms of poisoning in rabbits, but during the third season of its
existence many of the samples sent from the same area were much less
active, if not inactive.

       *       *       *       *       *

FOOTNOTES:

    [157] There was a slight odor of chloroform noticed on
    opening the stomach, so that perhaps the imperfect removal of
    the chloroform due to a hurried evaporation of the extract
    should be taken into consideration in this case.




=LABORATORY EXPERIMENTS--CHEMICAL.=


The fact that the aqueous extract of 500 grams of the fresh _Astragalus
mollissimus_, or of 200 grams (in some cases 100 grams) of the dried
plant, when fed by mouth, would regularly kill a rabbit weighing about
907 grams, with certain definite clinical symptoms and pathological
lesions, was at first arbitrarily selected as our test to aid in the
isolation of the active principle. Later the production of chronic
symptoms by the aqueous extract or digestion of 200 grams of these dried
plants given in doses of 100 grams each on two successive days was
considered essential. Carnivora, such as dogs and cats, vomit so easily
as to render them unsuitable for these investigations. The aqueous
extract was distilled with and without steam, also after acidifying with
sulphuric acid, and likewise after the addition of magnesium oxid, but
in all cases the distillate was inactive.

The concentrated aqueous extract was shaken by the Dragendorff method
with petroleum ether, benzol, chloroform, ether, and amyl alcohol, both
in alkaline and acid condition, but the shakings yielded no
physiologically active body. Shakings by the Otto-Stas method also
proved inactive. Lead acetate, lead subacetate, silver nitrate, mercuric
chlorid, alcohol, phosphotungstic acid, trichloracetic acid, ammonium
hydrate, sodium carbonate, sodium hydrate, Mayer's solution, uranyl
acetate, silver oxid, and barium carbonate also failed to remove the
active constituent. They gave heavy precipitates in all cases, but these
proved inactive. Hydrocyanic acid was sought for with negative results.
The pathological lesions in the very acute cases suggested in some
respects oxalic acid, a saponin, a metal, or perhaps a toxalbumin as the
active principle, but none of the precipitants for saponins, such as
lead and copper, or the magnesium oxid method yielded a body which was
active. Proteids were excluded by the fact that the various proteid
precipitants--alcohol, trichloracetic acid, lead subacetate, mercuric
sulphate or chlorid, and salting out with ammonium sulphate and sodium
chlorid (complete saturation and half saturation)--failed to give an
active precipitate. Glucosidal or alkaloidal bodies were also excluded.
On dialysing for twenty-four hours, some of the active principle went
into the dialysate and some remained in the dialyser. Ether yielded a
precipitate from alcoholic solution which failed to kill. The
possibility of the activity of the plants being due to its normal
acidity was excluded by neutralizing the extract with sodium hydrate and
precipitating the salts with alcohol. The filtrate proved active after
removing the alcohol.

The negative results in looking for active alkaloidal, or glucosidal, or
proteid bodies suggested that perhaps the action was due to some
inorganic constituent. The writer then boiled the extract three minutes
and as the filtrate was still found active and the proteid precipitate
inactive became convinced of the inorganic nature of the active
constituents, and finally incinerated the plant. The acid extract from
this was also active, but death was delayed several hours. This was
believed to be due to the insoluble form into which the compound was
converted.[158] In fact, the question of solubility and the avoidance of
an acid reaction, which of itself may kill, are the main points to keep
in mind.

These experiments indicated that the injurious action toward rabbits of
the _Astragalus mollissimus_ and _Aragallus lamberti_ collected at Hugo,
Colo., was due to one or more inorganic constituents,[159] but it does
not follow that all loco plants have the same poisonous principle nor
that the same species occurring on all soils has the same poisonous
action.[160]

Of _Astragalus mollissimus_ from Imperial, Nebr., collected in 1906, 200
grams were ashed in a platinum bowl and extracted with water. This
aqueous extract when neutralized produced no marked symptoms in a rabbit
and the weight of the animal remained about the same.

The ash undissolved after this extraction was then treated with acetic
acid and water overnight, and after carefully evaporating off the acetic
acid on the bath (tested by litmus paper) the residue was fed, partly in
solution and partly suspended in water, to a rabbit weighing 1,800.2
grams. Next day the rabbit weighed 1,771.8 grams, showed paralysis of
the limbs, and died during the morning. The stomach was intensely
reddened and contracted.

An extract of a similar ash was made by boiling the same amount with a
large quantity of 94 per cent alcohol. This was evaporated in vacuo and
taken in water and fed to a rabbit weighing 1,459.9 grams. On the sixth
day the animal died, having lost 70.9 grams in weight. The stomach
showed reddening but no ulcers.

An acetic acid aqueous extract, made from the ash after the alcoholic
extraction, proved inactive, showing that the alcohol had removed the
active bodies. A 70 per cent alcohol extract of another ashed lot proved
active, killing the rabbit overnight.

Of _Astragalus mollissimus_ from Imperial, Nebr., 200 grams were ashed
in a platinum bowl and the ash treated with acetic acid water. After
freeing from acid, one half of the solution and emulsion was fed one day
and the second half fed the following day. The rabbit at the time of
feeding weighed 1,275.7 grams. Fourteen days later the animal died,
weighing 1,105.6 grams. No autopsy.

A similar extract of the ash from between 100 and 150 grams of the same
dried plant produced death in a rabbit weighing 1,190 grams in two hours
and fifty-eight minutes.

The acetic acid extract of the ash of 125 grams of a mixture of the
dried _Astragalus mollissimus_ and _Aragallus lamberti_ received from
Hugo, Colo., June, 1907, after freeing from acid, was fed to a rabbit
weighing 1,304 grams on July 29. On July 30 it weighed 1,332.4 grams.
August 1 it weighed 1,219 grams, and it died the same day. The stomach
was reddened and showed ulcers.

A similar extract from 250 grams of the same dried plants on boiling
gave a heavy precipitate, but this precipitate was inactive, while the
filtrate killed a rabbit in four hours.

Of dry _Aragallus lamberti_ collected in September, 1906, 200 grams were
extracted with water and fed to a rabbit weighing 1,516.7 grams. Two
days later the animal weighed 1,360 grams and died the same day.

The ash from 200 grams of the same dried plant was extracted with acetic
acid, and after evaporating off the acid this was fed to a rabbit
weighing 2,045.3 grams. Seven days later the animal weighed 1,729.3
grams, having lost 316 grams in weight.

The ash from 250 grams of the same species of plant, after similar
treatment with acetic acid, induced death in a rabbit weighing 2,069
grams in 2 hours and 20 minutes. The stomach was inflamed.

       *       *       *       *       *

FOOTNOTES:

    [158] Work is now being done by the writer on the inorganic
    constituents of various plants.

    [159] Scattered throughout the veterinary literature one
    finds cases of poisoning in animals with symptoms similar to
    those occurring in locoed animals which are attributed to
    eating plants grown on a peculiar soil, as in Oserow, Ueber
    Krankh. d. Pferde, welche Aehnlichkeit mit der Cerebro-spinal
    meningitis haben, aber durch Vergiftungen mit Gräsern von
    Salzgründen (Salzmooren) verursacht werden, Journ. f. Allgem.
    Veterinär-Medicin, St. Petersburg, p. 486, 1906. Abstract in
    Jahresber. über d. Leistungen auf dem Gebiete d.
    Veterinär-Medicin, vol. 26, p. 226, 1906.--Compare also Étude
    sur Quelques Plantes Vénéneuses des Regions Calcaires, Bul.
    Soc. Cent. de Méd. Vét., vol. 48, p. 378. 1894.

    [160] After completing this work the writer found that Sayre
    had said that he "had the suggestion that the harm coming
    from this plant is due to the inorganic constituents; this
    clue has been followed up, but like the others has brought us
    no nearer to the solution of the problem." Kans. Acad. Sci.
    Trans., vol. 18, p. 144. 1903.




=EFFECT OF THE AQUEOUS EXTRACT OF ASHED LOCO PLANTS.=


The filtrate from the ash from 200 grams of dried _Astragalus
mollissimus_, from Imperial, Nebr., after similar treatment with acetic
acid water and freed from free acid, killed a rabbit in several hours.

Hydrochloric acid also rendered the toxic agent of the ash soluble in
water, but proved unsuitable for our work, as it was found impossible to
obtain neutral residues by mere evaporation on the bath. At first one of
the heavy metals or members of the H_{2}S group[161] was suspected, but
on passing H_{2}S into the slightly acid extract of the ash no active
precipitate resulted, but the filtrate remained active.[162] A special
Marsh test was, however, made for arsenic and antimony with negative
results. A test for tungsten with zinc and hydrochloric acid proved
negative.

Members of the ammonium sulphid group were then suspected, but while
ammonium hydrate alone gave a heavy white precipitate, this precipitate,
as also the black one with ammonium sulphid, proved inactive save when
not thoroughly freed from acid (used for solution). The action of this
ammonium sulphid precipitate on rabbits was watched for sixteen days,
but without result. Nevertheless, the writer still suspected some of the
rare earths.[163]

Sestini[164] had found that if certain plants were nourished with a
solution of a beryllium salt, in the ash of these plants could be shown
the presence of beryllium.

Two grams of beryllium chlorid were fed in aqueous solution to a rabbit
weighing 1,800.2 grams. In four days this animal lost 241 grams and
died. The stomach showed the same general pallor seen in chronic locoed
rabbits, but no ulcers. The tests for beryllium by Sestini's method,
however, failed to show beryllium in the active loco plants examined.

Thorium chlorid, cerium chlorid, and lanthanum chlorid in 2-gram doses
and zirconium chlorid in 3-gram doses produced no chronic symptoms in
rabbits or, in fact, any disturbance. Titanium chlorid, 2.5 grams,
evaporated in the air and then fed in an emulsion to a rabbit, also
proved inactive, but this inactivity may have been due to its
insolubility.

Thallium nitrate c. p., in aqueous solution, in 2-gram doses, killed a
rabbit weighing 2,154.6 grams in two hours and fifteen minutes. The
stomach in this case, while pink, was not hemorrhagic.

Zirconium chlorid has an astringent taste, and if fed repeatedly will
cause the metallic astringent action. On boiling an acetic acid solution
of the ash with sodium acetate a precipitate formed.[165]

The presence of zirconium was thus suspected and Dr. E. C. Sullivan, of
the United States Geological Survey, estimated it to be present in the
ash of a sample of _Aragallus lamberti_ in about 0.01 per cent zirconium
oxid, with also 0.1 per cent titanium dioxid.[166]

Zirconium chlorid, 3 grams, was fed in aqueous solution to a rabbit
weighing 850.5 grams. This rabbit lost 96 grams in seven days, and was
then fed 3 grams more of the same solution and the following day 2 grams
more. It died eight days later, weighing 656 grams. The stomach and
intestines were contracted, but showed no ulcers. However, 4 grams
killed a rabbit in two hours and thirty-two minutes.

The filtrate, after treating an active solution of the ash with hydrogen
peroxid, proved active, thus showing that zirconium was not entirely
responsible for the poisonous action.

Yttrium, while not found in the plant, was administered as yttrium
chlorid to a rabbit weighing 1,530 grams in 2-gram doses in solution.
This animal gained 113.4 grams in five days.

Didymium chlorid c. p., in 3-gram doses, was fed to a rabbit weighing
1,020 grams. This rabbit lost 70 grams in four days.

The administration of manganese acetate[167] in 2-gram doses was
followed by a gain in weight of a rabbit of 42.5 grams, while a dose of
3 grams killed a rabbit weighing 1,077 grams in two hours and thirty
minutes. Wohlwill[168] has emphasized the fact that the members of the
iron group owe their comparative harmlessness to not being absorbed by
the gastro-intestinal tract.

No zinc was found in the plant.[169]

It is well recognized that potassium salts given hypodermically are
decidedly toxic and that ammonium salts given per os will kill, so that
the writer considered the possibility of other members of the group
being responsible for the injurious action. The fact that the alkaline
distillate of the plant proved inactive eliminated the ammonium salts.

Cæsium chlorid c. p., 2 grams, was fed in aqueous solution to a rabbit
weighing 1,077.2 grams. In six days this animal lost 255 grams in
weight, when it died.[170]

A second rabbit, weighing 1,020.5 grams, was fed with 2 grams of the
same solution and lost 368 grams in twenty-one days. The spectroscopic
test, however, failed to show cæsium in the ashed plant. Rubidium
chlorid c. p., in 2-gram doses, proved inactive. The platinum chlorid
precipitate from the extract of the plant proved inactive.

The fact that the filtrate after precipitation of the phosphates by tin
and nitric acid and H_{2}S was active excluded the phosphoric acid
radical, and the filtrate after treatment with BaCO_{3} and AgO being
active excluded the H_{2}SO_{4} and HCl radicals as the toxic body.
Fluorine was proved to be absent.

A radio-active substance was suspected, but Dr. L. J. Briggs, Physicist
of Bureau of Plant Industry, reported that the dried plant showed no
special amount of radio-activity.[171]

Power and Cambier, Sayre, and Kennedy had previously called attention to
the abundance of calcium in the plant, and the writer's investigations
confirm this. Pharmacologists are averse to believing calcium given per
os poisonous. The writer has, however, fed 5 grams of the acetate of
calcium in solution to a rabbit weighing 652 grams. This animal died in
two hours, with marked irritation of the stomach, the result being due
to the so-called "salt action." Much larger amounts were fed in divided
doses, but without injury. Calcium phosphate and calcium sulphate in
2-gram doses proved harmless to a rabbit weighing about 1,400 grams.
Three grams of magnesium acetate[172] were fed in solution for five
successive days to a rabbit weighing 1,417 grams, but without apparent
effect.

Strontium acetate c. p., in 2-gram doses, likewise caused no
disturbance.[173] No strontium in any amount recognizable by chemical
tests was proved in the plant. So that by a process of exclusion the
writer was forced to think of barium as the main cause of the trouble.

The writer noted that if the ashed plant was extracted with H_{2}SO_{4}
water and this extract freed from sulphuric acid with PbCO_{3} and
H_{2}S the solution proved inactive to rabbits and also that after this
extraction the acetic acid extract of the ash failed to kill. In other
words, the sulphate of our body was insoluble in water. At times in
passing H_{2}S into active solutions of the ashed plant freed from the
acetic acid by evaporation the filtrate and likewise the precipitate
were inactive. Noyes and Bray[174] have noted that if H_{2}S is passed
into certain solutions in the presence of an oxydizing agent, such as
ferric iron, H_{2}SO_{4} would be formed, which would throw any barium
out of solution.

In one blood-pressure record made with a dog (vagi nerves cut), a rise
in blood pressure (a characteristic physiological action of barium) was
seen to follow the intravenous injection of the aqueous extract of the
plant, in spite of its normal acid reaction.

Accidentally the writer found that Sprengel[175] had reported the
presence of barium in _Astragalus exscapus_, a closely allied plant.
Barium has also been found in the vegetable world by Scheele in 1788,
and later by Eckard,[176] who found it in beech, while Forchhammer[177]
proved it in birch, and Lutterkorth found it in the soil of the same
area in which Eckard worked. Dworzak[178] noted the occurrence of traces
of this element in wheat grown along the Nile, and Knop[179] found it in
the soil. Doctor Balfour, of Khartum, Egypt, informed the writer that he
knew of no cases in which this barium in wheat had produced poisoning.
Hornberger[180] found barium both in the red beech grown in Germany and
in the soil on which these trees grew. It has also been claimed that
various marine plants may take up barium from the sea.[181]

Hillebrand[182] has called attention to the fact that the igneous rocks
of the Rocky Mountains showed a higher percentage of barium than rock
from other portions of the United States, so that under these conditions
one might expect the presence of barium in plants growing in this
region. A sample of _Aragallus lamberti_ and one of _Astragalus
mollissimus_ were sent to the Bureau of Chemistry for spectroscopic
examination for various elements and they reported traces of barium in
each.[183]

With these arguments the writer felt sure of the presence of barium, and
the matter was discussed with Dr. E. C. Sullivan, of the United States
Geological Survey, and he kindly corroborated the conclusions reached as
to the presence of barium, controlling its presence by means of the
spectroscope, and estimated it roughly as 0.1 per cent BaO in the ash of
a sample of _Aragallus lamberti_ (6.3 milligrams BaSO_{4} in 4 grams
ash). This determination was made by Hillebrand's method.

Kobert has anticipated this result, saying that "all plants are in the
position occasionally to take up barium combinations from the soil," and
"the plants which thus contain barium may act injuriously to men and
animals."[184]

       *       *       *       *       *

FOOTNOTES:

    [161] Swain, R. E., and Harkins, W. D. Arsenic in Vegetation
    Exposed to Smelter Smoke. Journ. Amer. Chem. Soc., vol. 30,
    p. 915. 1908.--Harkins, W. D., and Swain, R. E. The Chronic
    Arsenical Poisoning of Herbivorous Animals. Journ. Amer.
    Chem. Soc., vol. 30, p. 928, 1908.

    [162] A similar extract was sent to the Bureau of Chemistry,
    and that Bureau also reported an absence of the elements of
    the H_{2}S group.

    [163] Bachem, C. Pharmakologisches über einige Edelerden.
    Arch. Internat. de Pharmacodyn., vol. 17, p. 363. 1907.

    [164] Sestini, F. Esper. di Vegetaz. del Frumento con
    Sostituz. della Glucina alla Magnesia. Staz. Sper. Agrar.
    Ital., vol. 20, p. 256. 1891.--Di alcuni Elementi Chimici
    Rari a Trovarsi nei Vegetabili. Staz. Sper. Agrar. Ital.,
    vol. 15, p. 290. 1888.

    NOTE.--The ammonium sulphid precipitate was very small if the
    phosphates were first removed with tin and nitric acid.

    [165] Böhm, C. R. Darstellung d. seltenen Erden, vol. 1, p.
    40. 1905.

    [166] Wait, C. E. Occurrence of Titanium. Journ. Amer. Chem.
    Soc., vol. 18, p. 402. 1896.

    NOTE.--There seem to be no records of any study of the
    pharmacological action of titanium.

    [167] Compare Jaksch, R. v. Ueber Mangantoxikosen und
    Manganophobie. Münch. Med. Woch., p. 969. 1907.

    [168] Wohlwill, F. Ueber d. Wirkung d. Metalle d.
    Nickelgruppe. Arch. f. Exper. Path., vol. 56, p. 409. 1907.

    [169] Laband, L. Zur Verbreitung des Zinkes im
    Pflanzenreiche. Zeits. f. Untersuch. d. Nahrungs u.
    Genussmittel, vol. 4, p. 489. 1901.

    [170] Cæsium occurs in various plants and the possibility of
    poisoning by this element must be considered. It is hoped
    that the writer may be able to undertake a more thorough
    pharmacological study of this element.

    [171] Acqua, C. Sull'accumulo di Sostanze Radioattive nei
    Vegetali. Atti della Reale Accad. dei Lincei, 5 s, vol. 16,
    sem. 2, p. 357. 1907.

    [172] Compare Meltzer, S. J. Toxicity of Magnesium Nitrate
    When Given by Mouth. Science, vol. 26, p. 473. 1907.

    [173] Burgassi, G. Modificaz. del Ricambio per Azione dello
    Stronzio. Archiv. di Farmacol., vol. 6, p. 551. 1907.

    [174] Noyes, A. A., and Bray, W. C. System of Qualitative
    Analysis for the Common Elements. Journ. Amer. Chem. Soc.,
    vol. 29, pp. 168, 172, and 191. 1907.

    NOTE.--Barium sulphate is nontoxic on account of its
    insolubility. Orfila fed 16-24 grams to dogs without causing
    any disturbance. Bary, A. Beitr. z. Baryumwirkung. Dorpat,
    1888, p. 25.

    [175] Sprengel, C. Von den Substanzen der Ackerbrume und des
    Untergrundes, Journ. f. Techn. u. OEkon. Chem., vol. 3, p.
    313. 1828.

    [176] Eckard, G. E. Baryt, ein Bestandtheil der Asche des
    Buchenholzes. Annal. der Chem. u. Pharm., n. s., vol. 23, p.
    294. 1856.

    [177] Forchhammer, J. G. Ueber den Einfluss des Kochsalzes
    auf die Bildung der Mineralien. Annal. d. Physik u. Chemie,
    vol. 5, p. 91. 1905.--Lutterkorth, H. Kohlensäurer Baryt, ein
    Bestandtheil des Sandsteines in der Gegend von Göttingen.
    Annal. d. Chem. u. Pharm., n. s., vol. 23, p. 296. 1856.

    [178] Dworzak, H. Baryt unter den Aschenbestandtheilen des.
    Ægyptischen Weizen. Landw. Versuchs.-Stat., vol. 17, p. 398.
    1874.

    [179] Knop, W. Analysen von Nilabsatz. Landw.
    Versuchs.-Stat., vol. 17, p. 65. 1874.--Compare also
    Demoussy, E., Absorption par les Plantes de Quelques Sels
    Solubles, Thése, Paris, 1899.--Knop, W., Einige neue
    Resultate der Untersuchung über die Ernährung der Pflanze,
    Ber. ü. Verhandl. d. königl. sächs. Gesells. d. Wissens. zu
    Leipzig, Math. Phys. Cl., vol. 29, p. 113, 1877.--Suzuki, U.,
    Can Strontium and Barium Replace Calcium in Phænogams? Bul.
    Coll. Agric. Tokio Imp. Univ., vol. 4, p. 69, 1900-1902.

    [180] Hornberger, R. Ueber d. Vorkommen d. Baryums in d.
    Pflanze und im Boden. Landw. Versuchs.-Stat., vol. 51, p.
    473. 1899.

    [181] Roscoe, H. E., and Schorlemmer, C. Treatise on
    Chemistry, vol. 2, p. 455. 1897.

    [182] Hillebrand, W. F. Analysis of Silicate and Carbonate
    Rocks. Dept. Interior, U. S. Geol. Survey, Bul. 305, p. 18.
    1907.

    [183] This report came from the Plant Analysis Laboratory of
    the Bureau of Chemistry, a different one from that which
    later controlled the writer's tests quantitatively and
    qualitatively. In other words, the conclusions of the writer
    as to the presence of barium were controlled by three
    separate individuals.

    [184] Kobert, R. Kann ein in einem Pflanzenpulver gefundener
    abnorm höher Barytgehalt erklärt werden durch direkte
    Aufnahme von Baryumsalze durch die lebende Pflanze aus dem
    Boden? Chem. Zeit., vol. 10, p. 491. 1899.

    NOTE.--The writer has also found barium in entirely different
    botanical families from the loco-weed, and it is hoped a
    report can shortly be made of some of these.

    NOTE.--The first sample of ash analyzed by the Bureau of
    Chemistry had 0.21 per cent Fe_{2}O_{3}, 0.92 per cent
    Al_{2}O_{3}, 0.98 per cent CaO, 0.37 per cent MgO, 5.50 per
    cent SiO_{2}. The second lot was only examined for certain
    constituents, and gave K_{2}O, 2.25 per cent; CaO, 1.20 per
    cent; MgO, 0.41 per cent; P_{2}O_{5}, 0.52 per cent; and
    SO_{3}, 0.24 per cent.




=TOTAL ASH DETERMINATIONS OF LOCO PLANTS.=


The reports of the ash analyses of the loco plants show marked
variations in the total amount of the ash. Thus, from _Aragallus
lamberti_ Dyrenforth obtained 4.32 per cent and O'Brine 13.52 per cent
of ash. The Bureau of Chemistry analyzed two different samples of this
dried plant and reported in one case 11.15 per cent and in the second
11.64 per cent of ash. O'Brine[185] obtained 13.52 per cent of ash from
the same species. The writer's analysis[186] gave in one sample of
_Aragallus lamberti_, collected at Hugo, Colo., in 1907, 18.8 per cent
of ash; a second lot (1907), 12.44 per cent; a third (1906), 11 per
cent, and a fourth (May, 1905) gave 37.3 per cent of ash.[187] One lot
from Woodland Park, Colo. (October, 1906), gave 6.4 per cent. One lot
from Hugo, Colo. (October, 1907), yielded 9.6 per cent.

In the case of _Astragalus mollissimus_, Wentz obtained 6.76 per cent,
Sayre 12.01 per cent, Kennedy 20 per cent, O'Brine 12.15 per cent, while
the sample analyzed by the Bureau of Chemistry gave 18.4 per cent of
ash. One sample from Kit Carson County, Colo. (December, 1906), which
proved inactive physiologically, gave an ash content of 6.9 per cent. A
sample of _Astragalus missouriensis_ collected at Hugo, Colo., June,
1907, yielded an ash content of 21.8 per cent, and an _Astragalus
missouriensis_ collected at Pierre, S. Dak., September, 1907, yielded 27
per cent. An _Astragalus nitidus_ from Custer, S. Dak. (July, 1907),
gave 5.2 per cent ash, while an _Astragalus nitidus_ collected at
Woodland Park, Colo., in October, 1906, yielded 7.8 per cent, and
another specimen of _Astragalus nitidus_ also collected at Woodland
Park, Colo., in October, 1907, gave 12.2 per cent. An _Astragalus
drummondii_ from Custer, S. Dak. (July, 1907), gave 5.9 per cent.
_Astragalus pectinatus_ (Hugo, June, 1907) yielded 6.1 per cent. A fresh
(undried) specimen of _Astragalus mollissimus_ (unknown origin,
November, 1907) yielded 3.8 per cent of ash. One sample of _Astragalus
decumbens_ (Ephraim, Utah, August, 1907) gave 21.8 per cent of ash.

These determinations must necessarily be only approximate, as the plants
were collected by different persons who exercised different degrees of
care in freeing them from adherent soil, and possibly in drying the
plants, so that the main value of these figures is their aid in
determining the amount of barium present.

       *       *       *       *       *

FOOTNOTES:

    [185] The detailed analysis of O'Brine can be found on page
    32 of this report.

    [186] All ash and barium determinations were made from the
    dried plants save when otherwise specified.

    [187] Evidently these plants must have been imperfectly freed
    from soil.




=BARIUM DETERMINATIONS IN THE ASH OF LOCO PLANTS.=


Attention has been called to the fact that in ashing plants containing
barium a part at least of this barium is converted into the insoluble
sulphate and a part into the carbonate, so that the characteristic
pharmacological action of the ash will depend not upon the total barium
present, but upon the form in which it occurs--little action if much
BaSO_{4}, and more complete if more BaCO_{3} results. A further
difficulty in the recognition of barium in plants is due to the fact
that certain inorganic salts interfere with the precipitation by
H_{2}SO_{4}.

A specimen of _Aragallus lamberti_ (Hugo, summer of 1907) with 12.44 per
cent of ash was examined for its barium content by Hillebrand's
method.[188] The method was as follows:

Two grams of the ash were first fused with sodium carbonate and the
fused mass washed with water containing sodium carbonate. The residue
was washed into a beaker and treated with a few drops of sulphuric acid.
The residue now remaining was filtered and after ignition was treated
with hydrofluoric and sulphuric acids. After evaporating off these
acids, the residue was treated with sulphuric acid water, filtered, and
then fused with sodium carbonate. After extracting with sodium carbonate
water, the residue was dissolved in just enough hydrochloric acid and
precipitated with sulphuric acid. The precipitate was dissolved in
concentrated sulphuric acid and reprecipitated by water and weighed as
BaSO_{4}.[189] So far as the writer can ascertain, there have been no
control experiments made for this method to determine the experimental
error.

Of the above ash, 1.998 grams gave 5.2 milligrams of BaSO_{4}, which
would correspond to 75.75 milligrams of barium acetate crystals--
Ba(C_{2}H_{3}O_{2})_{2}+H_{2}O--in 200 grams of the dried plant. The
residue by the Hillebrand method after weighing was tested with the
spectroscope and gave a bright spectrum for barium. The same ash was
analyzed by the Bureau of Chemistry, using a shorter method, and they
reported 2.7 milligrams of barium sulphate in 1.1217 grams of ash. A
second sample collected earlier in the summer, with an ash content of
18.6 per cent, was shown to yield barium corresponding to 3.4 milligrams
of BaSO_{4} in 2.5 grams of the ash.[190]

One lot of _Aragallus lamberti_ collected at Hugo, Colo., in May, 1905,
and which gave an ash content of 37.3 per cent, was found to yield 3
milligrams of BaSO_{4} from 1.998 grams of ash, or 173.88 milligrams of
Ba(C_{2}H_{3}O_{2})_{2}+H_{2}O in 200 grams of the dried plant, but this
ash also contained 0.27 per cent of SO_{3}. The Bureau of Chemistry
reported the barium to correspond to 2.9 milligrams of BaSO_{4} in 2.45
grams of the ash.

The _Astragalus missouriensis_ (Hugo, June, 1907), with an ash content
of 21.8 per cent, gave 3 milligrams of BaSO_{4} in 2.01 grams of ash,
or 76.58 milligrams of Ba(C_{2}H_{3}O_{2})_{2}+H_{2}O in 200 grams of
the dried plant. The residue after weighing was tested spectroscopically
and gave a bright barium spectrum.

The _Astragalus drummondii_ from Custer, S. Dak. (1906), _Astragalus
mollissimus_ from Kit Carson County, Colo. (December, 1906), and
_Astragalus nitidus_ from Woodland Park, Colo. (October, 1907), were
reported by the Bureau of Chemistry to contain no barium.

The ash of the _Astragalus pectinatus_ (Hugo, June, 1907) was reported
by the Bureau of Chemistry to show no barium on spectroscopic
examination.

Two grams of active loco plant ash yielded from 5 to 6 milligrams of
BaSO_{4}, but it can be easily seen that in multiplying this amount to
correspond to 200 grams of the dried plant errors would be likely to
arise, so that the whole amount of barium would not necessarily be
accounted for.

       *       *       *       *       *

FOOTNOTES:

    [188] Hillebrand, W. F. Analysis of Silicate and Carbonate
    Rocks. U. S. Geol. Surv. Bul. 305, p. 116. 1907. See also
    Folin, O., On the Reduction of Barium Sulphate in Ordinary
    Gravimetric Determinations, in Journ. Biol. Chem., vol. 3, p.
    81. 1907.

    [189] All the determinations of barium which resulted either
    positively or negatively were made with the same bottle of
    sodium carbonate and H_{2}SO_{4}, so that impurities in the
    chemicals were thus eliminated.

    [190] Report from Bureau of Chemistry.




=ANALYSIS OF SOILS.=


One sample of the soil from near Hugo, Colo., from which the _Aragallus
lamberti_ was collected, was examined by the Bureau of Soils, and that
Bureau reported the absence of barium and zirconium, at least of any
recognizable by the chemical methods used, so that it can not be said
that the barium came from any soil accidentally mixed with the ash.
Traces of titanium were, however, found. Evidently the plant must
collect minimal quantities of these elements from the soil and store
them.

The water from a well of an adjacent area was examined by the Bureau of
Chemistry and reported to contain 37.4 parts of calcium and 13.7 parts
of magnesium in one million, and that the water contained no
barium.[191]

       *       *       *       *       *

FOOTNOTES:

    [191] Barium has been found in well water in England. See
    Thorpe, T. E., Contribution to the History of the Old Sulphur
    Well, Harrogate, in Philos. Mag., 5 s., vol. 2, p. 50, 1876.




=FEEDING EXPERIMENTS WITH BARIUM SALTS ON ANIMALS IN THE LABORATORY.=


On these figures the writer took 0.2 gram of crystallized barium acetate
c. p., using the acetate because acetic acid has been proved in certain
loco plants by Power and Cambier, and after dissolving it in water fed
it at 9.45 a.m. to a rabbit weighing 1,177 grams. The head soon fell
forward so that the nose rested on the ground. At 10.58 a.m. the rabbit
seemed unable to guide itself and would run into obstructions if forced
to move. There was no diarrhea but it urinated several times. There was
a peculiar tremor of the muscles noted. The animal would not startle by
sudden noises and at 11.06 a.m. could be placed on its back with ease.
The pupils appeared about normal. The whites of the eyes showed very
prominently. At 11.35 a.m. the fore legs were paralyzed. The following
morning the animal was dead, its weight being 1,120 grams. The heart was
dilated; the stomach was not hemorrhagic, but rather pale.

A second rabbit, which weighed 1,630 grams, was fed with a solution of
0.5 gram of the same salt at 9.42 a.m. At 10.35 a.m. the animal passed
soft stools and showed a marked disinclination to move, with evidence of
pain. The diarrhea[192] became more marked and the animal's hind
quarters were soiled with feces. At 10.48 a.m. there was marked
incoordination of the limbs and inability to stand. Finally, at 10.56 a.
m., convulsions began and the animal died at 11.02 a.m. The autopsy was
made about two hours later. The animal was then rigid. The kidneys
seemed rather congested. The intestines were relaxed; mesenteric vessels
dilated. The pyloric region of the stomach appeared hemorrhagic.

A third rabbit, fed like the preceding with 0.5 gram of barium acetate,
showed much the same result. In this case there was some retching, but
the other symptoms were as above, the animal dying in one hour and five
minutes. No hemorrhages were seen in the stomach walls. It was noted
that after the administration of certain doses, 0.2 gram, there was no
diarrhea.

On September 23, 1907, a rabbit weighing 1,757 grams was fed at 10.42 a.
m. with 0.1 gram of the same barium acetate. The temperature at the time
of feeding was 102.9°F. At 12.05 a.m. the animal urinated.
Temperature, 101.4°F. On September 24 the animal weighed the same.
Temperature at 10.55 a.m., 102.3°F. The same amount of barium was fed.
At 3.40 p.m. the temperature was 102.5°F. On September 25 the animal
weighed 1,800 grams. Temperature, 102.2°F. at 10.39 a.m. The dose of
barium was repeated. At 3.55 p.m. the temperature was 101.4°F. On
September 26 at 9.38 a.m. the temperature was 101.1°F., and again the
barium was given. At 3.57 p.m. the temperature was 101.5°F. On
September 27 the rabbit weighed 1,772 grams. The temperature at 9.53 a.
m. was 102.3°F. The barium was fed for the fifth time. At 10.27 a.m.
there were general convulsions. The eyes teared. At 10.32 a.m. soft
stools appeared and the animal urinated. Stools were passed at various
periods. At 11.30 a.m. there were no signs of pain on pinching the ear.
At 11.58 a.m. the animal retched. The animal was lying with the fore
legs wide apart and could not support itself. At 12.05 p.m. the
temperature was 98°F. and the rabbit died shortly after.

The peritoneal cavity seemed normal. The small intestines were relaxed,
while the mesenteric vessels were dilated. The kidneys seemed congested.
The stomach walls were pink and in places covered with mucus. The heart
was relaxed save the left ventricle, which seemed firm.

On September 23, 1907, a second rabbit, weighing 1,360 grams, was fed
with a similar solution and the feeding was repeated at the same time
the first rabbit was fed. On September 27 the animal weighed 1,416
grams. On this day a peculiar movement of the hind legs on jumping
appeared, apparently due to an inability to draw the legs completely up,
and the fore legs were spread wide apart, as if too weak to support the
animal. The temperature had also fallen. On September 28 the animal had
apparently recovered. Weight, 1,516 grams on October 21.

On September 23, 1907, a third rabbit, weighing 1,304 grams, was fed
with 50 milligrams of barium acetate. This dose was repeated each time
the other two rabbits were fed. On September 27 it weighed 1,304 grams.
Marked muscular twitching appeared, with disinclination to move. Finally
there were convulsions and paralysis of the limbs. No stools were seen.
This animal lay quiet all night, apparently unable to move, and
continued on its side until 3.15 p.m. on September 28, when it
gradually recovered, weighing 1,346 grams on October 24.

On October 24, 1907, a rabbit weighing 1,346.5 grams was fed with a
solution of 25 milligrams of crystallized barium acetate. On the next
day the weight was 1,318 grams, and the dose was repeated. On October 26
it weighed 1,275.7 grams, and the dose was repeated; on October 30 it
weighed 1,332 grams, and on October 31 its weight was 1,375 grams. The
animal died at night on November 6; weight, 1,134 grams. The post-mortem
examination, made with Dr. Meade Bolton, of the Bureau of Animal
Industry, was negative save for the presence of necrotic tissue in one
enlarged thyroid.

On October 24, 1907, a rabbit weighing 1,332 grams was fed with a
solution of 25 milligrams of crystallized barium acetate. On the next
day the animal weighed the same, and the dose was repeated. On October
26 it weighed 1,289 grams, and the same amount of barium was given. On
October 28 the weight was 1,219 grams and two days later 1,289 grams.

On October 31, 1907, a rabbit weighing 723 grams was fed with a solution
of 25 milligrams of barium acetate. This rabbit was fed in all nine
times during a period of ten days. At the end of this time it weighed
779 grams and died six days later, weighing 723 grams. The post-mortem
was negative.

A rabbit weighing 779 grams was also fed on October 31, 1907, with a
similar amount of barium. This dose was repeated six times during an
interval of eight days. At the end of that time the animal still
retained its normal weight. On November 14, 1907, it weighed 709 grams,
having lost 70 grams. Thus after daily doses of 0.1 gram of crystallized
barium acetate no symptoms appeared until the fifth day, when death
resulted. After the similar administration of 50 milligrams severe
symptoms developed on the same day, but the animal recovered. After the
administration of 25 milligrams on three successive days the animal
died. In other cases of feeding 25 milligrams for several successive
days, some lost weight and died; others merely lost in weight, but
recovered.

Bary fed a rabbit weighing 0.9 kilogram a solution of 30 milligrams of
barium chlorid on one day, on the second day 90 milligrams, and on the
third day 30 milligrams. The only symptom noted was diarrhea. The animal
died on the fifth day. In other words, after feeding small doses of
barium salts for several days acute symptoms suddenly set in, showing a
cumulative action. This cumulative action has been noted on man.[193]

Onsum[194] fed a medium-sized rabbit daily with small doses of barium
carbonate, beginning with 20 milligrams. When the total amount reached
0.19 grams the rabbit died. The animal before death showed paralysis,
respiratory disturbances, and fall in temperature. The sensibility of
the cornea diminished, but the pupils responded to light. The stomach
walls showed ecchymoses and the blood vessels of the brain, the spinal
cord, and the abdominal vessels were dilated. Emboli in the pulmonary
arteries were also noted.

In a rabbit the application of 0.66 gram of barium chlorid to a wound
was followed in twenty minutes by convulsions, paralysis, and finally
coma and death.[195]

Of barium nitrate 0.66 gram mixed with sugar and fed to a rabbit caused
death in less than one hour, and 0.33 gram induced death in another
rabbit in twenty-seven hours.[196]

Six grains (0.4 gram) of barium iodid fed in solution to a rabbit caused
death the following day. On this day there were tremors of the neck and
shoulders with convulsive movements of the limbs. There was also
grinding of the teeth. "The mucous membrane of the stomach was rose-red
at the cardia, and softened." Membranes of the cord and brain also were
congested.[197]

For rabbits weighing 1,500 to 2,000 grams the lethal dose of barium
chlorid on subcutaneous use is stated to be 0.05 to 0.06 grams.[198]

A rabbit weighing 1,106 grams was fed with a solution containing 50
milligrams of crystallized barium acetate c. p. and 50 milligrams of
zirconium chlorid (pure). In fifty-seven minutes the animal showed
difficulty in moving the fore legs, developing marked paralysis of the
same about five hours later, and died the following morning--that is,
twenty-two hours after feeding. The heart was found dilated, kidneys
congested, stomach walls pink and covered in places with mucus and
partly digested blood, and cerebral dural vessels dilated, but no clots
were seen; bladder full.

Mixtures of 0.5 gram of calcium acetate and 50 milligrams of barium
acetate failed to kill. Mixtures of titanium and barium were not tried,
as no titanium salt soluble in water and of neutral reaction was
accessible.

Mittelstaedt called attention to the fact that pregnant rabbits were
more easily affected by the barium administration than nonpregnant ones,
and noted abortion in one case.[199]

One gram of the barium carbonate killed a dog in eight hours. A second
dog died in fifteen hours. Both of these animals vomited so that a
portion of this must have been lost.[200] Barium carbonate was formerly
employed as a rat poison.[201]

Of barium chlorid 0.6 gram, fed in aqueous solution, caused death in a
dog in forty-eight minutes if vomiting was prevented.[202]

In Tidy's hands 2 grams of the barium nitrate caused death in a small
terrier in three and three-fourth hours. This dog had slight
convulsions, was almost unable to stand, and had vomiting and purging.
The reflexes were diminished. A small dog recovered only completely in
five days after being fed 0.66 gram, while a large dog after being fed
1.3 grams only recovered after two days.

In cats 0.8 gram of barium carbonate when introduced into a wound caused
on the third day languor, slow respiration, feeble pulse, twitching of
hind legs, dilated pupils, and death.[203]

       *       *       *       *       *

FOOTNOTES:

    [192] Magnus, R. Wirkungsweise u. Angriffspunkt einiger Gifte
    am Katzendarm. Archiv. f. Gesam. Physiol., vol. 108, p. 44,
    1905.

    NOTE.--Reports on the histological changes in acute barium
    poisoning can be found in Pilliet, A., and Malbec, A. Note
    sur les Lesions Histologiques du Rein Produits par les Sels
    de Baryte sur les Animaux. Comp. Rend. Hebd. Soc. de Biol.,
    vol. 4, p. 957. 1892.

    Literature on the pharmacology of barium not otherwise
    referred to is as follows: Boehm, R. Ueber d. Wirkungen d.
    Barytsalze auf d. Thierkörper. Arch. f. Exp. Path., vol. 3,
    p. 217. 1875.--Sommer, F. Beitr. z. Kennt. d.
    Baryum-Vergiftung. Dissert., Würzburg, 1890.--Neumann, J.
    Ueber den Verbleib der in den thierischen Organismus
    eingeführten Bariumsalzen. Archiv. f. Gesam. Physiol., vol.
    36, p. 576. 1885.--Hefftner, A. Ausscheidung körperfremder
    Substanzen im Harn, Ergeb. d. Physiol., pt. 1, p. 121.
    1903.--Binet, P. Recherches Compar. sur l'Action Physiol. des
    Métaux, Alcalins et Alcalino-terreux. Rev. Méd. de la Suisse
    Romande, vol. 12, pp. 535, 607. 1892.--Cyon, M. Ueber d.
    toxisch. Wirkung. d. Baryt u. Oxalsäureverbindungen. Archiv.
    f. Anat., Physiol. u. Wissens. Med., 1866, p. 196.--Mickwitz,
    L. Vergleich. Untersuch. ü. d. Physiol. Wirkung d. Salze d.
    Alcalien u. Alcal. Erden. Dissert., Dorpat, 1874.--Heilborn,
    F. Ueber Veränderungen im Darme nach Vergift. mit Arsen,
    Chlorbarium und Phosphor. Dissert., Würzburg, 1891.--Reincke,
    J. J. Ein Fall mehrfacher Vergiftung durch kohlensäuren
    Baryt. Viertelj. f. gerichtl. Med., n. s., vol. 28, p. 248.
    1878.--Orfila, Mémoire sur l'Empoisonnement par les Alcalis
    Fixes. Journ. de Chimie Méd., 2 s., vol. 8. p. 200.
    1842.--Santi, L. Se nel Veneficio per Sali di Bario questo
    Metallo passa alla Urina? Gazz. Chem. Ital., vol. 33, pt. 2,
    p. 202. 1903.--Weber, F. R. Barium Chloride. Milwaukee Med.
    Journ., vol. 12, pp. 39, 60. 1904.--Rabuteau. De l'Innocuité
    des Sels de Strontium Comparée à l'Activité du Chlorure de
    Baryum. Gaz. Méd. de Paris, 3 s., vol. 24, p. 218. 1869.--The
    very early literature is considered in detail by Bary.

    [193] Bary, A. Beitr. z. Baryumwirkung. Dissert., Dorpat,
    1888, p. 100.

    [194] Onsum, J. Ueber d. toxisch. Wirkung. der Baryt und
    Oxalsäureverbindungen. Arch. f. Path. Anat., vol. 28, p. 234.
    1863.

    [195] Brodie, B. C. Further Experiments and Observations on
    the Action of Poisons on the Animal System. Philos. Trans.,
    vol. 102, p. 218. 1812.

    [196] Tidy, C. M. On Poisoning by Nitrate of Baryta. Med.
    Press and Circ., vol. 6, p. 448. 1868.

    [197] Glover, R. M. On the Physiological and Medicinal
    Properties of Bromine and Its Compounds. Edinb. Med. & Surg.
    Journ., vol. 58, p. 341. 1842.

    [198] Kissner, G. Ueber Baryum Vergiftungen u. deren Einfluss
    auf d. Glykogengehalt der Leber. Scholten, 1896, p. 11.

    [199] Mittelstaedt, F. Ueber chronische Bariumvergiftung.
    Dissert., Greifswald, 1895, p. 19.

    [200] Pelletier, D. Observations sur la Strontiane. Annal. de
    Chimie, vol. 21, p. 119. 1797.

    [201] Christison, R. Treatise on Poisons. Edinburgh, 1845, p.
    579.--Crampe. Bewährte Mittel gegen Feldmäuse. Deutsch.
    Landw. Presse, vol. 5, p. 530. 1878.--Felletar, E. Fälle von
    Intox. mit kohlensäur. Baryum. Pest. Med.-Chir. Presse, vol.
    28, p. 1072. 1892.

    [202] Husemann, T. Ein Beitrag z. Kennt. d.
    Barytvergiftungen. Zeits. f. pract. Heilk., vol. 3, p. 235.
    1866. In this article Husemann has collected many cases of
    poisoning by barium in animals.

    [203] Christison, R. Treatise on Poisons. Edinburgh, 1845, p.
    579.




=BARIUM POISONING IN MAN.=


The high toxicity of barium was called attention to by early observers,
but it was attributed by some to admixed arsenic. The reports of feeding
experiments with barium on animals have varied markedly, but now care is
being advised in the use of barium salts.[204]

Barium was introduced into medicine in the treatment of scrofula, but
has fallen into disuse, and only recently attention has been called to
it on account of its action on the circulatory system. Filippi,[205]
however, says, "The effects on the heart and on the pressure are
already the first indication of poisoning." This metal has also been
used in the treatment of chronic diseases of the spinal cord, as
multiple sclerosis and paralysis agitans.[206]

After the administration to a woman of 1/12 grain (0.005 gram) of barium
chlorid three to five times a day for a few days, a total of 2-1/4
grains (0.135 gram), the patient developed rapid respiration, tenderness
over the epigastrium, nausea, constipation, cramps in the limbs, loss of
appetite, weakness, great emaciation, dysuria, some deafness with
tinnitus, difficulty in speaking and thinking, with vertigo.[207] In
this case the eyes were glassy, the vision indistinct, and the cheeks
flushed. Kohl after the use of small doses of the same noted salivation,
swelling of the gums, and falling out of the teeth, with a mercurial
odor to the breath. Christison[208] states: "I have known violent
vomiting, gripes, and diarrhea produced in like manner by a quantity not
exceeding the usual medicinal doses." According to Kennedy few persons
are able to bear 1/8 grain (0.0075 gram) of barium chlorid.[209]

In Carpenter's case after three doses of 1.6 grains (0.070 gram) of
barium chlorid the patient developed almost lethal symptoms.[210]
Carpenter calls attention to the drowsiness which developed in this
patient after the administration of barium, a fact which had already
been noted by Christison.[211]

A cartarrhal affection of various mucous membranes and a swelling of
various glands have been noted, especially of the lymph and salivary
glands, and in the male the testes have at times swollen.[212] The
inflammation of the glands may pass on to suppuration. The skin becomes
dry and shows a tendency to crack. Febrile attacks are reported after
the repeated use of small doses of barium.

Scheibler[213] has called attention to the possibility of producing
_chronic_ barium poisoning in man from the use of barium in the
manufacture of food products.

Acute cases of poisoning in man from four or more grams of barium
carbonate or chlorid or nitrate have been reported more or less
frequently.[214] In the acute case of poisoning in man reported by
Tiraboschi and Taito, no macroscopic changes were noted in the stomach
mucosa.[215] Lopes[216] has reported one case of acute poisoning in man
from less than 1 gram of barium chlorid. In this case paralysis of the
limbs was a marked feature. Stern[217] cites Perondi and Lisfranc to the
effect that "remarkably large doses of barium chlorid can be borne
without injury by gradually increasing the doses (dissolved in much
water)." Lisfranc[218] has suggested that the sensitiveness to poisoning
by barium salts is greater in certain climates than in others.

No data are as yet available as to the influence of altitude and partial
starvation on the toxicity of barium salts. As is well known, almost
all recorded cases of locoed animals have occurred at a high altitude.

It must also be remembered that the addition of one salt to the solution
of another may greatly increase the toxicity of the first one. Thus, the
addition of a few milligrams of barium chlorid to a solution of a
sulphocyanate renders the latter much more poisonous.[219] This may be
due to the fact that the salts are more completely ionized.

       *       *       *       *       *

FOOTNOTES:

    [204] According to v. Jaksch, "Sie ist bei der grossen
    Toxicität der Substanz immer ernst zu stellen." Vergiftungen,
    1897, p. 79.

    NOTE.--A thorough pharmacological study of some barium salt
    is much needed, and it is hoped that the writer will be able
    to complete this work.

    [205] Filippi, E. Modificaz. del Ricambio Organice per Azione
    del Cloruro di Bario. La Sperimentale, vol. 60, p. 610. 1906;
    Sull' Azione Cardiaca del Chloruro di Bario. Archivio di
    Farmacol. Speriment., vol. 5, p. 122. 1906.

    [206] Schulz, H. Vorles. ü. Wirkung. u. Anwendung d.
    unorganisch. Arzneistoffe. Leipzig, 1907, p. 234.--Hare, H.
    A. Use of Barium Chloride in Heart Disease. Med. News, vol.
    54, p. 183. 1889.

    [207] Ferguson, J. C. Symptoms of Poisoning from Muriate of
    Barytes. Dublin Quart. Journ. Med. Sci., vol. 1, p. 271.
    1846.

    [208] Christison, R., l. c., p. 580.

    [209] Kennedy, H. Dose of the Muriate of Barytes. Lancet,
    vol. 2, p. 28. 1873.

    [210] Carpenter, J. S. Barium Choride from a Clinical
    Standpoint. Med. News, vol. 59, p. 93. 1891.

    [211] Christison, R., l. c., 1845, p. 578.

    [212] Schulz, H. Vorles. ü. Wirkung. u. Anwendung d.
    unorganisch. Arzneistoffe. Leipzig, 1907, p. 233.--Schwilgué,
    C. J. A. Traité de Mat. Méd., 3 ed., vol. 1, p. 441. 1818.

    NOTE.--According to the files of the Office of
    Poisonous-Plant Investigations, E. D. Smith reported in the
    Orange Judd Farmer, 1897, that locoed animals showed a
    swelling of various glands. As yet the writer has been unable
    to verify this reference.

    [213] Scheibler, C. Ueber d. Verwendung giftiger Stoffe,
    besonders d. Barytverbindungen bei d. Zuckerfabrication.
    Chem. Zeit., vol. 11, p. 1463. 1887.

    [214] Schmidt's Jahrbücher, vol. 192, p. 131. 1881.--Walsh,
    J. Report of a Case of Poisoning by Chloride of Barium.
    Lancet, vol. 1, p. 211. 1859.--Walch. Seltener Fall einer
    tödlich. Vergiftung d. Baryta muriatica. Zeits. f.
    Staatsarznk., vol. 30, p. 1. 1835.--Carpenter, J. S. Barium
    Chloride from a Clinical Standpoint. Med. News, vol. 59, p.
    93. 1891.--Eschricht. Dødeligt forløbende Forgiftning med
    salpetersurt Baryt. Ugeskrift for Laeger, vol. 4, p. 241.
    1881.--Ogler and Socquet. Empoisonnement par le Chlorure de
    Baryum. Annal. d'Hyg. Publ., 3 s., vol. 25, p. 447.
    1891.--Chevallier, A. Note sur un Cas d'Empoisonnement
    Déterminé par l'Acétate de Baryte. Annal. d'Hyg. Publ., 2 s.,
    vol. 39, p. 395. 1873.--Courtin, Cas d'Empoisonnement par du
    Chlorure de Baryum. Rev. d'Hyg., vol. 4, p. 653.
    1882.--Poisoning by a Baryta Compound. Pharm. Journ., 3 s.,
    vol. 2, p. 1021. 1872.--Reichardt, E. Vergiftungsfall mit
    kohlensäurem Baryt. Arch. d. Pharm., 3 s., vol. 4, p. 426.
    1874.--Lagarde, P. Acétate de Baryte livré sous le Nom de
    Sulfovinate de Soude. Union Méd., 3 s., vol. 14, p. 537.
    1872.--Baum. Zwei Fälle von fahrlässiger Tödtung durch
    saltpetersäures Baryt. Zeits. f. Medizinalbeamte, vol. 9, p.
    759. 1896.--Funaro, A. Sul Veneficio per Sali di Bario.
    L'Orosi, vol. 12, p. 397. 1894.

    [215] Tiraboschi, A., and Taito, F. Avvelenamento da Bario.
    Il Risveglio Medico d'Abruzzo e Molise, vol. 1, p. 171. 1906.

    NOTE.--A criticism of this case is to be found in Bellisari,
    G., Su Di un Presunto Avvelenamento da Bario. Il Risveglio
    Medico d'Abbruzzo e Molise, vol. 2, p. 15. 1907.

    [216] Lopes, A. Caso Curioso de Envenenamento Pelo Chloret de
    Bario. Medicina Contempt., Lisbon, vol. 4, p. 109. 1886.

    [217] Stern, E. Vergiftung mit Chlorbarium. Zeits. f.
    Medizinalbeamte, vol. 9, p. 383. 1896.

    NOTE.--The writer has always theoretically questioned the
    danger of poisoning by loco weeds in well-fed and
    well-watered animals. Compare Stalker, M., The "Loco" Plant
    and Its Effect on Animals. Bur. Animal Industry, 3d Ann.
    Report (1886), p. 271. 1887.

    [218] Lisfranc. Leçon sur l'Emploi du Muriate de Baryte
    contre les Tumeurs Blanches. Gaz. Méd. de Paris, 2 s., vol.
    4, p. 215. 1836.

    [219] Pauli, W., and Fröhlich, A. Pharmakodynam. Studien.
    Sitz. Kaiserl. Acad. d. Wissens. z. Wien, vol. 115, III, pt.
    6, p. 445. 1906.




=PATHOLOGICAL LESIONS IN EXPERIMENTAL BARIUM POISONING.=


The post-mortem examinations in cases of acute experimental barium
poisoning, according to Schedel,[220] show punctiform or large
hemorrhagic effusion in the fundus ventriculi[221] and in the large and
small intestines, contraction of the bladder, and hemorrhage into the
walls of the bladder and uterus. The heart is usually found relaxed or
the left ventricle contracted in systole, while the right is relaxed.
Only once were ecchymoses under the endocardium seen. The liver and
kidneys showed nothing special. The urine was free from albumen and
sugar. In a few cases the lungs showed some infiltration with blood. In
chronic cases, according to our own investigations in rabbits, there are
no characteristic macroscopic lesions, a result which agrees with
Mittelstaedt's report.[222] Nothnagel and Rossbach[223] claim that in
chronic poisoning by barium the peripheral nerves are altered. The same
negative results have also been reported in chronic poisoning in higher
animals. Reynolds[224] noted a layer like a blood clot under the
cerebellum in a horse fed with barium chlorid. Fuchs[225] has called
attention to the fact that the flesh of cattle poisoned with barium
chlorid was harmless, perhaps owing to a conversion into an insoluble
salt, a fact which may be considered in the use of locoed animals for
food.

       *       *       *       *       *

FOOTNOTES:

    [220] Schedel, H. Beitr. z. Kennt. d. Wirkung des
    Chlorbariums. 1903, p. 13.

    [221] After subcutaneous injection of barium chlorid, Lewin,
    by means of the spectroscope, has found barium in the stomach
    walls. Lewin, L. Schicksal körperfremder chem. Stoffe im
    Menschen u. besonders ihre Ausscheidung. Deutsch. Med. Woch.,
    vol. 32, p. 173. 1906.

    [222] Mittelstaedt, F. Ueber chronische Bariumvergiftung.
    Dissert., Greifswald, 1895, p. 29.

    [223] Nothnagel, H., and Rossbach, M. J. Handb. d.
    Arzneimittel, p. 81. 1904.

    [224] Reynolds, M. H. A Study of Certain Cathartics. Minn.
    Agric. Exper. Sta., 15th Ann. Rept. 1907.

    [225] Fuchs, C. J. Vergiftungsfälle durch salzsäuren Baryt
    beim Rindvieh. Thierärztl. Mittheil., vol. 5, p. 159. 1870.
    Fuchs suggests that further investigations on this point are
    desirable. The literature of this class of experiments is
    very scanty. See Fröhner and Knudsen, Einige Versuche über d.
    Geniessbarkeit d. Fleisches vergift. Thiere. Monats. f.
    Prakt. Thierheilk., vol. 1, p. 529. 1890.




=TOXICITY OF VARIOUS AQUEOUS EXTRACTS OF LOCO PLANTS.=


On October 21, 1907, a rabbit weighing 1,531 grams was fed with an
extract of 95 grams of dried _Aragallus lamberti_ (Hugo, Colo., 1907),
with an ash content of 12.44 per cent, with a barium content estimated
as 2.6 milligrams of BaSO_{4} in 1 gram of ash. On the following day it
weighed 1,517 grams, and the same dose was again administered. On
October 23 the weight was 1,488 grams, and the dose was repeated. On the
next day the weight was the same and the dose was repeated. On October
26 the weight was 1,446 grams, and again the same extract was given. On
October 30 the animal weighed 1,502.5 grams; on October 31, 1,531 grams.
The animal received a total extract of 475 grams of the dried plant
without serious injury. This result was apparently contradictory to the
earlier work.

On October 21, 1907, a rabbit weighing 1,743 grams was fed with an
extract of 47.5 grams of the same dried plant. On the next day its
weight was 1,729 grams, and the same amount of the extract was fed. On
October 23 the weight remained the same, and the dose was repeated. On
October 24 the weight was 1,658 grams, and the same amount of extract
was fed. On October 26 the animal weighed 1,630 grams, when it was again
fed with the same amount of extract. On October 28 the animal weighed
1,573.5 grams, but two days later the weight had risen to 1,644 grams.
An extract of 237.5 grams had been administered. Here again the results
appeared contradictory.

On October 21, 1907, a rabbit weighing 1,517 grams was fed with an
extract of 77.5 grams. On the next day it weighed 1,545 grams, and the
dose was repeated. On October 23 the animal weighed 1,531 grams, and the
same amount of extract was given. On the following day it weighed 1,488
grams, and the dose was repeated. On October 26 it weighed 1,474 grams,
and again the dose was repeated. On October 30 the weight had risen to
1,545 grams, and on October 31 it was 1,559 grams. This animal received
in all an extract of 387.5 grams of the dried plant. An aqueous extract
of 200 grams of the same in one dose also failed to produce the acute
symptoms.

These feeding experiments show little of the characteristic action seen
in the earlier experiments made with aqueous extracts either of the dry
plant or of the fresh plant preserved with chloroform. In other words,
the aqueous extract of the dried plant was only slightly poisonous, yet
the plant from which the extract was made contained barium.

Of this same dried loco 200 grams were then extracted with water and
digested with pepsin and finally with pancreatin in the thermostat
(37.5°C.). The extract was concentrated and fed to a rabbit weighing
1,616 grams. After five hours and ten minutes the animal appeared weak
in the fore legs and unable to support himself, and he died during the
night. The intestines the following morning were found full of gas, the
stomach red, the lungs seemed normal, and the heart was relaxed.

A rabbit weighing 1,545 grams was fed on November 15, 1907, with a
preparation made in a similar manner, save that the plant was not
extracted with water before digestion. On the next day it weighed 1,517
grams and on November 19, 1,361 grams. The following day the weight was
1,318 grams; on November 21, 1,233 grams, and on the next day 1,162
grams. The animal died during the night, and the autopsy was made the
following morning.

The animal was greatly emaciated and the subcutaneous fat had almost all
disappeared. The mesenteric vessels were dilated, but the intestines
were not dilated. The peritoneal cavity was normal. The kidneys were
perhaps a little injected, and measured 3 cm. in length. The lungs were
normal. The left ventricle was contracted and the rest of the heart
relaxed. The liver was normal and the spleen apparently normal. The
stomach walls were dark, owing to decomposition. No ulcers were seen.
The suprarenals were perhaps a little enlarged. The examination of the
brain was negative, and no clots were found.

A similar digestion from 200 grams of the same dried plant was then
ashed and the ash treated with acetic acid and freed from acid by
evaporation on the bath. The ash which was insoluble in water was ground
up into a fine paste and the whole was fed to a rabbit weighing 992
grams. This animal died in forty minutes, showing the characteristic
symptoms seen in acute cases already described. In the autopsy the lungs
and other organs seemed perfectly normal macroscopically. The stomach
walls, however, were reddened and ecchymotic, and the mesenteric vessels
were dilated.

On January 8, 1908, a similar digestion of the same batch was treated
with a few drops of sulphuric acid to remove the barium, and the
filtrate was then treated with lead carbonate to remove the sulphuric
acid. After careful filtering, H_{2}S was passed into the solution and
after concentration was fed in one dose on January 9, 1908, to a rabbit.
The following morning the rabbit had gained in weight. On January 14
this animal weighed 30 grams more than its initial weight.

The residue of this plant after such a digestion, examined by the
Hillebrand method, showed no weighable amount of barium, so that it can
be seen that barium in relatively large amount was found in the plant
itself, but not after the digestion. It must therefore have been the
aqueous digestion which produced the characteristic symptoms. The
examination of this fluid for barium might, however, be misleading, as
the large amount of proteids would unquestionably interfere with the
determination of this amount of barium, unprotected by other salts and
silica, so that this side of the investigation was not pursued. Control
feedings with an emulsion of one-half gram each of pepsin and pancreatin
proved inactive.

Of the same _Aragallus lamberti_ 200 grams were similarly digested and
the barium was removed with a few drops of H_{2}SO_{4}, the sulphuric
acid by PbCO_{3} and a little lead acetate, and the lead by H_{2}S. Such
an extract it was shown in the previous experiment would not kill.
However, to this extract was added 100 milligrams of crystallized barium
acetate in a solution and a precipitate formed. Nevertheless, the liquid
and the precipitate were fed on February 1, 1908, to a rabbit weighing
1,304 grams. On February 3 the animal weighed 1,233 grams; on February
4, 1,176 grams; February 5, 1,120 grams; February 6, 1,006 grams;
February 7, 1,219 grams; February 8, 1,219 grams; February 10, 1,304
grams.

As a control for this animal, to make sure that the loss in weight was
not due to the acetic acid set free by the treatment with H_{2}S, a
similar aqueous extract of the same lot of _Aragallus lamberti_ was
precipitated with very much more lead acetate than in the preceding
cases and also with lead subacetate and then H_{2}S. After evaporating
to dryness this was fed on February 8, 1908, to a rabbit weighing 1,035
grams. On February 11 it weighed 1,021 grams; on February 13, 1,091
grams, and on February 15, 1,120 grams, showing a gain in weight.

Of the dried _Astragalus missouriensis_ (Hugo, Colo., June, 1907) 400
grams with an ash content of 21.8 per cent and which was known to
contain barium (3 mg. BaSO_{4} in each 2 grams of the ash) were
extracted with water and fed in four doses corresponding to 100 grams
each in a period of four days. On November 18, 1907, the first day of
feeding, this rabbit weighed 1,856.7 grams. Fifteen days later it
weighed 1,984.3 grams.

One hundred grams of this dried plant after extraction with water were
found to leave about 51.1 grams[226] of the plant undissolved. This when
ashed yielded 8.2 grams of ash. Two grams of this ash yielded 5
milligrams of BaSO_{4}. In other words, the aqueous extract of the plant
was inactive and the barium was found practically unextracted in the
residue of the plant.

Evidently the barium in these dried plants had been converted into an
insoluble form by drying or by some peculiarity of its metabolism, and
was not extracted by water, but could be extracted by digesting the
plants with the combined digestive ferments, pepsin and pancreatin.

Of the same dried _Astragalus missouriensis_ 200 grams were extracted
with water and the extract treated with lead carbonate to remove any
possible free sulphates and after filtering this was treated with H_{2}S
to remove the lead. As the preceding experiment showed that the aqueous
extract of this dried plant was harmless without barium, the writer
decided to add barium artificially, and 100 milligrams of barium
phosphate,[227] crystallized, was added to the liquid and the whole fed
to a rabbit weighing 2,423.9 grams. The following morning the rabbit was
found dead. The autopsy was made by Dr. H. J. Washburn, of the Bureau of
Animal Industry. He found that the suprarenals were enlarged and
congested, and there were small areas of hepatization at the apex of
each lung. There were also acute corrosion areas on the greater
curvature of the stomach and over the upper portion of the duodenum.

Of the _Astragalus missouriensis_ used in the preceding experiments, 200
grams were extracted thoroughly with water, and the extract
corresponding to 100 grams, together with 80 milligrams of barium
phosphate pure, was fed on March 12, 1908, to a rabbit weighing 1,261.5
grams. During this day the animal walked at times with an uncertain gait
and the following morning it weighed 1,233 grams. It was then fed the
rest of the solution, that is, the extract of the remaining 100 grams of
the plant, but without any barium. The animal soon developed convulsions
and died in a little over twenty-four hours after the original feeding.
The autopsy, which was made by Dr. J. R. Mohler, of the Bureau of Animal
Industry, showed that the mucous membrane of the stomach was markedly
hemorrhagic and in areas gelatinous infiltration was very marked. In one
portion of this hemorrhagic area there was distinct erosion. The large
intestines were full of gas, the lungs were normal, the heart was
relaxed, and the lungs collapsed. The blood vessels of the kidneys were
markedly engorged.

Of the dried _Astragalus nitidus_ (Woodland Park, Colo., October, 1907)
which was reported by the Bureau of Chemistry as containing no barium,
200 grams were extracted with water and fed in 100-gram doses for two
successive days. The animal increased steadily in weight and fifteen
days after the first feeding had gained 99.2 grams. This amount of the
plant was also extracted with water and the residue was then digested
with pepsin and pancreatin in the thermostat, as in the previous case,
and fed in two doses corresponding to 100 grams each. This animal
increased in weight, gaining 60 grams in six days and 165 grams in
addition after a further fifteen days.

An _Astragalus mollissimus_ (Kit Carson County, Colo., December, 1906),
which was also reported by the Bureau of Chemistry as containing no
barium, was extracted with water, and a dose corresponding to an extract
of 200 grams of the dried plant was fed in one dose without any serious
result. The same amount of the dried plant was also similarly digested
with pepsin and pancreatin and fed in two doses, but without the
production of any symptoms, the rabbit gaining 60 grams in four days.

Of the _Aragallus lamberti_ (Hugo, Colo., June, 1907), with an ash
content of 12.44 per cent, 250 grams were ashed and the ash treated with
acetic acid and, after evaporating off the acetic acid, was extracted
with water and the ash digested with pepsin and pancreatin. The aqueous
extract and the digestion products of the ash were then fed after
concentration, but without any serious effects to the animal, indicating
that in this plant the barium is in a form insoluble in water and in the
ashing is further changed so that it can not now be made soluble by
digestion--an opposite result to the experiment in which the barium was
first rendered soluble by digestion and the digestion products ashed,
suggesting a possibility that plants might be found in which the barium
is not extracted by digestion, at present a hypothesis.

Of dried _Astragalus decumbens_ (Ephraim, Utah, 1907), which was
reported by the Bureau of Chemistry to contain no barium, 200 grams also
failed to produce symptoms in rabbits by our test.

A solution containing 50 milligrams of barium acetate (crystallized) was
mixed with an aqueous extract of 200 grams of the dried _Aragallus
lamberti_ which had proved inactive pharmacologically, but a precipitate
formed (BaSO_{4}?) and the extract still remained inactive, suggesting
that the question of toxicity depended not only upon the presence of
barium, but also whether other agents, such as sulphates, etc., might
not be present in sufficient amount to render the barium insoluble; that
is, pharmacologically inactive.

This _Aragallus lamberti_ yielded an ash content of 37.3 per cent, and
the SO_{3} group was estimated at 0.27 per cent of the ash, while a
corresponding lot which was obtained two years later from the same area
yielded an ash content of 12.44 per cent and a SO_{3} content of 0.24
per cent of the ash.

It may be urged that the full lethal dose of the barium was not always
found in the plant, yet it must be remembered that the toxic action was
the resultant of the action of the total constituents and that if the
barium was removed the extract was practically harmless.

In looking back over the work the most suitable preparation for
producing the characteristic symptoms in rabbits seems to be the freshly
ground-up plant mixed with water and preserved in chloroform, for while
the dried plant might contain barium, yet the aqueous extract was often
inactive, suggesting, perhaps, the presence of something in the fresh
plant which aided the solution of the barium, thus accounting for the
variations in toxicity of aqueous extracts made from plants dried under
varying conditions. The nature of the compound in which barium exists in
the plant is as yet unknown and has not been investigated. _It is
important to remember that not only must barium be found in the plant to
prove poisonous, but it must be in such a form that it can be extracted
in the gastro-intestinal canal._

The amount of barium found in various species of loco plants will no
doubt vary, and perhaps the pharmacological test on rabbits as the
writer has used it may have to be modified for such plants, so that at
present the wisest plan to test these plants is to determine their
barium content and also make the physiological test, as has been
proposed, and if the barium content runs low, say below 0.11 per cent of
the ash, in plants yielding from 12 to 18 per cent of ash, then to
increase the number of feedings on the rabbit. No doubt on ranges where
a large number of loco plants are eaten, with little other food, plants
with a very low barium content may be poisonous, but if large amounts of
other food are fed the writer would expect few, if any, serious results.

As the writer's work has been confined to the laboratory side of the
loco-weed investigations no feeding experiments with barium salts have
been made by him on large animals. Such experiments should, of course,
be made under range conditions; that is, where the water and food supply
is deficient.

       *       *       *       *       *

FOOTNOTES:

    [226] Some was lost, being attached to the cloth used in
    squeezing the extract.

    [227] This barium phosphate was determined by the Bureau of
    Chemistry to be BaHPO_{4} and to contain traces of iron,
    sodium, and potassium, but it was free from arsenic.




=THEORETICAL ANTIDOTE FOR LOCO-WEED POISONING.=


The fact that treatment of the loco-weed extract with a few drops of
sulphuric acid, which will remove the barium, renders these extracts
harmless, and even apparently nutritious, would suggest the theoretical
antidotal treatment to be with sulphates, in the form, perhaps, of epsom
salts, but perhaps alkaline bicarbonates may be present in the stomach,
either due to lessened acidity of the stomach or from drinking alkaline
waters, in which case the precipitation of the barium by sulphates would
presumably be interfered with, and thus the treatment be rendered
ineffectual.[228] It is interesting to note that most of the remedies
proposed for the successful treatment of locoed animals contain
sulphates.[229]

In Storer's experiments on feeding rats with barium carbonate it was
found that the barium carbonate would kill them, but if calcium
carbonate was mixed with the barium the rats survived, suggesting an
antidotal action. This apparent antagonism deserves further study and
may lead to practical results.[230] A somewhat similar antagonism for at
least a part of the action of barium has been claimed to exist between
barium and potassium.[231] However, extracts of ashed plants, treated
with acetic acid, which contained calcium and potassium, caused death in
the experiments of the writer, but no work has yet been done by him as
to the antidotal action of calcium carbonate on barium. Then, too, as
Lüdeking[232] pointed out, large quantities of calcium chlorid may
interfere with the precipitation of barium as a sulphate. It is well
known that the presence of various salts influences the solubility of
barium sulphate in water,[233] and the fact that barium has been found
in solution in the urine in the presence of sulphates shows that the
precipitation of barium as a sulphate in the body is not so simple as in
test-tube experiments.[234] Again, in very dilute solutions, such as
must necessarily occur at any one time in the stomach, the precipitate
with sulphates only slowly forms and the barium may be absorbed before
the insoluble compound can be formed.[235] Evidently an important point
to be considered in the antidotal treatment of locoed animals with
sulphates is the possibility of inducing a gastritis, with its attendant
loss of weight. It therefore seems apparent that the proper treatment at
present is preventive--that is, removal from the plants.

Lewin[236] has suggested the possibility of acquiring some immunity to
barium, but our experiments point against the production of any
practical immunity.

       *       *       *       *       *

FOOTNOTES:

    [228] Mendel, L. B., and Sicher, D. F., l. c., p. 148.

    [229] Mayo, N. S. Some Observations upon Loco. Kans. State
    Agric. Coll. Bul. 35, p. 119. 1893.

    [230] Storer, F. H. Experiments on Feeding Mice with
    Painter's Putty and with Other Mixtures of Pigments and Oils.
    Bul. of Bussey Institute, vol. 2, p. 274. 1884.

    [231] Brunton, T. L., and Cash, J. T. Contribution to Our
    Knowledge of the Connection between Chemical Constitution,
    Physiological Action, and Antagonism. Philos. Trans. Royal
    Soc. London, I, vol. 175, p. 229. 1884.

    [232] Lüdeking, C. Analyse d. Barytgruppe. Zeits. f. Anal.
    Chem., vol. 29, p. 556. 1890.

    [233] Fraps, G. S. Solubility of Barium Sulphate in Ferric
    Chloride, Aluminum Chloride, and Magnesium Chloride. Amer.
    Chem. Journ., vol. 27, p. 288. 1902.

    [234] Santi has paid special attention to the solubility of
    barium in the body.

    [235] Fresenius, C. G. Man. of Qualitat. Chem. Anal. Tr. by
    H. L. Wells, 1904, p. 148.

    [236] Lewin, L. Nebenwirkungen d. Arzneimittel, 2 ed., p.
    439. 1893.




=ACTION OF BARIUM ON DOMESTIC AND FARM ANIMALS.=


Barium in the form of barium chlorid has been recently introduced into
veterinary therapeutics by Dieckerhoff[237] in the treatment of
constipation, but Winslow[238] says that "the doses required to produce
catharsis in the horse are almost toxic," and he advises against the
intravenous use of this remedy.

Fröhner[239] has carefully summarized the literature on the use of
barium chlorid in veterinary work, and reports that its use in the
Zürich clinic has recently been so unsatisfactory that it is now seldom
employed and that in the last ten years the preponderance of reports in
the literature are unfavorable to the use of this agent in colic.

After the administration per os, much of the barium must be carried off
in the diarrheal stools. A number of deaths in horses have been
attributed to the use of this agent. No doubt the presence of sulphates,
etc., derived from the food would render the barium insoluble in the
gastro-intestinal tract, and this would explain the lack of poisonous
action in certain of the cases in which large doses of barium proved
harmless.

Husard and Biron administered daily doses of 8 grams of barium chlorid
to one horse, and the same amount of barium carbonate to a second horse,
for several days. A fortnight later the first horse unexpectedly died,
and the second a few days later. The post-mortem examination was
negative.[240] A third horse fed with barium carbonate also died
suddenly. Recently barium occurring in brine has given rise to acute
poisoning in stock.[241]

In a case reported by Stietenroth[242] the horse died after the
injection of 0.5 gram of barium chlorid into the jugular vein. A number
of sudden deaths in horses after the intravenous injection of 0.7 gram
and over of barium chlorid have been collected by Fröhner.[243] The
lethal dose by mouth for acute poisoning with barium chlorid in horses
lies between 8 to 12 grams, while cattle require much larger doses (40
grams)[244] to induce death.

Dieckerhoff advises against the use of barium chlorid in the treatment
of constipation in sheep.

After a dose of 6 grams of barium chlorid a 2-year-old healthy ram
appeared perfectly well, but the following day he was depressed, refused
to eat, staggered, and became so weak that he was unable to stand. The
muscles of the extremities were paralyzed and the animal died. "The
post-mortem examination revealed oedema of the lungs, slight
cloudiness of the heart muscles, numerous small hemorrhagic spots on the
mucous membrane of the small intestine, and stagnation of the blood in
the vessels of the small and large intestines. Similar symptoms and
lesions were found in a lamb 4 months old which was given per os 6.0
grams of barium chlorid dissolved in 200 grams of distilled water."[245]

Poisonings with barium carbonate have also been reported in pigs.[246]
Domestic animals pastured in the neighborhood of barite deposits soon
succumb,[247] and accidental cases of poisoning are reported in cows.
Poisoning in dogs has also been reported after the subcutaneous use of
this agent.[248] Linossier says that if the barium salts are used for
any time the salts are deposited in various organs, largely in the
kidneys, brain, and medulla, but especially in the bones.[249]

       *       *       *       *       *

FOOTNOTES:

    [237] Dieckerhoff. Ueber d. Wirkung d. Chlorbaryum bei
    Pferden, Rindern und Schafen. Berliner Thierärztl. Woch., p.
    265; see also pp. 313 and 337, 1895; Abstract In Vet. Mag.,
    vol. 2, p. 360. 1895.

    [238] Winslow, K. Vet. Materia Medica and Therapeutics, p.
    152. 1901.

    [239] Fröhner, E. Lehrb. d. Arzneimittellehre, p. 399. 1906.
    Fröhner gives a detailed account of these cases.

    Original note in Ehrhardt, J. Erfahrungen ü. ältere u. neue
    Arzneimittel. Schweizer Archiv. f. Thierheilk., vol. 41, p.
    44. 1899.

    [240] Pelletier. Observations on Strontian. Journ. Nat.
    Philos., vol. 1, p. 529. 1797; original in Annales de Chimie,
    vol. 21, p. 127. 1797.

    [241] Howard, C. D. Occurrence of Barium in the Ohio Valley
    Brines and Its Relation to Stock Poisoning. W. Va. Univ.
    Agric. Exper. Sta. Bul. 103. 1906.

    [242] Stietenroth. Ueber Chlorbarium bei der Kolik der
    Pferde. Berliner Thierärztl. Woch., p. 16. 1899.

    [243] Fröhner, E. Lehrb. d. Toxikol., 2 ed., p. 116. 1901.

    [244] Fröhner, E., l. c., p. 116.

    See similar reports in Veterinarian, vol. 68, p. 572, 1895,
    and vol. 69, p. 228, 1896; Zeits. f. Veterinärk., vol. 8, pp.
    99 and 211, 1896; Nagler, F., Berliner Thierärztl. Woch., p.
    65. 1896.

    [245] Dieckerhoff, W. Vet. Mag., vol. 2, p. 362. 1895.

    [246] Kabitz, H. Ueber d. Wirkung einiger Baryumsalze beim
    Schwein. Deutsch. Thierärztl. Woch., vol. 13, p. 317. 1905.

    [247] Parkes. Chem. Essays, vol. 2, p. 213. Quoted by
    Christison, R., in Treatise on Poisons, Edinburgh, 4 ed., p.
    581, 1845.--Fuchs, C. J. Vergiftungsfälle durch salzsäuren
    Baryt beim Rindvieh. Thierärztl. Mittheil., vol. 5, pp. 133,
    154. 1870.

    [248] Falk. Zur Vergift. von Hunden mit Chlorbarium. Berliner
    Thierärztl. Woch., p. 40. 1897.--Schirmer,
    Chlorbariumvergift. beim Hunde. Berliner Thierärztl. Woch.,
    vol. 23, p. 268. 1897.

    [249] Linossier, G. De la Localisation du Baryum dans
    l'Organisme à la Suite de l'Intoxication Chronique par un Sel
    de Baryum. Comp. Rend. Hebd. Soc. de Biol., 8 s., vol. 4, p.
    123. 1887.

    NOTE.--Other cases of poisoning in animals may be found in
    Marder, Beitrag z. Giftwirkung des Baryum chloratum. Berliner
    Thierärtzl. Woch., vol. 37, p. 436. 1897; Absichtliche
    Vergift. mit Chlorbarium. Zeits. f. Veterinärk., vol. 9. p.
    72. 1897.




=APPLICATION OF THE RESULTS OF THESE INVESTIGATIONS TO THE RANGE.=


It has been calculated that a medium estimate of food for cattle on
green fodder is about 60 pounds (30 kilos) a day.[250] Calculating this
entirely in terms of _Aragallus lamberti_ and allowing 10 per cent of
moisture for these plants (Sayre) would make 27 kilos of dry loco eaten
by each animal per diem. In the analysis of the writer of one _Aragallus
lamberti_ from Hugo, Colo., it was found to yield 12.44 per cent of ash,
and the barium content corresponded to 2.6 milligrams BaSO_{4} in each
gram of the ash. This would correspond to 10.24 grams of barium acetate
(Ba(C_{2}H_{3}O_{2})_{2} + H_{2}O) or 9.15 grams of barium chlorid
(BaCl_{2} + 2H_{2}O) per diem. This amount daily administered would,
theoretically, readily produce chronic poisoning owing to the
accumulation in the system, as was shown in the case of rabbits.

There is, however, some question as to whether this full theoretical
amount of loco plants is eaten on the range, and the estimate has been
made that one-sixth of this amount only would be actually taken. It must
be remembered, as Stalker pointed out, that locoed animals develop an
especial taste for these plants and after a time reject other food, so
that while the number of loco plants at first taken may be small, yet
later, perhaps, it is greater. A part of this barium, however, may not
be taken up by the system, but may pass out undissolved. No actual
experiments have yet been made with cattle by feeding small doses of the
pure salt.

No doubt more of the pure barium salts will be required to produce
symptoms of poisoning in animals than would be necessary in the case of
the form of barium found in the plant, as in the loco-weed the barium is
probably better protected from precipitation than are the barium salts
when dissolved in water alone.

       *       *       *       *       *

FOOTNOTES:

    [250] Lane, C. B. Soiling Crop Experiments. N. J. Agric.
    Exper. Sta. Bul. 158, p. 18. 1902.--Woll, F. W. One Hundred
    American Rations for Dairy Cows. Univ. Wis. Agric. Exper.
    Sta. Bul. 38, p. 12. 1894.--N. J. State Agric. Exper. Sta.,
    20th Ann. Rept. (1899), p. 193. 1900.




CONCLUSIONS.[251]


(1) Conditions analogous to those met with in locoed animals occur in
other portions of the world, especially Australia.

(2) The main symptoms described in stock on the range can be reproduced
on rabbits by feeding extracts of certain loco plants. Those especially
referred to here under the term "loco plants" are _Astragalus
mollissimus_ and _Aragallus lamberti_.

(3) The production of chronic symptoms in rabbits is a crucial test of
the pharmacological activity of these plants.

(4) The inorganic constituents, especially barium, are responsible for
this action, at least in the plants collected at Hugo, Colo. Perhaps in
other portions of the country other poisonous principles may be found.

(5) A close analogy exists between the clinical symptoms and
pathological findings in barium poisoning and those resulting from
feeding extracts of certain loco plants. Small doses of barium salts may
be administered to rabbits without apparent effect, but suddenly acute
symptoms set in analogous to what is reported on the range.

(6) The administration of sulphates, especially epsom salts, to form
insoluble barium sulphate would be the chemical antidote which would
logically be inferred from the laboratory work, but of necessity this
would have to be frequently administered and its value after
histological changes in the organs have occurred remains to be settled.
But even the treatment of acute cases of barium poisoning in man is not
always successful, even when sulphates combined with symptomatic
treatment are employed. The conditions under which the sulphates fail to
precipitate barium must be considered. At present it seems best to rely
on preventive measures rather than on antidotal treatment.

(7) Loco plants grown on certain soils are inactive pharmacologically
and contain no barium. In drying certain loco plants the barium
apparently is rendered insoluble so that it is not extracted by water,
but can usually be extracted by digestion with the digestive ferments.

(8) The barium to be harmful must be in such a form as to be dissolved
out by digestion.

(9) In deciding whether plants are poisonous it is desirable not merely
to test the aqueous or alcoholic extract, but also the extracts obtained
by digesting these plants with the ferments which occur in the
gastro-intestinal tract.

(10) It is important that the ash of plants, especially those grown on
uncultivated soil, as on our unirrigated plains, be examined for various
metals, using methods similar to those by which rocks are now analyzed
in the laboratory of the United States Geological Survey.

(11) It is desirable to study various obscure chronic conditions, such
as lathyrism, with a view to determine the inorganic constituents of
lathyrus and other families of plants.

       *       *       *       *       *

FOOTNOTES:

    [251] Résumé of the results of the loco-weed investigations
    carried on by the Bureau of Plant Industry was issued as
    Bulletin 121, part 3, Bureau of Plant Industry, on January
    28, 1908, in the form of papers by C. Dwight Marsh and Albert
    C. Crawford, respectively, under the titles "Results of
    Loco-Weed Investigations in the Field" and "Laboratory Work
    on Loco-Weed Investigations."




INDEX.




                                                                   Page.
  Abortion, cows, caused by loco poisoning,                           13
            rabbits, caused by loco and barium poisoning,     41, 42, 62

  Acid, acetic, found in loco-weed,                                   26

  Acqua, C., reference to work,                                       52

  Africa, South, goat disease,                                        17

  Alfalfa, extract, experiments,                                      28

  Alkali deposits, supposed to cause loco disease,                    11

  Alkaloidal reactions, loco plants,                      20, 23, 27, 28

  Amaranthus graecizans, supposed cause of loco disease,              10

  American Pharmaceutical Association, proceedings, reference,        10

  Ammonia obtained from loco plants,                                  26

  Ammonium sulphid precipitate, effect on rabbits,                    50

  Anæmia, progressing, fundamental characteristic of loco disease,
                                                                  16, 19

  Analyses of loco plants,                                21, 22, 23, 32

  Anderson, F. W., references to work,                10, 12, 14, 18, 19

  Animals, carnivorous and herbivorous, varying immunity to loco
             disease,                                                 23
           domestic, barium poisoning, effects,                       72
           experiments with barium salts in laboratory,            57-62
           farm, barium poisoning, effects,                           72
           locoed, autopsies,           18-19, 24, 26, 30, 34, 36-43, 45
                   clinical symptoms,                              12-16
                   pathological conditions as described on the range,
                                                                   18-19
           poisoned by barium, autopsies,          57-61, 64, 67, 73, 74
           young, susceptibility to loco poisoning,                   15

  Antelopes, susceptibility to loco disease,                          12

  Antidote to loco poison, theoretical,                            71-72

  Aragallus lamberti, ash determination,                              54
                      barium determination,                       54, 56
                      extracts, uses in laboratory experiments, feeding
                        animals,     20, 23-25, 37, 42, 44-49, 66-68, 70
                      properties, investigations,       20-21, 23-25, 32
            spicatus, study and experiments,                          33
            spp., cause of loco disease,                       10, 20-34
                  uses, medicinal and toxic properties,               35

  Arsenic poisoning, references,                                      49

  Ash determinations of loco plants,                               54-55
      extract from loco plants, experiments,                       48-52
      loco plants, barium determinations,                          55-57
                   importance of analysis,                            76

  Astragalus bigelowii, extract, fatal to rabbit,                     38
             bisulcatus, extract fatal to rabbit,                     38
             decumbens, extracts, feeding experiments with rabbits,   70

  Astragalus exscapus, barium reported by C. Sprengel,                53
             hornii, poisonous properties, study,                     19
             lentiginosus, poisonous properties, study,               19
             menziesii, stock poisoning,                              20
             missouriensis, ash content and barium determination,     56
                            extracts, feeding experiments with
                              rabbits,                             68-69
             mollissimus, distillate, composition,                    26
                          extracts, experiments in feeding animals,
                                             22, 23-25, 27-33, 36-49, 70
                          investigations, experiments, and
                            analyses,                              21-34
                          physiological action,                22, 24-25
             mortoni, a deadly sheep poison,                          20
             nitidus extracts, feeding experiments with rabbits,  38, 69
             spp., cause of loco disease,                      10, 19-34
                   total ash determinations,                       54-55
                   uses, medicinal and toxic properties,              35
                   varieties containing no barium,                    57

  Australia, disease similar to loco poison, description,          16-18

  Autopsies on animals after barium poisoning,         57-61, 67, 73, 74
                             loco poisoning,
                                        18-19, 24, 26, 30, 34, 36-43, 45


  Bachem, C., reference to work,                                      50

  Bailey, F. M., reference to work,                                   17

  Barium acetate, feeding experiments on animals in laboratory,    57-62
         action on farm and domestic animals,                      72-74
         carbonate, feeding experiments on animals in laboratory, 61, 62
                                           rats,                      71
                    hypodermic injection, cats, fatal results,        62
         chlorid, effects on human beings,                         63-65
                  feeding experiments with animals in laboratory,  60-62
                  use in veterinary therapeutics, dangers,         72-73
         content of rocks in Rocky Mountains,                         54
         determination in ash of loco plants,                  54, 55-57
         discovery in loco plants, feeding experiments,                5
         feeding experiments with range cattle, desirability,         71
         harmful when in soluble form,                                76
         in brine, poisoning stock,                                   73
            well water in England,                                    57
         insoluble after drying loco plants, extraction with digestive
           ferments,                                                  76
         nitrate, feeding experiments on animals in laboratory, results,
                                                                  61, 62
         phosphate, analysis by Bureau of Chemistry,                  69
         poisoning, experimental, pathological lesions,               65
                    horses, sheep, and pigs,                      73, 74
                    man, symptoms, results,                        62-65
         presence in certain vegetable substances,                    53
         salts, feeding experiments on animals in laboratory,      57-62
                toxicity of different solutions,                      64
                         relation of altitude, climate, and varying
                           combinations,                              65
                use in medicine,                            62-65, 72-73
         sulphate, nontoxic on account of insolubility,               53

  Barrows, D. P., reference to work,                                  35

  Bary, A., references to work,                               53, 59, 60

  Baum, reference to work,                                            64

  Beech, barium present,                                              53

  Beer, Mexico, use of "crazy weed",                                  20

  Bellisari, G., reference to work,                                   64

  Beryllium chlorid, effect on rabbits,                               50

  Binet, P., reference to work,                                       59

  Birch, barium present,                                              53

  Birdsall, W. R., experiments with Aragallus lamberti,               20

  Blankinship, J. W., references to work,                         11, 34

  Blood, clots on brain,                              18, 26, 37, 42, 65

  Boehm, R., reference to work,                                       58

  Böhm, C. R., reference to work,                                     50

  Bray, W. C., reference to work,                                     53

  Brewer, W. H., reference to work,                                   20

  Brine, barium content, producing acute poisoning in stock,          73

  Brodie, B. C., reference to work,                                   61

  Brunton, T. L., reference to work,                                  72

  Burgassi, G., reference to work,                                    52


  Cæsium chlorid, experiments on rabbits,                             51
         occurrence in plants, toxicity,                              51

  Calcium acetate, experiments on rabbits,                            52
          carbonate, antidotal to barium,                             71
          experiments on rabbits,                                     52
          occurrence in loco plants,                              25, 27

  Cambier, J., experiments with loco plants,                       26-28

  Canada, disease caused by eating ragwort,                           17
          freedom from loco disease,                                   9

  Cannabis sativa, supposed cause of locoed conditions in Mexico,     10

  Caprioides aureum, supposed cause of loco disease,                  10

  Carpenter, J. S., references to work,                           63, 64

  Cash, J. T., reference to work,                                     72

  Cats, barium injection experiments,                                 62
        loco-plant experiments,                               22, 24, 30
          _See also_ Kittens.

  Cattle, barium feeding experiments under range conditions,
    desirability,                                                     71
          daily ration of green fodder, toxic effects of loco plants, 74
          loco poisoning, notes,                      12, 19, 20, 22, 28
          locoed, flesh harmless,                                     65
          poisoned with barium chlorid, flesh harmless,               65
          range, barium feeding experiments, desirability,            71
          susceptibility to loco disease,                             12

  Cerium chlorid, experiments on rabbits,                             50

  Chemical experiments with loco plants,                           46-57

  Chemicals in aqueous solution, effects on rabbits,               50-52

  Chemistry, Bureau, ash and barium determinations, loco plants,  54, 56

  Chesnut, V. K., references to work,                         10, 11, 33

  Chevallier, A., reference to work,                                  64

  Christison, R., references to work,                             62, 63

  Coffee substitute, use of seeds of Astragalus boeticus,             35

  Collier, Peter, study of loco plants,                               21

  Colorado, loco disease experiments, results,                         5
            loss of stock from loco disease, 1898,                     9

  Constipation, treatment of animals with barium, danger,             73

  Cotyledon ventricosa, cause of nenta, a goat disease,               17

  Courtin, reference to work,                                         64

  Cows, abortion caused by loco poisoning,                            13
        autopsies after loco poisoning,                               18
        locoed, symptoms,                                             25
        susceptibility to loco disease,                               12

  Crawford, Albert C., loco investigations, reference to published
    paper,                                                            75

  Crazy weed. _See_ Loco plants.

  Crotalaria sagittalis, cause of loco disease, chemical
    study,                                                     10, 26-27
                         experiments with horses,                  26-27

  Curtice, C., reference to work,                                     31

  Cyon, M., reference to work,                                        59

  Cyprus, loco disease of cattle, sheep, and goats,                   22


  Darling pea, effects on horses and sheep in Australia,              16
               feeding sheep, effects similar to loco poisoning,   16-17

  Day, M. G., experiments with Astragalus mollissimus and Aragallus
    lamberti,                                                  15, 23-26

  Delphinium spp., supposed cause of loco disease,                    10

  Demoussy, E., reference to work,                                    53

  Didymium chlorid, experiments on rabbits,                           51

  Dieckerhoff, W., references to work,                            72, 74

  Digestion of loco plants, experiments,                  66, 67, 68, 70

  Diuretic, use of Astragalus glycophyllus,                           35

  Dogs, barium feeding experiments, results,                          62
               poisoning, subcutaneous injection,                     74
        loco-plant feeding experiments,                   22, 23, 30, 53

  Donkeys, susceptibility to loco disease,                            12

  Dworzak, H., reference to work,                                     53

  Dyrenforth, reference to work,                                      54


  Eastwood, A., references to work,                               10, 12

  Eckard, G. E., reference to work,                                   53

  Ehrhardt, J., reference to work,                                    73

  Emory, W. H., reference to work,                                    19

  Eschricht, reference to work,                                       64

  Experiments, laboratory, with barium salts,                      57-62
                                loco plants,                36-56, 66-71
               loco poisoning and barium feeding, results,             5

  Extracts of loco plants, digestion with pepsin and pancreatin,
    experiments,                                                   66-68
                           testing, importance,                       76
                           use in laboratory experiments, varying
                             toxicity,                      36-49, 66-71


  Falk, reference to work,                                            74

  Faust, E. S., reference to work,                                    31

  Faville, reference to work,                                         18

  Felletar, E., reference to work,                                    62

  Ferguson, J. C., reference to work,                                 63

  Filippi, E., reference to work,                                     62

  Fletcher, J., reference to work,                                    10

  Fleurot, reference to work,                                         35

  Folin, O., reference to work,                                       56

  Food, use of loco plants,                                       35, 74

  Forage, use of Astragalus nuttallianus and A. crassicarpus,         35

  Forchhammer, J. G., reference to work,                              53

  Foster, F. B., reference to work,                                   26

  Frankforter, G. B., reference to work,                              35

  Fraps, G. S., reference to work,                                    72

  Fresenius, C. G., reference to work,                                72

  Fritillaria pudica, supposed cause of loco disease,                 10

  Frogs, loco-plant experiments,                              17, 22, 24
         poisoning,                                               17, 24

  Fröhlich, A., reference to work,                                    65

  Fröhner, E., reference to work,                                     73

  Fuchs, C. J., references to work,                               65, 74

  Funaro, A., reference to work,                                      64


  Garbanzillo, Spanish name for Astragalus mollissimus, derivation,   11

  Gibbons, H., reference to work,                                     21

  Givens, A. J., references to work,                              10, 35

  Glands, swelling, in locoed animals, note,                          63
                    result of use of barium on human beings,          63

  Glover, R. M., reference to work,                                   61

  Goat disease, South Africa, note,                                   17

  Goats, loco poisoning,                                              22
         susceptibility to loco disease,                              12

  Gordon, P. R., reference to work,                                   17

  Grass staggers, Texas loco disease, symptoms, description,          11

  Greshoff, M., reference to work,                                    35

  Guinea pig, autopsy after loco poisoning,                           43
         pigs, loco-plant feeding experiments,                    32, 43

  Guthrie, F. B., reference to work,                                  17


  Hairs on plants cause of loco disease, suggestion,              22, 28

  Hallucinations caused by loco poison,                               13

  Hare, H. A., reference to work,                                     63

  Harkins, W. D., reference to work,                                  49

  Hayes, M. H., description of Texas grass staggers,                  11

  Hefftner, A., reference to work,                                    58

  Heilborn, F., reference to work,                                    59

  Hill, J. R., reference to work,                                     22

  Hillebrand, method of determination of barium in ash of loco
    plants,                                                           56
              statement as to barium content of rocks in Rocky
                Mountains,                                            54

  Hoffmann, F., reference to work,                                    26

  Hogs, susceptibility to loco disease,                               12

  Holmes, E. M., reference to work,                                   35

  Hornberger, R., reference to work,                                  53

  Horses, autopsies after barium poisoning,                           73
                          loco poisoning,                         18, 26
          barium poisoning,                                           73
          disease caused by feeding on Darling pea (Swainsona
            galegifolia),                                             16
          loco-plant experiments,                                     33
          loco poisoning, notes,                          16, 19, 20, 26
          locoed, symptoms,                                           13
          susceptibility to loco disease,                             12

  Hough, W., reference to work,                                       35

  Howard, C. D., reference to work,                                   73

  Hugo, Colo., soils, analysis for traces of barium,                  57

  Hunt, Reid, study of and experiments with loco plants,           33-34

  Hurd, H. M., reference to work,                                     35

  Husemann, T., reference to work,                                    62

  Hydrocyanic acid, presence in loco plants, suggestion,              29


  Indigo disease, similarity to loco disease,                      16-17

  Ingersoll, study of loco disease,                                   30

  Injections, subcutaneous, experiments with barium salts,    62, 73, 74
                                             loco extracts,           43

  Insanity, treatment, use of Astragalus mollissimus,                 35

  "Insect Life," reference to work,                                   31

  Intoxication caused by loco plants,                     13, 16, 21, 22


  Jaksch, J. v., references to work,                              51, 62

  Janvier, reference to work,                                         11


  Kabitz, H., reference to work,                                      74

  Kansas, loss of stock from loco disease in 1883,                     9

  Kellogg, A., reference to work,                                     19

  Kelsey, F. D., reference to work,                                   10

  Kennedy, H., reference to work,                                     63

  Kennedy, J., experiments with loco-weed extracts,               23, 26

  Kingsley, B. F., reference to work,                                 12

  Kissner, G., reference to work,                                     61

  Kittens, loco-plant experiments, and autopsies,                  24-28
    _See also_ Cats.

  Kleuch, J. P., reference to work,                                   19

  Knop, W., reference to work,                                        53

  Knowles, M. E., references to work,                             13, 14

  Kobert, R., references to work,                                 33, 54


  Laband, L., reference to work,                                      51

  Laboratory experiments with loco plants,                         36-57

  Lagarde, P., reference to work,                                     64

  Lambs, experiments in feeding loco plants, symptoms and autopsies,
                                                              31, 45, 46

  Lane, C. B., reference to work,                                     74

  Lanthanum chlorid, experiments on rabbits,                          50

  Lathyrism, symptoms, resemblance to loco poisoning,                 15

  Leucocrinum montanum, supposed cause of loco disease,               10

  Lewin, L., references to work,                                  65, 72

  Lewis, Doctor, experiments with loco plants on rabbits,             30

  Linossier, G., reference to work,                                   74

  Lisfranc, reference to work,                                        64

  Lloyd, J. W., study of loco poison,                             31, 32

  Loco-acid, body supposed to be in loco plants,                      30
       disease, attributed to hairs on plants,                    22, 28
                              worms,                              31, 34
                experiments, Colorado, results,                        5
                symptoms, descriptions,
                                11, 12-16, 17, 24, 26, 28, 29, 33, 36-44
       eating habit, description,                                 14, 15
       intoxication,                                      13, 16, 21, 22
       investigations from a pharmacological standpoint, historical
         sketch,                                                   19-34
       plants, ash determinations,                                 54-55
               ashed, aqueous extracts, effect,                    48-52
               barium determinations,                              55-57
               eaten with large amounts of other food presumably not
                 dangerous,                                           71
               effects on human beings,                   15, 20, 22, 35
               extracts, digestion with pepsin and pancreatin,
                 experiments,                                      66-68
               extracts, variations in toxicity,                   66-71
                         use in laboratory experiments, varying
                           toxicity,                        36-52, 66-71
               list,                                                  10
               poison, varying in carnivorous and herbivorous
                 animals,                                             23
                               with season, variety, and origin,  25, 48
               uses as food, forage, medicine, etc.,                  35
               without barium not poisonous,                       68-71
                 _See also_ Loco weeds.
       poison, attempts to isolate the active principle,              47
       poisoning, laboratory study, results,                         5-6
                  symptoms,     11, 12-16, 17, 24, 26, 28, 29, 33, 36-44
                           reproduction in rabbits,    29, 33, 36-44, 75
                  theoretical antidote,                            71-72

  Locoed animals, clinical symptoms,                               12-16
                  pathological conditions as described on the
                    range,                                         18-19
         derivation of term,                                           9

  Locoin, experiments by Ruedi,                                       30

  Loco-weed disease, geographical distribution,                        9
            family, notes on use of various members,                  35
              _See also_ Loco plants.

  Lopes, A., reference to work,                                       64

  Lotus americanus, supposed cause of loco disease,                   10

  Lüdeking, C., reference to work,                                    72

  Lutterkorth, H., reference to work,                                 53


  McCullaugh, F. A., references to work,                  12, 13, 15, 19

  McEackran, Doctor, loco-plant experiments with horse,               33

  Magnesium acetate, experiments on rabbits,                          52

  Magnus, R., reference to work,                                      58

  Maiden, J. H., reference to work,                                   16

  Maisch, J. M., references to work,                              21, 35

  Malbec, A., reference to work,                                      58

  Malnutrition, cause of loco disease, suggestion,                29, 34

  Malvastrum coccineum, supposed cause of loco disease,               10

  Man, barium poisoning,                                           62-65
       loco poisoning, symptoms,                                      15

  Manganese acetate, experiments on rabbits,                          51

  Manitoba, occurrence of loco poisoning,                             10

  Marine plants, barium taken up from sea,                            53

  Marsh, Dr. C. Dwight, investigation and collection of loco plants,
    and reference to published paper,                             36, 75

  Marshall, H. T., loco plant study, reference to work,           31, 34

  Martin, C. J., description of effects of feeding the Darling
    pea to sheep,                                                  16-17

  Matthews, W., reference to work,                                    35

  Mayo, N. S., loco-plant studies, references to work,
                                                      11, 13, 18, 32, 71

  Meat from locoed cattle harmless,                                   65

  Medicago sativa. _See_ Alfalfa.

  Medicine, use of loco plants,                                       35

  Meltzer, S. J., reference to work,                                  52

  Mexico, plants causing "locoed" condition,                      10, 11

  Mickwitz, L., reference to work,                                    59

  Miller, C. H., reference to work,                                   13

  Mittelstaedt, F., references to work,                           62, 65

  Moffat, P., study of loco plants,                                   20

  Mules, susceptibility to loco disease,                              12


  Nagler, F., reference to work,                                      73

  Nausea, effect of loco plants on man,                       15, 20, 22

  Nelson, S. B., reference to work,                                   33

  Nenta, goat disease, South Africa,                                  17

  Neumann, J., reference to work,                                     58

  Neuritis, peripheral, in locoed animals in Australia,               17

  New South Wales, Agricultural Gazette, references,              16, 17

  Nightshade spp., supposed cause of locoed condition in Mexico,      10

  Nockolds, C., references to work,                               12, 14

  Nothnagel, H., reference to work,                                   65

  Noyes, A. A., reference to work,                                    53


  Oatman, H. C., experiments with alfalfa extract,                    28

  O'Brine, loco-plant studies and analyses and references to work,
                                              13, 18, 19, 27, 32, 33, 54

  Onsum, J., reference to work,                                       61

  Orange Judd Farmer, reference,                                      63

  Orfila, reference to work,                                          59

  Oserow, reference to work,                                          48

  Ott, Dr. Isaac, experiments with extract of Astragalus mollissimus,
    results,                                                          22

  Oxytropis lamberti, analyses,                                       20
    _See also_ Aragallus.


  Paralysis, result of barium poisoning in man,                       64

  Parasites, loco plants, suggested cause of loco disease,        31, 34

  Parker, W. T., reference to work,                                   13

  Parkes, reference to work,                                          74

  Pathological conditions in barium poisoning,                        65
                             locoed animals on the range,          18-19

  Patterson, A. H., reference to work,                                12

  Pauli, W., reference to work,                                       65

  Payne, J. E., reference to work,                                    34

  Pelletier, D., references to work,                              62, 73

  Pigs, barium poisoning,                                             74
        guinea. _See_ Guinea pigs.

  Pilgrim, C. W., reference to work,                                  11

  Pilliet, A., reference to work,                                     58

  Plants, marine, barium taken up from sea,                           53

  Plönius, W., reference to work,                                     41

  Poison, loco, attempts to isolate the active principle,             47
          properties of certain loco plants,                          35

  Poisoning, barium, experimental, pathological lesions,              65
                     horses, sheep, and pigs,                     73, 74
                     man,                                          62-65
                              acute cases, symptoms, results,         64
                              possibility of production from use of
                                food,                                 64

  Poisoning, loco, theoretical antidote,                           71-72
                   symptoms,        11, 12-16, 17, 24, 26, 29, 33, 36-44
                             reproduction in rabbits,  29, 33, 36-44, 75

  Porcher, F. P., reference to work,                                  35

  Post-mortems. _See_ Autopsies.

  Pott, E., reference to work,                                        35

  Power, F. B., experiments with loco plants,                      26-28

  Pregnancy, animals in, experiments in feeding barium salts,         62
                                                loco plants,      41, 42

  Prescott, A. B., study of Aragallus lamberti,                       20


  Rabbits, autopsies after barium poisoning,                   57-61, 67
                           loco poisoning,                 30, 34, 36-43
           barium salts, feeding experiments,                      57-62
           chemicals in aqueous solutions, feeding experiments,    50-52
           loco plants, ash extracts, feeding experiments,  48-49, 66-71
                        feeding experiments,      22, 24, 29, 30, 33, 34
                                             in laboratory,
                                                     36-44, 48-49, 66-71
           reproduction of symptoms of loco poisoning, 29, 33, 36-44, 75

  Rabies, treatment, use of Astragalus kentrophyta,                   35

  Rabuteau, reference to work,                                        59

  Ragwort, poisonous effects, Canada,                                 17

  Ram, barium poisoning, autopsy,                                     74

  Ration, daily, green food for cattle, toxic effects of loco plants, 74

  Rats, feeding experiments with barium carbonate,                    71

  Rattle-box. _See_ Crotalaria sagittalis.

  Rattleweed disease. _See_ Loco disease.

  Reichardt, E., reference to work,                                   64

  Reincke, J. J., reference to work,                                  59

  Resins from loco plants, experiments,                               26

  Reynolds, M. H., investigations with barium,                        65

  Rhamnus lanceolata, supposed cause of loco disease,                 10

  Rocky Mountains, high percentage of barium in rocks,                54

  Roscoe, H. E., reference to work,                                   53

  Rosenthal, D. A., reference to work,                                35

  Rossbach, M. J., reference to work,                                 65

  Rothrock, description of loco plants, effects on animals,       20, 21

  Ruedi, Carl, experiments with loco plants and references to work,
                                                           14, 19, 29-30


  Sages said to cause loco disease,                                   11

  Salivation, result of loco poison,                                  12
                        use of barium on human beings,                63

  Salt licks supposed to cause loco disease,                          11
       prevention of poisonous effects of Darling pea,                17

  Santi, L., references to work,                                  59, 72

  Sayre, L. E., investigations and experiments and references to work,
                  10, 11, 14, 18, 19, 22, 23, 25, 28, 29, 30, 31, 34, 48

  Schedel, H., reference to work,                                     65

  Scheibler, C., reference to work,                                   64

  Schirmer, reference to work,                                        74

  Schorlemmer, C., reference to work,                                 53

  Schuchardt, B., description of symptoms of locoed animals, similar
    to lathyrism,                                                     15

  Schulz, H., reference to work,                                      63

  Schwartzkopff, O., references to work,                          12, 13

  Schwilgué, C. J. A., reference to work,                             63

  "Science," references to papers on loco plants,                 11, 31

  Scrofula, treatment, use of barium,                                 62

  Senecio jacoboea, poisonous effects,                                17

  Sestini, F., tests for beryllium,                                   50

  Sheep, autopsies after barium poisoning,                            74
                        loco poisoning,                   18, 30, 33, 45
         disease caused by feeding on Darling pea,                 16-17
         loco-plant feeding experiments,                       30, 44-46
              poisoning, notes,                       20, 22, 30, 33, 34
         locoed, symptoms,                                         14-15
         susceptibility to loco disease,                              12

  Smith, J. G., reference to work,                                    35

  Snow, F. H., reference to work,                                     31

  Soils, analysis, Hugo, Colo., for traces of barium,                 57

  Sophora sericea, supposed cause of loco disease,                    10

  Spine diseases, treatment, use of barium,                           63

  Sprengel, C., reference to work,                                    53

  Staggers, grass, Texas loco disease, symptoms, description,         11

  Stalker, M., description of symptoms of locoed animals and
    references to work,               10, 11, 14, 15, 16, 18, 21, 26, 64

  Steele, C. D., reference to work,                                   31

  Stern, E., reference to work,                                       64

  Stietenroth, reference to work,                                     73

  Stipa vaseyi, supposed cause of loco disease,                       10

  Stock, losses from loco diseases,                                9, 34
         poisoning by barium in brine,                                73

  Stockman, Doctor, experiments with extracts of Astragalus
    mollissimus,                                                      22

  Storer, F. H., reference to work,                                   72

  Storke, B. F., references to work,                              19, 25

  Strontium acetate, experiments on rabbits,                          52

  Subcutaneous injections. _See_ Injections.

  Sullivan, Dr. E. C., determination of barium in Aragallus lamberti, 54

  Sulphates antidotal to barium, suggestions,                  71-72, 75

  Suzuki, U., reference to work,                                      53

  Swain, R. E., reference to work,                                    49

  Swainsona galegifolia. _See_ Darling pea.
            spp., effects on sheep and horses, similar to loco
              poisoning,                                           16-17

  Syphilis, treatment, use of Astragalus exscapus,                    35


  Taenia expansa. _See_ Tapeworm.

  Taito, F., reference to work,                                       64

  Tallquist, T. W., reference to work,                                31

  Tapeworm, sheep, suggested cause of loco disease,                   30

  Texas grass staggers, loco disease, symptoms, description,          11

  Thallium nitrate, experiments on rabbits,                           50

  Thorium chlorid, experiments on rabbits,                            50

  Thorpe, T. E., reference to work,                                   57

  Tidy, C. M., reference to work,                                     61

  Tiraboscht, A., reference to work,                                  64

  Titanium chlorid, experiments on rabbits,                           50

  Tixier, L., reference to work,                                      41

  Torrey, J., reference to work,                                      19

  Toxicity, variations in extracts of loco plants,                 66-71

  Turner, F., reference to work,                                      17


  Ulcers in stomach,                          18, 24, 37, 41, 43, 49, 69


  Vasey, George, investigations and references to work,
                                                  12, 13, 14, 19, 20, 21


  Wait, C. E., reference to work,                                     51

  Walsh, J., reference to work,                                       64

  Watson, S., study of Aragallus lamberti,                            20

  Weber, F. R., reference to work,                                    59

  Wheat, barium present,                                              53

  Wheeler, G. M., references to work,                             20, 21

  Wilcox, E. V., references to work,                              11, 33

  Wilcox, T. E., reference to work,                                   13

  Williams, T. A., reference to work,                                 10

  Winslow, K., reference to work,                                     73

  Wohlwill, F., reference to work,                                    51

  Woll, F. W., reference to work,                                     74

  Woolls, W., reference to work,                                      17

  Worms, cause of loco disease, suggestion,                   30, 31, 34


  Yttrium chlorid, experiments on rabbits,                            51


  Zirconium chlorid, experiments on rabbits,                       50-51

  Zygadenus elegans, supposed cause of loco disease,                  10

       *       *       *       *       *

TRANSCRIBER NOTES:

    Obvious typographical errors and punctuation has been
    corrected without note.

    Alternate spellings and mis-spellings in the original have
    been retained.

    Page 26: "analagous" changed to "analogous" (some plant
    analogous to).

    Footnote 96: "Crotallaria" changed to "Crotalaria" (Poisonous
    Effects of Crotalaria).

    Page 52: "Rubidum" changed to "Rubidium" (Rubidium chlorid c.
    p.).

    Page 76: "is" changed to "it" (so that it is not).