Effect of chronic poisoning with diisopropyl fluorophosphate on neurmuscular function in the cat

161

American Federation for Clinical Research patients recovered and three (37.5 per cent) died. In all fatal cases death occurred within twelve hours of the first dose of penicillin. All the patients who died were in unfavorable age groups and had been ill for some time before admission to the hospital. Among fifty-three patients treated by us with smaller amounts of systemic, plus daily intrathecal penicillin, 60 per cent died, and fever and pleocytosis were more prolonged than in those patients given no intrathecal penicillin or only given a single dose. Clinical and laboratory observations on the patients in the two groups are compared. ENZYME INHIBITION BY ALPHA-TOCOPHEROL PHOSPHATE: PIRATORY

EFFECT ON CERTAIN AND

PROTEOLYTIC

RES-

SYSTEMS

ON BLOOD COAGULATION. K. L. zierler, M.D. and (6_~!invitation) D. Grob, M.D. and J. L. Lilienthal, Jr., M.D., Baltimore, Maryland. (From the PhysioAND

logical Johns

Division, Hopkins

Department University

of Medicine, and Hospital.)

Alpha-tocopherol phosphate (a-TPh) slows the accelerated oxidative processes in muscle dystrophy associated with vitamin E deficiency. Lu-TPh, in vitro,inhibits the succinoxidase system. In an effort to elucidate the mechanism of inhibition, studies were undertaken concerning the effect of a-TPh upon a number of enzyme systems. The systems were selected because they shared with the succinoxidase system a requirement for ionic calcium or because they contained sulfhydryl enzymes. (1) The adenosinetriphosphatase system was not influenced by cu-TPh when optimal calcium concentration was maintained. (2) Coagulation of recalcified human plasma was prevented by cu-TPh even when the molar ratio of ionic calcium to a-TPh was 10: 1. Furthermore, as little as 1OV M of a-TPh inhibited clotting of a thrombin-fibrinogen system. (3) a-TPh slightly inhibited the sulfhydryl enzyme papain. cr-TPh inhibited trypsin, plasma protease and leukoprotease as effectively as did the specific antiproteases. When a-tocopherol phosphate was injected into normal rats, large doses uniformly produced ataxia and weakness; apparent drowsiness, occasionally, convulsions and death. When the animals were sacrificed during the period of succinoxidase activity of muscle “drowsiness,” and of brain was normal. Oxygen consumption

of the diaphragm in Ringer-phosphate solution, however, was reduced while that of the brain was normal. a-TPh, therefore, is anti-oxidative, anticoagulant and antiproteolytic. MYOTONIA. C. S. 3adler, M.D., Manrico Troncelleti, M.D. and (by invitation) William Steiger, M.D. and Thomas M. Durant, M.D., Philadelphia, Pennsylvania.

DYSTROPHICA

The present studies confirm Waring’s concept of dystrophica myotonia, i.e., it is a heredogenerative disease, predominated by a modified Mendelian dominant gene. This is further modified by a type of mutation which is exhibited by progressive inheritance. Dystrophica myotonia patients present the endocrine features of a specific type of hypogonadism. This is described by and called “Klinefelter’s syndrome” which is characterized by small testes, aspermatogenesis, increased excretion of follicle-stimulating hormones and decreased excretion of 17-ketosteroids. Our patients also were compatible with Heller and Nelson’s modification of this syndrome, i.e., “Leydig cell failure.” Autopsy of one male patient with dystrophica myotonia showed, in addition to hyalinization of the seminiferous tubules, a decrease in the size of the adrenal and thyroid gland. Participation of the latter glands in the etiology of dystrophica myotonia and Klinefelter’s syndrome is discussed. The beneficial effect of large doses of testosterone propionate in males is described. Thus clinical and laboratory evidence seems to indicate that the etiology of dystrophica myotonia is that of defective genes which, through an evolution of status degenerans, cause secondary changes. These changes characteristically affect the lens of the eye, the muscular, vascular and endocrine systems. EFFECT OF CHRONIC

POISONING WITH

DI-

ISOPROPYL FLUOROPHOSPHATE ON NEURMUSCULAR FUNCTION IN THE CAT. Carlton

C. Hun/, M.D. and Walter F. Riker, M.D., .New York, .Neze, York, (From the Department

of Pharmacology,

sity Medical

Cornell

Univer-

College.)

Di-isopropyl fluorophosphate (DFP) has been shown to inactivate irreversibly serum and tissue cholinesterase. Following large doses of DFP,

American

162

Federation

cats developed a protracted syndrome of muscular weakness lasting as long as five months. In the present study effects of repeated large doses of DFP in the cat were studied by symptomatology, neuromuscular function and cholinesterase activity of nervous and muscle tissue. Cats which had received from two to six (average of four) daily intramuscular injections of 1 mg./kg. of DFP in oil showed ,ataxia, extreme muscular weakness and generalized fasciculations. Following the disappearance of fasciculations on the third to fourth day after poisoning, the animals showed generalized weakness and fatiguability. Subsequent to this recurrence of the weakness developed which was chiefly confined to the hind limbs and which lasted from 21 to 147 days. At varying intervals after poisoning the response of the muscle to intra-arterial injection of acetylcholine and the response to nerve stimulation was studied. Increased sensitivity to acetylcholine was present (one to ten days) and a prolongation of the contractile response (four to eighteen days) resembling that seen after denervation. The muscle was unable to maintain a tetanus induced by indirect stimulation (one to six days). Regeneration of muscle cholinesterase activity was complete in two weeks. By one month the brain cholinesterase had reached 69 per cent and the nerve 85 per cent of their control values. It is concluded that the syndrome described results from extreme reduction of muscle and nervous tissue cholinesterase by DFP. Changes in the response of the muscle to acetylcholine following protracted inactivation of cholinesterase suggest the development of an injury at the myoneural junction resembling that associated with denervation.

for Clinical Research finger in water maintained at 0’~. Pain thus induced follows a conveniently cyclic course. In one hundred experiments upon twentytwo adult subjects “cold” pain was nearly always found to overflow to adjacent areas, notably to neighboring digits. Features common to this phenomenon in almost all of the experiments were a “latent” period, “facilitation” in subsequent phases of the pain cycle, “tapering” of intensity and “incomplete segmental filling.” The direction of spread was predominantly caudad in most instances. In no subject was contralateral extension of pain noted. Pain failed to spread from thumb to jaw (in cortical sequence). Overflow of pain was unaltered by preliminary interruption of the circulation to the arm or by procainization of an area into which spread of pain was to occur. In contrast to these typical features of spreading pain, other and less “orderly” characteristics were noted. Most prominent was the moderate intraindividual and marked interindividual variation in extent of spread. In a minority of instances the spreading pain “migrated” during the experiment, “skipped” a digit or reached a higher intensity than that of the primary pain (“insubordination”). Many of these listed features of spreading pain have also been observed in patients with traumatic digital lesions, dental disease or angina pectoris. It is inferred that such overflow of pain is a central phenomenon and probably occurs at the segmental level in the cord. This mechanism contrasts sharply with spread of pain due to a peripheral effect, as in secondary contraction of skeletal muscle, and with reference of pain throughout the domain of a sensory nerve trunk as the result of a proximal nerve or dorsal root lesion. EXPERIMENTAL

E. Charles Kunkle, M.D., George C. Armistead, M.D. and Helen Goodell, B.S., .New York, New York. (From the New York

OBSERVATIONS

Hospital

and

cine, Cornell

ON

the

SPREAD

OF

Department

University

Medical

PAIN.

of MediCollege.)

The digits of the hand as distinct projections of the body are particularly suitable for the study of spread of pain from a site of noxious stimulation. An effective and reproducible stimulus has been found in the immersion of a

STUDIES ON THE NATURE OF

H. G. Wolf, M.D., J. D. Hardy, M.D. and H. Goode/l, B.S., New York, New York. (From the New York HYPERALGESIA.

Hospital ology,

and Medicine

University

the

Departments and

Medical

Psychiatry,

of PhysiCornell

College.)

There are a number of varieties of hyperalgesia. Considered here is that which can be experimentally induced in areas of skin adjacent to sites of noxious stimulation as described by Sir Thomas Lewis. In these areas pain threshold is not lowered although pin pricks and thermal