Studies in congenital generalized lipodystrophy. IV. Effect of muscular exercise on carbohydrate and fat metabolism including plasma levels of IRI and HGH. Two patients with congenital generalized lipodystrophy have been studied at rest, and during and after long-term exercise at different carefully measured work loads. The two patients represented different stages of diabetes development. Both patients derived most of their energy used during muscular exercise from carbohydrate, and comparatively little from fat. FFA levels remained low throughout the period of observation in contrast to normal individuals and patients with juvinile diabetes. The data presented seem to show that deposition of glucose and free fatty acids (FFA) as triglyceride, must be impaired and are not compatible with the concept of increased triglyceride turnover in the adipocytes. The fall in blood glucose concentration (BCG) was less than in normal individuals and juvenile diabetes during exercise, and the glucose tolerance remained unchanged following work stop in both patients (k-values unchanged), in contrast to normal persons and patients with juvenile diabetes. Both patients showed significant falls in circulating immuno-reactive insulin (IRI) levels during exercise irrespective of a rise or fall in BGC. Thus, the exercise itself might activate endogenous mechanisms which could, on the one hand increase the circulating BGC, and at the same time force circulating IRI to decrease, thus disturbing the well-known relationship between circulating glucose and IRI levels as has been exhibited in normal subjects. The high IRI levels, also during exercise in these patients, indicate a relative insulin resistance in the muscles, but less marked than the insulin resistance in the adipose tissue. The IRI response after glucose infusion did not change significantly with increasing work loads with one exception. Exercose did not alter significantly the human growth hormone (HGH) levels in either the diabetic or the non-diabetic patient indicating an abnormal regulation of the HGH secretion in congenital lipodystrophy.


Changes in amniotic fluid phospholipids on treatment with glucocorticoids to prevent respiratory distress syndrome. Amniotic fluid was obtained by transabdominal amniocentesis in 51 women in the 29th-36th week of pregnancy. The lecithin/sphingomyelin ratio was determined. In 28 patients,the ratio was less than 2.2. Beta-methasone was given for three days to 14 of them; the rest served as controls. On the fourth day, a second amniocentesis was performed on all patients. The lecithin/sphingomyelin ratio rose to a value greater than 2.2 in 4 of the patients in the betamethasone-treated group and in one of the controls. The percentage of palmitic acid in the lecithin increased concomitantly with increasing lecithin/sphingomyelin ratio. These results suggest that glucocorticoid induced acceleration of fetal pulmonary maturation may be reflected in the amniotic fluid as changes in its phospholipid composition. The lecithin/sphingomyelin ratio was found to be greater than 2.2 in 23 patients at the first amniocentesis. In such cases treatment with glucocorticoids can be avoided.


Changes in erythrocyte lipid stroma in the premature infant according to dietary fat composition. Eighteen premature infants of similar gestational age, divided into three groups, were fed 3 milk formulas containing different amounts of linoleic acid. All the cases received 120 calories per kg of weight and day, of which formula A supplied 6.1% of the dietary total calories as linoleic acid, formula B 15.9% and formula C only 0.6%. The fatty acids of red cell ethanolamine and choline phosphoglycerides were studied in a first sample obtained during the first hours of life before the infants had received any food, and in a second sample taken at the age of three weeks. In the group fed formula C (0.6% of the total calories) changes similar to those described in EFA-deficient rats were found, namely, a decrease of linoleic acid, and an increase of oleic acid and of 20:3 (n-9), with a consequent rise of the triene to tetraene ratio. When the supply of linoleate was highest (15.9% of the total caloric intake) linoleic acid increased, oleic acid decreased and the 20:3 (n-9) practically disappeared. None of the three groups showed any clinical symptoms.


Oxisuran: a non-cytotoxic, differentially immunosuppressive agent.


Bromocriptine:dopamine-receptor agonist.


Nitrogen retention and plasma amino acids of adults who consumed isonitrogenous diets containing rice and milk or wheat versus their constituent amino acids. Nitrogen retention and concentrations of plasma amino acids were compared when young adults consumed isonitrogenous diets containing proteins (3.0 g of N from rice plus 3.0 g of N from milk or 3.0 g of N from rice plus 3.0 g of N from wheat flour) or mixtures of their constituent amino acids. Diets containing proteins induced greater nitrogen retention than did those containing corresponding amounts of amino acids in crystalline form, and the difference between the combinations of proteins was delineated more sharply. Concentrations of several amino acids were elevated by substituting crystalline amino acids for proteins, especially in postprandial plasma. Subjects responded differently to addition of the limiting amino acids, lysine and tryptophan, to the diets containing amino acids instead of rice plus wheat. Therefore, data obtained by means of combinations of cereals and by mixtures of their constituent amino acids cannot always be used interchangeably.


Ischemia of the small intestine.

Ischemia of the small intestine.


Gynecologic disease in young, sexually active women. There has been a significant change in adolescent sexual behavior in the past decade. This report of 1,594 young, sexually active women, primarily from middle and upper socioeconomic backgrounds, identifies the obstetric and gynecologic problems characteristic of the group. While supposedly in a low-risk category these patients displayed a high incidence of cervical epithelial abnormality, problem pregnancy, and other obstetric and gynecologic abnormality. The incidence of veneral disease  was somewhat lower than anticipated.


125I therapy in Graves' disease. Long-term results in 355 patients. Because of the physical and radiobiologic differences between 125I and 131I, a trial using 125I to treat hyperthyroidism was undertaken in the hope of controlling hyperthyroidism without causing subsequent hypothyroidism. Three hundred fifty-five patients with diffuse toxic goitres were treated and have been under review for an average of 49.4 months:  63.4% are euthyroid, 33.5% are hypothyroid, and 3.1% remain hyperthyroid. Different groups of patients received a wide range of doses of 125I (4.0 to 56.0 mCi), and the lowest incidence of hypothyroidism (23%) was in the group that received between 6.0 and 10.5 mCi. Sixty-three percent of the patients whose initial dose was greater than 20.0 mCi are hypothyroid. Persistent hyperthyroidism was common in patients who received small doses. Because of the high incidence of posttreatment hypothyroidism in this series and because 131I has stood the test of time, we believe that 131I is the radionuclide of choice for the routine treatment of hyperthyroidism.


Antibodies to Yersinia enterocolitica in thyroid disease. The prevalence of elevated antibody titers against Yersinia enterocolitica was studied in normal subjects, patients with a variety of nonthyroidal illnesses, and patients with thyroid disease. In contrast to the low prevalence of antibodies in controls (less than 8%), 48 of 67 patients (75%) with a variety of thyroid disorders had titers greater than 1:8. Antibodies were found in 24 of 36 patients with Graves' disease, five of six with autonomous adenoma, seven of seven with Hashimoto's thyroiditis, three of five with idiopathic primary hypothyroidism, four of 11 with nontoxic nodular goiter, and one of two with thyroid carcinoma. Antibodies to serotype 3 were the most prevalent, occurred in the highest titers, and were found particularly in patients with Graves' disease. These observations indicate that in spite of the infreqent occurrence of yersinia infection in the United States as compared with Scandinavia, patients with thyroid disorders have a higher prevalence of antibodies to Yersinia than normal subjects or patients with other disorders.


Hashimoto's thyroiditis, myasthenia gravis, idiopathic thrombocytopenic purpura.


Prolonged rupture of membranes, pre-eclamptic toxaemia, and respiratory distress syndrome. A retrospective analysis was made of the incidence and severity of the idiopathic respiratory distress syndrome (RDS) in babies of less than 35 weeks' gestation born at this hospital from January 1967-December 1974. There was a lower incidence of RDS in babies born after pregnancies complicated only by prolonged rupture of membranes (PRM) (19%) and in babies born vaginally after pregnancies complicated only by pre-eclamptic toxaemia (PET) (18%) compared with the incidence of RDS after uncomplicated pregnancies (35%). Babies born vaginally who developed RDS after pregnancies complicated by PRM or PET had less severe disease compared with those who developed RDS after uncomplicated pregnancies. Mortality in babies who developed severe RDS was not influenced by the occurrence of PRM or PET. The biological implication of the study is that certain complications of pregnancy may accelerate pulmonary surfactant production in preterm babies.


Intrathecal antibiotic therapy for neonatal meningitis. Twenty infants with neonatal meningitis were treated with systemic and lumbar intrathecal antibiotics upon initial diagnosis. Failure to sterilize the CSF in 2-3 days was associated with evidence of ventriculitis in these infants who were then treated with intraventricular antibiotics. 4 infants died, but only 2 of them may be regarded as treatment failure. It is suggested that many deaths from neonatal meningitis may be preventable by early detection and treatment of ventriculitis with intraventricular antibiotics.


The future of the Atlas of Tumor Pathology.


Acute renal failure following halothane anesthesia. Acute renal failure was observed postoperatively in a patient after halothane anesthesia. The clinical and pathologic findings in this case were remarkably similar to those found in patients with renal failure after methoxyflurane anesthesia.


Abnormal vessels in the urinary tract following analgesic abuse in man. A brownish discoloration of the bladder mucosa around the ureteric orifices has been observed on cystoscopy in three patients taking excessive quantities of analgesics. Biopsy specimens revealed an unusual degree of hyalinization of the vessels in the submucosa. Similar changes have been noted in the renal medulla, pelvis, and ureter of patients with classical analgesic nephritis. This vascular change may play an important part in the development of the characteristic infarct-like necrosis seen in the analgesic kidney.


Primary pulmonary neurilemoma. Report of a case with ultrastructural examination. The electron microscopic features of a primary neurilemoma of the lung, a very rare neoplasm, were studied. Characteristic Schwann cells were present, with cytoplasm and elongated cytoplasmic processes coated with a basal lamina. The highly characteristic Luse bodies were also seen. We add electron microscopic corroboration to the previous tissue culture confirmation of this unusual benign pulmonary neoplasm.


Pulmonary injury and repair. Organ culture studies of murine lung after oxygen. Samples of mouse lung were cultured at various stages of the injury-repair cycle induced by oxygen. At intervals during and after a six-day exposure, pulmonary explants were prepared and cultured in media labeled with tritiated thymidine. Lungs cultured during the first three days in oxygen, when only interstitial edema was observed, resembled control explants in morphologic features and labeling. Cultures prepared from animals after four to six days of exposure, when necrosis of type 1 epithelial cells and hyaline membranes were observed, showed reduced thymidine uptake and reduced epithelial regeneration. Fibroblastic proliferation and collagen deposition occurred directly beneath areas with hyaline membranes, indicating that, in severely damaged lungs, cellular proliferation is predominantly fibroblastic rather than epithelial. The results suggest that the organ culture system is suitable for studying the reparative capacity of injured tissue.


Tubular stenosis of the aorta with aortic fibromuscular dysplasia. The autopsy findings in a 2-year-old girl with severe hypertension resulting from stenosis of the lower part of the thoracic and the abdominal aorta were reviewed. The lower portion of the thoracic aorta and the abdominal aorta showed uniform narrowing down to the level of the bifurcation of iliac arteries. Histologically, the aortic wall of the stenotic site showed irregular proliferation of smooth muscle cells and collagen fibers. The elastic fibers had disappeared from outside the media. No intimal thickening and inflammatory cell infiltration were observed. These histologic changes of the aortic media in this case are apparently similar to fibromuscular dysplasia (medial hyperplasia).


Identification of calcium oxalate deposits in bone by electron diffraction. Oxalosis involving bone secondary to prolonged chronic renal failure and long-term dialysis occurred in a living patient. The cystalline deposit in the small fragment of bone was identified by electron diffraction.


Wilson disease. Comparative ultrastructure in a sibship of nine. Comparative electron microscopy was done on liver tissue from a family of nine siblings to determine whether presymptomatic, affected patients with Wilson disease could be differentiated from heterozygous, normal carriers. Two of the nine had developed the neurologic manifestations of the disease; three others were considered to be homozygous but normal, two were heterozygous and normal, and two were classified as genotypically uncertain because of borderline biochemical abnormalities. Alterations of the mitochondria and endoplasmic reticulum suggestive of copper toxicity were present in both the heterozygous and the genotypically uncertain siblings, and a clear distinction could not be made on this basis. The severity of the abnormalities appeared to correlate with liver copper level, and organelle changes were found to precede lipid accumulation.


Meningioma with sarcomatous change and hepatic metastasis. A 72-year-old patient had a meningotheliomatous meningioma that invaded through the skull and into temporalis muscle. One year following craniotomy for removal of the neoplasm, he developed headaches, diplopia, and proptosis of the left eye. Biopsy of the orbital contents revealed a malignant supporting tissue neoplasm having a resemblance to the previous meningioma. No curative therapy was possible and the patient died 33 months after diagnosis. Autopsy examination showed extensive residual intracranial neoplasm and a 3-cm metastasis in the liver. The metastatic tumor appeared similar to the meningioma and did not appear malignant histologically. The case illustrates the distinct histologic variations in meningiomas and the difficulties in predicting their biologic activity. Aggressive local behavior may indicate possible malignant areas in the neoplasm. Therefore, examination of the neoplasm should be thorough. Such a correlation may suggest malignant biologic potential.


Osmotic relation between blood and perilymph in guinea pig.


A comparison of acidic glycosaminoglycans in the inner ear and other organs: electrophoretic microanalysis. Acidic glycosaminoglycans in the ground substance of the membranous cochlear lateral wall, kidney, brain and liver of the guinea pigs were quantitatively and qualitatively analyzed, using electrophoretic microanalysis. The lateral wall of the cochlea showed highest content (0.46 +/- 0.08%/D.W.) of acidic glycosmainoglycans, which were chondroitin sulfate-B (75%), chondroitin sulfate-A (12%) and hyaluronic acid (13%). However, the pattern of these acidic glycosaminoglycans in the inner ear differed from the other organs. A possible role of acidic glycosaminoglycans in the inner ear was discussed.


Permeability of round window membrane to 22Na or RISA.


The damped pendular rotation test in central vestibular disorders. Nystagmic rhythm in the damped pendular rotation test (DPRT) was analysed electronystagmographically both in healthy subjects (control) and patients with peripheral and central vestibular lesions. The patients were tested in a semi-dark room with eyes open and, in addition, a serial subtraction task was performed to maintain the state of alertness throughout the rotation. In the controls 49 years of age and under dysrhythmia was found in 11%, while in persons 50 years of age and over the abnormal rate was 29%. In patients with acoustic tumors, who had undergone surgery in which the translabyrinthine and middle fossa approach had been utilized, dysrhthmia was present post-operatively in only a few cases. In patients 49 years of age and under, operated on through the suboccipital approach, dysrhythmia was found post-operatively, or was at least more remarkable than pre-operatively in most cases. Nystagmic rhythm was, on the other hand, regular with cerebellar degenerative process or atrophy. Pre-operative dysrhythmia in patients with cerebellar and cerebral tumors was in some cases post-operatively converted to regular rhythmic nystagmus in pendular stimulations. Therefore, in cerebellar and cerebral tumors, dysrhythmia was thought to be due to secondary effects in brainstem, as these tumors can cause intracranial hypertension and circulatory disturbances in surrounding brain tissues. In Menière's disease and sudden deafness, dysrhythmia and salvos in DPRT were found in the age groups, 49 years of age and under and 50 years and over, as frequently as in the healthy and control group. In one case with Menière's disease which showed dysrhythmia, labyrinthectomy was done. This surgical manipulation of the labyrinth did not eliminate dysrhythmia, though a temporary improvement was obtained. This result indicates that the dysrhythmia may be of central origin. These findings also suggest that nystagmic rhythm in DPRT with mental arithmetic is significant in assessing brainstem dysfunctions, when the age and state of alertness of the patient are taken into consideration, or when comparing the pre- and post-operative findings in intracranial lesions.


Loss of a homologous group of proteins in a dominantly inherited ectodermal malformation. Hair from mice bearing the dominantly inherited Naked trait (NN) and from normal (NN) mice of the same inbred strain was separated into its major protein components by standard techniques. The relative amounts of proteins in these components were then determined by a regression method from the amino acid composition of the hair samples and of the fractions into which they had been separated. The results indicated that the amount of soluble fibril in Naked-mouse hair is decreased. Polyacrylamide-gel electrophoresis of this fraction prepared from the hair of both normal and Naked mice revealed that all protein bands present in the normal are also present in the Naked mice. However, a densitometric scan of the gels at 280 nm showed that the soluble fibril fraction from Naked-mouse hair is deficient in several proteins which, on amino acid analysis, were found to contain 31% glycine and 10% tyrosine. Gel filtration of S-carboxymethylkerateine prepared from normal and mutant hair showed that the mutant hair is deficient in a heterogeneous, low-molecular-weight fraction also rich in glycine and tyrosine. Our present data do not reveal the mechanism whereby a single gene locus modulates the production of several different proteins.


The effect of O-(beta-hydroxyethyl)-rutosides on function and structure of the ganglion cells. The effect of O-(beta-hydroxyethyl)-rutosides (Venoruton) on function and structure of the motor anterior-horn cells of the lumbar spinal cord was investigated under conditions of ischemia in the rabbit. The determination of the functional parameters of the ganglion cells, such as maximal function time (Fm), disappearance time (SFm), relative efficiency (La), and regeneration expenditure (Ea) revealed that 50 mg/kg of Venoruton injected prior to repeated aortic occlusion of short duration (occlusion time A = Fm and A = 2 Fm, respectively) caused the efficiency of the anterior-horn cells to be decreased. Both qualitative and quantitative analysis of the mitochondrial structure after prolonged aortic occlusion (15-25 min) revealed that after prior injection of Venoruton irreversible structural changes in the mitochondrial membranes of the ischemic area in the spinal cord occurred after aortic occlusion of 15 min duration. In the untreated controls such changes were not observed before 20 min of occlusion. The mitochondrial structure of the non-ischemic area in the spinal cord was found to be undamaged, however, in both controls and experimental animals. Venoruton given after prolonged aortic occlusion resulted in less pronounced structural changes of the mitochondria in the ischemic area of the experimental animals than those found in the untreated controls; paralysis of the hind extremities was found to occur only after prolonged occlusion (25 min), whereas in the controls such changes were already observed after 20 min of occlusion. Since no ultrastructural changes in the ganglion cells of the non-ischemic area in the in the lumbar spinal cord were observed after application of Venoruton, it is assumed that the decreased efficiency of the motor anterior-horn cells found in the ischemic area when Venoruton had been injected before the aortic occlusion may be due to reactions of the cell that only occur when the blood supply has been completely cut off and Venoruton is present at the same time.


On the adrenergic neuron blocking activity of 1-methyl-3-keto-4-phenylquinuclidinium bromide (MA540) during acute and chronic administration. The quaternary quinuclidine derivative 1-methyl-3-keto-4-phenylquinuclidinium bromide (MA540) antagonized rabbit ileum and cat nictitating membrane responses to postganglionic sympathetic stimulation in a manner similar to guanethidine, indicating adrenergic neuron blocking activity. The potency of MA540 in relation to guanethidine varied according to the experimental procedure employed for assay, being equal to, less and greater than that of the reference agent in the rabbit ileum, and the acute and chronic nictitating membrane, respectively. Preferential blockade of nictitating membrane responses to both lower and higher frequencies of sympathetic stimulation were found with MA540 and guanethidine, depending on the dose used in acute experiments, or on the number of daily administrations in chronic tests. Significant tolerance to the adrenergic impairment induced by MA540 and guanethidine was not apparent in membranes subjected to supramaximal sympathetic stimulation, but was evident in membranes under the influence of normal sympathetic tone in unanesthetized cats. This phenomenon appeared much earlier with guanethidine than with the quinuclidine derivative. Tolerance was correlated neither with norepinephrine supersensitivity nor with catecholamine depletion, which was evaluated indirectly through measurement of membrane responses to tyramine. The results of this study indicate that MA540 may be a useful antihypertensive agent, possessing some advantages over guanethidine.


Cardiovascular and antihypertensive actions of 1-methyl-3-keto-4-phenylquinuclidinium bromide. The sympatholytic and norepinephrine depleting drug 1-methyl-3-keto-4-phenylquinuclidinium bromide (MA540) possessed significant chronic antihypertensive activity in mecamylamine- and renal-hypertensive dogs. The compound was approximately four times more potent than guanethidine in the former model and three times as potent in the latter. MA540 reduced orthostatic blood pressure responses in unanesthetized rabbits, but was approximately ten times less potent than guanethidine. The quinuclidine derivative did not affect cardiac output, heart rate or stroke volume in anesthetized open chest dogs and moderately increased mean blood pressure and total peripheral resistance. It produced diuresis and saluresis in anesthetized dogs, but did not influence water or electrolyte urinary excretion in conscious rats. In the latter test, guanethidine produced antidiuresis and antisaluresis. It was concluded that MA540 is a potent, orally effective antihypertensive agent acting through adrenergic neuron blockade, that it lacks undesirable effects on cardiac and renal functions, and that compared with guanethidine, it is more potent in lowering blood pressure but less so in interfering with orthostatic cardiovascular reflexes.


The biological disposition of 1-methyl-3-keto-4-phenylquinuclidinium bromide in the rat and dog. The biological disposition of 1-methyl-3-keto-phenylquinuclidinium bromide (MA540) has been studied in the rat and dog. Gastrointestinal absorption of the drug was considerably different in the 2 species; about 15% and 75% of the dose in the rat and dog, respectively. Tissue distribution after i.v. administration was characterized by generally high tissue/plasma drug ratios in the rat and by low plasma (the only tissue examined) levels in the dog. Drug localization was apparent in the liver and adrenals, and the highest average (24-h) concentration was found in those tissues. The distribution profile and the chemical nature of MA540 suggest that the compound was distributed, at least initially, in extracellular water. MA540 was not extensively metabolized by either species. Excretion, although initially fairly rapid, slowed such that whole body half-lives were estimated to be 21 h and 47 h in the rat and dog, respectively.


Influence of 1-methyl-3-keto-4-phenylquinuclidinium bromide on rat tissue monoamine levels in vivo. The effects of 1-methyl-3-keto-4-phenylquinuclidinium bromide (MA540) on tissue monoamine levels in male rats have been compared to those of guanethidine. Neither compound influenced norepinephrine (NE) or 5-hydroxytryptamine (5-HT) levels in brain or epinephrine (E) levels in adrenal medulla. MA540 is about twice as potent as guanethidine as a heart NE depleting agent at both 8 and 24 h after drug administration. The durations of action of the compounds are similar. Unlike guanethidine, MA540 does not deplete NE in small intestine, which suggests that the drug may not elicit guanethidine-like intestinal side effects.


The acute and target organ toxicity of 1-methyl-3-keto-4-phenylquinuclidinium bromide (MA540) and guanethidine in the rat and dog. The effects of acute and repeated increasing oral doses of 1-methyl-3-keto-4-phenylquinuclidinium bromide (MA540) and guanethidine in the rat and dog have been described. On repeated oral administration guanethidine produced histopathological changes in cervical ganglia of rats and dogs which were clearly dose-dependent and reproduced lesions reported in the literature. Repeated oral administration of MA540 resulted in no histopathological changes in either species. The maximum tolerated oral dose for guanethidine was estimated to be 515 mg/kg in the rat and 26 mg/kg in the dog compared with an estimated maximum tolerated oral dose for MA540 of 1750 mg/kg in the rat and 460 mg/kg in the dog. On the basis of these findings it is suggested that subchronic studies with MA540 in the rat and dog should provide evidence which would justify the use of MA540 in man at daily oral doses as high as 9 mg/kg.


The absorption of [G-3H]-acetylglycyrrhetate after oral administration to rats. A tritium-labelled form of aluminium acetylglycyrrhetate has been synthesised by catalytic exchange with tritiated water. An oral dose of aluminium [3H]-acetylglycyrrhetate to rats was mainly excreted in the faeces (a mean of 73%). A mean of 4% was excreted in the urine and after five days 17% of the radioactivity was retained in the carcass. The amounts of non-volatile (drug-related radioactivity excreted in faeces and urine during five days were 65% and 3%, respectively, while 6% was retained in the carcass. The total amount of tritiated water produced was 24% of the dose. Experiments in rats with cannulated bile ducts indicated that much of the faecal radioactivity represented unabsorbed drug. 15% of an oral dose was eliminated in bile during 2 days. A minimum value for the extent of absorption of an oral dose was estimated as 21%. Plasma levels of radioactivity were very low and peak levels of drug-related radioactivity were reached at 30 min and represented about 0.2% of the dose in total plasma.


Anticatabolic action of formebolone in the castrated rat treated with dexamethasone. The anticatabolic action of 2-formyl-17a-methylandrosta-1,4-diene-11a,17beta-diol-3-one (formebolone) was demonstrated by assessing the nitrogen elimination in the urine of castrated rats treated with dexamethasone-21-phosphate. The absence of a virilizing action is duly pointed out.


Behavioral effects of withdrawal of fluphenazine after long-term treatment. Male Wistar rats were treated i.p. with 10-(3-[4-(2-hydroxyethyl)-1-piperazinyl]-propyl)-2-(trifluoromethyl)-phenothiazine (fluphenazine dihydrochloride, FL, Mirenil) in a dose of 1 mg/kg for 28 weeks, or in a dose of 5 mg/kg for 21 weeks, beginning from the 6th day of life. Withdrawal of the drug caused an abstinence syndrome in the form of increased locomotor and exploratory activity and increased irritability of the animals. Behavioral observation during the period of drug administration indicated the development of tolerance to behavioral effects of FL. Male and female Wistar rats from mothers treated i.p. with 1 mg/kg of FL during pregnancy and lactation period were treated for 32 weeks with 1 mg/kg of FL beginning from the 8th day of life. In males, during the period of withdrawal as well as during renewed treatment, an increase in locomotor and exploratory activity was observed. The behavior of female rats during the withdrawal period was similar to that of control animals. The abstinence syndrome observed after withdrawal of FL is modified by the time of life at which treatment was started and by the sex of the animals.


Absorption and excretion of 4-prenyl-1,2-diphenyl-3,5-pyrazolidinedione (DA 2370) in man and dog. The blood levels and excretion of radioactivity administered as 14C- or 3H-4-prenyl-1,2-diphenyl-3,5-pyrazolidinedione (DA 2370) have been studied after oral administration to dogs and man. After a single dose of 14C- or 3H-DA 2370 (10 mg/kg) to dogs the daily loss of radioactivity in urine and faeces fell to less than 1% of the dose in 4 days and the plasma levels showed a biexponential decay with mean half-lives of 3.7 and 62 h. When a single 200 mg dose of 3H-DA 2370 was administered to human subjects maximum urinary excretion of radioactivity occurred during day 2 with 4% of the total during day 5. Maximum faecal excretion was on day 2-3 with 0.5% of the dose on day 7. The plasma half-life was 32.5 h. A similar dose three times a day for 3 days had a half-life of 39 h when dosing ceased; radioactivity in the urine and faeces was 2% and 2.5% of the dose, respectively, 4 days later.


Secretion and localization of cathepsin D in synovial tissues removed from rheumatoid and traumatized joints. An immunohistochemical study. The proteinase cathepsin D which degrades proteoglycan was never demonstrated in extracellular sites in tissues from patients with traumatized meniscoid cartilage, either before or after culture with an antiserum to human cathepsin D. In contrast, in synovia (but not usually cartilage) from the knees of 6 of 11 rheumatoid patients, extracellular cathepsin D was commonly detected by culturing tissues with an antiserum to this enzyme.


Chrysotile-induced asbestosis: changes in the free cell population, pulmonary surfactant and whole lung tissue of rats. Rats inhaling chrysotile asbestos contracted asbestosis and fibrosis of the lungs. Studies of biochemical and morphological changes (between normal and treated animals) show that chrysotile induces an increase in the lung free cell population and pulmonary surfactant levels. Lysosomal enzyme levels are elevated in both the whole lung and free cell population and there are considerable changes in macrophage morphology. It is suggested that the primary response of the lung to chrysotile is an increase in surfactant production coupled with an increase in free cell numbers, in order to prevent the cytotoxic effect of the dust.


Facilitated transport of di- and trinitrophenolate ions across lipid membranes by valinomycin and nonactin. The conductance of black lipid membranes in the presence of 2,4,6-trinitrophenol (or 2,4-dinitrophenol) is considerably enhanced, if the cation carriers valinomycin, enniatin B or nonactin are added. The effect is, however, largely independent of the cation concentration and is identical for the cations Li+, Na+ and Ba2+. This finding, as well as the sign and magnitude of the diffusion potential in the presence of a gradient of picrate are consistent with the assumption that the transport of picrate anions is facilitated by the above-mentioned macrocyclic compounds, but that cations are not directly involved. A model is suggested which, based on the generation of mobile defect structures by the incorporation of large molecules, allows one to explain facilitated transport without the assumption of stable chemical bonds between a carrier and its transported substrate. If K+ is present in the aqueous phase, the conductance is largely determined by the permeation of the cation complexes of valinomycin and nonactin. The conductance is, however, increases by adsorption of picrate anions to the membrane surface. The negative surface potential generated by the adsorption layer seems to be responsible for the saturation of the conductance at high picrate concentrations in the absence of valinomycin and nonactin.


Combined modality treatment of American Burkitt's lymphoma. Fifteen American patients with Burkitt's lymphoma were treated in a clinical trial employing chemotherapy, radiotherapy, and immunotherapy. Two patients died during induction, and 13 achieved complete responses. Eight patients relapsed at a median of 11 weeks from initial treatment, and seven of these have died. The remaining patient has enjoyed a prolonged third remission following intensive chemotherapy and bone marrow autograft. Five patients remain in their first remission in excess of 1 year. The major therapeutic goal in the management of Burkitt's lymphoma is the prevention of relapse; the identification of risk factors and various strategies to achieve this goal are discussed.


Luekemic infiltration of the prostate: a case study and clinicopathological review. A case of leukemic infiltration of the prostate occurring with acute retention of urine is reported. Examination of the blood showed chronic lymphocytic leukaemia (CLL). The number of reported cases of leukemic infiltration of the prostate is updated and a review of the literature on the subject is presented.


Sexually transmitted disease in Rhodesia.


The relationship between the ionic composition of the environment and the secretory activity of the endocrine cell types of Stannius corpuscles in the teleost Gasterosteus aculeatus. The corpuscles of Stannius of threespined sticklebacks contain two glandular cell types of presumed endocrine nature. To elucidate the function of both cell types the secretory activity of the cells was studied in fully adapted seawater and freshwater fishes and in specimens transferred from sea water to fresh water or adapted to media of various ionic composition. The secretory activity was established, in tissue sections and freeze-etch replicas, by estimating the volume of the nuclei, the density of the nuclear pores, and the frequency of exocytotic phenomena. The type-1 cells, ultrastructurally comparable to the predominant or only cell type described in many other teleosts, are more active in sea water than in fresh water. The activity of the type-2 cells, whose ultrastructural appearance is known only for salmonids and eels, is higher in fresh water. Transfer of seawater fishes to fresh water results in reduction of type-1 cells and activation of type-2 cells. The factors responsible for these changes were analyzed by exposure of fishes to solutions of various salts in fresh water and to artificial sea water with a reduced content of one of its components. The high activity of type-1 cells in sea water proved to be related to the high calcium content of this medium. These cells probably produce a substance comparable to hypocalcin, the endocrine factor isolated from the Stannius corpuscles of some other teleost species. The high activity of type-2 cells in fresh water appeared to be connected with the low sodium and potassium levels of this medium. Type-2 cells possibly produce a hitherto unknown hormone involved in the control of sodium and/or potassium metabolism.


The value of the foam stability test.

The value of the foam stability test.


Cytological factors and their predictive role in comparative radiosensitivity: a general summary. Various cytological factors, including interphase chromosome volume (ICV), nuclear volume (NV), cell volume, DNA content per nucleus and per chromosome, have been reviewed to determine their usefulness as indices to predict radiosensitivity. Fourteen topics are discussed. They are: a historical development of the concept of using karyotypic features to estimate radiosensitivity; interrelationships between cellular parameters; relationship of the karyotype to the duration of mitosis and meiosis; relationships between chronic and acute irradiation and ICV using several radiobiological end points for woody and herbaceous species; correlations between dose and cellular parameters ftween chromosome aberrations and cellular characteristics after chronic irradiation; polyploidy and plant radiosensitivity; radiation-induced petal mutations in plants and their relationship to cellular parameters; correlations between mean survival time facter irradiation and cellular parameters in amphibians and higher plants; correlations between radiobiological end points and cellular parameters after whole-body irradiation in amphibians. insects and mammals; correlations between radiosensitivity and cellular parameters in diverse single-cell organisms; correlations between radiobiological end points and cellular parameters in higher plants irradiated with neutrons and the value of cell parameters to estimate relative biological effectiveness (RBE); and energy absorption and trends in radiosensitivity among species and radiobiological end points. It is concluded that ICV is usually the most useful parameter for predicting radiosensitivity.


Degeneration of Leydig cells in the skin of the salamander treated with cholinolytic drugs or surgical denervation.


Changes in nucleotide metabolism of the liver and fate of [14C]orotate among various pyrimidines at the outset and during induction of drug-metabolizing enzymes and hepatomegaly.


Studies on the relationship between induction of drug-metabolizing enzymes, liver enlargement and ascorbic acid excretion in rodents.


Evidence that the fertilization envelope blocks sperm entry in eggs of Xenopus laevis: interaction of sperm with isolated envelopes.


Lack of effect of acute prolactin suppression on renal water sodium and potassium excretion during sleep. The possible role of endogenous prolactin (hPRL) in the regulation of renal water, Na and K excretion during sleep was tested in a group of 10 healthy female volunteers. Plasma hPRL and total urinary Na and K excretion were measured at 2- and 4-hourly intervals, respectively, in the control period and after prolactin inhibition with bromocriptin. Despite adequate prolactin suppression, no significant changes were observed in the nyctohemeral excretion rhythms of water, Na and K, suggesting that endogenous prolactin is not instrumental in the control of these parameters.


Urinary excretion of drugs in chronic renal impairment with respect to changes their tubular handling by residual nephrons. Decrease of the relative value of the renal clearance (the ratio between the value observed and the normal value) of a drug may be slower than the decrease of the relative value of the glomerular filtration rate. A slower decrease of drug renal clearance may be due to an increase in its effective secretion or a decrease in its effective reabsorption by residual nephrons. The mechanisms underlying these changes still remain obscure. One of the factors is assumed to be sodium osmotic diuresis in residual nephrons (associated with functional adaptation).


Effect of centrally applied monoamines on thermoregulation in the pigeon.


Articulation in early childhood autism.

Articulation in early childhood autism. Using a standardized articulation test, comparisons were made between the articulation of autistic children and (1) a group of predominantly subnormal language matched controls; (2) developmental receptive dysphasic controls. The autistic children's articulation was significantly superior to that of both control groups. The findings are discussed in relation to differences in the pattern of language impairment in the three groups.


Phonological investigation of verbal autistic and mentally retarded subjects. A review of the pertinent literature indicates that autistic children are likely to show normal but delayed development of speech sounds. In contrast, atypical phonological development is suggested by experiments demonstrating that autistic subjects are deficient in their ability to extract the components of structured auditory input. A systematic investigation of the speech sound systems of verbal autistic and mentally retarded children reveals a delay in phoneme acquisition, as well as a relative uniformity of error types in both groups. The autistic subjects, however, differ significantly from the mentally retarded in the phonemic substitutions which they make. Autistic subjects are also characterized by a high correlation between frequency of phonological errors and level of overall language development. The findings are interpreted as supporting the hypothesis that the autistic group shows a more global delay in language development.


Reassessment of elevated serotonin levels in blood platelets in early infantile autism. Blood platelet serotonin content was measured in 30 children with early infantile autism, as defined by Kanner, 30 age-matched normal subjects, and 45 children with various neurological and psychiatric disorders. Serotonin content in the autistic group was 980 +/- 357 ng/mg platelet protein (mean +/- standard deviation), a value significantly higher than that for normal children, 807 +/- 202 ng/mg (p less than .025). Autistic children under school age had higher platelet serotonin concentrations than other older autistic individuals. There was little correlation between age and serotonin levels in the normal children. Elevated serotonin was also seen in some of the non-autistic pathological group, who were disturbed and hyperactive. Elevated serotonin levels are not necessarily a specific biochemical finding for autistic children, but seem to be due to their behavioral distinction.


Platelet uptake and efflux of serotonin in subtypes of psychotic children. The only finding of a metabolic defect in psychotic children which has been replicated in a blind study is the discovery of an elevated efflux of serotonin from the platelets of children with early infantile autism (Boullin, Coleman, & O'Brien, 1970; Boullin, Coleman, O'Brien, & Rimland, 1971). The reported failure of Yuwiler, Ritvo, Geller, Glousman, Schneiderman, and Matsuno (1975) to replicate the Boullin et al. findings is attributable to differences in the method of selecting subjects. The Boullin et al. studies found that only children with classical infantile autism, as diagnosed by the Rimland E-2 check list, manifested the metabolic error. Since only 10% of psychotic children score in the autistic range on the check list, and since all children in the Yuwiler et al. study displayed the syndrome of "perceptual inconstancy," a syndrome inconsistent with "insistence on the preservation of sameness," an integral part of the syndrome of early infantile autism as scored on the E-2 check list, the failure of Yuwiler et al. to find elevated efflux in their sample was to be expected.


Neuropathologic aspects of psychosis in children. On the basis of a search of the literature and extensive inquiries to clinicians, this paper catalogues those cases that contain any information concerning possible neuropathologic changes in cases of childhood autism or psychosis. In all, 33 cases were identified. Twenty-nine cases are from the literature; six of these are sibling pairs. Four cases were folnd by inquiry and have not been reported heretofore. Because of limitations in both the clinical and neuropathologic data in most of the case reports, the paper serves primarily as a source of reference to the 33 cases identified. The information that is available is presented along with some tentative suggestions for further research.


Hashimoto's thyroiditis presenting as a solitary functioning thyroid nodule. A case of hypothyroidism is described in a young woman who on thyroid scan had a discrete functioning "nodule" with homogeneous radioactive iodine uptake, and surrounded by atrophic non-functioning thyroid tissue. Antithyroglobulin antibodies were not demonstrable, but anti-microsomal antibodies were positive at a titer of 1:25,600. Histologically, the "nodule" represented Hashimoto's thyroiditis with more extensive destruction of the remaining gland. Although it is unusual, Hashimoto's disease should be considered in the differential diagnosis of functioning thyroid nodules, and both anti-thyroglobulin and anti-microsomal antibodies should be obtained in such circumstances.


Vitamin B12 and potential fertility in male lactovegetarians.


Ovarian refractoriness to gonadotropins in cases of inappropriate lactation: restoration of ovarian function with bromocryptine. In ten patients with amenorrhea-galactorrhea who had hyperprolactinemia, ovulation could not be induced clomiphene citrate or exogenous gonadotropins. Treatment with bromocryptine in eight of these patients resulted in suppression of PRL in all, cessation of galactorrhea and ovulation in seven and conception in five.


The in vitro suppression of lectin induced 3H-thymidine incorporation into DNA of peripheral blood lymphocytes after the addition of propylthiouracil. A possible in vitro immunosuppressive role of propylthiouracil (PTU) was investigated by culturing peripheral blood lymphocytes (PBL) from normal subjects with plant lectins in the presence of PTU added at the onset of culture or near the time of peak cell division. When added at the onset of culture PTU caused a dose-related suppression of lectin stimulated 3H-thymidine uptake with an average of approximately 50% suppression at a PTU concentration of 100 mug/ml. When added at the time of peak cell division however, marked suppression was produced by 10 mug/ml of PTU. Prolonged remissions in patients with Graves' disease treated with PTU, and possibly other anti-thyroid drugs, may thus be due to an immunosuppressive role of the drug rather than the natural evolution of the disease.


Biotransformation of ioglycamic acid, iodoxamic acid and iotroxic acid in man. The biotransformation of the 131I-labeled cholegraphic media ioglycamic acid, iodoxamic acid and iotroxic acid in man is investigated. Plasma, urine and fistular bile were analyzed for unchanged and metabolized constituents of the administered substances using thin layer chromatography. No metabolites were found in plasma, but up to two were found in urine in addition to unchanged contrast media (a total of 50% of the total elimination in 24 hr. urine). A metabolite was only found in the fistular bile after the injection of iotroxic acid.


Antepartum prevention of respiratory distress syndrome (hyaline membrane disease).


Electron microscope assessment of fertilization of rabbit ova treated with concanavalin A and wheat germ agglutinin. Zonaless rabbit ova, exposed to Concanavalin A or Wheat Germ Agglutinin, then to uterine capacitated sperm produce pronuclear, 2 and 4 stage embryos that are indistinguishable from controls. Absence of cortical granules indicates that the ova were fertilized and not merely activated. Survival of lectin-bearing receptors during the period necessary for fertilization was evaluated in ova marked with ferritin-conjugated lectin.


Enhancement of haemolysis by Newcastle disease virus (NDV) after pre-treatment with heterophile antibody and complement. Pre-treatment of Newcastle disease virus (NDV) with fresh human plasma enhances its haemolytic (HL) capacity by several factors. The effect is due to complement activation by the heterophile anti-chick antibody present in human plasma. All the adult human plasmas tested were effective, also 91/100 human cord blood sera. The antibody was mainly of the IgM class. The enhanced HL was due to integration and transference of the complement 'holed' virus envelope membrane and subsequent leakage of haemoglobin. High concentration of activated complement destroys the integrity of the virus enevelope. Treatment of chick erythrocytes and fibroblasts with human plasma also produced lysis of the cells.


The recognition and management of blastomycosis.


Pregnancy following bromocryptine therapy for the amenorrhoea-galactorrhoea syndrome due to a pituitary tumour. A woman developed amenorrhoea and galactorrhoea after partial removal of a pituitary tumor during pregnancy. Hyperprolactinaemia was supressed by therapy with bromocryptine (CB 154, Sandoz) resulting in cessation of galactorrhoea in two months, spontaneous menstruation after eight months, and pregnancy after twelve months.


Diphenadione residues in milk of cattle.


Choosing an architect.

Choosing an architect.


Mechanism of action of benzilylcholine mustard at the muscarinic receptor.


Soil persistence and aquatic bioaccumulation potential of hexachlorobenzene (HCB).


The reaction of Cytembena with cellular thiol compounds. Cytembena has been shown to undergo a rapid addition reaction with a number of thiol compounds, including glutathione and cysteine, resulting in alkylation of the sulphur. Administration of Cytembena to Yoshida sarcoma cells and to L1210 leukemia cells resulted in a loss of titratable thiol groups within the cells, though the loss of thiol groups caused by pharmacologically active doses of the drug was not sufficient to account, in itself, for the observed toxicity. The addition product of Cytembena and glutathione was isolated and tested for cytotoxicity; it was much less effective than free Cytembena. It is concluded that this reaction acts as a route of detoxification of Cytembena.


Effects of amphetamine isomers and CNS catecholaminergic blockers on seizures in mice.


Sequelae of head and neck positions on auditory performance. Stapedius reflex level, slow auditory evoked potential (AEP), and hearing threshold level of 18 normal adult probands (11 female, 7 male) as well as of 14 normal hearing cerebral palsied children between 4 and 12 years of age (5 female, 9 males)--were determined in different postures which correspond to the influence of tonic reflex activities in supine and prone, and in the so-called "reflex inhibiting pattern" (Bobath) and in a symmetrical relaxed position of neck, trunk and extremities in supine (the last one could only be maintained by the normal volunteers). Influence of the postures was small but significant for all parameters in the volunteers group as well as for AEP in the patients group. In the latter group the influence of tonic reflex activities on auditory evoked potential was independent from their strength. The strength of tonic reflex activity had been graded from 1-5 as judged from clinical impression by observation and palpation.


Bobath-therapy, tonic reflex--activities and processing of acoustic stimuli. The influence of tonic reflex activities on the slow auditory evoked potential (AEP) as well as the influence of Bobath's reflex inhibiting patterns (r.i.p.) in a group of 14 cerebral palsied children is compared under the same conditions with simulated tonic reflex patterns in 18 adult normal volunteers and 15 cerebral palsied children. In the adult volunteers group the effect of a relaxed symmetrical position of neck, trunk, and extremities in supine on the AEP is also evaluated. There are none but age specific differences in the latence of AEP between both groups but clear cut differences in the amplitudes and in the specific effect of r.i.p. in both groups.


Muscle activity and postural behaviour in newborn infants. A polymyographic study. In a group of 9 healthy newborns, spontaneous activity of different muscles was studied for 6 or 8 hours by means of surface electromyography on the 5th or 6th day of life. According to the local nursing routine the infants were placed in alternating left and right side positions. Averaged EMG activities were analysed with respect to behavioural states and observed postural behaviour. An improved recording technique and the logarithmic presentation of averaged EMG activities allowed the study of characteristics of tonic activity in state 1. The chin muscles showed the most specific EMG pattern in state 1. Chin muscle quiescence was observed during only 15% of that state. Lack of tonic activity was observed more in the beginning than at the end, but never in the middle of state 1. By visual analysis of 41 patterns of averaged EMG activities from the chin muscle it was found that increases of tonic activity only happen stepwise following concomitant phasic activities. Relaxation of tonic activity is either asymptotic or abrupt or by steps. The latter two are especially characteristic for the transition to state 2. Long periods of sustained tonic activity and low motility were characteristic for a long lasting state 1. The interval between the beginning of state 1 and the first increase of tonic activity varied more than the interval between the end of state 1 and the final drop of tonic activity back to the noise level. Other muscles showed less tonic activity in state 1: the neck area (sterncleidomastoid muscle 48% of state 1 time, trapezius m. 32%) was followed by the muscles of the forearm (extensor carpi m. 18%, flexor carpi m. 16%). These muscles also lead the rank order of the modulation of tonic activity. Tonic activity sustained for more than 30 sec. was not observed in state 2, except during transitions. In state 2 as in state 1 the muscles from chin, neck and upper extremities were more active than the muscles from the lower extremities. Durations of activities ranged from 28% (chin) to 13% (ant. tibialis) of state 2 time. No dominance of flexor muscles, which might account for the observed flexed posture, was found. Systematically changed side positions during the recording had no consistent effect on either motility or presence of tonic activity when corresponding muscles from the upper- and the lower-lying body side were compared during state 1. Likewise in state 2 no consistent effect on the total duration of phasic activity was observed. The results are discussed in relation to other known state dependent motor phenomena. It is suggested that sustained tonic activity results from an increased gain of the gamma-loop which may also contribute to the regularity of respiration. Differences between muscles probably reflect maturational and functional differences.


Benign hereditary non-progressive chorea of early onset. Clinical genetics of the syndrome and report of a new family. The syndrome of benign non-progressive chorea (of early onset) is described in three brothers and some of their relatives. Clinical genetic study of the family showed an autosomal dominant mode of inheritance and suggested presence of the gene in both sides of the family. Thus, the propositi might be homozygous for the dominant gene (suggested by increased clinical manifestations as compared with other affected members on both sides of the family) which shows relatively high penetrance and variable expressivity. The phenotypic spectrum of the syndrome is differentiated from similar observations in the literature, and genetic implications are discussed. The condition is differentiated from hereditary essential tremor and from paramyoclonus multiplex.


Communicating hydrocephalus causing aqueductal stenosis. The cited evidence establishes that the pathogenetic sequence of generalized communicating hydrocephalus followed by various degrees of aqueductal stenosis occurs in many mammalian species. The aqueductal stenosis is caused by compression of the midbrain by the expanding cerebral hemisphere. Therefore the sharp separation of communicating and non-communicating hydrocephalus is no longer tenable.


Propanolol treatment of infantile polymyoclonia. Two infants with the classical involuntary movements of polymyoclonia and opsoclonus were treated with propanolol in a dosage of 2 mg/kg/24 hr. There was a marked improvement in the abnormal movements in both children. No side effects of treatment were encountered.


Spermatozoal migration and lymphatics: a hypothesis. The exact mechanism of sperm migration is still unknown. Lymphatics may act as transporting channels for the migration of sperms. The relevant literature is reviewed and it is suggested that myometrial contractions may allow the lymphatics of the uterus to take up the sperms and pump them actively towards the uterine tubes, where they are pumped again by tubal contractions towards their destination at the end of the tube where they fertilize the ovum.


The activation of human factor X in sodium citrate: the role of factor VII. Human factor X was purified by several different procedures yielding products which had varying amounts of factor VII and factor IX. Treatment with CHCl3 during the fractionation of the factor X removed 95% of the factor VII and factor IX activity and the resulting factor X activated more slowly when incubated in 25% sodium citrate. Removal of residual factor VII by DEAE cellulose chromatography yielded a factor X which activated still more slowly and less completely. When the factor VII, removed by chromatography, was added to the chromatographed factor X, the ability to be activated in 25% sodium citrate was restored. Confirmatory evidence for the role of factor VII in this reaction was the inhibition of the conversion of the factor X by both DFP and SBTI.


Bleeding in uremic patients after carbenicillin. Hemorrhagic diathesis was observed in patients with renal insufficiency after carbenicillin at serum levels greater than 300 mug/ml. Normal coagulation factors (F. I, II, V, VII, VIII, X), normal PTT, normal platelet counts, negative ethanol gelation test (fibrin monomers) were found as well as a prolongation of thromboplastin time (Quick), thrombin time, reptilase time and thrombin coagulase time. Platelet function was disturbed. In addition, the plasmatic system was involved: inhibition of fibrinogen-fibrin conversion (Belitser assay) and enhanced antithrombin III activity; in vivo the latter was ascribed to a heparin-like activity. In vitro, abnormal III was seen: however an enhanced antithrombin III activity in vitro was not found with carbenicillin and various penicillin derivatives. This study demonstrates that carbenicillin, in addition to its known effect on platelet function, also disturbs the plasmatic coagulation system. This additional effect of carbenicillin is clinically important since protamin chloride effectively blocks bleeding without interfering with antibacterial activity. Both penicillin and penicillin derivatives have been shown to interfere with hemostasis and to cause clinically manifest hemorrhagic diathesis (Fleming and Fish 1947, Lurie et al. 1970a, b, McClure et al. 1970, Yudis et al. 1972, Demos 1971, Waisbren et al. 1971). Carbenicillin interferes with ADP-, collagen- or thrombin-induced platelet aggregation and with the release reaction both in vivo (McClure et al. 1970, Cazenae et al. 1973) and in vitro (McClure et al. 1970, Cazenave et al. 1973). In addition Lurie and colleagues (1970b) concluded that an inhibition of the conversion of fibrinogen to fibrin is involved although no experimental details were given. Later Brown and colleagues (1974) concluded that carbenicillin at usual dose levels "only affects the platelet component of hemostasis and has little effect on fibrin formation or other phases of coagulation in patients with normal renal function".


Platelet adhesiveness and fibrinolysis after recent cerebro-vascular accidents and their relationship with subsequent deep venous thrombosis of the legs. In fifteen patients with a cerebro-vascular accident resulting in an acute hemiplegia there was a subsequent rise in the platelet count and plasma fibrinogen level. There were no significant alterations in platelet adhesiveness, plasminogen activator, plasminogen, FR-antigen and haematocrit. Patients diagnosed as developing deep venous thrombosis with the 125I-fibrinogen technique had a significantly lower platelet adhesiveness and plasminogen level than those who were not.


A pathomorphic study of chronic thyroiditis. The authors studied the pathomorphy of 364 cases of chronic thyroiditis including Hashimoto's thyroiditis (67 cases), Hashimoto's thyroiditis associated with thyroid cancer (21 cases), De Quervain's thyroiditis (10 cases), tuberculous thyroiditis (6 cases), and 260 cases of focal thyroiditis without manifest clinical symptoms appearing in 10% of euthyroid polynodular goitres. A personal classification of chronic thyroiditis is presented. The high incidence (24%) of association between thyroid cancer and the fibrous type of Hashimoto's thyroiditis is emphasized. A morphometric investigation showed the highest sclerosis percentage in De Quervalin's thyroiditis.


Molecular size distribution of fibrinogen derivatives formed in vitro and in vivo: a chromatographic study. Using gel chromatography, fibrinogen derivatives present in purified systems or in biological fluids were separated and partially characterized. Eight groups of fibrinogen derivatives could be separated by gel filtration through 6% agarose in large columns, four with an elution volume smaller and four groups with an elution volume larger than that of fibrinogen. Careful calibration of the column allowed estimation of the diffusion coefficients of some of the derivatives and, thus, comparison with derivatives previously identified. Three, rather than two, groups of intermediate derivatives were observed during the degradation of human fibrinogen by plasmin in vitro or in vivo. One of these had a marked tendency to polymerize. A rather distinct difference in elution pattern was found between plasma obtained during streptokinase administration and from patients with intravascular coagulation.


Microvascular haemostasis and the effect of local stimulation and inhibition of platelet function. An experimental study in rabbits. The local stimulation and inhibition of haemostatic plug formation was studied by local infusion and superfusion of different agents - ADP, thrombin, adenosine, heparin, prostaglandin E1 (PGE1) and laster injury. ADP and laser injury shortened venular haemostatic plug formation time whereas adenosine in the superfusate and PGE1 prolonged it. Thrombin infusion had no effect but thrombin in the superfusate significantly stabilised the haemostatic plugs. It is suggested that ADP released from red cells is the most potent stimulator for haemostatic plug formation in the rabbit mesenteric microcirculation.


The effect of defibrinogenation on pulmonary embolism in dogs.


Venous thrombosis in suspected pulmonary embolism: incidence detectable by Doppler ultrasound.


Low-dose heparin and deep-vein thrombosis after total hip replacement. The effect of subcutaneous low-dose heparin on postoperative deep-vein thrombosis (D.V.T.) (diagnosed by the 125I-labelled fibrinogen test) has been investigated in a trial of 143 patients undergoing the operation of total hip replacement. Two randomized studies were carried out: in one the scanning for D.V.T. was carried out daily for 7 days postoperatively andin the other for 15 days. In both, the incidence of D.V.T. was significantly lower in the heparin-treated patients (P less than 0.005). Bilateral D.V.T. was also prevented (P less than 0.05), through the extension of D.V.T. to the distal veins of the thigh was not significantly reduced. Heparin treatment was, however, followed by a higher incidence of severe postoperative bleeding (P less than 0.02) and wound haematoma formation (P less than 0.005), and the postoperative haemoglobin was significantly lower than in the control group (P less than 0.005). A higher number of transfused blood units was also needed by the heparin treated patients (P less than 0.001).


Comparison between a modified ethanol gelation test and protamine sulfate test. Experimental studies. A comparative experimental study has been made to correlate the protamine sulfate test and a modified ethanol gelation test, based on clinical observations of the solubility of a gel formed at 20 degrees C (Godal and Abildgaard procedure) when it was transferred to a bath at 37 degrees C. Two different results were obtained: the gel remained insoluble at 37 degrees C or it became completely soluble, with intermediate degrees of partial solubility. Our studies indicate that this is due to the amount of fibrin monomers formed and the level of fibrinogen: the first are responsible for the insolubility of the gel and the second for its solubility. This furnishes us with useful information for diagnostic purposes. We found the protamine sulfate test more sensitive than the ethanol gelation test, and its sensitivity increased when fibrinogen level decreased. An insoluble gelation test is a sure indication of the presence of fibrin monomers, but a soluble gel calls for the protamine sulfate test to confirm this or the existence of high fibrinogen level.


Platelet preservation. II. The response of human platelet suspensions to hypotonic stress. 1. Platelet suspensions were exposed to hypotonic stress. Several parameters of the changes in light absorbance were investigated i.a. the initial decrease in absorbance (A min), the maximal rate of the recovery process (V max), and the value of the absorbance two hours after mixing the platelet suspension with the hypotonic solution. 2. The ratio V max/A min appeared to be independent of both platelet concentration and, within a specific range, decrease in osmolarity. 3. Cryoprotectants appeared to disturb the response to hypotonic stress. 4. Cryopreservation caused a decrease in the light absorbance of the platelet suspension, of A min, and of the recovery process.


Platelet preservation. III. The influence of dimethylsulfoxide and cooling conditions on serotonin uptake velocity and response to hypotonic stress of human platelets. 1. Serotonin uptake velocity of human platelets was found to be reversibly inhibited by the presence of dimethylsfulfoxide (DMSO). 2. Incubation of platelet concentrates in the presence of DMSO for 90 minutes at room temperature decreased serotonin uptake velocity and response to hypotonic stress. 3. The serotonin uptake velocity was not substantially influenced by the temperature of incubation with DMSO. 4. The best recovery of serotonin uptake velocity after cryopreservation in the presence of DMSO was observed when DMSO was added quickly before cooling and removed quickly after thawing. 5. No significant differences were observed in serotonin uptake velocity and response to hypotonic stress cryopreservation in the presence of DMSO when cooling rates were varied from 2 to 10 degrees C/min.


Newborn platelet dysfunction: a storage pool and release defect. Per cent aggregation, release and content of adenine nucleotides, and specific radioactivity were evaluated in citrated platelet-rich plasma (PRP) prepared from paired samples of maternal and cord blood. Platelets of newborn infants aggregated normally in response to highdose ADP (20 muM), strong collagen suspensions, and thrombin; however, when compared with PRP from the mothers or from normal adults, per cent aggregation in response to lower concentrations of ADP (2 muM), weak collagen, and part particularly epinephrine was markedly reduced. Nucleotide release after stimulation of the newborns' PRP with the latter two inducers was also impaired. ATP and ADP content of the newborns' platelets was also significantly less than that of their mothers or of normal adults, but specific activity was normal. The data suggest that the impairment of ADP release in the platelets of newborn infants is due to decreased sensitivity to external stimuli. Since metabolic ATP is necessary for the platelet release reaction, it is postulated that the platelet dysfunction results from a lack of metabolic ATP.


The use of a chelating ion-exchange resin to evaluate the effects of the extracellular calcium concentration on adenosine diphosphate induced aggregation of human blood platelets.


The effect of dimethyl sulfoxide on in vitro platelet function.


The prothrombin time test: effect of varying citrate concentration. Blood samples from 12 normal subjects and 46 patients on oral anticoagulants were divided so that each was anticoagulated with four concentrations of trisodium citrate solution in the range 0.09-0.15 M, 9 vol blood being added to 1 vol citrate solution in each case. Citrated blood haematocrit and plasma prothrombin time was measured on each subsample; 0.025 M CaCl2-solution was used for recalcification throughout. Three laboratories participated, each using a different prothrombin-time technique.


Reference method for the one-stage prothrombin time test on hlman blood. International committee for standardization in hematology.


Registry of prospective clinical trials second report.


General classification system for hemorrhagic and thrombotic disorders.


Report of the working party on platelets.


Report of the working party on platelets. Stages in the interaction of platelets with collagen.


Report of the working party on platelets. Platelet factor 4 (PF4), Platelet protein with heparin neutralizing activity.


A micro-technique for determining platelet aggregability in whole blood.


The effects of drugs on platelet function tests.


Qualitative platelet abnormality due to absent collagen-induced aggregation.


ADP, ristocetin, bovine factor VII and thrombasthenic platelets.


Heparin and blood coagulation.

Heparin and blood coagulation.


Platelet aggregation by thimerosal.

Platelet aggregation by thimerosal.


Detection and prevention of a fibrinolysis after an extra-corporeal circulation in cardiac surgery.


Fibrin formation: the role of the fibrinogen-fibrin monomer complex. The process of fibrin formation using highly purified fibrinogen and thrombin was studied using laser fluctuation spectroscopy, a method that rapidly determines particle size in a solution. Two periods in fibrin clot formation were noted: an induction period during which no fibrin polymerization occurred and a period of rapid increase in particle size. Direct measurement of fibrin monomer polymerization and fibrinopeptide release showed no evidence of an induction period. These observations were best explained by a kinetic model for fibrin clot formation incorporating a reversible fibrinogen-fibrin monomer complex. In this model, the complex serves as a buffer system during the earliest phase of fibrin formation. This prevents the accumulation of free polymerizable fibrin monomer until an appreciable amount of fibrinogen has reacted with thrombin, at which point the fibrin monomer level rises rapidly and polymerization proceeds. Clinically, the complex may be a homeostatic mechanism preventing pathological clotting during periods of elevated fibrinogen.


Analysis of the disappearance curve of labelled fibrinogen at the time of hyperfibrinogenemia in rabbits with acute or chronic intravascular coagulation. In order to study fibrinogen metabolism, the disappearance curve of 125I-abelled homologous fibrinogen was investigated in the rabbits with experimentally induced acute or chronic intravascular coagulation by injection of Lycopodium spores or thromboplastin. The results obtained were as follows. 1. Using haemolysate, an intermediate phase with upward convexity was clearly recognized between the early rapid-decay phase and the late slow phase in each radioactivity decay curve obtained in groups of rabbits. This convexity was most marked with acute intravascular coagulation induced by injection of Lycopodium spores, and was less marked, although higher, with chronic intravascular coagulation induced by injection of thromboplastin than that in the normal control. 2. The disappearance curve with the intermediate phase could be expressed, in approximation, as a sum of 2 equations--the initial exponential decay equation and the late parabolic one. 3. From the results obtained by separate examinations of the disappearance curve of plasma, fibrin clots and serum in rabbits with acute intravascular coagulation induced by injection of Lycopodium spores, the intermediate phase appears to be influenced more by the secondary increase of labelled non-clottable part tahn recirculation of the labelled fibrinogen. 4. The half time (27.4 hours) of the radioactivity in fibrin clots at the late phase observed in the group of rabbits with acute intravascular coagulation induced by injection of Lycopodium spores was shorter than that in the normal rabbits (50.2 hours). This fact may indicate that the increase of fibrinogen in the group of rabbits with acute intravascular coagulation induced by the injection of Lycopodium spores is due to overproduction of fibrinogen. 5. The half time of labelled fibrinogen should be calculated from disappearance curve of fibrin clots, instead from that of haemolysate or plasma.


The recovery of factor VIII from fresh-frozen indated and outdated human plasma. The availability of factor VIII concentrates is frequently a limitation in the management of classical hemophilia. Such concentrates are prepared from fresh or fresh-frozen plasma. A significant volume of plasma in the United States becomes "indated", i.e., in contact with red blood cells for 24 hours at 4 degrees, and is therefore not used to prepare factor VIII concentrates. To evaluate this possible resource, partially purified factor VIII was prepared from random samples of fresh-frozen, indated and outdated plasma. The yield of factor VIII protein and procoagulant activity from indated plasma was about the same as that from fresh-frozen plasma. The yield from outdated plasma was substantially less. After further purification, factor VIII from the three sources gave a single subunit band when reduced and analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis. These results indicate that the approximately 287,000 liters of indated plasma processed annually by the American National Red Cross (ANRC) could be used to prepare factor VIII concentrates of good quality. This resource alone could quadruple the supply of factor VIII available for therapy.


Failure of immunosuppression in a severe haemophilia B patient with specific antibody. Prevention of a secondary response to factor IX by cyclophosphamide was attempted in an 11 year old patient with severe Christmas disease. An antibody to factor IX had been present for 4 years before immunosuppressive therapy was tried. Despite profound lymphopenia, synthesis of factor IX antibody was not depressed. The difficulties of modifying the anamnestic response to factor IX by chemical immunosuppression may be as real as has been reported for factor VIII in classical haemophilia.


Comparison of the actions of thrombin and the thrombin-like venom enzymes ancrod and batroxobin. Thrombin acts on several coagulant proteins to produce products with physiologic, pharmacologic and pathologic potential. The most sensitive thrombin substrate seems to be factor VIII. Some thrombin dependent reactions studied in vitro and proposed as control reactions seem too insensitive to the action of thrombin to be of in vivo significance. The only enzymic reaction the thrombin-like venom enzymes, Ancrod and Batroxobin, have in common with thrombin is the removal of fibrinopeptide A.


Properties of human tissue thromboplastins from brain, lung, arteries, and placenta. Properties of purified and delipidated human tissue thromboplastins (TTPs) from brain (BTTP), lung (LTTP), arteries (ATTP) and placenta (PTTP) were studied. The extinction coefficients were closely similar with a mean value of 8.3 +/- 0.01 (SD). The molecular weights were 200,000 +/- 3,000 (SD) BTTP), 90,000 +/- 2,000 (SD) (LTTP), 110,000 +/- 3,000 (SD) (ATTP) and 250,000 +/- 4,000 (SD) (PTTP). The maximum activity of each delipidated TTP after relipidation was obtained when phospholipid-delipidated TTP ratio was 2.0, and the maximum specific activity was 440 units per mg BTTP, 270 units per mg LTTP, 80 units per mg ATTP and 600 units per mg PTTP. Ouchterlony analysis with anti-delipidated PTTP antibody showed the reaction of partial identity between delipidated TTPs and the antibody. Studies of the reactivity of I-125-delipidated TTPs with the antibody gave the following average values for % bound I-125-TTPs in 2 hours: 3.6 +/- 0.2(SD) % (I-125-BTTP), 11.0 +/- 0.3 (SD) % (I-125-LTTP), 4.4 +/- 0.2 (SD) % (I-125-ATTP) and 13.7 +/- 0.3 (SD) % (I-125-PTTP). It was also found that the antibody markedly neutralized the coagulant activity of saline extracts of brain, lung and placenta. These results indicate that delipidated BTTP, LTTP, ATTP and PTTP are different while being similar in some aspects and that complete TTPs are not coated with lipids in a manner inaccessible to anti-delipidated PTTP antibody.


A new era in the laboratory evaluation of coagulation and fibrinolysis.


Some observations on the preparation of platelet-rich plasma. In order to prepare platelet-rich plasma a constant height and volume of citrated whole blood was centrifuged at different gravity forces and times. The supernatant plasmas were examined for platelet concentrations, plasma volumes and optical densities. Results are described showing that gravity force and time have an important influence on the platelet numbers and the plasma volumes recovered. The light attenuation by different concentrations of platelets in plasma, using light path lengths of 5 mm and 10 mm, was compared. The shorter light path provides greater linearity between optical density and platelet numbers especially at higher concentrations.


Effects of matrix contact during gel filtration of human platelets in plasma. When gel filtration is used to transfer platelets from plasma into an established environment, alterations in platelet characteristics may result from the change in environment or from the effects of platelet contact with the gel matrix. To approach the problem of evaluating the relative contributions from these sources, a Sepharose 2B matrix was employed and platelets transferred from citrate anticoagulated PRP into autologous PPP to yield plasma-GFP. Platelet recoveries averaged 93%. PRP: plasma-GFP pairs were found to be indistinguishable with respect to: morphology; ADP, thrombin or collagen-induced aggregation response; uptake of 5-hydroxytryptamine (5-HT) or adenosine; and thrombin or collagen-induced release of accumulated 5-HT or adenosine. Pairs are distinguishable by prostaglandin E2 synthesis assayed immediately after filtration.


Platelet dysfunction in migraine: effect of self-medication with aspirin. Circulating microembolic index (CMI) was determined by drawing one blood sample into EDTA-formalin and the other into DTA alone in patients with migraine and compared with matched normal controls. Platelet aggregates, if any, are fixed in EDTA-formalin but disaggregated by EDTA. Ratios of these two counts approximate "unity" in normals and are proportionately less than unity, depending on the number of platelet aggregates. 26 untreated migraineurs and 19 migraineurs with history of self-medication with aspirin taken within 72 hours of the test, were studied in headache-free intervals. Results were compared with those from 20 healthy, age and sex matched volunteers, without migraine, who were medication-free for at least one week. Mean CMI in untreated migraineurs (0.77 +/- 0.03 SEM) was significantly lower than the mean in normal controls (0.94 +/- 0.02, p. less than 0.002). Migraineurs with self administration of aspirin had mean CMI of 0.88 +/- 0.02, differing significantly from untreated migraineurs (p less than 0.01) but not from normal controls (0.1 less than p less than 0.2). Results suggest excessive platelet aggregation in migraineurs which tends to be corrected by treatment with platelet inhibitors such as aspirin.


Effects of fasting on plasma and platelet-free fatty acids and platelet function in healthy males. 10 healthy male volunteers fasted for 72 hours. Their plasma concentration of free fatty acid increased more than two-fold, to 1.8 mmol/l. The number of reversible venous "in vivo" platelet aggregates increased significantly (p less than 0.01); this figure correlated with the concentration of long-chain saturated free fatty acid in plasma (p less than 0.02). The correlation with the amount of long-chain saturated free fatty acid plus oleic acid (18:1) was even better (p less than 0.01). Plasma PF-4 concentration increased, suggesting increased platelet release reaction. In spite of the plasma increase, total platelet FFA concentration was reduced and there was a change in the distribution of platelet free fatty acid which correlated with the degree of aggregation.


Sedimentation and adhesion of platelets onto a horizontal glass surface. An experimental method for measuring platelet adhesion to a glass surface and platelet sedimentation rate is described. Anticoagulated platelet-rich plasma is placed on a horizontal glass slide for various contact periods. The number of platelets adhering to the slide per unit area is recorded as a function of time. The experimental results are used to verify theoretical predictions which account for the effect of the slow sedimentation rate of the platelets and for their escape over the potential barrier between them and the solid surface. By a least-squares fit of the theoretical equation to the experimental data, both the platelet adhesiveness, in terms of P the probability to overcome the potential barrier, and the platelet sedimentation rate V are evaluated. A range of values of P and V for healthy humans is presented.


Inhibition of ADP-induced platelet aggregation by adenosine tetraphosphate. In contrast to previous reports, highly purified adenosine tetraphosphate (AP4) does not induce the aggregation of platelets but inhibits the aggregation and release reaction in platelet-rich plasma promoted by ADP. The inhibitory action of AP4 on the aggregation by ADP is compared with that of AMP and ATP. The data presented suggest a competitive manner of inhibition of the ADP-induced aggregation by AP4.


Effect of platelet age on adhesiveness to collagen and platelet surface charge. Adhesion to collagen was investigated as a function of platelet age in rat platelets. Platelet adherence was measured using EDTA-containing platelet- rich plasma which was added to preparations of collagen fibers clamped between magnetic stirrers by recording changes in light transmission. The plot of light transmission versus logarithm of time was linear and allowed calculation of a slope factor which related to the rate of adherence. Neither the amount of collagen nor the platelet count were limiting in the test. Young platelet populations (less than or equal to 1 day old) were obtained during the recovery phase from immune induced thrombocytopenia. Old platelet populations were prepared by blocking thrombopoiesis with cyclophosphamide. Young platelets showed a moderate but statistically significant increase in adhesivity to collagen but old platelets did not differ significantly from randomly aged platelets in this function. The electrophoretic mobility of platelets was not affected by their age.


Platelet aggregation following defibrination with ancrod. In vitro platelet aggregation was studied in dogs following defibrination with Ancrod. There was marked inhibition of aggregation immediately after defibrination. A gradual return toward normal aggregation was observed over the 96 hours study period, but aggregation was still abnormal at 96 hours after defibrination. There was an inverse and highly significant correlation between aggregation and fibrin degradation product level. Fibrinogen was not measurable after defibrination for the entire study period. Aggregation was thus independent of fibrinogen concentration in this study.


Inhibition of human and animal platelet adhesiveness to glass bead columns by adenosine, dipyridamole, chlorpromazine and acetylsalicylic acid. The differences among human, rabbit and guinea-pig platelet adhesiveness as for inhibitions by adenosine, dipyridamole, chlorpromazine and acetylsalicylic acid are described, and the influence of measurement conditions on platelet adhesiveness is also reported. Platelet adhesiveness of human and animal species decreased with an increase of heparin concentrations and an increase of flow rate of blood passing through a glass bead column. Human and rabbit platelet adhesiveness was inhibited in vitro by adenosine, dipyridamole and chlorpromazine, but not by acetylsalicylic acid. On the other hand, guinea-pig platelet adhesiveness was inhibited by the four drugs including acetylsalicylic acid. In in vivo study, adenosine, dipyridamole and chlorpromazine inhibited platelet adhesiveness in rabbits and guinea-pigs. Acetylsalicylic acid showed the inhibitory effect in guinea-pigs, but not in rabbits.


Physico-chemical explanation of blood cell adhesion in thrombus formation. A model is suggested which assumes that the rate of deposition of cells is determined both by hydrodynamic factors and by Brownian motion over the potential barrier caused by London and double-layer forces in the immediate vicinity of the deposition surface. The height of the barrier in the potential energy of interaction between blood cells and various surfaces is analyzed in relation to the physical properties of the cells, surfaces, and solutions. Based on this analysis, the adhesion of platelets to injured blood vessel walls and to non-biologic materials, the lack of adhesion of red blood cells under the same conditions, the mechanism of ADP induced aggregation and the interaction with blood flow are explained. The qualitative predictions of the model are substantiated by available experimental information. Quantitative results are presented in terms of a time constant, which typifies a period of contact with a surface, during which appreciable deposition occurs.


An immunological method for detection of the carrier of hemophilia B. This paper presents the results of an immunological study of hemophilia B and its carriers which used two kinds of antibodies, a heterologous antibody of high specificity and a homologous antibody developed in a patient with severe hemophilia B. 1. The factor IX related antigen for hemophilia B could be determined by a neutralization test and not by a precipitation reaction. 2. The activity of factor IX in a definite carrier of hemophilia B was significantly lower than that of factor VIII in a definite carrier of hemophilia A. 3. In hemophilia B, there were no differences between the factor IX antigen determined by either the heterologous rabbit antibodies or the homologous antibodies. And there was no discrepancy between the factor IX antigen and the factor IX activity. Therefore, we cannot use this discrepancy for the detection of a carrier of hemophilia B. 4. However, there was a discrepancy between the factor IX antigen determined by the neutralization test and the factor IX procoagulant activity in the patients of both hemophilia BM and hemophilia B+. The identical results were obtained in the cases of carriers of both hemophilia BM and hemophilia B+. These facts are very useful for the detection of carriers of hemophilia BM and hemophilia B+.


Enhancement of fibrinolytic and thrombolytic potential in the rat by treatment with an anabolic steroid, furazabol. The effect of long-term ingestion of an anabolic steroid, furazabol, was studied on coagulo-fibrinolytic systems in the rat. During the administration of furazabol at the daily dose of 0.04, 0.2 or 1 mg/rat for 3 months, the most remarkable changes were increase in the plasminogen activator activity in blood and the lung tissue and decrease in plasma fibrinogen level as well as decrease in plasma cholesterol. It was a very important finding that in most of the rats the furazabol treatment was effective in reducing susceptibility to lactic acidosis-induced pulmonary thrombosis. No meaningful changes were observed in other parameters tested including ADP-induced platelet aggregability, plasma recalcification time, plasma plasminogen, plasma antiplasmin activity, plasminogen activator content of tissues other than the lungs and the release of vascular activator induced by venous occlusion. One month after cessation of the furazabol treatment, these altered parameters tended to return to normal. Independently on the furazabol treatment, highly significant positive correlation existed between the plasma activator activity and the pulmonary tissue activator content. This indicated that the major source of plasma activator in the rat was the lung tissue and that the furazabol treatment increased the circulating activator activity through enhancing activator content in the lungs.


Hyperaggregability of platelets in thromboembolic disorders.


Absorption of heparin by kaolin.

Absorption of heparin by kaolin.


Linear regression technique.

Linear regression technique.


Fibre inadequately replaced by cellulose or other forms of roughage in animal experimental diets.


Biogenesis and production of cycloheximide by Streptomyces species.


Geographical distribution of pediatric tumors.


The histological structure of dog knee menisci with comments on its possible significance. Knee-joint menisci are poorly understood terminologically, structurally and functionally in spite of their almost universal occurrence in mammals and their considerable clinical significance in man. A study was therefore undertaken of dog knee menisci utilizing several histological techniques. Terminologically, it is proposed that the part of the meniscus extending between the anterior and posterior horns and exclusive of them be called the meniscal "body." Structurally, the horns and body differ in anumber of ways. The horns are oval in cross section, the body triangular. Hyalinized areas are much more frequent in the body than in the horns. The collagen of the horns is organized into discrete bundles that are separated from one another by loose connective tissue septa, while that of the body is arranged in a "herringbone" pattern; no septa are present in the body. Finally, the meniscal horns are richly supplied with blood vessels are nerves (including large myelinated fibers which apparently terminate in the horns) while the body is almost completely devoid of blood vessels and nerves. Functionally, it is hypothesized that knee-joint menisci may serve important sensory functions.


Sex differences and psychiatric disorders.


Race, achievement, and delinquency: a further look at Delinquency in a Birth Cohort.


Economic strains and the coping functions of alcohol.


Anemia of azaribine in the treatment of psoriasis. Azaribine is an effective agent in the treatment of psoriasis. In this investigation the extent of clinical dermatologic remission appeared to correlate with the degree of metabolic block induced by 6-azauridylic acid, as quantitated by the urinary excretion of orotic acid and orotidine, and the development of anemia. Following azaribine therapy there was a coordinate rise of the specific activities of erythrocyte orotate phosphoribosyltransferase and orotidine-5'-monophosphate decarboxylase. There was no correlation between the pretreatment activity of these enzymes and the clinical response to azaribine. The anemia of azaribine therapy was mile and of a megaloblastic type. Uridine effectively corrected the azaribine-induced anemia, but led to exacerbation of the patients' psoriasis. Following uridine therapy there was a reduction in the urinary excretion of orotic acid and orotidine, presumable reflecting end-product inhibition or repression of the first steps of a repeated pyrimidine biosynthesis.


Vitamin A in times of disaster.

Vitamin A in times of disaster.


Ultrastructural study of testis in testicular feminization. Testicular tissue was investigated by electron microscopy in a case of testicular feminization. The seminiferous tubules were lined by spermatogonia and by Sertoli cells. Spermatocytic maturation was not observed. Leydig cells were numerous and contained well developed, abundant vesicular smooth-surfaced endoplasmic reticulum and large mitochondria with tubulovesicular cristae. Reinke crystalloids were absent. The ultrastructural findings were consistent with the assumption that Leydig cells were under adequate stimulation and were in a stage of active secretion. Hence, the results seem to indicate that testicular endocrine function was maintained in the studied case.


The ultrastructure of the interstitial cells in human fetal ovaries. Steroid-active interstitial cells (stromal lutein cells) in human fetal ovaries of 12, 15 and 22 weeks of gestation were studied by means of electron microscope. The large cells, which are predominantly situated in the vicinity of capillaries, show high structural similarity to Leydig cells (type A) of the fetal testis. Both are characterized by extensively development of smooth endoplasmic reticulum, accumulation of lipids, and numerous mitochondria of the tubular type containing osmiophilic inclusions. Whether the interstitial cell system of the fetal ovary has any specific function in developmental physiology of the genital system cannot be decided on the basis of the present results. Its differentiation may only indicate adequate response of competent mesenchymal cells to gonadotropic stimulation.


Investigations into the preservation of human ovaries by means of a cryoprotectivum. Human ovaries in the phase of follicular ripening were treated by means of a cryoprotectivum immediately after their removal. They were kept at --18degrees C for up to 8 weeks. After having gradually been thawed the ovaries were in vitro connected to a perfusion system. When completely revitalized they were examined in the steady-state for their metabolic behaviour. It was found that in comparison with the untreated controls, depending on the period of preservation, the oxygen consumption and the estrogen secretion had decreased, while the glucose absorption and lactate production had increased. As a morphological substrate a minor oedema was established in the tissue in the histological control after a preservation period of 2 months. This was mainly localized around the arteries. The method can be regarded as suitable for the preservation of ovaries for a limited period of time. It is possible to maintained a metabolism that can still be regarded as functioning.


A trend in the therapy of Amanita phalloides poisoning. Recent experimental evidences have been produced on the protection afforded by penicillin G in rats poisoned by Amanita phalloides extracts. A therapeutic trend which combines penicillin G infusions to the classical supportive measures was applied to 33 cases of severe A. phalloides poisoning, with 100% survival rates. The possible mechanism of the protective effect of penicillin G in A. phalloides poisoning is discussed.


The effect of N-alkyl groups of substituted phenyl-N-alkyl carbamates on the inhibition of human plasma cholinesterase. The inhibition constants for human plasma cholinesterase (dissociation, carbamylation, decarbamylation, overall bimolecular rate constants) were determined for two series of substituted phenyl-N-alkyl carbamates. N-propyl carbamates were found to be better inhibitors than the corresponding compounds carrying smaller N-alkyl groups. In both series the carbamylation constants of N-ethyl carbamates were lower than those of the N-methyl and N-propyl analogues, whereas the decarbamylation constants of the former were found to be higher than those of the latter carbamates. The experimental results obtained with human plasma cholinesterase are compared with published inhibition constants determined for several types of acetylcholinesterases.


A death case involving tilidine.

A death case involving tilidine. A fatal poisoning case due to the combination of a relative overdose of barbiturates (600 mg daily) and 750 mg of tilidine is reported. The concentrations of barbiturates and tilidine with its metabolites were determined in blood, liver, and urine.


Metabolic and toxic behavior of phthalimide derivates. I. Fate of imidan in the fetus. The organophosphate insecticide imidan includes a phthalimide group. Because of the structural relationship to the teratogenic compound thalidomide we have investigated its placental transfer and metabolic fate in rats. Its passage to embryonic tissues could be confirmed. After intraamniotic injection to the first amniotic cavity of the left uteri we could establish a distribution of imidan and 32P compounds throughout the uteri, the concentration depending upon the incubation time and the distances from the place of injection. The half-life of imidan, detected in the exterioized fetuses or in newborns, was 50--70 min. Imidoxon, i.e., the oxidized form of imidan, has a diminished half-life. This fact explicates the presence of imidoxon only in small concentrations after application of imidan.