[Jejunal interposition after radical gastrectomy: report of 51 cases (author's transl)]. Reservoir construction with interposition of a 35 cm long jejunal loop (method of Longmire and Gutgemann) was performed in 51 patients after total gastrectomy. The procedure largely succeeded in preventing the agastric syndrome. There were five postoperative deaths. Maintained weight gain in the remainder ranged from 2.5 to 22 kg.


[Results of operative treatment of chronic pancreatitis, especially exocrine and endocrine functions (author's transl)]. Studies were undertaken in 40 patients with chronic pancreatitis six months to seven and a half years (mean 25 months) after operation, results being compared with pre-operative findings. Measurements included: exercise capacity, absence of pain, body weight, endocrine (36) and exocrine (25) pancreatic function. Almost all patients returned to full or only slightly impaired activity, were free of pain or had less pain and weight increase. Exocrine pancreatic function (secretin-pancreozymin test and faecal fat) was noted in 11 of 25 patients. In another 11 pre-operative progression was arrested. But endocrine function improved in only three of 36 and worsened in 13 (manifestation of subclinical diabetes in eight, worse glucose tolerance in five). The results justify a more active surgical approach in the treatment of chronic pancreatitis in order to save the patients from an often long and painful "burning out" of the disease on purely conservative treatment. Furthermore, exocrine pancreatic function, at least, is maintained or improved.


[Radiological diagnosis of closed trauma to the aorta (author's transl)]. Closed injury to the thoracic aorta at the isthmus occurred after street accidents in eight persons (five males, three females, aged 17-55 years). The lesions ranged from isolated intimal rupture to complete loss of continuity of the aorta. Radiological diagnosis or thoracic surgical exploration took place in five patients within 48 hours of the accident, while in the remaining three--alle with a false aneurysm of the thoracic aorta-the time elapsed before accurate diagnosis ranged from three months to seven years. Five patients were successfully operated upon. It is stressed that successful surgical intervention depends on early and accurate radiological diagnosis (chest X-ray and, if necessary, aortogram).


[Colostomy continence achieved with an implanted circular magnet (author's transl)]. A new method of providing a colostomy continent for faeces and gas is described. It consists of the subcutaneous implantation of a magnetic ring which is led outside through the lumen of the colon and sutured to the skin. The colostomy is closed with a magnetic cover. The procedure has been used in 17 patients with a permanent colostomy after rectal excision and has been highly successful.


[Reconstruction of the oesophagus after scarring due to swalled alkali and 22 years of gastrostomy feeding (author's transl)]. The unusual life history of a man (now 24 years old) is reported who, at two years of age, swallowed an alkaline solution which caused severe oesophageal stricture due to scarring. It required feeding by gastrostomy exclusively for 22 years. Reconstruction of the oesophagus was then performed by interposing the colon (splenic flexure). Since secondary malignant degeneration is to be expected in this form of oesophageal stricture, removal of the residual oesophagus is recommended.


[Immediate one-stage total oesophagenal replacement by transmediastinal transposition of the stomach without thoracotomy in a case of hypopharyngeal carcinoma (author's transl)]. A case of hypopharyngeal carcinoma (in a 36-year-old man) is reported in which, after blunt dissection of the oesophagus via a posterior mediastinal tunnel without thoracotomy, the stomach was mobilized and its fundus anastomosed to the pharynx at the level of the vallecula. This form of oesophagectomy was first reported in 1936 by Turner for carcinoma of the thoracic oesophagus. Adopting this procedure in cases of carcinoma of the hypopharynx or cervical oesophagus (as recently reported) has as its main advantage the restoration of normal swallowing within a few days, as also took place in the described case.


[Pre- and postoperative investigations of patients after aortic valve replacement with prosthetic valves or homografts (author's transl)]. Two groups of patients with aortic-valve disease were compared. Group I (18 patients) received prosthetic valves, group II (12 patients) homograft valves. The symptoms and haemodynamic findings improved in both groups, postoperatively. Complications were more frequent with prosthetic than homograft valves, and the haemodynamic responses also were better in the homograft group, especially during exercise.


[Heterogenicity of mitochondrial antibodies (author's transl)]. Sera from 137 patients with mitochondrial antibodies were tested against two different mitochondrial antigens. The mitochondrial antibodies from patients with pseudo-lupus erythematosus (PLE antigen) reacted exclusively with antigen which sedimented on moving-zone centrifugation at a density of 1.10, and contained no antigenic activity when tested against sera from patients with primary biliary cirrhosis (PBC). Purified PBC antigen had no PLE antigen activity at a density of 1.19, and all sera from patients with autoimmune liver disease fixed complement with this fraction. Sera from 54 of 55 patients with PLE reacted with the antigen of the PLE-gradient fraction. But 71 patients with liver disease had no such uniform reaction: sera from 39 patients fixed complement only with the PBC fraction, whereas 32 reacted stimultaneously with both the 1.10 and 1.19 density gradient fraction. The latter pattern was especially found in patients with chronic active hepatitis in whom antibodies to smooth muscle and nuclei were frequently detected.


[Oxyphil cell adenomas associated with primary hyperparathyroidism (author's transl)]. Almost all functioning parathyroid adenomas are composed of chief or water-clear cells. In contrast, most oxyphil cell adenomas of this organ remain clinically silent. To date only occasional parathyroid adenomas consisting of oxyphil cells only have been found associated with primary hyperparathyroidism. The two additional examples described in this report confirm observations by others indicating that the parathyroid oxyphil cell can play an active metabolic role.


[Inhibition by somatostatin of pancreatic juice and enzyme secretion and gallbladder contraction in man induced by secretin and cholecystokinin-pancreozymin administration (author's transl)]. Somatostatin (200 mug/h) was administered to five healthy volunteers after submaximal stimulation of exocrine pancreatic secretion with 0.33 KU secretin or cholecystokinin-pancreozymin, given intravenously. In all instances there was a significant reduction in duodenal secretory volume after secretin, without any change in HCO3- concentration. Stimulation of enzyme secretion by cholecystokinin-pancreozymin was significantly inhibited and gallbladder contraction abolished.


Bumetanide: A preliminary report of its pharmacological properties and therapeutic efficacy in oedema. Bumetanide2 is a new diuretic with a rapid onset and short duration of action. It is advocated for the treatment of oedema of cardiac origin; that associated with cirrhosis of the liver and renal diseases, including the nephrotic syndrome oedema of pregnancy and in pulmonary oedema. Bumetanide produces a pattern of water and electrolyte excretion closely resembling that of frusemide although it differs structurally from frusemide and other diuretics. 1 mg of bumetanide produces a diuretic effect similar to that evoked by 40 to 60 mg of frusemide. Short-and long-term studies in oedema of varying aetiology have shown bumetanide to be an effective diuretic. Because it is chemically different from existing diuretics, bumetanide may be helpful in oedema resistant to other drugs. It is well tolerated, but like other natriuretics it causes hypericaemia and may cause hypokalaemia during long-term administration.


Amoxycillin: A review of its antibacterial and pharmacokinietic properties and therapeutic use. Amoxycillin2 is an acid stable semisynthetic penicillin closely related to ampicillin. Unlike pivampicillin and hetacillin, amoxycillin is not converted to ampicillin in the body. The antibacterial spectrum and level of activity of amoxycillin is essentially the same as for ampicillin, and there is complete cross-resistance between the two drugs. After oral administration, amoxycillin is better absorbed than ampicillin. Mean peak serum levels of amoxycillin are generally twice those of ampicillin after an equal dose. The better absorption and penetration into certain body tissues and fluids of amoxycillin and its greater activity against experimental infections in mice, suggest that it might be preferred to ampicillin in the treatment of some infections, but any clear superiority over ampicillin in clinical practice has yet to be demonstrated. However, these properties have enabled amoxycillin to be given at half the dose of ampicillin without loss of therapeutic efficacy, and the princpal side-effects of skin rashes and diarrhoea have tended to be less frequent with amoxycillin than with ampicillin. Other side-effects are essentially similar in nature to those reported with ampicillin.


Inhibition of gastrin release by somatosatin in vitro. An in vitro system which uses perifused pieces from the antrum of rat stomach has been used to study the effect of dihydrosomatostatin on gastrin release. The gastrin concentration in fractions of the perfusate was measured by radioimmunoassay. Dihydrosomatostatin (2 x 10-7M) had no effect on basal gastrin levels but virtually abolished the biphasic response seen with argine stimulation. The study demonstrates close functional similarities between G cells and pancreatic islet cells.


Biliary excretion of [3H]aldosterone and its sex dependence in adrenalectomized rats. The rate of excretion of 3-H-radioactivity via the bile into the intestine following intravenous injection of [3-H]aldosterone, was demonstrated to be rapid and sex-dependent in adrenalectomized rats. Within 1 h, female rats excreted into the intesting via the bile greater than 95% of the injected dose of [3-H]aldosterone, compared to 47% in the male rats. In both the male and female rats, greater than 90% of the total radioactivity excreted into the intestine represented dichloromethane nonextractable polar derivatives of aldosterone (NEPD). Similarly, the quantities of NEPD recovered in the bile following bile duct cannulation of the rats, were also sex-dependent. These findings account for the rapidity and sex-dependence of the rates of clearance of aldosterone and its metabolites from the plasma of adrenalectomized rats. The sex hormones appear to influence not only the extent and the routes of metabolism of aldosterone in the liver, but also the rates of clearance of aldosterone and its metabolites from the plasma into the bile.


Maintenance of rate testis fluid testosterone and dihydrotestosterone levels by pregnenolone and other C21 steroids in hypophysectomized rats. This study was undertaken to determine whether maintenance of spermatogenesis in hypophysectomized rats by pregnenolone and other C21 steroids may be due to in vivo conversion of these compounds to androgens. Hypophysectomized rats were treated sc with 2 mg of pregnenolone, 17-hydroxypregnenolone, progesterone, 17-hydroxyprogesterone or testosterone propionate in 0.2 ml sesame oil daily for 14 days beginning 2 days after hypophysectomy. Rete testis fluid (RTF), peripheral blood, and testicular venous blood were collected on the day of the last injection. Testosterone (T) and dihydrotestosterone (DHT) were measured by radioimmunoassay after chromatographic separation. Results demonstrate that T and DHT could be found in the RTF of C21 steroid-treated hypophysectomized rats at levels similar to those seen in the intact rat. Results imply that the maintenance of spermatogenesis by C21 steroids is probably due to the conversion of these compounds to T in the testis. Relatively little T was released from the testis into the peripheral circulation of these rats since T levels in testicular venous plasma were low and peripheral plasma T levels were not distinguishable from those seen in untreated hypophysectomized rats. Histological examination of the testes of C21 steroid-treated hypophysectomized rats showed nearly quantitative maintence of spermatogenesis and atrophy of Leydig cells. These findings suggest that most of the conversion of C21 steroids to androgens occurred in the seminiferous tubules.


Radioimmunologic assessment of the level of circulating LH antibodies after passive immunization of the rat: relation to the level of LH secretion. A double antibody radioimmunologic technique was used to estimate circulating levels of "free" LH antibodies (Ab) (i.e., Ab available for binding to radioiodinated rat LH in vitro) after a single injection of an equine antiserum to bovine LH (LH-AS) into cyclic (diestrus-1), early pregnant (d 6 or d 8), short-term (1 d) or long-term (12 d) ovariectomized, or 8-d hypophysectomized female rats. In both cyclic and pregnant rats given 0.5 ml LH-AS sc the blood Ab levles peaked 1 to 2 days after injection and then decreased exponentially (half-time: 14.6-17.0 h) and equally: vaginal estrus also appeared in the cyclic and the aborting pregnant rats on the 6th day, and ovulation on the 7th day after LH-AS treatment, when the blood levels had fallen to very low values. The rate of exponential decrease in blood Ab levels was not affected by other routes of administration (iv or ip) of LH-AS, or by sc doses of 1.0 or 0.25 ml, although the peak levels and their duration were related to dose and route of administration. Ovariectomy significantly increased the rate of exponential Ab decrease (half-time: 9.8 h in rats tested 12 days after operation) and hypophysectomy markedly diminished it (half-time: 63.0 h in rats tested 8 days after  operation). Daily treatment of hypophysectomized rats with 20 mu/day of ovine LH from the time of LH-AS injection increased the rate of exponential Ab decrease to one approaching that of the intact rats (half-time: 20.5 h). Free LH antibodies thus seem to disappear from the circulation at a rate proportional to the amount of LH in the circulation.


Serial serum levels of gonadotropins, prolactin and sex steroids in the nonpregnant and pregnant chimpanzee. Serum levels of FSH, LH, chorionic gonadotropin (CG), prolactin, estrone (E1), estradiol-17Beta (E2), estriol (E3) and progesterone were measured at 2-3-day intervals in 4 chimpanzees through 2-3 menstrual cycles, and serially through subsequent pregnancies. The hormone patterns of the menstrual cycles were similar to those in man, with high levels of FSH in the early follicular phase, followed by rising E2 concentrations to a peak (up to 35 ng/dl) at or just before a midcycle LH/FSH peak. In most cycles there was a secondary E2 rise and progesterone rose to values above 500 ng/dl during the luteal phase. There was no consistent pattern in prolactine levels through 3 menstrual cycles. A simultaneous increase in E2 and LH/CG levels and a fall in FSH about 10 days postovulation indicated fertilization and implantation. Other early signs of pregnancy were persistent luteal range progesterone concentrations and rising levels of E1 and E3. Peak CG levels (56-154 IU/ml) occurred 30-50 days after the midcycle LH/FSH peak, followed by a decline and then a small secondary rise to (to 1 IU/ml) before term. E1, E2 and E3 levels rose more rapidly after 80 days to a peak at term (E1: 180-300 ng/dl; E2: 500-800 ng/dl; and E3:400-1000 ng/dl). Progesterone levels showed one peak coincident with the CG peak, and a secondary rise after about 80 days to maximal values at term of 49-120 ng/ml. Prolactin levels increased during pregnancy with irregular fluctuations (7-127 ng/ml). These findings indicate in contrast to observations in rhesus monkeys and baboons, that the hormonal patterns during pregnancy in the chimpanzee are remarkably similar to those in man. Thus, the chimpanzee should prove to be an ideal model for research directly applicable to human reproduction.


The regional distribution of somatostatin in the rat brain. A sensitive and specific radioimmunoassay for somatostatin (SRIF) has been used to determine the regional distribution of SRIF in rat brain. The hypothalamus contained the highest concentration of SRIF. Lower, but significant amounts of SRIF were present outside of the hypothalalmus. Within the hypothalamus, the concentration of SRIF was highest in the median eminence and arcuate nucleus although all of the hypothalmic nuclei contained some fo this material. The implications of this distribution are discussed.


The rabbit fetal lung as a glucocorticoid target tissue. Fetal lung cells from 28 day gestation rabbits cultured in the presence of cortisol (5.5 times 10 - minus 6M) or dexamethasone (5.5 times 10- minus 8M) incorporated [3-H] choline into lecithin to a significantly greater extent than did control cultures. 11-Deoxycortisol, 21-deoxycortisol and 11beta-hydroxyprogesterone, at a concentration of 5.5 times 10- minus 5 M, had no effect on lecithin synthesis. However, when lung cells were simultaneously exposed to these steroids and to cortisol at the concentrations quoted, [3-H] choline incorporation was reduced to control values. Cortisone (5.5 times 10- minus M) also enhanced lecithin synthesis, the activity of the steroid likely being related to the capacity of the lung cells to convert cortisone to cortisol. This hypothesis was supported by the observations that 11-ketoprogesterone (1.3 times 10- minus 5M), which totally inhibited the conversion of cortisone to cortisol and which had no effect of its own on [3-H] choline incorporation, inhibited the effect of cortisone on lecithin synthesis but not that of cortisol. These data support the view that glucocorticoids affect lung cell maturation in a manner comparable to the interaction of other steroid hormones with their target tissues. The capacity of the fetal lung to convert cortisone to cortisol may be physiologically significant in light of the high concentration of 11-oxo-steroids in the fetal circulation throughout pregnancy.


Diminished prepartal plasma calcitonin concentration on cows developing parturient hypocalcemia. Immunoreactive calcitonin and calcium concentrations were determined on 581 plasma samples collected during 23 studies on 20 cows. Sample collections in each study was begun approximately 1 month prior to parturition and continued for about 1 month after parturition. The cows were grouped according to the degree of hypocalcemia encountered at parturition. The parturient paresis group consisted of 10 cows which developed severe hypocalcemia (3.91 plus or minus 0.22 mg/100 ml, mean plus or minus se) accompanied by paresis; the nonparetic hypocalcemic group consisted of 5 cows which developed severe hypocalcemia (5.70 plus or minus 0.03 mg/100 ml) but not paresis; and the control group consisted of 8 cows which experienced only a mild hypocalcemia (8.50 plus or minus 0.27 mg/100 ml) at parturition. In the prepartal period prior to the onset of hypocalcemia, the respective mean plasma calcium concentrations (plus or minus se) of the 3 groups were 10.1 plus or minus 0.11, 9.95 plus or minus 0.20, and 10.2 plus or minus 0.17 mg/100 ml. The development of severe hypocalcemia in the parturient paresis and nonparetic hypocalcemic groups was not accompanied by an increase in plasma calcitonin concentration. Furthermore, plasma calcitonin concentraion of these 2 groups was less than that of control cows during the parturient period as well as during the month before and the month after parturition. The plasma calcium nadir at parturition was positively related to the mean prepartal (encompassing the period from 30 days until 60 h before parturition) plasma calcitonin concentration (r = 0.57, t= 3.14, p less than 0.005); i.e., the lower the prepartal plasma calcitonin concentration the more severe the hypocalcemia at parturtion. These observations suggest that the development of hypocalcemia at parturition is not due to an increased secretion of calcitonin, but instead they suggest that parturient hypocalcemia may be associated with a diminished prepartal secretion of calcitonin.


Functional luteolysis in the rhesus monkey: ovarian estrogen and progesterone during the luteal phase of the menstrual cycle. In a continuing effort to elucidate the processes underlying in primates, the concentrations of estradiol, estrone and progesterone were measured in ovarian tissues and in ovarian vein plasma through the luteal phase of the menstrual cycle of the rhesus monkey. The concentration of progesterone in corpora lutea collected 4-6 days after the preovulatory  LH peak (early luteal phase) was more than twice that found in those collected 8-13 days after the LH surge (late luteal phase) while estradiol and estrone concentrations in the latter had increased 4-fold. These changes in luteal steroid concentrations were paralleled by a striking increase in the concentration of estrone in the ipsilateral ovarian vein. Estrone predominated in the venous effluent of the ovary beaing the corpus luteum while estradiol concentrations were similar in both ovarian veins suggesting that estrone is the principal estrogen released by the corpus luteum. The results of this study are consonant with the hypothesis that estrogen produced by the corpus luteum is the physiologic luteolsin in the rhesus monkey.


Studies on isoproterenol stimulation of adenyl cyclase in membrane preparations from the bovine thyroid. Catecholamine stimulation of adenyl cyclase activity associated with bovine subcellular fractions enriched in plasma membranes is described. The relative potencies of isoproterenol (IPNA), epinephrine (E), and norepinephrine (NE) were 4.7:1.0:0.02, which is characteristic for a beta-adrenergic receptor system. Stimulation with IPNA (5 times 10- minus 6 M) was inhibited by propranolol. The inhibition was stereospecific for the L-isomer of propranolol and a concentration as low as 2 times 10- minus 8 M was required to effect 50% inhibition. Both these observations, and the competitive kinetics of inhibition which applied to the system, confirmed the classification of a beta-adrenergic receptor system. Phentolamine, an alpha-antagonist, also inhibited IPNA stimulation, although high doses (5 times 10- minus M) were required to cause total inhibition. Inhibition was also observed with quinidine (1 mM) and lignocaine (10- minus 2 M).


The effect of food deprivation of the peripheral metabolism of thyroxine in rats. Starvation depresses thyroid gland function. In addition, the peripheral turnover of thyroxine (T4) is reduced, in part due to decreased fecal elimination of T4. The present studies were performed to determine if starvation also affects the deiodinative pathway for T4 degradation. Rats were isotopically equilibrated with daily injections of exogenous [131-I]T4 while endogenous thyroidal T4 secretion and concentration of iodide were blocked with KCl04. Following a period of equilibration, either complete or 50% food deprivation was imposed on half the animals. Within 48 h of starvation, the serum T4 concentration of the fully starved rats doubled and remained high throughout. A marked decrease in fecal excretion of T4 was partially responsible for the increase. In spite of variability in the quantity of urinary 131-I excreted, the dieodinative clearance was consistently reduced. These effects were readily reversible upon resumption of normal feeding. Similar though less severe changes were observed in the half-fed rats. In both fully and partially-starved animals, the decreased dieodinative clearance in the face of increased serum T4 levels indicates a significant impairment of peripheral deiodination by some as yet unknown mechanism. In contrast, normal rats equilibrated with doses of T4 sufficient to increase serum T4 levels exhibit increased urinary clearance of iodide derived from T4. Thus the increased serum T4 levels are a consequence of impairment of the deiodinative pathway by starvation as well as decreased fecal T4 excretion. Clearly, voluntary alterations in food consumption must be controlled for differences between groups during experimental studies of T4 utilization.


Estrogen action: induction of the synthesis of a specific protein (IP) in the myometrium, the stroma and the luminal epithelium of the rat uterus. The effect of estrogen on the synthesis of a specific uterine protein (estrogen-induced protein=IP) was investigated at the level of the epithelial, stromal and myometrial tissue fractions. For measuring IP induction, the procedure of Katzenellenbogen and Gorski was followed exactly (involving co-electrophoresis of soluble protein extracts from 3H-labeled estrogen treated uteri and 14C-labeled controls) except for the fact that the uteri were fractionated into their three main tissue components before homogenization. The results show that induction of IP synthesis by estradiol takes place in the three tissue fractions considered. This is consistent with hypotheses assuming a key function for IP in the development of the full estrogenic response in the uterus.


Changes in ultrastructure of rat ovaries after early postnatal x-ray irradiation. Female rate were irradiated with 190R of X-rays at 10 days of age and ovarian ultrastructures were studied 4 and 7 months after irradiation. Ultrastructural changes were found in germinal epithelial cells, fibroblasts in the tunica albuginea and interstitial cells. The germinal epithelial cells exhibited various signs of degeneration but no sign of proliferation. Electron density of their basal part was reduced considerably. Their mitochondria became swollen and free ribosomes decreased in number. The nuclei often protruded from the free surface of these cells. These cells frequently fragmented and,finally, the complete desquamation occurred. The basement membrane became unevently thickened. Nuclei of enlarged fibroblasts in the tunica albuginea became irregular ellipsoid in shape, and the nuclear envelope was occasionally invaginated. Various cytoplasmic organelles of the fibroblasts were well-developed. Some abnormal invasion of cytoplasm into the nucleus was found in the interstitial cells showing the ultrastructural characteristics of steroid hormone synthesis. Various cytoplasmic organelles and inclusions invaded into the nucleus of these cells and the nuclear envelope sometimes disappeared locally. These interstitial cells contained a large number of irregular-shaped electron dense mitochondria with vesicular cristae, and numerous dilated vesicles of smooth-surfacedendoplasmic reticulum (SER). The cells of anovular follicles in the irradiated ovariesresembled, in fine structure, the granulosa cells in normal primary follicles of the non-irradiated ovaries. These cells seem to be less affected by early postnatal irradiation.


Biochemical studies on the peroxidase activity in the normal and hyperplastic thyroids of rats. The total and specific activity of thyroid homogenate of normal rat was 0.95 times 10- minus 3 GU (guaiacol unit) per rat and 0.61 times 10- minus 3 GU per mg protein. These were increased 3.4 fold and 1.6 fold by chronic administration of thyroid stimulating hormone (TSH) and 5.1 fold and 2.5 fold by treatment with methylthiouracil (MTU), respectively. However, the soluble fractions, which were obtained by centrifugation at 105,000 xg for 120 min from the homogenates, manifested only 2-3% of the activity of the original homogenates, and the specific activity was scarcely affected by the administration of TSH and MTU. Moreover, even the low activity of the soluble fraction might be due to contaminated microsomes. None of the results obtained favors the view that the peroxidase is released from the cell to the colloid lumen. The number of peroxidase molecule per cell of thyroid was roughly estimated to be 1.5 times 10- minus 5 for normal and 3.9 times 10- minus 5 for MTU-treated rat.


Differential hydrolysis of bovine parathyroid hormone and its N-terminal peptide by rat kidney. Highly purified bovine parathyroid hormone (b-PTH 1-84) and its synthetic N-terminal peptide (b-PTH 1-34) were labelled with 125-I and incubated with rat kidney homogenate at 37 degrees C for 1 hour to assess the degree of hydrolysis of the iodinated peptides through measurement of the increase of trichloroacetic acid soluble 125-I fraction. Rat kidney homogenate rapidly hydrolyzed b-PTH 1-84 but was scarcely effective in hydrolyzing b-PTH 1-34. When 125-I labelled b-PTH 1-84 and b-PTH 1-34 were injected intravenously in rats, hydrolysis in vivo of the former appeared to be much more rapid than that of the latter, as shown by the faster disappearance from plasma of trichloroacetic acid precipitable fraction. Incubation of b-PTH (1-84) with rat kidney homogenate caused a shift of 125-I PTH peak almost to the position of salt peak, while the position of 125-I b-PTH (1-34) was almost unchanged by incubation with rat kidney homogenate. N-terminal peptide of bovine parathyroid hormone thus appears to be less susceptible to hydrolytic degradation by rat tissue than the intact hormone, with resultant longer retention in the blood stream.


Deciduoma formation in rats ovariectomized and androgenized during neonatal life. When rats ovariectomized at 3 days of age and given a single injection of 1.25 mg testosterone propionate on the next day became 60 days old, they were given 3 daily injections of 0.2 mug estradiol-17 beta followed by 7 daily combined injections of 2 mg progesterone and 0.2 mug estradiol. Incidence of deciduomata in reaction to uterine trauma applied on the 4th day of the progesterone-estradiol injections was almost as high as that in neonatally ovariectomized, non-androgenized rats, but the response was significantly smaller in size in androgenized rats than in non-androgenized animals. If females similarly operated on were given injections of 0.1 mug estradiol for 30 days prior to 7 daily injections of progesterone-estradiol, deciduoma formation in androgenized rats was markedly reduced in both incidence and size of the response. In non-androgenized group, deciduoma formation was not significantly affected by chronic administration of estradiol.Accordingly, it is likely that, although androgen injected during neonatal life is responsible for the reduction of uterine responsiveness in androgen-sterilized rats (Takewaki and Ohta, 1974) continued exposure of the uterus to estrogen may play a co-operative role in the event.


Contributions to an environmental impact statement. Assessment of the effects on land use, social, economic, historic and natural environment as a result of highway construction are discussed. Predictions of these effects on the various categories twenty years hence are also presented. Information of this type is a necessary segment of an environment impact study soas to conform to EPAand Department of Rransportation (DOT) guidelines.


The effect of a proposed transportation facility on noise levels in a suburban community. A nine month study of current noise levels was made at twenty-two sites within a community in Eastern Pennsylvania to evaluate the noise pollution factors for a proposed highway. An attempt was made to correlateamnient noise levels for each day of theweek with each location. Computer programs were utilized for datareduction, statistical calculations, and prediction of future noise levels. The prediction analyses were composed of contour analyses, sensitive receptor sites analyses, and the "Do Nothing" analysis. Results indicated no noise pollution problems existed during the survey, but future noise levels may exceed Federal Standards for certain sections of the proposed alignments. Factors that cause the unacceptable future noise levels are identified and modifications may be incorporated for adherence to the standards.


Ambient air pollutant analyses-integral part of an environmental impact study. Data for the major pollutants; carbon monoxide, nitrogen oxides, photochemical oxidants, suspended particulates, and total hydrocarbons, have been presented. In addition, lead analysis and a justification for no sulfur oxides data are also discussed. This study was an integral part of an Environmental Impact Study carried out by the Chemistry Department and the Institute of Transportation Studies a Villanova University. Some of the pollutants were found to cause a situation of concern; namely, photochemical oxidants, suspended particulates and nitrogen oxides. On the otherhand, carbon monoxide and total hydrocarbons were found to be well below limits set by the EPA. Although no standards are set for lead in ambient air, the data showed very low concentrations of this pollutant in our particulate samples. Since oxides ofsulfur are more an industrial, rather than transportation, pollutant little relevance could have been found for the type of study performed.


Distribution and properties of cholinesterases in subcellular fractions from rat jejunum and heart tissue. Homogenates of rat jejunum and heart tissue in 0.3 M sucrose have been separated into different subcellular fractions by centrifugation. The distribution of cholinesterases in these two tissues is different. Acetylthiocholine (Ac), propionylthiocholine (Pc), and butyrylthiocholine (Bc) iodides were used as substrates. Using 1 mmol/1 Ac in the presence of hexafluorenium, a local anaesthetic drug, inhibition percentages of these subcellular cholinesterases were found to be different. The differences in the effect of hexafluorenium were most marked at a concentration of 5 mumol/1. Four electrophoretically distinct subcomponents of cholinesterase have been identified in different subcellular fractions from both jejunum and heart tissues. The electrophoretic profile, as determined by polyacrylamide disc electrophoresis, of different subcellular cholinesterases in these two tissues also appears to be different.


Problems of quantities and units in enzymology. A knowledge of the molecular structure of an enzyme makes it possible to characterize it by different types of "amount": number (of elementary entities), mass, volume, and amount of substance. Another type of amount is obtained by measuring the rate of reaction of a suitable substrate change elicited by the enzyme in a special defined assay mixture; this way of using the catalytic effect has lead international bodies to different definitions of (kind of) quantity and unit. Their problems are discussed. A coherent scheme of the most important kinds of quantities employed by the enzymologist is presented. The dangers of converting results with one type of assay method to those of another are explained.


Phenylalanine hydroxylase from human kidney. In this report the presence, and level, of phenylalanine hydroxylase in the cortex of human kidney is established. The average activity found in 15 surgically removed kidneys was 47.2 plus or minus 11.2 mU/g wet weight of tissue. The average value, determined under the same experimental conditions, for two human liver biopsies was 217 mU/g tissue. Of five autopsy livers obtained 2.5-4 h postmortem, four contained no activity, and only 1-2 percent of normal was found in the fifth. Autopsy kidneys were similarly inactive. The presence of a highly active degradative enzyme could not be demonstrated in autopsy liver homogenates; it was established that the lack of activity was not due to an inhibitory component. A possible interpretation of this phenomenon is discussed. According to work published elsewhere [13] the kidney and liver enzymes appear to be similar. Thus, surgically removed kidneys provide an alternative source of human phenylalanine hydroxylase which can be used to study phenylketonuria.


Rhodanese activity during the embryonic development of mouse liver and kidney. Changes in specific activity and total activity levels of rhodanese in mouse kidney and liver were studied during development of the embryo, neonate and adult. The enzyme profiles during embryonic development were different for kidney and liver. The kidney showed a lower but constant activity from day 11 to 15, then an increase to reach the fully differentiated level at birth. The liver specific activity increased linearly from day 11 to reach a maximum 1 day before birth. The level of rhodanese may be correlated with the onset of organogenesis. The kidney results are discussed in terms of a protodifferentiated level of activity followed by a biphasic increase in specific protein synthesis.


Stability of membrane acetylcholinesterase in human erythrocytes treated with tetraphenylboron. Treatment of human erythrocytes with non-hemolytic concentrations of tetraphenylboron causes irreversible inactivation of acetylcholinesterase, an enzyme located at or near the outer cell surface. By contrast to other agents which also inactivate acetylcholinesterase activity such as 1,5-difluoro-2,4-dinitrobenzene and glutaraldehyde, tetraphenylboron does not affect the thermostability of the enzyme, alter its susceptibility to denaturation by urea or hinder the proteolytic digestion of the erythrocyte membrane.


Glycolytic enzyme levels of intraocular fluids and lens as compared to the respective sera of various animal species. The levels of glycolytic enzymes, aldolase, phosphohexose isomerase and lactic dehydrogenase, the latter as total and isozymes, were determined in the vitreous and aqueous humors and sera as well as in lens-saline extracts of the cat, Rhesus monkey, guinea pig, rabbit, rat and cattle. Although wide species differences were noted, the levels were generally lower in the aqueous as compared to the vitreous and serum. Aldolase and phosphohexose isomerase were invariably elevated in the lens of most species. The LDH isozyme patterns were quite unique in regard to the fluids and the species. The ratios of enzyme contents of the intraocular fluids to the respective sera were calculated and the findings compared. As tested in a few species, no remarkable enzyme differences could be discerned as a result of prior dark or light adaptation of the eyes.


Rat liver isozymes in acute carbon tetrachloride and ethionine poisoning. Changes in protein elution patterns and among others in the distribution profiles of some isozymes, as the lysosomal acid phosphatase, the microsomal alkaline phosphatase, the cytoplasmic fraction of aspartate aminotransferase and some fractions of glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, have been found in liver experimental fatty change induced in rats by carbon tetrachloride and ethionine. The possible meaning of these changes is discussed.


Identity of rat kidney and urine alkaline phosphatase actions and relation to the effect of nitrofuranfuradroxyl. The activities of alkaline phosphatases of kidney and urine appear similar and identical in action. Both are magnesium-dependent and inhibited by higher concentrations of 2-glycerophosphate. A band of similar mobility is obtained on electrophoresis of kidney and urine enzymes. In vitro magnesium competitively inhibits their activities when the ratio of Mg-+2 ions/2-glycerophosphate is above a definite level. Their activities are not affected by exogenous zinc and follow the Michaelis-Menten equation only when attention is given to the ratio of Mg-+2 ions/substrate. Nitrofuranfuradroxyl is a mixed type inhibitor showing a second-order rate of reaction with kidney and urine phosphatases.


Studies on aryl phosphate hydrolysis by human acid phsophatases. Acid phosphatases from human tissues were investigated with respect to the cleavage of six different aryl phosphates. The enzymes, except the prostatic one, showed increasing Km values with increasing substrate concentrations at a constant pH. Electrophilic substitution of the aromatic ring lowered the reaction velocity, but apparently did not change the Km. The optimum hydrolysis was at pH 3.0--6.0 without any regular pattern, which could depend on the substrate configuration.


Metabolism of trans-3-hexadecenoic acid in broad bean. 1. Broad bean (Vicia faba) leaves contain rather high concentrations (about 4% of total fatty acids) of the trans-3-hexadecenoic acid. 2. Amounts of the acid increase with the age of the leaves and are absent from etiolated tissue. 3. Changes in the levels of trans-delta-4-hexadecenoic acid can be produced by subjecting the intact plants to various light/dark periods. 4. Chloroplasts isolated from broad-bean leaves show high rates of fatty acid synthesis from [1-14C]acetate. Synthesis is dependent on coenzyme A and ATP but is insensitive to the addition of exogenous acyl carrier protein. 5. The pattern of acids made includes about 20% palmitic, 5% hexadeconoic, 10% stearic and 60% oleic. trans-3-Hexadecenoic acid synthesis was most active in chloroplasts from plants exposed to the dark for 5 days and light for 3 days. 6. Arsenite addition inhibited stearate formation by isolated chloroplasts but resulted in a two-fold stimulation of overall synthesis. 7. The rate of fatty acid synthesis by isolated chloroplasts paralleled the changes in endogenous trans-3-hexadecenoic acid levels in the leaves from which they were isolated.


Specific tritiation of indole derivatives by catalytic desulfenylation. Application to the labelling of tryptophan-containing peptides. A new method for tritiating indole derivatives was studied. The procedure consisted first of the formation of an o-nitrophenylsulfenyl tryptophanyl derivative by reacting the compound with o-nitrophenylsulfenyl chloride; then the sulfenylated product was submitted to catalytic hydrogenolysis in the presence of tritium gas. This latter reaction led to the desulfenylation of the compound and permitted the replacement of the thioether function by a tritium atom. By this procedure l-tryptophan, N-acetyl-l-tryptophanamide and a gastin-like pentapeptide derivative, Boc-Gly-Trp-Met-Asp-Phe(NH2), have been tritiated; 15, 16 and 7 Ci/mmol have been obtained respectively. The labelled compounds have retained the properties of the native materials.


The binding of tritiated elongation factors 1 and 2 to ribosomes from Krebs II mouse ascites tumor cells. Tritiated elongation factors 1 and 2 (EF-1 and EF-2) were obtained from Krebs II ascites cells which had been grown in mice injected with radioactive amino acids. The highly purified factors were sufficiently radioactive to be used in a study of the interactions between ribosomes and elongation factors. The following results were obtained. 1. EF-1 binding to ribosomes requires the presence of a polynucleotide, an aminoacyl-tRNA specified by the latter and a guanosine nucleotide carrying three phosphate groups. The hydrolysis of the GTP molecule involved in the binding reaction leads to the immediate release of EF-1. If GTP is replaced by Guo-5'-P2-CH2-P the factor remains bound to the ribosome and can be detected by sucrose gradient centrifugation techniques. 2. Likewise EF-2 binding to ribosomes can only be detected in the presence of GUO-5'-P2-CH2-P. 3. The affinity of ribosomes for EF-2 appears to be higher than for EF-1: PREINCUBATION OF RIBOSOMES WITH EF-2 inhibits the subsequent attachment of EF-1 almost completely. EF-1 prebound to ribosomes in the presence of GUO-5'-P2-CH2-P, POLY(URIDYLIC ACID) AND Phe-tRNA-Phe is partially removed from the ribosomes together with Phe-tRNA during a second incubation with EF-2. 4. Although EF-2 binding to ribosomes precludes any stable association between ribosomes and EF-1 it does not prevent the insertion of aminoacyl-tRNA into the ribosomal A-site. The attachment of aminoacyl-tRNA under these conditions enhances the binding of EF-2 to the ribosome. 5. The antibiotic showdomycin strongly inhibits the attachment of EF-1 to ribosomes and to a lesser degree impairs the binding of EF-2. 6. A-site ribosomes display a strong preference for the attachment of EF-2 and bind EF-1 only very poorly. The reverse is true for P-site ribosomes which are good substrates for the binding of EF-1 and bind EF-2 less efficiently than A-site ribosomes. These results and a number of additional findings made in this and in previous studies are discussed in the general context of the structure and function of mammalian elongation factors 1 and 2.


[Purification of kappa-caseins from sheep. Analysis of the glycan and peptide components (author's transl)]. Starting from whole individual ovine casein prepared according to the method of Shahani, K. M. & Sommer, H. H. [J. Dairy Sci. 34, 1003-1009 (1951)], kappa-casein was isolated and purified by successive steps of chromatography on columns of dextran gel and hydroxyapatite. On filtration through Sephadex G-150 in a buffer containing urea, the bulk of the kappa-casein behaved as aggregates appearing in the void volume. Dissociation of these aggregates by reductive cleavage of disulfide bonds with 2-mercaptoethanol, followed by a second filtration step on Sephadex G-150 in the presence of both urea and 2-mercaptoethanol, resulted in retardation of the kappa-casein, with separation from a contaminant representing 10-12% of the material applied. Further purification was achieved by chromatography on hydroxyapatite which eliminated the alpha-s- and beta-caseins. The purified kappa-casein had a molecular weight of about 20000, an absorption coefficient (see journal for formula) at 280 nm of 10.85 and a sialic acid and phosphorous content of 0.3% (w/w) each. The sugar fraction liberated on acid hydrolysis of the caseinomacropeptide showed the presence of N-acetylgalactosamine, galactose and neuraminic acid in equimolar ratio. Neuraminic acid existed mainly as the N-glycolyl derivative. The polypeptide chain of the ovine kappa-casein was composed of about 170 amino-acids residues. Compared to bovine kappa-caseins, the most notable difference was the presence of one additional cysteinyl and four additional aspartyl residues. Starch-gel and polyacrylamide-gel electrophoresis clearly revealed the heterogeneity of ovine kappa-casein. Chromatographic fractionation of whole kappa-casein on DEAE-cellulose also led to the separation of several fractions, the main characteristics of which are presented. Analysis of these fractions indicated that only those components which were firmly bound to DEAE-cellulose were glycosylated.


The reversible flexion contracture as a sign of peripheral nerve lesion. Three cases were observed with the same substantial clinical features: flexion contracture of the third, fourth, and fifth finger and less extensive of the wrist. The contracture appeared after a mechanical injury not related to the involved muscles. In two cases the lesion was situated above or in the elbow region, in the third on the ulnar border of the forearm. In all cases there were some ulnar nerve signs and symptoms but the contracture involved flexor muscles which were co-innervated by the median nerve. The signs and symptoms improved or disappeared entirely after neurolysis. The question is raised, whether the contracture is due to peripheral nerves damage.


Histochemical investigations on the presence of acetylcholinesterase and succinic dehydrogenase in fetal human spinal cord and brain stem at different stages of development. A comparison has been made of the localization and ontogenetic development of acetylcholinesterase (AChE) and succinic dehydrogenase (SDH) in sections of fetal human apinal cord and brain stem using histochemical methods. Spinal cord sections of young fetuses (8-10 weeks in utero) showed low to moderate enzymatic activity whereas sections of older fetuses (12-18 weeks in utero) revealed high concentrations of AChE and SDH in the ventral and laeral horns. A similar increase in enzymatic activity during development was also observed in brain stem sections where AChE and SDH were mainly confined to cranial nerve nuclei. A comparison of our histochemical findings with investigations on the development of motor activity in the spinal cord suggests that there is a correlation between the increase in AChE activity and functional development.


Neuromuscular failure in myotonic rats.

Neuromuscular failure in myotonic rats. Myotonia-like activity was recorded from various muscles of rats treated with 25-azacholesterol for a period of 2-8 weeks. 50% of myotonic rats showed a decline of amplitude of the evoked muscle potentials of the flexor digitorum muscle on stimulation of the median nerve with supramaximal stimuli at frequencies of 3, 5, 8, 15 or 50 cps. Administration of prostigimine increased neuromuscular failure. This temporary paresis of myotonic muscle resembles the transient impediment of motility of myotonic patients and it is entirely different from myasthenic transmission defect.


Comparative quantitation of immunoglobulin G (IgG) in cerebrospinal fluid and serum of children. Report on quantitation of IgG in cerebrospinal fluid (CSF) and serum of 84 children at different ages. A relation was shown between the content of IgG in CSF and serum depending on age. The decrease of the ratio CSF-IgG/serum-IgG as well as of the total protein in the CSF during the first trimenon points out a post-partal impediment of the diffusion from the blood to the CSF compartment. Beyond the first year of life the ratio of the concentrations mostly remains constant. Measurements in 135 children suffering from several neurological diseases showed that quantitation of IgG is of value only in case of suspicion of encephalitis with local synthesis of IgG.


'Iatrogenic' brain stem infarction. A complication of x-ray examination of the cervical spine and following posterior tamponation of the nose. Two patients sustained an ischemic brain stem infarction during medical examination and treatment. The first patient lost consciousness and the spontaneous respiration ceased during X-ray examination of the  cervical spine when the neck was hyperextended. After some minutes he regained conciousness but was found to be tetraplegic, and the patient deceased 4 months later. The angiogram revealed thrombosis of the basilar artery. The other patient had profuse nosebleed and was treated with posterior tamponation during which she sat for about 10 min with the neck hyperextended. Some hours after this procedure symptoms and signs of lateral caudal brain stem infarction emerged.


Intracardiac conduction defects following overdose of tricyclic antidepressant drugs. Atrioventricular and intraventricular conduction were assessed in 4 patients with tricyclic antidepressant overdosage. The proximal or A-V nodal conduction (A-H) was normal, but 3 patients showed a drug-related increase in the QRS duration and His-Purkinje (H-V) conduction time. One patient with a normal H-V interval had a normal width QRS. The findings were independent of the heart rate and suggested a "quinidine-like effect" of the tricyclic drugs when ingested in suicidal doses. All 4 patients had normal intracardic conduction when restudied 8 days later. Procainamide and quinidine have similar effects on the intracardiac conduction and would appear undesirable in the treatment of cardiac arrhythmias in patients with tricyclic overdosage. Practolol in a dose of 20 mg by intravenous injection reduced the heart rate and caused a relative increase in the A-H interval but did not affect either the distal atrioventricular or intraventricular conduction. Although there was a slight drop in blood pressure, it may be a safer drug to use.


New manifestations of dual A-V nodal pathways. Electrophysiological studies with extrastimulus technique demonstrated evidence of dual A-V pathways in two patients with paroxysmal supraventricular tachycardia (PSVT). In case one, the second P of paced Wenckebach sequences was followed by two conducted QRS complexes without an intervening P wave. The A-H of the first and second QRS were consistent with the fast and slow pathway conduction times. The second QRS was followed by an atrial echo and PSVT, suggesting that the first pathway was available for retrograde propagation following the second QRS. In case two, PSVT was induced with atrial extrastimulus, followed by development of A-V dissociation. The two cases suggest the following conclusions: (1) dual A-V nodal pathways may allow the occurrence of double antegrade conduction of one P; (2) the atria are not necessary for A-V nodal circus movements in "dual pathway" A-V nodal reentrant PSVT.


Aberrant origin of left pulmonary artery (vascular sling). Report of the clinical and anatomic features in three patients. The clinical and anatomical findings in 3 patients with aberrant origin of the left pulmonary artery from the right pulmonary artery ("vascular sling") are presented. All 3 children symptoms of severe respiratory distress shortly after birth. In 2 children the correct diagnosis was suggested from the roentgenogram of the thorax, because of an indentation in the anterior wall of the esophagus. The diagnosis was further endorsed by selective angiography of the aberrant left pulmonary artery. The second patient is of particular interest, since the correct diagnosis was missed because of the presence of a multitude of associated anomalies. These included a tracheobronchial anomaly, a ventricular septal defect with a dilated pulmonary trunk, and a left-ward shift of the heart secondary to pulmonary emphysema on the right. Therefore, the indentation in the esophagus was absent, while the shift and rotation of the heart led to a misinterpretation of the exact course of the left pulmonary artery on the angiocardiogram. These cases are presented to reemphasize that "vascular sling", although rare, is indeed a serious cause of respiratory distress in infancy. Early recognition is of vital importance, since surgical repair of the vascular anomaly seems to be the only benificial procedure in these patients.


Tricyclic antidepressive drugs and dopamine-sensitive adenylate cyclase from rat brain striatum. Tricyclic antidepressant drugs were examined as inhibitors of dopamine-sensitive adenylate cyclase in a cell-free homogenate of rat brain striatum. Amitriptyline (Ki 0.17 muM) and doxepin (Ki 0.24 muM) were found to be potent inhibitors of dopamine-sensitive adenylate cyclase, chlorimipramine (Ki 0.59 muM) and nortriptyline (Ki 0.50 muM) were moderate inhibitors and imipramine, desmethylimipramine, protriptyline and melitracene were weak inhibitors with Ki values higher than 1 muM.


Dependence of the cardiac uptake of digitalis glycosides on the extracellular calcium concentration in guinea pig isolated hearts. The purpose of the present study was to investigate, at the myocardial level, the divergent influences of Ca2+ on the action of various cardiotonic steroids. Therefore, the cardiac uptake of 3-H-digitoxin and 3-H-digitoxin was studied in experiments on guinea pig isolated hearts. The following results were obtained: with digitoxin the increase of the extracellular calcium concentration from 0.45 upto 7.2 mM resulted in a concomitant decrease of the myocardial glycoside uptake from about 1.8 nmoles/g wet weight down to about 1.2 nmoles/g wet weight. Similar results were obtained when digoxin uptake was studied under the same conditions: with 0.45 mM Ca2+ about 0.6 nmoles/g wet weight were bound, increasing the calcium concentration upto 7.2 mM lead to a concomitant decrease of the cardiac digoxin uptake down to about 0.45 nmoles/g wet weight. Despite the different physicochemical behaviour of these two drugs and the different amounts of drug present in the hearts the influence of Ca2+ was almost identical if calculated on a relative basis. So far, no experimental based explanation can be given for the above discrepancies. Other possible interpretations are discussed.


Influence of adenosine and lowered cerebral blood flow on the cerebrovascular effects of theophylline. The response of brain blood vessels to theophylline infused intra-arterially was evaluated. The experiments were performed on isolated canine brains perfused by donor dogs. Thus secondary effects due to theophylline were eliminated. Arterial pO2, pCO2, pH and brain temperature were kept constant. Cerebral vascular resistance (CVR) was calculated from total venous outflow and cerebral perfusion pressure. A 2 mg dose of theophylline per brain was given at normal cerebral perfusion pressure (about 81 mm Hg), at lowered cerebral perfusion pressure (about 37 mm Hg), and during an adenosine infusion lasting 10 min (10-minus 7 mol/min). At normal perfusion pressure theophylline showed a significant 15% decrease of CVR, but at lowered perfusion pressure a significant 19% increase occurred. During infusion of adenosine, which decreased CVR by 23%, theophylline again increased CVR by 20%, thus demonstrating an adenosine-theophylline antagonism. From our results, it is suggested that adenosine could be involved in the vasodilatation of cerebral vessels in the hypoxic brain.


Analysis of ergotamine - 5-HT interaction on the isolated rat stomach preparation. The effect of ergotamine on the isolated rat stomach and its influence on the response to ACh and 5-HT were investigated. The log dose-response curve of ergotamine was bell-shaped. Extension of the incubation time of ergotamine resulted in a parallel shift to the left of the curve. The response to ergotamine was inhibited by methyserigide and piperoxan. Incubation with ergotamine resulted in a decrease of the pD2-value of 5-HT together with a marked suppression of the maximum of the 5-HT curve. The response to ACh was affected in accordance with the prediction of an action of ACh and ergotamine on different receptors. The prolonged receptor stimulation by 5-HT or ACh resulted in a decrease of the apparent affinity towards their receptors. Incubation with ACh resulted in a parallel shift to the right of the 5-HT curve. However no inconsistency with the theoretical prediction of an action on separate receptors was observed with the ACh curve in the presence of 5-HT. It is concluded that ergotamine is a partial agonist on the D-tryptamine receptors of tbe isolated rat stomach. The marked decrease of the maximum of the 5-HT curve by ergotamine is probably caused by the slowly reversible character of its antagonism. The parallel shift to the left of the ergotamine curve with the extension of the incubation time and the persistence of its antagonism both are probably caused by a slow diffusion into and from the biophase.


Effects of papaverine on isolated rabbit papillary muscle. The effect of papaverine on the positive inotropic response to isopreqaline and to calcium was studied on the rabbit isolated papillary muscle; theophylline and the calcium antagonistic D600 were used for comparison. The dose-response curve for isoprenaline was shifted to the left by papaverine (3 times 10- minus 6 to 3 times 10- minus 5 M), in a dose-dependent manner, while that for calcium was not affected by the same concentration. In this respect papaverine was about 30 times more potent than theophylline. In the presence of papaverine isoprenaline induced arrhythmic contractions of the papillary muscle: the incidence of arrhythmic contractions was positively correlated to the concentration of papaverine. Papaverine 10- minus 5 to 10- minus 4 M caused only a positive inotropic response whereas 3 times 10- minus 4 to 10- minus 3 M induced a biphasic response, i.e., after a positive inotropic effect followed a negative one. In the presence of 3 times 10- minus 4 M papaverine isoprenaline failed to cause a positive inotropic response but exclusively induced arrhythmic contractions. Calcium, on the other hand, readily antagonized the negative inotropic effect of papaverine (3 times 10- minus 4 M) and caused a contracture of the papillary muscle. The results indicate that papaverine (3 times 10- minus 6 to 10- minus 5 M) like theophylline (10- minus 4 to 10- minus 3 M) produces its effect by phosphodiesterase inhibition and thereby specifically potentiates the response through beta-adrenoceptor stimulation. In higher concentrations (3 times 10- minus 4 to 10- minus 3 M) it acts as a calcium antagonistic, like D600, and furthermore may interact with calcium moving through myocardial cell membranes to cause a contracture via a mechanism which it shares with theophylline.


Evaluation of dopamine metabolism in rat striatum by a gas chromatographic technique. Dopamine metabolism in rat striatum was evaluated by gas chromatographic quantitation of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). The level of DOPAC (5.21 nmoles/g plus or minus 0.40 S.E.M., n equals 12) exceeded that HVA (3.63 nmoles/g plus or minus 0.25 S.E.M., n equals 12). 2 hr following administration of probenecid (200 mg/kg i.p.) the level of striatal HVA was approximately doubled whereas the level of DOPAC was not significantly elevated. Pargyline (75 mg/kg i.p.) poduced a rapid depletion of DOPAC and HVA. the rate of disappearance of DOPAC (t1/2 equals 10 min) exceeded that of HVA (t1/2 equals 18 min). Rates of metabolite formation were computed assuming steady state kinetics. The rate formation of DOPA (20.5 nmoles/g/hr) was much greater than that of HVA (10.1 nmoles/g/hr). We conclude that DOPAC is the major dopamine metabolite in rat striatum and that its measurement may provide the best index of functional neuronal activity in this species.


Differential effects of D- and L-amphetamine and methylphenidate on rat striatal dopamine biosynthesis. Methylphenidate and the optical isomers of amphetamine have differential effects, in vivo and in vitro on rat striatal synaptosomal dopamine (DA) biosynthesis. Whereas the systemic administration of D- or L-amphetamine produces a dose-dependent decrease in synaptosomal DA synthesis, with ED50's of 1.1 and 3.5 mg/kg, respectively, methylphenidate, at doses which produce comparable degrees of stereotypes behavior, has no effect on this measure of DA biosynthesis. In vitro, D- and L-amphetamine exhibit a three-fold difference in ED50's (1 times 10-minus 6 M and 3 times 10-minus 6 M, respectively) with respect to both activation of striatal synpatosomal DA synthesis, and to reversal of reserpine-induced inhibition of DA synthesis. In contrast, although in vitro methylphenidate can partially activate DA synthesis, it does not overcome the reserpeine-induced inhibition. The data are discussed in terms of the possible differential mechanisms by which these two types of stimulants may exert their effects on sterotypy.


Behavioral effects of d-amphetamine and caffeine in the squirrel monkey. Four Squirrel monkeys were trianed on a bar-press response with reinforcement available every 80 sec. The effects of d-amphetamine and caffeine upon this response were studied in both light and dark. In addition to differential drug effects it was found that both illumination and sex of the subjects were important variables.


Direct myocardial depressant effects of gentamicin. Effects of gentamicin on myocardial contractile performance were examined in isolated, electrically driven, rat left atria. This aminoglycoside antibiotic produced a maintained and concentration-dependent (0.0156-0.25 mM) depression of myocardial contractile tension that was reversible by replacing the incubation media with gentamicin-free solution. Time to peak tension and total contraction time were not discernibly altered by gentamicin. The negative inotropic response elicited by gentamicin was antagonized in a competivitive-like manner by increasing the calcium ion (Ca2+) concentration of the bathing solution, whereas, the depressant effects of gentamicin were antagonized by norepinephrine in a non-competitive-like manner. Present findings demonstrate a direct negative inotropic effect of gentamicin and suggest that this antibiotic interferes with the participation of Ca2+ in the events leading to mecahnical activity of atrial myocardium.


Drug effects in a novel biphasic writing syndrome induced by acetylcholine in mice. The writing induced in mice by i.p. administration of 3 mg/kg acetylcholine chloride showed a biphasic response with time. The primary phase of 1-15 sec after acetylcholine appeared to be the result of nicotinic receptor stimulation. The secondary phase from 30 sec following acetylcholine was selectively suppressed by anti-inflammatory agents and by atropine, while centrally acting analgesicw, other strong central nervous system drugs and ganglion blockers suppressed both phases of writhing to an equal extent. The narcotic partial agonists significantly suppressed primary writhing more readily. The method appears to be of value in testing new pharmacological agents.


Haloperidol-induced disruption of conditioned avoidance responding: attenuation by prior training or by anticholinergic drugs. Rats injected daily with haloperidol (0.15 mg/kg) failed to acquire a one-way avoidance response over a 9 day period (10 trails/day). When these animals were subsequently tested without haloperidol, on the first drug-free day they preformed as well as animals given saline throughout the training period and significantly better than naive saline-treated animals on the first day of training. The performance of rats which were trained for two days before receiving haloperidol was only partly blocked by the drug, while animals trained for 9 days before drug administration were immune to the disruptive effects. Three anticholinergic (muscarinic) drugs, atropine (10 mg/kg), scopolamine (1 mg/kg) and benztropine (2 mg/kg) significantly reversed the effect of haloperidol on the acquisition of the nigroneostriatal projection and support the view that this system is critically involved in the acquistion of learned instrumental responses. The nature of the avoidance deficit produced by these treatments is discussed with reference to the possibility that they selectively block the initiation of boluntary motor responses. According to this hypothesis, the failure of these teratments to disrupt escape responding may be due to the fact that the unconditioned stimulus generates reflexive motor responses (flinch, jump, etc.) which are sufficient to begin the motoric sequences that cannot be initiated voluntarily in response to the conditioned stimulus.


Prostaglandins, antipyretic analgesics and adrenergic stimuli on the isolated artery. In untreated, and cocaine- and DOCA-treated rabbit ear arteries, PGE2 and arachidonic depressed to responses to intramural sympathetic nerve stimulation. Constrictor responses to extraluminal NA in the treated arteries were also depressed. A comparison of its inhibitory potency on the two types of responses suggest that the effects of arachidonic acid, but not PGE2 on adrenergic nerve stimuli, were selectively blocked by aspirin 200 mug/ml and by indomethacin 3 mu/ml. In these concentrations, aspirin, but not indomethacin, enhanced the magnitude of the resoonses to the stimuli. Aspirin also selectively reduced the inhibition by arachidonic acid of the response to extraluminal NA (tested in cocaine0 and DOCA-treated arteries).


Norepinephrine-induced depolarization of skeletal muscle cells. I.v. administration of norepinephrine to anesthetized hamsters was followed by a significant depolarization of the cell membranes of skeletal muscle (gracilis anticus and sartorius). The occurrence of this depolarization in consistent with the suggestion that changes in ionic distribution across the cell membrane are associated with activation of non-shivering thermogenesis in muscle cells as has been proposed for brown adipocytes.


Enhancement of picrotoxin convulsions in chicks and mice by the prior intraperitoneal injection of hypertonic GABA or mannitol. Effects of i.p. injection of hypertonic solutions of GABA and mannitol on convulsant activity and latency to reduced or enhanced depending on whether picrotoxin was given i.p. or given i.v. or s.c. The principal cause of these changes appeared to be altered rates of absorption of picrotoxin. There was no evidence that cerebral dehydration afforded protection against picrotoxin.


Diazepam as a discriminative cue: its antagonism by bemegride. Gerbils trained to respond differentially to the presence or absence of diazepam (8.0 mg/kg) in a T-maze showed a dose-related antagonism when challenged with bemegride (5.0-40.0 mg/kg). Gerbils trained with a mixture of diazepam (8.0 mg/kg) and bemegride (20.0 mg/kg) evidenced response control more slowly than the group trained solely with diazepam.


Induction of drinking by insulin in the rat. Unanesthetized rats were injected i.v. either with commercial regular insulin, or the diluting fluid of the commercial insulin solution used, or with 0.9 percent NaCl, and placed in individual cages containing no food. Water intake was measured for 2 hr. Injection of the hyposmolar diluting fluid containing glycerol and phenol slightly, but significantly, enhanced the water intake. Insulin in doses from 0.05 to 43.0 U/kg induced an additional drinking response, while 0.02 U/kg had no effect. A linear log dose--response for insulin-induced drinking was obtained between 0.05 and 21.0 U/kg. Small doses of insulin, thus, undoubtly, enhance water intake. Insulin could play a minor role in body water honeostasis in mammals.


Effects of various psychoative drugs on the metabolism of delta-tetrahydrocannabinol by rats in vitro and in vivo. Metabolism of 14C-tetrahydrocannabinol (14C-THC) by rat liver microsomal preparations in vitro was studied in the absence and presence of other psychoative drugs. Disappearance of 14C-THC, and changes in metabolite patterns as shown by thin layer chromatography, were studied. SKF 525-A, pentobarbital, phenobarbital and amphetamine all produced an apparently non-competitive inhibition of THC metabolism. The inhibition produced by meprobamate was at least partly competitive. Morphine and mescaline had no evident effect. SKF 525-A and the barbiturates markedly decreased the concentrations of all the major THC metabolites found in the incubation media. In contrast, none of the drugs tested in vivo, with the exception of SKF 525-A, had any effect on the biliary 14C-excretion or metabolite pattern, or on final tissue levels of 14C, when administered in doses comparable to those used for studies of interaction with THC in vivo. SKF 525-A, however, did markedly decrease the excretion of total 14C and alter the pattern of THC metabolities in the bile, and increased the final tissue 14C levels. It is concluded that in vivo interactions between THC and other psychoactive drugs are probably not explainable primarily on the basis of altered THC metabolism.


Acute and chronic effects of beta9-tetrahydrocannabinol on seizures in the gerbil. Beta9-THC was injected daily for 6 days into gerbils from our breeding colony that exhibit spontaneous epileptiform seizures. At a dose of 20 mg/kg no effect was seen on the latency, duration or severity of the seizures induced after 1 and 6 days of treatment. Delta9-THC (50 mg/kg) completely abolished the seizures after a single injection but tolerance developed to this effect so that no protection was afforded after 6 daily doses. Severe toxic signs were evident at the higher dose level with marked depression of spontaneous motor activity. The toxic effect increased progressively with chronic treatment and half the animals failed to survive.


Adrenaline-induced cardiovascular changes after intrahypothalamic administration to rats. Adrenaline caused a decrease in arterial blood pressure and heart rate when injected into the anterior thalamic region of rats. The size and the duration of these effects depended upon the dose of adrenaline injected. Adrenaline is 10 times more potent than noradrenaline in inducing these intrahypothalamic effects on cardiovascular parameters. These data support the concept of the relevance of adrenaline receptors in central autonomic regulation.


The effect of LSD and 2-bromo LSD on the DOPA accumulation after central and peripheral decarboxylase inhibition. LSD and BOL were found to be equally potent in increasing the rat brain DOPA accumulation after decarboxylase inhibition. However, at the doses selected, the DOPA levels after haloperidol and apomorphine were increased by LSD but not by BOL. It is suggested that this difference is due to LSD's activating effect on central serotoninergic receptors.


Contrasting local effects of MAO inhibitors on caudate tremor activities. Hindlimb tremor was produced in chronic cats by intracaudate microinjection of the monoamine oxidase (MAO) inhibitors tranylcypromine and harmaline throughout a range of doses (150-385 mug). Pargyline, however, was non-tremorgenic within the same range, suggesting that interference with MAO is not sufficient in itself to elicit tremor. Tranylcypromine tremors differed from those of harmaline by exhibiting a slower onset, longer duration and susceptibility to antagonism by hemicholinium. In contrast, ongoing cholinergic tremors following intracaudate physostigmine were variably suppressed by all three MAO inhibitors at comparable dose levels (175-200 mug); pargyline produced the most complete suppression. These results indicate that MAO inhibitors can modify tremor activities in a differential manner dependent both on the functional state of the caudate nucleus and on the ability of cartain MAO inhibitors to exert other local actions.


The effect of hydrocortisone phosphate, methylprednisolone and phenytoin on pancreatic insulin release and hepatic glutathione-insulin transhydrogenase activity in the rat. Following i.v. injection of glucose to rats, blood was collected from the carotid artery and the portal vein, and insulin was determined by radioimmunoassay. Pancreatic insulin release and hepatic insulin extraction were increased following the administration of glucocorticoid drugs and reduced following phenytoin. Hepatic glutathione-insulin transhydrogenase activity (GITA) was measured in each animal and found to be increased after glucocorticoid therapy but unaffected by phenytoin. In alloxan-diabetic rats, GITA was significantly increased following treatment with both methylprednisolone and phenytoin compared with control alloxan-diabetic rats. This is suggestive evidence that both these drugs can initiate an increase in GITA. It is concluded that the markedly raised GITA in steroid-treated non-diabetic rats is the combined result of a drug-induced effect plus the major inducing effect of an increased hepatic uptake of insulin on insulin degradation, whereas the main effect of phenytoin is a reduction of pancreatic insulin release.


The action of amantadine on the rat uterus: its interaction with oxytocin and the effects of several ionic modifications of the medium. The influence of amantadine on the contractile responses of the rat uterus to oxytocin in the presence of several ionic modifications of the external medium was studied both in situ and in vivo. Oxytocic effects of amantadine were observed in vivo (1 and 5 mg/kg), and in vitro (9.3 times 10-7 M to 2.8 times 10-6 M); possible competitive partial potentiation of the contractile effect of oxytocin was also observed. Amantadine, 9.35 times 10-6, 1.3 times 10-5 and 1.8 times 10-5 M, significantly reduced oxytocic activity. Calcium ions antagonized the oxytocic and antioxytocic effects of amantadine. Excess K+ and the presence of Mg2+ ions (1.8 mM/l and 1.08 mM/l respectively) reversed the antioxytocic effect of amantadine. Propranolol also reversed the antioxytocic effect of amantadine. It is postulated that the oxytocic effect of amantadine may be related to antagonism of calcium; antioxytocic activity may be explained by stabilization of the resting cell membrane, inhibiting ionic flow, and also by its catecholamine-liberating activity.


Role of prostaglandins in tone and effector reactivity of the isolated rat stomach preparation. The influence of indomethacin (2 mug/ml) on the tone and on the response to ACh, 5-HT and tryptamine of the stomach strip preparation from normal and Essential Fatty Acid Deficient (EFAD) rats was examined. The pD2 value of ACh and 5-HT, but not of tryptamine, was significantly lower on the preparations obtained from EFAD rats than on those from normal rats. Contradictory results were obtained with respect to the influence of indomethacin on the pD2 value of ACh, 5-HT and tryptamine. No significant difference in initial tone and contractility of the stomach strips of both groups of rats was observed. However, the tone of the strips from normal rats increased with time. Preparations from EFAD rats showed a gradual decrease of the tome with time. Pre-incubation with indomethacin reduced the tone of strips from both groups of rats to a comparable extent. Thus further support is provided for the proposed role of prostaglandins in the maintenance of the tone of isolated smooth muscle. The possibility is raised that prostaglandins might not be predominantly involved in the generation of the initial tone and also not substantially contribute to the effector reactivity of the organ.


CNS site of antiarrhythmic action of diphenylhydantoin (DPH) in the cat. Diphenylhydantoin (DPH) is known to be a potent anticonvulsant agent, useful in treating and preventing grand mal seizures. More recently, DPH was reported also to be a potent antiarrhythmic agent acting by means of a depressant action on the heart. The present experiments demonstrated that DPH has also a potent antiarrhythmic action when administered to the CNS. The posterolateral hypothalamus was stimulated in cats to evoke cardiac arrhythmias of varying severity both during and after stimulation. In general, it was found that the post-stimulus arrhythmias were obtained more readily than those during stimulation. The mean effective dose of DPH required to prevent the arrhythmias via the i.v. route was 11.9 mg/kg, and that via the vertebral artery route and via the fourth ventricular route was only 1.9--1.4 and 1.4 mg/kg, respectively. These results suggest that though DPH has identifiable antiarrhythmic action on the heart itself it has a strong antiarrhythmic effect via the central nervous system as well.


Effect of prostaglandin E2 on pulmonary vascular resistance in intact dog, swine and lamb. The effects of prostaglandin E2 (PGE2) on pulmonary vascular resistance in the intact dog, swine and lamb were studied using a right heart catheterization technique to isolate and perfuse the left lower lung lobe at controlled blood flow. Infusion of PGE2 into the lobar artery increased lobar arterial perfusion pressure but did not alter pressure in the left atrium in all 3 species. The increase in lobar arterial pressure was associated with a rise in pressure in the small intrapulmonary lobar vein in the dog but no change in pressure in these veins in the swine and lamb. Infusion of PGE2 into the iliac artery produced a marked decrease in perfusion pressure in the hindlimb of the dog. The effects of PGE2 on the canine lung occurred in the absence of any significant change in arterial blood gases, pH, hematocrit or rate and volume of respiration, and this substance increased pulmonary vascular resistance when the lung was perfused with dextran instead of blood. These results show that in dog, swine and lamb, PGE2 increases pulmonary vascular resistance; however, the site of vasoconstriction is different in the dog and swine or lamb. In the swine and lamb vasoconstriction occurred primarily in vessels upstream to the small veins, presumably small arteries, whereas in the dog lung, the pre- and postcapillary vessels were actively constricted by this naturally occurring substance.


Dyskinetic phenomena caused by the intrastriatal injection of phenylethylamine, phenylpiperazine, tetrahydroisoquinoline and tetrahydronaphthalene derivatives in the guinea pig. The intrastriatal injection of dopamine-like compounds in the guinea pig caused the development of abnormal involuntary movements (dyskinesias) which were observed as facial grimacing, biting/gnawing/licking, severe hear and neck twisting, limb movements, whole body rocking, head and neck rocking and marked locomotor hyperactivity. With the exception of the whole body and head and neck rocking movements the dyskinesias were specifically induced by dopamine-like agents. The most conspicuous dyskinesias which followed the administration of phenylethylamine derivatives were the movements of biting/gnawing/licking and the development of marked locomotor hyperactivity. This effect was shown to be highly specific for dopamine. Tetrahydroisoquinohydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) caused locomotor hyperactivity and gnawing/biting/licking dyskinesias. Of all compounds investigated 1-(3,4-dihydroxyphenyl)pierazine (DHPP) induced the most marked dyskinetic disturbances upon intrastriatal injection: intense facial grimacing, biting/gnawing/licking, head and neck twisting and limb movements were observed although the locomotor hyperactivity was absent. Of the 1-phenylpiperazine derivatives examined, dyskinetic activity was only demonstrated using compounds with a hydroxyphenyl substitution. Results are discussed in terms of the structure--activity relationships for the stimulation of different types of dopamine receptive structures within the neostriatum.


Interocular transfer of the motion after-effect in normal and stereoblind observers. The extent of interocular transfer of the motion after-effect was measured in 4 stereoblind subjects and in 19 subjects having varying degrees of stereopsis. Stereoblind individuals failed completely to show any interocular transfer of this after-effect, while subjects with good stereopsis exhibited between 55 and 82 percent transfer (mean 73 percent). Furthermore, normal subjects who manifested a clear eye dominance tended to show greater transfer from the dominant to the nondominant eye than vice versa. Individuals who either had a history of a strabismus or possessed some other early impediment to clear binocular vision tended to show less transfer. Overall there was a significant positive correlation of 0.75 between the extent of interocular transfer and the subject's stereoacuity. It is argued that the extent of interocular transfer of this after-effect provides a measure of the proportion of the total number of visual cortical neurons that are binocular. Thus stereoblind humans, who show no transfer whatsoever may, like cats and monkeys deprived of concordant binocular visual input early in life, suffer from a lack of binocular neurons.


A quantitative study of subsurface cisterns and their relationships in normal and axotomized hypoglossal neurones. A quantitative ultrastructural survey was made of subsurface cisterns and their association with overlying structures in the left hypoglossal nucleus of normal rats, and rats which had received left hypoglossal axotomies 7-84 days previously. Subsurface cisterns in normal rats occurred in some hypoglossal neurones, and, sporadically, in proximal dendrites. They were mostly subsynaptic, and often associated with Nissl substance; From 7-14 days postoperatively, when many somatic boutons temporarily lost contact with the perikaryal surface, and were replaced by a microglial sheath, the percentage of perikaryon with underlying cistern was significantly reduced. The Nissl substance was also dispersed at this stage, and not restored until 28 days postoperatively. At 21 days normal percentages of subsurface cistern were restored, but the cisterns were now mostly subastrocytic, an astrocytic sheath having replaced the microglial sheath. From 63 days onwards the cisterns were mostly subsynaptic again as boutons returned to the regenerating perikarya and the temporary astrocytic sheath disappeared. It is suggested that subsurface cisterns might alter the overlying perikaryal surface in some way during neuronal regeneration, causing certain boutons to adhere there.


A pontine primary relay for ascending projections of the superior laryngeal nerve,. 1. In sheep anaesthetized with fluothane, electrical stimulation of the superior laryngeal nerve (SLN), which contains most of the afferent fibres for swallowing, evokes potentials in the medial part of the ipsilateral thalamic VPM (nucleus ventro-postero-medialis) within about 5 msec. This region constitutes the secondary synaptic relay for the laryngeal impulses projecting to the frontal cortex concerned with swallowing. 2. SLN fibres are synaptically connected with cells of the NTS (nucleus of the tractus solitarius), 2-4 mm rostral to the obex (see Car and Jean, 1971). Coagulation of this region abolishes reflexly and cortically induced swallowing, but does not influence the thalamic or cortical responses induced by SLN stimulation. 3. SLN stimulation evokes potentials with a short latency (2 msec) in a restricted pontine area localized 5 mm from the midline and above the trigeminal motor nucleus, just in front of the central emergence of the facial nerve (i.e; about 12 mm rostral to obex). Restricted coagulation of this pontine region eliminates both the thalamic and the cortical projection of SLN. 4. Repetitive stimulation (2 V; 0.2 msec; 20-30 Hz) of this same pontine region produces rhythmic swallowing with characteristics quite similar to those of swallowing induced by SLN or bulbar stimulation. 5. Other data show that SLN fibres, or at least part of them, bifurcate after entering the brain stem (about 6 mm in front of the obex), and give a caudal branch, which reaches the bulbar swallowing centre (3 mm rostral to the obex) by running through the tractus solitarius; and a rostral branch terminating in the pons where the primary synaptic relay for the ascending laryngeal pathway is localized.


Comparison of activity in pontine versus medullary neurones during swallowing. 1. On decerebellectomized sheep lightly anaesthetized with fluothane, the activity of 49 neurones in the pontine relay (see Car et al., 1975) was recorded with microelectrodes following stimulation of afferents in the superior laryngeal nerve (SLN), 2. These pontine neurones (PN) exhibited an "initial activity" (one or a few spikes) for stimulation either of the homolateral SLN (35 PN) or glossopharyngeal nerve (14 PN). This initial activity had a latency between 1.5 and 4 msec. When swallowing was induced by SLN stimulation, a later discharge appeared. This "swallowing activity" consisted of a variable burst of spikes. 3. The effect of curarization was tested for 13 PN. It always eliminated the "swallowing activity". 4. A clear antidromic response of 16 PN (26 tested PN) was induced by stimulating the thalamic VPM nucleus. This stimulation failed to elicit an antidromic response in medullary neurones (14 tested) located in the nucleus of the tractus solitarius. 5. It is concluded that PN are probably sensory relay neurones which inform higher nervous centres of the state of oropharyngeal receptors; whereas medullary swallowing neurones are really interneurones involved in the programming of the wallowing motor sequence.


Neural pathways from the vestibular labyrinths to the flocculus in the cat. In decerebrate, unanesthetized cats, responses in the flocculus were evoked by electric stimulation of the vestibular nerves and by natural stimulation of horizontal head angular acceleration. Field potentials in the flocculus and intracellular recording from Purkinje cells following vestibular nerve stimulation indicated that the responses were produced by mossy fiber inputs. Field potentials evoked from the contralateral labyrinth were as large as those from the ipsilateral one. There was considerable convergence of bilateral labyrinthine mossy fiber inputs to a Purkinje cell. In view of the effects of incision at the midline of the cerebellum and the brain stem, inputs from the contralateral labyrinth were mainly conveyed through the midline of the brain stem and partly through the midline of the cerebellum. Primary vestibular afferents were involved in the transcerebellar crossed pathway. Fibers of the secondary vestibular neurons projecting to the contralateral flocculus were implicated in the brain stem-mediated pathway and, in part, presumably in the transcerebellar crossed pathway. About one-third of the axon spikes examined in the flocculus responded to horizontal head angular acceleration. Commissural inhibition was observed in more than half of the axon spikes in the flocculus which were presumed to be mono- or polysynaptically activated from the vestibular nerve.


Chelating agents as possible artificial blood substitutes. The synthetic cobalt-containing oxygen carriers are briefly reviewed as well as some of the heavier metal systems. The earlier chemistry of the iron complexes with dioxygen is discussed. Some of the more recent results on the reversible binding of oxygen to iron complexes is presented. Initial results showed that low temperatures and steric hindrance in the vicinity of the binding site were important parameters. It is shown further that a rather extensive steric hindrance can yield iron complexes that are efficiently reversible at 25 C. Two such species are known at this date. It is possible that such compounds could act as artificial blood substitutes by attaching to them suitable permanent ligands. Furthermore, solubilization of such species either in fluorocarbon emulsions or by direct covalent attachment to water-soluble polymers offers an opportunity to render them physically compatible with plasma, as substitutes for the red cell.


Fluorocarbons: properties and syntheses. The paper discusses custom syntheses of fluorocarbons for potential use as artificial blood substitutes. The term "fluorocarbon" designates a perfluorinated carbon compound which does not contain another halogen or hydrogen. Prominent requirements of an artificial blood substitute are: 1) efficient oxygen/carbon dioxide transport, 2) biological inertness, 3) low vapor pressure, 4) dispersibility to form emulsion. Fluorocarbons are superior to other liquids in dissolving oxygen and carbon dioxide. The most biologically inert halogenated alkanes are fully fluorinated. Introduction of another halogen or unsaturation decreases biological inertness. Boiling points of fluoroalkanes can be estimated from the Kinney equation. The most common method of fluorination, namely electrofluorination, is briefly described and applied to several types of organic compounds. Hydrocarbons give low yields of perfluoroalkanes. Alternatively, perfluoroalkanes may be prepared through reaction of functionalized substrates. Innert perfluorocyclic ethers are obtained from substrate ethers or acid fluorides. All types of amines perfluorinate but only perfluorotertiary amines are inert. Divalent organo-sulfur compounds afford inert perfluorinated products with sulfur in the hexavalent state. Sulfonyl fluorides give perfluorosulfonyl fluorides which can be pyrolytically coupled producing perfluoroalkanes. The Schoniger combustion method and neutron activation are described as analytical means for determining fluorine content.


Artificial blood emulsifiers.

Artificial blood emulsifiers. Two sets of prerequisites for nonionic emulsifiers suitable for an artificial blood program are suggested; one set that is necessary and a supplemental set that is desirable. Of the commercially available emulsifiers, only one, poloxamer 188, meets all of the requirements of the first group, and also meets most of the prerequisites of the second group. The hydrophile-lipophile balance system, its relation to emulsifier structure, and its value in arriving at the optimum emulsifier system, are discussed. The ability of the poloxamer 188 to serve as a plasma expander is attributed to its unusual micellar nature. The emulsifiers used in the artificial blood program are reviewed. Some newer experimental fluorochemical surfactants are described, and suggestions made for developing modifications of existing emulsifier systems. A new simple method for preparing stable artificial blood emulsions is reviewed.


Cross-linked hemoglobins as potential plasma protein extenders. Reaction of hemoglobin solutions with members of a class of diimidate esters leads to the formation of cross-linked intermolecular or intramolecular complexes depending on the relative concentration of hemoglobin and the length of the carbon chain of the imidate esters. The products have a life-span in the circulation of rabbits significantly greater than that of unmodified hemoglobin and it is suggested that they may serve as plasma protein extenders.


Hemoglobin solution: a potential oxygen transporting plasma volume expander. The potential of a 6% stroma-free human hemoglobin solution (WXb8326) as a plasma volume expander with oxygen transport capabilities was evaluated in barbiturate-anesthetized spontaneously breathing dogs. WXb8326 compared favorably with dextran-70 and 5% albumin solution as a plasma volume expander. Serial phlebotomies to a blood pressure of 35 mm Hg and immediate replacement with the above colloid expanders showed that only WXb8326-exchanged dogs survived acute reductions in hematocrit to critical levels of smaller than or equal to 5%. After several exchanges with WXb8326 to levels as low as 1%, it was possible to demonstrate acute survival. With less drastic reductions in the hematocrit (between 5 and 10%) all dogs survived acutely regardless of the type of plasma volume expander used; however, subacute survival rates varied. Oxygen transport characteristics during isovolumic hemodilution (phlebotomy and simultaneous replacement with WXb8326) were studied in a separate series of spontaneously breathing dogs in which hematocrit was reduced to approximately 50% of control. Oxygen content of erythrocytic hemoglobin (EHb) and extraerythrocytic hemoglobin (EEHb) resulting from infusions of WXb8326 was studied in arterial and venous blood at different levels of hemodilution. WXb8326 did not interfere with the arterial oxygen saturation of EHb in the pulmonary vascular bed and EEHb was oxygenated as efficiently as EHb. Oxygen delivery to tissues differed between EHb and EEHb. Erythrocytic hemoglobin met oxygen demands under basal conditions while EEHb contributed oxygen to tissues during conditions of high oxygen extraction. It is concluded that WXb8326 is an attractive condidate as a plasma volume expander with the capacity to transport oxygen to tissues.


Emulsions of perfluorinated solvents for intravascular gas transport. During the past several years we have progressed from the use of perfluorinated substances, which were good gas solvents but often produced unexpected physiological reactions, to a point where emulsions of pure perfluorinated substances can be made in a reproducible way. A standardized method of making emulsions has now been developed. The physical properties of the perfluorinated substances needed to make useful emulsions have been defined. Specifically, perfluorinated substances having vapor pressures above about 40 torr must be avoided as they produce pulmonary gas embolism; also lower boiling components having vapor pressures above about 40 torr must be excluded. The relationship between chemical structure and several physiological and pharmacological effects has been delineated. Perfluorinated substances containing only carbon and fluorine, or those containing carbon, fluorine, and either bromine or iodine have reasonably short dwell times in the liver. Perfluorinated iodo- and bromo-compounds dissolve oxygen and are radiopaque. Present iodo-perfluorinates are unstable in the presence of light. Perfluorodecalin can enter and leave the liver without changing the liver's ultrastructure. Both egg phospholipid and Pluronic F68 are useful in making perfluorodecalin emulsions. Perfluorodimethyladamantane makes a fine-particle stable emulsion. There is a bright future for perfluorinated substances in a number of areas of research in biology and medicine.


Preparation of perfluorodecalin emulsion, an approach to the red cells substitute. The major problems unsolved in fluorocarbon emulsions have been the long lasting retention of the substance in tissues of organs and acute shock symptom in animals receiving "coarse" emulsion with particles larger then 0.2 mum. This report offers a new, stable and sterile preparation of 25% "fine" perfluorodecalin emulsion with yolk phospholipid that is eliminated from liver, spleen and other organs within a few weeks, and whose acute and subacute toxicity is as low as perfluorotributylamine/Pluronic F68 emulsion. Effects of the perfluorodecalin emulsion thus prepared for maintaining contractile force of isolated guinea pig heart by perfusion and survival of animals receiving repeated circulatory exchange proved similar to perfluorotributylamine/Pluronic F68 emulsion.


Studies on isolated rat liver perfused by perfluoro-compound emulsion. Isolated rat livers were perfused for 6 hours by different types of cell-free synthetic media. Some of the media included perfluoro-compounds as an oxygen carrier. The value of the perfusion medium as blood substitute was judged on the basis of observations and measurements of a number of parameters. These were: secretion of bile, fluid pressure in the portal vein, the level of GPT (ALAT) transaminase, urea nitrogen, and glucose in the perfusate. The rate of albumin synthesis and the rate of 14-C-lysine incorporated into circulating proteins were also measured. It was found that perfusion of the isolated rat liver with the TC-199 Difco medium containing the perfluoro-compound FC-80 emulsion maintained the liver in a good condition demonstrated, among other things, by the synthesis of albumin and other proteins. The liver could be kept in a good functional condition during 6 hours perfusion with this cell-free medium. With all the other types of perfusate tested the liver did not synthesize proteins. The isolated rat liver seems to be both convenient and advantageous for testing the perfusion media with respect to their capacity to maintain important metabolic functions.