Preventive health program for nickel workers. The possible hazards of exposure to certain nickel compounds during nickel refining have been recognized for over 40 years. Much progress has been made in worker protection by cleaning up the process and by other protective means, and improved personal hygiene. The problem in the past has been determining those employees who are most exposed. This has been accomplished in this project by regular plasma and urine nickel determinations, demonstrating that nickel process workers absorb nickel which can be measured in plasma and urine. It was found that the highest plasma and urine nickel levels were seen in workers in those departments in which the greatest incidence of respiratory cancer occurs. Whether persistently elevated plasma nickel can be correlated with the eventual development of respiratory tract cancer is the subject for continued years of follow-up. It is not possible to conclude at this time that there is any association between the raised plasma and urine nickel and the incidence of cancer.


Toxicology of petroleum naphtha distillate vapors. A unique opportunity was presented to observe the potentially toxic effects of an acute exposure to the vapors of petroleum naphtha distillate on a relatively large number of individuals. The immediate manifestation in all was dyspnea. The action on motor vehicle combustion suggested that some of this could have been due to oxygen deprivation; however, all individuals were dyspneic for several minutes after exposure. A few were cyanotic for several minutes after exposure. All were excited. Tremulousness and mild nausea followed the initial symptoms but were of brief duration. One individual manifested numerous premature ventricular contractions. Since his exposure was brief and since none of the others showed similar findings, it is unlikely that the exposure was causal. The central nervous system depression described in acute exposure cases of the intact (not distillate) petroleum naphtha fumes was not observed in any of this series. There were no delayed manifestations or complications.


Relative importance of growth hormone and sex steroids for the growth at puberty of trunk length, limb length, and muscle width in growth hormone-deficient children. We have followed the growth of stature, sitting height, skinfolds, muscle widths measured radiologically, and skeletal maturity in growth hormone-deficient patients in whom hGH was given and withheld in alternating three-month periods throughout puberty (referred to as "off-hGH" and "on-hGH" periods). Six boys and four girls had true isolated GH deficiency and developed puberty spontaneously. Two boys had gonadotrophin deficiency plus GH deficiency, and five boys had multiple deficiencies; in these boys the signs of puberty were induced by hormone treatment. Boys with true isolated deficiency grew about two-thirds as much in height in the off-hGH periods as in the on-hGH periods; their total gain in height during the adolescent spurt would have been about 20 cm, instead of 30 cm, if hGH had been discontinued at the beginning of puberty. The effect of hGH was entirely on growth in leg-length, however, which virtually ceased during the off-hGH periods. Growth in sitting height altered little when hGH was withdrawn. Growth in limb muscles, however, was GH dependent throughout puberty; during the majority of periods when hGH was withheld, muscle was actually lost; this occurred in the boys who were receiving large doses of testosterone as well as in those producing their own normal amounts. Subcutaneous fat diminished when hGH was given and increased when it was withdrawn; this occurred independently of administration of testosterone. There was little evidence that growth of pubic and axillary hair progressed faster during on-hGH periods, except perhaps in patients with multiple deficiencies. There was some evidence, however, that bone age progressed less rapidly during on-hGH periods than during off-hGH periods in the patients with isolated deficiency. The results in the girls agreed with those in boys so far as stature was concerned, but the relationship with sitting height and leg length appeared to be different; the reasons for this are discussed. We conclude that all children with GH deficiency should continue on treatment with hGH throughout puberty, ideally until growth ceases.


Successful treatment of Candida meningitis with amphotericin B and 5-fluorocytosine in combination. The combined use of amphotericin B and 5-fluorocytosine in the treatment of two children with Candida albicans meningitis is described. Therapy consisted of nine to 13 days of iv amphotericin B, combined with, or followed by six to nine weeks of oral 5-FC. Each organism was sensitive to 5-FC before starting therapy. Resistance did not develop during therapy. CSF administration was not necessary and toxic reactions were minimal and transient; neither patient has suffered a recurrence four years and 14 months, respectively, after discontinuance of therapy. The combination of short-term therapy with iv amphotericin B plus long-term oral 5-FC was successful in these two patients.


Recurrent hypernatremia; a proposed mechanism in a patient with absence of thirst and abnormal excretion of water. A 7-year-old girl twice developed severe hypernatremia (serum sodium values up to 194 mEq/l) without obvious cause. The ability of her kidneys to conserve water was normal, and increasing her plasma osmolality stimulated an appropriate ADH response. Unable to excrete a water load, her kidneys continued to conserve water even with a serum sodium concentration of 133 mEq/l. She was never thirsty and did not ingest sufficient fluid by choice. Although there was no demonstrable anatomic lesion, we postulate a localized defect of her thirst center. This may have modified release of ADH and resulted in an inability to dilute the urine by interrupting a pathway that could exist from the thirst center to the supraoptic nuclei. A therapeutic regimen based on these studies has prevented further hypernatremia.


Increased lead absorption with anemia and slowed nerve conduction in children near a lead smelter. Studies to evaluate the prevalence, sources, and health consequences of lead absorption were conducted among children living near a primary lead smelter. Lead levels in air, soil, and dust were highest at the smelter and decreased with distance. Ninety-nine percent of one- to nine-year-old children living within 1.6 kilometers had blood lead levels greater than or equal 40 mug/dl, indicating increased absorption, and 22% had levels greater than or equal 80 mug/dl. The prevalence of lead levels greater than or equal 40 mug/dl decreased with distance; at 72 kilometers from the smelter it was 1%. Erythrocyte protoporphyrin levels increased with blood lead levels: 17% of children with lead levels of greater than or equal 80 mug/dl were anemic. There was no overt neurologic toxicity. Significant negative correlation was found in 202 five- to nine-year-old children between blood lead levels and motor nerve conduction velocity (r = 0.38, p less than 0.02).


Chondrodysplasia punctata-23 cases of a mild and relatively common variety. A common form of chondrodysplasia punctata has been defined by characteristic clinical and radiologic features in 23 patients seen in Melbourne. The patients presented during infancy because of failure to thrive, apparent mental retardation, and/or unusual appearance. The typical facies is almost diagnostic, and the diagnosis is completed by finding punctate calcification in the calcaneum in lateral radiographs of the feet, and sometimes in other sites. Growth and developmental progress improved during childhood and the final outcome seems likely to comprise low normal height and intelligence with persistence of typical facies. Mild cases probably pass unrecognized at present. Seventeen patients were male. Paternal age was significantly increased; however, family data did not support a genetic cause. Illnesses during pregnancy were unusually frequent, and anticonvulsants taken during pregnancy may have had an etiologic role in some patients.


Macrodactyly, hemihypertrophy, and connective tissue nevi: report of a new syndrome and review of the literature. Macrodactyly and hemihypertrophy have been described in association with a number of syndromes which are reviewed. We describe a child who, in addition to macrodactyly and hemihypertrophy, has extensive connective tissue nevi. He does not conform to any known entity and would appear to represent a "new" syndrome.


Choledochal cyst: a review of 19 cases.

Choledochal cyst: a review of 19 cases. Nineteen cases of choledochal cyst are reviewed. Two distinct groups of patients were identified. Patients under one year of age, initially diagnosed as having biliary atresia, had a higher mortality rate, a higher incidence of severe cirrhosis with portal hypertension, and associated atresia or stenosis in the biliary tree. The second group, presenting between 3 and 20 years of age with more classic symptoms, had mild cirrhosis without portal hypertension and had associated choledocholithiasis and pancreatitis. It is suggested that the younger patients had a congenital form of cystic bile duct dilatation and that the older patients had an acquired form, perhaps related to a common channel with reflux of pancreatic juice into the common bile duct. Postoperative follow-up supports the current view that choledochocyst-jejunostomy with choleystectomy has a lower rate of long-term complications than does choledochocyst-duodenostomy.


The effects of large volume intravenous fluid infusion on neonatal renal function. Twenty healthy infants weighing less than 2,000 gm were studied at low (3.6 ml/kg/hr) or high (10.3 ml/kg/hr) rates of intravenous infusion. Inulin clearance determined by the constant infusion method was greater at the high rate of infusion (p = less than 0.05). Inulin clearance in two groups of infants over 2,000 gm studies at the same low or high rates of infusion did not increase at the higher rate of infusion. Since the GFR in infants less than 2,000 gm depends partially on the rate of intravenous infusion, small, healthy preterm infants may benefit from a rate of fluid administration greater than the low rate. When studies at low and high rates of infusion were compared in the 20 infants less than 2,000 gm, the fractional urinary sodium excretion increased with the increased fluid load. Delivery of fluid from the proximal tubule (CH2O =Na per dl GFR) increased (p less than 0.005). Free-water clearance and the absolute volume of urine increased at the high rate of infusion. These data indicate that the healthy preterm infant less than 2,000 gm, like the adult, compensates by increasing free-water clearance and urine volume when challenged with a large fluid load. Although fluid changes of short duration are appropriately handled, the effect of continuous rapid infusion on water and sodium balance in infants of this size remains to be determined.


Oral calcium supplementation in premature and asphyxiated meonates. Biochemical and hormonal effects of oral calcium supplementation in premature and asphyxiated neonates during the first few days of life are described. Eight pairs of infants were matched for gestational age and one-minute Apgar score. One member of each pair served as a control and the other was given supplemental oral calcium (75 mg/kg/24 hr) beginning at 12 and ending at 72 hours of age. The supplemental infants had significantly higher serum calcium values both during the time of supplementation and for 36 hours after supplementation was stopped. The oral calcium supplements had no significant effect on serum concentrations of phosphate, magnesium, 25-hydroxy-vitamin D3, or parathyroid hormone, The incidence of hypocalcemia after 12 hours of age was 0 in eight supplemented infants and three in eight control infants. In patients at risk for hypocalcemia, prospective use of oral calcium supplements during the period when there is inadequate calcium intake from feedings may prevent hypocalcemia, appears to be without deleterious effect on measurable chemical and hormonal factors important in calcium homeostasis, and results in maintenance of higher serum calcium levels after supplementation has been discontinued.


Neonatal renal arterial embolism syndrome. Attention is called to a poorly recognized syndrome of neonatal renal arterial embolism, presumably from the ductus arteriosum, resulting in malignant hypertension, congestive heart failure, respiratory distress, and increased renin secretion. Radiographic studies revealed a ductus diverticulum and multiple narrowed arteries including the lower pole branches of the right renal artery. Renal scan showed poor imaging of the lower pole of the right kidney. Nephrectomy resulted in a prompt return of the blood pressure into the normal range. Eight cases recorded in the literature resemble the one reported here, and six of the eight had an associated thrombosis of the ductus arteriosum. Our patient appears to be the first case recognized by modern techniques followed by nephrectomy and clinical cure.


Interrelation of the therapeutic effects of growth hormone and testosterone on growth in hypopituitarism. The present study evaluates the modifying effect of growth hormone on the growth-promoting action of testosterone in boys at pubertal bone age. Growth and bone maturation were analyzed in 42 boys with primary or secondary Leydig cell insufficiency who had been treated with testosterone in an attempt to induce puberty and the accompanying growth spurt. The dosage given was considered normal or high for physiologic replacement therapy at puberty. Sixteen boys had normal GH secretion (seven had isolated gonadotropin deficiency, nine had congenital anorchia); 26 were GH and Gn deficient (20 idiopathic, six craniopharyngiomas). Of the GH-deficient patients, 12 received hGH simultaneously, while 14 received only testosterone. Results from each group were compared with the normal pubertal growth spurt in 15 untreated healthy boys. In isolated Gn deficiency and in congenital anorchia, the growth rates increased to above normal during the first six months of treatment, indicating that the testosterone dosage was probably too high for the beginning of puberty. During two subsequent six-month treatment periods, the rates leveled off close to normal. The same was true in the GH- and Gn-deficient patients on adequate hGH replacement. For contrast, there was minimal or no stimulation of growth when an even higher testosterone dose was given to GH- and Gn-deficient boys without hGH therapy. Bone maturation was normal in the boys with normal GH secretion or with hGH replacement, but was subnormal in the GH-deficient boys not treated with hGH. We conclude that testosterone exerts its full growth-promoting action only in the presence of normal endogenous GH secretion or with sufficient hGH replacement and that both hormones should be continued simultaneously until final adult height is achieved.


Clinical management of malignant hyperpyrexia. Experience with eight cases of malignant hyperpyrexia are presented. The different types are described and illustrated by clinical cases. Early recognition of this condition is the cornerstone in the successful management of the complication. Early diagnosis and methods of treatment are described.


Lessening of adverse biochemical effects of shock in newborn puppies by general anesthesia. A shock preparation has been developed which produces the expected anaerobic metabolism in neonatal beagle puppies less than 7 days old. Lactic acid production was found to be significantly higher in shocked puppies operated upon under local anesthesia than when the same procedures were performed in shocked puppies under general endotracheal anesthesia. These findings suggest that general anesthesia may be safer in the very sick human neonate.


Colloid versus crystalloid resuscitation in experimental bowel obstruction. The physiologic effects of fluid resuscitation were studied in 20 piglets with advanced small bowel obstruction. Two solutions were compared: 5% albumin in normal saline and normal saline. Animals resuscitated with albumin-containing solution showed higher serum colloid oncotic pressure, greater loss of peritoneal fluid, lower urine output, and progression of muscular dehydration, when compared to animals resuscitated with similar volumes of normal saline solution.


Pulmonary fine structural changes in children with tissue hypoxia. Six children have undergone lung biopsy for evaluation of fine structure. Four children demonstrated increased DAVO2 preoperatively and had marked ultrastructural changes in their lungs. Such changes appear to result from embolization of microthrombi or microaggregates to the lung from under-oxygenated tissue.


Thoracoscopy for diagnosis of intrathoracic lesions in children. Disenchantment with available techniques for specific diagnosis of intrathoracic pulmonary lesions in children has led us to explore the usefulness of thoracoscopy. We have performed this technique in nine patients ranging in age from 17 mo to 16 yr. The procedure is performed under intravenous anesthesia with the patient spontaneously breathing oxygen. A fiberoptic rod lens system is employed for the direct observation and biopsy of pulmonary parenchymal or chest wall lesions. Adequate tissue has been obtained in each case to allow a specific diagnosis. There has been no mortality from this procedure and only minor morbidity. We believe that this technique offers a rapid and simple method for the diagnosis of diffuse or localized disease of pulmonary parenchyma or chest wall in children.


Circular esophagomyotomy of upper pouch in primary repair of long-segment esophageal atresia. A method of performing circular esophagomyotomy of the upper pouch is described as an effective technique for use in repair of esophageal atresia where the ends cannot be brought together.


Life-threatening anoxic spells caused by tracheal compression after repair of esophageal atresia: correction by surgery. Three infants who developed anoxic spells 2, 5, and 20 mo following repair of esophageal atresia developed apneic spells during or within a few minutes of feeding. These episodes began with stridor and cyanosis; when severe, they progressed to apnea and loss of consciousness. Mouth-to-mouth resuscitation was often necessary. Investigations failed to detect esophageal obstruction and/or a recurrent tracheoesophageal fistula. No neurologic or cardiac abnormalities were found. The cause was compression of a 1- to 3-cm segment of trachea anteriorly by a vascular structure and posteriorly by a dilated esophagus that emptied slowly because of poor motility. Endoscopy confirmed the x-ray findings. The aortic arch and innominate artery were suspended to the sternum anteriorly, which relieved the apneic spells in all patients.


Gastroesophageal fundoplication for reflux in infants and children. Fifteen infants and young children with symptomatic gastroesophageal reflux underwent fundoplication during a 6 1/2-yr period. Standard barium esophagrams clearly demonstrated reflux in only 10 of the 15 patients; however, cine esophagrams indicated reflux in the remaining patients. Esophagoscopy with mucosal biopsy demonstrated esophagitis in 9 of the 10 patients in whom it was performed, and it is a very helpful diagnostic procedure. Esophageal manometry showed low sphincter pressures in each of 7 patients. Fundoplication was performed when there was (1) persistent reflux after a 3-wk hospital course of vigorous medical management, (2) failure to gain weight, (3) malnutrition, (4) recurrent aspiration, (5) esophagitis, or (6) stricture. Concomitant gastrostomy prevented the gas bloat syndrome in all patients. All strictures were successfully relieved by postoperative dilatation (average four per patient). Esophageal replacement is rarely indicated for strictures due to reflux in children. No deaths or major complications occurred following operation. Each of the patients has been relieved of clinical reflux, and each has gained weight more rapidly than preoperatively. Follow-up esophagrams on each of the patients show absence of reflux, and manometry shows the low esophageal sphincter pressure to be increased an average of 10 mm Hg above preoperative values. Since the results of Nissen fundoplication to correct reflux in infants and young children are highly satisfactory, and since the consequences of persistent reflux may be severe, a fairly aggressive approach should be taken in the management of symptomatic reflux.


An analysis of the need for pediatric surgeons in the United States. A questionnaire study covering all major population areas in the United States indicated that pediatric surgeons and potentially capable hospitals are already well-distributed throughout the country. The estimation of need for pediatric surgeons based on the area questionnaires is close to the present number of surgeons. A computer analysis was made to project numbers of pediatric surgeons per unit population to the year 2000 with differing levels of trainee output. The study indicates that 14-15 training programs are sufficient to allow for slow, modest growth of the specialty if current population trends continue.


Continent ileostomy in the pediatric patient. Continent ileostomies have been performed in 10 juvenile patients. The operative technique and postoperative management are described. Nine patients wear only small dressings to cover the stoma. One patient is partially incontinent and frequently wears an appliance. Criteria for patient selection and contraindications are discussed.


Familial juvenile adenomatous polyposis. Most colonic polyps in children are of the juvenile type and occur either as single or scattered colonic polyps. The peak incidence occurs between 4 and 6 yr of age, with a spontaneous decline from 12 to 15 yr. Significant clinical symptoms are rare, and operative therapy is rarely indicated. Diffuse colonic juvenile polyposis, however, varies with different clinical, prognostic, and genetic implications. In infancy, colonic polyposis may be associated with diffuse gastrointestinal involvement leading to fatal complications unless treated aggressively. In childhood, colonic polyposis can occur with a genetic variance with an increased incidence of familial intestinal malignancies. Colonic polyposis in childhood, both familial and nonfamilial, can present with a mixed form of juvenile and adenomatous polyposis. In children with colonic polyposis, the biopsy of a single polyp that reveals the histologic appearance of a juvenile polyp does not rule out the simultaneous existence of adenomatous polyps.


Oral cholestyramine and paregoric therapy for intractable diarrhea following surgical correction of catastrophic disease of the GI tract in neonates. Ten surgical neonates with postoperative intractable diarrhea and secondary weight loss were treated with combination cholestyramine and paregoric therapy. Within 3-5 days all infants except two showed significant clinical improvement with a decreasing number of stools, an increase in the consistency of the stool, and gradual weight gain. The exact mechanism of action of cholestyramine is not clear. It may act by binding with bile salts and/or endotoxins in the bowel lumen or decreasing the motility of the bowel. Used in combination with paregoric, a known bowel motility depressant, the doses of each medication can be kept quite low thus avoiding undesirable side effects. Medium chain triglyceride formula is helpful in some of these infants to improve fat absorption further. Medication in all of these infants has been discontinued without any adverse effects.


Experience with 55 Silon pouches.

Experience with 55 Silon pouches. The application of a Silon pouch usually indicates a desperate if not impossible situation in which the abdominal contents cannot be returned to the abdominal cavity and therefore require some type of covering. Since 1968, we have had experience with 55 Silon pouches in infants and children. Almost all of these pouches were applied to newborns. There were 22 deaths in this series (40%), although 12 of these deaths were in the diaphragmatic hernia group and were almost all due to respiratory failure unrelated to the pouch itself. There were nine deaths in the gastroschisis and omphalocele group (28%) and in all these instances infection (especially Candida) was the underlying cause. While much debate exists as to how the Silon pouch should be handled after its application our series demonstrated that the longer it stayed in place the greater the chance of infection. Furthermore if broad spectrum antibiotics were used for a prolonged period of time, Candida overgrowth of the pouch followed by Candida sepsis and death were almost inevitable.


Hemangioendothelioma of the pancreas obstructing the common bile duct and duodenum. A 6-mo-old male with a hemangioendothelioma of the pancreas obstructing the common bile duct and duodenum required temporary bypass of these structures while awaiting involution of the tumor treated primarily by corticosteroids and radiation therapy.


Total thyroidectomy for occult familial medullary carcinoma of the thyroid in children. Experience with 17 children in one kindred with familial medullary carcinoma of the thyroid and pheochromocytoma has demonstrated the utility and validity of periodic provocative testing by calcium infusion or pentagastrin injection in the identification of children with early medullary carcinoma of the thyroid or its premalignant precursor, C-cell hyperplasia. In these 17 patients with two consecutive elevations of calcitonin levels greater than 0.55 ng/ml after stimulation all but one have had MTC or CCH at operation. Total thyroidectomy has been well tolerated and can be performed with an acceptably low incidence of complications in this group of patients.


Management of immature teratoma of the ovary in children by conservative resection and chemotherapy. Six patients with immature teratoma of the ovary were treated with surgery and chemotherapy. Surgical management consisted of unilateral salpingo-oophorectomy, biopsy and conservation of the contralateral ovary, and biopsy of peritoneal implants. Triple-agent chemotherapy with vincristine, actinomycin D, and cyclophosphamide was given to four patients and appeared to be beneficial. Radiation therapy was not employed. Local resection of teratomatous recurrences was frequently necessary. Thorough sampling of this tumor is mandatory for establishment of an exact pathologic diagnosis. All six patients are surviving in good health at 1-8-yr follow-up. The prognosis of immature teratoma in the child or adolescent appears more favorable than previously appreciated.


Lymphoid depletion in ileal loops: mechanism and clinical implications. Recent long-term follow-up studies of children undergoing ileal loop urinary diversion have shown a number of complications arising in these patients: recurrent urinary tract infections, deteriorating renal function, and late midloop stricture. We suggest that all three may be related to the same underlying problem, namely, a severe depletion of lymphoid elements in the intestine. In both clinical and animal studies urine exposure to intestinal segments resulted in a marked depletion of lymphoid elements from the Peyer's patches and from beneath the intestinal villi in the intestine. In addition there was an associated hypertrophy of the lymph nodes in the ileal loop mesentery. When the intestine was no longer exposed to urine, there was a prompt regeneration and reappearance of the lymphoid elements. The lymphocytes seemed to "home in" on the submucosal areas and reform Peyer's patches once the urine was removed. The hyperplastic lymph nodes in the ileal loop mesentery regressed when urine exposure was removed. Conventional treatment of ileal loop infections focuses on the upper urinary tracts. Mid-loop stenoses are treated by resection and creation of a new ileal loop conduit. Local therapy in the form of antibiotics and/or steroid enemas may relieve some late midloop obstruction and prevent further damage to renal parenchyma.


[Computer models of personality: implications for measurement]. Computer models of human behavior have long existed in the world of science fiction; however, in reality, progress has been slow. Research has concentrated, in recent years, on the simulation of memory and cognition. Computer models of personality, although fascinating and potentially useful, have been neglected. This paper reviewed the research done to date, categorizing it under five headings: (a) models of belief systems; (b) models of interpersonal behavior; (c) models of decision-making processes; (d) prediction models; and (e) theory-based simulations of specific processes. One practical application was then explored in depth, that of using the computer models in personality measurement. Although some practical development of the working simulations would have to precede their application to personality measurement, it was felt that such an application would be feasible and useful.


Judging personality assessments: putting the Barnum report in perspective. The ability of expert and naive judges to discriminate between genuine and Barnum assessment statements was assessed. In a 2 X 2 X 2 design (naive vs. expert judges, genuine vs. Barnum test statements, sex), judges rated assessment statements for their information value, usefulness, social desirability, and typicalness. Results indicated that judges were able to make expected discriminations between genuine and Barnum statements. These results were discussed in terms of previous findings which have suggested that judges have seen Barnum statements as "accurate" or "good" as genuine statements. In the present study, the discriminations seemed due to the use of a population of judges more representative of clinical assessment consumers and to the more specific judgments required.


The confusing area of disturbed thinking. The nature of disturbed thinking is explained from two different psychological perspectives and six major types of thought disorder are presented, classified, and discussed. The overlap between these different types of thought disturbance and some possible functions of disturbed thinking are outlined. A heuristic model for detecting thought disorder is presented; and, in addition, some complex conceptual and research issues involved with investigating and systematizing knowledge about disturbed thinking are explained.


Activating posthypnotic conflict: emergent uncovering psychopathology repression, and psychopathology. An attempt was made to observe the process of repression and symptom formation. Emergent uncovering techniques were used to weaken a spontaneous repression that was produced by the posthypnotic activation of sexual impulses stemming from an implanted oedipa paramnesia. Twelve hypnotic and ten simulating subjects were used in a modified real-simulator design. Although it was not possible to 'lift' the spontaneous repression of derivatives of oedipal strivings in the course of uncovering via visual imagery, a wide variety of spontaneous symptoms were produced in the hypnotically conditioned subjects. The type of symptom was shown to be related to the degree of repression. Simulating subjects produced only a few symptoms. The manifestation of a symptom was concomitant with an increase in the GSR, but not the blatancy of drive representation. These findings were consistent with the phenomena observed using free imagery in emergent uncovering psychotherapy.


Frequency and intensity of anxiety in university students. One thousand and ninety-seven university students (455 males; 642 females) named, "...three situations that make you anxious..." and rated the intensity of the anxiety in each situation. Correlations between frequency of occurrence and rated intensity for situations named more than once were negligible for both sexes. While the intensity rating of 62 situations occurring common between sexes was significantly greater for females, there was no difference in frequency of occurrence; however, both the correlations between male and female frequency and male and female intensity were positive and significant for the shared items, indicating that their experiences of these anxiety situations vary in similar ways. Analysis was also completed for three types of situations: interpersonal--ego threat, physical threat, and ambiguous.


Conservatism as a determinant of sexual experiences. An examination of the relationship of conservatism to reports of sexual experiences and reasons for nonparticipation was conducted using 64 male and 50 female introductory psychology students. Conservatism was found to be inversely related to the frequency and variety of sexual behaviors. High conservative subjects gave the reason that it was morally wrong more often than any other reason for not engaging in coital activities and more intimate forms of petting. Results were in accord with previous research and were interpreted as supporting the notion that the fear of loss of control of one's impulses and hence the basis for conservative attitudes are determinants of sexual experiences.


Qualitative difference in the experience of state-trait anxiety in emotionally disturbed and normal children. In order to investigate the state-trait anxiety distinction in emotionally disturbed and normal children, the responses of 120 emotionally disturbed children and 126 normal children to the State-Trait Anxiety Inventory for Children (Spielberger, 1973) were factor analyzed separately. For the emotionally disturbed group two A-State and two A-Trait factors were found with the A-State factors accounting for significantly more of the variance than did A-Trait factors. For the normal group four A-State and two A-Trait factors were found, but there was not a significant difference between the amount of variance accounted for by A-State and A-Trait factors. Results were discussed as supporting the state-trait distinction and as having several implications for future research on anxiety.


Illusory correlation and the MMPI.

Illusory correlation and the MMPI. The relationships between 10 behavioral descriptions and 10 Minnesota Multiphasic Personality Inventory (MMPI) scale names were judged by 28 naive and 26 experienced student subjects. Both groups of judges produced large amounts of illusory correlation, with the experienced judges producing more. Estimates of strength of semantic association between the behavioral descriptions and scale names provided by 45 naive and 18 experienced male and female subjects tended to support the notion that semantic association is an important factor in producing illusory correlations, but there were some interesting exceptions to this tendency. The testing model was discussed as an analogue to the clinical situation.


Demand characteristic effects on the subtle and obvious subscales of the MMPI. The MMPI was administered to 40 undergraduate students with 20 subjects asked to imagine that they were applying for a job and 20 subjects asked to imagine that they were applying for psychotherapy. Subjects in the job group dissimulated (faked good) and those in the therapy group malingered (faked bad) as evidenced by differences between the subtle and obvious scores. The combined subtle and obvious score was higher for the psychotherapy group. It was concluded that the subtle, obvious, and combined subtle and obvious scores on the MMPI were a function of the demand characteristics of the testing situation.


Autonomic responses to modeled distress in prison psychopaths. The present experiment was designed to study the physiological basis of the proposition that psychopaths are indifferent to the feelings of others. Young male subjects from a prison population were divided into groups according to their Minnesota Multiphasic Personality Inventory (MMPI) Pd score and then subdivided on the basis of MMPI Welsh Anxiety Scale (WAS) scores. Subjects in each group observed a model exhibiting either mild or severe distress to electric shock. Heart rate and skin conductance were measured over 15 trials in each subject. We hypothesized that the different clinical groups would exhibit different physiological emotional response patterns. The results showed that low-Pd subjects were more autonomically responsive to an emotional stimulus (modeled distress) than high-Pd subjects from the same prison population. Moreover, high-WAS subjects were more responsive than low-WAS subjects. The level of distress exhibited by the model had no effect.


Differential social perception and attribution of intergroup violence: testing the lower limits of sterotyping of blacks. In a modified 4 X 4 factorial design with race (black-white) of the harm-doer and race (black-white) of the victim as the major factors, the phenomenon of differential social perception of intergroup violence was established. While subjects, observing a videotape of purported ongoing ineraction occuring in another room, labeled an act (ambiguous shove) as more violent when it was performed by a black than when the same act was perpetrated by a white. That is, the concept of violence was more accessible when viewing a black than when viewing a white committing the same act. Causal attributions were also found to be divergent. Situation attributions were preferred when the harm-doer was white, and person (dispositional) attributions were preferred in the black-protagonist conditions. The results are discussed in terms of perceptual threshold, sterotypy, and attributional biases.


Compensatory aspects of dreams: an empirical test of Jung's theory. Jung's hypothesis that dreams have a compensatory function is clearly stated and well-known, yet has not been empirically tested. Three dream reports for each of 62 students were rated on 15 personality dimensions and compared with scores on the same dimensions as measured by the Edwards Personality Preference Schedule and the Adjective Check List (ACL). Six EPPS scales and 10 ACL scales correlated significantly with their appropriate dream rating scales. However, all significant correlations were positive, a finding that does not supoort Jung but is more in line with the theories of Adler, Fromm, and Hall, who regarded dream content as not substantially different from conscious functioning.


The power of suggestion: another examination of misattribution and insomnia. This experiment was conducted in an attempt to replicate and delimit the reverse placebo effect found by Storms and Nisbett in insomniacs. It was predicted that the reverse placebo effect would obtain when the pills' effects were described as affecting arousal (as in Storms and Nisbett's study) but that a direct suggestion effect would result when the pills were described as directly affecting sleep onset latency. Results indicated that direct suggestion effects obtained regardless of the focus of the instructions. The present study together with the findings of Kellogg and Baron call into question the reliability and clinical significance of the reverse placebo effect in the treatment of insomnia.


Relationship of preoperative fear, type of coping, and information recevied about surgery to recovery from surgery. This study investigated the relationship of preoperative level of fear, extent of information seeking (coping), and amount of information received about surgery to recovery from surgery. It was hypothesized that a curvilinear relationship would be found between level of preoperative fear and recovery and between extent of information seeking and recovery; it was also hypothesized that amount of preoperative information obtained would interact with extent of information seeking. The subjects were 57 female patients between the ages of 18 and 68 who were schedule for abdominal surgery. The recovery measures consisted of a self-rating of postoperative negative affect (fear, depression, and anger), number of postoperative analgesics and sedatives received, and total number of days to discharge. No curvilinear relationships were found between preoperative level of fear or type of coping and recovery from surgery. Results showed a linear relationship between level of preoperative fear and recovery, with the least favorable recovery associated with high levels of preoperative fear. A significant interaction was found between level of preoperative fear and amount of preoperative information, with high-fear subjects who reported little preoperative information experiencing the least favorable recovery period. The findings are discussed in terms of the parallel response model proposed by Leventhal.


Sex typing and androgyny: further explorations of the expressive domain. Previous research by Bem has indicated that androgynous individuals of both sexes display "masculine" independence when under pressure to conform as well as "feminine" nurturance when interacting with a kitten. In contrast, sex-typed individuals were low in one or both of these behaviors. The two studies reported here were designed to replicate the low nurturance of the masculine male and to clarify the unexpected finding that feminine females were low in both independence and nurturance. In the first study subjects interacted with a human infant, and in the second study they listened to a lonely student. Taken together, the results of these two studies conceptually replicated the low nurturance of the masculine male and demonstrated that the low nurturance of the feminine female does not extend to her interaction with humans. Finally, evidence was presented in support of Spence, Helmreich, and Stapp's distinction between "androgynous" individuals, who are high in both masculinity and feminity, and "undifferentiated" individuals, who are low in both of these characteristics.


Effects of noise and perceived control on ongoing and subsequent aggressive behavior. Two experiments examined the effects of high-intensity (95 dB [A]) noise on ongoing and postnoise aggressive behavior. In Experiment 1, subjects were angered or treated in a neutral manner and given an opportunity to aggress against another subject while being exposed to high-intensity (95 dB) or low-intensity (55 dB) noise. Results indicated that high-intensity noise facilitated aggression for previously angered individuals. Experiment 2 examined postnoise aggression in which subjects completed a math task under high-intensity noise with or without perceived control over the noise. In comparison to a no-noise control, it was found that angered subjects with no control revealed an increase in aggression, whereas perceived-control subjects were no different from no-noise subjects. Results are discussed in terms of the recent Glass and Singer work on noise and task performance and the effects of perceived control on mediating the effects of stressful conditions.


Frequency perception of individual and group successes as a function of competition, coaction, and isolation. The frequency perception of successful and unsuccessful outcomes obtained in serial tasks was investigated in two experiments. Subjects were assigned to serial tasks in which the outcome stimuli ("right" and "wrong") immediately followed subjects' responses to each task item. Subjects' perceptual judgment about the number of "rights and wrongs" obtained was requested at the end of the serial task (incidental event perception). In Experiment 1, subjects performing in groups of four were compared with individual performers both in competing and noncompeting (coacting) conditions. In Experiment 2, the influence of verbal communication and competition versus isolation was examined. Significant and predicted differences in frequeency perception were found (a) in group performers as compared with individual performers, (b) in groups with verbal communication as compared with groups without verbal communication, and (c) in competing groups as compared with noncompeting, especially isolated, groups. The frequency perception of success is discussed in the context of impression formation processes, and its impact on person perception and learning is mentioned. A tentative explanation in terms of affective and cognitive processes related to social interaction is submitted.


Operant autonomic conditioning and rod-and-frame test performance. Forty subjects were administered the portable rod-and-frame test (RFT) before and after operant autonomic conditioning training or control experiences. Ten subjects were assigned to each of four groups: a heart rate conditioning group; a false heart rate feedback group; a galvanic skin-response conditioning group; and a control group. Half of the subjects in the three experimental groups were informed of the response-reinforcement contingencies, and half were not informed. Informed subjects in the conditioning groups exhibited significantly lower portable RFT scores after conditioning. The results suggest that awareness of and control over autonomic functioning may be an important determinant of RFT performance.


Evaluation of the cognitive component of political issues by use of classical conditioning. The direct use of verbal and physiological response measures to assess the cognitive component of a sociopolitical attitude is made difficult by the multiple meanings of sociopolitical stimuli. In the present study a modified differential classical conditioning procedure was used to produce an unambiguous physiological (skin conductance) response to stimuli related to a discrete social concept (black relatedness and not black relatedness). It was demonstrated that conditioned stimuli clearly related to this specific concept produced a conditioned response. The results also showed that a series of more ambiguous test stimuli related to the 1972-1974 election campaigns produced a gradient of skin conductance responses that was related to the degree of black relatedness or not black relatedness of each stimulus as measured by other means. The implications of the results of this study to further research and other indicators of the cognitive component of attitude are discussed.


Altruism as hedonism: a social development perspective on the relationship of negative mood state and helping. A study was conducted to provide a means for reconciliation of the conflicting data on the relationship of negative mood state to altruism. Whereas some studies have shown that negative mood leads to increases in altruistic action, others have shown the reverse. It was hypothesized that the inconsistency of these results was due to differences in the ages and consequent levels of socialization of the subjects employed in the earlier studies. In order to test the hypothesis, subjects from three age groups (6-8, 10-12, and 15-18 years old) were asked to think of either depressing or neutral events and were subsequently given the opportunity to be privately generous. Consistent with predictions from the negative state relief model of altruism, the youngest, least socialized subjects were somewhat less generous in the negative mood condition, but this relationship progressively reversed itself until in the oldest, most socialized group, the negative mood subjects were significantly more generous than neutral mood controls. The data were taken as support for a hedonistic conception of altruism that views adult benevolence as self-gratification. It is suggested that the reward character of benevolence derives from the socialization experience.


Skin conductance response to both signaled and unsignaled noxious stimulation predicts level of socialization. The present experiment tested the hypothesis that the reduced skin conductance response (SCR) to noxious stimulation shown by sociopathic or undersocialized persons is mediated by the ability to use cues of impending noxious events to attenuate their impact. Eighty young adults, males and females scoring high, medium, or low on the Socialization Scale of the California Psychological Inventory, were exposed to 30 pairings of a warning signal with a 98-dB (SPL) noise while palmar skin conductance and subjective estimations of stimulus intensity were recorded. The interval between warning and noise was varied (0, .5, 1, 3, or 11 sec) for each subject. The low-socialization group gave significantly smaller SCRs to noise than the high-socialization group, revealing a negative relationship between level of socialization and amplitude of the SCR to a noxious stimulus in a normal population. Previous studies reporting this relationship contrasted clinical sociopaths with nonsociopathic control subjects. The differences between groups in the SCR were significant at the 0-sec, (i.e., no warning) as well as the remaining warning intervals, indicating that the difference between groups is not mediated by "cue-utlization" ability. Control procedures permitted excluding differential sensory sensitivity, rates of SCR habituation, and general skin conductance responsivity as mediators of the difference between groups in the SCR to noxious stimulation.


Aggression as a function of the interaction of alcohol and threat. Intoxicated and nonintoxicated subjects competed in a reaction time situation against either a potentially threatening opponent or a nonthreatening opponent. The results indicated that the intoxicated subjects initiated higher levels of attack than the nonintoxicated subjects only in the threatening situation. It was concluded that aggression is not just a consequence of the pharmacological action of alcohol. Instead, alcohol-induced aggression appears to be a function of the interaction of alcohol consumption and the degree of threat or provocation inherent in a particular situation.


Systems approach to vaginal delivery of drugs II: In situ vaginal absorption of unbranched aliphatic alcohols. The absorption of unbranched aliphatic alcohols in the rabbit vagina was studied using a perfusion method, and the absorption rates were found to be first order with respect to the drug concentration in the vagina from methanol to octanol. A physical model involving an aqueous diffusion layer in series with a membrane consisting of aqueous pores and lipoidal pathways was used for analyzing the data. The physically based parameters in the model were determined. An effective diffusion layer thickness ("unstirred layer") of around 0.035 cm was found. The increase in the permeability coefficient for the lipoidal pathway per methylene group was around 2.5 for this homologous series.


Systematic identification of drugs of abuse II: TLC. A limited number of spray reagents and solvent systems were selected or developed to separate and identify over 40 of the most commonly encountered drugs of abuse. A new reagent is reported, and new uses were developed for well-known reagents. A flowsheet for the systematic utilization of the spray reagents is given, and use of this sequence made it possible to to identify systematically an unknown drug using only two to four TLC plates, providing that the drug was one of the compounds investigated. This TLC system also can be used to complement and confirm results obtained from spot tests.


Bioavailability and pharmacokinetic analysis of chlorpromazine-induced rectal temperature depression in rabbits. Chlorpromazine-induced depression of rectal temperatures in rabbits kept at 20 degrees was used to determine relative biophasic drug levels corresponding to observed hypothermic response intensities, which then served to establish a triexponential linear mathematical model describing drug transference and drug action in this system. Comparisons of various experimentally known, slow intravenous infusion drug inputs of chlorpromazine with drug inputs computed by deconvolution, using the derived model and observed temperature depressions, served to verify the accuracy of the model for the 0.50-4.0 mg/kg dosage range.


High-pressure liquid chromatographic separation, identification, and determination of sulfa drugs and their metabolites in urine. A high-pressure liquid chromatographic method for the separation and quantitative determination of sulfamethazine, sulfathiazole, and their N4-acetylated metabolites on an amino-bonded reversed-phase column was developed. The method is suitable for the analysis of these compounds in pure solutions as well as in cattle urine. Retention times were reproducible. Injection volumes containing 0.2 mug of individual sulfonamides or their acetyl derivatives were successfully quantitated; coefficients of variation ranged from 0 to 0.073 for individual sulfonamides.


Preparation and properties of solid dispersion system containing citric acid and primidone. Solid dispersions containing 1--32% (w/w) primidone were prepared by fusing the drug with citric acid and rapidly cooling the melt. The solidified dispersions were clear glasses which devitrified on aging or when stored at 60 degrees for up to 3 days. The phase diagram of the devitrified system indicated that the drug may exist as a solid solution at 1--3% (w/w) concentrations but that a eutectic mixture is formed at higher concentrations. The solubility of primidone increased in the presence of citric acid. Preliminary dissolution studies showed that the dissolution rate from the solid dispersion was greater than that of the pure drug or the physical mixture.


In vitro studies of poly(methyl methacrylate) adjuvants. Poly(methyl methacrylate) adjuvants, prepared by polymerizing monomeric methyl methacrylate in the presence of influenza virions or by addition of the virions to previously polymerized poly(methyl methacrylate) particles, were studied by means of the hemagglutination test, antibody binding, and electron microscopy. The results indicated that the virions were coated partly when the polymerization was carried out in the presence of the virus, whereas the virions were probably adsorbed when added to polymerized particles.


Rapid spectrophotometric determination of salicylamide in analgesic tablets. An independent, simple, and rapid procedure is suggested for the routine analysis of salicylamide in analgesic tablets containing acetaminophen, phenobarbital, caffeine, codeine phosphate, prednisone, ascorbic acid, and chloroquine phosphate. The method does not require the preliminary separation of salicylamide from other constituents by the time-consuming solvent extraction technique or by chromatography prior to determination. The absorbance was linear for investigated concentrations of salicylamide from 0 to 4.0 mg/100 ml of solution at 308 nm.


In vitro and in vivo availability of spironolactone from oral dosage forms. Tablet formulations of spironolactone with hydrochlorothiazide were studied in vitro and in vivo to evaluate the effect of formulation parameters on the bioavailability of spironolactone. The time required for 50% tablet dissolution (T50) in simulated gastric fluid was linearly correlated with the disintegration times of four experimental formulations and one commercial tablet of spironolactone and hydrochlorothiazide. Bioavailability studies were conducted in four healthy, female beagle dogs. The mean time to peak concentration of canrenone,f cancrenone, the major metabolite of spironolactone, was proportional to the T50 dissolution parameter. A study of spironolactone administered orally with and without hydrochlorothiazide showed that the bioavailability of spironolactone is not affected by hydrochlorothiazide. No significant difference in the bioavailability of spironolactone from one 100-mg and four 25-mg tablets were observed. Estimates of some pharmacokinetic parameters for canrenone closely agreed with those previously reported.


Dissolution rate equations in column-confined dissolution. Equations are derived for the dissolution of a soluble solid in a column into a liquid stream. The equations are substantiated by experiments using oxalic acid dihydrate as a test substance. The dissolution rate constant, k, of oxalic acid dihydrate depends on linear velocity, v (centimeters per second), by the following equation: k = (2.54 +/- 0.76) X 10(-4) v, where k is measured in centimeters per second.


Microenvironmental kinetic effects within a lyotropic smectic biophase model: conformational restrictions in Fischer indole cyclization. The microenvironmental orientation effects, arising from an orderer solvent structure, were studied in a model liquid crystalline biophase for the cyclization of a series of 2-substituted cyclohexanone phenylhydrazones. The magnitude of such solvent-induced intramolecular conformational constraints were determined from a comparison of the kinetics of the Fischer indole rearrangement in a lyotropic smectic liquid crystal versus those in an isotropic liquid of similar chemical composition but lacking the structured nature of the mesophase. Solutions consisting of 50% (w/w) polyoxyethylene 6 tridecyl ether or 44% (w/v) polyethylene glycol in aqueous buffers comprised the smectic or isotropic media, respectively. The apparent dissociation constants of the conjugate acids of the phenylhydrazones were determined kinetically, as were their partition coefficients between lipid and polar isotropic phases approximating the compositions of the smectic lamellae. Intrinsic first-order rate constants, corrected for partitioning within the lamellar mesophase, were used to compute the enthalpies and entropies of activation. The somewhat slower intrinsic rates of cyclization and the accompanying less negative entropies of activation generally observed in the liquid crystalline medium, as opposed to the isotropic system, are attributed to the orienting effects of the lamellar lyotropic mesophase.


Correlation of dielectric constant and solubilizing properties of tetramethyldicarboxamides. The dielectric constants of aqueous solutions of four tetramethyldicarboxamides (tetramethylpimelamide, tetramethylsuberamide, tetramethylazelamide, and tetramethylsebacamide) were measured at 25 degrees. The values obtained were utilized in assessing the solubility behavior patterns of glutethimide, a semipolar, water-insoluble drug in these amide-water systems. At equimolar concentrations of water-rich amide solutions, the solubilizing power paralleled the chain length of the amides. The higher homologs appeared to favor more extensive solvation, as shown by the lower dielectric constants of their resulting solutions. Deviation in solubilizing action between the odd-carbon amides and the even-carbon amides, however, was exhibited at higher amide concentrations. The two odd-carbon amides, tetramethylpimelamide and tetramethylazelamide, showed consistently greater solubilizing action. This phenomenon was attributed to the greater association tendencies of the odd-carbon amides with water, which effectively reduced self-associations of glutethimide.


Effects of bis(2-ethylhexyl) phthalate on chromosomes of human leukocytes and human fetal lung cells. Blood from two male and two female donors was exposed at 37degrees for 4 hr to concentrations of 60.0, 6.0, 0.6, and 0.06 mug of a widely used plasticizer, bis (2-ethylhexyl) phthalate, per milliliter of blood. The bis(2-ethylhexyl) phthalate was solubilized with polysorbate 80. Appropriate polysorbate and nonpolysorbate controls also were established. Following the 4 hr of incubation, phytohemagglutinin was added and tissue cultures were established. In addition, human fetal lung cells were exposed in tissue culture to a medium containing 6.0 mug/ml of bis(2-ethylhexyl) phthalate in polysorbate 80 for 5 days. Similar controls also were established for these experiments. Analysis of chromosome preparations from all cultures obtained failed to show any increased evidence of isochromatid and chromatid breaks or gaps or abnormal forms at any studied concentration when compared to the control cultures. In addition, analysis of fetal lung cell preparations for aneuploidy failed to reveal any differences between cells from study and control cultures. This study involved a short-term exposure to bis(2-ethylhexyl) phthalate in various concentrations which did not cause damage in leukocytes or fetal lung cells.


Effect of temperature on binding of warfarin by human serum albumin. The in vitro binding of warfarin by human serum albumin was studied at various temperatures and at pH 7.4 by a frontal gel filtration technique. The results can be best described in terms of a two class-of-binding site model, in which the numbers of primary and secondary sites are constrained to the average values for all experiments (n1 = 1.38 and n2 = 3.73). Analysis of the temperature dependence of the binding yielded the following thermodynamic parameters: deltaH1 =-2.55 kcal/mole, deltaS1=16.1 eu, and deltaF1=-7.34 kcal/mole for the primary binding and deltaH2=-5.08 kcal/mole, deltaS2=-1.10 eu, and deltaF2=4.72 kcal/mole for the secondary binding. Calculations based on these results showed that, for the therapeutic concentration range, warfarin was over 99% bound to albumin present in physiological concentration. These findings are compared and contrasted to binding data in the literature for warfarin and salicylate.


Synthesis of substituted anilino-3-methoxy-4-substituted acetoxy) benzylidenes and their monoamine oxidase inhibitory and anticonvulsant properties. Several substituted anilino-(3-methoxy-4-substituted acetoxy) benzylidenes were synthesized and characterized by their sharp melting points and elemental analyses. All substituted benzylidenes competitively inhibited the in vitro monoamine oxidase activity of rat brain homogenates and possessed anticonvulsant activity against pentylenetetrazol-induced convulsions in mice.


Derivatives of apomorphine and of other N-substituted norapomorphines. Derivatives of apomorphine and of N-n-propylnorapomorphine were prepared to obtain modified pharmacological activity and enhanced chemical stability. Mouse profile and dog emesis screens were performed, and the activity of various N-substituted derivatives and their esters was evaluated and compared to the parent compounds. The N-n-propyl diacetate derivative and N-methyl and N-n-propyl ascorbate salts were remarkably stable to air: apomorphine etherate was no more stable than the free base. The dimers, the major products formed during the acid-catalyzed rearrangement of morphines to apomorphines, were all potent emetics. Additionally, two showed a significant antagonism to morphine in mice and dogs.


GLC assay for fenclorac.

GLC assay for fenclorac. A rapid stability-indicating GLC method is described for the determination of fenclorac as the diethylamine salt in dosage formulations. The procedure is also applied in detecting and quantitating the weight percent of 3-chloro-4-cyclohexylphenylglycolic acid and alpha-chloro-4-cyclohexylphenylacetic acid impurities associated with the synthesis of the fenclorac drug substance. The former compound, in addition to being an impurity, is also the degradation product of fenclorac. The procedure involves preparations of the silyl derivatives, addition of an internal standard (triphenylethylene), and use of a hydrogen flame-ionization detector. The column, with a phenyl methyl silicone liquid phase and operated at about 195degrees, is well suited for the separation. The silyl derivatives were characterized by GLC-mass spectrometry.


Synthesis and preliminary antimicrobial screening of two thiosulfonates. Tetramethylene bis(methanethiosulfonate), the S-ester analog of busulfan, was prepared by reacting 1,4-dibromobutane with potassium methanethiosulfonate. 2,4-Dichlorophenyl methanethiosulfonate was prepared by reacting sodium methanesulfinate with 2,4-dichlorobenzenesulfenyl chloride. Neither compound showed antifungal activity against Microsporum audouini or Trichophyton mentagrophytes. Although tetramethylene bis(methanethiosulfonate) was more active against Staphylococcus aureus than was 2,4-dichlorophenyl methanethiosulfonate, neither compound was as active as the streptomycin control.


Effect of compression force and corn starch on tablet disintegration time. An unusual occurrence of decreasing tablet disintegration time with increasing tablet hardness was explored. Tablets were made with varying ratios of starch disintegrant to starch paste and compressed with eight different forces. This unusual disintegration pattern is modified by changes in the starch ratios. The reason for this phenomenon is ascribed to gain swelling as the mechanism by which starch acts as a disintegrant.


Quantitative determination of morphine in paregoric USP by high-pressure liquid chromatography. The quantitative determination of morphine in paregoric by reversed-phase high-pressure liquid chromatography is described. The method is simple, accurate, and fast compared to the USP method. Benzoic acid in paregoric also can be determined quantitatively with the same column. The method was applied to two commercial samples with excellent results.


Potential CNS antitumor agents--phenothiazines I: Nitrogen mustard derivatives. Four phenothiazine derivatives containing the bis(beta-chloroethyl)aminopropyl side chain were prepared and evaluated in the murine L-1210, P-388, and B-16 melanoma intraperitoneal tumor systems. Moderate P-388 activity was observed. An aminoethyl phenothiazine mustard was compared with the aminopropyl analogs and was superior in all test systems. None of the compounds tested against the murine ependymoblastoma brain tumor system was active.


Enhancement of dissolution rates of poorly water-soluble drugs by crystallization in aqueous surfactant solutions I: Sulfathiazole, prednisone, and chloramphenicol. Effects of crystallization of poorly water-soluble drugs in aqueous surfactant solution on in vitro dissolution rates were investigated. Marked enhancement was observed for chloramphenicol, sulfathiazole, and prednisone. Differential thermal analysis studies indicated the presence of small amounts of surfactant in surfactant-treated crystals. Possible mechanisms of dissolution enhancement are discussed.


Molecular orbital studies of antischistosomal agents. Molecular orbital calculations were used to investigate the antischistosomal agent, niridazole, and an inactive derivative, 1-(5-nitro-2-thiazolyl)-2-ethylurea. The CNDO/2 calculations revealed that the inactive derivative had a preferred conformation stabilized by an intramolecular hydrogen bond. The molecular profile, the relative three-dimensional arrangement of constituent atoms, of the inactive derivative was different than that of the niridazole compound. The likelihood of similar intramolecular interactions rendering niridazole derivatives inactive is discussed. The results of the calculations suggest select structural modifications that might increase the efficacy of niridazole derivatives.


Quantitative determinations of phenol and resorcinol in pharmaceutical dosage forms by high-pressure liquid chromatography. The quantitative determinations of phenol in phenolated calamine lotion USP and of phenol and resorcinol in phenol-resorcinol-boric acid solution by high-pressure liquid chromatography are reported. The procedures are simple, rapid (no special preliminary treatment is required), and accurate. There is no interference from other ingredients of the lotion (bentonite magma, calamine, and zinc oxide) or solution (acetone and boric acid).


Electron-capture GC determination of subnanogram amounts of emepronium bromide in serum. Barium peroxide in an acidic medium was utilized to increase the sensitivity in the benzophenone method for the determination of the quaternary ammonium compound emepronium bromide. The method is comprised of ion-pair extraction, oxidation, and quantitative determination of benzophenone by electron-capture GC. By employing small extraction and reaction volumes, the method was used in the 0.2--8-ng/ml range with a relative standard deviation of 2.5% at the 1-ng/ml level. The application of the method to human serum samples after a single oral dose demonstrated that the elimination phase for emepronium in serum had a half-life of 7--11 hr.


Renal elimination of lithium in rats with lithium intoxication. The relation between urine flow (V), lithium clearance (CLi) and sodium clearance (CNa) was studied in rats given food containing lithium in amounts leading to inhibition of distal reabsorption of water and sodium. Maximum inhibition of the reabsorption of water was reached at serum lithium concentrations of about 1 mM. At higher serum lithium levels the rats developed intoxication due to a lowering of CLi and a consequent rise of the serum lithium concentration. The intoxication was characterized by a proportional decrease of V and CLi. The decrease of V and CLi was not related to changes of CNa. The results indicate that lithium is reabsorbed in the proximal tubules in parallel with sodium and that the lowering of CLi is due to increased fractional proximal reabsorption of lithium and sodium compensatory to inhibition of the distal reabsorption of sodium.


Relationship of urinary furosemide excretion rate to natriuretic effect in experimental azotemia. The relationship of natriuretic effect and furosemide excretion was studied in normal and azotemic dogs. Graded azotemia was produced in dogs by bilateral uretero-venous shunts of varying duration. The shunts were subsequently opened and urine and blood samples were taken to measure inulin, furosemide and sodium concentrations. Renal blood flow was measured by an electromagnetic flow probe. Two groups of dogs, control and experimental, were studied. The experimental group received a loading dose followed by a constant infusion of furosemide. This dose produced a natriuresis in nonazotemic normal dogs. The magnitude of this natriuresis correlated with furosemide excretion rate (P less than .005) and not with the plasma concentration of the drug. Furosemide clearance and extraction were inversely correlated with blood urea nitrogen. In the furosemide-treated group the augmentation of sodium excretion was not impaired except at blood urea nitrogen concentrations of greater than 200 mg/dl (two dogs). Thus the reduced clearance of furosemide may account in part for the high dose necessary. Further studies appear to be in order to clarify the relationship of the natriuretic response to furosemide to the rate of urinary excretion and plasma concentration of the drug.


The effect of acetazolamide on the movement of sodium into the posterior chamber of the dog eye. The rate of appearance (entry) of 22Na into the posterior chamber of the eye was determined in eight dogs under control conditions and again after pretreatment with acetazolamide, 50 mg/kg i.v. In comparison with the paired controls, pretreatment with acetazolamide decreased the average rate of entry of 22Na by 29% during the first 3 minutes after the intravenous administration of a tracer dose of the isotope. In separate experiments, the volumes of the chambers of the dog eye and the rate of aqueous humor formation were determined for the purpose of calculating nascent fluid ion concentrations. Comparisons of sodium data with the previously reported anion data are made. Results support the suggestion that reduction of intraocular pressure caused by acetazolamide is partially, if not wholly, the result of the action of the drug to reduce the secretion of aqueous humor.


Stimulation of 45Ca influx in rat parotid gland by carbachol. Secretion of alpha-amylase by rat parotid glands was stimulated by 10(-5) M carbachol when Ca was present in the bathing medium. The optimal Ca concentration was 1.0 mM in the absence of Mg ion. Lowering the extracellular Na to near one-half and one-quarter of normal levels produced a significant increase in carbachol-induced secretion. The metabolism of 45Ca by the slices could be described by three components of exchange. The faster two, with time constants of 4 and 16 minutes, each appeared to represent a mixture of free extracellular Ca and rapidly exchanging superficially bound Ca. Influx into the slower (tau = 78 minutes) component (apparently intracellular) was enhanced by 10(-5) M carbachol. This was apparent by standard flux techniques only in low (65 mM) Na solutions, but was readily discernible in normal Na (125 mM) with the "lanthanum-residual" technique. The increase in 45Ca influx due to carbachol resembles the secretory response to carbachol in being potentiated by low Na, blocked by 1.0 mM La, and blocked by 10(-4) M atropine. It was concluded on the basis of this and other evidence that the primary step in the induction of exocytosis by carbachol in the parotid gland is an increased influx of Ca.


Neuroexcitatory effects of digoxin in the cat. The effect of intravenous injections of digoxin (20 mug/kg every 15 minutes) on spontaneously occurring activity in autonomic efferent nerves, motor nerves, afferent nerves, electrocardiogram and on arterial blood pressure was evaluated in chloralose-anesthetized cats. Administration of digoxin enhanced neural activity in pre- and postganglionic cardiac synpathetic nerves and this enhancement occurred near the time the disturbances in ventricular rhym were noted. Neural activity continued to increase during ventricular tachycardia and maximum enhancement was observed just proir to ventricular fibrillation. Similar results were observed when digoxin was administered to animals in which neural activity was recorded from preganglionic splanchnic and superior cervical nerves. Digoxin administration also increased discharge frequency from vagus (efferent fibers), phrenic and carotid sinus nerves. Denervation of cardiovascular reflexogenic areas prevented the increased discharge in vagus nerves, reduced it in phrenic nerves, but did not affect nerve discharge in sympathetic nerves. These results suggest that digoxin-induced hyperactivity in synpathetic nerves was related to a central nervous system effect of the drug, whereas the mechanism for the digoxin-induced hyperactivity in vagus nerves involved a peripheral reflex effect of the drug. Both sites were involved in the digoxin-induced hyperactivity in phrenic nerves. Enhancement of cardiac sympathetic nerve activity appeared to be responsible for the ventricular arrhythmias provoked by digoxin as 1) a temporal relationship was observed between augmented nerve activity and arrhythmia development, 2) a centrally acting sympathetic nervous system depressant drug, clonidine, converted the ventricular arrhythmia to normal rhythm, and 3) removal of sympathetic influence to the heart by spinal cord transection decreased the sensitivity of the heart to the arrhythmogenic effect of digoxin. These results suggest that digoxin partially responsible for its cardiotoxic effects.


Prostaglandin-like substances in coronary venous blood following myocardial ischemia. Twelve anesthetized open chest dogs received an intracoronary infusion of 20 muCi of 3H-arachidonic acid through the left anterior descending coronary artery. A control blood sample was then taken from the great cardiac vein. The left anterior descending coronary artery was occluded for 10 minutes and then released. A second cardiac vein blood sample was obtained during the coronary reactive hyperemic response. The pre-and postocclusion blood samples were analyzed for prostaglandin (PG)-like substances using thin-layer chromatography and analysis for radioactivity. There was an increase in PGE2- and PGA2-like substances, and arachidonic acid found in the postocclusion samples. PGE2 appears to be the predominant prostaglandin formed. Three animals received 10 mg/kg of indomethacin intravenously 1 hour before the 3H-arachidonic acid infusion. Pretreatment with indomethacin abolished the release of PGE2 and PGA2-like substances but no arachidonic acid and reduced the reactive hyperemic response in magnitude and duration. Reactive hyperemia after a 10-minute occlusion was studied in five dogs before and 1 hour after the intravenous administration of 10 mg/kg of indomethacin. The control coronary flow and peak reactive hyperemic response were significantly reduced by the indomethacin. These studies suggest that myocardial ischemia promotes the synthesis and release of PG-like substances which may play a role in reactive hyperemia.


Relaxation of isolated rabbit arteries by fusaric (5-butylpicolinic) acid. The influence of fusaric (5-butylpicolinic) acid on vascular contractile or relaxing response was examined in different isolated arterial preparations of the rabbit. Prior exposure (10 minutes) to 1 x 10(-4) to 1 x 10(-3) M fusaric acid decreased contractile responses elicited with norepinephrine, histamine, serotonin, acetylcholine, angiotensin II and KCl in helical strips of rabbit aorta and superior mesenteric, carotid, renal, and femoral arteries. Fusaric acid produced a shift to the right and down in the dose-response curves to all tested agonists, and antagonized acetylcholine and serotonin most effectively among these agonists. These results indicate that fusaric acid antagonized nonspecifically these contractile agonists. When blood vessels were contracted with prostaglandin F2alpha, fusaric acid caused relaxation of rabbit aorta and superior mesenteric, carotid, renal, and femoral arteries in a dose-dependent fashion. Among blood vessels tested superior mesenteric arteries were relaxed the most effectively by fusaric acid. The concentration of fusaric acid which induced 50% relaxation of aortic strips was about 10-fold higher than that of papaverine. Propranolol and atropine did not affect fusaric acid-induced relaxation, suggesting that fusaric acid did not work through beta adrenergic or cholinergic receptors. Ethylene glycol bis(beta-aminoethyl-ether)-N,N'-tetraacetic acid which chelates with Ca++ caused blood vessel relaxation in doses similar to those of fusaric acid. As fusaric acid is known to chelate Ca++, a possible mechanism of fusaric acid to relax blood vessel through Ca++ depletion is discussed briefly.


Inhibition of the sympathetic nervous system by a series of heterocyclic congeners of dopamine. A series of heterocyclic congeners of dopamine (GJH-series) with different positions of phenolic oxygens and with the possibility of cis and trans isomerism at the 4a-10b ring juncture was evaluated in vitro and in vivo for dopaminergic activity. Two compounds, GJH-166 and GJH-171, were found to suppress the positive chronotropic response induced by stimulation of the right cardioaccelerator nerves. These effects were antagonized by haloperidol. GJH-166, in doses as low as 9.5 x 10(-4) mugmol/kg reduced the resting heart rate in cats anesthetized with alpha-chloralose. GJH-166 and GJH-171 antagonized pressor responses induced by bilateral carotid occlusion and stimulation of the central stump of the sciatic nerve. The results outlined in this manuscript support the hypothesis that the extended conformation of the dihydroxyhenylethylamine moiety of dopamine with a trans isomeric form is favorable for dopaminergic agonist activity.


Effect of variations in adrenocortical function on dopamine beta-hydroxylase and norepinephrine in the brain of the rat. The effect of adrenalectomy and corticosterone treatment on dopamine beta-hydroxylase (DBH) activity, catecholamine content and norepinephrine formation and metabolism were studied in the hypothalamus and other parts of the brain of male rats. Two days after adrenalectomy, there was a decrease in DBH activity in the hypothalamus and the brain stem but no change in norepinephrine or dopamine content. Conversion of intraventricularly administered tritiated dopamine to tritiated norepinephrine was slightly increased and norepinephrine was metabolized at a more rapid rate than normal. Corticosterone in a dose of 100 mg/kg increased DBH activity but decreased hypothalamic norepinephrine and copamine content. In adrenalectomized rats, smaller, more physiological doses of corticosterone did not change DBH activity or catecholamine content. The fact that norepinephrine formation and metabolism were increased at the same time that DBH activity in vitro was decreased suggests that DBH is not rate-limiting in adrenergic neurons in the hypothalamus, or that a change in the in vitro activity of the enzyme was not accompanied by a parallel change in its activity in vivo.


Molecular geometry of inhibitors of the uptake of catecholamines and serotonin in synaptosomal preparations of rat brain. Several compounds of relatively rigid molecular structure have been found to exert strong blockade of monoamine uptake by synaptosomal preparations of rat corpus striatum (dopamine and serotonin) and hypothalamus (norepinephrine). These include CP-24,441 (1R, 4S-N-methyl-4-phenyl-1,2,3,4-tetrahydro-1-naphthylamine), EXP-561 (4-phenylbicyclo[2.2.2]octan-1-amine), nomifensine and nefopam. The well-defined molecular geometry of the potent inhibitor EXP-561 is a fundamental structural/conformational requirement for uptake blocking activity for the large family of phenylbutylamine- and phenoxypropylamine-related inhibitors. The tubular configuration of EXP-561 may be the most appropriate for blocking serotonin uptake. The requisite conformation for blocking dopamine uptake appears to be defined by the combination resulting from superimposition of the CP-24,441 and nomifensine structures. The conformation defined by the combination resulting from superimposition of the CP-24-441 and desipramine structures is apparently optimal for blocking norepinephrine uptake. The conformational requirements for diphenylpropylamine-related uptake blockers may be defined by the rigid compound CP-39,332 (N-methyl-4-phenyl-1,2,3,4-tetrahydro-2-naphthylamine). The actual potency of any given inhibitor is probably modulated by additional structural and stereochemical factors.


Effects of carbon disulfide and FLA-63 on operant behavior in pigeons. Carbon disulfide (CS2) and FLA-63 [bis(4-methyl-1-homopiperazinylthiocarbonyl)disulfide] were studied in pigeons working on a differential-reinforcement-of low-rates or a multiple fixed-interval fixed-ratio schedule of food reinforcement. Response rate on both schedules decreased after 8-hour exposures to CS2 (2 mg/1) of administration of FLA-63 (40 and 80 mg/kg). The effects of two successive 8-hour exposures to CS2 were cumulative and ten successive 4-hour exposures produced changes in differential-reinforcement-of-low-rates performance resembling those following acute exposure. Fixed-interval performance was disrupted by exposures to CS2 and doses of FLA-63 that left fixed-ratio performance intact.


Chloroquine-3H: mechanism of uptake by Chang liver cells in vitro. The mechanism of uptake and release of the lysosomotropic agent chloroquine-3H (CQ-3H) in cultures of Chang (CH) liver cells was investigated. The data were correlated with the morphological effects of CQ on mammalian cells, observed by other investigators. It was found that CQ-3H accumulated rapidly into CH cells. Accumulation was reduced to about 10% by NaN3 and cytochalasin B and to 3% upon exposure to 2degreesC. Colchicine had no effect on drug uptake. Serum albumin stimulated and serum inhibited uptake, indicating the presence of factors in the serum influencing CQ-3H uptake. Efflux of cellular CQ-3H was fast, energy independent and markedly reduced at 2degreesC. The course of CQ-3H uptake with time, as measured in the present report, together with morphological studies of other investigators, suggests that the process of CQ uptake consists of several distinct phases occurring rapidly and succeeding each other rapidly, as follows: Influx by diffusion, adsorption to a receptor concomitant with induction of membrane-bound cytoplasmic vesicles into which CQ is trapped, followed by fusion of the vesicles with lysosomes. Only the latter process appears energy-dependent and accounts for the major accumulation of CQ in cells. CH cells grown in sucrose-containing medium accumulated 2 to 3 times more CQ-3H, apparently because of expansion of the lysosomes. Such cells respond more strongly to the inhibitory effect of CQ on DNA synthesis than control cells.


The effect of aminoacetonitrile on calcium metabolism and bone in the rat. 1. The effect of the osteolathyrogen aminoacetonitrile (AAN) on plasma calcium, phosphate and alkaline phosphatase, on bone, on growth rates, on absorption of calcium and phosphate in the gut and on their urinary excretion, has been examined in rats. 2. AAN caused a general deterioration in the health of the rat and reduced its rate of growth. 3. AAN reduced plasma calcium and increased plasma alkaline phosphatase but did not affect plasma phosphate. 4. AAN caused obvious deformity of the long bones with large exostoses. The femurs of the lathyritic rats had an increased fat-free weight and increased fat-free weight to ash weight ratio. 5. AAN increased true and apparent absorption of calcium but did not consistently affect urinary excretion of phosphate or apparent absorption of phosphate. 6. AAN did not produce a significant reduction in the plasma calcium of parathyroidectomized or thyroparathyroidectomized rats. 7. Absorption of calcium from ligated jejunal loops was increased in AAN-treated parathyroidectomized rats. 8. In some experiments parathyroidectomy or thyroparathyroidectomy protected the bones from the effect of AAN.


Reversal of the physiological effects of monocular deprivation in the kitten's visual cortex. 1. Twenty-three kittens were monocularly deprived of vision until the age of 4, 5, 6 or 7 weeks. Their deprived eyes were then opened, and their experienced eyes shut for a further 3-63 days. After this time physiological recordings were made in the visual cortex, area 17. Three control kittens, monocularly deprived for various periods, showed that at the time of reverse-suturing, few neurones could be influenced at all from the deprived eye. 2. Following reverse-suturing, the initially deprived eye regained control of cortical neurones. This switch of cortical ocular dominance was most rapid following reverse-suturing at the age of 4 weeks. Delaying the age of reverse-suturing reduced the rate and then the extent of the cortical ocular dominance changes. 3. The cortex of reverse-sutured kittens is divided into regions of cells dominated by one eye or the other. The relative sizes of these ocular dominance columns changed during reversed deprivation. The columns devoted to the initially deprived eye were very small in animals reverse-sutured for brief periods, but in animals that underwent longer periods of reversed deprivation, the columns driven by that eye were larger, while those devoted to the initially open eye were smaller. 4. Clear progressions of orientation columns across the cortex were apparent in many of the kittens, but, in contrast to the situation in normal or strabismic kittens, these sequences were disrupted at the borders of eye dominance columns: the cortical representations of orientation and ocular dominance were not independent. 5. Binocular units in these kittens were rather rare, but those that could be found often had dissimilar receptive field properties in the two eyes. Commonly, a cell would have a normal orientation selective receptive field in one eye, and an immature, unselective receptive field in the other. Cells that had orientation selective receptive fields in both eyes often had greatly differing orientation preferences in the two eyes, occasionally by nearly 90 degrees. 6. During the reversal of deprivation effects, the proportion of receptive fields exhibiting mature properties declined in the initially experienced eye, while the proportion increased in the initially deprived eye. Similarly, the average band width of orientation tuning of receptive fields in the initially deprived eye decreased, while that of receptive fields in the initially experienced eye increased. 7. One kitten was reverse-sutured twice, to demonstrate that cortical ocular dominance may be reversed a second time, even after one reversal of ocular dominance. 8. It is suggested that the sensitive period for cortical binocular development consists of two phases. In the first phase, all cortical neurones may be modified by experience, but the rate at which they may be modified decreases with age. In the second phase, an increasing number of cortical neurones becomes fixed in their properties, while those that remain modifiable are as modifiable as they were at the end of the first phase. 9...


Reversal of the behavioural effects of monocular deprivation in the kitten. 1. Eighteen kittens were monocularly deprived of vision until the age of 5, 6 or  7 weeks. Their eyes were then reverse-sutured, and they were allowed to survive for 3-63 days, before physiological recording from area 17. 2. At the time the reverse-suture was performed, and immediately before the recording session, each kitten was tested separately in the two eyes to elicit five simple behavioural responses: optokinetic nystagmus, visual startle reaction, visually-guided paw placing, visual following and negotiation of a "visual cliff". 3. Following the opening of their initially deprived eye, all kittens appeared behaviourally blind when forced to use that eye; their performance through the initially open eye was then perfect on all tests. After the period of reversed lid-suture, however, their performance when using the initially deprived eye had improved, while that through the initially open eye deteriorated. This complementary improvement and deterioration was most rapid in kittens reverse-sutured at the age of 5 weeks, and less rapid when reverse-suturing was delayed until the age of 6 or 7 weeks. 4. Most of the kittens showed gross abnormalities of interocular alignment, and exhibited marked exotropia or esotropia. 5. The results of these tests were well correlated with the changes seen in cortical ocular dominance in the same animals.


Reversal of the morphological effects of monocular deprivation in the kittens's lateral geniculate nucleus. 1. Eleven kittens were deprived of vision in one eye until the age of between 5 and 14 weeks. Their eyes were then reverse-sutured, they were allowed to survive for a further 3-63 days, and their brains were then examined histologically. 2. Measurement of the cross-sectional area of cells in the lateral geniculate nucleus (LGN) showed that when the reversal of lid suture was performed at the age of 8 or 14 weeks, the mean cell size was smaller in laminae connected to the initially closed right eye than it was in other laminae. 3. When the reversal of lid suture took place at 5 or 6 weeks of age there was a reversal of interlaminar size differences: the initially deprived eye was then connected to laminae containing larger cells. Even within 3 days after the reversal of lid suture, most of the morphological effects of the initial suture had been abolished, and they were fully reversed within 12 days. 4. These results are compared with physiological changes in the visual cortex of these and similarly reared animals.


The effect of noradrenaline, injected into the hypothalamus, on thermoregulation in the cat. 1. Noradrenaline (NA) was microinjected into the anterior hypothalamic/preoptic area(AH/POA) of unanaesthetized cats held at ambient temperatures of 10, 22 or 35 degrees C. Loci in which injection of NA caused body temperature changes were also found to be sensitive to the febrile action of PGE1. 2. At all ambient temperatures, NA caused a dose-dependent fall in body temperature. However the mechanisms by which these temperature changes were brought about varied at different ambient temperatures. In cats maintained at the higher ambient temperature, NA activated heat loss mechanisms whereas in the cats maintained in the 10degrees C environment, the major effect of NA injection was an inhibition of heat conservation and heat production mechanisms. 3. We conclude that NA acts in cats not only as an inhibitor of heat conservation and production, but also acts in an excitatory manner on an active heat loss pathway within the AH/POA.


The effect of noradrenaline and 5-hydroxytryptamine injected into a lateral cerebral ventricle, on thermoregulation in the new-born lamb. 1. Respiratory frequency, shivering, ear skin temperatures and rectal temperatures were observed following intraventricular injections of noradrenaline (NA), 5-hydroxytryptamine (5-HT) and saline (NaCl) into new-born lambs exposed to ambient temperatures of 4, 21, or 30 degrees C. 2. Intraventricular NA caused respiratory rate to decrease and body temperature to increase in the 30 degrees C environment. At 21 degrees C, it increased ear skin temperature but did not significantly affect rectal temperature. At 4 degrees C, NA decreased shivering and rectal temperature fell. 3. 5-HT elevated respiratory rate in the 30 degrees C environment and increased ear skin temperature in the 21 and 4 degrees C environments. In the 4 degrees C environment rectal temperature decreased. 4. In general, the change in rectal temperature was related to the dosage of drug administered. Control injections of NaCl had no significant effect on any of the variables measured. 5. The monoaminergic pathways involved in thermoregulation in the new-born lamb appear to be organized in a manner similar to that of the adult sheep and are functional at birth.


Biphasic changes in body temperature produced by intracerebroventricular injections of histamine in the cat. 1. Intracerebroventricular administration of histamine to cats caused hypothermia followed by a rise in body temperature. 2-Methylhistamine caused a similar biphasic response, while 3-methylhistamine had no effect on body temperature and 4-methylhistamine produced a delayed hyperthermia. Some tolerance to the hypothermic activity developed when a series of closely spaced injections of histamine was given. 2. Doses of histamine and 2-methylhistamine which altered body temperature when given centrally were ineffective when infused or injected I.V. 3. Pyrilamine, an H1-receptor antagonist, prevented the hypothermic response to histamine. 4. Hypothermic responses to histamine at an environmental temperature of 22 degrees C were comparable to responses in a cold room at 4 degrees C in both resting animals and animals acting to depress a lever to escape an external heat load. A change in error signal from the thermostat could account for these results. However, lesser degrees of hypothermia developed when histamine was given to animals in a hot environment. In some, but not all animals, this smaller response could be attributed to inadequate heat loss in spite of maximal activation of heat-loss mechanisms. 5. The hyperthermic response to histamine was antagonized by central, but not peripheral, injection of metiamide, an H2-receptor antagonist. 6. The results indicate that histamine and related agents can act centrally to cause both hypothermia, mediated by H1-receptors, and hyperthermia, mediated by H2-receptors.


Functional and morphologic maturation of superficial and juxtamedullary nephrons in the rat. The development of single nephron glomerular filtration rate (SNGFER) was studied in both superficial and juxtamedullary nephrons in rats in relation to concomitant morphologic maturation. These experiments were carried out in rats between 23 and 91 days of age (between 36 nad 275 g body weight) with the [14C]ferrocyanide infusion technique. 2. SNGFR of the superficial and juxtamedullary nephrons increased with body weight, glomerular volume and proximal tubular length. 3. The ratio SNGFR of the superficial (S) nephrons/SNGFR of the juxtamedullary (JM) nephrons rose from 0-60 in the 40-60 g rats to 0-84 in the adult rats, demonstrating the centrifugal functional maturation of the nephrons. 4. The S/JM ratio for both glomerular volume and tubular length was constant and averaged 0-72+/--0-12 and 0-81+/-0-05, respectively, indicating that while the increase in SNGFR was greater for S than for JM nephrons, this was not accompanied by concomitant disproportionate increases of glomerular volume and/or proximal tubular length between these nephron categories during development in the rat.


Identification of algogenic substances in human erythrocytes. Lysates of human erythrocytes produce pain when applied to a human blister base. The algogenic material is not potassium, acetylcholine, bradykinin, 5-hydroxytryptamine, histamine or a prostaglandin, and is dialysable. 2. Fractionation of dialysates of freshly lysed erythrocytes by Sephadex gel filtration coupled with assays on the human blister base preparation showed that the algogenic material was a mixture of the adenyl compounds adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate (AMP). 3. On the human blister base preparation ATP, ADP and AMP had comparable activity and produced threshold pain in a concentration of 2 muM. 4. The rabbit isolated jejunum preparation was found useful in these studies since ATP, ADP and AMP produced a relaxation which was proportional to their concentration in test samples obtained from dialysates. Of more limited usefulness was the rat isolated stomach strip preparation on which ATP and ADP produced contractions which also were proportional to their concentrations in text samples. 5. The possible role of adenyl compounds in the production of pain in vivo is discussed.


Relationship between internal calcium and outward current in mammalian ventricular muscle; a mechanism for the control of the action potential duration? In sheep and calf ventricular bundles, increasing the internal calcium by increasing the frequency of voltage-clamping to plateau range potentials increased the time-independent outward current. This effect was more marked with higher [Ca]o, and was reduced if the Ca current blockers Verapamil or D 600 were used. 2. If the internal Ca was increased by the addition of cyanide and reduction of external sodium the outward current was also increased. The frequency-dependent increase in outward current also occurred in this Na-poor (12 mM) solution. 3. Tension measurement on the ventricular bundles showed that a Na-free solution with cyanide did not cause a contracture. On changing from Tyrode to a Na-free solution containing cyanide, and on changing back to Tyrode there was a potentiation of the twitch. 4. In Na-poor solution with cyanide, although no contracture was found, ECa was less positive, suggesting that under these circumstances Ca accumulates at the inner side of the membrane, but not around the myofibrils. 5. The prolongation of the action potential in Cl-free solution is frequency-dependent. A greater prolongation is seen at lower frequencies suggesting that Cl current is relatively more important for repolarization at lower frequencies of stimulation. 6. It is suggested that calcium at the inner side of the membrane sets the level of the background outward current. A feed-back mechanism on this basis is proposed for the control of the action potential duration. Various factors that could influence this basic mechanism are discussed.