The relationship of perceptual field orientation to measures of cognitive functioning and current adaptive abilities in alcoholics and nonalcoholics.

The present study investigated the influence of perceptual field orientation, as measured by the Group Embedded Figures Test (GEFT), on cognitive functioning among alcoholics and nonalcoholics. The subjects were classified as field dependent, intermediate, or field independent based upon their GEFT scores. Cognitive function was assessed by the Wechsler-Bellevue Intelligence Scale as well as the Category Test. Tactual Performance Test, and Trail Making Tests of the Halstead-Reitan Neuropsychological Test Battery. Three primary findings emerged. First, the alcoholics appeared to be significantly impaired on measures of abstraction, problem solving, and adaptive abilities relative to nonalcoholics. Second, a direct relationship was found between GEFT scores and level of cognitive function within both alcoholic and nonalcoholic samples, with field-dependent subjects evidencing the most impaired performance. Third, the level of perceptual field orientation accounted for a large portion of the variance between the alcoholic and nonalcoholic samples, with field-independent alcoholics performing at a level comparable to or greater than other nonalcoholic subroups on a number of the cognitive variables. These results provide validational support for the GEFT and indicate that field orientation may be a relevant variable in the assessment of cognitive function in both alcoholics and nonalcoholics.


The clinical value of boredom. A procedure for reducing inappropriate sexual interests.

A combination of aversive therapy and orgasmic reconditioning failed to produce the expected changes in sexual activities and arousal patterns. A procedure that involved verbalizing deviant fantasies while engaged in continual masturbation for nine sessions each of 1 1/2 hours duration, led to marked changes in sexual interests in an appropriate direction.


Who are the "committed"?

A record review of patients who were committed by the court during the course of a hospitalization at an acute urban facility was carried out. Court-committed patients represented 4% of total patients admitted during a 2-year period. Black patients and patients over the age of 70 were more likely to reach the stage of a court hearing and be committed. Schizophrenia was the most frequent diagnosis, being present in well over one half of court-committed patients. Approximately one third of the patients had a hospital stay exceeding 3 months, and transfer to a long term inpatient program occurred significantly more often among court-committed patients as compared to the rest of the hospitalized population. The majority of court-committed patients were eventually returned to the community; about one fifth were placed in intermediate facilities such as boarding or nursing homes. When legal status of previous and subsequent hospitalizations of this sample of court-committed patients was examined, a clear predominance of uncomplicated voluntary hospitalization became apparent.


Neurosurgery 1977: problems and attainments. The 1977 AANS presidential address.

The President of the American Association of Neurological Surgeons (AANS) discusses the many elements that appear to restrict the professional activities of neurosurgeons and other physicians. He stresses the importance of the active role required of the AANS, the American Medical Association, and the American College of Surgeons in finding solutions to problems related to neurosurgery.


Indications for nonoperative treatment of spinal cord compression due to breast cancer.

A retrospective series of 12,478 patients with breast cancer included 2467 patients with spinal metastases. Local treatment was not necessary in 688 patients. Neurological dificit did not develop in 1735 patients who underwent radiotherapy. Forty-four patients developed myelopathy due to spinal cord compression as demonstrated by neurological examination and myelography. Twenty-six of these patients were initially treated by laminectomy and 18 were initially treated with radiotherapy. The two groups did not significantly differ in their outcome with respect to motor power, pain relief, or ability to walk. Six patients who underwent radiotherapy deteriorated during 2 months of treatment. Four of these patients were not operative candidates because of poor general condition (three patients) or long duration of paraplegia (one patient). Of two patients who underwent emergency laminectomy, one became paraplegic; however, the other patient was significantly improved. For this reason it is essential that patients undergoing radiotherapy for spinal cord compression be followed closely by a neurosurgeon. The authors believe that in appropriate cases radiotherapy alone can yield results as good as laminectomy combined with radiotherapy.


Pain relief in metastatic cancer other than breast and prostate gland following transsphenoidal hypophysectomy. A preliminary report.

Hypophysectomy was performed in six patients with advanced carcinoma other than from breast and prostate gland to alleviate pain. Two patients received significant and lasting relief of pain; one achieved relief but died from progression of disease 5 weeks after surgery; one patient, initially relieved, had recurrence of pain 3 months later; one had about 50% relief; and one received no benefit. Possible mechanisms for pain relief include changes in pituitary hormones, prostaglandins, and the newly isolated brain peptides, alpha and beta endorphin. These preliminary observations will require further critical evaluation in a larger series to determine the effectiveness of hypophysectomy in relieving pain in cancer other than from the breast and prostate. The results, nevertheless, do imply that a different approach to pain, namely endocrine manipulation, may be beneficial in certain cancer patients.


The pressure-volume function of brain elasticity. Physiological considerations and clinical applications.

The intracranial pressure-volume function as determined by brain elasticity is reported in normal dogs. Rapid subarachnoid infusions clearly define an exponential relationship between pressure and volume. An aliquot technique to measure elastance (dP/dV) at multiple intracranial pressures demonstrates a linear relationship between elastance and pressure. This follows mathematically from the exponential nature of the basic pressure-volume function. The clinical significance of brain elastance measurements is discussed. It is emphasized that the effects of pressure on CSF dynamics are superimposed on the pressure-volume function of brain elasticity and probably account for the process of spatial compensation for an expanding mass lesion. It is not apparent that elastance measurements can serve as indicators of impending decompensation, since the pressure-volume function of brain elasticity provides no direct information about CSF dynamics. Accordingly, the clinical usefullness of elastance measurements is seriously questioned.


Decerebrate rigidity in acute head injury.

A comprehensive study of the motor patterns, usually grouped under the heading "decerebrate rigidity," was carried out in a series of 800 patients with severe head injuries. The incidence of these manifestations was 39.6%, and when they were present chances of survival were reduced from 79.4% to 28.1%. Clinical and electromyographic investigations revealed heterogeneous and unstable motor manifestations that did not fit into the classical groups of experimental models of decerebrate rigidity. Combinations of extensor and flexor attitudes and/or responses were frequently found in same patient, but could be separated into homogeneous groups. Each recognized postural pattern had its own distinct neurological signs and prognosis. Age did not significantly affect the outcome, however, intracranial exapnding lesions (73.5%), impairment of the brain-stem oculomotor system (49.8%), and deep coma (88.9%) all contributed to an unfavorable course. Surgical treatment was effective when performed for intracranial hematomas and in patients with incomplete extensor rigidity. Good recovery was achieved in 16% of decerebrate patients, while 12.1% survived in prolonged coma or with severe disabilities. All clinical and neuropathological data suggest that extensor motor abnormalities in the acute phase of cerebral traumatic disease do not always conclusively indicate structural brain-stem damage. A critical analysis of so-called "decerebrate rigidity" (rejecting in some instances its Sherringtonian implications) may allow for a more accurate clinical assessment of the severity of head injury.


Compartmental analysis of regional cerebral blood flow in patients with acute severe head injuries.

Bicompartmental analysis for the calculation of regional cerebral blood flow (rCBF) from 133Xe clearance in brain tissue has not been thoroughly explored in clinical studies. Most authors rely either on the average rCBF obtained by height/area analysis of the clearance curves or on the initial-slope flow index. Possibly the reason is that the validity of the bimodal flow distribution in abnormal brain tissue is considered questionable. In the present study, bicompartmental analysis, performed by a least-square computerized iterative approach, was used in the calculation of the flow and weight of the tissue of the brain of patients with severe head injuries. The analysis was found to give important information of the nature and course of the brain lesions even if the clearance curves did not have the normal bi-exponential shape, provided the results obtained were properly interpreted. In such cases, the values of the flow and relative weight could not be taken as flow and weight values of gray and white matter, but rather as indices of fast and slower flow components. The interpretation of the results was based on the identification of three types of 13-minute clearance curves, each being characteristic of a type of brain lesion. The clearance curves from fairly normal brain tissue appeared to be bi-exponential; curves from areas of severe cortical contusion had, in addition, an initial and rapid "third" component, a tissue peak, whereas curves from severely edematous brain tissue approached the monoexponential shape.


Microsurgical exposure of the petrous portion of the carotid artery.

Occlusion of the cervical portion of the internal carotid artery (ICA) has been treated by vein graft bypass from the common carotid to the supraclinoid segment. However, this procedure has the disadvantages of requiring temporary occlusion of collateral flow, the short length of ICA available for anastomosis, and the retraction required for exposure of the supraclinoid area. In an attempt to find a more suitable bypass site for grafting, the petrous portion of 50 carotid arteries was studied in cadavers. It was found that there was a 1-cm length of the horizontal segment of the petrous carotid that could be exposed in the floor of the middle fossa lateral to the trigeminal nerve. This segment was covered by dura only or a thin layer of cartilage in approximately half of the specimens. In the remainder, there was often a thin shell of bone covering the artery, which could be drilled away. The petrous portion of the carotid artery had branches in only 38% of specimens, a Vidian branch in 30%, and a periosteal branch in 8%. The carotico-tympanic artery, previously reported to be the most common branch, was not found in a single case. These branches allow the retrograde flow needed to maintain the patency of this segment following proximal occlusions. The relationship of the carotid artery to structures include the cochlea, middle ear, Eustachian tube, tensor tympani muscle, geniculate ganglion, and facial, greater petrosal, and trigminal nerves.


Late morbidity and mortality of common carotid ligation for posterior communicating aneurysms. A comparison to conservative treatment.

The long-term evaluation of 60 patients who suffered a subarachnoid hemorrhage and survived 6 months is reported. By bilateral carotid arteriography, all patients were shown to have a single aneurysm at the vicinity of the posterior communicating artery at its junction with the internal carotid artery. The patients had previously been randomly assigned to treatment either by bed rest or by common carotid ligation. Average duration of survival among those followed is 8 years. Late rebleeding episodes were found to occur at a similar rate, irrespective of mode of treatment in the studied populations, but morbidity following operation continued to remain somewhat less over the ensuing years of follow-up study compared with the patients treated conservatively. On final assessment many years after the original hemorrhage, there is little improvement in degree of morbidity in either treatment group, and hypertension is noted to develop in the patients undergoing carotid ligation. A larger number of cases will be required to validate these findings.


Nerve allografts and histocompatibility in dogs.

The histocompatibility requirements for successful frozen nerve allografts were studied in 46 dogs. Major canine histocompatibility (DLA) differences appeared to be of vital importance for nerve regeneration and function, as judged by histological and electromyographic performance 7 to 9 months after grafting. Minor histocompatibility differences did not appear to lead to rejection of the frozen nerve allografts. Graft irradiation did not improve the acceptability of frozen DLA-mismatched grafts. The effect of DLA matching was much more pronounced in allografts 7 cm long than in allografts 4 cm long. The results indicate the need for a bank of frozen human histocompatible (HLA) nerve allografts, and a study of the effect of partial or complete HLA matching on their survival.


Femoral nerve repair with nerve autografts. Report of two cases.

Two cases of femoral nerve lesions are reported, one in the pelvic region, and one in the femoral triangle. In both cases, secondary microsurgical autografting resulted in a good functional and electrophysiological recovery.


Fatal meningitis secondary to undetected bacterial psoas abscess. Report of three cases.

Three unusual cases of fatal meningitis secondary to undetected bacterial psoas abscess occurred at this institution over an 11-year period. All three patients had suffered chronic debilitating disorders before the abscess formation. The superimposed variable clinical presentations led to the initial diagnosis of a progressing cerebrovascular accident in one case, herniated nucleus pulposus at the L3-4 level in another, and osteomyelitis of the hip joint in the third. Analysis of these cases revealed that before the meningeal dissemination, all of the patients had shown evidence of intraabdominal pathology with positive psoas signs. Diagnostic and therapeutic guidelines are discussed.


The management of ruptured intracranial aneurysm in sickle cell anemia. Case report.

The problems of sickle cell disease and its complications is discussed. Subarachnoid hemorrhage is not a common complication of sickle cell disease and should be evaluated in the same way as if it were not associated with the disease. Patients with sickle cell trait have an added risk during angiography and hypotensive anesthesia. Guidlines are given for angiography and craniotomy with hypotensive anesthesia and reduction of brain volume in these patients.


Spontaneous transdural extension of malignant astrocytoma. Case report.

A case of malignant astrocytoma in the frontoparietal parasagittal region with transgression into the overlying dura mater and the skull is presented. Spontaneous transdural extension of a glioma is an extremely rare growth pattern. A mode of transdural extension of this tumor is discussed and related reports are reviewed.


A metastasizing ependymoma of the cauda equina. Case report.

A case is described in which a metastatic ependymoma of the cauda equina recurred after prolonged remission. Similarities to five previously reported cases are discussed, with emphasis on the mode of metastasis. Factors most closely associated with distant metastases include early onset, numerous local operations, long survival, and massive local recurrence at the time of distant metastases.


Pineocytomas presenting as subarachnoid hemorrhage. Report of two cases.

Two cases of pineocytoma are reported in patients whose initial symptoms resembled a subarachnoid hemorrhage. The underlying tumor became obvious only later in the disease. Several episodes of subarachnoid bleeding occurred. These are the first documented cases of pineocytoma with this type of clinical presentation.


Closure of large skin defect associated with thoracolumbar rachischisis. Case report.

The management of a premature infant with a large skin defect associated with thoracolumbar rachischisis is presented. Full-thickness closure was achieved in 8 days using a new technique, adapted from a method of closing large omphaloceles.


Primary fibrosarcoma of the skull. Case report.

A case of primary fibrosarcoma of the skull is presented. Only one other case with this uncommon site of occurrence of this tumor has been previously reported.


A simple method of measuring aneurysm clip tension. Technical note.

The opening force of aneurysm clips can be determined easily with a dynamometer tension guage. The method is described.


A new method of cranioplasty. Technical note.

A new method of cranioplasty is described. The skull defect is exposed, and an impression is taken which is used for the construction of a plaster of Paris model of the defect. Methyl methacrylate is molded to the model and thus an accurate reproduction of the skull defect is produced. The technique has the main advantage of good cosmetic appearance and strength.


Modified suction tip. Techical note.

A modification of the standard suction tip is described that decreases risk to delicate tissues.


Protein utilization of mechanically deboned meat by growing rats.

The protein quality of mechanically deboned red meat was investigated using amino acid analysis, protein efficiency ratio and the slope ratio technique. Nine different meat products were studied utilizing Sprague-Dawley weanling albino rats. Protein quality of the mechanically deboned meat varied greatly with the amount of lean left on the bones prior to mechanical deboning. Deboned meat which contained more lean, and less collagen, was superior in protein quality to the deboned meat obtained from bones which contained less lean and more collagen. Total sulfur amino acids (cystine and methionine) and isoleucine were the most limiting amino acids in all nine of the meat products when compared with lactalbumin. The contents of total sulfur amino acids and isoleucine, as well as the ratio of essential amino acids to total amino acids, reflected the protein quality of the meat.


Increased muscle phosphorylase in rats fed high levels of vitamin B6.

The present study was undertaken to test the hypothesis that muscle phosphorylase may function as a repository for vitamin B6 in the animal. Since a repository would be expected to accumulate surplus material, one would predict that phosphorylase, which contains stoichio-metric amounts or pyridoxal phosphate, would increase in muscle of animals surfeited with the vitamin. Rats were fed a vitamin B6-free diet supplemented with pyridoxine providing levels 10, 1.0 and 0.1 of those recommended by the National Research Council (NRC). At the high intake level, muscle phosphorylase and total muscle vitamin B6 increased steadily and in almost constant ratio for at least 6 weeks, whereas both alanine and aspartate transaminase increased initially, but reached a plateau within 2 weeks. At the intermediate level of pyridoxine intake, muscle phosphorylase also increased, but less rapidly than in rats fed the higher level. When vitamin B6 intake was restricted to 10% of the NRC-recommended level, no increase in phosphorylase concentration occurred during a period of 10 weeks. These results support the hypothesis that muscle phosphorylase acts as a reservoir for vitamin B6 in the animal and provide experimental evidence that muscle enzyme content expands as vitamin is accumulated during high dietary intake.


A multifactor analysis of growth in the rat epididymal fat pad.

Adipose tissue is known to consist of at least two compartments, the adipocytes and the non-lipid filled cells. During normal growth and development of the rat epididymal fat pad, these two compartments changed in different manners. From 12 to 35 days of age, the DNA contained in both compartments increased linearly, indicative of hyperplastic growth. From 35 to 70 days of age, the DNA in the non-lipid filled cells continued to increase linearly; DNA in the adipocyte fraction increased more slowly. From 70 to 182 days of age, DNA accretion continued in the non-lipid filled cells while remaining unchanged in adipocytes. From 35 to 70 days of age, an abrupt change in the rate of tissue lipid accumulation occurred, shown both by a tripling of fat cell size and a markedly increased slope in the accumulation of lipid per pad. These data confirm that adipose tissue growth proceeds as suggested by radioactive thymidine incorporation studies and further suggest that a critical period for the onset of lipid filling may begin around 35 days of age.


Mediation of calcium adaptation by 1,25-dihydroxycholecalciferol.

Vitamin D-depleted chicks which were repleted with 25-hydroxycholecalciferol adapted to the feeding of a low or high calcium diet by respectively increasing or decreasing their rate of intestinal calcium absorption. The synthesis of 1,25-dihydroxycholecalciferol in chicks fed differing calcium diets correlated directly with intestinal calcium absorption activity, suggesting that the intestinal calcium adaptation response is mediated by the modulation of kidney 25-hydroxycholecalciferol-1-hydroxylase activity. This view was strongly supported by the demonstration that repletion of the chicks with 1,25-dihydroxycholecalciferol eliminated the ability of the chicks to adjust their rates of intestinal calcium absorption to dietary levels of calcium.


Effect of treadmill speeds and slopes on voluntary exercise in rats.

Male rats 87 days of age were given daily 90-minute sesions of voluntary exercise on self-operated treadmills pre-set to deliver speeds ranging from 6.1 to 73.2 m/minute and slopes of 0 to 27 degrees. Voluntary motivation to operate the treadmills was induced by maintaining the rats at constant body weights of 203 +/- 2 g. Under the conditions of the experiment, the rats selected 24.4 m/minute and 0 degree slope with running bursts averaging 21 to 24 seconds in duration as a preferred condition for greatest running. Since all activity was voluntary, the consistent patterns of running bursts at 24.4 m/minute are believed to be potentially capable of serving as reference baselines for detection of food contaminants, toxicants and other insults to normal metabolic processes.


Maternal-fetal exchange during protein malnutrition in the rat. Placental transfer of glucose and a nonmetabolizable glucose analog.

Maternal-fetal transfer of glucose and methyl alpha-D-glucopyranoside (AMG) was studied in rats fed either a 6% or a 27% casein diet. On day 21 of pregnancy 3H-labeled glucose and 14C labeled AMG were injected into the maternal circulation of both groups of dams and concentration of tritium and 14C in maternal plasma, placentas and fetuses were determined 10 and 20 minutes later respectively. In malnourished rats both substances tended to be slightly, although non-significantly, increased in maternal plasma and were significantly decreased in placentas and fetuses. This lower concentration in fetal tissues reflected a marked reduction in the amount of glucose and AMG transported into the fetuses per g of placental tissue per minute. The proportionality of the changes found for both substances suggests that their reduced rate of transfer may be due to similar mechanisms.


Maternal-fetal exchange during protein malnutrition in the rat. Placental transfer of alpha-amino isobutyric acid.

The influence of protein restriction on the maternal-fetal transfer of nutrients was explored in rats fed a 6% casein diet. At days 20 and 21 of gestation, 1 muCi/100 g of body weight of 14C-alpha-amino isobutyric acid was injected inthe maternal circulation of controls fed a 27% casein diet, and experimental rats. Samples of maternal blood, and one placenta and one fetus were removed from each dam 10, 20, 40 and 60 minutes later. In malnourished dams, the radioactively labeled amino acid had a slower rate of disappearance from the maternal plasma, stayed longer in the placenta and was transported in reduced amount to the fetuses.


A comparison of hypocholesterolemic activity of beta-sitosterol and beta-sitostanol in rats.

The hypocholesterolemic activity of beta-sitosterol and its hydrogenated product, beta-sitostanol (dihydrositosterol or stigmastanol) has been compared in young male rats. When cholesterol was included in the diet, sitostanol consistently exhibited significantly greater hypocholesterolemic activity than sitosterol. There were no apparent differences in the effects of the sterol and the stanol on the concentration of liver cholesterol and triglyceride. Increases in plasma triglyceride due to feeding sitosterol were not observed with sitostanol. Incorporation of dietary sitostanol into plasma, liver and other tissues was always negligible, and thus this stanol was almost completely recovered in feces, while there was considerable deposition of sitosterol (mean fecal recovery being 85% to 92%). The increase in fecal output of dietary cholesterol was significantly greater with the stanol than with sterol. There was no demonstrable negative effect on growth and weight of major visceral tissues in rats fed the sterol as well as the stanol. These observations together with those reported previously indicate that hydorgenation of phytosterols is a novel approach to enhance their hypocholesterolemic activities without influencing the relative safety of the initial sterols.


Sulfur amino acid requirement of channel catfish: L-methionine and L-cystine.

Growth studies, utilizing a 24% crude protein diet containing an amino acid pattern similar to whole egg protein, indicate that the methionine requirement in the absence of cystine for fingerling channel catfish (Ictalurus punctalus) is about 0.56% of the diet (dry weight basis) or 2.34% of the dietary protein. The dietary requirement was confirmed by serum free methionine analysis. A marked increase in serum free methionine occurred at a dietary methionine level between 0.50% and 0.75% of the diet. The cystine replacement value for methionine on a mmole sulfur basis was found to be about 60%.


Gluconeogenesis in ruminants: propionic acid production from a high-grain diet fed to cattle.

Effects of amount of feed intake on in vivo remen propionate production and the reproducibility of measurements of propionate production rates were investigated in five dairy steers weighing 142 to 228 kg. Each steer received 275 g of an 80%-grain diet every 2 hours, and three of the five steers later received 500 g/2 hours. Rumen propionate pool sizes and production rates were determined at both intakes by administering a single dose of [1-14C] propionate via rumen fistula and observing decreasing specific activity of rumen propionate for 4 hours. A linear regression equation was calculated from the natural logs of decreasing specific activity. Propionate pool sizes averaged 30.6 and 47.4 g, and production rates averaged 579 and 1032 g/day at feed intakes of 275 and 500 g/2 hours. Thus, propionate production changed in almost direct proportion to feed intake. Acetate to propionate ratios were about 3:1 in rumen fluid. Considerable variability in estimates of propionate pool sizes and production rates was found both within and among steers. The results indicate propionate production is nearly equivalent to blood glucose turnover determined previously; all propionate produced in the rumen, however, is not used for glucose synthesis.


Control of blood cholesterol levels in suckling and weanling rats.

The high blood cholesterol and glucagon levels of suckling rats can be rapidly decreased within 24 hours by prematurely weaning rats to a high carbohydrate diet on day 18. The fall in the cholesterol level is much smaller if rats are starved for 24 hours. This decrease can partly be inhibited by injections of glucagon. The only factor so far found to decrease blood cholesterol levels in suckling rats was starvation. Insulin, which slightly but significantly, depressed the level in 40 day old rats, increased it in suckling ones, as does prednisolone. It is concluded that blood cholesterol levels are more easily manipulated in suckling rats than in older rats, and that this is probably related to a different hormonal balance.


Effects of dietary histidine and arginine on nitrogen retention of men.

Effects of dietary histidine and arginine on nitrogen retention were compared in six young men consuming for 1 week, each of six semipurified diets containing eight indispensable amino acids proportioned as in casein and 6.3 g nitrogen daily. Nonspecific nitrogen was either A) a mixture of six dispensable amino acids and arginine (diet 1) or arginine and histidine (diet 2) in casein proportions, or B) an isonitrogenous mixture of glycine and diammonium citrate alone (diet 3), with histidine (diet 4), arginine (diet 5), or histidine and arginine (diet 6). Nitrogen retention was significantly greater when the nonspecific nitrogen source was dispensable amino acids, arginine and histidine (diet 2) than when it was glycine and diammonium citrate (diet 3). mean balances were positive only when diets contained histidine (diets 2, 4, and 6). Histidine with arginine (diets 2 and 6) significantly improved nitrogen retention compared to arginine alone, but the balance, although positive, was not significantly improved when histidine was fed without arginine (diet 4). Urinary urea nitrogen confirmed these data. Indicators of erythrocyte status, plasma enzyme activities and proteins, and creatinine clearance were unaffected by diet. In summary, histidine supplementation of the low nitrogen diet improved total nitrogen utilization when arginine was present in the diet.


Effects of dietary histidine and arginine on plasma amino acid and urea concentrations of men fed a low nitrogen diet.

The effects of dietary histidine and arginine on fasting and 1 and 2 hour postprandial plasma free amino acid and urea concentrations were studied in six young men. For 1 week each, they were fed six different diets containing 6.3 g of nitrogen daily. Each diet contained eight indispensable amino acids, cystine and tyrosine proportioned as in casein and a different mixture of dispensable nitrogen: A) six dispensable amino acids plus argine (diet 1) or plus histidine and arginine (diet 2) in the casein pattern, or B) an isonitrogenous amount of glycine and diammonium citrate alone (diet 3), with histidine (diet 4), with arginine (diet 5) or with histidine and arginine (diet 6). The fasting plasma concentrations of the seven indispensable amino acids assayed and their similar postprandial patterns were unaffected by the dietary treatments. Both fasting and postprandial plasma histidine concentrations were significantly lower when the histidine-low diets were fed than when the histidine-supplemented diets were fed. Histidine supplementation promoted a reduction in fasting plasma urea nitrogens. Proline concentrations were lowered significantly when proline was removed from the dietary amino acid mixtures, but plasma arginine concentrations were unaffected by arginine removal. Plasma histidine was maintained at lower concentrations in dietary histidine deficiency than when histidine was added to the low nitrogen diets.


Measurements of edge-induced visual contrast and a spatial-frequency interaction of the Cornsweet illusion.

Measurements were made of the perceived contrast that results from the Cornsweet illusion as a function of the edge contrast and edge width. The physical contrast was varied from 3% to 5%, and the visual extent of the Cornsweet edge varied from 0.1 degrees to 3.0 degrees on each side. Results show that, for low-contrast (less than 20%) and wide edges, the Cornsweet edge yields as much contrast as a real-step lumininance transition with the same edge magnitude. At high contrast (30%-40%) the illusion is reduced relative to a real step, regardless of whether the illusion consists of a conventional Cornsweet edge or an additive combination of a real step and a Cornsweet edge. As a general rule, wide edges yield more contrast than narrow edges. The results are interpreted in terms of the visual describing funtion; a nonlinear model is proposed. The correspondence between the predictions of the model and the perceptual measurements on the Cornsweet edges is good.


Visual texture discrimination using random-dot patterns.

A method for generating random-dot textures is described that provides statistical control of any n adjacent points (n-grams), while leaving constant the statistics of shorter spans. The method thus allows the experimenter to isolate statistics of n-grams of any span length to determine the nature of their influence on texture discrimination. Variables that control phase are relatively unimportant. The most significant variables are constraints imposed upon span lengths less than 3 that regulate gray level and spatial frequency content. However, span lengths of 3 or greater may still influence discrimination by altering the distribution of the spatial-frequency content.


Phase-versus-time analysis of the steady-state evoked potential latency.

Steady-state EP (evoked potenial) latency can be derived either from a phase or time difference between stimulus and EP. Phase derivation employs a sinusoidal stimulus and assumes a linear stimulus-EP system. Time derivation employs any stimulus waveform and does not require linearity. The two methods are complementary in application.


Hepatitis B e antigen and antibody activity in hepatitis B virus infection.

Groups of institutionalized subjects, volunteer blood donors with serologic evidence of asymptomatic hepatitis B virus infection, and patients with acute type B viral hepatitis were studied for the presence of hepatitis B e antigen and antibody in a sequential manner over a period of two to three years. HBeAg was detected in 9.5% of institutionalized residents and volunteer blood donors and in 24% of patients with acute type B viral hepatitis. HBeAg positive subjects frequently had persistently elevated pyruvic glutamic transaminase levels in the serum. Anti HBe activity was observed in 26 to 32% of subjects positive for hepatitis B surface antigen. Long-term follow-up indicated that HBsAg positive subjects with anti HBe did not eventually become seronegative for HBsAg.


Role of lower esophageal sphincter incompetence in recurrent pneumonia after repair of esophageal atresia.

The etiology of recurrent aspiration pneumonitis after the successful repair of esophageal atresia has not been defined. In order to explain this occurrence, we performed esophageal manometric examinations on eight patients who had undergone repair of EA and tracheoesophageal fistula. Two patients who had had recurrent pneumonia had subnormal pressure of the lower esophageal sphincter; they also had a history of severe regurgitation, and a barium esophagram demonstrated free gastroesophageal reflux. The LES incompetence in these patients was apparently corrected by administration of bethanechol.


Familial resemblance of body weight and weight/height in 374 homes with adopted children.

Body weight and weight/height were measured in 535 children adopted at the median age of 3 months, and in 250 natural children in French-Canadian origin living in 374 Montreal homes, to determine whether the shared environment contributed to the familial resemblance of weight in children aged one to 21. The mid-parent vs natural children's correlation ( r2 X 100) was 9.55% for body weight and 6.60% for W/H (p less than 0.01), whereas the mid-parent vs adopted children's correlation was 0.00% for both characteristics. The sib-sib correlation in 80 homes with greater than 1 natural child was 15.2% for weight and 13.48% for W/H (p less than 0.001), whereas in 138 homes with greater than 1 adopted child, the adoptee-adoptee correlations were, respectively, 0.00% and 0.07%. It is concluded that heredity explains most of the familial aggregation of patterns of weight and weight/height in children. This conclusion does not necessarily apply to obesity, since weight indices in children do not accurately reflect excess fat tissue, and half of the adoptees were adopted after the age of three months.


Nutritional anemia. VI. Fetal hepatic storage of metabolites in the second half of pregnancy.

The non-heme iron, folates, and vitamin B12 in the liver of 77 fetuses were assayed as were serum levels of these metabolites in 70 of their mothers. The findings indicate the existence of independent placental transport mechanisms, switched on and off at different stages of late gestation, and peculiar to each metabolite.


Free amino acids in liver of patients with homocystinuria due to cystathionine synthase deficiency: effects of vitamin B6.

Patients with homocystinuria due to cystathionine synthase deficiency do not have free homocystine in the liver when it is present in high concentrations in the plasma and the urine. The liver of these patients is capable of maintaining normal concentrations of cystine at a time when the plasma cystine concentration is severely reduced. There is an increase in the methionine concentration of the liver which is reduced to normal concentrations during pyridoxine therapy.


Iminopeptiduria, skin ulcerations, and edema in a boy with prolidase deficiency.

A 12-year-old boy with recurrent skin ulceration, chronic generalized lymphedema, and mild mental retardation was found to excrete massive amounts of dipeptides, most (but not all) of which had proline or hydroxyproline as the carboxyl terminal residue. Glycylproline predominated. Prolidase deficiency was demonstrated in red blood cells and in fibroblastic cells. Prolidase activity was present in continuous lymphoid cell cultures at the same low level observed in control cells.


Cytotoxicity to isolated rabbit hepatocytes by lymphocytes from children with liver disease.

A test of lymphocyte cytotoxicity for isolated adult rabbit hepatocytes has been performed using lymphocytes from 40 children with acute or chronic liver disease. Positive cytotoxicity was not observed in 26 children without liver disease and rarely in 13 children with disease affecting primarily the biliary tract. Temporarily positive tests were found in those with acute hepatocellular disease, but tests remained positive in patients with chronic active hepatitis, while liver function tests remained abnormal. Persistently positive test occurred in those with liver disease associated with alpha-antitrypsin deficiency. Such altered immunoresponsiveness could be an important pathogenic mechanism leading to chronic liver disease in childhood.


Persistence of fetal circulation syndrome: an echocardiographic study.

Serial echocardiograms were performed on 17 infants with persistence of fetal circulation syndrome to measure right ventricular systolic time intervals from pulmonic valve echograms and left ventricular systolic time intervals from aortic valve echograms. Right ventricular pre-ejection period/right ventricular ejection time ratio was prolonged in PFCS when compared to that in normal newborn infants, and diminished with clinical improvement. Left ventricular pre-ejection period/left ventricular ejection time ratio was prolonged in infants with PFCS. Echographic RPEP/RVET was consistent with the elevated pulmonary artery pressure and pulmonary vascular resistance of PFCS; elevated LPEP/LVET suggested left ventricular dysfunction.


Neonatal seizures associated with narcotic withdrawal.

Among 302 neonates passively addicted to narcotics, 18 had seizures that were attributed to withdrawal. Of those 18 infants, 10 were among the 127 infants exposed to methadone (7.8%), whereas only one of them was among the 83 infants exposed to heroin (1.2%). Generalized motor seizures and myoclonic jerks were the predominant convulsive manifestations. Paregoric was more effective than was diazepam in controlling and preventing these seizures once they occurred. Electroencephalograms were obtained on 13 neonates in the interictal period; 12 of these ECGs were normal. Three infants, two with myoclonic jerks, had paroxysmal brain wave activity at the time of the seizures.


Neonatal pattern vision: a predictor of future mental performance?

The visual fixation responses of 33 high-risk neonates to patterned stimuli were rated as normal, suspect, or abnormal in an attempt to predict future intellectual performance. For comparison purposes, a neurologic examination was aslo administered. Follow-up studies based on autopsies and neurologic and psychological testing agreed with the neonatal visual preference ratings in 27 cases, but with the neurologic examination ratings in only 22 cases. This preliminary study suggests that neonatal visual testing is a promising technique for evaluating brain integrity in the newborn period.


Selective bronchial intubation for the treatment of severe localized pulmonary interstitial emphysema in newborn infants.

As an alternative to lobectomy and in order to preserve lung tissue which may be potentially functional we have selectively intubated the right main bronchus in four infants 12 to 25 days old with severe, pulmonary interstitial emphysema of the left lung. In each case the localized hyperinflation disappeared within 5 to 48 hours of contralateral selective bronchial intubation. The duration of SBI was 1.5 to 5 days. Three patients benefited from the procedure; there were no serious complications. We propose that SBI should be tried in infants with severe, localized PIE which has caused mediastinal shift, compressive atelectasis, and respiratory acidosis requiring mechanical ventilation despite vigorous pulmonary therapy and usual supportive measures.


Relationship of theophylline clearance to oral dosage in children with chronic asthma.

Theophylline clearance was examined in 23 children with chronic asthma by administering constant intravenous infusions of theophylline until steady-state serum concentrations were documented. Clearance was subsequently related to peak and trough serum concentrations during a multiple-dose oral theophylline regimen. Although theophylline clearances tended to decrease with age, considerable interpatient variability was observed. Clearances correlated inversely with a standardized index of serum concentration response to oral dosage resulting in a wide range of dosage requirements to maintain therapeutic serum concentrations of 10 to 20 microgram/ml. Intrapatient variability over an interval up to seven months, however, was acceptably small, suggesting that dosage requirements, once established for an individual, should remain relatively stable under normal conditions. Differences in serum theophylline values during a 6-hour dosing interval among children who were receiving theophylline on a continuous basis correlated with clearance and averaged 9 +/- 3 microgram/ml (mean +/- SD), exceeding to 10 microgram/ml interval width of the therapeutic range among 40% of the children. This observation supports the clinical need for reliable sustained-release preparations of theophylline for children who are receiving continuous therapy in order to avoid unrealistically short dosing intervals.


D-penicillamine therapy of acute arsenic poisoning.

Severe poisoning resulting from single ingestions of rodenticides, herbicides, or insecticides containing arsenic have been frequently recognized. We record three cases of solubilized arsenic trioxide poisoning in Navajo Indian children and one case of sodium arsenate ingestion in an infant. One fatality occurred during dimercaprol therapy prior to initiation of therapy with D-penicillamine. Three survivors were treated with 2.3-dimercaprol intramuscularly and with oral D-penicillamine. The use of D-penicillamine in arsenic poisoning has not been generally appreciated. Excretion data from the three children are presented which document the effectiveness of D-penicillamine, administered orally in four daily doses of 25 mg/kg/dose, in the therapy of arsenic intoxication. Excretion data for the trace metals, zinc and copper, during D-penicillamine chelation therapy are also reported.


A secular increase in the incidence of juvenile diabetes mellitus.

Data from a 1973 survey of diabetes mellitus among schoolchildren in Michigan have been analyzed to derive age-specific incidence and prevalence rates. The annual incidence of new cases of diabetes is approximately 20/100,000 children from age four through age 17, with the highest incidence rates at age nine through age 12. The prevalence rates to be expected, if the most recent incidence rates persist, are approximately 50/100,000 at age five, 150/100,000 at age ten, 270/100,000 at age 15, and 325/100,000 by age 18. The incidence rate of diabetes in Michigan children appears to have doubled between 1959 and 1972. Data from Erie County, New York, suggest that this secular trend has been evident since 1949, and data from Norway suggest that the trend could be noted 50 to 70 years ago.


Glycemic response to 24-hour fast in normal children: III. Influence of age.

A 24-hour fast was performed in 28 normal children-17 boys and 11 girls, 2 to 17 years of age. After the fast, blood was drawn for blood sugar, plasma growth hormone and cortisol, serum free fatty acids and alanine measurements. Blood sugar values ranged between 30 and 77 mg/dl and were significantly correlated to age (R = 0.68, P less than 0.001). Plasma cortisol (R = 0.73, P less than 0.001), GH (R = 0.57, P = 0.01), and FFA (R = 0.76, P less than 0.001) were negatively correlated to age. Serum alanine fasting values ranged between 10 and 36 micrometer/dl and were significantly correlated to age (R = 0.86, P less than 0.001) and to blood sugar values (R = 0.54, P less than 0.01). These data demonstrate that carbohydrate regulation during fast improves with age in children, correlating with higher levels of gluconeogenic substrates and a lower rate of lipolysis.


Persistence of maternal antibody in infants beyond 12 months: mechanism of measles vaccine failure.

A serologic study was made in 34 children immunized against measles at the age of 12 months. Using a sensitive virus neutralization test, it was found that many of the children had pre-existing maternal antibody to measles virus. Children with high pre-existing antibody titers failed to seroconvert. Children with lower pre-existing antibody titers seroconverted, but the resulting antibody titer was significantly lower than in children without pre-existing antibody titer. The results of this study demonstrate a probably mechanism for measles vaccine failure in 12-month-old children and support the recommendation of the Public Health Service Advisory Committee on Immunization Practices to postpone measles vaccination to 15 months of age.


Radionuclide bolus angiography: a technique for verification of brain death in infants and children.

Fifteen infants and children, 11 of whom had clinical brain death and four of whom were comatose, were evaluated with the radionuclide bolus study and electroencephalography. Clinical criteria for brain death included: (1) absence of spontaneous respirations, (2) absence of cephalic reflexes, and (3) unresponsiveness. Results demonstrated complete correlation among clinical examination, EEG, and radionuclide study in 79% of cases. An approach to the evaluation of the infant or child with possible brain death is outlined utilizing serial examinations, radionuclide bolus study, and electroencephalography. The radionuclide bolus study appears to be a safe, rapid, portable technique which can be used for this purpose in infants and children.


Plasma prostaglandin E concentrations from birth through childhood.

The prostaglandins are synthesized in a variety of tissues and participate in an extensive number of physiologic processes. As prostaglandin concentrations have not been reported in infants and children, we measured PGE levels from birth through childhood. PGE levels in cord blood were significantly higher than those in adults. By 48 to 72 hours of age, however, they had fallen to levels that were significantly lower than those in adults. Although PGE concentrations increased with age, they remained significantly lower than did adult levels. These low levels may be related to some of the functional pecularities of the immature kidney.


The renal lesion in congenital chloride diarrhea.

Congenital chloride diarrhea is an inherited defect of active intestinal Cl- transport which results in a large wastage of electrolytes and water. The effects of this disease and of replacement therapy on renal histology, function, growth, and the renin-angiotensin-aldosterone system were studied in 18 patients. When the patients were given KCl supplement, histologic findings included juxtaglomerular hyperplasia hyalinized glomeruli, calcifications, and arteriolar changes. Renal function and growth were reduced, and the hormonal activities were high. These abnormalities were evidently due to chronic dehydration. The dehydration could be corrected by increasing the dose of KCl, but only the addition of NaCl corrected the hyperaldosteronism. Adequate replacement therapy prevented the renal involvement.


A female patient with "Aase syndrome".

A girl with congenital hypoplastic anemia and triphalangeal thumbs (Aase syndrome) is described. This is the second report of these features is a female patient, making autosomal recessive inheritance a probable explanation.


Treatment of neonatal hypoglycemia with continuous intravenous glucose infusion.

The treatment of neonatal hypoglycemia by constant infusion of glucose at the rate of 8 mg/kg/minute was studied in 22 hypoglycemic neonates. In 18 neonates glucose levels rose above the hypoglycemic range within ten minutes of infusion and in three, within 30 to 50 minutes of infusion. The remaining neonate had hyperinsulinemia and responded only to diazoxide. Constant glucose infusion was found to be useful therapeutically for neonatal hypoglycemia.


Lack of gastrointestinal enhancement of the insulin response to glucose in newborn infants.

Forty-five normal newborn infants were infused with glucose at constant rates by intravenous or nasogastric routes. Blood glucose rose to higher levels during IV than during NG infusions at identical rates; however, the glycemic responses were similar when NG glucose infusions at 12 mg/minute/kg were compared with IV infusions at 6 mg/minute/kg. The plasma insulin responses to glucose were not enhanced by NG administration. Thus, enterohormonal responses to glucose may not affect pancreatic beta cell regulation of glucose assimilation in the newborn period.


Postnatal growth of infants of less than 1.3 kg birth weight: effects of metabolic acidosis, of caloric intake, and of calcium, sodium, and phosphate supplementation.

Weekly increments of length, weight, head circumference, and skinfold thickness in response to a series of dietary changes were measured in 108 healthy infants who weighed less than 1.3 kg at birth. The serial manipulations included prevention of late metabolic acidosis, increased caloric intake, and calcium, sodium, and phosphorus supplementation. The study comprised four phases; the infants were divided into ten groups according to dietary regimen. AGA and SGA infants were studied separately. Growth in length was primarily influenced by a change to a formula providing a higher caloric intake and a 60:40 whey protein/casein ratio. Correction of late metabolic acidosis, sodium, and phosphorus supplementation had minor additive effects on growth in length. Increased caloric intake also influenced growth of head circumference, but only in AGA infants. Only the sodium intake was shown to influence body weight increments significantly with the range of caloric intake used in the study (132 to 160 calories/kg/day).


The use of prostaglandin E1 in an infant with interruption of the aortic arch.

Infusion of prostaglandin E1 into the main pulmonary artery of an infant with interruption of the aortic arch and a closing ductus arteriosus resulted in dilation of the ductus arteriosus and improved systemic perfusion. Treatment with prostaglandin E1 is recommended for infants with interruption of the aortic arch, critical coarctation of the aorta, and other lesions in which systemic perfusion is limited by a restrictive ductus arteriosus.


Propranolol therapy during pregnancy, labor, and delivery: evidence for transplacental drug transfer and impaired neonatal drug disposition.

The administration of 160 mg of propranolol during pregnancy, labor, and delivery was associated with profound hypoglycemia and respiratory depression in a newborn infant. The neonate's plasma propranolol level rose from 40 ng/ml at the time of birth to 90 ng/ml four hours later. This increase in plasma propranolol concentration might be due to redistribution of the drug in the neonate as well as to different elimination mechanisms than in adults. The elevated propranolol level four hours after delivery was not associated with any signs or symptoms of drug toxicity, but drug effect was apparent on the electrocardiogram. The administration of propranolol during pregnancy in doses capable of producing therapeutic maternal blood levels may be dangerous to the neonate.


Miconazole in the treatment of chronic mucocutaneous candidiasis: a preliminary report.

Miconazole, a new imidazole antimycotic agent, was given intravenously to five children with chronic mucocutaneous candidiasis over an 18-month period. There was marked improvement of mucosa and skin in two patients, moderate-to-milk improvement in two, and no improvement in one. Nail lesions were not improved in any patient. Adverse reactions included phlebitis, pruritus, nausea and dizziness, rash, wheezing, mild transient anemia, and mild transient transaminase (SGOT and SGPT) elevations; it was necessary to discontinue treatment in only one patient. No renal toxocity was noted. Miconazole appears to be a relatively safe and promising alternative to amphotericin B in chronic mucocutaneous candidiasis.


Dose-dependent kinetics of theophylline disposition in asthmatic children.

Prior assumptions of first-order elimination for theophylline were tested by administering theophylline by intravenous infusion at two dosage levels to 20 children with chronic asthma. The resulting steady-state serum concentrations increased to a greater degree than would have been predicted if increases in serum concentration were proportional to changes in dose, and the subsequent calculation of clearance revealed values of 1.37 +/- 0.09 ml/kg/minute (mean +/- SE of the mean) at the lower infusion rate and of 1.21 +/- 0.06 ml/kg/minute at the higher infusion rate (p less than 0.02). Even greater differences in clearance were present among ten of these children whose higher infusion rates were at least two times greater than the lower rate. An additional child was observed who experienced a seizure following a medication error that resulted in a 50% increase in daily dosage and a greater than threefold increase of serum concentration. The nonlinear nature of the relationship between dose and serum concentration suggests that theophylline dosage adjustment should be performed cautiously using small increments.


Absorption of iodine in the neonate following topical use of povidone iodine.

Topical application of povidone iodine on the umbilical cord and normal intact skin of newborn infants resulted in significantly elevated plasma iodine levels. High iodine levels were also found in two neonates who had povidone iodine applied to denuded skin. No significant alteration in thyroid function was seen. The possible toxic manifestations of high plasma iodine levels are discussed.


Self-focused attention and the experience of emotion: attraction, repulsion, elation, and depression.

Four experiments were conducted to study the effect of self-focused attention on affective reactions. In addition, the research was also intended to help resolve the controversy over attentional versus arousal explanations of self-awareness research. In Experiment 1, undergraduate men were asked to view and rate slides of nude women in the presence of a mirror or with no mirror. In Experiment 3, subjects were either exposed or not exposed to a mirror and read a set of mood statements which became either increasingly positive or increasingly negative. Experiments 2 and 4 conceptually replicated Experiments 1 and 3 by selecting subjects on the basis of private self-consciousness. In each study, self-focused attention increased the person's responsiveness to his transient affective state. The convergence between mirror-manipulated self-awareness and private self-consciousness was offered as support for an attentional interpretation of the findings. The implications of the research for self-awareness theory are discussed.


Patterns of interest similarity in adoptive and biological families.

Twin studies have indicated that genetic differences among individuals also contribute to interest and personality differences among them. In this study, 114 biologically related families and 100 adoptive families were administered the Strong-Campbell Interest Inventory. The protocols of parents and their adolescent children (total N = 870) were scored on the six scales of Holland's model of interest styles (Realistic, Investigative, Artistic, Social, Enterprising, Conventional). Biological parent--child correlations ranged from -.13 to +.40, with 15 of the 24 scale correlations achieving significance; only 2 of the adoptive parent--child correlations were significant (range from -.15 to +.25). Biologically related pairs were also significantly more correlated than adoptive pairs for interest profiles. Same-sex biological siblings were more similar to each other than either opposite-sex siblings pairs or parent--child pairs. Pairs of unrelated children in the adoptive families were not too similar either on Holland's scales or the profile analysis.


Self-reference and the encoding of personal information.

The degree to which the self is implicated in processing personal information was investigated. Subjects rated adjectives on four tasks designed to force varying kinds of encoding: structural, phonemic, semantic, and self-reference. In two experiments, incidental recall of the rated words indicated that adjectives rates under the self-reference task were recalled the best. These results indicate that self-reference is a rich and powerful encoding process. As an aspect of the human information-processing system, the self appears to function as a superordinate schema that is deeply involved in the processing, interpretation, and memory of personal information.


Effects of adrenalectomy and adrenergic antagonists on potassium metabolism.

We had previously reported that drugs which stimulate beta-2 adrenergic receptors decreased the hyperkalemia produced by infused KCI and thus protected animals against KCI intoxication; these effects were mediated by an action of beta-2 agonists which enhanced tissue uptake of K+. In this study, cats were given an i.v. infusion of KCI which was not lethal in control animals. Acute adrenalectomy markedly increased the hyperkalemic and mortality responses to infused KCI. This impairment in K+ metabolism was corrected by the administration of epinephrine but not by hydrocortisone. Pretreatment with propranolol (which blocks beta-1 and beta-2 receptors) and H35/25 (which blocks beta-2 receptors) produced a similar impairment in K+ metabolism; on the other hand, practolol (which blocks beta-1 receptors) had little or no effect on the mortality and hyperkalemic responses to infused KCI. Evidence that KCI stimulates an adrenal release of catecholamines is presented. This stimulation of adrenal release may be important in conferring resistance to intoxication produced by infused KCI since the released amines can attenuate the KCI-induced hyperkalemia via a beta-2 action which enhances tissue uptake of K+.


Dose-response behavior on the isolated rat uterus of oxytocin analogs with modifications at binding sites.

The dose-response behavior on the in vitro rat uterus of analogs of oxytocin with modification at sites in the molecule which have been predicted to contribute to the binding of the peptide to the smooth muscle receptor have been studied. Dose-response curves of [7-(3,4-dehydroproline)]oxytocin, [7-glycine]oxytocin, [7-alanine]oxytocin, deamino-[7-glycine]oxytocin and [4-threonine,7-glycine]oxytocin were determined and compared with that of oxytocin. The authors found that neither the slope of the curves nor the maximal response obtained for any of the analogs differed significantly from the hormone. The uterotonic potencies of the analogs corresponded to the relative positions along the concentration axis of their dose-response curves and to their affinities as determined by their pD2 values. The authors tentatively concluded that differences in uterotonic potencies of these analogs are in fact the result of differences in their affinity for the uterine receptor. The experimental identification of position 7 of neurohypophyseal peptides as a hormone-receptor binding site corroborates such a proposed role for the side chain of this residue based on earlier conformation-activity considerations.


Central and peripheral adrenergic mechanisms regulating gastric secretion in the rat.

Subcutaneous injection of sympathomimetic agents reduced gastric secretion in pylorus-ligated rats, and the decreasing order of activity was: isoproterenol, norepinephrine, naphazoline and phenylephrine. The effect of naphazoline and phenylephrine was antagonized with 4 mg/kg s.c. of phentolamine, and that of isoproterenol with 4 mg/kg s.c. of propranolol. Thus there exist separate, alpha and beta adrenergic receptors which control gastric secretion in the rat. Intracerebroventricular (i.c.v.) injection of the sympathomimetic agents also reduced secretion, naphazoline being the most potent. The ED50 of i.c.v. naphazoline was 12.3 times less than that of s.c. dose. The antisecretory effect of i.c.v. naphazoline was antagonized with i.c.v. phentolamine (0.016 and 0.064 mg/kg), but not with propranolol. These results suggest that naphazoline stimulates central alpha adrenergic receptors which has a tonic inhibiting role in rat gastric secretion. Analogous to the results with naphazoline, i.c.v. phentolamine, but not propranolol, blocked an antisecretory effect of chlorpromazine. Phentolamine administered s.c. also reduced the antisecretory activity, but the dose required for the antagonism was 250 times that of i.c.v. phentolamine. An antisecretory effect of imipramine was not blocked by phentolamine or propranolol. These results suggest that an activation of central alpha adrenergic receptors is important for the antisecretory effect of chlorpromazine.


Adjuvant polyarthritis. II. Suppression by tilorone.

Tilorone (5-35 mg/kg/day) suppressed the development of adjuvant-induced arthritis and the concurrent development of cell-mediated immune response to a secondary immunogen(EL4 cells) in a dose-related manner. Its influence on the development of the humoral immune response tp EL4 cells was found to be dependent on dosage: stimulatory at low doses (7.5 and 11.0 mg/kg/day), but inhibitory at high doses (24.0 and 35.0 mg/kg/day). Single doses of tilorone (30-300 mg/kg), administered at 24 hours or 1 hour before the injection of carrageenan, suppressed the development of acute inflammation in the rat. Evidence is presented that neither the anti-inflammatory effect of tilorone, nor its influence on the immune response could account for its antiarthritic effect. It appears plausible that the compound may act via interferon induction.


Relationships, among the steroids, of anti-inflammatory properties and inhibition of prostaglandin production and arachidonic acid release by transformed mouse fibroblasts.

Anti-inflammatory steroids inhibit the serum-stimulated prostaglandin synthesis and release of [3H]arachidonic acid by methylcholanthrene-transformed mouse fibroblast, MC5-5. The half-maximal concentration for inhibition of both effects parallels the relative anti-inflammatory potencies of these steroids. The fatty acid cyclooxygenase activities of microsomal fractions isolated from cells that had been pretreated with dexamethasone were similar to the activities of microsomal fractions isolated from untreated cells. Intracellular as well as extracellular levels of prostaglandins in dexamethasone inhibited cells were decreased. The anti-inflammatory steroids seem to be blocking deacylation of the phospholipids or transport of the arachidonic acid, after deacylation to the cyclooxygenase.


Pharmacokinetics of some homologous series of barbiturates in the intact rat and in the isolated perfused rat liver.

The pharmacokinetics of a number of 5,5-dialkyl-substituted barbiturates was studied both in the intact rat and in the isolated perfused rat liver. The half-life or the clearance of a reference compound was used as parameter for the drug metabolic activity of the animal and perfused liver. The rate of elimination of the barbiturates was structure-dependent and seemed to be correlated with the lipophilicity of the compounds which was expressed as the octanol-water and hepatocytes-water partition coefficient. Three features could be distinguished. Firstly, there was a decrease in half-life with the introduction of a larger alkyl side chain. Secondly, substitution of a bromoallyl instead of an allyl group had the same effect and thirdly, a more rapidly eliminated barbiturate could be obtained by the introduction of a methyl group onto the nitrogen of the barbiturate nucleus. The elimination clearance constants relative to the heptabarbital clearance were in the same order of magnitude as those found in man. This result suggests that it is possible to predict the clearance values in man by studying relative values in rats.


Naloxone antagonizes narcotic self blockade of emesis in the cat.

Morphine, levorphanol, fentanyl and methadone given by intracerebroventricular (i.c.v.) injection blocked the vomiting response to a standard emetic test dose of apomorphine subsequently injected i.c.v. Of these narcotics, only morphine initially evoked vomiting. Systemic pretreatment with naloxone (5 mg/kg i.p. or i.v.) uniformly abolished the antiemetic activity of all the represented narcotic agents, moreover, naloxone thus administered was followed consistently by emetic responses to those narcotics which separately failed to evoke vomiting. When naloxone was injected i.c.v. in addition to being given systemically, both antiemetic and emetic activities of the narcotic agents were essentially abolished, whereas apomorphine continued to evoke vomiting. In the presence of systemic naloxone, given to counteract self-blockade of vomiting, the narcotics were shown to induce vomiting through excitation of the medullary emetic chemoreceptor trigger zone and emetic receptor tolerance as well as cross-tolerance developed acutely. The present differentiation by naloxone of the emetic and antiemetic properties of narcotic agents placed in the cerebrospinal fluid indicates that the opposing narcotic actions are exercised at different sites in the brain and that the narcotic receptor specificity of the chemoreceptor trigger zone does not encompass the emetic action of apomorphine.


Inactivation of norepinephrine in an isolated vein.

Canine isolated vein strips were labeled with tritiated norepinephrine (NE). Tritiated NE and its metabolites appearing during spontaneous outflow and during electric stimulation (10 Hz, 100 V, 2 msec, 5 minutes) were determined. The spontaneous outflow of tritiated compounds from the vein contained 90.5% metabolic products of NE, chiefly, the O-methylated and deaminated products (OMDA) and 3,4-dihydroxyphenylglycol (DOPEG). During electric stimulation we observed approximately a 3-fold increase in the outflow of radioactivity, consisting of 39% NE, 25% OMDA and 19% DOPEG. Normetanephrine (NMN) and 3,4-dihydroxymandelic acid represented only 10 and 6%, respectively. Blockade of reuptake of NE into nerve terminals by cocaine did not prevent the appearance of deaminated metabolites in the spontaneous outflow. However, when the vein was electrically stimulated the increase of DOPEG was alomst completely blocked. Blockade of extraneuronal uptake of NE by desoxycorticosterone did not modify significantly the composition of spontaneous outflow. However, desoxycorticosterone caused a marked decrease of NMN and OMDA during electric stimulation. The inhibition of catechol-O-methyltransferase by U-0521 caused a decrease of NMN and OMDA during the spontaneous outflow, and a shift from O-methylation to deamination of NE. During electric stimulation, U-0521 markedly decreased the formation of NMN and OMDA and caused an increase in outflow of NE.


Phenytoin teratogenesis: correlation between embryopathic effect and covalent binding of putative arene oxide metabolite in gestational tissue.

The possibility that phenytoin (DPH) teratogenesis is due to an arene oxide (epoxide) metabolite was examined. On gestational day 11, Swiss mice were given teratogenic doses of DPH (50, 75 and 100 mg/kg) with and without a nonteratogenic dose of 1,2-epoxy-3,3,3-trichloropropane (TCPO; 100 mg/kg), an epoxide hydratase inhibitor. TCPO significantly increased the incidence of DPH-induced cleft lip and palate and enhanced the embryolethality 2-fold over DPH alone. Four hours after treatment with 14C-DPH (75 mg/kg, 80-90 muCi) the covalent binding of DPH radioactivity in fetuses and placentae was enhanced 2-fold in groups cotreated with TCPO (100 mg/kg). Enhancement was still evident in placentae 24 hours after treatment. There was no effect of TCPO on maternal plasma DPH level, which was comparable to that found in clinical therapeutics (20-30 microgram/ml). Likewise, fetal and placental DPH uptake was not increased by TCPO. DPH teratogenesis is postulated to result from DPH-epoxide formation and covalent binding of epoxide, the ultimate teratogen, to constituents of gestational tissue.


Dilatation of the mesenteric vascular bed of the dog produced by a peptide, urotensin I.

Urotensin I, a peptide derived from the urophysis of bony fish, produced hypotension when administered intravenously in small doses to pentobarbital-anesthetized dogs. The mechanism of this hypotensive response was mainly, if not exclusively, due to dilatation of the cephalic and caudal mesenteric arteries. Neither the hypotensive response nor the mesenteric vasodilator response was prevented by adrenergic, histaminergic or muscarinic receptor blockade. In the doses employed, urotensin I constantly caused minimal increases in heart rate and left ventricular dp/dt; these changes could be prevented by prior administration of propranolol, indicating that they were probably reflex in origin. The authors suggest that the unique mechanism of action of the peptide may make it a valuable tool in studies of the mesenteric circulation, particularly in experimental shock; moreover, the peptide may prove useful in situations in which afterload reduction in the absence of cardiac stimulation is desired.


Facilitation of Chemoreceptor-induced reflex vasoconstriction by intravertebral arterial administration of clonidine.

The influence of clonidine on the reflex vascular responses to stimulation of carotid body chemoreceptors and bilateral carotid occlusion was studied in morphine, chloralose-urethane anesthetized dogs. Bilateral carotid occlusion and intracarotid injection of nicotine (30 and 100 microgram) or sodium cyanide (200 and 500 microgram) elicited reflex vasoconstriction in the perfused gracilis muscle vascular bed. Infusion of clonidine (2-4 microgram/kg) into the vertebral artery significantly lowered blood pressure. Reflex vasoconstrictor responses to chemoreceptor stimulation were significantly enhanced after clonidine administration whereas reflex vasoconstrictor responses to carotid occlusion were markedly reduced. The facilitation of chemoreceptor reflex responses by clonidine was observed in dogs with intact or sectioned vagi and in animals in which the carotid arteries were perfused at constant blood flow. Inhibition of carotid occlusion responses by clonidine was observed in dogs with intact or sectioned vagi. Infusion of clonidine directly into the carotid arteries did not significantly alter responses to chemoreceptor stimulation. These experiments demonstrate that clonidine antagonizes the reflex vasoconstriction caused by carotid occlusion while potentiating the vasoconstriction elicited by chemoreceptor stimulation. The data suggest that clonidine exerts central actions which result in a facilitation of the chemoreceptor reflex and a simultaneously occuring hypotension which is probably due to an action on baroreceptor pathways.


Effect of ortho-iodo sodium benzoate on hemoglobin-oxygen affinity in normal and ischemic myocardium.

The effect of ortho-iodo sodium benzoate (OISB) on the oxyhemoglobin dissociation curve of coronary venous blood was studied in an isolated canine heart preparation perfused at a constant coronary blood flow. Changes in P-50 (millimeters of mercury) [the oxygen tension (pO2) at which hemoglobin is 50% saturated], were used to express hemoglobin-oxygen affinity. Intracoronary infusion of OISB (200, 400 and 800 mg/min) produced a dose-related increase in coronary venous P-50 and a concurrent increase in coronary venous pO2. In addition, OISB produced a significant decrease in heart rate and increase in coronary artery perfusion pressure. During cardiac pacing at 150, 190 and 230 beats/min, OISB (400 mg/min) significantly increased coronary venous P-50, myocardial oxygen exrraction (O2E) and oxygen consumption (MVO2) whereas coronary venous PO2 was not changed. Furthermore, a 5-minute intracoronary infusion of OISB (200 mg/min) during myocardial ischemia produced an increase in O2E, MVO2 and myocardial contractility with little change in coronary venous pO2. These results suggest that acute pharmacological manipulation of the oxyhemoglobin dissociation curve may enhance oxygen release to the myocardium while maintaining the effective driving pressure (as reflected in coronary venous pO2) for diffusion of oxygen to the myocardium.


Hemodynamic and natriuretic effects of bumetanide and furosemide in the cat.

Renal hemodynamic and natriuretic effects of bumetanide and furosemide were studied by clearance and micropuncture methods in cats. Furosemide (0.04-5.0 mg/kg i.v.) effects increased with increasing doses up to a maximal fractional sodium (FEna) and water (V/GFR) excretion of 23%. GFR and superficial single nephron GFR remained constant. Renal blood flow (RBF) increased up to 45% over control. A preferential increase in outer cortical RBF occurred at 5.0 mg/kg. Bumetanide (0.001-0.14 mg/kg i.v.) raised FEna and V/GFR maximally by 26%. Only at a supramaximal dose (0.69 mg/kg) did bumetanide raise RBF and depress filtration fraction. Probenecid (50 mg/kg i.v.) failed to block the natriuretic effect of bumetanide (0.025 microgram/kg-min) when infused into one renal artery but abolished the natriuretic action of furosemide (1.0 microgram/kg-min). Probenecid failed to displace the dose-response curve for bumetanide.


An extracorporeal complexing hemodialysis system for the treatment of methylmercury poisoning. II. In vivo applications in the dog.

An extracorporeal regional complexing hemodialysis procedure is described which has been successfully applied for the enhancement of removal of methylmercury in the dog. The procedure utilizes the extracorporeal addition of cysteine to arterial blood entering a hemodialyzer, forming a large pool of complexed dialyzable methylmercury in plasma. Diffusion of this methylmercury complex across the dialyzer membrane into dialysate accounts for large amounts of methylmercury being removed from the animal. In conjunction with methylmercury removal, the majority of the infused cysteine is also removed resulting in comparatively low systemic doses of cysteine to the animal. At blood flow rates of 45 ml/min, and dialysate flow rates of approximately 550 ml/min, the mean percentage of methylmercury cleared from blood passing through the dialyzer was 39%. Rates of elimination of methylmercury from the dog could be increased by a factor of 100 during the extracorporeal regional complexing hemodialysis procedure. Regional collimated counting of radioactivity along the length of the dog revealed a decline in all areas including the head region. The procedure was void of any noticeable side effects during treatment or as evidence by histological evaluation of liver and kidney after treatment.


Development of tolerance to the disruptive effects of cocaine on repeated acquisition and performance of response sequences.

Pigeons obtained food by making four responses on three keys in a specified sequence. Errors produced 5-second timeout periods, during which the keylights were off and responses had no effect. To establish a base line of repeated acquisition, the sequence of correct responses was changed from session to session. Cocaine (3 mg/kg) disrupted the behavior: total errors increased, the relative frequency of perseverative errors increased, the rate of within-session error reduction (learning) decreased and the total trial time (pausing) increased. During repeated drug administration (30-50 sessions), these effects disappeared, i.e., tolerance developed. Tolerance did not develop, however, to cocaine-induced increases or decreases in timeout responding; such effects were nondisruptive in the sense thay they did not reduce the rate of food reinforcement. For comparison, cocaine (3-10 mg/kg) was also studied under a "performance" condition, in which the sequence of correct responses was the same from session to session. Cocaine increased performance errors and produced pausing, but tolerance developed more quickly under the learning  condition . The more rapid development of tolerance was presumably due to the stronger stimulus control of behavior under the performance condition.


Studies on tolerance. II. The effect of timing on inhibition of tolerance to morphine by cycloheximide.

Cycloheximide (CX) given 1 hour before each weekly dose of morphine inhibits the development of tolerance. The temporal relationship of the doses of CX and morphine sulfate seems to be a most important factor. CX (1 mg/kg s.c.) given 24 hours before, 6 hours before or 6 hours after weekly morphine injections (10 mg/kg s.c.) does not affect the rate or the degree of tolerance development. The inhibition of tolerance seen after weekly administration of CX plus injections of morphine is not seen until several weeks after drug treatment has begun and the difference between the morphine only and the morphine plus CX groups persists for a number of weeks after drug treatment has been terminated. The inhibition of tolerance seen after CX does not appear to be due to any nonspecific debilitating effect of CX. However, it may be related to the ability of CX to suppress protein synthesis. The identity of the proteins involved or how they are involved in the tolerance phenomenon remains unclear.


The effect of maternally administered methadone on brain development in the offspring.

Chronic methadone administration to female rats before, during and after gestation resulted in a delay or deficiency in brain development in their offspring compared with offspring of control rats. This deficiency in development was most noticeable as a decrease in protein and RNA content. A reduction in overall brain weight and DNA was less marked and paralleled a slight reduction in overall body weight. A comparison of the RNA/DNA and RNA/protein ratios suggested that the primary cause of the deficiency was associated with the RNA synthesis. Preliminary behavioral studies showed a significant decrease in ability of offspring of treated females to respond to a conditioning stimulus in order to avoid an electric shock. Even though upon gross observation the offspring from treated females seem normal, biochemical analysis and behavioral testing suggest that minimal brain deficiencies lasting weeks to months do occur.


The purification of antimorphine antibodies by affinity chromatography.

Affinity chromatography was employed successfully to purify extensively antimorphine antibodies produced in rabbits. Morphine succinylated at position 6 was attached to bovine serum albumin to make it immunogenic and to Sepharose beads for affinity chromatography. A crude gamma-globulin fraction of antimorphine serum, prepared by salt fractionation, was used for purification. After unbound gamma-globulin was washed off the column with phosphate-buffered saline, two populations of antimorphine antibodies were eluted in succession by two low pH buffers. Each of these two purified antibody fractions had an index of heterogeneity of approximately 1. Immunoelectrophoresis indicated that the antibodies were immunoglobulin G and that they formed a single precipitation band with antirabbit serum. The average association constants for morphine of the two purified antibody fractions were similar and ranged from 4.5 to 4.8 X 10(7) LITERS/MOL-1. A 67-fold purification of the antimorphine antibodies could be achieved by a single pass through an affinity column.


The in vitro metabolism of halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) by hepatic microsomal cytochrome P-450.

Incubation of halothane with rabbit liver microsomes in the presence of NADPH and oxygen resulted in the formation of trifluoroacetic acid (TFAA). No TFAA was detected in the absence of either NADPH or oxygen. TFAA also was found when a 9000 x g supernatant fraction (with NADPH and oxygen) was used instead of the microsomal fraction. The 105,000 x g supernatant fraction (with NADPH and oxygen), however, did not produce detectable levels of TFAA. Phenobarbital pretreatment of the animals resulted ina significant increase in both the formation of TFAA and the cytochrome P-450 content of microsomes. A good correlation was found between formation of TFAA and microsomal cytochrome P-450 levels. The amount of TFAA formed in hepatic microsomes was significantly inhibited by carbon monoxide (CO), SKF 525-A (2-diethylaminoethyl-2,2,-diphenylvalerate HCl) and p-chloromercuribenzoic acid. On the other hand, TFAA was formed when NADH was used as an electron donor instead of NADPH. In conclusion, these results clearly demonstrate the metabolism of halothane by the hepatic microsomal mixed-function oxidase system.


Radioimmunoassay of atropine in plasma.

Antibodies, against atropine, were produced in rabbits immunized with atropine conjugated to bovine serum albumin. The antisera possessed a high binding affinity and were quite specific. The sensitivity of the method allowed detection of 6.25 ng of atropine per ml of plasma in a 10-microliter specimen. The method does not require an extraction procedure and can be performed using very small volumes  of plasma. Plasma concentration-time profiles were determined by this method in dogs after rapid i.v. administration of atropine. Atropine declined from plasma in a biexponential fashion, exhibiting a terminal half-life of approximately 2.1 hours.


The effects of temperature acclimation on monoamine metabolism.

Serotonin and dopamine content in the central nervous system of Mytilus edulis (Bivalvia) was assayed fluorometrically. Acclimating the animals for 2 to 4 days at a constant temperature higher than the environmental temperatures produced substantial increases in endogenous central nervous system serotonin and decreases in dopamine. p-Chlorophenylalanine and alpha-propyldopacetamide not only prevented this increase but reduced serotonin levels below those of unacclimated animals. Cycloheximide decreased the magnitude of the serotonin rise due to acclimation. Endogenous gill serotonin after acclimation also was higher. Gill filaments closest to the visceral ganglia were the first to increase. The study shows that hydroxylation of tryptophan is a temperature-sensitive step and axonal transport of tryptophan hydroxylase to the periphery accounts for terminal serotonin synthesis. A central pool of serotonin distinct from the peripheral pool was demonstrated. The study supports previous evidence of dopamine exerting a regulatory influence on serotonin metabolism in M. edulis.


The influence of prostaglandins E1 and E2 on ouabain cardiotoxicity in the cat.

The capacity of prostaglandins E1 (PGE1) and E2 (PGE2) to influence the lethal dose and lethal myocardial content of ouabain was studied in intact cats and cats whose spinal cords had been transected. The administration of PGE1 and PGE2 to intact cats was associated with an increase in lethal dose and ventricular content of ouabain. Spinal cord transection alone was also associated with an increase in lethal dose and ventricular content of ouabain. The administration of either PGE1 and PGE2 to animals whose spinal cords had been transected changed neither the lethal dose nor the lethal ventricular content of ouabain compared with cats whose spinal cords were transected but who received only ouabain. The present data suggest that PGE1 and PGE2 are effective agents for prophylaxis of ouabain-induced arrhythmias in the cat. The failure to observe an additional antiarrhythmic effect in animals whose spinal cords had been transected implies that the nervous system plays an important role in the antiarrhythmic action of the prostaglandins.


Renin inhibitory effect of 2-[4-(4'-chlorophenoxy)phenoxyacetylamino]-ethylphosphorylethanolamine (PE-104) in vitro and in vivo.

The renin inhibitory activity of 2-[4-(4'-chlorophenoxy)phenoxyacetylamino]ethylphosphorylethanolamine (PE-104) was examined in vitro and in vivo. PE-104 inhibited the reaction between dog renal renin and homologous plasma angiotensinogen. The Ki value was 2 mM and the inhibitory mode was competitive and reversible. Data concerning the relationship between renin inhibitory activity and the chemical structure indicated that the whole structure was required for inhibitory activity of PE-104. PE-104 did not inhibit the caseinolytic activities of pepsin, papain and trypsin at 10 mM, the dose of which inhibited renin activity by more than 80%. In normotensive rats, infusion of PE-104 (20 mg/kg/min) abolished increases in blood pressure, plasma renin activity and plasma angiotensin I concentration after injection of renin. In two kidney model renal hypertensive rats, infusion of PE-104 resulted in decreases in blood pressure, plasma renin activity and plasma angiotensin I concentration.


Dynamic properties of polyelectrolyte calcium membranes.

Shashoua observed spontaneous oscillations in a polyelectrolyte membrane formed by interfacial precipitates of polyacid and polybase. We have here undertaken experimental and theoretical studies of polyglutamic acid-Ca++ membrane in order to clarify the processes involved in this dynamic behavior. We find a region of distinct hysteresis in the voltage current curve for this system. A sharp transition from a state of low membrane resistance to one of high resistance occurs at a current density different from that of inverse transition. This membrane system is modeled as a two layer structure: a negatively charged layer alpha made of ionized polyelectrolyte in series with a neutral region beta in which the polymeric ionic sites are masked by calcium ion. This structure results in a difference in the transference number for the mobile ions, causing salt accumulation at the interfacial region during a current flow in the alpha to beta direction. This altered salt concentration induces a change of polymeric conformation, which in turn affects the membrane permeability and the rate of accumulation. Based upon nonequilibrium thermodynamic flow equations, and a two-state representation of membrane macromolecular conformation, this model displays a region of hysteresis in the current range of experimental observations.


High school contact among persons with leukemia and lymphoma.

We studied frequency of contact among Connecticut high school students and teachers with leukemia and lymphoma diagnosed during or after high school from 1960 through 1971. Risk of having attended the same grade at the same school during the same year was greater among students with Hodgkin's disease (HD) than among simulated controls drawn in proportion to school enrollment (relative risk = 1.44; approximate 95% lower confidence limit = 1.05). Risk of developing HD was also greater among students enrolled simultaneously at the same school as students already diagnosed with HD than among students not so enrolled (relative risk = 2.05; 95% lower confidence limit = 1.39). However, fewer HD cases (16) were diagnosed from 1965 through 1970 at schools that formerly had patients enrolled (1959-64) than at matched schools without such patients (24). We found no evidence of increased contact among persons with non-HD lymphomas or leukemias, except between HD and non-HD lymphomas (relative risk = 1.41; approximate 95% lower confidence limit = 1.11).


Comparison of urinary and plasma hormone levels in daughters of breast cancer patients and controls.

Plasma and urinary levels of estrogens and progesterone were studied on days 11 and 22 of the menstrual cycle in 27 teenage daughters of breast cancer patients and 25 teenage daughters of controls. Plasma and urinary values correlated well, which implied that most previous findings based on urinary levels of these hormones were applicable to their plasma levels. The "estriol ratio" (urinary estriol:urinary estrone plus estradiol) hypothesis was not supported by this study, the ratio having been no lower in the daughters of breast cancer patients than in daughters of controls. The day-11 results showed elevated plasma prolactin-estrogen values in daughters of breast cancer patients; the day-22 results did not.


Regular drug use and cancer.

An extensive survey study of 25,000 patients admitted to 24 Boston-area hospitals during the first 10 months of 1972 provided data which were used to estimate the proportion of cancer that is likely to be due to recent regular intake of drugs normally used to treat illness. Cancer was diagnosed for the first time in some 800 patients. The regular drug use before admissions among these patients was compared to that of 3,443 non-cancer patients admitted for conditions thought to be unrelated to any regular drug use. Controlling for age and sex, the risk ratio point estimate for any regular drug use among cancer patients was 0.88 when compared to that of reference patients. The 90% upper confidence bound was 1.02. These data indicate with 90% confidence that less than 1% of the cancers identified in this study were likely to have been caused by any recent regular use of drugs.


Metabolism of acyclic and cyclic N-nitrosamines in cultured human bronchi.

The metabolism of carcinogenic N-nitrosamines was studied in normal-appearing bronchial specimens obtained from 4 patients. Explants of bronchi were cultured in a chemically defined medium for 7 days. N-Nitrosamines [N-nitrosodimethylamine (DMN), N-nitrosodiethylamine (DEN), N,N'-dinitrosopiperazine (DNP), N-nitrosopyrrolidine (NPy), and N-nitrosopiperidine (NPd)] labeled with 14C were each then added at 100 mumoles for 24 hours. Measurable CO2 was formed by bronchial explants from: 1) DMN, DEN, and NPy in all 4 patients; 2) DNP in 3 of 4 patients; and 3) NPd in only 1 of 4 patients. In all bronchial specimens, these N-nitrosamines and/or their metabolites bound to bronchial mucosal DNA and protein. Binding levels were higher to protein than to DNA. Binding levels of DNP were as high as those with the two acyclic N-nitrosamines DMN and DEN, but binding levels of NPy and NPd were lower. Human bronchus was shown to metabolize and bind acyclic and cyclic N-nitrosamines found in the environment and in tobacco smoke.


Geographic patterns of breast cancer in the United States.

To seek explanations for the geographic variation of breast cancer across the continental United States, we calculated the correlations between mortality rates for premenopausal and postmenopausal women and demographic data for the 3,056 U.S. counties. The northern predominance of this tumor was primarily among postmenopausal women, whereas mortality among premenopausal women was distributed almost uniformly across the country. Socioeconomic status (particularly income), German ethnicity, and colon cancer mortality were strong indicators of the rates for postmenopausal women, but only partly explained the northern excess and latitudinal gradient. In contrast, fertility patterns and ovarian cancer mortality were more closely linked to breast cancer among premenopausal women. The geographic peculiarities of this tumor in older women suggest extrinsic risk factors that remain to be identified, whereas the patterns for younger women point to the primary role of reproductive and genetic determinants.


Families with multiple cases of urinary system tumors: brief communication.

A study of three families living in villages with endemic nephropathy (EN) in Vratza district, Bulgaria, revealed 9 members with urinary system tumors (UST), 7 with UST and EN, and 7 with EN. Most cases were registered from 1962 to 1976. The predominant form was transitional cell neoplasms of the kidney pelvis and ureter in patients 40-60 years old. In about 40% of the patients more than one site in the urinary system was involved. One ovarian carcinoma was also registered in these families during this period. Persons related by marriage and coming from nonendemic families and villages were also affected by both diseases. In other branches of the three families living in other households or villages, only one case  of EN was found.


Lung cancer risk among beauticians and other female workers: brief communication.

Lung cancer risk among occupational groups of women was reviewed. A previous suggestion of a sixfold risk of developing lung cancer among beauticians was not confirmed; however, an approximately twofold risk was found.


Systemic effect of benign and malignant mammary tumors on the spin-lattice relaxation time of water protons in mouse serum.

The spin-lattice relaxation time (T1) for water protons in sera was significantly (P less than 0.001) elevated above that for normal sera in mice bearing benign ductal papilloma and malignant mammary carcinoma. Serum T1 values did not differ significantly in mice with ductal hyperplasia or preneoplastic alveolar nodules. Elevated serum T1's could not be explained on the basis of serum iron levels or serum protein concentrations. This was the first report of a "systemic effect" of serum T1 elevation by a benign tumor.


Immunotherapy of metastatic cancer in guinea pigs: failure of intralesional BCG to influence the results of radical surgery.

Guinea pigs with growing intradermal transplants of a syngeneic hepatoma treated by intralesional injection of living BCG at a time when lymph node metastases were detectable by palpation were not cured but survived longer than did the controls. Treatment of the animals by excision of the transplant and draining lymph nodes, instead of by BCG, resulted in a significant number of cures. The cure rate of animals receiving both treatments was not demonstrably greater than that obtained in animals receiving surgery alone.


Further studies on the effect of leupeptin, a protease inhibitor, on induction of bladder tumors in rats by N-butyl-N-(4-hydroxybutyl)nitrosamine.

The effect of a microbial protease inhibitor, leupeptin, on the induction of urinary bladder tumors in W rats by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was examined. Three groups of animals were given 0.01% BBN in their drinking water for 12 weeks. A basal powder diet supplemented with 0.1% leupeptin was given to group A throughout the experiment and to group B when BBN administration was stopped. Group C was given the basal  diet without leupeptin throughout the study. The total preservation period was 40 weeks. Results clearly showed that when leupeptin was given during the promotion step of bladder carcinogenesis (as in group B), it increased the size of tumors and the incidences of cancer and invasion. When leupeptin was given throughout the experiments, its effect was counteracted (as in group A).


Mycobacterium bovis (BCG) infection of the lymph nodes of normal, immune, and cortisone-treated guinea pigs.

Strain-2 inbred guinea pigs were infected intradermally with 10(5)-10(7) viable BCG (Pasteur) organisms by means of multiple scarifications of shaven midflank skin. The spread of the BCG to the draining lymph nodes and on to the spleen was followed quantitatively for 28 days. The population of bacilli at the inoculation site increased as much as tenfold the first 14 days. The number of viable BCG organisms recovered from the primary draining superficial dorsal axillary and inguinal lymph nodes varied from 0.1 to 1.0% of the inoculum, with a further tenfold to 100-fold drop in counts for the secondary subclavian and lumbar lymph nodes. The bacterial counts for the various nodes increased substantially the first 14 days. By 28 days, as many as 1,000 viable bacilli were recovered from the spleen. Increasing the inoculum size or the number of inoculation sites increased the primary node counts and promoted a more extensive and rapid spread by the BCG population to the secondary lymph nodes and spleen. Prior vaccination of the host with living BCG decreased the spread of the BCG inoculum from the scarification site to the various draining lymph nodes. Multiple injections of cortisone tended to reverse this effect.