Why monitor serum levels of gentamicin?

Why monitor serum levels of gentamicin? Although it is widely recommended that serum levels of aminoglycoside antibiotics be monitored by assay, the justification for this approach has not been clearly presented. A number of studies indicate that serum levels of these agents cannot be predicted reliably on the basis of simple dosage formulae; the major confounding factors being abnormalities of renal function and of extracellular fluid volume in addition to less well defined variables such as fever and anaemia. The influence of haemodialysis and concomitant administration of carbenicillin further complicate dosage estimations in patients with renal insufficiency. On the basis of currently available data, it is reasonable to suggest an optimum range of 5 to 8 microgram/ml for peak serum levels of gentamicin. There are no reliable studies from which to derive a comparable value for trough (pre-dose) concentrations. The relative importance of peak and trough values for nephrotoxicity and ototoxicity is an unresolved subject of controversy. However, it seems possible that neither of these individual values, but rather the 'area under the time-concentration curve' is the major risk factor for toxicity. In view of the unpredictability of serum levels, especially in seriously ill patients in a fluctuating physiological state, periodical serum gentamicin assays should be performed. The main objective of these assays is to ensure that the peak serum levels attained are adequate, but not unnecessarily high.


Correlation of the "EMIT" with a gas-liquid chromatographic method for determination of antiepileptic drugs in plasma. We report a study of the comparison of antiepileptic drugs (phenobarbital, phenytoin, primidone, and carbamazepine) by the Enzyme Multiplied Immunoassay Technique "EMIT" and the gas chromatography (GLC) method. Overall, reasonable correlations were observed for all of the above-mentioned assays by both methods in the majority of samples included in this study. Our observations for statistical and clinical differences at various levels of phenobarbital and phenytoin are discussed. A suggestion is provided in order to avoid a major discrepancy (approximately 30% higher values by EMIT vs GLC) in results observed from the "Bottom of the Bottle Effect" for EMIT reagent.


Covariance analysis (for comparison of caries increments) in clinical trials of caries-prophylactic agents. The validity of the assumptions of linearity, parallelism and homogeneity underlying the use of covariance analysis were tested using data from two 3-year clinical trials of caries-prophylactic agents in which over 900 children aged 11-12 years participated. Three covariables were used; initial DMFS (IDMFS), initial surfaces at risk (ISAR) and IDMFS X ISAR/IDMFS + ISAR. For all three covariables the assumptions of linearity and parallelism could not be rejected. However, wide departures from the assumption of homogeneity were found, and it was concluded that analysis of covariance was not appropriate for comparing the caries increments investigated.


Clinical and immunological aspects of sporotrichosis cutanea. A series of 14 cases of sporotrichosis cutanea is reported. Epidemiological and clinical aspects of the disease are discussed in the light of recent data. In addition to cultures, the diagnostic methods to be considered include an indirect immunofluorescence test, which is positive at variable titre and for which use may be made of normal human antiserum or anti-immunoglobulin, mainly IgG and IgM, antisera. The mainstay of the treatment is preparations of iodine, with trimethoprim- sulpha-methoxazole as a possible alternative.


The treatment of chronic pyelonephritis with carindacillin. Forty-two patients with a radiologically confirmed diagnosis of chronic pyelonephritis were treated with 1 g carindacillin every 6 hours over a period of 6 weeks. An underlying urological disease was present in 84% of the 38 patients for whom sufficient data were available for evaluation. The results of carindacillin treatment, as judged by bacteriological evaluation 1 month post-treatment, were good in 12 (32%) and moderate in 9 of the patients. This success rate was remarkable in that all of the patients had been treated previously with one or more other antibiotics and chemotherapeutic agents with little or no response. The authors recommend that, because carindacillin has proved so valuable in treating chronic as well as acute urinary tract infections, its use should be limited to patients with serious disease who have not responded to other treatment.


Treatment of adult respiratory distress syndrome with diuretics, dialysis, and positive end-expiratory pressure. Twelve patients were treated prospectively for adult respiratory distress syndrome with diuresis and low levels (less than or equal to 20 mm Hg) of positive end-expiratory pressure. Eight patients responded to diuretics and two to dialysis by an increase in static compliance of the respiratory system, improvement in arterial oxygen tension and an increased urine output. Two patients did not respond with an improvement in these tests. Responses were transient and multiple doses were required to produce a sustained effect. Even with improvement of pulmonary function after treatment, the mortality was 67%, similar to that reported from other centers since 1975. Recently a new treatment protocol has been proposed that uses high positive end-expiratory pressure (greater than or equal to 20 mm Hg) early in the course of adult repiratory distress syndrome; mortality using this technique was 20%. The difference in survival may be more apparent than real since each center has a unique population of patients and time of initial therapeutic intervention. A randomized collaborative study comparing treatment protocols is needed.


The relationship of bronchopulmonary dysplasia to the occurrence of alveolar rupture during positive pressure ventilation. The effect of altered mechanical ventilation on the incidence of alveolar rupture and bronchopulmonary dysplasia (BPD) was reviewed in infants who had neonatal respiratory distress syndrome (RDS) (N = 99). From 1971 to 1974 we attempted to minimize pulmonary oxygen exposure. Accordingly, during the resolution of respiratory distress syndrome, the ventilator pressures were not reduced until the FIO2 had been lowered to 0.4 (n = 61). In 1974 to 1975 earlier reduction of pressure was instituted as the FIO2 was lowered to 0.6 or less (N = 38). Birth weight and gestational age were comparable in the two groups. With earlier reduction of ventilator pressures, there was a significant decrease in the duration of exposure to peak inspiratory pressures greater than or equal to 40 cm H2O (p is less than 0.004) and greater than or equal to 50 cm H2O (p is less than 0.002). The incidence of alveolar rupture during postive pressure ventilation fell from 51 to 24% (p is less than 0.015) and bronchopulmonary dysplasia from 41 to 13% (p is less than 0.003). In addition, there was a decrease in the duration of mechanical ventilation (p is less than 0.02) and exposure to an FIO2 is greater than or equal to 0.6 (p = 0.07). The results confirm the intimate relationship of pulmonary barotrauma, as reflected by the occurrence of alveolar rupture during positive pressure inflation of the lungs, to the subsequent development of bronchopulmonary dysplasia and that prevention of the former is associated with a concomitant fall in incidence of the latter.


Double-blind trial comparing bufexamac infiltrations with triamcinolone acetonide infiltrations in patients with periarthritis of the shoulder. A double-blind trial was carried out in 40 patients with an acute episode of periarthritis of the shoulder to compare the effectiveness and toleration of local infiltrations of bufexamac and triamcinolone acetonide. Patients received 1 or 2 local infiltrations with either 20 mg bufexamac or 40 mg triamcinolone acetonide. The results were evaluated by objective and subjective assessments of pain, loss of function, mobility, and by doctors' and patients' opinions of relief. There was a significant, comparable reduction in pain and discomfort in both groups after the first injection. Fourteen patients in each group required a second injection, with slightly more improvement in those receiving bufexamac. Local intolerance of the injections was noted in approximately 25% to 30% of the patients.


The bird Mark 8 time cycled servo ventilator. A bird Mark 8 ventilator has been modified by a time cycled servo mechanism to function as an inexpensive ventilator with high peak pressure capabilities. This system was designed to deliver IMV-PEEP therapy at levels not usually available on commercial ventilators. IMV rate can be varied from 1 to 60/min, Vt from 0.1 to 2 liters. Inspiratory pressure in excess of 200 torr and PEEP from 1 to 25 torr can be generated. Modifications to the Mark 8 cost $750.00. The ventilator has been successfully used in over 100 patients. Transport and operating room use are facilitated because it is solely pneumatically powered. Thus, an inexpensive, reliable and versatile ventilatory support system with high peak pressure capabilities has been developed and successfully used.


'Patient failure' as a reliability model for the 'minipill': a clinical study. A trial was carried out in 10 healthy women to study the effects of withdrawal of treatment with 0.5 mg lynestrenol per day, for 3 successive days during the pre-ovulatory phase, on the physiological properties of the cervical mucus, vaginal cytology and pituitary and ovarian functions. In most cases, the amount, Spinnbarkeit and ferning of the cervical mucus and sperm penetration remained the same as that before interruption of treatment. In 2 women, the ferning altered to 'good' for 2 to 3 days as the amount of mucus increased slightly. Spinnbarkeit increased at the same time and sperm penetration was good. The changes in LH and FSH excretion suggested that ovulation possibly took place in 1 of the women studied. A mid-cycle oestrogen peak was seen in 2 women. No side-effects were reported during the study apart from irregular intermenstrual bleeding in 1 woman.


Glipizide in the treatment of maturity-onset diabetes: a multi-centre, out-patient study. A multi-centre clinical assessment was carried out in 592 diabetic patients to study the efficacy and tolerance of glipizide under normal out-patient conditions. Of the total group, 347 patients were maturity-onset diabetics who had received no previous treatment or only dietary control. The other 245 patients had previously received treatment with other hypoglycaemic agents, including insulin in 23 cases. Mean initial dosage was 7.5 mg glipizide per day and this increased over the 3-month period of the study to 10.1 mg in the total group (9.3 mg in new patients). Mean post-prandial blood glucose levels and glycosuria fell rapidly during the first week and then continued to decrease slowly. Changes in mean body weight were somewhat erratic during the trial and at 12 weeks there was an apparent mean increase of 1 kg. After allowing for dropouts, analysis of the results showed that 96.7% of the new patient group and 90.5% of the total group were satisfactorily controlled and maintained on glipizide. Patient tolerance was good, and only 28 (4.7%) patients complained of side-effects, almost half of which related to mild, transient hypoglycaemia.


Poor hypotensive response and tachyphylaxis following intravenous labetalol. Three renal patients with transplant kidneys and uncontrolled hypertension were treated with intravenous doses of labetalol. Only minor depressor effects were noted and tachyphylaxis developed in 1 patient. Other parenteral hypotensive agents reduced blood pressure satisfactorily.


Oxaprozin versus aspirin in rheumatoid arthritis: a double-blind trial. A parallel double-blind trial was carried out over a 3-month period in 40 patients suffering from active rheumatoid arthritis to compare the anti-inflammatory effectiveness and side-effects of treatment with oxaprozin and aspirin. The results showed that 1200 mg oxaprozin daily had similar anti-inflammatory properties to those of 3.9 g aspirin daily in rheumatoid arthritis. Better results were produced with 1200 mg oxaproxin daily than with a 600 mg dosage level, suggesting that there is a close dose-response relationship. The incidence of side-effects was similar with both drugs. Gastrointestinal intolerance was more frequent and severe in the aspirin group, whereas rash and headache were noted more often in patients receiving oxaprozin.


Efficacy of co-trimoxazole in infantile gastro-enteritis. A comparative, randomized trial was carried out in 105 children, aged between 2 months and 2 years and who were suffering from acute gastro-enteritis, to assess the effectiveness of co-trimoxazole with that of streptomycin and neomycin. Patients were treated in hospital for 5 days or longer and received daily doses either of 50 mg/kg streptomycin or neomycin, or of 6 mg trimethoprim plus 30 mg sulphamethoxazole/kg. Clinical and bacteriological assessments of response to treatment showed that better results were achieved in the co-trimoxazole group, and the duration of illness was also shorter in this this group. In the 3 patients on neomycin and the 12 on streptomycin who did not respond clinically, symptoms were controlled in all of them within 2 to 3 days of being changed over to co-trimoxazole treatment.


Comparative study of salsalate and aspirin in osteoarthrosis of the hip or knee. A short-term, double-blind controlled crossover study was carried out in 20 patients with osteoarthrosis of the hip or knee to compare the effectiveness and tolerance of salsalate and aspirin. After a 1-week placebo washout period, patients received either 3 g salsalate per day or 3.6 g soluble aspirin per day for 2 weeks before being crossed over to the alternative treatment. Paracetamol was used as a rescue analgesic. The results of clinical assessments of pain, stiffness and sleep disturbance, using visual analogue scales, showed that salsalate produced a comparable clinical improvement to that with aspirin, and similar serum salicylate levels. Salsalate, however, was significantly superior to aspirin with regard to side-effects and faecal occult blood loss.


Clinical therapeutic evaluation of methylcysteine hydrochloride in patients with chronic obstructive bronchitis: a balanced double-blind trial with placebo control. A double-blind, between-patient, placebo controlled trial was carried out to investigate the effects of methylcysteine hydrochloride in patients with chronic obstructive bronchitis. After a 2-week washout period on placebo, 30 patients were allocated at random to treatment for 6 weeks with either methylcysteine (1200 mg daily in Week 1, 800 mg daily in Week 2, then 600 mg daily) or with identical placebo tablets on the same regimen. During the post-treatment period, all patients returned to a single-blind placebo regimen (6 tablets daily) for a further 14 days. Assessments were made at the start, at regular intervals during the trial, and at the end of the post-treatment period, of subjective and objective measures of clinical response, and measurements of pulmonary function and certain physico-chemical properties of sputum. The results showed that methylcysteine increased sputum volume, reduced the viscidity of sputum, and significantly improved the subjective assessments of ease of expectoration and severity and frequency of cough, leading to a definite improvement in the patients' clinical state. No side-effects of clinical significance were reported and no abnormalities were found in any of the haematological, hepatic and renal function tests carried out.


Night medication in rheumatoid arthritis. III. the use of sulindac. A double-blind controlled trial was carried out in 18 in-patients with classical or definite rheumatoid arthritis to assess the effectiveness of night-time medication with 100 mg indomethacin plus 10 mg diazepam, 200 mg sulindac, and 200 mg sulindac plus 10 mg diazepam in improving sleep and reducing night pain and the duration of morning stiffness. Patients received each treatment regimen for 1 night. The results from the 17 patients completing the full trial protocol indicated that indomethacin plus diazepam was the most effective of the three regimens, although the differences did not reach conventional statistical significance. It is suggested that in further such studies with sulindac a larger dose and a longer duration of treatment should be used.


A comparative trial of ketoprofen and ibuprofen in patients with rheumatic disease. A comparative controlled study was carried out in 40 patients suffering from rheumatoid arthritis, osteoarthrosis or ankylosing spondylitis to assess the efficacy of ketoprofen and ibuprofen. Patients were allocated at random to receive either 100 mg ketoprofen twice daily or 400 mg ibuprofen 3-times daily over a period of 3 months. Subjective overall assessments of symptoms, based on rating scale scores for pain, duration of morning stiffness and inflammation, showed that there was a greater, more rapid and more sustained improvement in those patients treated with ketoprofen. Measurements of inflamed joint size and of grip strength also improved more with ketoprofen than with ibuprofen. Side-effects, notably nausea, epigastric discomfort and abdominal pain, were more frequent and severe with ketoprofen, leading to the withdrawal of 2 patients in the early stage of the trial, and were probably related to the high dosage used. Three patients receiving ibuprofen needed 7 injections of ACTH to control their symptoms.


A double-blind comparison of 0.1% dithranol in a 17% urea base ("Psoradrate") and base alone in the treatment of active chronic psoriasis. A preliminary double-blind controlled trial was carried out in 8 patients with active chronic psoriasis, whose lesions were more or less bilaterally symmetrical, to assess the efficacy of topical treatment with 0.1% dithranol in a specialized carbamide (17% urea) base. The trial preparation was applied twice daily to one side only over a period of 3 weeks, and lesions on the other side of the body were treated in a similar manner with the base alone. Assessments of clinical improvement, based on severity rating scores, were carried out at weekly intervals. The results showed that, although use of the base alone led to some improvement, the preparation including dithranol was twice as effective, and this finding was supported by the patients' preference. It was easy to apply and remove and was well tolerated, the only side-effects reported being stinging and/or smarting.


Systemic complications of commonly used dermatologic drugs. Systemic complications of drugs commonly prescribed by dermatologists fortunately are uncommon. Nevertheless, it is extremely important that the dermatologist be aware of medical contraindications to the use of these agents, as well as their potential systemic side effects. These considerations for methotrexate, sulfones, tetracyclines, and corticosteroids are reviewed.


New cream vehicle for flurandrenolide.

New cream vehicle for flurandrenolide. New methods are now available to help select vehicles for topical corticosteroids. In the development of a new cream vehicle for flurandrenolide, the goal was a cream base with optimal solubility for release of the drug, minimal irritation potential, and no sensitizing preservatives. Vasoconstriction tests make selection much more scientific, and a newer method for such testing is described in detail. Irritation testing then helped determine the vehicle concentration that was least irritating. Final studies included double-blind comparisons with the previous formulation in the treatment of psoriatic patients.


Effects of terbutaline aerosol in reversible airway obstruction. Aerosol terbutaline is an effective bronchodilator agent with at least a seven-hour duration of action in patients with reversible obstruction of the airways. Inhalation of up to 1.5 mg of this drug is not associated with significant alterations of pulse rate and blood pressure. Although a dose-related improvement of specific airway conductance was demonstrated 30 minutes after administration of the drug, no such effect was observed in measurements of the forced expiratory volume in one second.


Beta-adrenergic blockade of the lung. Dose-dependent cardioselectivity of tolamolol in asthma. Beta-adrenergic blocking agents are widely used to treat disorders of cardiac rhythm and rate, angina, and hypertension. Propranolol is the most widely used beta-adrenergic blocking agent in this country. Because of its nonselective beta-adrenergic blocking effect, propranolol may be associated with significant bronchoconstriction in asthmatic subjects and in some patients with chronic obstructive pulmonary disease. Since tolamolol, a new beta-adrenergic blocking agent, has cardioselectivity in animals, we studied asthmatic subjects for six hours on three separate days in a double-blind crossover comparison of oral therapy with 40 mg of propranolol, its beta-adrenergic blocking equivalent dose of tolamolol (50 mg), and a high dose of tolamolol (100 mg). All three dosages had equipotent effects on heart rate and systolic pressure. The 50-mg dose of tolamolol had no effect on pulmonary function over six hours; however, both propranolol (40 mg) and the 100-mg dose of tolamolol had equivalent deleterious effects on airway resistance and on rates of expiratory flow. We conclude that the cardioselectivity of tolamolol is dose-limited but is present at the dosage of 50 mg, which is equivalent to the usual antiarrhythmic beta-adrenergic blocking dose of propranolol (40 mg).


Differential susceptibility of indole-positive and -negative strains of Klebsiella pneumoniae to cefazolin, choramphenicol and tetracycline. Biochemical properties and antibiotic susceptibilities of 168 clinical isolates of Klebsiella pneumoniae were tested. On the basis of the indole reaction, 30 isolates (18%) were indole-positive and 138 isolates (82%) were indole-negative. A significant difference in antibiotic susceptibility was found in each of the two groups of isolates. Of the indole-negative isolates, 82.6% were susceptible to cefazolin at 6.25 microgram/ml or lower, while the indole-positive isolates varied in susceptibility to cefazolin. All of the indole-positive isolates were susceptible to chloramphenicol and tetracycline, but the indole-negative isolates varied in their susceptibility to these antibiotics. Whereas there was no relationship between indole production and susceptibility to cephalothin among the K. pneumoniae isolates studied, it appeared that there was a correlation between the indole reaction and susceptibility to cefazolin, chloramphenicol and tetracycline.


[Intraoperative biliary tract injuries]. Twelve iatrogene bile duct injuries are reported. Eleven occurred in operations of the bile system, and one in a gastric resection (B II). The injury should be diagnosed immediately, especially by intraoperative cholangiography. Operative treatment is discussed. Eleven patients survived, one died of pulmonary embolism (operative mortality, 8,3%). One patient had to be reoperated because of stenosis of the common bile duct. Choledochoduodenostomy was performed. The follow-up of 11 patients showed good results without any recurrence of jaundice or pain.


Signals for insulin secretion.

Signals for insulin secretion. Glucose is an effective stimulus for the release of insulin from pancreatic beta-cells but its pre-eminence for the physiological control of insulin secretion is now challenged. The insulin response to oral glucose is much greater than the response to intravenous glucose because an intestinal factor, or factors, has a powerful stimulant effect on insulin secretion. Conversely, the hyperglycaemia which accompanies sympathetic overactivity is accompanied by reduced plasma insulin levels because adrenaline inhibits pancreatic insulin by an alpha-adrenergic mechanism. Other hormonal and chemical factors also modify pancreatic insulin release. Plasma insulin levels will be determined not only by the interplay of signals which stimulate or inhibit insulin release but also by the rate at which insulin leaves the circulation. Because insulin is secreted into the portal circulation the concentration of insulin to which hepatocytes are exposed is normally greater than that affecting peripheral tissues. This ratio will be affected by portal venous diversion and might be altered by hepatic damage. Both factors might also influence the intestinal control of insulin secretion, as the gut 'hormone' would not have to traverse the liver, which might remove some of it, before it arrived at the pancreatic islets. If insulin is the key 'hepatotrophic factor' stimulating hepatic growth and regeneration, as well as preventing atrophy, we might expect it to induce hepatic growth in otherwise normal liver and we would expect it to be secreted in larger amounts when regeneration is active.


Ultrastructural and metabolic studies of isolated and cultured hepatocytes. Cells isolated from adult rat liver form distinct cell populations: the parenchymal cells or hepatocytes and the non-parenchymal cells, mainly endothelial and Kupffer cells. These two groups are easy to separate by centrifugation methods, including centrifugal elutriation. The single-cell suspension of hepatocytes seems to be constituted of subfractions which are located roughly in the centrilobular and perilobular regions of the liver lobule and are differentiated so that they form cell lines with distinct metabolic activities. The basic means of characterizing the isolated hepatocytes consists of determining their size distribution, their sedimentation and elutriation properties, and their metabolic activities. Cultures of hepatocytes offer the possibility of prolonging their survival and of studying the differentiation of new bile canaliculi and the reconstitution of biliary polarity in the cytoplasm. The combination of Kupffer cells with hepatocytes improves the culture condition, as a result of elimination of cell debris by phagocytosis by the non-parenchymal cells. The application of the isolation and partition methods to pre-neoplastic liver allows us to classify the cells according to their degree of hyperplasia and opens up a new field of investigation.


The roles of mediators, irritants and allergens in causing mucin secretion from the trachea. Two species, the cat and the goose, have been investigated to determine whether a variety of pharmacological mediators, irritants and allergens change the rate at which mucins (mucus glycoproteins) are secreted into the trachea. Mucins were labelled by the administration of radioactive precursors which the mucous cells took up and incorporated into glycoproteins. These were periodically washed out of a segment of trachea with physiological saline solution. Changes in the amount of mucin secreted were estimated from measurements of the amount of bound radioactivity in tracheal washings. Histamine increased mucin secretion but the effects were stronger and more consistent in the goose than in the cat. A variety of prostaglandins increased the secretion in both species. 5-Hydroxytryptamine failed to stimulate mucin output in the cat. Ammonia and cigarette smoke both increased mucin secretion in the cat and preliminary results suggest that this was by a combination of local and reflex mechanisms. O-Chlorobenzilidine malononitrile increased secretion from  the goose trachea entirely by a local mechanism. Preliminary experiments in which sensitized cats were challenged by various routes have equivocal results on whether anaphylaxis increases airway mucin secretion. It is concluded that irritants cause mucin secretion both by reflexes and local mechanisms. The mechanisms for the latter may well include release of pharmacological mediators.


Physiological and clinical aspects of circadian variations in glucose tolerance. Significance of the circadian periodicity in glucose tolerance has been presented from physiological and clinical points of view in mechanisms responsible for this periodicity of which afternoon glucose intolerance is most evident. In healthy subjects, circadian fluctuations in insulin secretion and in sensitivity to insulin at tissue level are dominating. Circadian oscillations in insulin response to a glycemic stimulus as well as inherent periodicity in activity of the beta cells have been demonstrated by many authors.


Total fecal diversion by the temporary skin-level loop transverse colostomy. The temporary skin-level loop transverse colostomy has been described. Proof of its ability to divert the fecal stream totally is illustrated by complete diversion in 25 patients ingesting a postcolostomy barium meal. There was no postoperative complication.


[Combination of adriamycin and cis-diammine-dichloro-platinum (II) in the treatment of advanced, therapy-resistant, ovarian carcinoma (author's transl)]. Adriamycin (doxorubicin, Adriblastin) and cis-diammine-dichloro-platinum (II) (DDP, NSC 119 875) were used in the treatment of 18 patients with ovarian carcinoma, usually after intensive pre-treatment, both in a dosage of 50 mg/m2 once every 4 weeks. Forced diuresis was initiated at the same time. On average three such treatments were given. Six patients showed partial remission defined as decrease of tumour mass by more than 50% or as almost complete disappearance of ascites during more than two months without concomitant diuretic treatment. The remission time was 2+, 3, 3+, 3.5, 7+, and 9+ months. In all patients severe gastrointestinal toxicity occurred, however the myelosuppressive action was only moderate. Nephrotoxicity was negligible. Combined chemotherapy with Adriblastin and DDP thus seems effective even in intensively pretreated patients with ovarian carcinoma.


[Pharmacokinetics of ticarcillin in patients with normal and impaired renal function (author's transl)]. Elimination half-life of ticarcillin was measured in 61 patients with different levels of renal function after intravenous rapid infusion (1--20 g). Assuming a single-compartment model for elimination, there was in those without renal disease a half-life of approximately 71 minutes, although there were considerable individual variations. In patients with impaired renal function (glomerular filtration rate 30--60 ml/min) the values were between 60 and 120 minutes, while in one patient with a filtration rate of 2.08 ml/min it was over 400 min. If there is a correlation between dose and half-life, it was obscured by the individual variations. Distribution volume was 21 1/100 kg body-weight.


Disopyramide: a review of its pharmacological properties and therapeutic use in treating cardiac arrhythmias. Disopyramide is a new antiarrhythmic drug with a pharmacological profile of action similar to that of quinidine and procainamide. In a few controlled therapeutic trails and a large number of uncontrolled studies in patients with arrhythmias, often following a myocardial infarction, disopyramide has been relatively effective (more so in ventricular than in atrial arrhythmias) and usually well tolerated. In treating premature atrial and ventricular contractions, the best-studied area of its therapeutic use, disopyramide was superior to a placebo and of similar efficacy to but better tolerated than quinidine; the drop-out rate due to adverse effects of the disopyramide group (10%) being less than one-third that of the quinidine group (36%). In an open ward setting, disopyramide used prophylactically after myocardial infarction appeared to reduce both the incidence of reinfarction and the mortality rate, while in patients treated in coronary care units although the incidence of reinfarction was lower with disopyramide than with a placebo, the mortality rate was not significantly different. Further well-designed trials with adequate numbers of patients are needed before the routine use of disopyramide in infarct patients treated in either setting can be justified. Comparative studies are also required to determine if disopyramide has advantages over other antiarrhythmic agents in this area of use. Side-effects with disopyramide are usually a result of its anticholinergic activity, a dry mouth and difficulty in urination being the most common. Like other antiarrhythmic agents, disopyramide exerts a negative inotropic action on cardiac muscle, and development of acute heart failure has been reported. Development of worsening of heart block and hypotension have also occurred. Disopyramide is largely excreted unchanged and dosage should be reduced in patients with impaired renal function, in accordance with creatinine clearance values.


Aspects of the pharmacology and pharmacokinetics of nitroimidazoles with special reference to tinidazole. Tinidazole has been reported to be highly effective against trichomoniasis, giardiasis and amoebiasis. In vitro, tinidazole is more active against trichomonads than metronidazole and possesses antiprotozoal activity at least comparable to metronidazole against Entamoeba histolytica, Tinidazole gives higher serum levels in animals following oral administration than metronidazole and is well distributed in organs and tissues. When tinidazole or metronidazole is given to healthy volunteers at a dose of 2g orally, the serum level of tinidazole at 48h is considerably higher than that of metronidazole. At 72h tinidazole is still present but metronidazole is not. These pharmacokinetic differences result from the longer half-life of tinidazole. These findings suggest that tinidazole might prove to be more useful than metronidazole in the treatment of protozoal infections when given in once daily oral doses of 2g.


Drug-induced gastrointestinal disease.

Drug-induced gastrointestinal disease. Clinicians administering potent therapeutic agents must be aware of their side-effects. The gut is an important site of adverse drug reactions and drug-induced disease must always be considered in the differential diagnosis of patients presenting with gastrointestinal symptoms. A careful drug history must therefore be taken in all such patients. Symptoms can often be related to drug ingestion, but late effects also occur. The presence of blood in vomitus or stool is pathognomonic of serious pathology which may be drug-induced and requires further investigation. Upper gastrointestinal haemorrhage and pseudomembranous colitis are potentially fatal manifestations of drug therapy. Gastrointestinal symptoms can often be avoided if therapy is taken with meals or in a smaller dose, but drug withdrawal is always the first line of management in patients whose symptoms may be drug-induced.


Treatment of symptomatic intestinal amoebiasis with tinidazole. Tinidazole was given in a single dose of 2g a day for 2 days to 17 adults, and in a single dose of 50mg/kg bodyweight daily for 3 days to 4 children, with symptomatic, but not severe, intestinal amoebiasis. All 21 patients showed clinical improvement but only 20 (95%) were parasitologically cured as evinced by failure to demonstrate Entamoeba histolytica in 3 stool samples collected on the 4th, 15th and 22nd day after treatment. Two subjects had mild nausea within a few hours of taking the first dose, while 8 had constipation of 3 to 5 days duration after treatment. 1 patient had nausea and constipation and another had palpitations.


Treatment of amoebic liver abscess with tinidazole and metronidazole. 20 patients with amoebic liver abscess, confirmed by aspiration of typical amoebic 'pus', were treated in random order with either tinidazole or metronidazole in a dose of 2g once daily for 2 days. Clinical, radiological, and biochemical follow-up was done for 1 month. One patient, given metronidazole, absconded and 19 completed the trial. Complete recovery occurred in all 10 patients given tinidazole but in only 5 of the 9 given metronidazole (p = 0.05). Patients on tinidazole required repeat aspirations less frequently than those on metronidazole. Mild gastrointestinal side-effects  occurred in 1 patient on metronidazole but in none on tinidazole. From the present study, tinidazole appears to be a more effective, better tolerated drug with a more rapid therapeutic effect than metronidazole.


Tinidazole and metronidazole in hepatic amoebiasis. The efficacy of metronidazole and tinidazole has been compared in 31 patients with hepatic amoebiasis. Only those with unequivocal clinical, radiological and laboratory evidence of hepatic amoebiasis were included; diagnostic and therapeutic aspiration was performed where necessary. 15 patients received metronidazole and 16 tinidazole, in random order. The 2 groups were comparable. Both drugs were given orally in a single daily dose of 2g for a minimum of 3 days, with treatment extended if considered clinically advisable. 12 of 15 patients (80%) were cured with metronidazole given for an average period of 7 days (range 4 to 14 days). 15 of 16 patients (93.8%) given tinidazole were cured and the mean duration of treatment was 4 days (range 3 to 6 days). There were fewer side-effects with tinidazole. In this study of hepatic amoebiasis in Bangladesh, tinidazole was found to be superior to metronidazole in overall efficacy because a shorter course of treatment was necessary and it caused fewer side-effects.


The management of amoebic hepatic abscess. 83 well documented cases of amoebic hepatic abscess, treated in the Philippines between 1967 and 1975, are presented with a view to showing the results of 3 different methods of management and comparing the diagnostic accuracy and overall mortality in 2 separate groups. It is concluded that conservative medical management is generally successful and that the abscess cavity can resolve rapidly without the need for aspiration. Death is certain in those who are not treated and mortality is high in those whose abscesses are complicated by perforation. The combination of dehydroemetine, chloroquine and tetracycline is still an effective treatment.


Treatment of multiple intestinal helminthiasis with oxantel and pyrantel. 32 elementary school children were treated for multiple intestinal helminthiasis (ascariasis, trichuriasis and hookworm infections) with a combination of the pamoate salts of oxantel and pyrantel in a dose of 15 to 20mg/kg body weight of each in 1 daily dose for 3 consecutive days. The cure rate for ascariasis was 96.7%, and 84.4% for both trichuriasis and hookworm infections. 68.7% were completely cured of all 3 helminths. However, among those not completely cured, only 1 species of the previous 3 infecting helminths was present after treatment and then with a very marked reduction in egg count.


A comparative trial of oxantel-pyrantel and mebendazole in multiple helminth infection in school children. In a pilot study in 17 children, oxantel-pyrantel as one single dose of 10 to 20mg/kg of each, gave good results in ascariasis but poor cure rates in both trichuriasis and necatoriasis. However in the latter groups the infection was extremely heavy. In a controlled trial in 51 children, using oxantel-pyrantel at the same dose, but given daily for 3 consecutive days, or mebendazole 100mg twice daily for 3 days, the drugs gave similar response rates. Both gave 100% cure rates, as assessed by the absence of ova by both Beaver and brine-flotation techniques, in Ascaris lumbricoides infection. The percentage cures and egg reduction rates were 66.7 and 94.5 in trichuriasis and 53 and 93.6 in necatoriasis respectively. Those for mebendazole were 52 and 91.2 in trichuriasis and 37.5 and 89.7 in necatoriasis. Oxante-pyrantel treatment was associated with more cures, and a marginally greater reduction in ovum excretion than mebendazole but the differences were not statistically significant. No side-effects were seen with either treatment.


Oxantel-pyrantel in various regimens for the treatment of soil transmitted helminthiasis in rural and urban communities. 204 individuals from a rural community were given a single dose of oxantel-pyrantel at 15mg/kg bodyweight and if still infected, 20mg/kg bodyweight, with cure rates of 100%, 53% and 71% for ascariasis, trichuriasis and hookworm infection, respectively. From an urban community, 124 patients were given the same drug either as 15mg/kg bodyweight given twice in one day, with an interval of about 12 hours, or 20mg/kg bodyweight given daily for 2 days. Cure rates obtained were 100% in both groups for ascariasis; 89.2% of those given the first regimen were cured of trichuriasis compared with 71.2% of those on the second. For trichuriasis, oxantel-pyrantel given twice, 12 hours apart, appears to be the best treatment schedule and further clinical trials using this regimen are suggested.


A review of trichuriasis, its incidence, pathogenicity and treatment. The incidence and pathogenicity of trichuriasis is reviewed. Reference is made to earlier, largely unsuccessful, treatments, and to mebendazole. Oxantel, the most recent drug shown to be effective against Trichuris is discussed, as is oxantel-pyrantel which promises to be effective against mixed helminthic infections.


[Local and systemic antimycotic therapy of Candida-induced denture stomatitis]. 15 patients with clinically outstanding prosthesis stomatitis due to microscopically proved candida infection underwent treatment with the antimycotic agent Clotrimazol. After two weeks' therapy improvement was observed in 6 patients (40%), healing in 4 patients (27%); 4 patients did not respond and in one patient the condition was temporally made worse. Examination two weeks after cessation of therapy showed that the clinical condition in 8 patients was as bad as before therapy (53%), and 4 patients (27%) were symptom-free. 3 patients (20%) had improved further. Suggestions for the treatment of prosthesis stomatitis can be derived from these findings.


Prevention of implantation by [D-Trp6-LH-RH in the rat: comparative study with the effects of large doses of HCG on pregnancy. Effect of large doses of [D-Trp6]-LH-RH and HCG on implantation of fertilized ova was examined in the rat. Subcutaneous administration of 6ug[D-Trp6]-LH-RH per day from days 1 to 5 of pregnancy by an implanted minipump completely prevented the implantation of fertilized ova associated with a dramatic reduction of plasma progesterone on days 4 and 8, with a slight reduction of estradiol on day 4. There was no balooning of the uterus in the exploratory laparatomy on days 8 and 14. Administration of 1000 U of HCG daily from days 1 to 5 partially prevented implantation and completely terminated gestation. However, plasma progesterone and estradiol levels did not differ from those in the control animals. Ovaries in the [D-Trp6]-LH-RH treated rats appeared to be the same in size as those of the control pregnant rats, whereas the ovaries of the HCG-treated rats were hypertrophied. The results suggest that [D-Trp6]-LH-RH prevents nidation through a mechanism different from that for the adverse effect of excess of HCG on pregnancy.


The binding of kirromycin to elongation factor Tu. Structural alterations are responsible for the inhibitory action. The influence of kirromycin on the elongation factor Tu (EF-Tu) in its binary and ternary complexes was investigated. The equilibrium constant for the binding of the antibiotic to EF-Tu . GDP and EF-Tu . GTP was determined by circular dichroism titrations to be 4 x 10(6) M-1, and to EF-Tu . GTP . aa-tRNA by a combination of circular dichroism titrations and hydrolysis protection experiments to be 2 x 10(6) M-1. In the presence of kirromycin the binding of aminoacyl-tRNAs to EF-Tu . GTP is weakened by a factor of two. The antibiotic changes the conformation of the ternary complex in such a way that the aminoacyl moiety of the aminoacyl-tRNA is more accessible to the non-enzymatic hydrolysis. It is concluded that this structural alteration is responsible for the inhibitory action of the antibiotic.


On the significance of the prosthetic group composition of citrate lyase. 1. Klebsiella aerogenes contains two different acyl carrier proteins, one specific for citrate lyase, the other for fatty acid synthetase. 2. The acyl carrier protein of fatty acid synthetase from K. aerogenes was isolated and compared with the corresponding protein from Escherichia coli and with the acyl carrier protein of citrate lyase from K. aerogenes. 3. As judged from prosthetic group compositions as well as amino acid and fingerprint analyses, the acyl carrier proteins of the two fatty acid synthetases are nearly identical but different from that of citrate lyase from K. aerogenes. 4. Therefore, the different prosthetic groups alone cannot be responsible for the different specificities of the acyl carrier proteins of fatty acid synthetase and citrate lyase in K. aerogenes. 5. The prosthetic group of citrate lyase, phosphoribosyl dephospho-CoA, apparently represents no incidental, phosphopantetheine-replacing aberration. The requirement of citrate lyase for the CoA-like prosthetic group may arise from the substrate requirement of both subunit enzymes of the enzyme complex.


Specific ribonucleases involved in processing of tRNA precursors of Escherichia coli. Partial purification and some properties. Ribonucleases O and Q, the two putative nucleolytic activities which we detected previously in the crude extract from a thermosensitive ribonuclease P mutant (TS241) of Escherichia coli and which were shown to function in the processing of tRNA precursors in vitro, were partially purified from the 1000000 x g supernatant fraction of E. coli Q13. In the course of purification of these enzymes, the total RNAs synthesized in the thermosensitive mutant at the restrictive temperature were used as the substrates and the activities were identified from disappearance or alteration of specific tRNA precursor molecules in polyacrylamide gel electrophoresis. The purified ribonuclease O preparation cleaved specifically the multimeric tRNA precursors at the spacer regions. The purified ribonuclease Q preparation removed, in accordance with the definition of this enzyme, extra nucleotides from the 3'-terminal ends of monomeric tRNA precursors. Some properties of these two nucleases were investigated. In addition to these nucleases, another exonuclease (tentatively designated ribonuclease Y) and ribonuclease P, a well-characterized endonuclease, were also purified. The sequential mode of the processing of tRNA precursors, originally observed in the cleavage reactions with the crude extracts in vitro, was supported by studies with the purified enzyme preparations.


The acceptor for polar head groups of the lipid A component of Salmonella lipopolysaccharides. We describe here experiments which determine at which stage in the lipid A biosynthesis the polar head groups 4-aminoarabinose, phosphorylethanolamine and 3-deoxy-D-manno-octulosonic acid are transferred to the diphosphorylated glucosamine backbone of the lipid A structure. Use was made of a conditional lethal mutant of Salmonella typhimurium (Ts1) which is defective in the synthesis of 3-deoxy-D-manno-octulosonic acid 8-phosphate and accumulates under nonpermissive conditions an underacylated lipid A intermediate [Lehmann, Rupprecht and Osborn (1977) Eur. J. Biochem. 76, 41-49]. Pulse-chase experiments, including a detailed analysis of radioactive pulse and chase products, demonstrated that this underacylated compound is a key intermediate in the lipid A synthesis. It can serve as direct acceptor for the incorporation of the polar head groups 4-aminoarabinose, phosphorylethanolamine and 3-deoxy-D-manno-octulosonic acid. On the basis of these findings some steps in the sequence of reactions involved in the lipid A biosynthesis are proposed.


Use of the T4 polynucleotide ligase in the joining of flush-ended DNA segments generated by restriction endonucleases. Double-stranded DNA segments with completely base-paired ends were obtained by the action of various restriction endonucleases on phage and plasmid DNAs. These segments were joined covalently by the T4 polynucleotide ligase. The joining was monitored by the electron microscopy count of intramolecularly circularized segments. The highest extent of joining, close to 75%, was observed at 15-25 degrees C with the segments resulting from the action of the Bacillus subtilis (strain R) restriction endonuclease Bsu on the DNA of bacteriophage SPPI or of the plasmid pSC 101. The joining of double-stranded termini required about 10 times more enzyme than the short single-stranded termini produced by the Escherichia coli restriction endonuclease EcoRI. A shortened purification of the T4 ligase was found to give an enzyme devoid of interfacing nucleases.


Evidence for synthesis of alkaline phosphatase on membrane-bound polysomes in Escherichia coli. Polysomes containing nascent chains of alkaline phosphatase have been isolated from a membrane-bound polysome preparation. Indirect immunoprecipitation using conformation-specific antibodies has been employed. This technique provides a good enrichment of these polyribosomes since routinely no more than than 10--15% of non-specific immunoprecipitation was observed. The yield of the procedure is generally 40% but can be increased if higher non-specific immunoprecipitation is tolerated. Antibodies, previously described, directed against uncoiled or folded monomers of alkaline phosphatase can be used as primary antibody to recognize the nascent chains contained in membrane-bound polysomes which suggests that these chains are partially folded.


Frequency of leukopenia incidents following azathioprine therapy after kidney transplantation. The frequency of leukopenia incidents and its dependence on the dose of azathioprine and kidney function were analyzed in 149 patients during the first 3 months after kidney transplantation. The results were compared with the data of 42 transplantation centers of the world. We found that the frequency of leukopenia increases significantly following azathioprine dosage exceeding 1.99 mg/kg body weight/day. The toxicity of the drug depends on the kidney function. Most of the leukopenia incidents were detected during the first 5 weeks after kidney transplantation. In 70% of the cases a first leukopenia incident is followed by a second. Low azathioprine dosage after the first episode diminishes the number of second incidents.


Suiciding of lymphocytic precursor cells by tritiated nucleosides, in vitro. Differences in suiciding by various tritiated nucleosides were observed between two functional assays for in vitro lymphocytic precursor cell development, the hemolysin plaque-forming cell (PFC) assay and the B lymphocytic colony-forming cell (CFC-L) assay, using BDF1 mouse spleen cells. PFC growth was markedly reduced by an early (days 0-1) pulse of tritiated deoxyadenosine ([3H]dAdo), but relatively unaffected by a pulse of tritiated thymidine ([3H]dThd) during the same interval. In contrast, CFC-L formation significantly dropped after an early (day 0) [3H]dThd pulse, as well as after pulses of [3H]dAdo and the corresponding tritiated ribosides, uridine and adenosine. This implied a cycling state in an early lymphocytic precursor cell, as opposed to the PFC insensitivity to an early [3H]dThd pulse. The response pattern of colonies and clusters to [3H]dThd supported our notion of a delayed suiciding of CFC contributing to the increase in cluster numbers.


Antigen-antibody complexes suppress antibody production by mouse plasmacytoma cells in vitro. Preformed complexes of 2,4-dinitrophenylated keyhole limpet hemocyanin (DNP-KLH) and anti-DNP or anti-KLH antibodies selectively, suppressed the production of anti-DNP IgA by the plasmacytoma cell line, MOPC 315, in vitro. Compexes made with DNP8.5KLH (8.5 moles DNP/10(5) daltons carrier) inhibited the secretion of IgA but not its synthesis, whereas complexes prepared with the more highly substituted DNP20KLH inhibited synthesis as well. Moreover, complexes of DNP-KLH and anti-DNP F(ab')2 fragments were as suppressive as those made with IgG antibodies, suggesting that the mode of presentation of antigenic determinants and not surface Fe receptors may play a major role in this phenomenon.


Vascular actions of arachidonic acid and its metabolites in perfused mesenteric and femoral beds of the dog. The effects of arachidonate and its major metabolites were examined in vascular beds perfused via the femoral and mesenteric arteries of chloralose-anaesthetised dogs. Close intra-arterial injection of prostacyclin (PGI2, 0.02--2 microgram), PGE2 (0.05--1 microgram) and their precursors, the endoperoxide PGH2 (0.5--2 microgram) and sodium arachidonate (100--550 microgram), all induced vasodilatation. Sodium linoleate (500 microgram) was inactive. Prostacyclin was equally active in both vascular beds, but PGE2 was more potent in the femoral and less so in the mesenteric bed. PGH2 was of similar potency to prostacyclin in both beds, but 6-oxo-PGF 1 alpha (10--100 microgram) was inactive. Thromboxane A2 (TXA2, 1--2 microgram) was a potent vasoconstrictor of the mesenteric bed, but not the femoral bed, although the endoperoxide analogue U46619 was vasocontrictor in both vasculatures. Fatty acid hydroperoxides did not specifically modify the vasodilator effects of PGH2 or arachidonate, presumably because these inhibitors are rapidly reduced in vivo. Indomethacin and meclofenamate potentiated vasodilatation induced by prostacyclin or endoperoxide, but reduced or abolished that caused by arachidonate. The rise in perfusion pressure induced by TXA2 was potentiated and prolonged by indomethacin. Inhibition of synthesis of endogenous prostacyclin, by exacerbating the vasoconstrictor action of TXA2, may have contributed to this effect.


Origin of bone marrow stromal mechanocytes in radiochimeras and heterotopic transplants. Strain histocompatibility antigens (detected by indirect immunofluorescence reaction) and sex chromosomes were used as markers of donor and recipient cells in monolayer cultures of bone marrow from radiochimeras and from heterotopic transplants. In contrast to macrophages and hemopoietic cells all bone marrow fibroblasts precursors in radiochimeras were of recipient origin; in heterotopic transplants they were of donor origin. These data point to the decisive role of stromal mechanocytes, and not macrophages or hemopoietic cells, in creating the bone marrow hematopoietic microenvironment.


Brain stem neurons projecting to neocortex: a HRP study in the cat. The cortical projections of the brain stem were investigated in detail in the cat by means of the horseradish peroxidase (HRP) retrograde axonal transport. Most of the cells providing ascending fibers to the neocortex were located in the pons (locus coerulus and related structures, central gray substance, dorsal tegmental nucleus, raphe nuclei, reticular nuclei); labeled neurons were also identified in the mesencephalon, mainly in the periaqueductal gray and in the nucleus linearis rostralis. These projections, and particularly the pontine fibers, were diffusely distributed throughout the cerebral cortex.


Cerebellar afferent projections from the vestibular nuclei in the cat: an experimental study with the method of retrograde axonal transport of horseradish peroxidase. Details of cerebellar afferent projections from the vestibular nuclei were investigated by the method of retrograde axonal transport of horseradish peroxidase (HRP) in the cat. The distribution of labeled cells in the vestibular nuclei following HRP injections in various parts of the cerebellum indicates that vestibular neurons in the medial and descending nuclei and cell groups f and x project bilaterally to the entire cerebellar vermis, the flocculus, the fastigal nucleus and the anterior and posterior interpositus nuclei. In addition, labeled cells (giant, medium and small) were consistently found bilaterally in the superior and lateral vestibular nuclei following HRP injections in the nodulus, flocculus, fastigal nucleus, and following large injections in the vermis. No labeled cells were observed in cases of HRP injections in crus I and II, the paramedian lobule, paraflocculus and lateral cerebellar nuclei. The present findings indicate that secondary vestibulocerebellar fibers project to larger areas in the cerebellum and originate from more subdivisions and cell groups of the vestibular nuclear complex than previously known.


Carboxypeptidase Y from Saccharomyces cerevisiae: circular dichroism and fluorescence studies. Carboxypeptidase Y was isolated from Saccharomyces cerevisiae and its molecular structure investigated. The enzyme in the native state possesses 40% of its amino acid residues in a beta-conformation. Its tryptophan residues seem to be largely buried in an apolar and unsymmetrical environment.


The transcendental meditation technique, adrenocortical activity, and implications for stress. The practice of the transcendental meditation technique in subjects eliciting this state regularly for 3--5 years is correlated with acute decline of adrenocortical activity not associated with sleep during the practice.


Effect of pretreatment with acetylsalicylate on surgical bleeding and peroperative mortality in rats undergoing kidney transplantation. 42 rats were pretreated with L-ASA before kidney transplantation, 43 rats acted as controls. 9 rats with L-ASA, but no control rats, died with i.p. haemorrhage. However, in animals surviving the operation, the intraoperative blood loss did not differ significantly between the 2 groups.


Disaccharidase rhythm in rat small intestine; no relationship with mitosis rhythm. Same circadian difference in the specific activities of sucrase and maltase was observed in the purified brush border fraction as in the crude homogenate of the mucosa of rat small intestine, suggesting that the disaccharidase rhythm is not due to the mitosis rhythm of epithelial cells.


Cytoskeletal filaments of heart conducting system localized by antibody against a 55,000 dalton protein. Cow heart conducting cells characteristically contain cytoplasmic intermediate-sized filaments. We report here the preparation of a specific antibody to a 55,000 dalton protein of isolated cow Purkinje fibres. Confirmation has been obtained that these filaments consist of the 55,000 dalton protein, using the indirect immunofluorescence technique. Cross-reaction is seen with vascular endothelium and smooth muscle cells of various origin, suggesting close identity of different types of intermediate-sized filaments.


Possible presence of autoantibodies to zone pellucida in infertile women. Of 52 serum samples from infertile women tested against isolated porcine oocytes by immunofluorescence, 8 produced intense reactions in zonae pellucidae, while only one of 52 sera from control subjects showed the reaction. Autoantibodies to the zona may be present in these women.


Effect of an LH-RH antagonist on reproductive status of immature female rats. Administration of the LH-RH antagonist, D-Phe2-D-Ala6-LH-RH (Wy-18, 185) to immature female rats from days 25--35 of age was without significant effect on day of vaginal opening (puberal onset), weights of the ovaries, uteri and anterior pituitary, and on ovarian histology on autopsy day 39.


[Clinical pharmacokinetics of azabutyron, a new short-term action neuroleptic]. Pharmacokinetics of azabutyron--a new Soviet-made neuroleptic was studied clinically without anesthesia and also during surgery against the background of deep and surface fluorothan anesthesia in conjunction with artificial nitrous oxide and oxygen ventilation of the lungs (2:1). After intravenous administration of the drug in a dose of 4 mg/kg its maximum concentration (about 8 gamma/ml) was recorded in 5 minutes and the amount eliminated during 2 hours of observation comprised 1--2 per cent of the dose introduced. In practically healthy individuals with no anesthesia the pharmacokinetics of azabutyron lies within the limits of a bicompartment pharmacokinetics model, while surface anesthesia, blood loss changes the pharmacokinetics of the drug to such an extent that is has to be described from the standpoint of the unicompartment model system.


[Basic mechanism of the histotoxic action of chelating agents]. Chelant injections in animals cause intravital histochemical reactions with zinc thus deranging this metal metabolism and disturbing the cellular structure with subsequent changes in the main histochemical components. The degree of alterations depends on the intensity and persistence of the intravital reaction. The basic mechanism of the chevant histotoxic action consists in the damage it produces in the mechanical structure of the cells.


[Azabutyron concentration in the blood plasma and the hemodynamic effects of the preparation]. In patients presenting mitral and aortal valvular defects with contemplated valve prosthetics it was shown that after an intravenous administration of azabutyrone in a dose of 4 mg/kg the drug produced a hypotensive effect in the large circulation, reduced insignificantly the cardiac output, venous pressure and the total peripheral resistance, inducing, at the same time, a short-term rise of the heart rate. The drug forced down materially (by more than 50 per cent) the pulmonary artery pressure in patients with pulmonary hypertension. The azabutyrone effects were seen to continue for 30 minutes with its blood plasma concentration of 1.5--3.0 gamma/ml. A clearcut correlation between the plasma content and the effect of the drug could be noted only as concerns the hypotensive action of azabutyrone in the lesser circulation.


Ionic mechanisms of pacemaker activity in cardiac Purkinje fibers. Rhythmic activity in cardiac Purkinje fibers can be analyzed by using the voltage clamp technique to study pacemaker currents. In normally polarized preparations, pacemaker activity can be generated by two distinct ionic mechanisms. The standard pacemaker potential (phase 4 depolarization) involves a slow potassium current, IK2. Following action potential repolarization, the IK2 channels slowly deactivate and thus unmask a steady background inward current. The resulting net inward current causes the slow pacemaker depolarization. Epinephrine accelerates the diastolic depolarization by promoting more complete and more rapid deactivation of IK2 over the pacemaker range of potentials. The catecholamine acts rather selectively on the voltage dependence of the gating mechanism, without altering the basic character of the pacemaker process. The nature of the pacemaker depolarization is altered by intoxication with high concentrations of cardiac glycosides or aglycones. These compounds promote spontaneous impulses in Purkinje fibers by a mechanism that supersedes the ordinary IK2 pacemaker. The digitalis-induced depolarization is generated by a transient inward current that is either absent or very small in untreated preparations. The transient inward current is largely carried by sodium ions. Its unusual time course probably reflects an underlying subcellular event, the oscillatory release of calcium ions from intracellular stores.


Possible involvement of central pacemakers in clinical disorders of movement. This review considers the evidence for possible involvement of central nervous system pacemaker neurons in several clinical disorders of movement. Two basic types of tremor are discussed from this point of view, i.e., 4--7/sec parkinsonian tremor, of possible thalamocortical origin, and 7--11/sec essential tremor of possible olivo-cerebellar origin. The importance of motor programs and abnormalities in their utilization are considered with reference to the loss of motor function in parkinsonism (? loss of motor programs), and the inappropriate release of such programs as a possible basis for the involuntary movements seen in other movement disorders, such as chorea, athetosis, dystonia, and hemiballismus. The possible role of pacemaker neurons controlling such programs is considered. Finally, the subject of locomotion and the pacemaker model of the spinal locomotor pattern generator for stepping are considered in relation to clinical disorders of gait. While critical evidence is lacking for pacemaker inovlvement in any of these disorders, their possible role is emphasized.


Ergot drugs and central monoaminergic mechanisms: a histochemical, biochemical and behavioral analysis. The effects of ergot drugs on central monoaminergic mechanisms, particularly dopaminergic mechanisms, have been investigated in histochemical, biochemical and behavioral studies. It is concluded that the behavioral effects and the antiparkinsonian properties of ergot drugs can to a large extent be explained by the hypothesis that ergot drugs act at various dopamine receptor sites in the brain as partial agonists, the ratio of agonist-antagonist activity varying from one dopamine receptor population to another.


Ntau-methylhistidine (3-methylhistidine) and muscle protein turnover: an overview. Actin and myosin, the contractile proteins of skeletal muscle, are methylated following peptide bond synthesis, with production of Ntau-methylhistidine (3-methylhistidine, 3-MeHis). During intracellular breakdown of these proteins, the 3-MeHis is released and excreted in the urine. Studies on tissue distribution of 3-MeHis and on its qunatitative excretion following administration to rats and to man show that urinary output of this amino acid provides a reliable index of the rate of myofibrillar protein breakdown in the musculature of intact rats and human subjects. Estimates of the fractional rate of muscle protein breakdown based on 3-MeHis data are consistent with rates computed by other techniques. By this technique, it has been shown that the fractional rate of muscle protein breakdown is not significantly different in the elderly as compared with young adults. However, since muscle mass is less in the elderly, it makes a smaller contribution to whole body protein breakdown with aging in humans. Output of 3-MeHis diminishes in growing rats and obese human subjects with protein or energy restriction, though the initial response of myofibrillar protein breakdown in growing rats to protein and protein-energy restriction differs. Measurement of 3-MeHis excretion has also proved useful in exploring the effects of physical and thermal trauma on the rate of muscle useful in exploring the effects of physical and thermal trauma on the rate of muscle protein breakdown.


Pituitary gonadotropin responsiveness with danazol. Danazol (17alpha-pregn-4-en-20-yno-[2,3-d]isoxazol-17-ol) was administered daily for 4 days to castrated female rats. As previously demonstrated, danazol lowered serum levels of luteinizing hormone (LH) in an apparent dose-dependent fashion. Animals which received danazol in a dose sufficient to lower serum LH responded to administered LH-releasing hormone (LHRH) with increases in serum LH levels which were not diminished as compared with those of control animals. Although these experiments do not preclude an effect of danazol directly on the pituitary, the results indicate that this agent probably lowers serum LH primarily by inhibition of hypothalamic LHRH secretion.


Sexual function and hormonal abnormalities in uremic men on chronic dialysis and after renal transplantation. Twenty-one adult uremic males on chronic hemodialysis were studied to determine the circulating levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and prolactin and their relationship to sexual function. Ten of the twenty-one patients were on exogenous testosterone, and its effects were measured. Twelve adult males with successful renal transplants were likewise examined. Testosterone concentrations were low in dialysis patients not on androgens (429 ng/dl +/- 85 SE), but FSH and LH levels were elevated (8.0 mIU/ml +/- 1.4 SE and 31 mIU/ml +/- 5.4 SE, respectively. Testosterone returned to normal after transplantation, but FSH and LH levels remained elevated. Prolactin levels were significantly increased in dialysis patients (25.5 ng/ml +/- 5.6 SE) and remained so despite androgen therapy, but returned to normal after transplantation. There was no correlation in any group between laboratory data and potency before androgen therapy. However, excessive testosterone replacement was shown to have an adverse effect on potentia.


Cyclic and temporal differences in LH-RH-stimulated LH release in cultured rat pituitary cells. To establish whether the enhanced LH-RH responsiveness shown by pituitary gonadotrophs at proestrus in vivo could be maintained in vitro, rat anterior pituitary cells were investigated to determine differences in LH release in response to LH-RH through the estrous cycle and with time in primary culture. Pooled or individual anterior pituitary glands from each day of the cycle were dissociated with collagenase, hyaluronidase and Viokase and cultured for from 1 to 4 days. Four-day cultures of proestrous cells did not show differences in LH-RH responsiveness when compared to estrous, diestrous I and diestrous II cells. In addition, proestrous cells did not show differences in LH-RH responsiveness when compared to diestrous II cells after 1, 2, 3 or 4 days of culture; however, over the same 1--4 days of culture, proestrous cells contained higher amounts of LH and released greater quantities of LH into the growth medium than did diestrous II cells. It was also observed that both proestrous and diestrous II cells exhibited significantly greater LH-RH responsiveness after 3 or 4 days of culture than after 1--2 days of culture. These results suggest that the differential LH-RH responsiveness shown by pituitary gonadotrophs at proestrus in vivo is not maintained when pituitary cells are placed in primary culture.


Phosphate metabolism and glucose-initiated efflux of phosphate ions in islets of fetal pancreas. Elsewhere we have proposed that the rapid transient efflux of 32P orthophosphate that occurs when prelabeled pancreatic islets are exposed to nutrient secretagogues (the "phosphate flush") reflects one of the earliest steps in islet stimulus-secretion coupling. We have now shown that the "phosphate flush" is much smaller with islets from fetal rats 21 1/2 days old. This could be attributed to decreased cellular stores of radioactivity, especially inorganic orthophosphate (32P), at the onset of stimulation, which may have been due, in part, to the diminished ability of fetal islets to retain the radiophosphorus accumulated during the labeling period. Certain other differences in phosphate metabolism were also observed. With prelabeled islets from adult rats, exposure to 3.0 mg. per milliliter glucose effected acute increases in the tissue content of AT32P and GT32P. Comparable stimulation of prelabeled fetal islets with 3.0 mg. per milliliter glucose did not elicit detectable changes in the labeling of ATP or GTP. The findings indicate that selected aspects of phosphate metabolism may be immature in fetal islets and, perhaps, implicated in their obtunded secretion of insulin in response to stimulation with glucose.


Selective calcification of pancreatic islets of Langerhans. An unusual association with hypercalcemia and diabetes mellitus. An unusual and extensive calcification of islets of Langerhans was found at autopsy in a man, 58 years old, who developed myeloma and, subsequently, hypercalcemia and diabetes. Although the islet cell calcification appears to be related to the hypercalcemia, the pathogenesis of the calcification is not clear, as primary metastatic calcification of pancreatic islets due to hypercalcemia does not occur. In support of this, a retrospective study of pancreatic tissue from 52 hypercalcemic patients with parathyroid adenoma and 34 patients with multiple myeloma, who frequently have hypercalcemia, did not reveal islet calcification. The islet calcification is ascribed to primary islet cell degeneration and necrosis, with hypercalcemia playing an augmenting but crucial role. It is considered that the combination of islet degeneration and calcification resulted in the diabetic state.


C-peptide secretion during the remission phase of juvenile diabetes. C-peptide secretion was studied in eight juvenile diabetics during the remission phase of the disease. The release of C-peptide was measured after a (1) normal intravenous glucose tolerance test, (2) a double glucose tolerance test, (3) an arginine infusion, and (4) after an intravenous glucose tolerance test followed by an arginine infusion. Under all conditions the intravenous glucose load had only a minimal effect on the secretion of C-peptide, while arginine alone or after the intravenous glucose tolerance test stimulated the release of the peptide in all patients. Pretreatment with glucose did not augment the effect of arginine on C-peptide release. The results indicate that during the remission phase of juvenile-onset diabetes the endocrine pancreas does not recognize glucose as and appropriate signal for C-peptide release and cannot transform the amplifying effect of glucose into a higher hormonal secretion rate.


Virus-induced diabetes mellitus. XI. Replication of coxsackie B3 virus in human pancreatic beta cell cultures. The capacity of Coxsackie B3 virus to infect insulin-containing beta cells was studied in human pancreatic cell cultures. Antibody to Coxsackie B3 virus was labeled with fluorescein isothiocyanate, and antibody to insulin was labeled with rhodamine. By use of a double-label antibody technique, three populations of cells were identified: uninfected insulin-containing beta cells, which stained only with rhodamine-labeled anti-insulin antibody; Coxsackie-infected (noninsulin-containing) cells, which stained only with fluorescein-labeled anti-Coxsackie antibody; and Coxsackie-infected insulin-containing beta cells, which stained with both antibodies. Radioimmunoassay showed that intracellular immunoreactive insulin decreased rapidly beginning at 24 hours after infection, and the decrease in insulin roughly paralleled the increase in viral titer. It is concluded that, under in vitro conditions, human beta cells are susceptible to Coxsackie B3 virus.


Indirect immunofluorescence microscopy of microtubular structures in male germ cells of wildtype and l(3)pl (lethal-polyploid) Drosophila hydei. Tubulin-containing structures of the male germ cells of Drosophila hydei crossreact in indirect immunofluorescence microscopy with antibody directed against homogeneous porcine brain tubulin. There is no detectable difference in reactivity between germ cells of wildtype flies and the mutant l(3)pl (lethal-polyploid) which is characterized by microtubular abnormalities. However, the technique of indirect immunofluorescence microscopy allows the direct visualization of several abnormalities in the arrangement of the microtubular system of the mutant, particularly in the axonemal complex.


[Exerimental study of enterotoxic activity in some strains of Salmonella typhimurium: observations on the model of ADP-induced platelet aggregation]. In a previous report it has been shown that enterotoxin preparations (cholera and E. Coli) able to activate adenylatecyclase system, abrogated platelet aggregation induced by ADP. In the present study the same experimental model has been applied to some purified filtrates from Salmonella typhimurium strains. Preparations from 986 and TLM (invasive strains causing also fluid secretion) interfere with platelet aggregation, while 1027 strain (invasive but not evoking fluid secretion) didn't show such effect. It has been argued, as Sandefur and Peterson have demonstrated with different experimental models, that the system of platelet aggregation induced by ADP is valid for some strains of Salmonella typhimurium, which act with a mechanism partially involving adenylatecyclase system (i.g. cholera-like).


[Effects of anesthesia and surgical trauma on the immune response of pediatric patients]. The AA. have evaluated the effects of anaesthesia and surgical trauma on the ability of lymphocytes from 10 patients to release Leukocyte Inhibiting Factor (LIF) after stimulation with phytohaemoagglutinin (PHA). In addition, they have studied the electrophoretic mobility of Polymorphonuclear-cells (PMN) and lymphocytes of 8 patients after incubation in autologus plasma. The experimental results show decrease of LIF production after operation in 6 individuals and reduction of eletrophoretic mobility of PMN and lymphocytes. The last finding is not significant on statistical point of view.


Self-actualization as a developmental structure: a profile of Antoine de Saint-Exupéry. The characteristics of self-actualization are fully reflected in excerpts from Saint-Exupéry's autobiographical writings. The correspondence between the characteristics of self-actualization and Saint-Exupéry's developmental profile gains special significance because there exists, independently, a theoretical structure corresponding both to self-actualization and to Saint-Exupéry's material. This structure--level IV in the theory of positive disintegration--has previously been shown to represent Saint-Exupéry's behavioral organization. The characteristics of self-actualization and the properties of level IV structure are isomorphic. Self-actualization is the consequence of level IV structure and of the potential necessary for its development.


[Transmission of bacteriophage T4 amber mutants. I. Temperature sensitivity of gene 26 T4 phage mutant amN131 multiplication in Escherichia coli B cells]. When studying the single cycle of the multiplication of gene 26 mutant amN131 of phage T4, like in temperature shift experiments, the yield of this mutant in non-permissive host depends greatly on the temperature. The burts size of phage in Escherichia coli B is found to be 3.3 phage particles at 25 degrees C, 1.6 at 30 degrees C, 0.051 at 37 degrees C and 0.0007 at 41 degrees C. In the case of permissive host (E. coli CR-63) the burst size per cell decreases from 158 to 49 phage particles at the same temperature interval. The results of the single-burst experiments indicate, that when the incubation temperature increases, the number of E. coli B cells, in which the phage particles maturate, also decreases. It results in the dependence of the transmission coefficient value on the temperature. The transmission coefficient in the conditions favourable for the maturation of the phage is found to be 0.80. It is shown by several methods that the temperature sensitivity of the multiplication of the mutant amN131 in bacterial cells is entirely due to amber mutation in genome of the phage. Therefore the amber mutants having high temperature sensitivity when maturating in non-permissive host cells exist among ordinary amber mutants of phage T4.


[Penetration of exogenous DNA through the membranes of Escherichia coli treated with Ca2+ cations]. Possible role of electrochemical potential as driving force for exogenous DNA penetration inside Ca2+ treated Escherichia coli was investigated using carbonyl-cyanide-m-chlorophenylhydrasone (CCCP), an uncoupler of oxidative phosphorylation. CCCP at concentrations of 10(-6) -10(-5) M did not affect the number of plague forming units. The inhibitory effect was observed under higher concentrations (5.10(-5) -10(-4). This effect was not due to the loss of cell viability and is attributed to the reduced capacity of the cells to interact with DNA. It is suggested that conformational changes in biomembranes might be at least partially involved. It is concluded that the electrochemical potential is not the driving force for penetration of exogenous DNA inside Ca2+ -treated E. coli cells. Bronian movement is suggest as an alternative.


Use of matrix-immobilised recombinant plasmids to purify chain-specific rabbit globin complementary DNAs. The cloning of DNA sequences in plasmid recombinants has made it possible to amplify specific sequences to an extent that they can be used for preparative purposes. We describe the use of rabbit globin DNA sequences cloned in the plasmid pCR1 and covalently bound to Sepharose 4B for the purification of chain-specific rabbit alpha- and beta-globin cDNAs. These purified probes were then used to estimate the length of the alpha- and beta-globin DNA sequences inserted into the recombinant plasmid. The technique should allow the rapid isolation of sequence-specific cDNA, RNA and genomic DNA.


Deletions within E. coli plasmids carrying yeast rDNA. Deletions occur in recombinant DNA plasmids that contain yeast ribosomal DNA (rDNA) inserted into the E. coli plasmids pSC101 and pMB9. Deletions within a pMB9 plasmid containing an insert longer than one tandem rDNA repeat apparently are due to homologous recombination because (1) all of the independently derived deletion products of this plasmid lost one complete rDNA repeat (8.6 kb) and retained only a single copy of the segment repeated at the ends of the original insert and (2) deletions were detected only when the insert had terminal redundancy. Deletions also occur within a pSC101 plasmid containing a tandem duplication of a segment (4.7 kb) including both pSC101 DNA and rDNA. Once again these deletions appear to be due to the presence of a duplicated region because all deletion products have lost one complete repeat. Deletions within both of these plasmids took place in both rec+ and recA- host cells, but occurred more frequently in rec+ cells. Oligomerization of the deletion products also occurred in both hosts and was more frequent in rec+ cells.


Mapping of functions in the R-plasmid R388 by examination of deletion mutants generated in vitro. Mutant plasmids in which large segments of R388 DNA are deleted were constructed in vitro from two R388::TnA (Tn801) plasmids, using the BamHI site of TnA and the BamHI and BglII sites of R388. These deletion mutants permitted mapping of genetic functions into the restriction map of R388.


Cloning of restriction and modification genes in E. coli: the HbaII system from Haemophilus haemolyticus. The genes for a Class II restriction-modification system (HhaII) from Haemophilus haemolyticus have been cloned in Escherichia coli. The vector used for cloning was plasmid pBR322 which confers resistance to tetracycline and ampicillin and contains a single endonuclease R-PstI site, (formula: see text), in the ampicillin gene. The procedure developed by Bolivar et al. (1977) was used to form DNA recombinants. H. haemolyticus DNA was cleaved with PstI endonuclease and poly(dC) extensions were added to the 3'-OH termini using terminal deoxynucleotidyl transferase. Circular pBR322 DNA was cleaved to linear molecules with PstI endonuclease and poly(dG) extensions were added to the 3'-OH termini, thus regenerating the PstI cleavage site sequences. Recombinant molecules, formed by annealing the two DNAs, were used to transfect a restriction and modification-deficient strain of E. coli (HB101 r-m-recA). Tetracycline-resistant clones were tested for acquisition of restriction phenotype (as measured by growth on plates seeded with phage lambdacI-0). A single phage-resistant clone was found. The recombinant plasmid, pD110, isolated from this clone, had acquired 3 kilobases of additional DNA which could be excised with PstI endonuclease. In addition to the restriction function, cells carrying the plasmid expressed the HhaII modification function. Both activities have been partially purified by single-stranded DNA-agarose chromatography. The cloned HhaII restriction activity yields cleavage patterns identical to HinfI. A restriction map of the cloned DNA segment is presented.


The elderly and the control of simple behaviour by probabilistic information. The probabilities of events in the environment are important as controllers of how we cope with that environment. Attention is deployed to parts of the visual field where important events are most likely to happen; in predicting what will happen next in a situation, probable things tend to be predicted. This paper assess adult age differences in the use of probabilistic information, using the laboratory task-settings of choice reaction time, simple prediction, and selective attending. In almost all situations the elderly are less influenced by event probabilities than their juniors, although they are just as capable of registering the probabilities involved. This consistent age effect contradicts the predictions of Griew's theory which assumes that behavioural experience operates by increasing the use of probabilistic information. A second finding was that value and reward manipulations which alter the response patterns of the young do not influence the elderly to the same extent. It is tentatively concluded that attenuated use of probability information characterises the elderly, as does a reduced response to simple payoffs. Some avenues of theoretical exploration are discussed, together with some caveats concerning the applicability of the findings.


Pancreatic and salivary amylase/creatinine clearance ratios in normal subjects and in patients with chronic pancreatitis. The clearance of pancreatic and salivary amylase relative to creatinine was measured in 26 control subjects and 22 patients with chronic pancreatitis. Control values for pancreatic amylase clearance (+/- SD) were 2.64 +/- 0.86% compared with 1.54 +/- 0.95% for salivary amylase. In chronic pancreatitis, pancreatic amylase clearance ratios were significantly higher than controls (P less than 0.0005, mean 4.09 +/- 1.63 SD). The difference in clearance rate of salivary amylase did not reach a level of significance when compared with the control group. Twelve of the 22 patients showed pancreatic amylase clearance values above the normal limit of 4.4, while only five were abnormal when the clearance of total amylase was measured. The patients also showed statistically higher (P less than 0.0005) levels of serum salivary amylase when compared with 69 control sera. No such difference was found for the pancreatic component of serum amylase. Comparison of beta2-microglobulin clearance values showed no statistical difference between patients and controls.


Electron immunohistochemical evidence for the human intestinal I cell as the source of CCK. Evidence was obtained by the use of alternate semithin-thin serial secretions for light and electron microsocpy that the I cell is the source of CCK PZ. The antibodies used were raised to a synthetic fragment of the mid part (9-20) of the (1-33) CCK-PZ molecule, and were thus free from any contamination with cross-reacting subpopulations of antibodies that might bind to gastrin.


Immunohistochemical localisation of urogastrone to human duodenal and submandibular glands. Urogastrone has been localised by immunostaining to granules of the cells of human duodenal (Brunner's) glands and their ducts and of acinar cells in the human submandibular gland. The immunoreactive peptide is present in large quantities in duodenal glands and their secretory ducts. Urogastrone or human epidermal growth factor promotes cellular proliferation in vivo as well as in vitro and inhibits gastric acid secretion and may, therefore, be one of the duodenal factors inhibiting gastric activity. Thus it may have an important regulatory and protective function for the intestinal mucosa and may possibly become a useful therapeutic agent.


Antithrombin III: critical review of assay methods. Significance of variations in health and disease. Thrombin or factor Xa added to plasma are inactivated by antithrombin III (At-III). The inactivation is accelerated by heparin, permitting assay systems which rapidly measure the At-III content of diluted plasma. Without heparin, the slow inactivation rates may be measured. Existing activity assays (fibrinogen or chromogenic substrates) and immunoassays of At-III have been reviewed. Correlation studies show a close correlation between the results of immunoassay and the results of most activity assays. In health, a narrow range of At-III has been found. The level is low in infancy. Fertile women have on the average somewhat lower levels than men. In old age, the level tends to drop. In clinical material studied with amidolytic assays, subnormal At-III levels were found in hereditary deficiency, liver disease, disseminated intravascular coagulation and in some cases with acute thrombosis. The amidolytic assays are rapid to perform, do not require experience in clotting technique and seem preferable in clinical routine work.


Current concepts on action of synthetic thrombin inhibitors. The development of synthetic inhibitors of thrombin and of related arginine-specific esteroproteases is reviewed. The superiority of bis- and tris-benzamidines over benzamidine is disccussed and related to the presence on the enzyme of secondary binding sites beyond the specificity pocket. It is demonstrated that inhibitors with marked specificity for a single enzyme can be produced, and with the help of such selective compounds it is shown that inhibition of factor Xa is more significant for overall anticoagulant effect than inhibition of thrombin.


[Effects of gamma-oryzanol on gastric secretions in rats (author's transl)]. gamma-Oryzanol has been reported to inhibit gastric secretion and experimental ulcers in rats. In this paper, the inhibitory effects of gamma-oryzanol on gastric secretions caused by three stimulants have been compared. gamma-Oryzanol was slightly effective for histamine-stimulated acid secretion, non effective for carbachol-stimulated secretion and significantly inhibited the tetragastrin-stimulated secretion. The effect of gamma-oryzanol on acid secretion stimulated by tetragastrin was prevented by vagotomy but not by splanchnicotomy. It is assumed that the gastric antisecretory effect of gamma-oryzanol is mediated by the vagus nerve which plays a role in the action of gastrin.


A double-blind controlled study of clinical efficacy of maprotiline and amitriptyline in depression. A multiclinic double-blind controlled study was performed on the effects of MAP in both inpatients and outpatients with AMT as control drug. 1. Subjects consisted of 41 male and 45 female patients suffering from various types of depression. MAP was assigned to 42 cases and AMT to 44 cases. Of these patients, 14 MAP cases and 10 AMT cases were subsequently dropped for a variety of reasons to obtain 28 MAP cases and 34 AMT cases as evaluable. 2. The global improvement ratings were compared and found not significantly different for any week between the two treatments. 3. The global improvement ratings by the characteristic features of patients did not show any significant difference in any items studied between the two treatments. 4. The symptomatic improvement ratings (on the Hamilton R.S. for assessment by the physician) indicated that AMT was more effective on "anxiety (psychic)." 5. The symptomatic improvement ratings (on the Beck self-assessment scale by the patient) indicated that MAP was more effective on "work" and AMT on "pathos", "feeling of satisfaction", "withdrawal" and "loss of libido." 6. During the treament period, 74.3 percent of the MAP group and 76.9 percent of the AMT group of patients showed some side effects of accompanying symptoms, with no significant difference recognized between the two treatments. Itemwise, however, the incidence of tremor was significantly lower (p-=0.06) in the MAP group. Moreover, the MAP group tended to be less liable to such anticholinergic side effects as dry mouth, constipation, trouble of accomodation, urinary disturbance and palpitation. 7. On the basis of the above findings, it is concluded that MAP is as effective against depression as AMT and less liable to the anticholinergic side effects. It is, therefore, a very useful antidepressant.


[Subcutaneous rupture of the long thumb extensor tendon. Etiology, clinical aspects and therapy]. Subcutaneous ruptures of the extensor pollicis longus tendon are mostly due to an earlier wrist trauma and rarely caused by a degenerative systemic disease. The tendon usually ruptures close to the distal edge of the retinaculum extensorum where it is vulnerable in various respects and in addition exposed to increased mechanical strain. Functional loss of the extensor pollicis longus greatly impairs the function of the entire hand and requires surgical therapy. Transfer of the extensor indicis tendon has proven successful in 95% and thus appears to be the most appropriate therapeutic procedure.


[Growth and development in normal puberty]. Puberty is a period of life with a great number of closely correlating aspects. For early recognition of pathological puberty, for rational assessment and effective treatment, interrelations and normal course of the stages are to be considered. Early or late appearance of puberty is mainly due to genetic factors. Therefore, the developmental history of the parents is of great importance. Considerable dispersion in the development of pubertal characteristics must be borne in mind. Recording of clinical data and measurements in percentile graphs permits clear and complete demonstration of the individual development pattern and offers immediate judgment of the growth process. Being familiar with the normal developmental stages and growth physiology, particularly growth velocity, and use of known clinical courses as simple techniques allows exact recognition of abnormal events in growth and development. These methods can often replace expensive hormonal assessments.


[Prevention of intra, and postoperative complications. Capabilities of the anesthesist]. Prevention of intra- and postoperative complications is one of the main tasks of the anesthesiologist. It is achieved by avoidance of specific anesthesiological dangers and mistakes and by adjustment of anesthetic techniques to the course of operation. Recognition and consideration of preexisting diseases as possible causes of complications and appropriate preoperative measures are the responsibility of the surgical-anesthesiological team. Depending on the given situation and the risk state of the patient during and after operation, special anesthetic procedures may be necessary.


Ecophylaxis: preventive treatment with gentamicin of rabbit lincomycin-associated diarrhea. In rabbits the oral or parenteral administration of lincomycin result in a severe and usually fatal form of diarrhea. The rabbits treated simultaneously with lincomycin and gentamicin do not present any sign of disease and behave exactly, therefore, as the control subjects. The same occurs in subjects treated with gentamicin alone. In all the subjects which died with diarrhea there was a marked alteration of the intestinal bacterial flora. Among the aerobic bacteria there was an overgrowth of coliforms and less frequently of enterococci, while bacilli were reduced and lactobacilli completely disappeared. Among the anaerobic bacteria, bacteroides and bifidobacteria disappeared and there was an overgrowth of clostridia instead. In rabbits treated contemporaneously with lincomycin and gentamicin, coliforms were absent and the mean number of clostridia was at least one hundred times lower; as in rabbits treated only with lincomycin, enterococci were present in greater number, while lactobacilli, bifidobacteria and bacteroides completely disappeared. Some of the bacteria which are able to overgrow in lincomycin treated subjects, in particular coliforms and clostridia, can be considered potentially pathogenic and their overgrowth could therefore explain the onset of diarrhea. Actually in faecal specimens of rabbits with lincomycin-associated diarrhea, together with the overgrowth of E. coli and clostridia, there is an absence of lactobacilli, bifidobacteria and bacteroides. It is known that these last bacteria contribute, in normal conditions, to maintaining the ecological equilibrium of the intestinal microbial flora. The diarrhea itself can be attributed most likely to the ecological alteration of intestinal microbial flora, with an overgrowth of some potentially pathogenic bacteria and the suppression of others which normally exert an inhibiting effect on the former. It has been suggested to call this form of gentamicin prophylaxis of lincomycin-associated diarrhea 'ecophylaxis', in the sense that it prevents or corrects certain types of ecological alteration of the intestinal microbial flora which lead to diarrhea.


Inhibitory effects of various progestins and deoxycorticosterone on the rapid onset of maternal behavior induced by ovariectomy-hysterectomy during late pregnancy in rats. The inhibitory effects of progesterone (P), 5 alpha-dihydroprogesterone (5 alpha-DHP), 17 alpha-hydroxyprogesterone (17-HP), and deoxycorticosterone (DOC) upon the rapid onset of maternal behavior induced during late pregnancy in primigravid rats by ovariectomy-hysterectomy (OH) were examined. Progesterone administration at a dosage of 5.0 mg oil vehicle daily (beginning on Day 17 and ending when the subject responded maternally to foster pups) significantly delayed by about 1.5 to 2.0 days the onset of maternal behavior. In contrast, P at dosages of either 1.0 or 2.5 mg daily, 5 alpha-DHP at 5.0 mg administered daily in either an oil or Tween-80 vehicle, 17-HP at 5.0 mg in oil daily, and DOC at dosages of either 5.0 or 10.0 mg in oil daily failed to effect the rapid onset of maternal behavior induced by ovariectomy-hysterectomy on Day 17 of pregnancy. These data suggest that during pregnancy the onset of maternal behavior is inhibited in a rather specific manner by progesterone.


Adrenocortical activity during meditation. We studied acute plasma cortisol and testosterone concentration changes during the practice known as "transcendental meditation" (TM) and during control rest. Three groups of normal, young adult volunteers were studied: a group of controls, these same controls restudied as practitioners after 3 to 4 months of TM practice, and a group of long-term, regular TM practitioners (3 to 5 years of practice). No change was found in controls during rest. Cortisol declined, but not significantly, in restudied controls, while cortisol decreased significantly in long-term practitioners during meditation and remained somewhat low afterward. No change in testerone concentration was noted during either rest or TM. Apparently, the practice of TM becomes associated with psychophysiologic response(s) which acutely inhibit pituitary-adrenal activity.


Sponsor of Texas health laws brings expertise to Congress. An opponent of government regulation of hospital costs, Rep. Bob Gammage of Texas thinks that Congress should have the right to veto the triggering of mandatory cost controls. It makes no sense, he says, to single out a particular industry for what, in effect, would be wage and price controls, especially because hospitals don't control what they buy, in terms of goods and services.