Adenine nucleotide metabolism of blood platelets. X. Formaldehyde stops centrifugation-induced secretion after A23187-stimulation and causes breakdown of metabolic ATP. A23187 induced shape change, aggregation and secretion of platelets in plasma. When rapid cooling was used to stop secretion and centrifugation to separate the cells from the medium, maximal amounts of storage ATP plus ADP and preadsorbed [14C]serotonin were found in the supernatant immediately (less than 5 s) after A23187 addition. These results suggested that A23187 could cause shape change and aggregation through secreted ADP and not directly. When secretion was stopped with chilling and formaldehyde treatment before centrifugation, the secreted substances appeared after a lag of 60-120 s, i.e. after shape change was terminated and aggregation was well on its way. These two platelet responses thus seemed to be independent of secretion and induced directly by A23187. The absence of a lag period when secretion was stopped by chilling alone was thought to be due to centrifugation-induced secretion of platelets conditioned by A23187. Formaldehyde completely inhibited centrifugation-induced secretion. At 37 degrees C, formaldehyde caused rapid breakdown of metabolic ATP in platelets with a pattern dependent on the formaldehyde concentration: Below 50 mM, ATP was converted to inosine plus hypoxanthine via ADP, AMP and IMP and the adenylate energy charge was preserved. Above 100 mM, AMP was the end product with a drastic reduction in the adenylate energy charge. These changes were not due to lysis of the platelets, but were apparently caused by an formaldehyde-induced increase in cellular ATP consumption. Platelet secretion is usually associated with a conversion of metabolic ATP to hypoxanthine. Formaldehyde had to be used to stop secretion and since it caused breakdown of ATP, additional smaples were taken out for nucleotide determination during stirring of platelet-rich plasma with A23187. It was found that metabolic ATP was converted to inosine plus hypoxanthine only during the secretion step.


Effects of continuous distending pressure on lung volumes and lung mechanics in the immediate neonatal period. The effects of CPAP and CNEP on lung mechanics and lung volumes were investigated in a group of 12 healthy newborn infants. Both resulted in a mild suppression of respiration. The fall in TPR50 was far greater during CPAP than during CNEP. Both led to a one third fall in dynamic compliance. Approximately 50% of the distending pressure was transmitted to the mediastinal structures whether applied as CPAP or CNEP.


Computer-aided material balancing for prediction of fermentation parameters. Despite the importance of biomass as a parameter in fermentation processes, there are no commercially available sensors suitable for its measurement. An indirect approach for the assessment of biomass concentration can be based on material balances and on the direct monitoring of fermentation parameters for which there are established sensors (e.g., gaseous oxygen and carbon dioxide). As a consequence, this method requires no assumption of cellular yield coefficients or rate constants. This approach is also readily adaptable to general use since it requires only some knowledge of the compositions of the substrate, cells, and noncellular products.


Computer-aided baker's yeast fermentations. The economics of yeast production depend heavily upon the cellular yield coefficient on the carbon source and the volumetric productivity of the process. The application of an on-line computer to maximize these two terms during the fermentation requires a continuous method of measuring cell density and growth rate. Unfortunately, a direct sensor for biomass concentration suitable for use in industrial fermentations is not available. Material balancing, with the aid of on-line computer monitoring, offers an indirect method of measurement. Laboratory results from baker's yeast production in a 14-liter fermentor (with a PDP-11/10 computer for on-line analyses) show this indirect measurement technique to be a viable alternative. From the oxygen uptake and carbon dioxide production data, gas flow rate, and ammonia addition rate, the cell density during the fermentation has been estimated and found to compare well with actual fermentation data.


The immobilization of microbial cells, subcellular organelles, and enzymes in calcium alginate gels. Saccharomyces cerevisiae cells, Kluyveromyces marxianus cells, inulase, glucose oxidase, chloroplasts, and mitochondria were immobilized in calcium alginate gels. Ethanol production from glucose solutions by an immobilized preparation of S. cerevisiae was deomonstrated over a total of twenty-three days, and the half-life of such a preparation was shown to be about ten days. Immobilized K. marxianus, inulase, and glucose oxidase preparations were used to demonstrate the porosity and retraining properties of calcium alginate gels. Calcium alginate-immobilized chloroplasts were shown to perform the Hill reaction. Some experiments with immobilized mitochondria are reported.


Aeration without air: oxygen supply by hydrogen peroxide. Oxygen has been supplied to suspensions of microorganisms kept under nitrogen by the addition of hydrogen peroxide. If catalase was present in the suspension and the flow was adjusted to the rate of oxygen consumption, the cells grew at rates identical to the controls incubated under air. The applicability of oxygen supply by hydrogen peroxide and its limits are discussed.


An analysis of extended and exponentially-fed-batch cultures. Under certain conditions it is shown that an extended culture is equivalent to an exponentially-fed-batch culture, that an exponentially-fed-batch culture (and an extended culture) can be maintained at a steady state and that an exponentially-fed-batch culture may be mimicked by a continuous-flow culture with a constant dilution rate. Operational conditions required to maintain steady states are specified.


Pulmonary defense mechanisms and the interaction between viruses and bacteria in acute respiratory infections. Pulmonary virus infections are known to predispose to bacterial infections in the lung. The mechanism by which the virus renders the pulmonary system more susceptible to bacterial infection is reviewed. The bacterial multiplication associated with virus infections is related to defects in in situ bactericidal (phagocytic) mechanisms of the lung. This phagocytic dysfunction is localized to the intracellular killing mechanisms of the alveolar macrophage phagocytic process.


Alterations in bacterial defense mechanisms of the lung induced by inhalation of cadmium. Exposure to an aerosol of CdCl2 has a marked proclivity to reduce the ability of the lung to defined itself against microbial insults. A significant enhancement of mortality was observed in mice exposed to CdCl2 concentrations ranging from 80 to 1600 mug/m3 prior to being challenged with viable streptococci. The increase in percent mortality above control varied from 15% at the lowest CdCl2 concentration to approximately 70% at the highest concentration. In order to determine the various mechanistic factors which may explain the observed effect of reduced host resistance to infection, a variety of pulmonary defense systems was studied. There was a significant decrease in the total number of alveolar macrophages recoverable from rat lungs immediately after completion of the exposure regimen. The number of macrophages returned to normal (about 5.5 million) within 24 hours after cessation of the exposure. However, total polymorphonuclear leucocytes increased 1.5 million immediately after completion of the exposure and 13 million within 24 hours after cessation of the exposure. Lymphocyte numbers were not affected by these exposure levels. Data concerning clearance of streptococci from the lung following CdCl2 exposure closely correlated with the observed mortality pattern.


Selected list of books and journals for the small medical library. This revised list of 472 books and 138 journals is intended as a selection guide for small or medium-sized hospital libraries or for the small medical library serving a specified clientele. It can also be used as a core list by small hospital library consortia. Books and journals are categorized by subject, with the books being followed by an author index and the journals by an alphabetical title listing. Items suggested for initial purchase by smaller libraries are indicated by an asterisk. To purchase the entire collection of books and to pay for annual subscriptions to all the journals would require an expenditure of about $18,200. The cost of only the asterisked items recommended for first purchase totals approximately $4,500.


[The protein constituents of human bronchial washings. Their relationship to the defenses of the respiratory tract (author's transl)]. In an attempt to define the composition of normal bronchial secretions, bronchial washings were obtained from normal areas of the lung in six patients. An analysis of proteins in the washings was carried out by crossed immunoelectrophoresis. The proteins detected were derived mainly from plasma and a very low content of secretory proteins was found. The composition of bronchial secretions and bronchial washings from a bronchitic patient was established and compared by crossed immunoelectrophoresis and gel filtration. The most important components were IgA, alpha1-antichymotrypsin and alpha1-antitrypsin, all of which are defense factors for the respiratory tract.


Role of the alveolar macrophage in pulmonary bacterial defense. This review concerns the role of the alveolar macrophage as part of the coordinated mucociliary, macrophge and immune bacterial defense mechanisms of the lung. Alveolar macrophages are end-stage phagocytes that are derived from two precursor sources; an uncommitted pleuripotential hematopoietic stem cell, and a committed differentiated pulmonary precursor which can renew itself, as well as mature into functional alveolar macrophages. Sufficient numbers of alveolar macrophages are distributed throughout the lungs to ensure their proximity to any bacteria that penetrates alveolar regions. Studies with rodents have shown that these alveolar macrophages ingest, inactivate, and degrade inhaled microorganisms within eight hours of their entrance into alveolar regions. The biochemical mechanisms responsible for this antibacterial function involve the elaboration of chemotactic factors consequent to the interaction of bacteria, antibody, and complement, and the presence of bactericidal substances within the macrophage itself. Normally, these cellular mechanisms enable the alveolar macrophage system to maintain the lungs bacteria-free. However, if macrophage function is impaired due to pollutant or viral exposure, the host-parasite balance is upset and bacterial proliferation ensues. In such circumstances, polymorphonuclear leucocytes and additional macrophages enter the area of bacterial proliferation to produce the classical inflammatory reaction of pneumonia.


[Kinetics of pulmonary defense in deep lung (author's transl)]. The association of different experimental methods using radioactive particulate aerosols with bronchial washing and morphometric techniques reveals the importance of alveolar macrophages in antibacterial defense and the interest of their quantitative evaluation. The study of the kinetics of pulmonary phagocytic systems has shown a "capillary compartment", which consists of a reserve of monocytes which are temporarily present in the lung and in transit through it. This reserve represents 4.6% (sigma=1.4) of the cells from deep in the lung and is much larger than the systemic monocytic pool. 0.5% of these monocytes are in a phase of DNA synthesis. This capillary compartment must be clearly separated from interstitial phagocytes, the number of which is insignificant under physiological conditions. The phagocytic relay by polynuclear elements appears during bacterial aggression and is interdependent with macrophagic population. The particularities of the immune defenses of the distal parts of the lung are stressed especially in comparison with systemic defenses.


Respiratory tract cell-mediated immunity. Cell mediated immunity in the respiratory tract, operating somewhat independently of systemic cell mediated immunity CMI, has been recognized only rather recently. Local CMI has been shown to be more consistently and more potently stimulated following local administration of immunogen. In addition, in the few studies that have been done relative to protection, local immunization has resulted in greater resistance to organisms usually considered protected against by CMI. Thus, like the humoral immune system, CMI appears to operate locally in the respiratory tract, at least partially independent of systemic CMI. This paper deals with the evidence relative to local CMI, as well as a discussion of the role of the pulmonary macrophage, the mechanisms whereby local CMI may operate in protection, and the evidence for the presence of T-cell memory in the respiratory tract.


The management of dementia: a review of some possibilities. Evidence relating to the effects of therapeutic intervention on the behaviour of elderly demented patients is reviewed. Contrary to common prejudice there is strong evidence that improvements in functioning can be achieved by social and behavioural manipulations although maintaining such gains may be more difficult. There are some indications as to what type of intervention is likely to be most effective and some specific techniques that might be of use are discussed.


Gastro-oesophageal reflux, hiatus hernia and the radiologist, with special reference to children. Gastro-oesophageal reflux can lead to peptic oesophagitis and stricture formation. This is particularly true in infants in whom the condition should be suspected if the patient presents with vomiting, anaemia and failure to thrive. The anatomy of the oesophago-gastric junction is described. The inferior oesophageal sphincter is the main barrier to reflux, and marks the functional junction between oesophagus and stomach. It is under nervous and hormonal control. It is weak in the neonate who therefore frequently refluxes. An hiatus hernia can cause problems due to its bulk but the main problem of peptic oesophagitis is due to gastro-oesophageal reflux. The radiological examination should be carried out carefully with the patient swallowing in a prone position. The patient should be put in the Trendenlenberg position and compression applied to the abdomen. Reflux is intermittent and a negative examination should be repeated if the clinical findings suggest a diagnosis of peptic oesophagitis.  Associated pyloric stenosis should always be excluded. Radiological examination of the gastro-oesophageal junction remains the quickest, simplest, and most convenient and safe technique as long as its limitations are appreciated.


Controlled trial of active immunotherapy in management of stage IIB malignant melanoma. The prognosis for patients who undergo surgery for stage IIB malignant melanoma is poor. Animal studies have suggested that BCG and tumour cell vaccines given together may provide effective immunotherapy. To assess the effectiveness of this treatment 15 patients with stage IIB malignant melanoma who had their tumour excised were studied. Seven were treated conservatively, and eight were vaccinated with BCG and autologous irradiated cells. Three vaccinated patients suffered widespread recurrence within three months. All four vaccinated patients who suffered a recurrence within the first year died, while none of the three controls with recurrent disease died. In view of this alarming trend the trial was stopped after a year. BCG and the tumour cells may have enhanced the tumour growth, although there was no apparent reason for this. The results of uncontrolled or unrandomised trials that have suggested that this treatment is beneficial should be treated with scepticism.


Metronidazole in prevention and treatment of bacteroides infections in elective colonic surgery. A double-blind randomised trial was carried out among 46 patients undergoing elective colonic surgery; 27 patients received prophylactic metronidazole and 19 received placebo. Anaerobic infections did not develop in any of the metronidazole-treated patients, but did develop in 11 (58%) of 19 controls who were subsequently successfully treated with metronidazole.


Predicting child abuse: signs of bonding failure in the maternity hospital. Fifty children referred to the Park Hospital because of actual or threatened abuse were compared with 50 controls born at the same maternity hospital. Five factors were significantly more common in the abused group than among their controls: (a) mother aged under 20 at birth of first child, (b) evidence of emotional disturbance, (c) referral of family to hospital social worker, (d) baby's admission to special care baby unit, (e) recorded concern over the mother's ability to care for child. Thirty-five of the abused group had two or more of these factors compared with only five of the control group. As these data were collected from information recorded routinely at the maternity hospital, it is possible to identify most abusing families when the child is born. Such identification must lead to a comprehensive assessment of each case followed by constructive preventive action.


Levamisole in aphthous stomatitis: evaluation of three regimens. One hundred and twenty-four patients who had had recurrent aphthous stomatitis (RAS) for two to 53 years took part in three studies to assess the effectiveness of levamisole and determine an adequate regimen. In study 1 and the first half of study 2 both of which were double-blind, levamisole 150 mg/day (or placebo) was given on three consecutive days in every fortnight. In the second two months of study 2 and in the open trial (study 3) three-day courses were given only when an episode of RAS occurred. The drug was well tolerated. The signs and symptoms of RAS improved gradually and significantly in those treated with levamisole but not in those on placebo, and intergroup differences were also significantly in favour of the active drug. Improvement occurred earlier in study 3 than in the other two studies. Hence levamisole may prevent new episodes of RAS.


Cholestyramine in treatment of postvagotomy diarrhoea--double-blind controlled trial. A double-blind controlled trial was performed to assess the effectiveness of cholestyramine in treating severe continuous postvagotomy diarrhoea. Each patient and a clinician assessed the results, and those treated with cholestyramine showed a considerable improvement over those given placebo. There were no significant side effects or changes in laboratory values in the cholestyramine group. Although the numbers were too small for statistical analysis, these results suggest that cholestyramine may be of value in the management of some patients with severe continuous postvagotomy diarrhoea who are unresponsive to other forms of treatment.


Selection of multiresistant coliforms by long-term treatment of hypercholesterolaemia with neomycin. Patients with hypercholesterolaemia are often treated with the antimicrobial agent neomycin. Such treatment is potentially dangerous, however, as it may favour the emergence of multiresistant, R-factor-carrying, enteric bacteria among the intestinal flora. In 11 out of 14 patients who had received neomycin for three months to eight years most of the faecal coliforms were resistant to at least four antimicrobial drugs and capable of transferring this resistance to others. In contrast, only one out of nine patients who were treated with other lipid-lowering drugs had resistant bacteria in their faeces. Neomycin may cause multiresistant strains to emerge because, like tetracycline, it forms high concentrations in the gut. Long-term treatment of non-infectious conditions like hypercholesterolaemia with neomycin is potentially dangerous not only to the patient but also to the community because of the creation of a reservoir of multiresistant organisms.


The role of tetracyclines in the treatment of non-specific urethritis. An asssessment of the clinical findings and treatment in 400 patients with non-specific urethritis (NSU) is reported, and the effect of treating their contacts is analysed. Three tetracyclines were compared ina randomised trial which showed that low-dose oxytetracycline (250 mg twice a day) was as effective as preparations formulated specifically for twice daily administration (triple tetracycline and sustained-release tetracycline hydrochloride). The question of multiple aetiology was explored by testing statistically whether various clinical features such as age, incubation period, severity of symptoms, and previous infection were related to outcome. No subgrouping of the condition could be found. Clinical relapse proved to be independent of empirical treatment of asymptomatic contacts, which therefore appeared not to confer any benefit on either partner. It is suggested that the infective aspect of NSU is readily controlled, and that other factors, probably psychological, determine relapse.


Ornidazole: a new antiprotozoal compound for treatment of Trichomonas vaginalis infection. A new anti-protozoal compound, ornidazole, a derivative of nitroimidazole, was given in a single 2 g dose to 20 women with Trichomonas vaginalis infection. All the women were cured, but they suffered some side-effects. Plasma levels of ornidazole reached a peak five to eight times higher than minimum inhibitory concentrations and exceeded this level for at least 36 hours. It is therefore possible that a smaller dose might have had an adequate trichomonicidal effect and fewer side-effects. Further studies are in progress.


S-100 in the central nervous system of rat, rabbit and guinea pig during postnatal development. The accumulation of the brain-specific S-100 protein has been studied during postnatal development of rat, rabbit and guinea pig quantitatively, using immunoelectrophoresis, and qualitatively, by immunoelectron microscopy. Newborn guinea pigs show high levels of S-100. The distribution was similar to that of adult animals with an enrichment of S-100 to the postsynaptic membranes and to the astrocytic filaments. The neuronal plasma membranes as well as the neuronal nuclear membranes, astrocytic and oligodendroglial plasma membranes, also showed a specific activity for S-100. The amount of S-100 increased linearly from birth until the 3rd and 4th postnatal week of rabbit and rat, respectively. During the 2nd and 3rd week rabbit and rat nervous systems showed an accumulation of S-100, especially in the postsynaptic membranes and in the astrocytic filaments. In this study we present evidence that the S-100 protein quantitatively and ultrastructurally appears according to a pattern which parallels the muturation of brain, showing adult characteristics already at birth in early developing brains (guinea pig) and a change towards adult pattern after birth in late developing brains (rat and rabbit). In the latter two species change towards an adult S-100 distribution pattern proceeds during the postnatal period concomitant with the enzymatic and electrophysiogical maturation of the brain.


On the state of anionic groups of demineralized matrices of bone and dentine. Calcium-binding and biochemical studies have been applied to characterize the state of the carboxylate and protein-bound phosphate groups in the EDTA-demineralized matrices of rat bone and dentine. The organic phosphate and carboxylate content of demineralized bone is virtually identical to that of purified steer skin collagen whereas demineralized dentine has a significantly higher phosphate and carboxylate content, presumably due to the presence of an acidic non-collagenous phosphoprotein. Two classes of calcium-binding sites can be detected in demineralized bone, demineralized dentine, and purified, reconstituted collagen. The number of strong calcium-binding sites correlates with the number of protein-bound phosphate groups. Depending on the preparative procedure, seven to nine such sites (per collagen molecule) are present in dentine, and one to two in the purified reconstituted collagen and in bone. The binding constant for the dentinal sites (1.1 X 10(4) M-1), however, is 20 times greater than that for bone or reconstituted collagen fibrils from skin. We tentatively conclude that the strong calcium-binding site in bone and reconstituted collagen is of the form protein-PO-4Ca++ whereas in dentine it is of the form protein (formula: see text); the weak binding sites in bone and dentine are of the form protein-COO-Ca++; and that approximately 160 of the 217 carboxylate groups of the collagen molecules of dentine or bone are present as electrostatic linkages of the form protein-COO-+H3N-protein.


The use of aminophylline for correction of haemodynamic repercussions of clamping of the aorta. Occlusion of the abdominal aorta induces an increased impedance to ejection, leading to a reduction in cardiac output. The magnitude of the haemodynamic disturbances seemed important enough to justify the use of a vasodilator drug. In that respect the use of aminophylline was evaluated in twelve patients. The potentially dangerous increase in systemic resistance is prevented by aminophylline, which effectively neutralizes the increase in afterload. Moreover, a positive inotropic action can be inferred from the increase in stroke volume and ventricular systolic work. It must be stressed that this drug must be withheld in patients with cardiac irritability, for it has a beta-mimetic action.


Double-blind evaluation of buprenorphine hydrochloride for post-operative pain. In a double-blind, random assignment study of four groups of 40 patients, relief of severe pain with buprenorphine hydrochloride 0.2 mg or 0.4 mg was evaluated and compared with morphine sulphate 5 or 10 mg. Evaluations included pain intensity, pain relief, sedation and other effects for up to 12 hours after drug administration, following recovery of wakefulness from anaesthesia for major abdominal surgery. Analyses of five parameters showed that the four groups were statistically comparable and that buprenorphine hydrochloride is at least 50 times more potent than morphine sulphate and has a substantially longer duration of analgesic action. Further clinical evaluation is, therefore, recommended.


The prevention of autolysis in stored corneas by lysosome stabilization. A histochemical study. We wished to determine if dexamethasome, acting as a lysosome stabilizer, could reduce the release and activation of the lysosomal acid hydrolases, and thus retard autolysis of stored corneas. One cornea (experimental) of a rabbit was soaked in a 2 per cent steroid solution and the other cornea (control) in physiological saline for 3 hours at 23 degrees C. The experimental and control corneas were then processed histochemically to show the localization of the lysosomal marker enzymes beta-glucuronidase and acid phosphatase. Compared to the controls the steroid treated corneas showed reduced enzyme activity suggesting that autolysis during storage had been retarded.


Systemic sensitization of corneal allograft recipients before the clinical onset of graft reaction. We wished to know if full-thickness corneal allografts placed centrally in clear host corneas would cause systemic sensitization. Keratoplasty was done in 13 rabbits and a leucocyte migration inhibition test was done on their systemic blood five to seven days operation using donor specific corneal antigen. All but two animals had positive results (mean inhibition 27% "/- 2.2) showing that, following keratoplasty, systemic sensitization does occur. Absence of blood vessels and lymphatics thus does not constitute an absolute barrier to sensitization of the recipient.


Chronic subphrenic abscess: the missed diagnosis. This report of a case of chronic subphrenic abscess, with a brief review and recommendations for diagnosis and prevention, draws attention to this clinical entity as a potential cause of chronic ill health. The clinical presentation and laboratory findings in this case were unremarkable. It is clear that the condition can be easily missed and the patient may be exposed unnecessarily to prolonged illness and to inappropriate investigation and therapy.


Radiolucent urinary calculus in a transplant patient: an unsuspected cause of ureteropelvic obstruction. The occurrence of nephrolithiasis and nephrocalcinosis in the patient who has undergone a renal transplant is rare and is usually related to parathyroid hypersecretion. A case is presented in which the patient had a radiolucent stone that arose as a result of the use of nonabsorbable sutures. It is clear that nonabsorbable sutures. It is clear that nonabsorbable sutures should be avoided in renal allotransplant recipients.


Lung disease in farmers.

Lung disease in farmers. Lung diseases in farmers attributable to their occupation include (a) farmer's lung, caused by exposure to mouldy hay, (b) the asthma caused by exposure to grain dust and (c) silo-filler's disease. Their prevalence in Canada is unknown. Farmer's lung results from inhalation of mould spores in hay; the mechanism is immunologic. The exact cause and mechanism of grain dust asthma are unknown but may be immunologic. Silo-filler's disease is caused by the toxic effects of inhaled nitrogen dioxide.


Microsome-mediated mutagenesis in V79 Chinese hamster cells by various nitrosamines. A microsome-mediated mutagenesis system has been established with the V79 Chinese hamster cell line. The cells, grown in monolayer, were treated with various nitrosamines in the presence of a postmitochondrial fraction ((S15) from rat liver and a reduced nicotinamide adenine dinucleotide-generating system for 1 hr, washed and incubated for 2 to 3 hr in fresh culture medium, and then plated for toxicity and mutagenicity assays. Mutation was determined by resistance to 20mug 8-azaguanine per ml. In this assay system, the S15 fraction and cofactors by themselves were not toxic to the cells; dose-related mutagenicity and cytotoxicity were induced by N-nitrosodimethylamine (DMN) only in the presence of the S15 fraction and cofactors. Pretreatment of rats with phenobarbitone led to an approximately 2-fold increase in the mutation rate over that with tissues from untreated rats with concentrations of DMN from 10 to 50 mM, while aminoacetonitrile pretreatment reduced the mutagenic effect. Methylcholanthrene pretreatment resulted in an increase in the mutation frequency with a higher concentration of DMN (50mM). Various other nitrosamines were also assayed in the presence or absence of the S15 fraction from phenobarbitone-pretreated rats and a reduced nicotinamide adenine dinucleotide phosphate-generating system. With the exception of N-nitrosomethylphenylamine, the carcinogenic nitrosamines (DMN, N-nitrosodiethylamine, N-nitrosodi-n-propylamine, N-nitrosodi-n-butylamine, N-nitrosodi-n-pentylamine, N-nitrosomethyl-n-propylamine, N-nitrosomorpholine, N-nitrosopyrrolidine, N-nitroso-N'-methylpiperazine, and N-nitrosomethylphenylamine) were mutagenic to the V79 Chinese hamster cells in the presence of the S15 fraction and cofactors. Neither N-nitrosodiphenylamine nor N-nitrosomethyl-tert-butylamine had a mutagenic effect. These findings show that chemical carcinogens can be tested for mutagenicity in cultured mammalian cells in the presence of a metabolic activation system. The results are discussed in relation to the carcinogenicity and mutagenicity of these compounds in other test systems.


Effects of methanol extraction residue of Bacillus calmette-Guérin in humans. Forty patients with histologically confirmed neoplastic diseases were treated with the methanol extraction residue of Bacillus Calmette-Guérin (MER). Thirty-six received concomitant chemotherapy. MER was initially given intradermally twice a month, 1 week apart, at a dose of 200 mug into each of five sites draining different lymph node-bearing areas on the anterior body surface. Thirty-seven patients developed local ulcerations at least 0.5 cm in diameter at MER injection sites. Typical lesion evolution was characterized by erythema and induration followed by vesicle formation and central necrosis. Either granulation tissue or a thick nonulcerated eschar preceded healing, leaving a linear, flat scar. Systemic toxicity consisted of malaise, fever, and myalgias on the day of MER administration. No hematological or biochemical changes directly attributable to MER were observed. Dose titrations in decreasing 10-fold dilutions in a linear array in a single anatomical region were carried out on 35 occasions. All patients but three developed at least a 5-mm induration to the 1-mug dose within 2 weeks of titration. Dose reductions were necessary in 19 instances. The minimal dose that produced a 1-cm inflammatory lesion with central necrosis was 0.01 mug. Serial biopsies were performed. These indicated a time-related series of changes from a nonspecific inflammatory lesion to an acute inflammatory response with microabscesses, followed by noncaseating granulomata and ultimately fibrosis. MER is a quantifiable nonviable immunostimulant that obeys dose-response relationships in its cutaneous lesions.


Effects of cyclophosphamide and of busulfan on spleen colony-forming units and on hematopoietic stroma. The effects of cyclophosphamide (CY) and busulfan (BU) on the hematopoietic stromal function (HS-P) of mouse marrow were evaluated. Stromal function of femoral marrow was assessed by implanting the test femur s.c. into an isogeneic host and determining the number of CFU-S in the implant 6 weeks later. Since the CFU-S have been shown previously to be primarily of host origin, this presumably measures the abilit- of donor hematopoietic sites to harbor host CFU-S. After injection of CY, the number of CFU-S in the marrow fell but recovered to normal within 6 weeks. The HS-P function fell to half-normal after 10 mg of CY and did not regenerate detectably in 6 weeks. On the other hand, 2 mg of BU i.p. caused a lesser initial decline in the number of CFU-S, but recovery was still incomplete after 6 weeks. BU given p.o. had a more marked effect on CFU-S and caused a significant decline in the HS-P function. Doses of CY (5 mg/dose) given intermittently appear to cause cumulative damage to HS-P function. HS-P function did not, in any experiment, recover significantly in the 6 weeks following the last dose of CY. This result suggests that large doses of the alkylating agent CY causes prolonged and perhaps permanent HS-P damage. This damage to the HS-P is cumulative when the CY is given at weekly intervals. Despite lack of HS-P recovery, CFU-S regenerate rapidly after CY therapy is stopped. On the other hand, BU also causes damage to the HS-P. However, even when BU is given at a dosage that does not significantly affect the HS-P, CFU-S recovery is delayed, suggesting that BU affects the CFU-S in a manner that differs qualitatively from that of CY.


Effects on gonadal function by lesioning tanycytes in the median eminence of the rat and Japanese Quail. The ependymal linings of the median eminence were destroyed by electric cautery or intraventricular injection of picric acid in the rat and Japanese quail. In these animals the ventricular lumen near the median eminence disappeared due to adhesion of lesioned walls on both sides of the third ventricle. Electric lesions of the ependymal layer containing tanycytes did not induce appreciable disturbance in the estrous cycles. Rats in which tanycytes were lesioned by picric acid displayed 4-day estrous cycles after prolonged diestrus (10-22 days). After destruction of tanycytes in the quail, a photostimulated gonadal growth was observed. It is concluded that the tanycyte transport of the ventricular fluid to capillaries of the portal vessels appears unnecessary for maintenance of adenohypophysial gonadotrophic activities.


Electron microscopic immunocytochemical demonstration of separate mesotocinergic and vasotocinergic nerve fibres in the pars intermedia of the amphibian hypophysis. With the use of the unlabeled antibody peroxidase-antiperoxidase (PAP) method at the electron microscopic level, it has been shown that the pars intermedia of the hypophysis of Rana temporaria contains a diffuse intercellular network of separate mesotocinergic and vasotocinergic nerve fibres.


Ontogeny of rat pancreatic polypeptide (PP) cells. Cells storing pancreatic polypeptide (PP) appear in rat pancreas at the time of parturition, much later than insulin and glucagon cells. At this stage, the pancreatic polypeptide (PP) cells occur scattered in the exocrine parenchyma and in the islets. Subsequently, 5-7 days postnatally, an abrupt increase in the number of PP cells occurs. At this stage, they are fairly numerous in the islets and comparatively rare in the exocrine parenchyma. Not until 8-10 days after birth is the number of PP cells similar to that in the adult pancreas. A few PP cells were seen in the antral mucosa during the first 10 days after birth. They were not seen elsewhere in the gut.


Effect of alloxan on rat pancreatic polypeptide (PP) cells. Injection of alloxan caused an almost total disappearance of insulin cells in the rat pancreas. Planimetric analysis revealed a 50 per cent reduction of the mean islet volume. The number of immunoreactive pancreatic polypeptide (PP) cells per sectioned islet was significantly increased, and the PP cell volume per islet doubled. Assuming an unchanged number of islets, the results indicate an increase in total PP cell mass following alloxan administration.


Immunohistochemical localization of neurotensin in endocrine cells of the gut. Endocrine cells displaying neurotensin immunoreactivity are found scattered in the jejuno-ileum of all mammals studied, including man. They are rather scarce in rat, guinea pig, rabbit and pig and fairly numerous in cat, dog and man. In most mammals the neurotensin cells predominate on the villi. Only in the dog are they more numerous in the crypts. In the chicken, neurotensin cells occur all along the intestinal tract. They are particularly numerous in the zone that joins the gizzard with the duodenum. The ontogeny of the neurotensin cells in the gut was studied in rats and chickens. In the rat, the cells are first observed in the jejuno-ileum immediately before birth. The adult frequency is reached 4-5 days later. In the chicken, neurotensin cells first appear in the colon in the 18 day old embryo and in the small intestine two days later (i.e. one or two days before hatching). A few days after hatching, the gut has achieved the adult number of neurotensin cells per unit area.


Alteration in cell surface LETS protein during myogenesis. Cell surface alterations during myogenesis have been investigated in Yaffe's myogenic cell line L8, using indirect immunofluorescence with an antibody against the large external transformation-sensitive (LETS) protein. The immunofluorescent technique reveals a susbstantial alteration in the distribution of this surface antigen. With the prefused myoblasts, LETS protein is dispersed all over the cell surface; following myoblast fusion, this pattern is markedly changed. All of the fibril-like surface LETS protein disappears, and in some myotubes, discrete clusters of LETS protein become conspicuous. By use of radioimmunological assay, the total LETS protein is quantitatively reduced upon myoblast fusion.


Number and distribution of polyadenylated RNA sequences in yeast. The poly(A)-containing RNA, isolated from the budding yeast Saccharomyces cerevisiae, has been characterized with regard to the number and distribution of sequences by a kinetic analysis of RNA-cDNA hybridization. In agreement with results previously obtained on metazoan eucaryotes (Bishop et al., 1974), discrete complexity classes were observed. There exist low, medium, and high complexity classes which contain approximately 20, 400, and 2400 sequences, respectively. This measurements of the number of sequences has been verified by hybridization with single copy DNA. 20% of the single copy fraction of the yeast genome is rendered double-stranded by poly(A)-containing RNA. Assuming asymmetric transcription, this is equivalent to approximately 4000 poly(A)-containing sequences, verifying the results obtained with RNA-cDNA hybridization. In addition, the first-order kinetics of the hybridization with single copy DNA verified the notion that most of the sequence complexity is present at the same intracellular concentration. The same number and distribution of sequences were found in poly(A)-containing polysomal RNA and in total RNA, suggesting that most or all of the sequence complexity is on polysomes and is adenylated. The results indicate that RNA-cDNA hybridization is an accurate method for determining sequence complexity values and that yeast, grown under vegetative conditions, has 3000-4000 different mRNA sequences.


Regulation of a set of abundant mRNA sequences. The temperature-sensitive mutant of yeast, rna2-, when incubated at the nonpermissive temperature, has a qualitatively distinct distribution of mRNA sequences as compared to wild-type. Quantitative comparison with the wild-type distribution indicates that after 1 hr at the nonpermissive temperature, the concentration of approximately 100-150 abundant sequences is significantly decreased. Control experiments indicate that this effect is not simply a function of the increase in incubation temperature nor a general effect on all mRNAs. Gorenstein and Warner (1976) have shown that the synthesis of ribosomal proteins is preferentially depressed at the non-permissive temperature in rna2-. It is proposed that among these 100-150 sequences are the mRNAs which code for the ribosomal proteins.


Augmentation of serum CPK activity by digitalis in patients with acute myocardial infarction. The effect of acetyl strophanthanin on the rate of creatine phosphokinase (CPK) efflux was evaluated in 59 predominantly class I and II patients randomly allocated between treated and control. Therapy (0.5 mg) was begun 11-15 hours after the onset of symptoms and repeated four hours later (0.25 mg). Accumulated CPK activity (ACA) was determined from serial serum CPK changes sampled every two hours and compared to predicted CPK activity (PCA) determined from the first seven hours of CPK changes. In the control group, ACA was not significantly different from PCA. Digitalis consistently resulted in an augmentation of CPK efflux into serum which was temporally related to drug administration and resulted in a corresponding increase in ACA (P less than 0.001). Thus acetyl strophanthanin appears to increase apparent CPK activity in serum in class I and II patients.


Assay of phenobarbital: adaption of "EMIT" to the centrifugal analyzer. We have adapted the centrifugal analyzer to the homogeneous enzyme immunoassay ("EMIT") for phenobarbital. The assay was modified to give greater range and sensitivity, and less reagent is needed. The transfer disc is prepared with totally automatic pipetting. Results are calculated with a micro-computer that provides a logit transformation of absorbance data. Precision and accuracy are excellent, and results correlate well with those by gas-liquid chromatography.


Specific conductivity of urine and sensitivity of enzyme immunoassay methods of analysis for drugs of abuse. We studied the sensitivity of the EMIT assays of amphetamine, benzodiazepines (diazepam), methadone, opiates (morphine), and propoxyphene at different specific conductivities in urine. The specific conductivity was varied by adding NaCl. For a sensitivity of 0.5 mg of drug per liter,  the urine must have a specific conductivity of less than about 35 mS/cm in all these assays except that for benzodiazepine, for which it must be less than about 20 mS/cm.


Octopamine and ammonia plasma levels in hepatic encephalopathy. It has been recently proposed that hepatic encephalopathy could be due to the accumulation of octopamine acting as a false neurotransmitter, and the increase of ammonia might reflect this accumulation. The simultaneous determination of octopamine and ammonia was performed in 88 cases with or without encephalopathy. The correlation between the two substances appeared to be good (P less than 0.01; r = 0.5), except in shunted patients. All the cases with low octopamine and high ammonia were patients who had been submitted to surgical portal-systemic anastomosis. This finding does not seem to be coincidental; in this type of patients, the mechanism of hepatic encephalopathy could involve other beta-hydroxyphenylethanolamines in addition to octopamine. The presence of the inhibition of the reaction of transmethylation constantly observed during octopamine plasma assay is in favour of this hypothesis.


Luteinizing hormone, follicle stimulating hormone and testosterone in normal and impotent men following LHRH and HCG stimulation. The effect of synthetic LHRH on plasma concentrations of LH, FSH, testosterone and testosterone response to i.v. HCG was studied in fifteen normal men and in fifteen men with impotence. The mean basal concentrations of LH, FSH and testosterone in the men with impotence were not significantly different from those of the normal group. A normal response of gonadotrophins and testosterone was also observed. It is concluded that a normal pituitary sensitivity to synthetic LHRH and a normal response to endogenous and exogenous gonadotrophins exist in this particular disorder.


Haemolytic assays in agarose plates for components of the classical complement pathway: interference by the alternative pathway. It has been observed that when serum C6 is measured by the haemolytic radial diffusion technique a heat labile factor limits the size of the haemolytic rings. This reduction is haemolysis has been shown to be due to alternative pathway activation of C6 in the agarose plate; and that the heat labile factor is Factor B of the alternative pathway. This phenomenon is of practical importance when assaying for C6; however, it does not explain the observations of a C6 inactivator reported by Nelson & Biro (1968).


A functional comparison of blood and gingival inflammatory polymorphonuclear leucocytes in man. Polymorphonuclear leucocytes from the human gingival crevice (CREV-PMN) have a defective phagocytic capacity when compared with peripheral blood polymorphonuclear leucocytes (PB-PMN) from the same individual. In a study of fourteen clinically healthy subjects, significantly smaller numbers of CREV-PMN phagocytosed fewer Candida albicans blastospores as compared with PB-PMN. The intracellularkilling capacity of the two cell populations was similar. Removal of specific antibody but not complement significantly depressed blastospore uptake by both cell types. It is postulated that the intrinsic defect of the CREV-PMN is acquired in vivo and may be a general property of PMN from inflammatory sites.


Drug-induced immunological unresponsiveness: selective inhibition of T-cell 'helper function' by cyclophosphamide in mice pretreated with phytohaemagglutinin. Studies involving the combined use of phytohaemagglutinin (PHA) and cyclophosphamide (CY) indicate that both agents can act together to produce immunological unresponsiveness: following injection of PHA into mice, splenic DNA synthetic responses [14C]thymidine incorporation) and haemolysin plaque formation against sheep red blood cells were determined in daily intervals. Both immunosuppression and DNA synthetic activity were maximally developed 5 days after treatment with PHA. Administration of CY at this time resulted in immunological unresponsiveness lasting for about 18 days. Antibody production could be completely restored with antigen-activated T cells (but not with B cells), thus indicating a selective inhibition of T-cell 'helper function' in mice treated with PHA and CY. This observation is consistent with the general assumption that cells involved in the response to PHA are predominantly T cells. Apparently, these cells are highly sensitive to an inactivation by CY after stimulation with PHA.


A defect of the alternative pathway of complement. The sera of patients defective at opsonization for yeast phagocytosis fix haemolytic complement poorly following incubation with the alternative pathway complement activators, inulin and bacterial endotoxin. This suggests that the defect lies early in the alternative pathway of complement.


Streptococcal cross-reacting antigen and the bundle of His. Five sera raised in rabbits against three strains of Streptococcus pyogenes (grown in semi-synthetic media) were shown by immunofluorescence to have antibodies reacting with both myocardial and conducting fibres. The pattern of staining on the conducting fibres was different to that on myocardial fibres and suggested the presence of larger amounts of cross-reacting antigen. Most work was done on ox heart, but the results were confirmed on human heart and rabbit heart. Absorption studies, carried out with three sera on ox heart only, showed that absorption with the homologous organism abolished in parallel the staining of both types of fibre. Absorption with heterologous organisms was less effective indicating the existence of more than one cardiac cross-reacting antigen. Absorption with myocardium, suggested that the conducting fibres contained streptococcal cross-reacting antigens additional to those found in the contractile fibres.


The reactivity of the antistriational antibodies associated with thymoma and myasthenia gravis. Using immunofluorescence forty-nine sera giving striational staining of skeletal and cardiac muscle have been tested on glycerinated myofibrils. By comparing immunofluorescence and phase contrast it has been found that these antibodies are rather heterogeneous but at least three different staining patterns can be identified. Some patterns may be associated with the presence of a thymoma or may be induced by penicillamine treatment of patients with rheumatoid arthritis. Routine screening for antistriational antibodies may lead to the recognition of undiagnosed myasthenia gravis and thymoma. Antistriational autoantibodies may be useful in the further study of the structure and function of the sarcomere.


Cell-mediated immunity in an ageing population. Eight hundred and eighty patients hospitalized in a geriatric hospital were routinely tested with 2, 10, 30 and 100 i.u. tuberculin. Among these, fifty-four patients were selected on the basis of negative skin tests and absence of evident diseases interfering with the function of the immune apparatus. A battery of tests analysing cell-mediated immunity was applied to those fifty-four patients. It appears that elderly patients having a negative test to 100 i.u. tuberculin show very infrequent sensitization to three other thymus-dependent antigens. The capacity of this selected population to become sensitized to DNCB is poor (20%). Furthermore they exhibit a low per cent of peripheral blood T cells (36%) and a poor capacity to respond in vitro to mitogens such as PHA. Testing the in vitro response to a battery of antigens demonstrates a good correlation with the results of the skin tests. Finally the leucocytes of 25% of this selected population failed to produce LIF in vitro in the presence of PHA. These results suggest not only an absolute decrease in the population of circulating T lymphocytes in those elderly humans; but very likely, at least in some cases, a functional impairment of T cells.


Retrospective screening for lymphocyte-dependent antibody in recipients of renal transplants. Pretransplant sera from thirty-two patients who had received cadaveric renal transplants were screened retrospectively for lymphocyte-dependent antibody (LDA). An 18-hr 51Cr-release assay, using neat serum and an effector: target ratio of 10:1 was employed, each serum being screened against 10 normal target cells. Ten per cent of all reactions tested were positive, compared with 2% when ten normal sera were screened in the same way. No relationship between the presence of LDA pregraft, and the subsequent course of the renal allograft, was apparent in the group as a whole. Patients who had received blood transfusions and who developed LDA before transplantation, had marginally worse graft courses than transfused patients who did not develop LDA, but the difference was not significant. Eight male patients who had never been transfused, nevertheless were found to have LDA. Twelve patients were screened postoperatively for LDA, but only five out of 433 sera tested were positive. It appears that pregraft LDA do not influence the course of a subsequent renal transplant, nor does the appearance of LDA after transplantation allow prediction of acute rejection episodes,


Experimental smooth muscle antibodies.

Experimental smooth muscle antibodies. Attempts were made to induce smooth muscle antibody (SMA) in rats by various procedures causing cell necrosis. Ligation of a liver lobe and cryosurgical damage to a liver lobe both resulted in subsequent appearance of SMA, provided the damage tissue was not removed. Transfer of the damaged liver tissue to the peritoneal cavity of a normal rat did not result in SMA production in the recipient. The SMA produced showed anti-actin and anti-heavy meromyosin specificity. Damage induced by hepatotoxic agents failed to give rise to SMA.


T lymphocytes bearing complement receptors in a patient with chronic lymphocytic leukaemia. A patient is described who presented with a disease clinically resembling chronic lymphocytic leukaemia, characterized by generalized lymphadenopathy, pleural and peritoneal effusions, a blood lymphocyte count of 700,000/mul and failure to respond to conventional therapy. At least 95% of these cells formed rosettes with sheep erythrocytes (E) and with erythrocytes coated with 19S antibodies and complement (EAC). All of these cells bound rabbit anti-human thymocyte serum; this serum bound to 0--22% of the lymphocytes from twenty other patients with chronic lymphocytic leukaemia. These unusual cells did not bear surface immunoglobulin detectable by immunofluorescence. The clinical and cellular features of this malignancy are compared to previously reported cases of T cell chronic lymphocytic leukaemia. As this case illustrates, T-cell chronic lymphocytic leukaemia may present without skin lesions and may be a more aggressive disease than the more common B-cell neoplasm.


Restoration by levamisole of low E-rosette forming cells in patients suffering from various diseases. One hundred and fifteen patients presenting with various clinical conditions (multiple sclerosis, recurrent infections, HBAg-positive chronic hepatitis, Crohn's disease, ataxia-telangiectasia, SSPE and atopic dermatitis) were evaluated for E-rosette formation. Forty-two patients were found to have a low number of E-rosettes. Eighteen patients with low E-rosettes were treated with levamisole, an anti-anergic chemotherapeutic agent, and were compared with an untreated control group of sixteen patients. Levamisole treatment significantly increased low E-rosettes in these patients and this was accompanied by a remarkable clinical improvement and a significant reduction of haemolytic complement activity. Therefore our results suggest the important role of T-cell function in these various clinical conditions, in which cell-mediated immunity is thought to play a major role.


Levamisole and human lymphocyte surface markers. The action of various concentrations of levamisole on normal human lymphocytes was investigated in vitro. The action of levamisole (10(-1) mg-10(-8) mg%) upon rosette formation was studied using two rosette assays with SRBC (the active and the total T-rosette tests) to quantify T cells and the EAC assay to quantify B cells. Levamisole at only 10(-3) mg% significantly increased the percentage of both active and total T cells. In sharp contrast, levamisole between 10(-2) and 10(-7) mg% significantly decreased the EAC percentage. It is concluded that levamisole promotes a better expressivity of T-cell receptor and decreases the expressivity of C3 receptor.


Bovine lymphocytes: recognition of cells forming spontaneous (E) rosettes. About 20% of thymus lymphocytes from neonatal calves formed spontaneous (E) rosettes with SRBCs in medium consisting of 50-100% foetal calf serum (FCS); other media were less satisfactory. FCS was necessary both to allow rosette formation to occur and to maintain stability of the rosettes once formed. Rosettes were stable at 0 degrees C but unstable at 18 degrees C and 37 degrees C. Dead thymus cell (sodium azide treated) did not form rosettes. Treatment of thymus cells with antiserum to bovine Ig-inhibited rosette formation, but this inhibition was considered non-specific since it also occurred with normal rabbit serum. Treatment of SRBCs with neuraminidase slightly enhanced rosette formation by thymus cells, but did not induce peripheral blood lymphocytes to form rosettes. Rosette formation did not occur under a variety of conditions with normal or neuraminidase-treated human, horse, pig, rabbit, guinea-pig, chicken or autologous RBCs. SRBC rosette forming cells were also found in lymph nodes (2-14%) and spleen (less than 5%), but rarely or never in peripheral blood and bone marrow of calves and adults. In foetuses at 80 days of gestation, 49% of thymus cells formed E rosettes. Foetal lymph node cells formed E rosettes at 160 days and spleen at 180 days. Cells with membrane-bound Ig were observed by IFT; their distribution did not coincide with the occurrence of E rosettes. E-rosette formation might be a marker for a subpopulation of bovine T cells.


Immunological studies of human placentae: identification and distribution of proteins in mature chorionic villi. Cryostat sections of fifteen full-term, normal, human placentae have been studied by indirect immunofluorescence, using characterized antisera to a large number of proteins, in order to localize particular protein antigens to well-defined anatomical regions. Actin, plasminogen, and transferrin were identified in trophoblasts. Beta-2-microglobulin was uniformly absent from these cells. The complement component C3, the immunoglobulin IgG, and fibrinogen and collagen were identified in trophoblastic basement membranes. Of these IgG was the most sparingly represented, and C3 was not found on all trophoblastic basement membranes. Many proteins were identified within the stroma of chorionic billi, collagen being the most abundant. Many of these persisted following prolonged washing of the tissues. All four IgG subclasses were present in stroma, IgG1 and IgG3 being most prominent. Stromal cells were positive for beta-2-microglobulin, suggesting a unique sequestration of this protein on stromal cells but not on trophoblasts. Placental stem vessels were surrounded by collagen, and the walls of these vessels stained brightly for myosin: the vascular endothelium contained beta-2-microglobulin and actin. Peri- and inter-villous fibrin were faintly positive for several proteins, but these areas stained intensely for fibrinogen, plasminogen, alpha-2-macroglobulin and C4. This approach has proven to be useful in establishing precise definitions of the molecular morphology of normal human placentae.


The therapeutic equivalence of oral and intravenous iron in renal dialysis patients. Oral and intravenous iron were compared in patients treated with renal dialysis by a cross-over trial. Intravenous iron was given over 2 weeks as an iron dextran (equivalent to 100 mg elemental iron). Oral iron was given daily as ferrous sulphate (equivalent to 100 mg elemental iron) in a wax matrix tablet. Each treatment period lasted 26 weeks. There was no significant difference in therapeutic or unwanted effects between the treatments.


Immune complex glomerulonephritis associated with Klebsiella pneumoniae infection. The kidneys of three patients who died of pneumonia due to Klebsiella pneumoniae were studied at autopsy by light and immunofluoerescent microscopy. One had no clinical evidence of renal disease; two had only microscopic hematuria and mild proteinuria. Light microscopy revealed focal proliferative glomerulonephritis in all three cases. Also in all three, immunofluorescent microscopy revealed a granular deposition of capsular polysaccharide antigens of Klebsiella pneumoniae in association with immunoglobulins and complement components in the mesangium and along the glomerular basement membrane. Furthermore, the glomerular bound immunoglobulins were eluted and demonstrated to contain antibodies specific to a capsular polysaccharide antigen of Klebsiella pneumoniae isolated from each patient. These findings may illustrate that the capsular polysaccharides of Klebsiella pneumoniae are antigenic, and that the immune complex deposition in the kidney during infection with this agent can be associated with renal morphological changes. Whether or not clinical evidence of nephritis occurs may depend on the characteristics of the infection and the host factors.


Hexachlorophene in the newborn nursery. A risk-benefit analysis and review. A critical review of the available data on the risks and benefits of hexachlorophene suggests that there is ample evidence fror the toxic potential; whereas there is no substantial evidence of its benefit in life-threatening staph 80/81 epidemics, and effective less toxic alternatives are available. In view of its limited usefulness and definite toxicity, the routine use of hexachlorphene is unjustified;


The central hypotensive effect of clonidine. Studies in tetraplegic subjects. A single oral dose of 300 microng of clonidine lowered systolic blood pressure by 20 +/- 4 mm Hg and diastolic blood pressure by 13 +/- 4 mm Hg in five healthy normotensive subjects (controls). Heart rate fell from 56 +/- 2 to 52 +/- 2 beats/min. In six tetraplegic subjects with physiologically complete chronic cervical spinal cord transection above the level of the sympathetic outflow, the same dose of clonidine did not significantly lower either systolic or diastolic blood pressure. Heart rate fell from 67 +/- 4 to 53 +/- 2 beats/min. Peak plasma concentrations of clonidine, measured by mass fragmentography, and elimination of the drug from plasma were similar in tetraplegic and control subjects and there was no difference in the incidence of the principal side effects of clonidine--sedation and dry mouth. Although the number of subjects studied is small, the absence of a fall in blood pressure after clonidine in the tetraplegic subjects suggests that the hypotensive action of clonidine in man is dependent on intact descending bulbospinal pathways and is mediated by withdrawal of sympathetic tone and provides direct evidence that some antihypertensive drugs may lower blood pressure in man by a direct action on the brain.


Effects of levodopa on the renin-aldosterone system. Plasma renin activity and plasma aldosterone, supine and erect, and urinary aldosterone levels were measured in 18 patients on normal sodium diets and 11 patients on low sodium diets, all of whom also were on long-term levodopa therapy. Of the 230 hormone measurements, 185 were normal, 11 were high, and 34 were low. Most of the low levels were in 3 patients who had recently received fludrocortisone for orthostatic hypotension, and the renin-aldosterone systems might have been suppressed by it. In another phase of this study, 4 subjects were maintained on a constant diet for 6 wk, while the effect of gradually increasing dosages of levodopa on mineral balance and renin-aldosterone was determined. In 3 of the 4 patients there was a mild natriuretic effect of levodopa (previously demonstrated for acute levodopa therapy). There were no significant consistent changes in renin or aldosterone levels while levodopa was being administered. These studies indicate that levodopa does not usually suppress the elements of the renin-aldosterone system and that such a mechanism is unlikely to be the cause of orthostatic hypotension during the course of levodopa therapy. Since levodopa may induce natriuresis, in this situation unchanged lvels of renin and aldosterone may, however, represent an inappropriately low set of this hormonal system.


Effect of triamterene on potassium excretion in cirrhotic patients receiving furosemide. In a three-way crossover study, 23 patients with hepatic cirrhosis, ascites, and dependent edema received 40 mg/day of furosemide alone and combined with triamterene 50 mg/day and triamterine 100 mg/day. Baseline potassium excretion did not increase when furosemide was given alone, but potassium excretion fell when 50 mg or 100 mg of triamterene was also given. Both doses of triamterene augmented the natriuretic effect of furosemide.


Naproxen, aspirin, and codeine in postpartum uterine pain. The analgesic efficacy of oral naproxen and its sodium salt was compared with that of aspirin and codeine in two separate trials involving 140 and 90 patients, respectively, with postpartum uterine pain in a single-dose, parallel, stratified, randomized, placebo-controlled, double-blind design. With 300 or 600 mg naproxen and with 275 mg naproxen sodium, significant analgesia, measured subjectively by pain intensity differences (PID), was prolonged at least 7 or 8 hr; onset tended to be delayed 2 hr or more. With 650 mg aspirin analgesia began within 1 hr and continued until the fifth hour, while with 60 mg codeine responses were indistinguishable from placebo responses throughout the 8-hr time course. Although time-effect patterns with naproxen sodium and aspirin were different, summed analgesic effects (SPID) showed equal efficacy and superiority over placebo (p less than 0.005). With each of the 2 doses of naproxen, SPID separation from placebo was comparable to that above (p less than 0.02 and 0.005, respectively), but analgesic dose response, though measurable, was not significant. Side effects were not significant with any of the treatments. It appears that naproxen and naproxen sodium are analgesics with efficacy equal to aspirin and may prove to be rational substitutes for currently available analgesics in some painful states in which longer pain relief would be desireable.


Disposition of diazepam and its major metabolite desmethyldiazepam in patients with liver disease. In six patients with cirrhosis and five patients with fibrosis of the liver elimination of diazepam (D) was compared after single and subchronic dosage. The pharmacokinetics of the major metabolite desmethyldiazepam (DD) was investigated in four healthy individuals and four patients with hepatic dysfunction and compared to its parent compound D. In the initial study, 11 patients with liver disease (cirrhosis and fibrosis) had a longer half-life (T 1/2(beta) of 99.2 +/- 23.2 hr after a single intravenous bolus of 0.1 mg/kg of D than to age-matched normal subjects (46.6 +/- 14.2). After subchronic treatment with 10 mg of D for 7 days T 1/2(beta) was prolonged only slightly (p = 0.043) in these patients (107.6 +/- 25.2 hr). Neither total plasma clearance (Cl) nor the apparent volume of distribution (VdSS or VdCl) showed significant changes. After intravenous injection of DD (0.1 mg/kg) plasma levels declined in the same biexponential manner as after D. The cross-over study in the four normal subjects demonstrated that DD was eliminated much more slowly than D. Whereas for D, T 1/2(beta) and Cl were 32.6 +/- 11.3 hr and 32.3 +/- 11.0 ml/min, respectively, the corresponding values for DD were 50.9 +/- 6.2 hr and 11.3 +/- 3.1 ml/min, respectively, the corresponding values for DD were 50.9 +/- 6.2 hr and 11.3 +/- 3.1 ml/min. The accumulation of DD after multiple dosage could be explained by the fact that it is formed faster from D than it is eliminated. In four patients with liver disease the elimination of D and the elimination of DD were altered. In these patients T 1/2(beta) for DD was prolonged (p = 0.015) to 108.2 +/- 40.3 hr. This prolongation was caused by a decrease in Cl of 4.6 +/- 1.1 ml/min, (p = 0.003) whereas Vd(Cl) did not change significantly. This indicates that at least two steps in diazepam metabolism are impaired in patients with liver disease.


The role of the false neurotransmitter octopamine in the hypotension of fulminant hepatic failure. 1. An investigation was carried out into the mechanism of unexplained hypotension in patients with fulminant hepatic failure. The cardiac output and peripheral resistance were compared in normotensive and hypotensive patients. In addition, the serum concentration of the false neurotransmitter octopamine and the pressor response to noradrenaline, and to the indirectly acting sympathomimetic agent tyramine, were measured in hypotensive and normotensive patients with fulminant hepatic failure and in healthy subjects. 2. The cardiac output and the peripheral resistance were decreased in the hypotensive patients, and their mean heart rate was slower than in the normotensive patients. Although the serum octopamine concentration was significantly elevated in the patients compared with the control subjects, the highest octopamine concentrations were unexpectedly found in the normotensive patients and a significant positive correlation could be demonstrated between the resting blood pressure and the serum octopamine concentration. The pressor response to tyramine and noradrenaline were similar in the hypotensive patients, the normotensive patients and control subjects. 3. These results suggest that neither increased serum concentrations of the false neurotransmitter octopamine, nor end-organ insensitivity to released noradrenaline are responsible for the hypotension. A more likely explanation is toxic depression of the vasomotor centre. The opening of peripheral arteriovenous shunts, possibly as a result of endotoxaemia, might be an additional factor.


A 3-year clinical trial of the effect on dental caries of a dentifrice containing 2% sodium monoflurophosphate. A clinical trial of a dentifrice containing 2% sodium monofluorophosphate was carried out on 782 schoolchildren in Shropshire, England. After 3 years, a reduction of 23.8% was found in the DMFS increment obtained from clinical examination. The reduction was 38.8% using radiographs. The children were divided into three groups according to baseline DMFS. Those with a "medium" caries experience were found to benefit most from using the dentifrice. There was a difference in the effect on individual tooth sites; the approximal surfaces of the posterior teeth received the most benefit and the occlusal surfaces the least.


Effects on plaque and gingivitis of a chlorhexidine dental gel in the mentally retarded. The effectiveness of a 1% chlorhexidine-containing dental gel on dental plaque and gingival health was evaluated over a period of 6 months using a double-blind procedure. One hundred and seventeen mentally retarded subjects aged between 10-17 years resident in an institution were divided into two groups. One group was assigned daily brushing with the 1% chlorhexidine gel, the other group a placebo quinine sulfate-containing gel. No other form of oral hygiene was used during the experimental period. Assessment of dental plaque accumulation and gingivitis was made at 0, 1, 3, and 6 months. An assessment was also made 2 months after the gel was withdrawn from use and normal toothbrushing procedures resumed. No clinical or statistical advantage was noted in plaque or gingivitis scores in the group receiving chlorhexidine treatment during the 6-month period. This group showed a higher prevalence of tooth staining. It was concluded that periodontal severity and poor oral hygiene exceeded the plaque- and gingivitis-preventing potential of chlorhexidine.


Comparison of sulindac and aspirin in rheumatoid arthritis. Thirty-one out-patients with rheumatoid arthritis took part in a 10 week double-blind comparison of sulindac (cis-5-fluoro-2-methyl-1-[p-(methylsulphinyl)-benzylidene]-indene-3-acetic acid) 200 mg twice daily and aspirin 3.6 g daily, with a 2-week placebo control period. Both drugs were superior to placebo. The incidence of side-effects was approximately the same on the two drugs, but there was a higher drop-out rate due to side-effects on aspirin.


The effect of oxpentifylline ('Trental') on fibrinolytic activity and plasma fibrinogen levels. Twenty healthy volunteers were treated for 3 months with oxpenifylline (200 mg 3-times a day) or a placebo in a controlled double-blind randomized trial. The volunteers taking the oxpenifylline showed a significant increase in their fibrinolytic activity, as assessed by the dilute blood clot lysis time and fibrin plate lysis area, and a significant reduction in their plasma fibrinogen levels. No change was found in the control group. These findings suggest that oxpentifylline may be valuable in the treatment of small vessel occlusive disease associated with lowered fibrinolytic activity and raised fibrinogen levels.


A multi-centre surgical trial of intravenous doxycycline ('Vibravenous') in the Netherlands. One hundred and thirteen surgical patients were included in a trial of the use of doxycycline. The majority of the patients were initially started on intravenous therapy and then switched to oral medication when their condition permitted. The patients were categorized into 5 groups as follows: appendicitis 32, peritonitis 29, infections of the biliary tract 10, other infective processes 9, and prophlactic therapy 33. The efficacy was excellent ant the majority of the patients had a very good (excellent) and good therapeutic response. The mean temperature in most of the groups fell significantly by the fourth or fifth day of therapy. Side-effects were (4.4%) and usually self-limiting.


Necrobiosis lipoidica diabeticorum in a juvenile diabetic: treatment by excision and skin grafting. A fifteen year old female juvenile diabetic had severe ulceration of NLD lesions, which were treated by skin grafting. Twenty-four months postoperatively, she has an excellent cosmetic result.


Meningocoele manqué.

Meningocoele manqué. Meningocoele manqué is a congenital anomaly relating to the spinal cord, cauda equina and the filum terminale commonly found on exploration of the spinal cord in cases of spina bifida occulta. The anomalies consist of fibrous bands, aberrant nerve roots and adhesions within the theca which may tether or press on the neural structures so interfering with nerve conduction and causing increasing neurological deficit. Treatment is to free the neural structures from these bands and adhesions surgically. An account is given of 45 cases with a discussion of their similarity to cases of meningocoele, thus justifying the naming of a previously undescribed clinical entity. Meningocoele manqué demonstrates the relation of spina bifida occulta to spina bifida cystica as having a similar origin differing only in degree of severity. All the cases discussed are drawn from a personal series of 200 cases of spina bifida occulta which have had surgical exploration of the spinal cord.


[Surgical treatment of malignant skin epitheliomas. Principles, methods, results]. From personal experience in the treatment of 655 patients with malignant epitheliomas of the skin, treated from 1966 to 1973 at the Department of Plastic and Reconstructive Surgery at the University Hospital, Innsbruck, the basic principles, methods, and results of treatment are reported. An adequate resection and a primary reconstruction is the method of choice. The clinical data and follow-up observations are analyzed and special types of treatment and indications are discussed. With it the 5-year-cure-rate of basal-cell carcinomas was 92%, of squamous-cell carcinomas 83%.


Mesoridazine (Serentil) in personality disorders--a controlled trial in adolescent patients. A double-blind study vs. placebo was carried out over a 6-week period in thirty adolescent patients to determine the efficacy and safety of mesoridazine, in the form of 10 mg tablets, in the treatment of symptoms associated with various personality disorders. The average daily dose for the 15 patients in the mesoridazine group was 27.3 mg in the first and 44.7 mg in the sixth week. Mesoridazine relieved anxiety to a highly significant degree when compared with placebo and proved significantly more effective than placebo also in terms of mean improvement scores for depression and hostility. Significant reductions were likewise achieved in the overall severity of the disorders and in the severity of nearly all the other symptoms. The incidence of adverse reactions did not differ significantly from that following placebo administration. No extrapyramidal symptoms were noted.


[Blocking of pancreatic exocrine function in the treatment of chronic pancreatitis (author's transl)]. In 6 patients with chronic pancreatitis the exocrine function was inhibited by occlusion of the pancreatic exocrine ducts leading to atrophy of the glands. The function of the pancreatic islets remained intact. This procedure can be combined to advantage with partial resections. Preliminary clinical results are promising and in all cases pancreatic pains disappeared immediately after the operation.


[Immunodiagnosis of malignant disease. I. The electrophoresis-mobility test in the diagnosis of bronchial carcinoma (author's transl)]. The electrophoresis-mobility test is an in-vitro method for demonstrating specific sensitized lymphocytes. After incubation with the encephalitogenic factor, lymphocytes from patients with malignant disease liberate a factor which causes a decrease in migration velocity of indicator cells (tanned and sulphosalicyl acid-stabilised sheep erythrocytes = ETS) in an electrical field. 84 patients with pulmonary disease and 20 control persons were examined. An inhibition of ETS migration was found only in patients with malignant pulmonary disease, while in the control subjects and those with inflammatory or degenerative pulmonary disease or benign pulmonary tumour ETS migration was accelerated. The difference between the two groups is statistically significant so that it provides a reliable differentiation between benign and malignant disease. False-negative results, however, occur under radiotherapy and chemotherapy.


[Rapidly fatal myocarditis due to group B streptococci (author's transl)]. The case of acute purulent group B streptococcal myocarditis in a 29-year-old Turk is described, no similar case having previously been published. He fell ill suddenly with gastro-intestinal symptoms, high fever and pain in arms and legs. The ECG had low voltage in the limb leads and signs of a large acute myocardial infarct. The sedimentation rate was slightly raised, an initial leukopenia was followed by leukocytosis and high enzyme activity. He died in cardiogenic shock on the third day of illness. The post-mortem examination revealed acute purulent myocarditis, and numerous group B streptococci (Strept. agalactiae) were found in the myocardium.


Doxepin up-to-date: a review of its pharmacological properties and therapeutic efficacy with particular reference to depression. Doxepin is closely related in structure and general pharmacological properties to other tricyclic antidepressant drugs such as amitriptyline and imipramine. It combines antidepressant activity with a sedative effect and in this respect resembles amitriptyline, with which it shares a similar profile of clinical action. The mood elevating effect of doxepin appears to be similar to that of amitriptyline but is probably less marked than that of imipramine and in some studies has been slower to take effect than imipramine. At dosages which have achieved a similar overall response rate, doxepin tends to cause fewer or less troublesome side-effects than imipramine, amitriptyline or amitriptyline-prephenazine. The more marked sedative properties of doxepin make it more useful than imipramine in depressed patients with sleep distrubances and in depression associated with anxiety. The benzodiazepines remain the drugs of choice in anxiety states. but when anxiety is accompained by significant depression, doxepin is more effective than chlordiazepoxide or diazepam. Doxepin is usually well tolerated, and in particular by the elderly and those with cardiovascular disease. Side-effects are similar in nature to those of other tricyclic antidepressants, with dry mouth, drowsiness and constipation being the most common. Postural hypotension is uncommon. Although doxepin appears to cause fewer cardiovascular side-effects in usual therapeutic doses, it has an intrinsic cardiotoxicity on overdosage similar to other tricyclics.


[Therapy and treatment results in functional disorders of the masticatory apparatus]. Thirty-three patients with the tentative diagnosis of a myofacial pain syndrome were treated symptomatically and causally after standardized diagnostic exmaination. Eleven months after the termination of therapy, twelve patients were without symptoms, seventeen showed improvements and the clinical picture of four patients had not changed at all. When supporting the therapeutic success by prosthetic measures the choice of the articulator system (Dentatus, Condylator) was irrelevant.


[Anatomical and functional results after preprosthetic surgery and prosthetic treatment]. Within three years, 85 patients underwent surgery prior to prosthetic treatment. In 53 of these patients, the properties of the denture-bearing region and the result of the prosthetic treatment were studied. In all cases the denture-bearing base offered favorable conditions for the prosthetic treatment. 45% of the dentures, however, showed avoidable shortcomings which were detrimental to the newly created base and thus jeopardized the overall success.


[Prosthetic measures with reference to the temporomandibular joint and the masticatory pathway]. The gnathological aims, i.e. consideration of anatomy, histology, physiology and pathology of the stomatognathic system and therapy on the basis of accurate examination, diagnosis and treatment planning, have been known for a long time. To try and achieve such aims is a natural demand in any prosthetical measure.


[Comparison of cast and metal-ceramic veneer crowns; results of a follow-up study in wearers of partial prostheses]. The results of follow-up examinations of 635 gold cast and 359 metal ceramic veneer crowns inserted primarily for caries prophylaxis and static reasons in patients with partial dentures on the average 4 1/2 years ago are reported. All crowns fulfilled their caries-preventing functions well. More than 93% were free of secondary caries, this was especially so when the crown margin was still below the gingiva. The conditions at the crown margins were studied. It was found that margin seal, type of crown as well as interdependent variables like age, periodontal condition and personal oral hygiene had a significant influence on whether the crown margin was still in the gingival sulcus. Metal ceramic veneer crowns were vestibularly exposed more frequently than cast crowns. The reason for this was found to be defective construction. The study showed further that lesions at the baked veneer crown occurred more often than had been expected so far. It is estimated that they amount to 3% with widely used ceramic crowns.


[Impression materials and the wettability of dentin surfaces]. Two reversible hydrocolloidal impression materials as well as two light-bodied polysulfide and silicone impression materials were tested with regard to their properties of coating plain ground dentin surfaces. With a wet surface, hydrocolloids produce flatter contact angles between dentin surfaces and the impression material, i. e. a more effective coating than polysulfide and silicone impression materials. The conditions are reversed with dry dentin surfaces and those pretreated with silicone oil. If the dentin surfaces of which an impression is to be taken are treated with silicone oil, coating is less effective with all impression materials tested.


[Bacterial count in the sulcus fluid of healthy and inflamed marginal gingiva]. Even with a plaque index of 1, peak values of germ count per micronl were found which remained almost constant with plaque increasing up to an index of 3. Germ count and degree of inflammation correlated in the range of the gingival indices 0 to 2. A further intensification of the inflammation showed a significant reduction of germ count per micronl. When studying the relationship between germ count and depth of pocket, the same behavior was observed, starting at a pocket depth of 4.5 mm.


Effects of iodoacetate, mannoheptulose and 3-O-methyl glucose on the secretory function and metabolism of isolated pancreatic islets. The ability of iodoacetate, mannoheptulose, and 3-O-methyl glucose to alter islet cell metabolism and glucose-stimulated insulin secretion was examined. A method for the sequential analysis of the releasing and fuel function of glucose in isolated islets was applied. Insulin release was measured by radioimmunoassay and the metabolism of glucose by determining the rate of tritiated water production from [5-3H]glucose and lactate accumulation. It was found that iodoacetate, in the range of 0.2-1.0 mM, inhibited the metabolism of glucose linearly while release was not blocked until metabolism was reduced by 30-40%. The KI for both processes, release and metabolism, was the same. Pyruvate did not protect against or reverse the effects of iodoacetate. Mannoheptulose inhibited both release and metabolism half-maximally at about 5 mM when 27.5 mM glucose was used as the stimulatory agent. A mannoheptulose-resistant component of glucose metabolism, amounting to 30% of the maximal rate was observed. 3-O-Methyl glucose had no effect on insulin release but reduced glucose utilization and lactate production from low glucose. The results are discussed in light of the two prevailing hypotheses explaining glucose induced insulin release, i.e., the receptor and the metabolism hypotheses.


Effect of in vivo treatment with estrogen on luteinizing hormone synthesis and release by rat pituitaries in vitro. The influence of estrogen on uptake of [3H]glucosamine and [14C]alanine and their incorporation into LH and total protein was investigated. Ovariectomized rats were sacrificed 22 h after injection with either oil or estradiol benzoate (EB, 50 microng/rat). Quartered anterior pituitary glands were incubated for 4 h with radioactive precursors in the presence or absence of 3.6 X 10-8M synthetic gonadotropin-releasing hormone (GnRH). Labeled LH was isolated by immunoprecipitation with specific anti-LH-beta serum. Both EB and GnRH significantly elevated the amount of [3H]glucosamine-LH appearing in the medium, the tissue, and the total system (medium + tissue), but they increased the amount of [14C]alanine-LH only in the medium. There was a significant positive interaction between EB and GnRH on the amounts of [3H]glucosamine-LH and [14C]alanine-LH in the medium and of [3H]glucosamine-LH in the tissue and total system. EB enhanced [3H]glucosamine uptake and incorporation into total protein, but GnRH had little or no effect on these parameters. In time course studies rats were injected with either oil or EB at 22, 11, or 5.5 h prior to sacrifice. At all times EB significantly increased synthesis and release of [3H]-glucosamine-LH and release of total immunoreactive LH (IR-LH) by pituitaries incubated with GnRH. The amounts of labeled and IR-LH released into the medium increased linearly with time after EB injection, but the amount of labeled LH in the total system plateaued at 5.5 h after EB injection. In another study, estradiol (E2, 5 microng/rat) dissolved in 1% ethanol-saline was injected at 0.5, 1.0, 2.0, or 4 h prior to sacrifice. Incorporation of [3H]glucosamine into tissue protein and release of [3H]glucosamine-LH was stimulated within 2 h after E2 injection. However, incorporation of [3H]glucosamine into LH was not stimulated until 4 h after E2 injection. These results suggest that estrogen and GnRH regulate LH synthesis at different sites, and that the effect of estrogen is non-specific compared to that of GnRH. The synthesis of the carbohydrate moiety of LH appears to be subjected to hormonal regulation more readily than the synthesis of the polypeptide moiety.


Characterization of distinct segments in mouse satellite DNA by restriction nucleases. The long-range periodicity of mouse satellite DNA has been analyzed by digestion with five restriction nucleases. With all nucleases tested, a major repeat unit approximately 245 nucleotide pairs became apparent. Minor registers of shorter length were also detected. The total number of cleavage sites per haploid genome for each restriction enzyme as well as their positions relative to each other were determined. While endo R-EcoRII was known to cleave all of the satellite DNA, the other four restriction enzymes were found to generate only weak degradation patterns. The results taken together with quantitative analyses of codigestion experiments indicate that the recognition sequences for each of these four nucleases are clustered on separate parts of the satellite DNA. It is concluded that the satellite DNA, which appears homogeneous by digestion with endo R-EcRII, contains distinct segments each susceptible to degradation with one of the other nucleases. These results have certain implications for theories on the evolution of mouse satellite DNA. A simple mechanism of multiplication and divergence by mutation is not sufficient to explain the data. Additional and alternative processes which are relevant to the evolutionary considerations are discussed.


Bromopyruvate as an affinity label for baker's yeast flavocytochrome b2. Kinetic study of the inactivation reaction. Bromopyruvate was shown to completely inactivate cytochrome b2 in a reaction that obeyed the kinetic criteria required for affinity labels: it inactivated flavocytochrome b2 according to saturation kinetics, and the inactivation reaction was competitively inhibited by the substrate or competitive inhibitors. Inactivation was irreversible. The behaviour of both forms of flavocytochrome b2 (lintact and proteolytically cleaved) was examined. It was found that the reduced cleaved enzyme was not inactivated by bromopyruvate; this phenomenon can probably be ascribed to a structural change undergone upon reduction. The value of the lactate dissociation constant of intact cytochrome b2 cytochrome b2 was determined in competition experiments with bromopyruvate. By comparison with the divergent published values for the Ks of the cleaved from, it appears that only those that differ from the Km by a factor of two or three are reasonable. This study opens the way for the identification of an active site residue and localization in the peptide chain of the bifunctional enzyme.


beta-D-Galactoside transport in Escherichia coli. Reversible inhibition by Aprotic Solvents and its Reconstitution in transport-negative membrane vesicles. At relatively low concentrations (less than 3M) the aprotic solvents: dimethylsulfoxide, N-methylpyrrolidone, tetramethylurea and hexamethylphosphoric triamide, inhibited beta-D-galactoside transport by whole cells, and the derived membrane vesicles of Escherichia coli. Inhibition was not due to gross leakiness of the membrane and could be largely reversed  by a simple washing procedure...


The reactivity of one essential cysteine as a conformational probe in Escherichia coli tryptophanase. Application to the study of the structural influence of subunit interactions. It is first shown that the inactivation of Escherichia coli apotryptophanase byN-ethylmaleimide results from the labeling of a single particularly reactive cysteine per protomer. The reactivity of this cysteine under various conditions is investigated and the results indicate that the protein can exist under two classes of conformation: one, corresponding to inactive protein,in which the cysteine is reactive, and second, corresponding to active enzyme, where the cysteine is masked. The rate of the isomeriation step involved in this change in conformation is measured by the stopped-flow technique(tou = 0.4s). Finally, the reactivity of the cysteine is used to characterize the conformation of dimeric holotryptophanase (i.e. a dissociated form of the enzyme obtained as a transient species between dimeric apoenzyme and the natural tetrameric holoenzyme). By this criterion, it is shown that dimeric holotryptophanase falls in the class of 'inactive' conformations. These results are used to discuss the influence of the quaternary structure on the functional and conformational properties of tryptophanase and the nature of the conformational change involved in the activation of the enzyme by its cofactor and specific cations.


Ultimate fate of heart transplantation. Seven years survival in a dog. The morphological study of a canine cardiac transplantation whose survival was 7 years, without treatment for 6 years, is described. The pathological examination demonstrated a right-side heart failure due to pulmonary stenosis. A histological study revealed marks of chronical rejection induced by vascular fibrosis and perivascular infiltration of lymphocytes. This unusual kind of tolerance could be induced by donor blood transfusion at the time of transplantation.


Antidepressant evaluation and the pharmacological actions of FG4963 in depressive patients. FG4963 a phenylpiperidine derivative and potent 5-HT reuptake inhibitor at neuronal sites was investigated in a group of 10 depressive patients, and its effect was compared with that of amitryptyline in a group of 10 depressive patients treated with amitriptyline. FG4963 was found to be significantly inferior as an antidepressant compared to amitryptyline over a 6-week period. FG4963 did not appear to be anticholinergic as judged by its lack of effect on salivary flow. Its effect (in the dosage used) on the tyramine dose--pressor response and NA dose--pressor response tests were less than those of amitryptyline.


Stimulation of erythropoiesis in a grafted animal by mouse fetal liver culture media. Erythropoietin given to polycythemic, irradiated mice receiving a bone marrow transplant restores the number of erythroid colonies produced. In this study mouse fetal liver culture media administered to polycythemic, irradiated mice also restored the number of erythroid colonies and erythropoiesis as measured by 59Fe incorporation. Thus, mouse fetal liver in culture produces a factor which resembles erythropoietin.


Bone marrow transplantation for an infant with neutrophil dysfunction. A child with severe neutrophil dysfunction and intractable infections received bone marrow transplants from histocompatible siblings. After a first transplant preceded by cyclophosphamide (CY), antithymocyte serum (ATS) and procarbazine (PCB) preconditioning, there was no evidence for engraftment and autologous marrow function rapidly returned. Cell mediated lysis showed no evidence of patient sensitization against the marrow donor suggesting that graft rejection did not cause the transplant failure. A second transplant was performed utilizing another matched sibling donor. Total body irradiation was added to CY, ATS, and PCB for preconditioning after in vitro studies of the colony forming capacity (CFUc) of the patient's marrow cells showed normal sensitivity to radiation. Full engraftment ensued with correction of granulocyte function abnormalities. The patient eventually died of intractable pulmonary disease. Our experience with this child suggests that cyclophosphamide alone may be insufficient preparation for marrow transplantation in some patients with non-neoplastic hematologic disorders. Experimental and clinical data supporting this contention are reviewed.


Isolation and fusion studies on protoplasts from pollen tetrads. Different enzymes were tested for isolation of intact protoplasts from pollen tetrads. About 80% isolation was achieved from pollen tetrads of Cajanus cajan and Zea mays and about 60% from Luffa cylindrica and Lycopersicon esculentum after 4 h of treatment with 5% cellulase. When these mononucleate protoplasts were incubated in presence of 0.05 M CaCl2 in 0.3 M glucose at pH 10.5, 70-80% fusion was achieved. Fusion was rare in sodium nitrate solutions.


Demonstration of a tryptaminergic mechanism in the rat beta-cell. Yellow 5-HT fluorescence has been histochemically demonstrated in rat pancreatic islet cells in animals injected with L-5-HTP with or without pretreatment with the monoaminoxidase inhibitor nialamide. This fluorescence was not observed after inhibition of the aromatic amino acid decarobxylase. The results strongly suggest the presence of a tryptaminergic mechanism in the rat islet cells.


Investigations on the mechanism of action of narciclasine. The Authors have investigated the possible interaction between narciclasine and DNA using various physico-chemical techniques useful for demonstrating the complex formation between a small molecule and a marcomolecule. The data obtained clearly indicate that a complex between DNA and narciclasine does not occur. The mechanism of the antimitotic activity of narciclasine must therefore be of a different nature, such as interference with the enzymatic systems involved in the duplication of DNA or with the protein structures involved in nuclear division.


Environmental agents altering lung biochemistry. Environmental agents may enter the lung via the tracheobronchial tree or via the bloodstream. They can interact with lung cell metabolism and set in motion a sequence of events that leads to damage, adaptation, and repair. Biochemical signs of lung damage described include lipid peroxidation, decreased biosynthesis of macromolecules, depressed enzyme activities, and the binding of metabolites of the offending agent to tissue macromolecules. As a response to acute damage, lung can activate several biochemical pathways. The selenium-glutathione peroxidase system affords protection against lipid peroxidation and increased activity of superoxide dismutase provides oxygen tolerance. Biochemical adaptation occasionally occurs very quickly: the herbicides paraquat and diquat produce an acute loss of cellular NADPH in lung. This is accompanied by a sudden increase in pentose phosphate pathway activity. Biochemical events accompanying tissue repair following lung injury are increased synthesis of nucleic acids and of protein and enhanced enzymatic activity. The repair following lung damage caused by drugs may be inhibited by oxygen.