Innominate artery disruption due to blunt trauma.

Two patients had innominate artery disruption due to blunt trauma. Compression forces between the sternum and vertebral column and rotational forces were the mechanisms of injury. Mediastinal widening led to the diagnosis in one patient who underwent successful repair with preservation of cerebral flow by an aortic to subclavian bypass graft prior to oversewing the innominate artery. A normal mediastinal shadow led to a delay in diagnosis in the second patient who underwent surgery after the appearance of focal neurologic signs. The use of a temporary indwelling aortic-carotid shunt during repair did not prevent residual hemiparesis.


Management of surgical gastrointestinal complications in renal transplant recipients.

Gastrointestinal (GI) complications developed in 19 (7.2%) of 265 patients after renal transplantation, and 3 (16%) patients died. Complications included colon perforations, colonic bleeding, small-bowel infarction, pancreatitis, subphrenic abscess, and upper GI tract bleeding. Ulcers located in the second portion of the duodenum developed in six patients; four of them required operation for massive hemorrhage, which occurred during or immediately after the administration of high-dose methylprednisolone for rejection. However, the association of methylprednisolone and colon perforation was not clear from this report. Early diagnosis and prompt operation for surgical-type GI complications in transplant recipients contribute to a low mortality.


Race as a risk factor in cadaver kidney transplantation.

Recipients of 93 first-cadaver kidney transplants were studied for the effect of recipient and donor race on graft and patient survival. Both graft and patient survival were lower for black recipients than for whites. The difference was not explained by racial mismatch between donor and recipient. Black recipients had more rejection episodes and more instances of bacterial pneumonia. Pretransplant splenectomy reduced the likelihood of rejection episodes for black recipients and increased their rate of graft survival.


Techniques of splenic conservation.

The scope of surgical procedures on the spleen has undergone a dramatic change in the past few years. Efforts directed toward splenic preservation have intensified with the emerging realization that sepsis is a sequela not to be ignored in asplenic subjects. Successful operations on splenic parenchyma require modified techniques of exposure and mobilization of the spleen. The segmental vasculature of the spleen makes possible controlled resection of traumatized or diseased segments of parenchyma. Hemostatic measures include the use of metal clips, ligation of small intrasplenic vessels, and application of topical agents for residual surface bleeding. With the use of such techniques, conservative splenic surgery is possible in minor and major splenic trauma, splenic cysts, and selected pathologic states in the spleen.


Early positive end-expiratory pressure in the adult respiratory distress syndrome.

This prospective study was designed to determine the effect of positive end-expiratory pressure (PEEP) instituted early in the course of adult respiratory distress syndrome (ARDS). Seventy-nine (7%) of 1,200 patients admitted to the surgical intensive care unit were selected because of a high probability that ARDS would develop, and were randomized into two treatment groups. Of the 79 patients, 45 were immediately treated with 5 cm H2O of end-expiratory pressure (early PEEP group), and 34 received PEEP only when severe hypoxemia developed (late PEEP group). The incidence of ARDS was significantly lower in the early PEEP group than in the late PEEP group (20% vs 53%; P less than .002). Fewer pulmonary deaths occurred in this group (11% vs 29%; P = .02), and there was less pulmonary morbidity. This study supports the efficacy of early low-level PEEP in the treatment of patients for whom there is a high probability that ARDS will develop.


The determination of trace levels of arsenic in human biological materials.

The authors have reviewed the techniques developed for measuring the concentration of total arsenic and that of some specific arsenic species (As V, As III, aromatic and aliphatic arsenic derivatives) in biological materials mainly in urine. Whether the relative concentrations of these arsenical species found in human urine represent their true distribution in the urine secreted by the kidney (possible change in valence state in the bladder mainly at alkaline pH, breakdown of arsenical derivatives during urine pretreatment) remains to be investigated further. No technique is yet available for measuring specifically the organoarsenic derivative(s) excreted after ingestion of marine animals. No available system has been found that will digest tissues without changing the original valence states of arsenic. Therefore only total arsenic can be measured with accuracy in tissue.


[Formation of human islands of Langerhans cells from the epithelium of the acini and ducts].

The contents of endocrine cells in the epithelium of ducts and the number of acino-insular elements in exocrine parenchyma and in pancreatic islets were estimated by means of the dotted method in semithin sections prepared from the pancreas of the human embryos (4--7 months of embryogenesis) and of adult persons (40--50 years of age). Endocrine cell formation was noted in all stages studied in ontogenesis. Quantitative data demonstrated that the epithelium of the ducts is the main source for insulocyte formation. In the pancreas of both human embryos and adult persons, acino-insular transformation participated in the formation of endocrine elements. The data obtained gave a certain evidence on entodermal origin of the pancreatic islets in the human pancreas.


[Blood vessels of the pancreatic islets in different portions of the adult human pancreas].

The pancreatic islets and their blood vessels have been studied in the head, the body and the tail of the human pancreas. The following methods have been applied: injection, histological and quantitative estimation, graphic and plastic reconstruction. A rather great variability in the form of the pancreatic islets has been stated, with presence of one--two peculiar processes in large islets. In different parts of the pancreatic gland, relative volume of the endocrine parenchyma has been stated to be statistically greater (2.16 +/- 0.45%) in the caudal portion than in the head of the gland (1.31 +/- 0.26%). In every pancreatic islet an afferent arterial vessel is described, two types of its branching are determined: magistral and scattered. Relative volume of the pancreatic islets and morpho-functional coefficient reflecting the ratio of the capillary surface area to the volume of the islet capillaries in different parts of the pancreatic gland have been estimated.


[Reinnervation of internal organs and vessels by the neuropexy technic].

Some new data on reinnervation of organs and vessels by means of transplantation of vegetative ganglia and sewing of neural branches are presented. When transplanting the cranial cervical ganglion to a muscle, and the caudal mesenteric ganglion to the urinary bladder wall, some neurocytes in the periphery of the ganglia are preserved; simultaneously, massive outgrowth of neural fibres occurs in the area of transplantation. These facts are considered as formation of a new local innervation center of the organ "recipient". The central part of the dog hypogastric nerve is sewed to the renal artery, in other experiments it is sewed into the rectum wall. A massive regeration of neural fibres along the course of the renal artery and the appearance of a neural ganglion in the rectum wall are stated. The sewed hypogastric nerve grows thicker, especially under the conditions of increased functioning of the organ "recipient". In a number of experiments, the large otic nerve is sewed to the common carotid artery. The development of a young connective tissue growing into the adventitia of the vessel is noted. Numerous regenerating neural fibres surrounding the vessel are noted in this tissue. Thus, a possibility of creating new or supplementary innervating connections of internal organs and vessels by means of sewing to them sensitive nerves or vegetative ganglia is morphologically substantiated.


The microscopic characterization of multinucleated giant cells formed on polymeric surfaces perfused with blood.

Multinucleated, foreign body giant cells were formed by the fusion of blood monocytes on polymeric membranes perfused with blood during extended extracorporeal circulation. In the current study, heparinized blood, flowing in an arteriovenous shunt in a sheep, perfused polycarbonate, polypropylene and silicone rubber membranes of a recently developed bioartificial tissue culture system. The multinucleated giant cells were studied by light, scanning electron, and transmission electron microscopy, after membrane perfusion for periods of one to two weeks. The giant cells, which were the predominant cellular components of the blood-polymer interface layer, contained from a few to more that one hundred nuclei and varied in diameter up to 400 microns. The cellular interaction with the three membrane types was similar, although fewer mononuclear cells were observed adhering to the silicone rubber membrane. The presence or absence of micropores in the membranes had no effect on the formation of giant cells, nor did the presence of foreign tissue in culture behind the microporous membranes. High blood flow rates and chronic anticoagulation with heparin permitted observation of this foreign body reaction of blood independent of thrombosis.


Tracheostoma construction with a deltopectoral flap.

We describe a technique of tracheostoma construction utilizing a deltopectoral flap. This method can be used when entry into the superior mediastinum and low tracheal resection is required.


[The value of fine-needle-cytology, imprint-cytology and histology in the head-neck-region (author's transl)].

Comparative studies about the fine-needle-cytology, imprint-cytology and histology furnished an almost complete agreement between imprint-cytology and histology. Suspected tumor findings by way of fine-needle-biopsy deserve the same place as similar histological examinations. Negative cytological results have to be critically evaluated. Fine-needle-cytology presents a quick and not too painful procedure that is both relatively free of complications and repeatable examination.


[Our experiences about the value of laryngeal cytology (author's transl)].

Cytology is a harmless and an important examination method in laryngeal cytology. Cytology controlled by biopsy and histology can lead with increasing experiences to diagnostic consequences. In a number of our cases cytology led to an early laryngofissur. In all these cases histology had justified the procedure.


[Alternatives to the posterior nasal pack by Bellocq (author's transl)].

233 cases with posterior nasal pack are compared, two third being treated with Foley catheter technique. Using the Bellocq technique there are 47% of bleeding at intervals and 9% of bleeding while using the Foley catheter. Local and general complications are 3.5 times lugher Bellocq technique than in Foley catheter use.


New parachute cuff and positive end-expiratory pressure to minimize tracheal injury and prevent aspiration.

A new parachute cuff has been tested in combination with a positive end-expiratory pressure (PEEP) on mongrel dogs. During positive-pressure ventilation the intracuff and intratracheal pressures showed synchronous, identical pressure variations, and therefore theoretically with this type of cuff the pressure against the tracheal wall would be minimal. The cuff provided a seal against gas leakage from the lungs throughout the entire test period, i.e., for up to 7 h. To avoid aspiration of mouth contents during the passive exhalation phase, different amounts of PEEP were tested. A PEEP of 4.0--8.0 cm H2O always produced a seal against a column of fluid in the mouth exerting a hydrostatic pressure of 5.4--8.8 cm H2O against the cuff. This seal was maintained during the whole test period. No difference in sealing capacity was found when the cuff was used with a normal respiratory frequency (20/min) and with high-frequency positive-pressure ventilation (60/min). When the PEEP is eliminated, e.g., when the respirator is disconnected for suction of the endotracheal tube, the sealing effect will be abolished. As the cuff extends up into the larynx there will be no pooling of fluid above the cuff. The risk of aspiration can therefore be diminished by suction of oral cavity before disconnecting the respirator. With the use of the pneumatic valve principle together with high-frequency positive-pressure ventilation, an open respirator system can produce a continuous PEEP, thereby preventing aspiration even during suctioning of the tracheal tube.


Some observations on the diagnosis and treatment of complete denture problems.

Diagnosis of problems in the wearing of complete dentures can only be made after taking a complete history of the difficulties encountered by the patient. This necessitates careful attention whilst the patient relates the various difficulties. The record of these statements should be scrutinized carefully and this will assist in making the correct diagnosis of the cause of the difficulties. Specific problems encountered by elderly patients are examined and some methods of overcoming them are presented.


A controlled trial of cervical manipulation of migraine.

The efficacy of cervical manipulation for migraine was evaluated. In a six-month trial, 85 volunteers suffering from migraine were randomly allocated to three treatment groups. One group received cervical manipulation performed by a medical practitioner or by a physiotherapist, another received cervical manipulation performed by a chiropractor, while the control group received mobilization performed by a medical practitioner or by a physiotherapist. For the whole sample, migraine symptoms were significantly reduced. No difference in outcome was found between those who received cervical manipulation, performed by chiropractor or orthodox therapist, and those who received the control treatment. Chiropractic treatment was no more effective than the other two treatments in reducing frequency, duration or induced disability of migraine attacks, but chiropractic patients did report a greater reduction in pain associated with their attacks.


Alternative pathway of complement activation by Candida albicans.

Activation of the alternative pathway of complement by Candida albicans was examined using a chemotactic assay. Two serologically defined strains and eight clinical isolates of Candida albicans were used in these experiments. The results showed that all ten strains of Candida albicans were capable of alternative complement pathway activation. These findings may provide an insight into host resistance to this infection.


Interpretation of the whole-nerve action potential off-effect in response to tone bursts.

The growth of an off-effect in the whole-nerve action potential (AP) at the end of a tone burst is explained by means of some fundamental laws of systems theory applied to the available knowledge of the mechanisms of generation of the AP. The dependence of the amplitude and of the shape of the off-AP on the burst paradigms (frequency, amplitude and phase) is successfully predicted on the ground of a simple model for the cochlear events.


Immune reactions in patients with bladder and prostatic cancer.

Although there are many reports of cellular immune reactions in bladder and prostatic carcinoma patients, few have demonstrated the presence of humoral reactivity. The use of microtechniques, especially the enzyme-linked immunosorbent assay (ELISA), has made sequential studies possible on patients with early or small tumours. Using this assay, the presence of serum antibodies has been demonstrated in both bladder and prostate patients, the specificities of these reactions being checked against a battery of different tumours and normal tissues. In many of the patients, with low or transient antibody levels, the presence of circulating immune complexes was shown by the Raji cell assay and analysed by double counter-current immunoelectrophoresis (DCIE). The content of these complexes appeared to be either antibody and tumour antigen or antibody and antiimmunoglobulin. In a small series of cryosurgically treated prostatic carcinoma patients, the course of these antibodies was monitored over several weeks, and the fluctuations in antibody levels were related to the presence of these different types of complexes.


Effects of Gal-E-mutant of Salmonella typhimurium on experimental salmonellosis in chickens.

Compared with unvaccinated challenged birds, day-old chicks vaccinated orally with live Salmonella typhimurium galactose epimerase mutant (G30D) and challenged orally after 14 days with a field strain of S. typhimurium had statistically significant reductions in fecal shedding (P less than 0.01), in salmonella carrier status at slaughter (P less than 0.05), in salmonella in the broiler-house environment (P less than 0.005), and in serological response in the fourth week after challenge (P less than 0.005). The vaccine did not elicit a serological response as measured by plate, microagglutination, and microantiglobulin tests. The vaccine had a significant depression on live-weight gain which was not apparent after 6 weeks. The vaccine did not significantly reduce live weight at 8 weeks below that of unvaccinated control birds. The field strain produced an 8% reduction in live weight at 8 weeks below that of controls. The potential role of vaccines in salmonella control, and economic losses due to salmonellosis, are discussed.


[New findings on the immunology of protozoan blood parasitoses in domestic animals].

Intensive research in the field of the immunology of protozoan blood parasitoses has led to a further clarification of the interrelations between parasites and hosts. Progress in the analysis of the antigen character of the parasites and investigations of the immune response form the basis for extending serological diagnosis and improved vaccines. The effectiveness of the vaccines against babesioses could be increased. Vaccines have been tested successfully against tropical theileriosis and East Coast fever. It is only with African trypanosomes that immunoprophylaxis seems to be impossible at present.


Occurrence of Escherichia coli in feces of psittacine birds.

The feces of 125 psittacine birds, representing 12 species, were cultured on selective media to determine the presence of Escherichia coli. Only 13.6% (17) of the birds yielded E. coli.


Survival of Salmonella typhimurium in poultry feed and litter at three temperatures.

Poultry feed and litter were contaminated with a large number of Salmonella typhimurium cells and then stored at 11, 25, or 38 C. Samples of feed and litter were cultured at daily or weekly intervals. The organisms survived best at the two lower temperatures. Persistence was as follows: at 11 C, at least 18 months in both feed and litter; at 25 C, 16 months in feed and 18 months in litter; and at 38 C, about 40 days in feed and only 13 days in litter. Hence, samples of feed and litter collected for bacteriologic examination should be stored at low temperatures.


Studies on Pasteurella multocida. VII. Dynamics and temporal development of local humoral immunity induced by a live avirulent fowl cholera vaccine.

Vaccination of turkeys by administering the CU strain of Pasteurella multocida in drinking water induced local antibodies in the tracheal secretions. Their appearance and persistence were demonstrated by the indirect immunofluorescence technique. Local antibodies were induced by the 10th day and persisted up to the 42nd day postvaccination, whereas none were induced by an oil-adjuvanted bacterin throughout the observation period (56 days). Thus, the CU strain of P. multocida appeared to generate a local humoral immunity in the respiratory system whereas the bacterin did not.


Oxidation--reduction potentials of molybdenum and iron--sulphur centres in nitrate reductase from Escherichia coli.

The potentials of the couples Mo(IV)--(Mo(V) and Mo(V)--Mo(VI) in nitrate reductase from Escherichia coli K12 were measured as + 180 mV and + 220 mV respectively at pH 7.14. The potentials associated with two other e.p.r. signals, believed to be due to iron--sulphur centres, were measured as + 50 mV and + 80 mV.


Energy coupling to the transport of inorganic phosphate in Escherichia coli K12.

The nature of the energy source for phosphate transport was studied in strains of Escherichia coli in which either one of the two major systems (PIT, PST) for phosphate transport was present. In the PIT system, phosphate transport is coupled to the proton-motive force. The energy source for the PST system appears to be phosphate-bond energy, as has been found in other systems involving binding proteins. High concentration gradients of phosphate (between 100 and 500) are established by both systems.


Polarization of chlorotetracycline fluorescence in pancreatic islet cells and its response to calcium ions and D-glucose.

Suspensions rich in pancreatic beta-cells were prepared from non-inbred ob/ob-mice, incubated with 10 micrometer-chlorotetracycline, and analysed for fluorescence polarization in a microscope. Throughout the temperature range 16--38 degrees C, fluorescence was enhanced by 5 mM-Ca2+ in the incubation medium; 20 mM-D-glucose decreased the fluorescence measured in the presence of Ca2+. Fluorescence showed a curvilinear negative regression on temperature. The curves were rectified to a virtually ideal degree by Arrhenius transformations of data. Non-parametric testing of differences between linearized regression lines forms the basis for the following conclusions. The temperature-dependence of fluorescence intensity appeared to be smaller for Ca2+-specific signals than for the background fluorescence of chlorotetracycline in Ca2+-deficient cells. D-Glucose significantly diminished the polarization of fluorescence in cells incubated with Ca2+. It is suggested that D-glucose increases the mobility of Ca2+ in beta-cell plasma membranes; this mobility increase may help to explain previously reported effects of D-glucose on 45Ca2+ fluxes and membrane electric potential.


Glucose transport of Escherichia coli growing in glucose-limited continuous culture.

Dilute cultures of wild-type Escherichia coli K12 and of derivatives impaired in one or other Enzyme-II component of the glucose phosphotransferase system were grown in continuous culture under glucose limitation. Cells harvested from the chemostat took up [U-14C]glucose from 0.1 mM solutions at rates directly related to the rates at which those cells had grown; the activity of the phosphotransferase system in those cells, rendered permeable with optimal accounts of toluene, parallels the ability of the cells to take up glucose. The capacity of these systems was rate-limiting for growth under the negligibly low glucose concentration in the chemostat, but was adequate to account for the stimulation of respiration observed when the cells were presented suddenly with excess glucose.


The redox state and regulation of amino acid metabolism in man.

Traditionally, regulation of amino acid metabolism in both postabsorptive and prolonged-fasted man has been generally regarded as being hormonal in nature. In particular, insulin, and to a lesser extent glucagon, have been nominated for key roles in this process. More recently, however, reconsideration of previous studies involving insulin, glucagon, and protein meals as well as previously unreported studies (cortisol and tri-iodothyronine) from this laboratory, have suggested another means of regulating amino acid metabolism in fasting man. This new hypothesis is centered on the redox state of muscle of fasting man, which is remarkably reduced in both cytosolic and mitochondrial compartments. It was found that insulin, and to a lesser extent glucagon, when infused into fasting subjects (1) rendered muscle significantly more reduced, and (2) resulted in a diminution in urinary nitrogen excretion. In contrast, when either tri-iodothyronine or cortisol were administered to fasting individuals (1) muscle was found to become more oxidized when compared with the control period, and (2) increased urinary nitrogen excretion was observed in both cases. It was noteworthy that the ingestion of a protein meal by a nitrogen-depleted individual was followed by a dramatic change in muscle redox state (the muscle became more reduced), together with marked uptakes of a variety of amino acids. It is therefore proposed that the protein conservation evidenced by fasting man may be dependent on the reduced state of muslce tissue.


Control of hepatic glucose output by glucagon and insulin in the intact dog.

The regulation of hepatic glucose production by glucagon and insulin has been studied in the intact dog. An attempt has been made to evaluate the role of basal physiological concentrations of the hormones in the regulation of glycogenolysis and gluconeogenesis. Somatostatin was infused continuously into postabsorptive dogs to inhibit the secretion of both glucagon and insulin. Either or both hormones were then replaced intraportally by continuous infusion as desired. The main observations were as follows. (1) When both hormones were simultaneously replaced for periods up to 4.5h, plasma insulin and glucagon concentrations, total glucose output (glycogenolysis plus gluconeogenesis), glucose utilization and the plasma glucose concentration closely matched the same parameters in 0.9% NaCl-infused controls. (2) When glucagon alone was infused, thereby creating a selective insulin deficiency, glucose output (primarily glycogenolysis) rapidly increased by as much as threefold. Glycogenolytic glucose production then fell off progressively and returned to the control value within 4h. The gluconeogenic conversion of [14C]alanine and [14C]lactate into [14C]glucose was stimulated markedly and increased progressively throughout the test period. Glucagon therefore converted the liver from an organ largely dependent on glycogenolysis for glucose production to one heavily dependent on gluconeogenesis. The potent inhibitory effect of basal insulin on postabsorptive glucose output was also clearly apparent. (3) When insulin alone was infused, thereby creating a selective glucagon deficiency, glucose output (glycogenolysis) fell abruptly by about 30% and remained decreased. Gluconeogenesis also decreased (20%) after the selective removal of both insulin and glucagon, but it only remained suppressed for 1h. The low glucose output led to a modest fall in the blood glucose concentration. Thus glucagon plays an important role in maintaining basal glucose production. (4) When insulin was infused and the plasma glucose was kept at its control concentration by infusion of glucose in similar experiments to the above, the hepatic output of glucose fell by as much as 75%. This demonstrates the presence of a glucagon-independent metabolic reflex triggered by a low plasma glucose concentration, the purpose of which is to maintain glucose output at a rate capable of preventing castastrophic hypoglycaemia.


Regulation of pyruvate oxidation and the conservation of glucose.

In animals the pyruvate dehydrogenase reaction is mainly responsible for the irreversible loss of glucose carbon by oxidation. Regulation of this reaction is shown to be a major determinant of glucose conservation in starvation and diabetes. Estimates of conservation in man in starvation and diabetes are reviewed. The pyruvate dehydrogenase complex is inhibited by products of its reactions; it is also regulated by a phosphorylation-dephosphorylation cycle catalysed by a kinase intrinsic to the complex and by a more loosely associated phosphatase. Inactivation is largely accomplished by phosphorylation of the tetrameric decarboxylase component (alpha2beta2) to alpha2Pbeta2. Complete phosphorylation produces the (alpha2P3)beta2 form. Both forms are completely reactivated by phosphatase action but the initial rate of reactivation of a complex containing alpha2Pbeta2 is approximately three times that of (alpha2P3)beta2. The proportion of active (dephosphorylated) complex is decreased in rat tissues by starvation and diabetes and in perfused rat heart by oxidation of fatty acids and ketone bodies. In adipose tissue in vitro, insulin increases the proportion of active complex and lipolytic hormones may decrease this proportion. It is suggested that rates of oxidation of lipid fuels may be a major determinant of the activity of pyruvate dehydrogenase in tissues in relation to the actions of insulin and lipolytic hormones and the effects of diabetes and starvation. Phosphorylation and inactivation of the complex are enhanced by high mitochondrial ratios of [acetyl-CoA]/[CoA], [ATP]/[ADP], [NADH]/[NAD+] and low concentrations of pyruvate, Mg2+ and Ca2+, and vice versa.


[Comparative study on the efficacy of diflucortolone valerate in the psoriasis plaque test (author's transl)].

Diflucortolone valerate was administered to 35 psoriatic patients of both sexes in 0.3% concentration as a W/O emulsion in comparison with various commercially available preparations to study its action in the psoriasis plaque test according to Scholtz and Dumas. The study showed the test substance to be equipotent with the halcinonide, clobetasol-17-propionate and desoximetasone preparations and significantly superior to those containing betamethasone-17,21-dipropionate, betamethasone-17-valerate and fluocinonide.


Pharmacokinetics of sodium valproate in dog and mouse.

The pharmacokinetics of sodium di-n-propyl-acetate (sodium valproate, Ergenyl) after i.v. and oral administration in dogs and mice were studied. After i.v. administration of 20 and 40 mg/kg sodium valproate in dogs a biphasic exponential decay of valproate serum concentrations was found, so that a two-compartment open model could be assumed. With mice a monophasic exponential decay of valproate serum concentrations was found after i.v. administration of 200 and 420 mg/kg sodium valproate corresponding to a one-compartment open model. Valproate was rapidly eliminated in both species, the half-life being 90--120 min in dogs (T0.5 beta) and 50 min in mice. After oral administration, valproate was readily absorbed in both species. The transfer of valproate from blood to brains of mice was likewise rapid, and the observed concentrations in brain were 1/4 to 1/5 of that in serum. The binding of valproate to serum proteins determined in dog serum was calculated to 88%. The pKa of valproate was determined to 4.56 and valproate is, therefore, nearly lipid-insoluble at pH 7.4.


On the mechanism of amphetamine-induced behavioural changes in the mouse. II. Effects of agents stimulating noradrenergic receptors.

The effects of three "noradrenergic stimulants", norepinephrine and alpha-methylnorepinephrine administered into the cerebral ventricles and of parenterally injected clonidine, have been observed on 18 separate items of dexamphetamine-induced behaviour in the mouse. Stereotyped behaviour was depressed by the "noradreneric stimulants" except for compulsive gnawing, which was markedly enhanced. Aspects of locomotor activity were enhanced except when compulsive gnawing was strong, at which time they were suppressed. Elements of heightened arousal were enhanced. It is suggested that these may be a positive noradrenergic component in the genesis of compulsive gnawing, locomotor activity and heightened arousal. The dominance of compulsive gnawing over certain other dexamphetamine-induced behaviours may lead indirectly to the suppressor effects of the noradrenergic stimulants on these behaviours.


[Isosorbide dinitrate and bupranolol in the therapy of coronary heart disease (author's transl)].

Sixteen patients with coronary heart disease (CHD) and three healthy volunteers were treated with a combination of a long-acting nitrite and a beta-receptor blocking agent. The drug proved effective in diminishing haemodynamic changes after physical and mental stress, respectively. The implications of these findings are discussed in the light of recent knowledge on CHD pathogenetic mechanisms.


[The effect of an oral aminophylline compound with protracted activity on respiratory resistance and blood gases in obstructive respiratory diseases (author's transl)].

The effect of theophylline ethylenediamine oblong tablets (Euphyllin retard) was tested in 40 patients by means of a double-blind trial, applying a dose of 2 X 350 mg/d and 2 X 700 mg/d. At the dose of 2 X 700 mg/d Euphyllin retard showed a good bronchodilatory effect. A reduction of the obstruction in the airways and an improvement of the arterial blood gases was statistically secured. At the dose of 2 X 350 mg/d a sufficient bronchodilation could not be recorded.


[Clinical results in the treatment of chronic obstructive bronchitis with ambroxol in comparison with bromhexine (author's transl)].

Preclinical studies of trans-4-[(2-amino-3,5-dibromobenzyl)-amino]-cyclohexanol hydrochloride (ambroxol, NA 872), the metabolite VIII of bromhexine, show that it is superior to the basic substance with respect to its bronchosecretolytic properties. In a double blind study 30 patients suffering from chronic obstructive bronchitis received in randomized order 36 mg bromhexine/d or 45 mg ambroxol/d, each over a period of 4 weeks. The following parameters were studied: mean bronchial flow resistance, forced expiratory volume, static lung volumes, arterial blood gases as well as clinical and laboratory results. Bromhexine was not associated with a change in lung function parameters. Ambroxol was associated with a 25% reduction of the average bronchial flow resistance. The forced expiratory volume improved over the period on the average by 14%. Patients with slight arterial hypoxemia had an increase in the partial pressure of arterial oxygen. The patients found both substances facilitated expectoration. Further studies appear necessary to confirm the improved respiratory performance under the influence of ambroxol.


[The respirophonogram as a means of drug screening (author's transl)].

Respirophonography is an objective method of measuring respiratory and adventicious sounds. Current techniques make a perfect, albeit somewhat tedious registering of these respiratory murmurs possible, which can then be analysed for frequency. In this paper the method is investigated for its applicability to drug screening and proved satisfactory in a double blind trial and a pilot study. During treatment with secretolytic drugs the pathological respiratory sounds change or cease. In the respirophonogram this is recognisable by the fact that the volume peaks are either displaced to another frequency area or that they disappear altogether. The frequency range 100--500 Hz is the most significant as far as the respiratory murmurs are concerned. The concepts familiar to the clinician experienced in auscultation are set out in an unaccustomed way in the frequency-volume diagram. The respirophonogram offers the advantage that it can be documented and that findings can therefore be compared objectively. From the point of view of the clinician respirophonography is despite its far reaching perfection already attained, still technically in a preliminary stage.


Serological aspects of rat tumour xenograft growth in athymic nude mice.

The serum of athymic nude mice bearing rat tumour xenografts has been examined for tumour-specific antigen. With a sarcoma and a hepatoma, tumour-specific antigen expression continued in xenograft growths, and sera of tumour-bearing mice contained free antigen, assayed by its ability to neutralise reactivity of tumour-immune rat sera against tumour target cells in an indirect membrane-immunofluorescence test. In contrast, no anti-rat antibody was detectable in sera of mice bearing the xenografts, or rejecting cells injected in admixture with BCG.


Legionnaires' disease: a clinical description of thirteen cases.

We describe 13 patients with legionnaires' disease in Nottingham, all presenting with lobar pneumonia. Six patients required artificial ventilation and 2 died. No common source of infection has yet been identified, but the disease appears to be prevalent and possibly endemic in this city.


Fenoterol in asthma.

Fenoterol is a beta 2-sympathomimetic bronchodilator. In a double-blind cross-over trial in 17 asthmatic patients with reversible airway obstruction inhalation of both fenoterol (0.4 mg) and terbutaline (0.5 mg) produced a statistically significant greater increase in peak expiratory flow rate than did placebo. The magnitude and duration of response to fenoterol exceeded that to terbutaline in the doses used. The patients' subjective assessment also suggested the relief of their symptoms with the active drugs. Side effects were minimal.


Localization of specific carbohydrate configurations in human skin using fluorescein-labelled lectins.

The binding of three fluorescein-labelled lectins by normal human skin has been studied. The patterns of bound fluorescence seen were characteristic for each lectin, indicating that saccharide residues were available for lectin localization in the skin. Concanavalin A (glucose and mannose specific) and ricin 120 (galactose specific) presented similar patterns of localization of fluorescence in the epidermis and dermis. Both lectins presented a continuous band at the dermo--epidermal junction, but with concanavalin A the band was broader, while with ricin 120 the junctional band was thinner and more closely associated with the epidermal interface. With the peanut lectin (galactose specific) fluorescence outlined the periphery of the keratinocytes in the upper Malpighian and granular cell layers only; no junctional band was seen and the dermal appendages and collagen did not fluoresce. The stratum corneum did not fluoresce with any of the lectins studied.


Formation of transcobalamin II--vitamin B12 complex by guinea-pig ileal mucosa in organ culture after in vivo incubation with intrinsic factor--vitamin B12.

The in vivo incubation of intrinsic factor--[57Co]vitamin B12 in an ileal loop of a guinea-pig followed by in vitro culturing of segments of the ileum for 180 min has been used to study the transepithelial transport of vitamin B12. Analysis of the solubilized supernate of mucosa following the in vivo phase demonstrated that 44% of the [57Co]vitamin B12 was bound to intrinsic factor (IF), 26% was free, and 16% was bound to transcobalamin II (TCII). Following culture, similar analysis demonstrated that 18% of the vitamin was now bound to IF, 49% was free, and 35% ws bound to TCII. In the culture medium, 54% of the [57Co]vitamin B12 was free and 37% was bound to TCII. The formation of TCII-[57Co]vitamin B12 did not occur if homogenized mucosa was incubated with free[57Co]vitamin B12, but it did form in cultures of ileal segments from animals given an excess of unlabelled vitamin to saturate all circulating TCH, and in the medium containing puromycin. Indirect immunofluorescence using chicken anti-TCII demonstrated that TCII was associated with the mucosal cells of both the ileum and jejunum.  These studies demonstrate that following transepithelial flux of vitamin B12 through the ileal mucosa, the vitamin becomes coupled to TCII. This coupling requires a structurally intact mucosa and the source of the TCII appears to be the ileal mucosal cell rather than unsaturated TCII circulating in the blood.


A randomized double-blind trial of two low dose combined oral contraceptives.

Fifty-five women using Loestrin-20 (20 microgram ethinyl oestradiol and 1 mg norethisterone acetate) as an oral contraceptive have been compared with a like number using Microgynon-30 (30 microgram ethinyl oestradiol and 150 microgram levonorgestrel) in a randomized, double-blind trial. Despite the small sample size, the main finding in the trial is clear-cut; Loestrin-20 provides poor cycle control and is thus less acceptable as an oral contraceptive than Microgynon-30. Although there is also a suggestion that Loestrin-20 may be less effective than Microgynon-30, the difference in the accidental pregnancy rates is not statistically significant.


Normocapnic anaesthesia for intraocular surgery.

Measurement of intraocular pressure (IOP) by applanation tonometry in 23 patients undergoing lens extraction showed that a normocapnic general anaesthetic technique with controlled ventilation of the lungs (IPPV) reliably reduced the IOP by 50% for the duration of the operative period. This was not associated with large falls in systemic arterial pressure which are often a feature of spontaneously breathing halothane anaesthesia for eye surgery. Normocapnia and IPPV were easy to achieve by use of the single-limb coaxial Bain anaesthetic breathing circuit in conjunction with an electrically driven, small, and inexpensive ventilator while the anesthetic mixture of 33% oxygen and 0.5% halothane in nitrous oxide was delivered at a rate of 70 ml/kg body weight per minute.


Keratoplasty sensitivity.

Analysis of graft sensitivity showed a return to normal after 3 years in only one-third of the eyes. It is not known whether this is due to regeneration of abnormal or superficial nerve fibres. Contact lens wearers showed less sensitivity than spectacle wearers.


Keratoconus keratoplasty curvatures and contact lens wear.

Fifty-three grafted keratoconus corneas chosen at random from several hundred operated upon over a 10-year period showed an increase in myopia after removal of sutures but a decrease in astigmatism. With the photoelectrokeratograph machine the spherical zone was shown to be limited to 3 mm with gross eccentricities. Half the patients chose to wear contact lenses after surgery and 10% had no correction. Contact lens wearers showed a much greater decrease in astigmatism than spectacle wearers.


Subunit interaction in tryptophan synthase of Escherichia coli: calorimetric studies on association of alpha and beta 2 subunits.

Association of the apo-beta 2 and the holo-(beta-PLP)2 subunits of tryptophan synthase from Escherichia coli (L-serine hydro-lyase (adding indole) (EC 4.2.1.20)) with alpha subunits of the same enzyme has been studied by microcalorimetry. The results obtained from thermometric titrations clearly demonstrate that only the native complex alpha2beta 2 is formed, independent of an excess of alpha protein. The reaction of the holo-(beta-PLP)2 with alpha subunits at 25 degrees C is accompanied by a negative enthalpy change, which is almost twice as large as that for complex formation with the apo-beta 2 protein, thus indicating that the interaction enthalpy becomes more favorable in the presence of the coenzyme pyridoxal 5'-phosphate (PLP). Both reaction enthalpies show very large negative temperature coefficients, -3600 +/- 100 cal K-1 (Mol of beta 2)-1 being the value for the formation of the apoenzyme and -2300 +/- 100 cal K-1 (mol of beta 2)-1 pertaining to formation of the holoenzyme. The studies on the association of alpha and beta2 subunits in the two buffers revealed that at 25 degrees C approximately 0.75 proton are absorbed in the presence and absence of the coenzyme, whereas at 35 degrees C one proton is taken up from the solution when PLP is present, but two if the apo-beta 2 complex reacts. These results are a clear indication of energetic linkage between intersubunit interaction, hydrogen ion equilibria, and the binding of the coenzyme.


Conformation of Escherichia coli ribosomal protein L7/L12 in solution: hydrodynamic, spectroscopic, and conformation prediction studies.

The conformation of Escherichia coli ribosomal protein L7/L12 in solution has been studied using spectroscopic and hydrodynamic methods. Circular dichroism studies in the near-ultraviolet region reveal two bands at 262 and 268 nm originating from the tertiary conformational environment of the phenylalanyl residues. Additional characterization of the phenylalanine environment includes an intrinsic fluorescence emission spectrum arising from the phenylalanine fluorophores. Computer analysis of the far-ultraviolet circular dichroism spectrum suggests that L7/L12 contains as much as approximately 76% alpha helix. Hydrodynamic properties of L7/L12, measured with the purpose of providing relevant shape information, include the frictional coefficient ratio (1.84 +/- 0.03) and intrinsic viscosity (28 +/- 0.4 mL/g). The experimentally determined frictional coefficient (6.15 +/- 0.15 X 10(-8) has been compared with theoretical calculations of the same value employing two independent methods and assuming various dimensions for the L7/L12 dimer. Combining the experimental results from this work with those available from the literature, and using conformation predictive methods of Chou & Fasman [P. Y. Chou & G. D. Fasman (1974) Biochemistry 13, 211-222, 222-245] and of Maxfield & Scheraga (F. R. Maxfield & H. A. Scheraga (1976) Biochemistry 15, 5138-5153), several possible molecular models of the L7/L12 dimer have been constructed and critically examined. A model which is consistent with all of the available data is proposed.


Phenylalanyl-tRNA synthetase of Escherichia coli K 10. Multiple enzyme-aminoacyl-tRNA complexes as a consequence of substrate specificity.

The interaction between Phe-tRNA(Phe) or other acyl-tRNA derivatives thereof and phenylalanyl-tRNA synthetase of Escherichia coli K 10 has been investigated by nonequilibrium dialysis, by fluorescence titration in the presence of 2-p-toluidinylnaphthalene-6-sulfonate, by the kinetics of the aminoacylation of tRNA(Phe), and by the kinetics of the catalytic hydrolysis of Phe-tRNA(Phe). Phe-tRNA(Phe), or derivatives thereof, forms two types of complexes with the synthetase. One type involves the attachment of the phenylalanyl moiety to the phenylalanine-specific site of the enzyme, and the other type, to the tRNA(Phe)-specific binding site. They resemble alternative modes of a destabilized enzyme-product complex and are predicted on the basis of thermodynamic considerations. The two modes of binding of acyl-tRNA compete with each other. The attachment of Phe-tRNA(Phe) to the phenylalanine-specific site dominates. At equilibrium, this complex is present at a fourfold higher concentration than the other type of complex. The HNO2 deaminated Phe-tRNA(Phe) binds exclusively to the site specific for L-phenylalanine. On the contrary, Ile-tRNA(Phe) adds at 94.1% to the tRNA(Phe)-specific site. The association of Phe-tRNA(Phe) with this site leads to enzymatic hydrolysis into L-phenylalanine and tRNA(Phe). The complex involving the phenylalanine-specific site is hydrolytically unproductive. L-Phenylalanine acts as an activator of the hydrolysis by occupying the amino acid specific site and by shifting the equilibrium between the complexes toward the binding ot Phe-tRNA(Phe) at the tRNA(Phe)-specific site. The association of Phe-tRNA(Phe) at the phenylalanine-specific site does not interfere sterically with the binding of free tRNA(Phe). The sequential addition of free and aminoacylated tRNA(Phe) exhibits negative cooperativity. Such a mechanism could help to expel the product from the enzyme.


Study of the cytoplasmic and outer membranes of Escherichia coli by deuterium magnetic resonance.

The cytoplasmic and outer membranes of Escherichia coli were studied between 0 and 40 degrees C by deuterium magnetic resonance quadrupolar echo spectroscopy. The L51 strain of E. coli was used to incorporate perdeuterated palmitic acid into the membrane phospholipids. The cytoplasmic and outer membranes were separated using standard techniques. The spectrum of each membrane preparation was dominated at high temperatures (greater than or equal to 37 degrees C) by the characteristic liquid-crystalline plateau previously observed for perdeuterated palmitate chains in model phospholipid membranes. At low temperatures, the shape and width of the spectrum were characteristic of the gel phase. The relative intensities of the liquid-crystalline and gel features varied systematically with temperature. A quantitative analysis of the acyl chain orientational order was carried out by using the method of moments. The orientational order at each temperature was greater in the outer membrane sample than in that of the cytoplasmic membrane, indicating that the liquid-crystalline-gel transition region in the outer membrane is shifted to higher temperatures than that of the cytoplasmic membrane by about 7 degrees C. It is clear from the results that most of the phospholipid molecules participate in the phase transition.


Mechanistic studies with vinylglycine and beta-haloaminobutyrates as substrates for cystathionine gamma-synthetase from Salmonella typhimurium.

Cystathionine gamma-synthetase (EC 4.2.99.9), a key enzyme in bacterial methionoine biosynthesis, has been found to use L-vinylglycine (2-amino-3-butenoate) and L-beta-haloaminobutyrates (X = F, Cl) as substrates in addition to the physiological gamma-substituted substrate O-succinyl-L-homoserine (OSHS). Vinylglycine is a substrate both for alpha-ketobutyrate formation (the normal product from gamma elimination with OSHS) and for cystathionine formation (the normal gamma-replacement product with OSHS) in the presence of cysteine. This behavior substantiates that the stabilized vinylglycine--pyridoxal phosphate (PLP) alpha carbanion is the key partitioning species in this enzyme's catalysis. The Vmax values for ketobutyrate production and cystathonine formation from vinylglycine are equivalent at approximately 45 U/mg, whereas the corresponding Vmax values from OSHS are 20 and 200 U/mg, respectively, suggesting different rate-determining steps with these two substrates. The beta-haloaminobutyrates undergo catalyzed HX elimination to yield bound aminocrotonate--PLP directly as a an initial intermediate and as a precursor of ketobutyrate. Little or no cystathionine formation is detectable when these substrates are incubated with enzyme and the normal cosubstrate cysteine, strongly indicating that the aminocrotonate--PLP intermediate is not in rapid, reversible equilibrium with the stabilized vinylglycine--PLP carbanion; in normal catalysis, the prototropic shift from alpha carbanion to aminocrotonate appears functionally unidirectional. The HX-elimination step from beta-chloroaminobutyrate is nonconcerted as demonstrated by a 3H2O in equilibrium chloroaminobutyrate exchange reaction. Further suggestion for discrete beta-halo-alpha-carbanionic intermediates derives from the observation that the haloaminobutyrates appear to a partition between ketobutyrate formation and enzyme inactivation. Since neither vinylglycine nor OSHS causes any detectable inactivation during turnover, it is likely that the inactivation species is not a common intermediate, i.e., the electrophilic aminocrotonate--PLP species (a potential Michael acceptor), but rather a species peculiar to the beta-haloaminobutyrate pathway. The beta-halo-alpha-carbanion--PLP intermediate has beta-halo-alpha-iminodihydropyridine character in the p-quinoid resonance contributor and is a good candidate for an alkylating agent by an SN2--displacement mechanism. Spectroscopic analyses of incubations with the various amino acid substrates show a number of long-wavelength absorbing species forming during turnover, tentative assignments are suggested.


Small angle x-ray scattering from the inner and outer membranes from Escherichia coli.

Small angle X-ray data from purified forms of inner or cytoplasmic and outer membranes from Escherichia coli have been obtained and appear to be qualitatively similar. Transitory changes are apparent in the circularly averaged X-ray profiles from inner membranes. Such results could be due to the loss or denaturation of peripheral membrane proteins. Some partially dried forms of outer membrane are partly ordered and produce diffraction patterns which support an underlying bilayer structure. An extra light membrane fraction which results from membrane preparations utilizing a French pressure cell for spheroplast disruption has been characterized and shown to be similar to inner membrane. The purified membranes produce small angle X-ray diffraction patterns which are much different from those of lipid dispersions and the differences are attributable to the high protein content of the intact membranes. While the small angle X-ray region may be useful for characterizing the membrane preparations, the paucity of detail in the diffraction pattern suggest that it will be of little value in describing the complex underlying membrane structure.


Specificity of chromatin transcription in vitro. Anomalies due to RNA-dependent RNA synthesis.

In the presence of Mn2+, globin mRNA can be transcribed into a partial RNA copy by Escherichia coli RNA polymerase. This process also occurs when the mRNA is transcribed together with chromatin. A fraction, at least, of the newly synthesized RNA copy (anti-globin RNA) can serve as a template for the synthesis of globin sequences of the same polarity as the original mRNA. This process is sufficient to explain the specific synthesis of a subset of the globin RNA on mouse foetal liver chromatin. It also accounts for the synthesis of double-stranded RNA sequence by E. coli RNA polymerase, on chromatin as well as on pure mRNA. Results are presented suggesting that the poly(A) tract of the mRNA could be preferentially transcribed. In the presence of Mg2+, the RNA-dependent transcription is strongly inhibited, as well as the synthesis of double-stranded RNA. Under these conditions, the transcription on chromatin appears to be largely DNA dependent, and the synthesis of globin sequences is completely asymmetric. Spermine (0.3 mM) seems to improve the specificity of transcription. The transcription of chromatin in vitro is thus largely dependent on the nature of the divalent cation present in the in the incubation mixture.


DNA synthesis with methylated poly(dC-dG) templates. Evidence for a competitive nature to miscoding by O(6)-methylguanine.

The alternating copolymer poly(dC-dG) has been methylated with either dimethyl sulphate or N-methyl-N-nitrosourea and the levels of the various methylation products determined. In addition to the 3-methylcytosine, 3-methylguanine and 7-methylguanine (produced by both agents) reaction with N-methyl-N-nitrosourea also yielded easily detectable amounts of O(6)-methylguanine and phosphotriesters. These methylated polymers were then used as templates in an in vitro assay with Escherichia coli DNA polymerase I measuring the incorporation of complementary (dCMP and dGMP) and noncomplementary (dAMP and dTMP) nucleotides. When the dimethyl sulphate-methylated polymer was used as template there was virtually no detectable incorporation of non-complementary nucleotides indicating that no miscoding could be attributed to the presence of 3-methylcytosine, 3-methylguanine or 7-methylguanine. However, when the N-methyl-N-nitrosourea-methylated polymer was used as template there was a specific incorporation of dTMP but not of dAMP. The amount of dTMP incorporated was always less than the level of O(6)-methylguanine in the template and was found to vary with the relative concentrations of the deoxynucleoside 5'-triphosphates in the assay. As the amount of dCTP present in the assay was decreased the wrong incorporation of dTMP increased and approached the level that would have been expected for a one-to-one miscoding by O(6)-methylguanine as the concentration of dCTP approached zero. The results indicate that O(6)-methylguanine is capable of miscoding with a DNA polymerase but the miscoding is competitive with the normal incorporation of dCMP: when the 5'-triphosphate precursors are present in equal amounts approximately one O(6)-methylguanine in three miscodes leading to the incorporation of dTMP.


Glycerol 3-phosphate analogues as metabolic inhibitors in Escherichia coli, 3-hydroxy-4-oxobutyl-1-phosphonate, a drug that interferes with normal phosphoglyceride metabolism.

3-Hydroxy-4-oxobutyl-1-phosphonate, the phoshonic acid analogue of glyceraldehyde 3-phosphate, enters Escherichia coli via the glycerol 3-phosphate transport system. There is no differential effect upon the accumulation of deoxyribonucleic acid, ribonucleic acid, or phosphoglycerides, although the accumulation of proteins was less effected. Examination of the phospholipids revealed that phosphatidylglycerol accumulation was most severely inhibited and cardiolipin accumulation was least affected. Concentrations of glyceraldehyde 3-phosphate and its phosphonic acid analogue that markedly inhibit macromolecular and phosphoglyceride biosynthesis have no effect upon the intracellular nucleoside triphosphate pool size. The phosphonate is a competitive inhibitor of sn-glycerol 3-phosphate in reactions catalyzed by acyl coenzyme A:sn-glycerol-3-phosphate acyltransferase and CDP-diacylglycerol:sn-glycerol-3-phosphate phosphatidyltransferase. A Km mutant for the former enzyme was susceptible to the phosphansferase activity. Studies with mutant strains ruled out the aerobic glycerol-3-phosphate dehydrogenase, glycerol-3-phosphate synthase, and fructose-1,6-biphosphate aldolase as the primary sites of action.


Characterization of peptic inhibitory activity associated with sulfated glycoprotein isolated from gastric mucosa.

Sulfated glycoproteins were extracted and purified from porcine stomach mucous scraping. Four sulfated glycoprotein fractions were separated and subsequently purified. These compounds always accompanied the apparent peptic inhibitory activity and consisted of 15-18% (w/w) protein. The carbohydrate portions contained an equimolar ratio of galactose and hexosamine (mainly glucosamine), together with lesser amounts of fucose and sialic acid. The sulfate content of the above fractions was 2-9% (w/w) of the total sulfated glycoprotein. The mode of inhibition of the sulfated glycoproteins to peptic activity was investigated and suggested that there was binding of the sulfated glycoproteins to the substrate of pepsin, making the substrate resistant to peptic activity. The sulfated glycoproteins neither bound pepsin at pH 1.8 nor inhibited the hydrolysis of a synthetic dipeptide substrate of pepsin. Desulfation of the sulfated glycoproteins resulted in the loss of both the inhibitory activity and the precipitate formation. The precipitation curve for sulfated glycoprotein and porcine serum albumin showed that both bound in varying proportions and suggests that both components are multivalent in this precipitate formation.


[Dependence of the rate of aspartate ammonia-lyase reaction catalyzed by free and immobilized cells of E. coli on temperature and preliminary thermal treatment].

The effects of temperature (45--55 degrees) and duration of thermal treatment on the L-aspartase activity of free and immobilized on polyacrylamide gel cells of E. coli, strain 85 were studied. It was found that preliminary thermal treatment of the cells at 50 degrees for 40--60 min is optimal for a high aspartase activity. Within the temperature interval of 20--55 degrees the temperature dependence of effective rate constants of L-aspartate synthesis obeys the Arrhenius equation, whereas the effective energy of activation is decreased from 12,6 to 3,6 kcal/mole, when the "activation" of the cells shows an increase.


The behavioural significance of heart rate: the Laceys' hypothesis.

The Laceys' account of the significance of heart rate changes for behaviour is critically evaluated. Two interwoven propositions are discerned in their account: first, the cardiac variations regulate central attentional activities via an afferent feedback mechanism; second, that environmental intake-rejection comprises a basic dimension underlying directional cardiac changes. Examination of pertinent psychophysiological research reveals that the first of these propositions lacks substantive support. The intra-cardiac cycle method has yielded highly equivocal results. Inter-cardiac cycle studies offer only modest correlational support and the two studies which have directly manipulated heart rate found that sensori-motor performance was largely unaffected. Difficulties also surround the other proposition. Consideration of the verbalization, pleasantness-unpleasantness and time estimation studies indicates that the relationship between heart rate and attention is variable and that heart rate is associated with factors other than attentional requirements. While the Laceys have attempted to reconcile such unfavourable evidence, conceptual clarity is frequently sacrificed in the process. It is concluded that the interpretation of cardiac responses must be sought in superordinate variables that account for both heart rate changes that can be related to attention and those that cannot, and that any afferent feedback mechanism, based on heart rate, most likely fulfills functions other than that proposed by the Laceys.


The analysis of failure times in the presence of competing risks.

Distinct problems in the analysis of failure times with competing causes of failure include the estimation of treatment or exposure effects on specific failure types, the study of interrelations among failure types, and the estimation of failure rates for some causes given the removal of certain other failure types. The usual formation of these problems is in terms of conceptual or latent failure times for each failure type. This approach is criticized on the basis of unwarranted assumptions, lack of physical interpretation and identifiability problems. An alternative approach utilizing cause-specific hazard functions for observable quantities, including time-dependent covariates, is proposed. Cause-specific hazard functions are shown to be the basic estimable quantities in the competing risks framework. A method, involving the estimation of parameters that relate time-dependent risk indicators for some causes to cause-specific hazard functions for other causes, is proposed for the study of interrelations among failure types. Further, it is argued that the problem of estimation of failure rates under the removal of certain causes is not well posed until a mechanism for cause removal is specified. Following such a specification, one will sometimes be in a position to make sensible extrapolations from available data to situations involving cause removal. A clinical program in bone marrow transplantation for leukemia provides a setting for discussion and illustration of each of these ideas. Failure due to censoring in a survivorship study leads to further discussion.


Measures of association between disease and genotype.

This paper is concerned with the statistical aspects of the phenomenon of disease occurring more frequently in individuals with some genotypes than in individuals with others. A correlation coefficient is defined to quantify association between disease and genotype. A distinction is made between the concepts of independence of allele and disease and independence of genotype and disease. This distinction is used to define two components of association which describe separate aspects of association of disease with genotype. One component is a measure of the association of disease with allele; the other a measure of the effect of allele interaction on association of disease and genotype. One aspect of the usefulness of the partition into components which is discussed is in expressing the recurrence risk of disease for a relative of an affected individual. A chi-squared analysis is provided to test hypotheses about the components of association and other hypotheses of genetic interest. This analysis is illustrated using a study done to determine the effect of the sex-linked dwarfing gene in male chickens on resistance to E. coli infection. This analysis shows a significant allele interaction effect on resistance to disease but no association of disease with alleles. In conclusion, some extensions and limitations of the proposed concepts and procedures are discussed.


[Determination of human leukocyte interferon by a microfluorimetric immunologic method].

The possibility of quantitative determination of human leucocyte interferon using FITC-labeled antiinterferon antibodies was studied. A highly specific antiinterferon immunoglobulin was obtained as a result of longterm immunization of a donkey with human leucocyte interferon followed by fractionation and immuno-absorbtion of immune plasma. This immunoglobulin was labeled with FITC and used for human leucocyte interferon assay in direct and indirect reactions of fluorescence immunoinhibition. The titres of different human leucocyte interferon preparations in this immunoassay were comparable with the titres of the same preparations detected by interferon inhibition of viral cytopathic effect.


[Electron microscopic study of conjugative plasmids from serologically typed E. coli AP1].

The plasmid DNAs isolated from E. coli AP1 were studied by electron microscopy. Two plasmid DNA forms (FB1-1 and FB1--2) with the mol wt of 35.9 +/- 0.5 x x 10(6) and 51.5 +/- 0.6 x 10(6) daltons, respectively, were revealed.


[Role of bone marrow stroma in the phenomenon of hybrid resistance].

In the site of hemopoiesis produced by implantation of an irradiated bone marrow plug beneath the kidney capsule all dividing hemopoietic cells were of recipient origin, as shown by karyologic analysis. In such implants hybrid resistance was of the donor's type. It is suggested that the migrating cells of hemopoietic origin, including lymphocytes and macrophages, do not participate in producing the hybrid resistance.


[Tissue-specific antigen of chick adenohypophysis appearing at early stages of histotypic differentiation].

The tissue-specific water-soluble antigen characterized by alpha1-globulin electrophoretic mobility was revealed in chick adenohypophysis. The antigen was shown to appear in embryogenesis at early stages of histotypical differentiation of the adenohypophysis by indirect immunofluorescence. The first cells with specific fluorescence were found simultaneously in the cephalic and caudal lobes of 6-day embryo adenohypophysis. The bright patterned fluorescence was observed in all cellular cords of the adenohypophysis by the 8--10th day of the development. This antigen may be used as a common marker for pituitary cell differentiation.


Two populations of granulocytes in paroxysmal nocturnal hemoglobinuria.

The granulocytes in paroxysmal nocturnal hemoglobinuria (PNH) are defective, and the defect is similar to that previously described for the PNH erythrocyte. Using anti-I antibody to activate complement and 51Cr release to detect cell lysis, we found two populations of granulocytes that differed in their susceptibility to lysis by complement in 5 of 6 patients. A proportion of the cells were lysed by one-fifteenth to one-twentieth the amount of complement required to lyse normal cells; the remainder of the granulocytes appeared to be normal in their susceptibility to the lytic action of complement. The binding of the third component of complement (C3) to PNH granulocytes was at least twice that bound to normal cells, even though the binding of antibody was the same for normal and PNH cells. This suggests that the binding of C3 and probably the efficiency of the terminal steps of complement lysis are increased in the abnormal PHN granulocyte. These defects affect only a portion of the granulocytes, thus suggesting that the disorder is a clonal stem cell abnormality.


Genetic control of F cells in human adults.

Hb F levels were determined on samples from 750 normal blood donors. Six individuals (0.8%) had Hb F levels in excess of 1.1%, the upper end of the continuous distribution. Eight individuals at the upper end and 7 individuals at the lower end of the range were selected for family studies. These studies revealed that the control of Hb F levels in adults, as judged by the more sensitive F-cell technique, has a major genetic component. Structural analysis of the Hb F in several cases demonstrated that both G gamma and A gamma chains were present, but in variable proportions. These results are discussed in light of current concepts of adult F-cell production.


Ioxaglate, a new low osmolar contrast medium used in femoral angiography.

Ioxaglate, a new monoacid, dimeric contrast medium was compared with diatrizoate (Urografin 60%) in a series of 61 femoral angiographies. In a double blind group of 34 examinations all patients preferred ioxaglate which caused slight pain in only five cases, whereas after diatrizoate 14 patients felt severe pain (six were unable to keep their legs still) and 12 felt slight pain. Increase in heart rate and decrease in systolic and diastolic arterial blood pressure was seen after both contrast medium injections, but significantly less after ioxaglate than after diatrizoate.


Antibiotic prophylaxis in total hip replacement.

A controlled prospective trial to compare the efficacy of the antibiotics cephaloridine and flucloxacillin in preventing infection after total hip replacement was conducted at three hospitals. The antibiotic regimens began before surgery, cephaloridine being continued for 12 hours and flucloxacillin for 14 days afterwards. Over an 18-month period 297 patients undergoing a total of 310 hip replacements were entered into the trial and randomly allocated to one of the regimens. The follow-up period ranged from one to two and a half years. All operations were performed in conventional operating theatres; at two of the hospitals these were also used by various other surgical disciplines. Four patients developed deep infection, two having received the cephaloridine and two the flucloxacillin regimen. The overall rate of deep infection was therefore 1.3%. Thus three doses of cephaloridine proved to be as effective as a two-week regimen of flucloxacillin. Giving a prophylactic systemic antibiotic reduced the incidence of infection to a level comparable with that obtained in ultra-clean-air operating enclosures.


Urinary tract infections after renal transplantation: do they matter?

The effect of urinary tract infections on renal function was assessed in 86 patients with renal allografts that had functioned for more than one year. Follow-up periods ranged from one to 10 years. Recurrent or persistent urinary sepsis was quite common in these long-term survivors but had no observable effect on graft function or survival of patients or grafts. Treatment of asymptomatic urinary tract infections was largely unsuccessful. Probably such infections may be safely ignored.


Dissociation of absorptions of calcium and phosphate after successful cadaveric renal transplantation.

Calcium and phosphate absorptions were studied by radiotracer techniques in 30 patients after successful cadaveric renal transplantation, and results were compared with those in a group of normal subjects and in groups of patients with chronic renal failure (CRF). Both calcium and phosphate absorptions were impared in patients with CRF, including those receiving haemodialysis. Abnormalities of calcium absorption, however, seemed to occur earlier in the course of advanced renal failure than abnormalities in phosphate absorption. Calcium absorption improved dramatically after successful renal transplantation, while phosphate absorption remained the same. A dissociation between calcium and phosphate absorptions is not often seen clinically, and the mechanisms for it are unknown. Phosphate malabsorption may be a further contributing factor in the development of persistent hypophosphataemia after transplantation.


Why blame the obstetrician? A review.

Because of superficial thinking obstetricians have been blamed unjustifiably for causing brain damage, cerebral palsy, mental subnormality, congenital torticollis, and facial palsy. It is essential to look behind obvious difficulties in labour, such as abnormal presentation or anoxia, to the underlying causes, which are often genetic or social, or concern other prenatal factors.


Comparison of salbutamol given intravenously and by intermittent positive-pressure breathing in life-threatening asthma.

A double-blind crossover trial was carried out during 22 episodes of life-threatening asthma in 19 patients to compare salbutamol given as a 500 microgram intravenous injection and as a 0 . 5% solution administered by intermittent positive-pressure breathing (IPPB) for three minutes. Relief of pulsus paradoxus was significantly better after IPPB than the intravenous treatment. Both treatments significantly improved the peak expiratory flow rate. Salbutamol given intravenously produced a mean increase in heart rate of over 20 beats/min five minutes after treatment compared with the relief of tachycardia that occurred after administration by IPPB. Four patients had noticeable cardiovascular side effects after salbutamol given intravenously, but no such effects were noticed after administration by IPPB. Two patients withdrawn shortly after entry into the trial because of a worsening clinical condition had received intravenous salbutamol. It is concluded that salbutamol given by IPPB is better than that given by slow intravenous injection in severe acute asthma.


Neural-tube defects: importance of a history of abortion in aetiology.

The overall incidence of anencephaly and spina bifida (ASB) in 69,056 pregnancies was 4.7/1000 births. ASB was more common (8.4/1000 births) among children of mothers who had had two or more abortions, but the increased risk was confined to spina bifida. A history of abortion was more common in older women and women of higher parity, but this was not matched by a similar increase in the incidence of ASB. The incidence of ASB was related to social class, but the prevalence of previous abortions was similar in all classes. The results suggest that expectant mothers with a history of two or more abortions have an increased risk of producing a child with spina bifida. The abortions are considered to be a manifestation of previous abnormal conceptions rather than the primary cause.


Organization of vestibular afferents to the vestibular nuclei of the dogfish.

Electrophysiological and light microscopical studies were made on the vestibular area of the dogfish hindbrain. Three vestibular nuclei were distinguished: the superior nucleus (VES), the magnocellularis nucleus (VEM), and the ventral nucleus (VEV). The distribution of field potentials evoked in the hindbrain by stimulation of nerve VIII confirms the location and extent of the vestibular nuclei. It also raises the possibility of a direct contralateral projection of vestibular nerve fibres. Unit studies confirm the interpretation of the field potentials and provide evidence of mono- and polysynaptic activation of vestibular nuclear neurons by vestibular afferents.


Immunohistochemical localization of enkephalins in median eminence and adenohypophysis.

Immunohistochemical staining for methionine-enkephalin and leucine-enkephalin were used to reveal an enkephalins-like substance in the median eminence and adenohypophysis of guinea pig and rat. Nerve endings were stained for enkephalins in the external layer of the median eminence. By successive staining of two different antigens, somatostatin fibers in the guinea pig were also shown to be enkephalin-immunoreactive. Staining of the adenohypophysis varied with the species and the antisera used. Intermediate lobe and corticomelanotrophs were stained moderately. In both species, and with all the antisera, thyrotrophs were shown to contain an immunoreactive substance. In the guinea pig, gonadotrophs were stained particularly by the anti-leucine-enkephalin antiserum used. The locus of enkephalin action on pituitary functions can be discussed: enkephalins possibly have an inhibiting action on somatostatin fibers, which agrees with the stimulating action of enkephalins on GH already known. Furthermore, enkephalins could have a direct action on pituitary glycoprotein proceducing cells, which would explain their inhibiting action demonstrated previously on LH, FSH and TSH.


Bile acids of a 3200-year-old Egyptian mummy.

The bile acids of the gall bladder and hepatic tissue of a 3200-year-old Egyptian mummy were isolated by thin-layer chromatography and identified by combined gas-liquid chromatrography and mass spectrometry. Except for complete deconjugation and extensive dehydration, the bile acids were found to correspond in their qualitative and quantitative composition to the gall bladder bile acids of modern man. The secondary bile acids constituted about 50% of the total and were identified as the normal bacterial oxidoreduction products of the primary bile acids and their dehydration products. In addition a series of unsaturated bile acids were identified, which corresponded to the dehydration products of cholic and chenodeoxycholic acids. It is suggested that both bile acid deconjugation and the limited oxidoreduction were probably brought about by the Clostridium organisms identified in the tissue. On the basis of the bile acid composition it is concluded that the ancient man metabolized cholesterol along the same pathways as modern man.


Degradation of bacterial lipopolysaccharide by the slime mould Physarum polycephalum.

A strain of the acellular slime mould Physarum polycephalum degraded lipopolysaccharides (LPS) from a variety of bacteria. The anticomplementary (AC) activity of LPS was greatly reduced, as was the content of lauric, myristic, and palmitic acids, and the ability to sensitize erythrocytes to agglutination by antibody. These results indicate that Physarum has enzymes which reduce the lipid A moiety of LPS. In contrast, 2-keto-3-deoxy-D-manno-actanoic acid (KDO), immunodominant sugars, and beta-hydroxymyristic acid were scarcely affected. Both supernates and plasmodial extracts of Physarum had LPS-degradative activity and were able to attack both purified LPS and LPS in killed bacteria.


Effect of cardiopulmonary bypass and hypothermia on pancreatic endocrine function and peripheral utilization of glucose.

Extracorporeal circulation has been reported to produce abnormalities of glucose, metabolism. Pancreatic endocrine function and peripheral glucose utilisation were studied in 11 nondiabetic patients who underwent myocardial revascularization. Nonpulsatile flow with hemodilution and moderate hypothermia to 28 degrees C were used in each case. Following the onset of cardiopulmonary bypass, serum glucose values rose rapidly to a mean of 972 mg/dl (54.0 mmol/l) and were associated with high circulating concentrations of insulin in the range of 216 microU/ml [1549.8 pmol/l]. High circulating concentrations for both insulin and glucose were maintained throughout the bypass period. These returned to normal postoperatively when the patient was in the recovery room. The results of this study indicate that both the pancreatic endocrine response and the peripheral utilization of glucose are impaired during cardiopulmonary bypass with hemodilution and moderate hypothermia to 28 degrees C.


Comparison of ampicillin with clindamycin plus gentamicin in the treatment of postpartum uterine infection.

A prospective randomized study of the treatment of postpartum endometritis was conducted with 43 patients. The bacterial origin of the infection was determined by uterine aspiration. Treatment was successful in 17 of the 19 patients receiving ampicillin (12 g/d) and in 21 of the 24 patients receiving clindamycin (2.4 g/d) plus gentamicin (5.1 mg/kg daily).


Clinical involvement of Aeromonas hydrophila.

Aeromonas hydrophila has for some time been regarded as an opportunistic pathogen in hosts with impaired local or general defence mechanisms. Infections in such individuals are generally severe. The organism is also being isolated with increasing frequency throughout the world from a variety of focal and systemic infections of varying severity in persons that are apparently immunologically normal. Most commonly it causes acute diarrheal disease by producing an enterotoxin. Thus the organism appears to have greater clinical significance that was hitherto suspected. The organism has been infrequently reported from humans in Canada, but its correct laboratory identification, together with increased awareness that it can contribute to illness, will undoubtedly lead to more reports of its isolation in Canada.


Mutagenicity of some N- and O-acyl derivatives of N-hydroxy-2-aminofluorene in V79 Chinese hamster cells.

Mutagenicity of 4 N- and O-acyl derivatives of N-hydroxy-2-aminofluorene (acyl: acetyl or myristoyl residue) was examined in V79 Chinese hamster cells in the absence of a metabolic activation system. N-Myristoyloxy-N-acetyl-2-aminofluorene (N-MyO-AAF) was toxic and weakly mutagenic, inducing 8-azaguanine-resistant (AZAr) mutants in V79 Chinese hamster cells in a concentration-dependent fashion; while N-acetoxy-N-myristoyl-2-aminofluorene (N-AcO-MyAF) and N-myristoyloxy-N-myristoyl-2-aminofluorene (N-MyO-MyAF) were neither cytotoxic nor mutagenic. Under the same conditions, N-acetoxy-N-acetyl-2-aminofluorene (N-AcO-AAF) was highly toxic and mutagenic. Neither of the 2 N-myristoyloxy derivatives was mutagenic in Salmonella typhimurium. These esters have been reported to produce local tumours at the site of their injection in rats, bo be electrophilic towards methionine, and to induce unscheduled DNA synthesis in cultured human fibroblasts. In view of the fact that some of the esters were mutagenic in neither S. typhimurium nor V79 Chinese hamster cells, our findings emphasize the need for multiple short-term tests in predicting potential carcinogenic activity of chemicals.


[Poisoning due to tricyclic antidepressants in children and adolescents].

During the last decade there has been a substantial increase in the number of poisonings due to tricyclic antidepressants in both children and adults. The main toxic manifestations are of anticholinergic origin, and the most frequent constitute the so-called central anticholinergic syndrome. Most of the deaths result from the cardiac complications. Three cases are presented that illustrate chiefly the toxic manifestations related to the central nervous system. The therapeutic management is reviewed in the light of the metabolism of the tricyclic antidepressants, their pharmacologic action and the mechanism of their toxic effects.


Maintenance of human skin on nude mice for studies of chemical carcinogenesis.

The feasibility of utilizing neonatal human foreskins grafted to congenitally athymic nude mice for carcinogenesis studies was explored. Human grafts could be maintained morphologically intact for at least as long as 27 weeks. Topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) induced hyperplasia in human skin. Systemic administration of urethane followed by twice weekly topical TPA applications induced no mouse skin tumors in ungrafted nude mice and a moderate number in grafted nude mice. Two benign squamous papillary lesions developed in the human graft sites receiving TPA. One of these was likely of human origin but definitive origin of the second was uncertain.


Distribution of LHRH in the rat and mouse brain with special reference to the tanycytes.

The distribution of luteinizing hormone-releasing hormone (LHRH) was studied in the rat and mouse brain by means of light and electron microscopic immunohistochemistry using the peroxidase-antiperoxidase method. An immunoreactive product to LHRH antiserum was found near the blood vessels of the vascular organ of the lamina terminalis. In the arcuate nucleus-median eminence region, an immunoreactive material occurred bilaterally in the hypothalamic tissue around the tuberoinfundibular sulci. Electron microscopy revealed that immunoreactive fibers observed light microscopically contain numerous granules 100--130 nm in diameter. No immunoreactive product was located in the tanycytes of the median eminence, the perikarya of hypothalamic neurons, and the parenchyma of several circumventricular organs (subfornical organ, subcommissural organ, pineal organ, area postrema).


Ultrastructural changes in neurohaemal tissue of the stick insect, Carausius morosus, induced by the ionophores Br-X-537 A and A-23187.

The antibiotic ionophores Br-X-537A and A-23187 alter the ultrastructure of neurohaemal tissue on the transverse nerve of the stick insect, Carausius morosus. Br-X-537A induces dramatic changes in the ultrastructural appearance of all three types of neurosecretory fibres present in the neurohaemal tissue. The neurosecretory granules become more electron-lucent and the mitochondria become more electron-opaque. The bounding membrane of the granules is frequently ruptured. A-23187, on the other hand, has no effect on two of the three types of fibres, but does produce an increase in the number of exocytotic profiles in the third. The two ionophores therefore have different effects on the same tissue. The results are discussed in the light of previous work with the use of these ionophores.


Metabolic-morphologic events in the integument of the Pacific hagfish (Eptatretus stoutii).

Light- and electron-microscopic autoradiography were used to obtain a coordinated metabolic-morphologic view of some of the events of cellular differentiation that occur across the epidermis of the Pacific hagfish (Eptatretus stoutii) and which enable this animal to secrete copious amounts of mucus. As judged by epidermal incorporation of [3H]-thymidine in vivo, about 98% of DNA replication is confined to the basal three layers of the total of 6--8 layers of cells. Small mucous cells (SMC), the most numerous of the three major cell types involved in mucigenesis, show in vitro and in vivo radioincorporation profiles of [3H]-L-lysine and [3H]-D-glucosamine which differ markedly from those of [3H]-L-fucose and [3H]-D-galactose. Time-course incorporation profiles (mean silver grains/cell and percentage of cells with at least one cluster of silver grains) of [3H]-L-lysine and [3H]-D-glucosamine not only reflected the metabolic activities of cell renewal and differentiation in basally-located cells but also the high mucigenic activity in cells near the epidermal surface. By contrast, [3H]-L-fucose and [3H]-D-galactose were mainly incorporated by the more mature SMC in juxtanuclear regions near Golgi complexes and newly formed secretory vesicles. The intensity of [3H]-fucose labeling appeared proportional to the intensity of histochemical staining of the apical cytoplasm. The prominent capsule, within SMC in basal and lateral regions, which arises from a tight intermingling of tonofilaments, appears to restrict secretory vesicles to apical regions while the cell progressively differentiates and migrates to the epidermal surface. The other mucigenic cell types, large mucous cells and thread cells, each show distinctive differentiation and radioincorporation patterns.


The relation between solid cell nests and C cells of the thyroid gland: an immunohistochemical and morphometric investigation.

Thyroid tissue of 300 routine autopsies was processed in a standardized manner. So-called solid cell nests (SCN) were found in 21 patients (7%). These cases were investigated carefully by serial step sectioning. In order to explore the correlation of SCN to the C-cell system, the sections were stained by silver impregnation and the immunoperoxidase method. Morphometric analyses revealed a significant increase in the density of C cells in the proximity of the SCN. With progressive distance from the SCN, the C-cell density decreased and reached normal values. In 30% of the cases argyrophilic and calcitonin-positive cells were found lying within the SCN. Occasionally, mixed follicles could be discerned: These were lined on the one side by a multilayered squamous epithelium, on the other side by normal monolayered cubic follicular epithelium, and contained a peculiar granular material. In one case, SCN were associated with intrathyroid portions of the parathyroids and adult adipose tissue, in a second case with adipose tissue only. Most probably SCN are vestiges of the ultimobranchial body and should be interpreted as such, despite the fact that other authors have expressed different views. The lack of disturbances in the calcium metabolism of the patients and the absence of medullary carcinoma in their family histories led us to interpret locally confined C-cell hyperplasia not as reactive nor premalignant, but rather as normal.


Single-dose therapy of falciparum malaria with mefloquine or pyrimethamine-sulfadoxine.

A single oral dose (1.5 g) of mefloquine hydrochloride cured all of 37 patients with falciparum malaria, and a single dose of pyrimethamine (75 mg) plus sulfadoxine (1.5 g) cured 34 of 38 patients. The rates at which parasitaemia and fever abated were similar for the two regimens but mefloquine was associated with a higher incidence of gastrointestinal side effects.


Cardiotoxic effects of antitumor agents.

Cardiotoxic effects related to treatment with some antitumor agents (chiefly anthracycline antibiotics, cylophosphamide, corticosteroids, 5-fluorouracil, and radiation therapy), their association, and contemporaneous administration of other (potentially) cardiotoxic drugs are reviewed. Experimental models, clinical findings, and diagnostic methods are briefly described. Pathogenetic factors and interactions of antitumor drugs with biomembranes, DNA, and immune reactions are discussed.


Sequential combination chemotherapy in advanced breast cancer.

The results of a prospective controlled study with alternating cycles of two effective non-cross resistant combinations in advanced breast cancer are reported. The two combinations consisted of adriamycin plus vincristine (AV) and cyclophosphamide, methotrexate and fluorouracil (CMF). The study was carried out with the main intent to obtain a higher incidence and a longer duration of response compared to that obtained with either combination alone. A total of 110 evaluable patients (55 for each treatment group) not previously treated with chemotherapy were randomly allocated to receive either Therapy A (2 AV followed by 2 CMF) or Therapy B (2 CMF followed by 2 AV). Complete plus partial response (53% vs 60%) as well as duration of remission (11 vs 12 months) were similar in both treatment groups. At the time of present analysis, 20 patients died from cancer (Therapy A: 9; Therapy B: 11) and in 9 of them death occurred during the first 12 months. The administration of sequential combinations was no more toxic than the administration of either combination alone.


Combined chemotherapy-radiotherapy approach in locally advanced (T3b-T4) breast cancer.

Combined treatment modality was applied in 110 consecutive women with primary inoperable (T3b-T4) Breast cancer. Treatment was started with four cycles of adriamycin plus vincristine (AV). This was followed in responders by high-energy radiotherapy (RT). At the end of combined therapy, patients in complete remission (CR) were randomized to either no further treatment or six more cycles of chemotherapy. AV induced objective response in 89% of patients (complete 15.5%, partial 54.5%, improvement 19%). At the end of RT, 81% of 98 (82.7%) patients responding to AV were classified in CR. The median duration of CR was 15 months. The median free interval was statistically prolonged by additional chemotherapy. The three-year survival was 52.8%. Altogether, present findings indicate that combined treatment modality has improved the three-year survival compared to the previous series treated with radiotherapy alone. However, to achieve a satisfactory control of T3b-T4 breast cancer a more aggressive and prolonged treatment is required.


Pharmacokinetic and clinical studies of 24-h infusions of high-dose methotrexate.

Cytocidal activity of a drug is dependent on both drug dosage and duration of exposure. In contrast to the 'conventional" 6-h infusion and in an attempto to improve its efficacy, the high-dose methotrexate therapeutic regimen was given over a 24-h period with 10% of the dose administered in the first hour. Citrovorum factor was initiated at hour 24 and continued for 72 h. Treatment was administered every 2-3 weeks. 57 infusions were performed in twelve patients aged 7-20 years (six with osteogenic sarcoma and six with acute lymphoblastic leukemia). Determinations of serum methotrexate levels revealed that the levels were dependent on the dose. Levels assayed at 24 h revealed the following results: 4.4 +/- 1.4 x 10(-5) molar with 4.5 g/m(2), 2.04 +/- 0.34 x 10(-4) molar with 7.5 g/m(2) and 4.59 +/- 0.80 x 10(-4) molar with 12.5 g/m(2). Major toxicity was myelosuppression in 12 of 57 patients. There were no responses. The study demonstrates that 24-h infusions of high-dose methotrexate can be tolerated every 2-3 weeks in patients without bone marrow involvement and levels of at least 10(-4) molar can be maintained during the infusion.


Initial clinical experience with a simultaneous combination of 2,4-diamino-5(3',4'-dichlorophenyl)-6-methylpyrimidine (DDMP) with folinic acid.

DDMP, a diaminopyrimidine folate antagonist, was given to 26 tumor patients in a dosage of 50 mg/m2 per week orally, simultaneously with 3 mg CF i.m. or i.v. The CF dose was increased to 30 mg in patients showing evidence of toxicity, and withdrawn in the absence of toxicity. The dose-limiting toxicity was seen in myelosuppression, particularly thrombopenia and skin rashes. At the 3 mg CF level, 18 out of 26 patients developed toxicity. No toxicity was seen at the 30 mg CF level in 11 patients. After cessation of CF, toxicity occurred in five out of seven patients. After the onset of toxicity, CF was added as a delayed rescue, in a dosage of 15 mg every 8 h or 30-60 mg daily. One patient died of sepsis with agranulocytosis. All other patients recovered from myelosuppression within 1 or 2 weeks. Objective responses were observed in seven patients, four of the ten with epidermoid cancer of the head and neck, two out of eight with epidermoid cancer of the lung, and one out of three with melanoma.


Combination chemotherapy for advanced non-Hodgkin's lymphoma of unfavourable histology.

Thirty previously untreated adults with diffuse histiocytic and diffuse undifferentiated lymphoma were treated with a combination of adriamycin, vincristine, prednisolone, and L-asparaginase. Complete remission was achieved in 11 out of 12 cases with stage III and 7 out of 18 cases with stage IV disease (P less than 0.005). Bone marrow infiltration, clinical central nervous system involvement, and massive intra-abdominal disease all influenced the prognosis adversely. Complete remission was followed by cranial irradiation and intrathecal methotrexate, and maintained with weekly cyclophosphamide and methotrexate and daily 6-mercaptopurine. The duration of remission was significantly longer for patients with stage III disease (the median of which has not been reached), than for patients with stage IV disease (P = 0.007). Survival was significantly longer for patients in whom complete remission was achieved than for those in whom it was not (P = 0.001), and also for patients with stage III than for those with stage IV disease (P = 0.02).


Prognosis and treatment of acute lymphoblastic leukemia. Study of 650 patients.

The complete hematological remission (CHR) rate, duration of remission and survival were studied in relation to age, peripheral blast cell (PBC) count, presence or absence of tumor masses, cytological type, and treatment in 650 patients with acute lymphoblastic leukemia. Prognostic factors were considered separately and divided into prognostic classes. Age and PCB count correlated with both the rate and the duration of CHR. This correlation was still observed for more recent treatment schedules though it appears to be becoming progressively less significant. Meningeal relapses were more common in patients less than 1 year old and in those with a high PCB count. It is suggested that stratification of patients according to such factors as age, PCB count, presence or absence of tumor, and cytological type might be necessary for the design of new treatment protocols and for the evaluation of their results.


The fluoropyrimidines: biochemical mechanisms and design of clinical trials.

Our understanding of the biochemical events of fluoropyrimidine-induced cytotoxicity remains incomplete. However, we have a good perception of the activation and degradation pathways of these agents. Additionally, from studies performed in vitro we are gaining a new appreciation of the interactions between methotrexate and the fluoropyrimidines. These studies suggest that the common clinical practice of simultaneously administering methotrexate and 5-fluorouracil may be disadvantageous. Several simple scheduling modifications of combination therapies with these two drugs could lead to improved clinical efficacy and deserve further investigation.


Hepatic estrogen and progesterone receptors in an estrogen-associated hepatic neoplasm.

A patient with a benign hepatic neoplasm developing after treatment with estrogenic hormones is described. After excision, the neoplastic tissue was analyzed for the presence of cytosol estrogen and progesterone binding proteins. The neoplasm was classified as focal nodular hyperplasia of the liver and was demonstrated to contain high-affinity cytosol estrogen and progesterone hormone receptors. The estrogen-binding affinity of the neoplasm was three times greater than that of normal liver. Further investigation of cytosol hormone receptors in estrogen associated hepatic neoplasms will be required to define the role of these binding proteins in the possible etiology of certain liver tumors.


Clinical, toxicological, and pharmacological studies of combination chemotherapy of adenocarcinoma with adriamycin and Baker's antifolate.

Ten patients with disseminated adenocarcinoma were treated with combination chemotherapy employing Adriamycin and Baker's Antifolate (BAF). There were seven patients with lung adenocarcinoma, two of whom achieved partial remission while the remaining five had their disease stabilized. Drug toxicity to the bone marrow, gastrointestinal mucosa, and skin was dose-limiting and was greater than the known toxicities of the individual drugs. Pharmacological studies of both drugs were performed on five patients to determine whether abnormal pharmacokinetics could explain this collateral toxicity. Adriamycin plasma concentrations and disappearance seemed to be unaffected by BAF. However, BAF levels were prolonged, apparently due to an Adriamycin effect on the plasma elimination of BAF, resulting in a prolonged exposure of sensitive tissues and organs to BAF. Consequently, when BAF and Adriamycin are used in combination, appropriate dose and schedule changes must be made to avoid any potentially serious side effects.