The role of prostaglandins in inflammation. Our work suggests that aspirin-like drugs suppress inflammatory oedema not by reducing vessel wall permeability but by inhibiting the production of vasodilator mediators (prostaglandins), which results in a reduction in plasma exudation. Thus aspirin-like drugs appear to inhibit inflammatory swelling in the same manner as the traditional method of cooling with an ice-pack--by constricting the dilated blood vessels.


[Effects of clomiphene and estrogens on circulating gonadotropins, testosterone, androstenedione, in old menopausal women (author's transl)]. The threshold of sensitivity of the gonadostat has been tested in 20 old menopausal women by clomiphene (50 or 200 mg/day for 5 days) and/or low doses of ethinyl oestradiol (EE2) (10 or 20 microgram/day). Clomiphene did not increase nor decreased serum levels of LH-FSH and testosterone (T) but increased significantly androstenedione (A) levels. Even at the lower dosage used, EE2 decreased drastically the levels of LH but less completely that of FSH. Clomiphene breaks off partially the oestrogen's blockade on FSH but not on LH. No modification was observed for T and A even after 30 days of estrogen therapy. This data shows the peculiar sensitivity of the gonadostat in advanced menopaused women. It also suggests that the gonadostat exhibits a low threshold of sensitivity analogous to that observed in late prepubertal period. Moreover, the different behaviour of LH and FSH in response to the negative feedback of oestrogens supports that an ovarian factor, distinct from estrogens and missing during menopause plays a role in the regulation of FSH.


[Effect of LH-RH infusion on plasmatic testosterone level in normal man and in pathologic cases (author's transl)]. LH-RH INFUSION with 250 microgram in eight hours increases testosterone level in normal man by 40% (alpha less than 0,01). Results in hypogonadic patients and in pituitary tumours are presented. No correlation is found between LH-RH responses and pituitary enlargement.


[Plasma LH response to LHRH in hypothyroid and thyroxin-treated rats (author's transl)]. Plasma LH response after intravenous injection of synthetic LHRH (50 ng) was studied in male rats (normal, after thyroidectomy, after treatment by dl thyroxin 50 microgram/a day, 10 days). LH response was significantly elevated in hypothyroid animals although it was not influenced by thyroxin injections. Prolonged plasma LH half-life in hypothyroid rats can account in this result.


Biology of drowning.

Biology of drowning. The near-drowning victim must be treated immediately for ventilatory insufficiency, hypoxia, and the resulting acidosis. The cause and pathophysiologic changes of pulmonary insufficiency vary, depending on the tpe and volume of fluid aspirated. Success or failure of the overall resuscitative effort frequently depends on the adequacy of prompt emergency resuscitation and on effective intensive pulmonary care. Each patient should be evaluated and treated individually, since abnormalities of multiple organ systems can occur, their degree and form varying considerably from patient to patient (28).


The prenatal diagnosis of genetic disorders. Prenatal diagnosis has proven highly effective in assessing the status of fetuses at risk of all cytogenetic and of several biochemical and structural disorders with genetic etiologies. The original methodology, based on the cytogenetic and biochemical analysis of cultured amniotic fluid cells, has now been complemented by a wide variety of new techniques. These include several methods for fetal visualization (sonography, fetoscopy, x ray), sampling of fetal blood, and analysis of very small quantities of material. Additional approaches, based on these and other technologies, are likely to permit the prenatal diagnosis of an ever increasing number of genetic disorders. At the same time, the number of pregnancies monitored will increase as greater resources become available and as screening programs identify couples at risk of having genetically abnormal children prior to the birth of an affected child. Prenatal diagnosis is already a powerful means of preventing the birth of individuals with significant genetic defects, thereby sparing both individuals and society from the burdens that such disorders produce. In the future, it is likely to be even more effective.


E. coli meningitis: K1 antigen and virulence. It is clear from the preceding material that bacterial infection is a significant threat to the newborn infant. The most common gram-negative organism causing meningitis in the neonate is E. coli, and the invasive capacity of this organism is correlated with its polysaccharide antigen, K1. Careful studies of supportive care and antimicrobial therapy of these infections are continuing. If antibodies could be generated which protect the infant, it would be theoretically possible to guard against infasive disease by conferring antibody positivity to the mother and hence to the infant. Investigations along these lines are continuing.


Prostaglandins and hypercalcemic states. There is considerable circumstantial evidence to support the concept that prostaglandins of the E series can mediate hypercalcemia in neoplastic disease. However, other metabolites of prostaglandin endoperoxides could contribute to the hypercalcemia and the site of the production of prostaglandins is not established. Further analysis of prostaglandin endoperoxide metabolism in tumor and bone tissue and in the circulation will clarify the specific mechanism. The development of quantitative analysis of prostaglandin metabolites had made it possible to identify prostaglandin-dependent hypercalcemia. Therapeutic application of the inhibitors of prostaglandin cyclo-oxygenase in the treatment of patients with prostaglandin-mediated hypercalcemia is feasible, but its general usefulness remains to be evaluated. The development of antagonists to the action of prostaglandin at the affected end organ site, presumably bone, would represent an important therapeutic advance.


Gastrointestinal hormones.

Gastrointestinal hormones. Much has been learned about the nature, localization, and biological actions of a wide assortment of peptides present in the gastrointestinal tract. Measurement of some of these peptides has been made possible by development of immunoassay techniques. In some instances, ample information has been gained about the roles of these gastrointestinal peptides in physiological events and in pathophysiological states. It is evident, however, that our knowledge of the true regulatory roles of these peptides and their participation and significance is in its earliest stages of development.


Slow-channel depolarization: mechanism and control of arrhythmias. The secondary inward current that flows through the slow channel is probably carried primarily by calcium ions. This current is responsible, in part, for the plateau phase of the cardiac action potential. Inward calcium current through the slow channel is essential to excitation-contraction coupling, and enhancement of this current exerts a positive inotropic effect. Transmembrane electrical potentials generated as a consequence of this slow inward current, so-called slow-channel depolarizations or slow responses, have been useful models in recent studies of cardiac autonomic interactions. The significance of the slow response in ventricular arrhythmias remains controversial and awaits more definitive experiments. The role of slow-channel depolarization as a basis for SA and AV nodal electrical activity is suggested by the electrophysiological similarities between these tissues and slow responses produced in vitro. This hypothesis is supported by the responses of these nodal tissues to interventions that augment of impede the slow inward current. More direct evidence in support of this notion may not be obtainable in the near future, since the critical voltage-clamp studies of ionic currents in SA and AV nodes are not technically feasible at this time.


Genetic transmission of schizophrenia.

Genetic transmission of schizophrenia. There is convincing evidence form consanguinity, twin, and especially adoption studies that schizophrenia has a genetic component. There is also evidence from studies of MZ twins for an environmental component. It is not known whether the relevant environmental factors are prenatal or postnatal, psychosocial or physical; the presence of schizophrenia in the rearing family does not seem to be etiologically significant. It is likely that schizophrenia, especially if defined by symptoms alone, is etiologically heterogeneous. Study of pedigrees with several affected individuals is a useful approach to resolving this heterogeneity. The relevant genes may not code directly for schizophrenia, but for risk factors that predispose to the illness under particular environmental conditions. Careful methodology is needed to distinguish cause from effect of studying psychosocial factors. Genetic counseling is possible on the basis of empirical risk figures, but clarification of biological risk factors and environmental preciptants will make possible a much more rational approach to counseling and prevention.


Left ventricular stiffness.

Left ventricular stiffness. Left ventricular stiffness is defined by the relationship between pressure and volume and can be altered by a variety of disorders. In disorders with high VLVED, such as mitral regurgitation, protection of pulmonary capillaries from high pressure is provided by a PV shift. In contrast, increased stiffness is produced by ventricular hypertrophy or ischemic heart disease, which puts the patient at increased risk for pulmonary capillary hypertension. Changing the ventricular PV relationship by therapy is an exciting prospect.


Cardiac assist devices.

Cardiac assist devices. We reviewed current concepts and techniques of cardiac assistance, including orthotopic and heterotopic cardiac allografting. Whereas intraaortic balloon counterpulsation has had the greatest clinical use, other techniques are now becoming available, including the implantable abdominal left ventricular assistance device, and much effort is being expended on the development of artificial hearts and their power sources. Despite the present technical shortcomings, exciting advances have occurred in the clinical management of intractable acute or chronic ventricular failure and cardiogenic shock since the introduction of circulatory assistance in man. The continued development and implementation of these techniques will help reduce the still unacceptably high mortality rate in this group of patients.


The XYY genotype.

The XYY genotype. The epidemiological data pertaining to the XYY genotype suggest that there is a three- to fourfold overrepresentation of XYY individuals in mental and penal settings and a twentyfold overrepresentation of mental-penal (special security) settings. The reasons behind the risk for behavioral disability are not known at this time. Tallness and ondulocystic acne are reported frequently to be associated with the genotype. Since much of the available information about the XYY sex chromosome complement is biased, more data is required before definitive statements can be made about the personality characteristics or intelligence of the vast majority of XYY men not appearing in social settings oriented towards behavioral deviancy.


Recent membrane research and its implications for clinical medicine. Our understanding of the molecular organization of even the simplest mammalian cell membrane--that of the red blood cell--is still incomplete, yet we are reasonably sure of where and how the major components are arranged. The so-called integral membrane proteins are the most likely candidates to serve as receptors and transport sites of surface membranes, and these may be organized as macromolecular complexes with parts of their polypeptides in contact with both sides of the bilayer. These complexes may be either mobile or fixed, and if the latter, perhaps by specific interactions with other membrane proteins. The exposed segments of such glycoproteins could have recognition sites that confer cell, tissue, and/or species specificity created by oligosaccharides attached to the peptide backbone, or by specific amino acid sequences, or a combination of both.


Dialysis encephalopathy syndrome.

Dialysis encephalopathy syndrome. Increasing evidence has been presented with suggests that the dialysis associated encephalopathy syndrome is a distinct syndrome characterized by typically clinical and electroencephalographic features. This syndrome is widespread in  distribution and a major cause of death in chronic dialysis patients. Although the specific etiology of this syndrome has not been clearly defined, aluminum intoxication appears to be the most likely possibility at this time.


The generation and conduction of activity in smooth muscle. Smooth muscle, especially gastrointestinal smooth muscle, spontaneously generates oscillatory electrical activity that can control contractions in time and space by altering excitability. The origin and ionic mechanisms underlying these electrical control activities are still controversial, but they behave as coupled relaxation oscillators and they control muscle excitability. Normally, contractions are produced by the addition, during the depolarized phase of the oscillations, of further depolarization by acetylcholine or other means. Pharmacologists who wish to study drug actions on such muscles must be aware of the possibility that drug effects may be determined by these oscillations and may influence contractions by affecting these oscillations as well as by releasing, mimicking, or inhibiting the effects of nerve mediators or by affecting excitation-contraction coupling. Also the use of simplified organ bath preparations may eliminate or alter these control potentials so that results in vitro may not apply in vivo.


Biochemical pharmacology of the intestinal flora. Animal and bacteriological techniques have been developed for clarifying the role of the flora in the metabolism of drugs and other exogenous compounds. In general the flora tends to catalyze reductive and hydrolytic reactions, some of which reverse the detoxification reactions normally occurring in the liver. These reactions and others have been implicated in the pharamacological or toxicological action of exogenous compounds. Only in a few instances, however, have practical consequences of these reactions been documented. The major challenge at present is to develop methods capable of further defining the implications of reactions due to the flora.


Biliary excretion of drugs and other xenobiotics. A vast number and variety of xenobiotics appear in the bile. For some this is a final excretory process, for others it is merely one step in the active enterohepatic circulation. For still others it may be a vital step in a toxicologic or carcinogenic process. During the past ten years there has been a steady accumulation of observations in the literature bearing on biliary excretion mechanisms. Phenomena such as molecular weight thresholds and other aspects of species variation as well as response to inducing agents are described in many papers and much speculation is available as to their meaning. The clinical significance of this work is still somewhat dependent upon results obtained from lower animals, although studies occasionally appear on patients who have temporary bile drainage subsequent to surgery. It is important that efforts persist in obtaining data in humans since extrapolation from lower animals in the area of drug disposition is often precarious. The basic physiological and biochemical mechanism governing the biliary fate of drugs and other xenobiotics have yet to be elucidated fully. Perhaps the use of drugs and other pharmacological tools will hasten progress toward this goal.


Patterns of resistance and therapeutic synergism among alkylating agents. Alkylating anticancer drugs are varied in chemical structure, alkylating moieties, and likely mechanisms of cytotoxic activity for vital normal cells and sensitive tumor cells. This has been objectively documented by numerous examples illustrating: (1) different in vitro and in vivo reaction products; (2) greater than additive, additive, and less than additive cytotoxicity of drug combinations for vital normal cells in the mouse; (3) readily reproducible and often marked therapeutic synergism between a variety of 2-drug combinations of alkylating agents against a wide variety of histologic types of murine tumors, and (4) observed resistance and cross-resistance of a variety of murine tumors, selected for resistance to specific alkylating agents, compatible with recognized chemical and functional differences between these drugs. The most important observations on resistance and cross-resistance reported are: (a) L1210 cells selected for complete resistance to cyclophosphamide (CPA) retain full sensitivity to selected nitrosoureas (BCNU, CCNU, MeCCNU), chlorozotocin), dianhydrogalactitol, and cis-DDPt, while retaining marked but somewhat reduced sensitivity to L-PAM, piperazinedione, and thioTEPA. (B) L1210 cells selected for resistance to BCNU retain full sensitivity to CPA, L-PAM, and dianhydrogalactitol. They show complete cross-resistance to BIC and variable cross-resistance to other selected nitrosoureas and piperazinedione. (c) L1210/L-PAM has incomplete but marked resistance to L-PAM. It is similar to the parent drug-sensitive line (L1210/0) in response to BCNU, CCNU, MeCCNU, and BIC. It is variably (usually moderately) cross-resistant to CPA, chlorozotocin, dianhydrogalactitol, and thioTEPA, but is completely cross-resistant to cis-DDPt. These resistance and cross-resistance patterns, which are consistent with most other biological and chemical principles established with these alkylating agents, may be useful in selecting alkylating drug combinations for inclusion in chemotherapy protocols in man which, on the basis of diverse observations in animal tumor systems, appear to be clearly indicated.


Yeast mutants with distorted cell membranes as a detection system for antitumor antibiotics. Yeast mutants with distorted cell membranes, which are selectively inhibited by anticancer antibiotics and are not affected by antibacterial antibiotics, could be of considerable interest as test organisms. They could be used for the isolation of active antitumor substances from complex mixtures of natural compounds.


Mechanism of action and mechanism of resistance to antineoplastic agents that bind to DNA. The interaction with DNA of acridines, actinomycins, anthracylines, and bleomycin causes the inactivation of the DNA template in transcription and replication. The lethal effect is probably related to an irreversible damage to the structure of DNA. The acquisition of resistance is a multistep process in which changes in the uptake of the drug, which are related to basic processes such as ion transport, energy production, and regulation of macromolecular synthesis, have crucial importance.


Mechanisms of selectivity of intercalating agents. Intercalation, insertion of a conjugated polycyclic aromatic ligand between stacked bases of helical DNA, is a common means of binding for a number of agents. This mode of binding generally accounts directly for a number of effects which are broadly uniform for most cells under appropriate conditions. Intercalating agents bind to plasma and intracellular membranes and interact with phospholipids to varying degrees. Biotransformation and activation may also occur at the membrane sites. Besides effects attributable to DNA binding, many of the therapeutic and cytotoxic effects that are characteristic of these agents may be a function of binding and activation in membranes, appearing to be independent of intercalation in some cases but also enhancing DNA-related actions in others. The range of differential effects of intercalating drugs stemming from binding at DNA and membranal sites seems sufficiently diverse to explain selectivity which is expressed in cell- and organ-specific changes, individual and species variability, and numerous drug actions apparently unrelated to intercalation alone.


Model systems for cardiotoxic effects of anthracyclines. The use of anthracycline antibiotics in cancer chemotherapy is limited by their cardiotoxic qualities. For the evaluation of new derivatives animal model systems are required. Cardiomyopathy can be induced in rabbits and monkeys, but these models are too expensive for screening purposes. In rats, anthracycline antibiotics cause morphologic lesions of the heart muscle, but these are more difficult to demonstrate than in larger animals. However, significant changes of the heart function (electrocardiogram (ECG), cardiac output), the function of heart mitochondria (inhibition of electron transfer, uncoupling of oxidative phosphorylation and inhibition of Ca translocation) occur in a dose-related manner. Intraventricular conduction defect demonstrated in the ECG is one of the earliest and most consistent expressions of the cardiotoxic properties of anthracyclines. It was therefore used as primary screening parameter. The results of the screening of over 50 new anthracyclines has shown that the cardiotoxic properties vary considerably and that they are not closely related to the chemotherapeutic and the hematotoxic properties. Interesting structure-activity relationships were observed in a series of rubidazone derivatives substituted at the benzhydrazone part of the molecule.


Some examples of interactions between drugs in cancer chemotherapy. Drug combinations in cancer treatment are widely utilized because they frequently result in better therapeutic activity than the single treatments. The mechanism(s) by which this can be achieved may reside in an enhanced chemotherapeutic effect or in reduced toxicity, it being difficult to dissociate the two aspects. To underline this difficulty, experimental studies will be reported. A first example illustrates the interaction between phenobarbital and cyclophosphamide. Depending on the schedule of administration, different effects can be obtained. These effects cannot always be explained by pharmacokinetic data. A second example deals with the combination of anthracycline antibiotics (daunomycin and adriamycin) with immunostimulant treatment (C. parvum). Both in vitro and in vivo adriamycin was less toxic than daunomycin for macrophages. As predicted on the basis of this finding, adriamycin resulted in a synergistic antitumoral effect when combined with macrophage activators.


ARA-C analogs.

ARA-C analogs. Ara-C, a phase-specific antitumor agent, is rapidly deactivated by the enzyme cytidine deaminase. A prolongation of the biological activity of ara-C can be achieved either by the concomitant use of a cytidine deaminase inhibitor or by the development of ara-C derivatives with increased resistance to deamination and a longer half-life in serum. Among such derivatives are cyclocytidine (cyclo-C), anhydro-ara-5-fluorocytidine (AAFC) and the N4-acyl-derivatives. AAFC has been recently shown to be active in human leukemias and in solid tumors of the digestive tract. The tolerance to AAFC is sufficient for clinical use, and AAFC does not produce parotid pains and hypotension, characteristic side effects of cyclo-C. The main toxicity consists of myelodepression, nausea and vomiting. The schedule dependence of AAFC is far less pronounced than for ara-C, so that a weekly application by rapid i.v. injection of 30-40 mg/kg (1,200-1,500 mg/m2) reaches the level of activity with acceptable toxicity. AAFC seems to be as active as ara-C in acute leukemias and is probably active too in malignant lymphomas. In a large phase II trial of the EORTC on selected solid tumor types, AAFC showed a significant activity in GI tract adenocarcinomas with 2 responses/3 evaluable in pancreas, 7/14 in stomach and 2/32 in colorectal tumors (4/30). Hints of activity were also detected in breast cancer (1/17) and anaplastic small cell carcinoma of the lung (1/9). No responses were obtained in 27 patients with epidermoid carcinoma of the lung. These results confirm that ara-C, or newer ara-C analogs, are potentially active in various solid tumor types, and suggest that an extensive further clinical study of such new derivatives is warranted.


Platinum complexes in cancer chemotherapy. Cis-diamminedichloroplatinum (DDP) leads the series of platinum coordination complexes and shows definite and striking efficacy against germinal tumors of the testis. Results are also promising in epithelial malignancies including carcinoma of the ovary, bladder, prostate, cervix, and carcinomas of head and neck origin. Toxicities include nephrotoxicity, ototoxicity, and mild to moderate myelosuppression; severe nausea and vomiting have occurred in all schedules tested. After several years of limited clinical investigation, interest in DDP has been renewed by: (a) recent discovery that induced diuresis circumvents the nephrotoxicity seen in earlier trials; (b) subsequent definition of safer larger doses than previous ones; (c) better understanding of pharmacology, and (d) the expectation of synergistic effects with several other anticancer agents. Extensive future use of DDP may be predicted in the treatment of cancer patients although its clinical potential remains to be investigated in a number of tumor types. Major ongoing efforts also include studies on the mechanism of action and pharmacologic properties of DDP, and development of other platinum compounds with improved therapeutic indices.


[Ampicillin concentration in the blood when administered by jet injection and needle-syringe methods]. The studies were carried out on 50 persons. Ampicillin was administered with the help of a jet injector B1-2 and needle syringe in doses of 250 or 500  and 500 mg respectively. When the drug was administered by infusion, its maximum blood levels were achieved earlier than after needle-syringe administration of the drug and were higher (22.83+/-4.10 and 6.3+/-0.09 gamma/ml respectively). Even when ampicillin was administered with the help of the injector in a dose of 250 mg its blood levels were much higher than those after needle-syringe administration in a dose of 500 mg. After jet infusion the prolongation of the drug retention time in the blood at therapeutical levels was observed as compared to the needle-syringe administration.


[Effect of amigluracil and levorin on membrane permeability and protein synthesis in Candida albicans protoplasts]. It was shown that amigluracyl, a water soluble derivative of methacyl which decreased the nephrotoxic effect of polyens activated the membrane permeability in Candida albicans for a mixture of 14C-amino acids but had no significant effect on protein synthesis in this microorganism. The level of inhibition of the membrane permeability in C. albicans for the amino acids and protein synthesis in the fungus by levorin did not practically depend on the presence of amigluracyl in the incubation medium. The minimum levorin concentration inhibiting the growth of Candida albicans in the presence or absence of levorin was 0.039 gamma/ml. Therefore, amigluracyl may be used in combination with polyenic antibiotics for the treatment of mycoses.


Netilmicin: clinical efficacy, tolerance, and toxicity. Netilmicin, a new aminoglycoside antibiotic, has increased in vitro bactericidal activity against many strains of Enterobacteriaceae as compared to other aminoglycosides. It is a poor substrate for some of the common gentamicin-inactivating enzymes, and it has minimal toxicity in experimental animals. In 27 hospitalized patients, clinical cure was achieved in all, and the initial infecting organism persisted in only one. Therapeutic serum and urine levels were easily obtained in most patients. No ototoxicity was observed in two patients whose treatment required inordinately high serum levels and in whom other risk factors were present. Ototoxicity in 1 of 21 patients studied was unilateral, partially reversible, and not associated with high serum levels. Although nephrotoxicity occurred in 4 of 25 patients (16%), other host factors could have accounted for the toxicity in two patients. A new observation, not noted with other aminoglycoside antibiotics, was the elevation of serum alkaline phosphatase in 43% of the patients studied.


Outbreak of multiply drug-resistant Proteus mirabilis originating in a surgical intensive care unit: in vitro susceptibility pattern. A multiply drug-resistant strain of Proteus mirabilis was isolated from 14 patients on a surgical service. Antimicrobial susceptibility studies demonstrated that the organism was highly resistant to numerous antibiotics, including gentamicin, tobramycin, and sisomicin. The organism was susceptible in vitro to amikacin but had low-level resistance to netilmicin. In vitro susceptibility studies with combinations of cephalothin with netilmicin and trimethoprim with sulfamethoxazole showed these drugs to be synergistic. Other drug combinations failed to act synergistically.


Gentamicin use and Pseudomonas and Serratia resistance: effect of a surgical prophylaxis regimen. An outbreak of prosthetic valve endocarditis due to methicillin-resistant Staphylococcus epidermidis prompted a change in antimicrobial prophylaxis for open heart surgery in a general hospital from a regimen of aqueous penicillin G, methicillin, and kanamycin to a 5-day regimen of cefazolin and gentamicin. As a result, total gentamicin use in the hospital more than doubled. Increased resistance of pseudomonas and serratia isolates paralleled the increased total use of gentamicin. For pseudomonas species, the incidence of gentamicin resistance increased from 3 to 15%; for serratia species, from 8 to 88%; and for the total of both organisms, from 4 to 28%. Resistance decreased rapidly after removal of gentamicin from the prophylaxis regimen. Review of serratia isolates from the urinary tract showed that gentamicin resistance was associated with prior antibiotic therapy, especially with gentamicin, care on the surgical services, especially the surgical intensive care unit, and presence of indwelling bladder catheters. Gentamicin use in a 5-day antimicrobial prophylaxis regimen for open heart surgery can represent a large proportion of the total hospital use of that antibiotic, with potential adverse effects on hospital flora.


Reevaluation of the mode of action of streptolydigin in Escherichia coli: induction of transcription termination in vivo. Growth of the permeable strain AS19 of Escherichia coli B is more sensitive to the antibiotic streptolydigin than is in vitro ribonucleic acid (RNA) synthesis. The in vivo chain elongation rates of lacZ messenger RNA and ribosomal RNA are not affected at 1.5 x 10(-6) M, a concentration that reduces the growth rate threefold. The synthesis of large proteins is inhibited preferentially, and a considerable fraction of the polypeptides synthesized is unstable. The synthesis of complete beta-galactosidase is inhibited relative to the synthesis of short, unstable polypeptides, which include the first 60 to 70 amino acids of beta-galactosidase. The expression of the following polycistronic transcription units is strongly biased against promoter-distal genes: trp, deo, rpoBC, and rrn. The extent of polarity is proportional to the distance transcribed and to the streptolydigin concentration. Streptolydigin appears to destabilize active transcription complexes irreversibly irrespective of the type of transcript (messenger RNA, ribosomal RNA) and of transcription intensity. We suggest that streptolydigin leads to premature termination of transcription, resulting in release of incomplete transcripts and, thus, a decrease in overall messenger RNA concentration, which becomes limiting for protein synthesis, i.e., for growth.


Prospective comparison of cefoxitin and cefazolin in infections caused by aerobic bacteria. Intravenous cefazolin and cefoxitin were compared in a prospective randomized trial in infections where the suspected pathogen was expected to be susceptible to both antibiotics. In the cefazolin group (12 patients) the diagnosis was pneumonia in 4, including 2 with pneumococcal bacteremia, soft tissue infection in 5, Staphylococcus aureus bacteremia in 1, acute pyelonephritis in 1, and disseminated gonococcal infection in 1. In the cefoxitin group (10 patients) the diagnosis was pneumonia in 4, including 2 with pneumococcal bacteremia, soft tissue infection in 4, acute pyelonephritis in 1, and disseminated gonococcal infection in 1. In the cefazolin group receiving an evaluable course of therapy, a good clinical response was seen in 10 of 11 patients, and a bacteriological response was seen in 5 of 7. Cefazolin failed to eradicate S. aureus bacteremia in 1 patient and S. aureus in a skin ulcer of another patient. All 10 cefoxitin patients had good clinical and bacteriological responses, but in 1 patient S. aureus colonization of a postoperative wound recurred after discontinuation of the drug. Side effects in both groups included skin rash, phlebitis, and elevation of the serum alkaline phosphatase. Both cefoxitin and cefazolin appeared effective in infections caused by susceptible aerobic pathogens with the possible exception of S. aureus, although all 11 strains of S. aureus isolated in this study were susceptible in vitro to both antibiotics. Cefoxitin appeared to be equivalent to cefazolin in efficacy and occurrence of side effects.


Susceptibility of Escherichia coli to bactericidal action of lactoperoxidase, peroxide, and iodide or thiocyanate. The bactericidal action that results from lactoperoxidase-catalyzed oxidation of iodide or thiocyanate was studied, using Escherichia coli as the test organism. The susceptibility of intact cells to bactericidal action was compared with that of cells with altered cell envelopes. Exposure to ethylenediaminetetraacetic acid, to lysozyme and ethylenediaminetetraacetic acid, or to osmotic shock were used to alter the cell envelope. Bactericidal action was greatly increased when the cells were exposed to the lactoperoxidase-peroxide-iodide system at low temperatures, low cell density, or after alteration of the cell envelope. When thiocyanate was substituted for iodide, bactericidal activity was observed only at low cell density or after osmotic shock. Low temperature and low cell density lowered the rate of destruction of peroxide by the bacteria. Therefore, competition for peroxide between the bacteria and lactoperoxidase may influence the extent of bactericidal action. Alteration of the cell envelope had only a small effect on the rate of destruction of peroxide. Instead, the increased susceptibility of these altered cells suggested that bactericidal action required permeation of a reagent through the cell envelope. In addition to altering the cell envelope, these procedures partly depleted cells of oxidizable substrates and sulfhydryl components. Adding an oxidizable substrate did not decrease the susceptibility of the altered cells. On the other hand, mild reducing agents such as sulfhydryl compounds did partly reverse bactericidal action when added after exposure of cells to the peroxidase systems. These studies indicate that alteration of the metabolism, structure, or composition of bacterial cells can greatly increase their susceptibility to peroxidase bactericidal action.


Synergistic action of amphotericin B and antioxidants against certain opportunistic yeast pathogens. Results of earlier turbidimetric growth experiments showed that certain antioxidants prolonged the antifungal activity of amphotericin B (AB) against Candida albicans, presumably by retarding autoxidative destruction of the drug. Viability studies were designed to examine this in more detail. Subinhibitory concentrations of either butylated hydroxyanisole, n-propyl gallate, or nordihydroguaiaretic acid in combination with fungistatic levels of AB exerted synergistic fungicidal activity against two strains of C. albicans and one of C. parapsilosis. Although synergism was not seen in tests with a strain of Torulopsis glabrata, antioxidants prolonged the inhibitory action of AB against this organism. On the basis of these findings and other considerations that are discussed, it is suggested that stabilization of AB and the ability to act synergistically with AB represent two distinctly different effects of the antioxidants.


Treatment of experimental murine cryptococcosis: a comparison of miconazole and amphotericin B. Miconazole was compared with amphotericin B in the treatment of murine cryptococcosis. Both subcutaneous and intraperitoneal administration of miconazole produced serum levels higher than the minimum inhibitory concentration for the challenge strain. However, maximal tolerable doses of miconazole gave no increase in survival. When combined with amphotericin B, miconazole demonstrated neither additive nor antagonistic effects on survival. Spleen and brain counts of cryptococci were not lowered by miconazole; also, miconazole did not alter the effect of amphotericin B on reducing tissue counts. In vitro studies confirmed that the strain of Cryptococcus neoformans was quite susceptible to both miconazole and amphotericin B. However, miconazole had a delayed onset of antifungal activity. This was apparent even at miconazole levels 20 times greater than the minimum inhibitory concentration. Also, the antifungal activity of miconazole was markedly inhibited by serum. Delayed antifungal activity and serum inhibition may limit the in vivo effectiveness of miconazole in murine cryptococcosis.


Common plasmid specifying tobramycin resistance found in two enteric bacteria isolated from burn patients. Tobramycin-resistant burn wound isolates of Klebsiella pneumoniae and Enterobacter cloacae, together with Escherichia coli K-12 transconjugants from these two strains, were examined for plasmid deoxyribonucleic acid (DNA). All the resistant strains contained a common, high-molecular-weight, covalently closed circular DNA plasmid that was absent in the tobramycin-susceptible E. coli recipient strain. The common plasmid residing in E. cloacae was designated pIE098, and that residing in K. pneumoniae was designated pIE099. Both plasmid species were found to have a molecular mass of approximately 60 x 10(6) daltons and a guanine-plus-cytosine content of 50 mol%. The DNA that was extracted from all of the tobramycin-resistant strains tested was able to hybridize to 86 to 100% with pIE098 and pIE099 [(3)H]DNA generated by EcoRI to produce fragments of a size similar to those generated by BamHI. This study illustrates the usefulness of simple screening methods for antibiotic resistance plasmids in a hospital epidemiological situation.


Interaction of neomycin with ribosomes and ribosomal ribonucleic acid. Neomycin binds ribosomes and ribosomal ribonucleic acid (rRNA) in vivo and in vitro producing changes detectable by increases in gel electrophoretic mobility. These changes were observed in gels that contain ethylenediaminetetraacetic acid or no added magnesium ion. The progressive increase in gel electrophoretic mobility with increasing antibiotic concentrations suggests that neomycin is binding at multiple sites on RNA. The binding was reversible but sufficiently stable to survive dialysis and electrophoresis. It is proposed that bound neomycin stabilizes the ribosome and RNA structures, restricting the unfolding of the particles during electrophoresis and thus allowing for a more rapid migration in the gel. Gentamicin produced an effect similar to that of neomycin. Paromomycin, differing from neomycin by only one amino group, had considerably less effect on ribosome and rRNA mobilities. The binding of neomycin to rRNA improved the linearity of the plot of log molecular weight versus mobility and thus may be of benefit in providing a more accurate estimation of molecular weights of large RNAs.


Temperature-sensitive mutants of Saccharomyces cerevisiae variable in the methionine content of their protein. Temperature-sensitive mutants were derived from Saccharomyces cerevisiae Y5alpha by ethyl methane sulfonate mutagenesis, in a search for mutants that would produce methionine-rich protein at the nonpermissive temperature. A total of 132 mutant strains were selected which showed adequate growth on minimal medium at 25 degrees C but little or no growth on the same medium supplemented with a high concentration (2 mg/ml) of l-methionine at 37 degrees C. Several of these mutants were found to increase the proportion of methionine in their protein to much higher levels than that of the wild-type parent after a temperature shift from 25 to 37 degrees C. Two strains, 476 and 438, which were temperature sensitive only in the presence of methionine, produced cellular protein with methionine contents as high as 3.6 and 4.3%, respectively, when incubated in the presence of methionine. The former strain contained 2.5% methionine even when incubated at 37 degrees C in the absence of methionine. Wild strain Y5alpha, on the other hand, had 1.75% methionine under all conditions tested. Most temperature-sensitive mutants isolated had the same methionine content as the wild strain. It is concluded that the proportion of a specific amino acid, such as methionine, in S. cerevisiae protein can be altered by culturing certain temperature-sensitive mutants at an elevated temperature.


Lack of mutagenicity to Salmonella typhimurium of some Fusarium mycotoxins. The mutagenicity of eight Fusarium toxins (mono-, di-, and triacetoxyscirpenol, T-2 toxin, deoxynivalenol, 3-acetyl-deoxynivalenol, zearalenone, and moniliformin) and of two positive controls (aflatoxin B1 and sterigmatocystin) to histidine-requiring strains TA 98, 100, 1535, and 1537 of Salmonella typhimurium was tested both with and without metabolic activation. Both aflatoxin B1 and sterigmatocystin, but none of the eight Fusarium toxins, were mutagenic to S. typhimurium. The lack of mutagenic activity of T-2 toxin and diacetoxyscirpenol supports the negative results that have been obtained with in vivo carcinogenicity tests. The negative mutagenicity of the four other 12,13-epoxytrichothecenes tested, and of zearalenone and moniliformin, could not be correlated with in vivo tests because published accounts of their chronic toxicity were not available.


Quantification of two viruses in technical preparations of Orgyia pseudotsugata baculovirus by means of buoyant density centrifugation of viral deoxyribonucleic acid. A reliable method was developed for the quantitative determination of two nuclear polyhcdrosis viruses present in commercially prepared viral insecticides used against Orgyia pseudotsugata. Deoxyribonucleic acids, from nuclear polyhedrosis bundle virus and nuclear polyhedrosis single-rod virus, were separated on CsCl gradients according to their respective buoyant densities, 1.715 and 1.704 g/ml. The proportions of the two viruses were quantified by measuring the relative absorbance at 254 nm of their deoxyribonucleic acid peaks.


Use of ethanol for selective isolation of sporeforming microorganisms. When mixed cultures containing sporeforming bacteria were treated with heat or with ethanol, the latter consistently resulted in better recovery of Clostridium and Bacillus species. Both techniques were effective in eliminating vegetative cells. An ethanol concentration greater than 25% and exposure for 45 min or longer were necessary to kill all vegetative cells in mixed-culture samples. Ethanol treatment (50% ethanol for 1 h) was effective for isolating sporeforming bacteria from intestinal specimens. Seven different species of Clostridium were the only bacteria isolated from the ethanol-treated specimen of intestinal contents from the large bowel of a patient. It was concluded that treatment with ethanol for 1 h is an effective technique for selective isolation of sporeforming bacteria from mixed cultures and certain types of clinical specimens.


Chemiluminescent detection of bacteria: experimental and theoretical limits. The limit of sensitivity of the chemiluminescent assay for detection of bacteria by hemeprotein catalysis of luminol oxidation was determined, both experimentally and theoretically, to be no lower than 10(5) to 10(6) viable bacterial per ml.


Plating procedure for the enumeration of coliforms from dairy products. A "repair-detection" procedure consisting of pour plating of food samples with Trypticase soy agar, followed by 1-h repair incubation at room temperature and subsequent overlay with violet red bile agar, was found to be an effective method for the detection of injuried and uninjuried coliforms from dairy products. This method was relatively less effective for the detection of coliforms in many semipreserved foods as compared with dairy products, but more effective than the most-probable-number method.


Epidermal nucleolar IgG deposition in clinically normal skin: clinical and serologic features of eight patients. Epidermal nucleolar IgG deposition in clinically normal skin reflects high serum concentrations of antibody to nucleolar antigen. This immunopathologic finding occurred in six patients with scleroderma and in two patients with a scleroderma-systemic lupus erythermatosus overlap syndrome.


Fetal and maternal risk factors in herpes gestationis. Forty-one cases of immunologically proved herpes gestationis (HG) are reviewed and there appears to be an increased risk of fetal morbidity and mortality. The onset of HG is most frequent in the second and third trimesters of pregnancy although postpartum onset or exacerbation is common. The presence of high-titer, antibasement membrane zone antibody seems to correlate with a severe clinical disease. Systemic treatment with corticosteroids is frequently necessary in order to control maternal signs and symtpoms of HG.


Papulonecrotic tuberculid secondary to Mycobacterium bovis. A patient with papulonecrotic tuberculid had a pruritic papular eruption associated with constitutional symptoms. The eruption flared whenever the patient received low doses of prednisone to control symptoms of temporal arteritis. A cervical lymph node biopsy specimen demonstrated acid-fast bacilli, and Mycobacterium bovis grew on the cultures. The eruption cleared completely with antituberculous therapy. This case demonstrated the clinicopathologic findings compatible with a diagnosis of papulonecrotic tuberculid. Skepticism regarding the existence of papulonecrotic tuberculid is probably a result of the current decreased prevalence of untreated tuberculosis, and the subsequently increased rarity of this entity.


Cutaneous signs of spinal dysraphism. Report of a patient with a tail-like lipoma and review of 200 cases in the literature. The term "spinal dysraphism" was coined in 1940 by Dr Lichtenstein to designate incomplete fusion or malformations of structures in the dorsal midline of the back, particularly congenital abnormalities of the vertebral column and spinal cord. Raphes develop on the face and head, brancheal arches, sternum, and spinal column. When dysraphism occurs in these sites, failure of closure of fontanelles, cleft lip and palate, brancheal cysts, and abnormalities of the ribs and spine result. A review of 200 cases of occult spinal dysraphism showed the condition to be more common in female patient and to be associated with cutaneous signs in more than 50% of instances. The age at which neurologic symptoms appeared in recorded cases is from birth to 76 years, the average being three years. A case of spinal dysraphism with a tail-like cutaneous structure is presented. The cutaneous manifestations accompanying spinal dysraphism that may lead to early recognition of this syndrome and early institution of treatment are discussed.


Speckled (particulate) epidermal nuclear IgG deposition in normal skin. Correlation of clinical features and laboratory findings in 46 patients with a subset of connective tissue disease characterized by antibody to extractable nuclear antigen. Clinical and laboratory findings were correlated from 46 patients with IgG localization in epidermal nuclei in a speckled (particulate) pattern on direct immunofluorescence of normal skin. Cutaneous manifestations included lupus erythematosus (LE), swollen hands or sclerodactyly, alopecia, vasculitis, and dyspigmentation. Systemic manifestations included arthritis or arthralgia, Raynaud's phenomenon, serositis, vascular headaches, mild renal disease, myositis, and sicca syndrome. High titer (mean = 1:142, 800) serum antibody to extractable nuclear antigen (ENA) was found in 81%. Eighty-six percent had antibody to an RNase-sensitive antigenic component of ENA (ribonucleoprotein or RNP); 14% had antibody to an RNase-resistant ENA termed Sm. Deposition of IgG in a speckled pattern in epidermal nuclei is an immunopathologic marker for a subset of connective tissue disease characterized by antibody to ENA. Those with Sm specificity had systemic LE (SLE); Those with RNP specificity had Raynaud's phenomenon usually associated with overlapping features of SLE, scleroderma, and/or dermatomyositis.


Palmar and plantar pustulosis elicited by Candida antigen. Intracutaneous injection of Candida albicans was done on the forearm of 30 patients with palmar and plantar pustulosis. This induced an aggravation of pustular eruptions on the palms and soles in 11 (37%) of the 30 patients. The aggravation occurred only in those patients who had a positive delayed skin reaction to the Candida antigen. It is suggested that a delayed hypersensitivity inflammatory reaction somewhere in the body is attended with an aggravation of palmar plantar pustulosis.


Sister chromatid exchanges in Bloom's syndrome. The importance of chromosome instability in Bloom's syndrome is reviewed, and the recently developed technique for demonstrating sister chromatid exchanges (SCE) is described. In Bloom's syndrome, but not in other heritable syndromes associated with chromosome instability, there is a nine- to ten-fold increase in the frequency of spontaneous SCE. We present a case of Bloom's syndrome in which this test facilitated the diagnosis. In four obligate heterozygotes (the parents of children with Bloom's syndrome), however, an increase in the frequency of spontaneous SCE was not observed.


Childhood pemphigus treated with gold.

Childhood pemphigus treated with gold. A case of childhood pemphigus is reported. The natural history of this rare entity and past methods of treatment are reviewed. We also report on what is to our knowledge the first known use of gold in the treatment of childhood pemphigus. This modality appears to have been of benefit in our patient to date.


Cicatricial pemphigoid (Brunsting-Perry type). Case report and immunofluorescence findings. We describe clinical and immunofluorescence findings of a patient with Brunsting-Perry-type cicatricial pemphigoid. Direct immunofluorescence showed tissue-fixed basement membrane zone antibodies similar to those characteristic of bullous pemphigoid. Circulating antibodies to the basement membrane zone were not found. Brunsting-Perry-type cicatricial pemphigoid probably represents a clinical variation midway in the cicatricial pemphigoid-bullous pemphigoid spectrum of disease. Management with intralesional corticosteroids was successful in controlling the skin lesions.


Reflex anoxic seizures ('white breath-holding'): nonepileptic vagal attacks. From clinical history 58 children were diagnosed as having reflex anoxic seizures secondary to provoked cardioinhibition (also known as white breath-holding attacks). Before referral, these seizures were commonly misdiagnosed as epileptic either because the provocation was ignored, not recognised, or was a febrile illness, or because there was no crying, no obvious breath-holding, little cyanosis, and often no pallor to suggest syncope and cerebral ischaemia. The duration of cardiac asystole after ocular compression was measured in these children and in 60 additional children with other paroxysmal disorders. In 45 (78%) of the 58 with reflex anoxic seizures asystole was 2 seconds or over, and in 32 (55%) it was 4 seconds or greater, an abnormal response. Review of the literature supports the concept that these seizures result from vagal-mediated reflex cardiac arrest which can if necessary be prevented by atropine. The simple name 'vagal attack' is proposed. Ocular compression under EEG and ECG control supports the clinical diagnosis if asystole and/or an anoxic seizure is induced; the procedure described is safe and should be routine in seizure or syncope evaluation, when a meticulous history still leaves room for doubt.


Ligation of patent ductus arteriosus in the very low birthweight newborn infant. Surgical closure of a patent ductus arteriosus was performed in 8 low birthweight infants suffering from cardiorespiratory failure secondary to a large left-to-right shunt. Mortality from the operation was nil, but only 4 (50%) ultimately survived. Earlier intervention may reduce mortality in these high-risk infants.


Oral rehydration in infantile diarrhoea. Controlled trial of a low sodium glucose electrolyte solution. The paper describes the first controlled trial of an oral glucose electrolyte solution designed on the basis of the optimum pathophysiological needs for rehydration in infantile diarrahoea. The solution, having a sodium concentration of 50 mmol/l, was tried in a group of 20 infants with moderate to severe dehydration due to acute diarrhoea and was compared with a matched group of 19 infants predominantly under 2 years of age taking a 'standard' oral solution with a sodium concentration of 90 mmol/l. They could be hydrated as well with a low sodium oral solution alone as with the standard solution. Intravenous fluid was not required in either group. The group treated with the high soldium 'standard' solution appeared to develop hypernatraemia and/or periorbital oedema more frequently than the other group. Also, the low sodium solution eliminated the need for additional free water orally.


Gonadotrophin release in untreated congenital virilising adrenal hyperplasia. A 9.9-year-old boy and a 9.8-year-old girl with virilising congenital adrenal hyperplasia were subjected to an IV LH-RH (luteinising hormone-releasing hormone) test (so microgram/m2 before initition of therapy with corticosteroids. The pattern of response of LH and follicle-stimulating hormone to LH-RH was found to correspond to the stage of their precocious sexual development and advanced bone age, but not to their chronological age. This finding has implications with regard to the mechanism controlling gonadotrophin secretion at puberty.


Immunological studies of the placenta in systemic lupus erythematosus. An immunological study was made of the placentae from 5 mothers with lupus erythematosus. 3 of the 5 mothers had anti-DNA antibodies in their sera at the time of delivery and in one of these anti-DNA antibodies were detected in the cord blood. This patient had active renal disease and serological evidence suggestive of circulating immune complexes in her blood at the time of delivery. Immunofluorescence studies showed granular deposition of immunoglobulin and C3 on the trophoblast basement membrane similar to that previously described on the glomerular basement membrane in systemic lupus erythematosus. Anti-DNA antibodies were eluted from the placenta in this case. We suggest that immune complex deposition on the trophoblast basement membrane in patients with active systemic lupus erythematosus may play a part in the increased fetal mortality in this disease.


Sequential studies in ankylosing spondylitis. Association of Klebsiella pneumoniae with active disease. A study of 163 patients with ankylosing spondylitis seen on 433 occasions showed that active inflammatory disease was strongly associated with the presence of Klebsiella pneumoniae in the faeces (P less than 0.001). Sequential studies showed that in patients with inactive disease the presence of a positive culture for Klebsiella was associated with the subsequent development of active inflammatory disease (P less than 0.001). These findings support the hypothesis that Kl. pneumoniae may be an initiating agent in ankylosing spondylitis.


No effect of transfer factor in juvenile rheumatoid arthritis by double-blind trial. A previously pilot study of treatment with transfer factor in 3 patients with juvenile rheumatoid arthritis (JRA) gave promising results. However, in this small and open study no definite conclusions could be drawn. Therefore, a double-blind group trial was performed in 12 JRA patients treated with transfer factor, and in 12 placebo-treated control patients. The patients were evaluated clinically, by laboratory tests, and by estimation of different lymphocyte populations and cell-mediated immunity in vitro and in vivo. Transfer factor was not found to be of significant therapeutic value in patients with JRA. The only statistically significant difference between the two groups was a greater reduction in the percentage of T lymphocytes in transfer factor-treated patients than in control patients. The significance of this is difficult to explain and could have appeared by chance. No side effects of treatment with transfer factor were noted.


Heavy metal residues in plants cultivated on and in small mammals indigenous to old orchard soils. Six vegetables and millet were grown on the site of an old orchard which had received heavy applications of lead arsenate and organic mercury fungicides for many years. Carrots and millet absorbed about 7 ppm (dry weight) of lead, the other crops containing smaller concentrations. Concentrations of arsenic and mercury showed only modest increases in crops grown on the orchard soil as compared to controls. Lead concentrations in kidney, liver, and bone tissue of meadow voles trapped in two old orchards were markedly higher (up to 300 ppm in bone) than control animals (up to 33 ppm). Intranuclear inclusion bodies diagnostic of lead poisoning were found in the renal epithelial cells of the proximal convoluted tubules in voles from lead arsenate treated orchards.


Modified continuous suture technique for mitral valve replacement. A modified continuous suture technique for mitral valve replacement is described which retains desirable features of the less expedient interrupted suture technique. An initial experience with this technique in more than 300 patients has encouraged its continued use.


Amikacin therapy of gram-negative bacteremia and meningitis. Treatment in diseases due to multiple resistant bacilli. The therapeutic efficacy of amikacin was evaluated in patients with serious hospital-acquired infections caused by Gram-negative bacilli susceptible to amikacin, but usually resistant to kanamycin, gentamicin, and tobramycin. The infections for which amikacin was given were Gram-negative bacteremia in 15 patients and Gram-negative meningitis in two patients. Therapy with amikacin resulted in a cure in 13 patients, improvement in 1, and failure in 3. Continuous intravenous infusion of amikacin yielded a high cerebrospinal fluid to serum ratio of amikacin in one case of meningitis and intrathecally administered amikacin yielded high ventricular fluid levels in another case of meningitis. The emergence of resistance to amikacin was noted in one patient treated with amikacin in whom Serratia bacteremia persisted. Treatment with amikacin was usually tolerated well. This study indicates that amikacin is an effective antibiotic in the treatment of serious Gram-negative infections caused by gentamicin-resistant organisms.


Streptococcal endocarditis initially seen as septic arthritis. Two patients were initially seen with culture-positive streptococcal arthritis as an early manifestation of bacterial endocarditis. The organisms were an alpha-hemolytic, nongroup D streptococcus and a beta-hemolytic, group b streptococcus. One patient had a persistent septic monarthritis; the other had migratory arthritis in which a positive synovial culture was followed by a negative culture from the same joint before antimicrobial treatment was started. This experience suggests that some sterile synovial aspirates encountered in patients with bacterial endocarditis may be explained by delay of arthrocentesis.


Corynebacterium pyogenes septic arthritis with plasma cell synovial infiltrate and monoclonal gammopathy. A chronic septic process developed in the right knee of an elderly man with advanced degenerative arthritis of both knees. Open exploration, culture, and biopsy of the joint found that the pathogen was Corynebacterium pyogenes and that the synovium was involved with a remarkable perivascular infiltrate of plasma cells. Serum protein electrophoresis demonstrated a prominent M component. Following antimicrobial therapy, the M protein level has gradually declined, and no evolution of multiple myeloma has become apparent. The findings are consistent with a benign monoclonal gammopathy and localized plasmacytic reaction in the knee associated with infection by an unusual diphtheroid organism.


Nonobstructive pyelonephritis initially seen as acute renal failure. The triad of elevated SGOT and lactic dehydrogenase levels, positive blood and urine cultures, and acute renal failure was noted in a patient with severe pyelonephritis. Bilateral medullary necrosis was found on biopsy and at postmortem examination. These findings may help establish a prompt antemortem diagnosis.


Xanthine nephropathy during chemotherapy in deficiency of hypoxanthine-guanine phosphoribosyltransferase. We describe an episode of obstructive uropathy produced by xanthine precipitation in the tubules of the kidney of a patient with histiocytic lymphoma during intensive chemotherapy, despite allopurinol therapy. Urinary oxypurine-uric acid ratio suggested a subclinical deficiency of hypoxanthine-guanine phosphoribosyltransferase. Results of an assay of this enzyme confirmed the abnormality. Both parents and three brothers of the patient had normal enzyme activity. The continued importance of adequate hydration for patients who receive allopurinol during initial periods of cancer therapy is emphasized.


Cell yields of Escherichia coli during anaerobic growth on fumarate and molecular hydrogen. Escherichia coli was grown anaerobically on sodium fumarate and molecular hydrogen or sodium formate in continuous culture. The maximal growth yield and the maintenance coefficient were determined. In a mineral medium a Ymax(fum) value of 6.6 g dry weight per mol fumarate was found. This value increased to 7;5 when casamino acids were present in the medium. From these data and the corresponding Ymax(ATP) values it could be calculated that per mol of fumarate reduced, 0;4 mol of ATP became available for growth. In batch culture a Yfum value of 4.8 g dry weight per mol fumarate was determined.


Pleiotropic consequences of mutations towards antibiotic-hypersensitivity in Serratia marcescens. Various mutants (oxas) were isolated from Serratia marcescens SM-6 by selecting for hypersensitivity towards oxacillin. All mutants found are highly pleiotropic and able to yield spontaneous revertants which behave like the wild-type. Mutant W 1421 mostly studied shows the following phenotypic properties not found in the wild-type: (1) The growth is hypersensitive to various antibiotics, detergents and dyes which differ remarkably in their chemical structure and antibacterial action-mechanism, (2) the cells can be easily solubilized by 0;05% Sodium-dodecyl-sulfate, (3) the cells allow the adsorption of the rough-mutant specific Salmonella phage 6SR; (4) strong cellular binding of crystal violet, (5) agglutination of the cells in 0.3% auramin solution and (6) reduced formation of red pigment. Strain W 1421 is assumed to be a lipopolysaccharide-defective mutant. The outer membrane of mutant W 1421 analyzed by Sodium-dodecylsulfate-polyacrylamide gel electrophoresis possesses a single protein less than that of the wild-type. Mutant W 1421 is further characterized by its low exolipase activity; exoprotease and exonuclease activities are as in the wild-type. This specific exoenzyme deficiency can be overcome either by backmutation to oxacillin-resistance or by growing mutant W 1421 in a medium supplemented with certain non-metabolizable polysaccharides, e.g. glycogen or pectin B. Both polysaccharides increase the exolipase activity of the wild-type too.


Localization of polyphosphate in vacuoles of Saccharomyces cerevisiae. Virtually all of the polyphosphate (PP) present in yeast protoplasts can be recovered in a crude particulate fraction if polybase-induced lysis is used for disrupting the protoplasts. This fraction contains most of the vacuoles, mitochondria and nuclei. Upon the purification of vacuoles the PP is enriched to the same extent as are the vacuolar markers. The amount of PP per vacuole is comparable to the amount of PP per protoplast. The possibility that PP is located in the cell wall is also considered. In the course of the incubation necessary for preparing protoplasts, 20% of the cellular PP is broken down. As this loss of PP occurs to the same extent in the absence of cell wall degrading enzymes, it is inferred that internal PP is metabolically degraded, no PP being located in the cell walls. It is concluded that in Saccharomyces cerevisiae most if not all of the PP is located in the vacuoles, at least under the growth conditions used.


Combined action of phosphomycin with streptomycin and gentamicin. The combined action of phosphomycin with streptomycin and gentamicin against 41 strains of Gram-positive micrococci (S. aureus and Str. faecalis) and 87 strains of Gram-negative bacilli (including 38 strains of Pseudomonas) was evaluated. The combination of phosphomycin with streptomycin acted synergistically against 12 strains of Gram-positive micrococci, and the combination of phosphomycin with gentmicin against 10 strains. The combination of phosphomycin with streptomycin acted synergistically against 31% of strains (except Pseudomonas), and the combination of phosphomycin with gentamicin against 65% of strains. Only six of 38 Pseudomonas strains were acted synergistically by phosphamycin with streptomycin, and four by phosphomycin with gentamicin. The results indicate that the combination of phosphomycin with aminoglycoside antibiotics shows greater synergistic activity against Gram-negative strains than against Gram-positive micrococci.


The influence of dfp, atropine and toxogonine on tryptophan pyrolase activity in mouse liver. It was found that fluorostigmine (DFP) in doses 0-4 mg/kg i.p. reduced significantly tryptophan pyrolase activity in mouse liver homogenates.se liver homogenates 120 and 180 min after the administration of the drug. On the other hand, fluorostigmine administered in doses 0-8 mg/kg i.p. increases the activity of the enzyme studied at 30 and 60 min after the injection. DFP (0.4 mg/kg i.p.) given in combination with atropine (10 mg/kg i.p.) causes a significant increase in enzyme activity determined 30, 60, 120 and 180 min after the administration of the drug. Toxogonine (in doses 5 mg/kg s.c.) given together with DFP (0.4 mg/kg i.p.) intensifies the activity of tryplophan pyrolase at 180 min after their administration. Simultaneous treatment with toxogonine (5 mg/kg s.c.), atropine (10 mg/kg i.p.) and DFP (0.4 MG/KG I.P.) reduced significantly the activity of the enzyme studied at all time of determination. Moreover,  the experiment in vitro showed that DFP in concentrations of 4x10(-9) M; 8X10(-9) M; 1.6X10(-8) M and 3.2x10(-8) M increased tryptophan pyrolase activity in mouse liver homogenates.


N-glycosides of nitroaniline as acceptors of glucose in nonphosphorylative transglycosylation reactions. N-glycosides of nitroaniline, D-glucose, D-mannose, D-galactose, D-ribose, D-xylose and L-arabinose were examined as acceptors of glucose in transglycosylation reactions. In the presence of these compounds, higher N-glycosides of nitroaniline were formed in the course of incubation of acid glucoamylase with maltose or glycogen. With the exception of N-glycosides of D-galactose and L-arabinose, the remaining compounds were acceptors of glucose. It follows that the acceptor properties of N-glycosides of nitroaniline are dependent on the spatial position of the hydroxyl group on the fourth carbon of the sugar moiety.


Clinical observations with pizotifene (Sandomigran) in the treatment of nonmigrainous depressed women. Based on earlier clinical experiences a group of 52 nonmigrainous depressed women were treated with 3-6 mh/day pizotifene (Sandomigran-Sandoz) in order to evaluate a presumed antidepressant action. The Bunney-Hamburg behavior-rating scale was employed to quantify the results. Thirteen patients showed marked improvement and 22 patients partial improvement after three weeks' treatment. Involutional and psychoreactive depressions responded better than endogenous forms. Symptomatically, anxiety and dysphoria were significantly more favorably influenced than retardation or paranoia. No serious side effects were observed.


Renal perfusion preservation without cannulation. Prevention of posttransplantation renal artery stenosis. Cadaver kidneys were preserved by a technique that uses hypothermic pulsatile perfusion without cannulation of the renal arteries. This avoids the mechanical trauma that is inevitably associated with cannulation and preserves a maximum of untraumatized arterial tissue. Cannulation injury is thus eliminated as a potential cause of renal artery stenosis. Revascularization is simplified, especially when multiple renal arteries are attached to a cuff of aorta.


Radioprotective activity of interferon inducers. The radioprotective activity of interferon inducers (tilorone, Acranil, poly I:C and LPS) was investigated against acute X-ray irradiation and prolonged 60Co-gamma rays irradiation. The endogenous spleen colony formation test and percentage of surviving mice 30 days after irradiation were used as indicators. All interferon inducers investigated proved to have radioprotective activity.


[Effect of reinnervation on the state of transplanted kidneys in dogs]. In the experiments lasted for 2 years, the effect of surgical reinnervation on the morphofunctional state of autotransplanted and denervated kidney was studied in 175 dogs. General morphological, impregnational, special neurohistological investigations and kidney scanning demonstrated that 2 months after surgical reinnervation of the autotransplantated and denervated kidneys, active sprouting of nerve fibers, adrenergic and cholinergic including, was started along the degenerated nerve trunks, and by the 4th month the nerve fibers reached the renal glomeruli, tubules and pelves. A rather complete restoration of the organic innervation resembling that of the intact organ provided stability of the general morphological structure in the reinnervated kidney, its functional ability and prevented atrophy, sclerosis and stable functional depression observed in cases of renal transplantation and denervation without surgical reinnervation. From this point of view, the problem of necessary active surgical reinnervation of the renal transplantation is discussed.


[Multipotent primary bone sarcoma].

[Multipotent primary bone sarcoma]. The results of clinical and roentgen-morphological studies on 17 cases of multipotent primary sarcoma of the bone are presented. The difficulties of the tumor recognition are due to the fact that it occurs rarely, has no specific clinical-roentgenological picture and shows marked tissue polymorphism. Most frequent are differentiations of the type of osteogenic sarcoma, chondrosarcoma, reticulosarcoma with simultaneous combination with areas having the structure of Ewing's tumor, or extensive fields of undifferentiated primitive tumor cells. Further studies are necessary to decide whether or not this tumor is an independent form among other known skeletal neoplasias.


[Changes in the intermediary glands of the gastric mucosa in peptic ulcer of different localization in morphometric interpretation]. Histologically and morphometrically (by the method of V.A. Samsonov). 80 stomachs resected for peptic ulcers were studied. Intermediary glands without atrophy were found in 16.3% of cases, atrophic changes in 51.2% of cases; in 32.5% of cases they disappeared completely and were substituted mainly by fields of intestinal metaplasia they disappeared completely and were substituted mainly by fields of intestinal metaplasia and pseudopyloric glands. In the atrophic process the number of cells increased in the gastric fossas and decreased in the glands; the gland-fossa epithelial cell index and the ratio of chief and parietal cells decreased. In the epithelial formula of intermediary gland the percentage of secondary and undifferentiated cells increased and that of parietal and particularly chief cells decreased. When the ulcers were localized in the stomach the glands were involved more frequently and extensively than in duodenal ulcers.


[Endocrine function of the salivary glands]. The concept of the incretory activity of the parotid and submandibular salivary glands stems from numerous clinical and experimental data indicating a close association between them, sex and pancreatic glands and the pituitary. The paper presents the data on the mechanism of action of the salivary glands hormone, parotine. The participation of the salivary glands, especially at early stages of body formation, in the processes of mineralization of bones and teeth, and in proliferation of the elastic carcass of mesenchimal tissues, has been proved. The compensatory role of the salivary glands has been established in damages of the insular apparatus of the pancreas with formation of an insulin-like substance. By the example of Sjögren syndrome, the possibility of the development of the salivary glands diseases associated with disorders in the neuroendocrine and immune systems has been demonstrated.


Cerebral malaria. A disseminated vasculomyelinopathy. Neuropathologic examination of 19 fatal cases of cerebral malaria and a review of the literature showed that the epidemiologic, clinical, and pathologic features of this entity suggest consideration of cerebral malaria as a form of disseminated vasculomyelinopathy, a hyperegic reaction of the CNS to the antigenic challenge of Plasmodium falciparum infection. Experimental evidence also substantiates this view The initial event seems to be vasculopathy, with alteration of the endothelial permeability, followed by brain edema, perivascular infiltrates and ring hemorrhages, perivascular demyelination, and gliosis (malarial granuloma) in the late stages. This chain of events could be interrupted early in its course by corticosteroids. Parenteral dexamethasone should then be seriously considered at the first signs of involvement of the CNS during P falciparum malaria along with the standard forms of antimalarial therapy.


Ocular toxoplasmosis in three consecutive siblings. Ocular toxoplasmosis in consecutive siblings is rare. We report positive ocular and serologic findings in three consecutive teenaged siblings. Results of immunologic studies that were performed on members of the family failed to reveal deficiencies.


Congenital ocular toxoplasmosis. Possible occurrence in siblings. In two siblings, we saw bilateral macular lesions that were consistent with the diagnosis of congenital toxoplasmosis. Although the congenital nature of this type of infection cannot be proven conclusively, there is considerable evidence that the lesions in our young patients were scars from congenital toxoplasmic retinochoroiditis. To our knowledge, congenital ocular toxoplasmosis in siblings has not previously been reported.


Cornea guttata in donor material.

Cornea guttata in donor material. Specular microscopy made it possible to detect cornea guttata changes within the regular reflection off the posterior surface of the cornea in donor matrial. Small, roundish lesions were present in mild forms within an otherwise intact endothelium, and in advanced cases, large warts were seen free of endothelial cell coverage.


Reinnervation of an Abbe-Estlander and a Gillies fan flap of the lower lip: electromyographic comparison. Electromyographic examination of a left Gillies fan flap 29 months after operation and of a right Abbe-estlander flap 17 months after operation showed complete motor innervation of both.


[The principles of the "bi-lobed flap" and its use for the construction of "multiple flaps" (author's transl)]. We have shown some constructions of pedicled bi-lobed and tri-lobed flaps, "transposition-rotation flaps" and "double-rotation flaps". Using the big regional flaps in this matter we are able to close large defects primarily without the use of thin split grafts.


Rationale for bevelled should veneer crown preparations. The advantages of bevelled shoulder preparations for full veneer gold crowns are discussed from the point of view of marginal fit, retention, health of the pulp and the supporting tissues.


Duplication variables related to partial denture castings. 1. The duplicating flask. A metal die simulating a model of a partially dentate upper jaw prepared with milled facets for reference measurement with vernier calipers was used for the making of duplicate stone models, in three different duplicating flasks. The observation showed that irrespective of the flask size, the duplicated models were slightly wider.


The treatment of burns in children.

The treatment of burns in children. As a cause of accidental death in childhood, burns are exceeded only by motor car injuries and drownings. The mortality has been reduced substantially in recent years, but very many children must still carry scars both physical and emotional for the rest of their lives from burning accidents, many of which were preventable.


Reconstruction of the breast following radical mastectomy. A method of reconstruction of the breast following radical mastectomy is presented. The technique involves the use of an individually made Silastic prosthesis inserted three to six months after the mastectomy. A new simple method of nipple reconstruction is described, and the total restoration can be achieved in one operation. It is suggested that reconstruction of the breast be considered more frequently in patients subjected to mastectomy.


What shall we teach our students about breast cancer? A personal view. The incidence of breast cancer in Australia is as high as in most parts of the world. The usual presentation is with a breast lump. Invasive and preinvasive malignant changes may be identified in both duct and lobular epithelia. There are clinical features of malignancy, but histological proof is necessary. Aspiration of cysts and reexamination of clinically benign lumps are acceptable in certain circumstances, but a tissue diagnosis should be made by needle or open biopsy. Earlier diagnosis is possible by radiological screening of asymptomatic patients, but the cost is high. Total excision of the breast (simple mastectomy) is the minimum treatment advisable for infiltrating cancer; If there is a high chance that the draining lymph nodes will contain tumor, they should be treated by surgical excision or radiotherapy. Early chemotherapy does reduce the incidence of systemic metastases after mastectomy, but its precise place in management is not yet clear. The social impact of mastectomy is considerable and deserves more attention than has been paid to it in the past. Clinical trials of treatment should continue, as they are beginning to answer some fundamental questions.


The New South Wales mastitis control program. 2. Effect upon bacterial infections. Bacteriological examinations were made on quarter samples from cows in 35 herds over a 3 year period to monitor the response in a mastitis control program. Initially, Staphylococcus aureus predominated in 32 of the herds and the mean herd prevalence was 26%. The control measures halved this rate but there was considerable variation in response between herds. The decline occurred rapidly and there was a significant reduction (P less than 0.01) by 3 months. Streptococcus agalactiae predominated in 3 herds and the overall infection rate was 4.9%. Control measures eliminated the infection completely from most herds but reinfection occurred in 2 herds. The greatest decline occurred in the first 6 months and was significant (P less than 0.05). The measures had little effect upon Str. uberis and Str. dysgalactiae which remained fairly consistently at low levels. Initially, strains of Staph. aureus resistant to penicillin were dominant in most herds. In a minority of herds strains resistant to streptomycin predominated and in these herds there was a concurrent resistance to penicillin. These patterns did not change greatly over the control period. Resistance by Str. agalactiae to streptomycin occurred in most herds at the start of the program.


A simple vascular perfusion technique for use in waterfowl. A simple vascular perfusion technique is described for fixation of avian tissues for study at the light-microscope level. The technique relies on gravity feed of perfusate and gives reliable fixation of the nervous system, liver, kidney, and cardiac and skeletal musculature.


Evaluation of secondary enrichment for detecting Salmonellae in bobwhite quail. Secondary enrichment of cultures in tetrathionate-brilliant-green broth substantially increased Salmonella recovery over that achieved with primary tetrathionate-brilliant-green broth or primary selenite-cystine broth.


Virulence of Escherichia coli strains for chicken embryos. The virulence of 66 Escherichia coli strains was evaluated in 12-day-old chicken embryos inoculated by the allantoic route. The index of virulence used was the proportion of dead embryos within 3 days of inoculation. The strains were classified into "highly virulent," "moderately virulent," and "avirulent" groups. Although both virulent and avirulent strains grew equally well in vivo in the allantoic and yolk sacs, virulent E. coli invaded the whole embryo but avirulent ones failed to do so.


Genetic protein polymorphisms in human saliva: an interpretive review. The purpose of this review is to summarize recent progress in the field of genetic protein polymorphisms found in human saliva since 1972. Prior to 1972 most of the investigations were related to amylase. The genetics of salivary amylase will not be considered here, since it has recently been thoroughly reviewed elsewhere (Merritt and Karn, 1977). In this review, special attention will be devoted to the complex interrelationships of the proline-rich (Pr), double-band (Db), acidic protein (Pa), and peroxidase (SAPX) systems. The biochemically related Pr, Db, and Pa systems show distinctive genetic patterns, and there are associations between the phenotypes indicating linkage relationships. There is also evidence for probable interaction of products of the Pa and SAPX loci. Electrophoretic properties of these proteins can be defined in several gel systems, permitting an accurate definition of phenotypes. The usefulness and limitations of the different gel systems in the interpretation of these electrophoretic patterns will be illustrated. Allelic frequencies of the systems to be discussed are given in Table I. To aid comprehension, the systems will be discussed in logical rather than historical sequence.


An enzyme-labeled antibody test for detecting antibodies in chickens infected with Mycobacterium avium serotype 2. An enzyme-labeled antibody test was used for detecting antibodies in serums from chickens infected experimentally with Mycobacterium avium serotype 2. Positive ELA reactions were observed in the serums of each of 8 chickens 2, 4, 6, and 8 weeks after infection; no reactions were observed in uninfected controls. Tuberculin skin tests did not induce positive ELA test reactions in uninfected chickens.


The presence of dolichol in a lipid diphosphate N-acetylglucosamine from Saccharomyces cerevisiae (baker's yeast). The lipid moiety of a lipid diphosphate N-acetylglucosamine, an intermediate in glycosylation of proteins, was studied. Ozonolysis of the compound gave evidence for an alpha-saturated isoprene unit. Alkaline hydrolysis of the glycolipid, followed by high-pressure liquid chromatography, showed the presence of a series of polyprenol homologues identical with those isolated directly from Saccharomyces cerevisiae (baker's yeast). No particular homologue was preferred in the enzymic transfer of N-acetylglucosamine 1-phosphate to endogenous dolichol monophosphate.


The preparation and purification of individual human pepsins by using diethylaminoethyl-cellulose. A procedure was devised for isolating human pepsins 1, 2, 3 and 5 from gastric juice by repetitive column chromatography on DEAE-cellulose. The combined yields in four different experiments varied from 14% to 90% of the total peptic activity of the starting material. The isolated individual pepsins were shown to behave as single homogeneous proteins on agar-gel electrophoresis at pH 5.0 and on sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. There is preliminary evidence, requiring further study, of two other pepsins, one migrating between pepsins 1 and 2 and the other a pepsin-3 component associating closely with pepsin 5 on chromatography.


Novel kinetic and structural properties of the class-I D-fructose 1,6-bisphosphate aldolase from Escherichia coli (Crookes' strain). Investigation of aldolase 1, the class-I D-fructose 1,6-bisphosphate aldolase (EC4.1.2.13) from Escherichia coli (Crookes' strain), showed it to have unusual kinetic and structural properties. The enzyme appeared to be larger than was previously supposed and may be a decamer with a mol. wt. of approx. 340000. Its fructose 1,6-bisphosphate-cleavage activity was unaffected by these compounds. The enhancement exhibited a strong dependence on pH. These novel kinetic properties do not seem to be shared by any other fructose 1,6-bisphosphate aldolase, but recall the activation by polycarboxylic acids of the deoxyribose 3-phosphate aldolases from some other organisms. In view of its unusual properties, it is unlikely that aldolase 1 from E. coli is closely related to the class-1 aldolases that have been detected in several other prokaryotes, or to the typical class-1 enzymes from eukaryotes.


Metabolic signals produced by purine ribonucleosides stimulate proinsulin biosynthesis and insulin secretion. Inosine, guanosine and adenosine strongly stimulated proinsulin biosynthesis and insulin secretion in isolated mouse pancreatic islets. None of the purine ribonucleosides stimulated insulin secretion in rat islets, although as reported [jain & Logothetopoulos (1977) Endocrinilogy 100, 923-927] inosine and guanosine, but no adenosine, were potent stimulants of proinsulin biosynthesis in this species. The purine bases had no effect in either species. D-Ribose, which enhanced proinsulin biosynthesis at 0.3 and 0.6 mM but not at 5mM in rat pancreatic islets [jain & Logothetopoulos (1977) Endocrinology 100, 923-927], produced no secretory signals in rat islets and was without any effect on proinsulin biosynthesis and insulin secretion in mouse islets. The rates of oxidation of 14C-labelled purine ribonucleosides and D-ribose in islets of the two species correlated well with their effectiveness as inducers of insulin secretion and proinsulin biosynthesis. Specific inhibitors of purine ribonucleoside phosphorylase, adenosine deaminiase and of purine ribonucleoside transport suppressed the stimulatory effects of nucleosides in pancreatic islets without altering the effect of D-glucose. The same inhibitors also markedly diminished the oxidation rats of the labelled purine ribonucleosides. The experiments clearly indicate that porinsulin biosynthesis and insulin secretion are modulated through metabolic signals and not through interactions of intact substrate molecules with cell receptors.


Calcium transport and porton electrochemical potential gradient in mitochondria from guinea-pig cerebral cortex and rat heart. A method is described for the preparation of ;free' and ;synaptosomal' brain mitochondria from fractions of guinea-pig cerebral cortex respectively depleted and enriched in synaptosomes. Both preparations of mitochondria have a low membrane H(+) conductance, a high capacity to phosphorylate ADP, and a capacity to accumulate Ca(2+) at rates limited by the activity of the respiratory chain. Ca(2+) transport by ;free' brain mitochondria is compared with that of heart mitochondria. The Ca(2+) conductance of ;free' brain mitochondria was at least 20 times that for rat heart mitochondria. Ca(2+) uptake by brain mitochondria increased the pH gradient and decreased membrane potential, whereas little change occurred during the much slower uptake by heart mitochondria. In the presence of ionophore A23187, dissipative Ca(2+) cycling decreased the H(+) electrochemical potential gradient of brain mitochondria from 190 to 60mV, but caused only a slight decrease with heart mitochondria, although the ionophore lowered the pH gradient and increased membrane potential. The Ca(2+) conductance of ;free' brain mitochondria is distinctive in showing a hyperbolic dependency on free Ca(2+) concentration. In the presence of Ruthenium Red, a rapid Na(+)-dependent Ca(2+) efflux occurs. The H(+) electrochemical potential gradient is maintained during this efflux, and membrane potential increases, with both ;free' brain and heart mitochondria. The Na(+) requirement for Ca(2+) efflux appears not to be related to the high Na(+)/H(+) exchange activity but may represent a direct exchange of Na(+) for Ca(2+).


Proinsulin biosynthesis in broken-cell preparations of islets of Langerhans. 1. Rabbit islets of Langerhans were disrupted by ultrasonic methods and the sonicated preparations were used to study proinsulin biosynthesis. 2. When [3h]leucine is incubated in such preparations, incorporation takes place into proinsulin, as evidenced by characterization on polyacrylamide gels, and by the conversion of this labelled material into insulin, by using trypsin. 3. The labelled proinsulin may also be purified by antiinsulin antibody bound to Sepharose. 4. With the broken-cell preparation it was shown that incorporation of leucine is accelerated by increasing the glucose content of the medium from 2mM to 16mM. However, 16mM-galactose or -sucrose did not stimulate incorporation significantly from basal values. This effect of glucose was abolished by cycloheximide. 5. The significance of these findings in relation to the mechanism of glucose stimulation of proinsulin biosynthesis is discussed.


The rate of deoxyribonucleic acid synthesis by cultured Chinese-hamster ovary cells. An application of isotope-dilution analysis. The rate of DNA synthesis is exponentially growing cells was determined by isotopedilution analysis of the incorporation of [me-3H]thymidine. Thymidine concentrations greater than 7 micrometer were used so that the rate-limiting step governing incorporation would be at the level of DNA polymerase rather than at the level of thymidine kinase [Sjostrom & Forsdyke (1974) Biochem. J. 138, 253-262]. In early exponential phase the rate determined by isotope-dilution analysis closely correlated with the rates calculated either from growth curves or from known cell-cycle parameters. However, in late-exponential phase the rate calculated from the growth curve was less than that determined by isotope-dilution analysis. We conclude that, under certain conditions, the pool-corrected rate of incorporation of [me-3H]thymidine, as determined by isotope-dilution analysis, can accurately reflect the rate of DNA synthesis. Discrepancies between the observed rate of DNA synthesis and increase in cell number could reflect an exponential degeneration of post-S-phase cells.


The lability of the products of mitochondrial protein synthesis in Saccharomyces cerevisiae. A novel method for protein half-life determination. A method for the determination of the half-life of mitochondrial translation products in yeast in vivo is proposed. The method uses inhibitors of cytoplasmic and mitochondrial protein synthesis and is based on double-labelling pulse-chase techniques, the second label being used to estimate 'post-incorporation' during the 'chase'. For the first time the difference between post-incroporation and the widely known recycling of the label is considered. These studies show that, in the turnover of mitochondrial translation products, the problem is of post-incorporation into mitochondria (especially from the cell sap) is predominant. The results obtained with this procedure indicate that the half-life of the products of mitochondrial protein synthesis in yeast at the late-exponential phase is about 60 min. The results suggest that mitochondrial transplantation products are subject to proteolysis to acid-soluble forms.


Decreased lymphocyte response to PHA, Con-A, and calcium ionophore (A23187) in patients with RA and SLE, and reversal with levamisole in rheumatoid arthritis. The mechanism of poor lymphocyte transformation to mitogens was studied in selected patients with rheumatoid arthritis and systemic lupus erythematosus. Low lymphocyte response to PHA and Con-A in media containing autologous and homologous sera was usually associated with poor response to the calcium ionophore A23187, which induces blastogenesis by a different mechanism. The low lymphocyte response to mitogens in patients with rheumatoid arthritis could be restored by in vivo treatment with the anthelmintic drug, levamisole. The present findings suggest that intrinsic defects are responsible for the decreased cellular response in patients with rheumatoid arthritis and systemic lupus erythematosus.


[Clinical observations during accumulative oral glycoside therapy with meproscillarin (author's transl)]. In heart failure of the severity degrees II and III according to Friedberg's classification, administration of a daily maintenance dose of 0.5--0.75 mg of 14-hydroxy-3beta-[(4-O-methyl-alpha-L-rhamnopyranosyl)oxy]-14beta-bufa-4,20,22-trienolide (mesproscillarin, Clift) induces a cumulative blood level of 1--1.5 mg after 8--10 days. This level eliminates manifestations of heart failure both clinically and with regard to objective criteria. Increased heart rate returns to normal particularly in types of the tachycardiac atrial fibrillation. The frequency corrected QT-time is significantly reduced by about 30 ms. The relative heart volume decreases. The heart's work is increased by about 15%. No side effects are observed under this oral accumulative glycoside therapy.


[Long-term study with the novel cardiac glycoside meproscillarin (author's transl)]. In a multicentre open therapeutic study 64 physicians provided 650 questionnaires of patients who had been treated with the new cardiac glycoside 14-Hydroxy-3beta-[(4-O-methyl-alpha-L-rhamnopyranosyl)oxy]-14beta-bufa-4,20,22-trienolide (meproscillarin, Clift) for more than 3 months; 647 questionnaires had been filled in completely and could be evaluated. The major part of all patients suffering from heart failure of the severity degrees I--III required 2 tablets of 0.25 mg, a smaller part 3 tablets to achieve complete recompensation and/or maintenance of compensation, which was possible in 79% of all cases. The rate of side effects corresponded to that of other cardiac glycosides.


Long-term trial with colestipol plus clofibrate in familial hypercholesterolemia. Twenty subjects with familial hypercholesterolemia (12 Type IIa and 8 Type IIb), previously treated with Colestipol for 16 months, were subjected to therapy with Colestipol (15 g/day) + clofibrate (2 g/day) for 15 months. During the second treatment period these patients continued to follow the isocaloric hypocholesterolemic diet initiated during the original trial. In Type IIa patients, the association of these drugs enhanced the decrease in plasma cholesterol levels. The total mean decrease was -40 +/- 17 mg/dl (P less than 0.05). In Type IIb patients, on the other hand, the association of clofibrate with Colestipol induced an increase in plasma cholesterol levels. The total mean increase was +24 +/- 7 mg/dl (P less than 0.05). A markedly significant decrease in plasma triglyceride levels was observed in this group (- 107 +/- 30; P less than 0.01). These results seem to indicate that, in Type IIa, clofibrate increased the resin's hypocholesterolemic effect. In Type IIb, on the other hand, the association of these drugs did not seem to be indicated since a marked hypotriglyceridemic effect was accompanied by an increase in plasma cholesterol levels. These results are briefly discussed in the light of recent data obtained on the effects of Colestipol and clofibrate on lipoprotein metabolism.


[HCG proved by enzyme labelled antibody technique in a suprasellar tumour--an autopsy case report (author's transl)]. An 11-year-old female case of suprasellar tumour was reported. She presented consciousness disorder without precocious puberty. Microscopically, two cell pattern pinealoma and choriocarcinoma with no metastasis were revealed. By means of enzyme-labelled antibody technique, the authors proved HCG in syncytial cells of the tumour.


[Evaluation of racemic epinephrine with intermittent positive pressure in the treatment of acute infections laryngotracheitis]. Fourteen children admitted to the Hospital de Pediatría of the C.M.N. of the I.M.S.S. with the diagnosis of acute infectious laryngotracheobronchitis were divided into two groups with similar conditions for their study. The benefit derived from the application of recemic epinephrine with intermittent positive pressure was confirmed 15 and 30 minutes later by means of a double blind study; the improvement was swift and spectacular, but temporary; therefore, such treatment must be given only in hospitals, since relapses may show up two to four hours later, making in dangerous to send the patients home or to apply to ambulatory cases. The use of racemic epinephrine is proposed for hospitals having equipment and personnel trained in its management and the convenience of further studies is set forth to determine the period of effectiveness of racemic epinephrine and the advantage of giving repeated doses.