The National Exercise and Heart Disease Project. The pre-randomization exercise program. Report number 2. The National Exercise and Heart Disease Project (NEHDP) was funded by the Rehabilitation Services Administration (RSA) of the Department of Health, Education and Welfare, to determine the effects of regular physical activity on the rehabilitation, morbidity and mortality of patients with healed myocardial infarctions. Planning and development lasted from June 1972 through September 1974. Since 1974, 932 subjects were referred for evaluation. At randomization, 651 subjects were assigned to exercise treatment (323) or control (328) groups. Those who qualified for randomization had to complete an initial evaluation, attend 14 of 18 consecutively scheduled, low-level physical activity sessions during a period of 6 weeks, and complete a second evaluation. This prerandomization phase was accompanied by significant alterations in work capacity, heart rate levels at rest and during three levels of physical stress, systolic blood pressure reductions during stress but not at rest, and by changes in the level of anxiety and depression. The subjects will be followed for a minimum of 2 years at regular intervals to determine if regularly performed physical activity is beneficial to the rehabilitation of myocardial infarction survivors.


Pitfalls in the diagnosis of pericardial effusion. Echocardiography has proven to be a sensitive and reliable technique in the diagnosis of pericardial effusion. Care must be taken in recording to maintain proper angulation of the transducer, to scan adequate sites, and to maintain proper gain settings. The following entities may mimic pericardial effusion and must be excluded by careful analysis: left pleural effusion, mitral annulus calcification, anterior mediastinal space-occupying lesions, fibrinous pericardial reactions, and right heart catheters. Care must also be taken in the quantitation of pericardial fluid and in hemodynamic extrapolation.


Clinical applications of real-time two-dimensional scanning in congenital heart disease. Real-time two-dimensional visualization of cardiac anatomy has been a major advance in the noninvasive evaluation of congenital heart disease. Performed from precordial or suprasternal notch sites, the techniques allow noninvasive evaluation of the cardiac chambers, atrioventricular valves, and great arteries for the diagnosis of common and complex forms of congenital heart disease. Two-dimensional real-time echocardiography, therefore, can be expected to become an integral part of the noninvasive diagnosis and serial followup of children and infants with congenital heart disease.


Echocardiography in current perspective. Expensive cross-section echocardiographic recorders have been introduced only recently in a small number of medical centers in this country. More information is needed to determine the sensitivity and specificity of this technique for the diagnosis of various cardiac abnormalities. In contrast, M-mode echocardiography is an accepted and routine laboratory procedure. However, the clinician should be aware of the problems of technique and interpretation so that information obtained can be correctly utilized in relation to the clinical setting. The physician should assume a flexible attitude in this expanding field, and rigid dogmatic criteria should be avoided. Only in this way will echocardiography develop and be used to fullest advantage in clinical medicine.


The functional and structural border of the neurohemal region of the median eminence. In stressed rats the tanycytes of the ventrolateral wall of the third ventricle exhibit by light microscopic immunohistochemistry a positive staining for neurohormones which is distinctly limited to the distal perivascular end of the tanycyte process. Since by electron microscopic immuncytochemistry the tanycyte cytoplasm does not show any reaction product, the light microscopic reaction most likely results from a labeling of the intercellular space in the direct vicinity of the subendothelial cleft. Whether this subendothelial space is permeable to neurohormones was tested by injection of HRP1. In the region of the arcuate nucleus 30 min after intravenous application, the marker is affixed to the membranes of the perivascular tanycyte processes in the subendothelial cleft of capillaries possessing non-fenestrated endothelia. Occasionally, HRP penetrates for a short distance between the tanycytes. Then the labeling of the intercellular cleft ends abruptly. Here, several parallel ridges of tight junctions between the perivascular distal tanycyte processes are found by the freeze-etching technique. Since HRP cannot reach the subendothelial clefts of this region by passing through capillary walls due to the presence of a blood-brain barrier, it is suggested that the marker penetrates from the median eminence this far via the subendothelial extracellular space. It is prevented from spreading further by the tight junctions of the perivascular tanycyte endings. The same way may be taken by the neurohormones. Hence, a border area exists adjacent to the dorsolateral aspect of the neurohemal region of the median eminence where the tanycytes isolate the neuropil from the cerebrospinal fluid not only by their apical tight junctions, but also by basal tight junctions from the subendothelial cleft. This communicates with the perivascular space of the portal vessels.


Paddle cilia and discocilia - genuine structures? Observations on cilia of sensory cells in marine turbellaria. Kinocilia of epidermal sensory cells in fixed marine Turbellaria often terminate as flattened biconcave discs. The distal part of the ciliary axoneme curves back upon itself forming a 360 degree loop which is enveloped by the plasmalemma. In living animals this structure can be induced by the addition of sodium cacodylate, monobasic sodium phosphate, dibasic sodium phosphate, sucrose, calcium chloride, or formaldehyde to the sea water. Specimens treated with sodium chloride, glutaraldehyde, or osmium tetroxide do not show modified cilia. In animals prepared for EM at low temperature and with a buffered hypotonic fixative less kinocilia are modified than in animals treated with a buffered iso- or hypertonic fixative and at a higher temperature. It is assumed that the unusually shaped cilia, described as "paddle cilia" or "discocilia" in other invertebrates, do not represent a genuine but an artificial structure.


Gastrin and the ultrastructure of G cells after stimulation with acetylcholine. The effect of intragastric administration of acetylcholine on serum and antral gastrin concentrations of rats has been examined using a radioimmunoassay and quantitative electron microscopy. Exposure of the stomach of rats, previously fasted for 24h, to 2% acetylcholine for either 0.5 or 2h resulted in a significant 4--5 fold increase in serum gastrin concentrations to levels similar to those found in fed animals. Such treatment produced no detectable change in antral gastrin concentration or in the number or electron density of secretory granules in the G cells. This lack of detectable change in the G cells was not unexpected since our calculations suggest that less than 10% of the total gastrin stored in the antrum is released over 2h as a result of the stimulation with acetylcholine. The proportion of electron-lucent secretory granules was, however, markedly increased by prolonged fixation in aldehydes. The increase was similar in both ACh stimulated and control animals. These results indicate that the ultrastructural appearance of G cell secretory granules in influenced far more by the conditions of fixation than by the release of gastrin. They therefore cast considerable doubt on the hypothesis that gastrin is released by molecular dispersion from the granules.


Isolation and characterization of a promoter mutant in the str ribosomal protein operon in E. coli. The lambda fus3 transducing phage carries several operons for ribosomal proteins of E. coli, including the str operon. A mutant transducing phage with a promoter mutation in this operon has been isolated. This mutant shows reduced stimulation of synthesis of proteins encoded by the operon, S12, S7, and elongation factors G and Tu, in ultraviolet-irradiated cells. This mutation also abolishes in vitro transcription from the str promoter. The DNA sequence of the mutant promoter shows that it is a point mutation 6 bases upstream from the in vitro transcription start site, changing the "Pribnow box" sequence from TAAAATT to TAAAACT. These results indicate that the site altered by the mutation, which is in the region just preceding the transcription start site, is important for the expression of the str operon.


Characterization of a xenogeneic antiserum raised against the fetal germ cells of the mouse: cross-reactivity with embryonal carcinoma cells. A xenogeneic antiserum (PG-1) raised against the germ cells of the 13.5d p.c. mouse conceptus reacts with the fetal germ cells of both sexes and adult male germ cells, but not with any nongerminal tissue that has been tested. PG-1 can also react with the EC cells of four different teratocarcinoma cell lines. There are, however, marked differences in the absorptive capacity of the different EC cell lines. The antigen(s) recognized by the antiserum are confined to only a proportion of cells in some EC lines. This antiserum has a number of potential applications in studies of the origin and development of the mouse germ cell lineage.


Biochemical significance of the hard and soft acids and bases principle. The hard and soft acids and bases (HSAB) principle, which states that hard acids bind preferentially to hard bases and soft acids to soft bases, may serve to assess specific chemico-biological interactions. As living systems are composed mainly of "hard" elements, molecular events taking place within the cell are dominated by "hard-hard interactions". On this premise, it becomes likely that extraneous "soft" agents are particularly injurious to life. In the HSAB context a selected number of variegated phenomena are briefly discussed qualitatively; these include biocidal actions, heavy metal poisoning, chemical carcinogenesis, some enzymic reactions, and nucleic acid complexations. Although the HSAB principle cannot be used as a tool for mechanistic explanations of biochemical processes, it may provide clues to likely target molecules and the loci of action.


Efficiency of bacterial filtration in various commercial air filters for hospital air conditioning. Filtration efficiency of high-efficiency particulate air (HEPA) filters is said to be over 99.97% of removal rate against the mist of thermogenerating-type of dioctyl phthalate with average particles diameter of 0.3 micrometer, as tested by the U.S. Military Standard 282 (1956). Filtration of bacterial aerosols through commercial air filters was tested to examine the efficiency of bacterial filtration with eight kinds of air filters. Percentage of bacterial filtration efficiency (% BFE) of three kinds of HEPA filters showed 100% BFE, while NBS-95 and NBS-85 showed over 99% BFE. BFE of NBS-75 air filter was 91.75%.


Marginal closure of non-gamma2 amalgam.

Marginal closure of non-gamma2 amalgam. In order to investigate the effect of burnishing on the marginal closure of non-gamma2 amalgam restorations, a single-composition high-copper alloy (Indiloy), a conventional lathe-cut alloy (Lunargent Alloy), and a conventional spherical alloy (Shofu Spherical) were each mixed with mercury and filled in transparent plastic cavities. Half of the specimens were burnished along the cavity margins immediately after packing and again after carving. The remainder was unburnished. A dye was sprayed on their occlusal surfaces after 24 hr and leakage indicated by the dye penetration was observed through the plastic walls, and following facts were found: 1. Burnishing markedly decreased the leakage of all type alloy amalgams. 2. When burnished, the marginal leakage with the high-copper alloy was remarkably less than with the conventional spherical alloy but slightly more than that with the lathe-cut alloy. 3. The difference in the marginal leakage and in the effect of burnishing among the three amalgams was apparently related to their setting dimensional change curves.


Quantitative metabolic profiling based on gas chromatography. The quantitative metabolic profiles of volatilizable components of human biological fluids, particularly urinary organic acids, is reviewed, with emphasis on the use of gas-chromatography/mass spectrometer/computer systems. Various definitions of metabolic profiling are considered and techniques for obtaining such profiles are discussed. The role of computer processing of such data is examined, and statistical techniques for treating quantitative metabolic profiles are suggested.


Non-equilibrium enzyme immunoassay of gentamicin. We describe a fast, accurate non-equilibrium enzyme immunoassay for serum gentamicin. With use of isokinetic conditions an assay takes a total of 12 min, including regeneration of the immunosorbent. The coefficient of correlation between the present method and conventional microbiological assays was 0.98.


A sensitive manual enzyme immunoassay for thyroxine. We describe an immunoassay for thyroxine in serum. In the assay specific antibody covalently bonded to latex particles is used, along with horseradish peroxidase as the label, and o-phenylenediamine as the chromogen. The flexible protocol is designed for manual execution. Performance is similar to that of the highest-sensitivity thyroxine radioimmunoassays. Results correlate well with radioimmunoassay (r = 0.99, slope = 0.93, y-intercept = 2.4 microgram/liter for 201 samples) and an automated enzyme immunoassay (r = 0.97, slope = 0.99, y-intercept = 4.7 coefficients of variation are less than 7.2% over the entire useful range of the assay (20--240 microgram/liter). The limit of detection is less than 94 pg/tube at 20 microgram/liter. Only D-thyroxine is known to interfere with serum assays. This assay has no discernible protein effect from 40 to 80 g of protein per liter, unlike many thyroxine radioimmunoassays. Serum preservatives known to be peroxidase inhibitors do not adversely affect assay performance because of the 56-fold dilution in the final assay mixture. Hemolyzed serum and EDTA-treated plasmas are unsuitable for this assay.


Drug screening by enzyme immunoassay with the American Monitor KDA. The methods for barbiturate, opiate, methadone, and amphetamine have been modified for use with the American Monitor KDA. The modification, which incorporates automatic correction for endogenous lysozyme activity, was evaluated by comparing results obtained with the KDA for human urine samples containing known amounts of drug(s) with results obtained with the procedure recommended by Syva for the Gilford 3500. There was 98% agreement bewteen the two systems. Six calibrators and 40 samples can be assayed for all four drugs in about 2.5 h. The procedure has proven to be reliable for screening urine samples obtained from clients at a methadone treatment center.


Simultaneous gas-chromatographic analysis for diazepam and its major metabolite, desmethyldiazepam, with use of double internal standardization. Electron-capture gas-liquid chromatography was used for simultaneous quantitation of plasma diazepam (I) and its major metabolite, desmethyldiazepam(II). Because concentrations of I can greatly exceed those of II after single doses of I, two benzodiazepine-analog internal standards were added to all samples, thereby allowing reliable quantitation of high concentrations of I and low concentrations of II. After extraction at neutral pH with benzene (containing isoamyl alcohol), the organic extract is evaporated and the residue is reconstituted in a small volume of solvent and chromatographed on a 3% OV-17 column. The sensitivity limits are 2 to 3 ng of I or II per milliliter of original sample, with a CV for identical samples of less than 5%. The applicability of the method to single-dose pharmacokinetic studies of I in humans is illustrated.


Ectopic insulin and Occam's razor: reappraisal of the riddle of tumour hypoglycaemia. The concept of ectopic insulin production is challenged on the basis of a review of 120 cases from the literature on extrapancreatic tumours associated with hypoglycaemia in which insulin or insulin-like activity were measured. No case met two or more of five criteria of ectopic hormone production. The evidence indicates that hypoglycaemia of extrapancreatic tumours cannot be attributed to insulin. In those rare cases in which plasma insulin was reported as high, pancreatic beta-cells could not be excluded as the source of insulin. Interestingly, many of these dubious cases had carcinoid histology. The review also points out a close association between some spindle-cell tumours and carcinoid tumours which may be relevant to discussion on the disputed origin of some "mesothelial" tumours. Nonsuppressible insulin-like activity (NSILA) consists of a number of factors mimicking insulin activity which compete with insulin or proinsulin for membrane receptors and may crossreact in bioassays, immunoassays, and receptor assays. The question of whether one or several of these substances may be responsible for extrapancreatic hypoglycaemia remains to be elucidated.


Gonadotrophin, thyrotrophin and prolactin reserve in beta thalassaemia. Gonadotrophin (Gn), thyrotrophin (TSH) and prolactin (PRL) reserve was evaluated in patients (aged 12-26 years old) with beta thalassaemia. Abnormalities were detected in Gn reserve only. When compared with young adult controls, three of the four female patients and one of the two adult males had markedly impaired Gn responses to LH-releasing hormone (LHRH). Of the five prepubertal males, one had no Gn rise following LHRH, while responses in the other four patients were comparable to those in boys with delayed puberty. Only one adult male had an exaggerated LH response to LHRH. TSH and PRL dynamics were normal. No correlation could be found between the severity of the disturbance in the gonadal axis and the total number of blood transfusions. Our findings correlate best with the severity of the disease process itself.


Anesthesia related muscle paralysis in renal failure. We present 3 patients with chronic renal failure who had postoperative paralysis due to the administration muscle relaxants. One of them received gallamine, a non-depolarizing blocking agent that is mainly excreted by the kidney (70--90%). Two of them received pancuronium bromide, also a non-depolarizing blocking agent which is partially excreted by the kidneys (37--44%). All of them received succinylcholine. Succinylcholine is hydrolyzed by the serum cholinesterase into succinylmonocholine and choline. These active metabolites are excreted by the kidney. These patients serve as examples of the importance of considering the route of excretion of drugs and their metabolites in clinical situations involving the renal failure patient. The pharmacology of drugs administered relative to surgical procedures is reviewed.


An unusual variant of membranous nephropathy with abundant crescent formation and recurrence in the transplanted kidney. A patient with what initially appeared to be a typical membranous nephropathy had a progressive course to renal failure, nephrectomy, and transplantation. The nephrectomy specimen revealed abundant glomerular crescents and capsular synechiae. Post-transplantation the patient again developed a membranous nephropathy with florid crescents. Radioimmunoassay and indirect immunofluorescence tests failed to reveal anti-glomerular basement membrane antibody in the serum or kidney. It appears that there is a form of membranous nephropathy with crescent formation, unrelated to anti-GBM antibody, which has the capacity to recur after transplantation.


Recurrence of the hemolytic uremic syndrome in a 3 1/2-year-old child, 4 months after second renal transplantation. Terminal renal failure secondary to the hemolytic uremic syndrome (HUS) developed 18 months after initial transplantation and 4 1/2 months after the child received his second cadaveric renal allograft. Recurrence of the syndrome was evidenced by gross hematuria and hypertension after a 'flu-like' illness, sudden decrease in platelet count and hemoglobin, and erythrocyte fragmentation. Renal biopsy findings were compatible with HUS. Evidence is presented that the HUS was a recurrence of the original disease.


Successful immunosuppression of renal allograft recipients with alternate day steroid therapy. Twenty-five renal transplant recipients have been treated long-term with immunosuppressive therapy with conversion from a daily dose to an every other day dose of steroids in conjunction with daily administration of Imuran. The patients were selected by having stable grafts for 6 to 9 months prior to conversion, not by the presence of steroid-induced complications. Alternate day steroid administration has continued to provide successful immunosuppression in that only of 25 patients (4%) has had any evidence of renewed rejection activity during a treatment interval of 7--95 months, median 22 months and mean 28 months. One graft was lost to an acute rejection reaction that occurred in association with a flu-like syndrome 8 months after the conversion was started. It is concluded that in the patient with documented stability of the graft, every other day steroid administration is a successful immunosuppressive regimen.


Effect of trimazosin on hemodynamics in chronic heart failure. The effect of the oral vasodilator trimazosin on hemodynamics in 16 patients with chronic left ventricular failure was compared with placebo in a double-blind, randomized study. Eight patients received trimazosin 100 to 300 mg, and 8 received placebo. Over the 6-hr period after medication trimazosin caused no significant change in heart rate, stroke work index, or pulmonary vascular resistance, but there were significant reductions in mean arterial pressure (p less than 0.05), mean right atrial pressure (p less than 0.01), mean pulmonary artery pressure (p less than 0.01), mean pulmonary capillary wedge pressure (p less than 0.01), and systemic vascular resistance (p less than 0.01), and significant increases in stroke index (p less than 0.05) and cardiac index (p less than 0.05). None of 8 patients improved after placebo, whereas 5 of 8 patients (63%) had a good or excellent hemodynamic response after trimazosin (p = 0.006). Four of 4 patients who received 300 mg of trimazosin had a good or excellent response. Trimazosin is a long-acting orally effective vasodilator which improves ventricular function in patients with left ventricular failure.


Oral nefopam and aspirin.

Oral nefopam and aspirin. Analgesia through nefopam (30 mg, 60 mg, 90 mg), aspirin (325 mg, 650 mg), and placebo were compared in 122 hospitalized patients with moderate to severe postoperative, fracture, or other somatic pain. A double-blind noncrossover study design was used, and patients were evaluated for pain intensity and pain relief over a 6-hr period. Based on sum of pain intensity differences (SPID) scores, treatment effects were consistent and indicative of good dose response to both active medications. Pain relief scores were more variable but were generally in accordance with SPID values. Time-effect curves were similar. Estimated relative potency of nefopam to aspirin was 10.4 with a 95% confidence interval of 6.3 to 20.8 for SPID, indicating that the analgesic potency of nefopam, 60 mg, was equivalent to that of aspirin, 650 mg. Side effects were minimal.


Clinical pharmacokinetics of pethidine.

Clinical pharmacokinetics of pethidine. Pethidine is commonly used in single doses as a preoperative medication or in multiple doses as an analgesic. The clinical consequences of altered disposition are more likely to result from its analgesic use. Correlations between plasma pethidine concentration, analgesia and side effects such as respiratory depression, have been established, but considerable overlap exists between concentrations producing therapeutic and non-therapeutic effects. The current practice of intermittent pethidine administration (intravenous, intramuscular and oral) for analgesia results in fluctuations in pethidine plasma concentrations which are associated with incomplete pain relief and side effects. Continuous intravenous infusion of pethidine may avoid these difficulties. Changes in pethidine disposition have been observed in patients with liver disease and in the elderly. Measurement of plasma pethidine concentrations may be helpful as an aid to the management of such patients. In renal disease, metabolites may accumulate and cause side effects.


Clinical pharmacokinetics of phenylbutazone. More than 25 years after phenylbutazone was introduced as a non-steroidal anti-inflammatory agent, basic knowledge is still accumulating on its pharmacokinetics in man. Phenylbutazone is almost completely absorbed after oral administration. A large fraction of the drug in plasma is bound to proteins, and the drug has a small volume of distribution. Phenylbutazone is eliminated by metabolism, only 1% being excreted unchanged in the urine. Approximately 10% of a single dose of phenylbutazone is excreted in bile as metabolites. About 60% of the urinary metabolites have been identified. A novel type of drug metabolite in man, the C-glucuronide, is formed by direct coupling of the pyrazolidine ring of phenylbutazone to glucuronic acid via a C-C bond. Phenylbutazone is oxidised in a phenyl ring or in the side chain to hydroxylated metabolites, which may undergo subsequent O-glucuronidation. After a single dose, C-glucuronidation seems to be the dominant reaction, while oxidation becomes increasingly important after repeated administration. Due to different pharmacokinetic properties of the metabolites, the C-glucuronides are detected in highest concentrations in the urine, while the pharmacologically active compounds oxyphenbutazone and gamma-hydroxyphenbutazone predominate in plasma. The biological (elimination) half-life of phenylbutazone in man is long, with a mean of about 70 hours, and exhibits large interindividual and intraindividual variation. The interindividual variation is largely due to genetic factors. The intraindividual variation is dose and time dependent. In an individual there may be several critical dose levels where a change in the elimination kinetics takes place. Since there is no correlation between the plasma level and the clinical or toxic effects of phenylbutazone, there is at present no need for routine monitoring of plasma concentrations of the drug.


Clinical pharmacokinetics of chlordiazepoxide. Chlordiazepoxide was the first benzodiazepine derivative made available for clinical use. The metabolic pathway of chlordiazepoxide is complex, since the drug is biotransformed into a succession of pharmacologically active products: desmethylchlordiazepoxide, demoxepam, desmethyldiazepam, and oxazepam. The elimination half-life (tl/2beta) of chlordiazepoxide following single doses, in healthy individuals generally ranges from 5 to 30 hours, and the volume of distribution from 0.25 to 0.50 liters/kg. The hepatic extraction ratio is well under 5%. Elimination of the parent compound is mirrored by formation of the first active metabolite. Clearance of chlordiazepoxide is reduced and tl/2beta is prolonged in the elderly, in those with cirrhosis, and in those receiving concurrent disulfiram therapy. Oral chlordiazepoxide is rapidly and completely absorbed, but intramuscular injection is painful and results in slow and erratic absorption. Multiple-dose therapy with chlordiazepoxide results in accumulation of the parent compound, as well as two or more of its active metabolites. The rate and extent of accumulation varies considerably between individuals. A relation between plasma concentrations of chlordiazepoxide and its metabolites to clinical effects has been suggested in some studies and is currently under further investigation.


Salvage of the ear in acute trauma.

Salvage of the ear in acute trauma. Salvage of the ear in major acute trauma has been refined over the years. When severed parts were merely discarded, patients had to accept the defect or seek correction by secondary reconstruction. As primary reconstruction improved, the severed parts were reattached minimizing late deformities. Even when severed parts were not available, primary reconstruction advanced to meet the need. In the future it appears that immediate microvascular reconstruction will surpass our present achievements.


Reconstruction of traumatic ear deformities. Post-traumatic auricular deformity is a unique and varied problem that taxes the ingenuity of the plastic surgeon. Case individualization is repeatedly demanded and a systematic assessment of the residual tissue is requisite to planning an appropriate reconstruction. A basic guideline is presented to emphasize fundamental principles of plastic surgery and tissue transplantation as they are applied to this challenging area of our specialty.


Correction of prominent ears with multiple sutures. Mattress sutures from conchal cartilage to mastoid fascia, from scaphoid fossa to temporal fascia, from scapha to concha, and from the earlobe to the sternocleidomastoid muscle insertion give a satisfactory correction of most prominent ears.


Relation of tubular interstitial disease to renal function. In vitro concentrative transport of PAH-3H was evaluated in human renal biopsies by section freeze-dry autoradiography. Renal cortical tissue obtained by biopsy was incubated in vitro in medium containing PAH-3H, and section freeze-dry autoradiographs prepared. The autoradiographs demonstrated that the number of proximal tubules which accumulate PAH-3H in vitro varies inversely with the amount of tubular interstitial disease and directly with glomerular filtration rate. In order to further examine the mechanisms of tubular-interstitial disease, we have developed a technique for simultaneous fluorescent microscopy and autoradiography in single freeze-dried sections. This technique permits evaluation of the relationship between concentrative transport and immunoglobulin deposition in individual tubules and should increase our knowledge of the biologic significance of immunoglobulin deposits in proximal tubules.


Clinical application of the kidney to aortic blood flow index (K/A ratio). The kidney to aortic blood flow index (K/A ratio) is the ratio of the slopes of the upstrokes of renal and aortic histograms, derived from regions of interest applied to sequential gamma camera images of the first transit of a 99mTc bolus. This index proved in our previous dog studies to have a good correlation with renal artery blood flow. In the 190 clinical studies of renal allografts reported here, the K/A ratios correlate well with independently established retrospective clinical-pathologic assessment of renal functional status. Normal range for the K/A ratio was established in 50 patients with no demonstrable renal disease. Tests of inter-observer reproducibility show a mean relative standard deviation of 7% for independently performed analyses on the same data.


Stimulation of the renal kallikrein-linin system by vasoactive substances and its relationship to the excretion of salt and water. Large doses of angiotensin when infused intravenously or into the renal artery cause natriuresis. The initial effect is release of prostaglandin (probably PGE) and this leads to release of kallikrein. This latter step can be inhibited by noradrenaline. Activation of the kallikrein/kinin system is followed by release of a large molecular weight natriuretic hormone which is absent in glomerulonephritis. A small molecular weight hormone follows the large one and probably effects natriuresis by inhibition of renal Na/K ATPase. This inhibition is reversed by noradrenalint or renal nerve stimulation. Natriuresis is the result of a chain reaction and not a single specific natriuretic hormone.


Intra-renal factors in renin release.

Intra-renal factors in renin release. Renin release is believed to depend more on vasodilatation in the afferent arteriole than on any other factor. This allows for opposing effects of vasoconstriction and vasodilatation produced by sympathetic nerve stimulation by drugs or by autoregulation, to be interpreted in relation to the study of stretch of the afferent arteriole. This reduces but does not remove the necessity for alternate control through the macula densa. A final common pathway for all these stimuli is suggested through alterations in net calcium flux in the juxtaglomerular cell where increased intracellular calcium inhibits, and decreased intracellular calcium increases, renin release.


Prostaglandins and high blood pressure.

Prostaglandins and high blood pressure. Prostaglandins A1, B1, E2, Falpha and PRA have been measured by radioimmunoassay in peripheral or renal venous blood of different groups of hypertensive and control subjects. PGA1 and PGE2 were significantly increased in renal, renovascular, labile and essential hypertension. PGFalpha was significantly increased only in patients with unilateral renal atrophy and in some patients with renovascular and essential hypertension. There was a significant positive correlation between PRA and PGA1 or B1, but not with PGE2 or Falpha. The increase of PGA and PGE represents a secondary antihypertensive, diuretic and natriuretic mechanism, the increase of PGF a direct hypertensive mechanism.


Case for a renomedullary blood pressure lowering hormone. Ablation of renal tissue makes the subject sensitive to hypertension-inducing mechanisms, especially those due to fluid expansion, either by Na-volume or whole blood. Such hypertensive mechanisms are prevented by deviation of urine flow into a vein. Ablation of the renal medulla, by acute hydronephrosis or chemically, also potentiates the hypertensive state. Transplantation of either the renal medulla or its interstitial cells (RIC) can prevent or reverse hypertension. Under the latter conditions, the protective mechanism appears to result from the secretion of an antihypertensive hormone by the RIC. Lipid extracts of renal medulla not only prevent and reverse the hypertensive state in the same manner as medullary transplants but, under certain conditions, exert an acute depressor effect. The RIC can undergo hyperplastic changes much in the manner of an endocrine structure. For these reasons, it is proposed that the RIC represent an antihypertensive endocrine organ whose putative hormone may be termed the renomedullary antihypertensive hormone (ARH). Additional data in support of these contentions are presented.


The renal prostaglandin system: localization and some biological effects. The renal prostaglandins (PGs) are formed mainly in the endoplasmatic reticulum from locally available precursor, arachidonic acid (C20:4). Although the main PG formation occurs in the papilla, significant amounts of PGs are also formed in the cortex. PGs are not stored, but at once released to the cytosol and metabolized by soluble enzymes, 15-OH-PG-dehydrogenase (PGDA), delta13-PG-reductase and PGE-9-keto-reductase. PG metabolism by the PGDH pathway occurs predominantly in cortex. C20:4 can be used to study the biological effects of the renal PG system. C20:4 given to rabbits increases renal biosynthesis of PGs, renal blood flow, predominantly in the juxtamedullary cortex, and plasma renin activity. These effects are inhibited by PG synthesis inhibitors like indomethacin.


The chemistry, pharmacology and clinical pharmacology of diflunisal. Studies are reviewed on diflunisal, a new analgesic agent with an improved therapeutic index, compared with acetylsalicylic acid, in animals and humans. Pharmacokinetic data indicate that a twice-daily dosage regimen of diflunisal is adequate for therapeutic purposes. Diflunisal inhibits prostaglandin E synthesis, but in humans at clinically effective doses it does not alter bleeding time or platelet aggregation. Diflunisal is uricosuric at clinically effective doses. No clinically important drug interactions with diflunisal have been found to date, although some slight alterations in blood and urine drug levels have been noted. The slight increase in prothrombin time seen when diflunisal and acenocoumarol were co-administered is not considered to be of major clinical importance.


The analgesic and anti-inflammatory efficacy of diflunisal and codeine after removal of impacted third molars. A double-blind, randomized trial was carried out in 90 patients to compare the analgesic and anti-inflammatory efficacy of 500 mg diflunisal twice daily with that of 25 mg codeine phosphate 4-times daily and placebo in relieving pain and swelling after surgical removal of impacted third molars. Diflunisal was found to be superior to codeine and placebo on the first post-operative day, but the difference in efficacy of the drugs had diminished by the third post-operative day. In the diflunisal group of 30 patients, 10 (33%) developed 'dry socket' or alveolitis sicca dolorosa. Only 2 patients in the codeine group and 1 patient in the placebo group developed this very painful condition. The possible explanation of 'dry socket' is discussed.


The use of diflunisal in post-operative pain: a report of double-blind comparative trials in patients after meniscectomy. A series of double-blind randomized trials was carried out in patients suffering from moderate to severe pain after meniscectomy to assess the analgesic effectiveness of diflunisal. In a single-dose study, 150 patients received either diflunisal (125 mg, 250 mg or 500 mg), aspirin (600 mg), or placebo, and hourly assessments were made of pain severity over an 8-hour period. The results showed that 500 mg diflunisal produced comparable relief to aspirin within 3 to 4 hours, but the analgesic effect continued for longer and was still very marked after 8 hours. A multi-dose study in 120 patients receiving doses of diflunisal (375 mg or 500 mg) or placebo confirmed the overall effectiveness of twice daily treatment with diflunisal. In a comparative study against oxyphenbutazone (200 mg t.i.d.), hourly pain scores made on the first post-operative day showed that a single dose of 500 mg diflunisal produced comparable relief over a 12-hour period to that with 2 doses of 200 mg oxyphenbutazone. Overall response to multiple doses was assessed as excellent or good by all the patients receiving diflunisal. Preliminary results are reported on the use of diflunisal in other painful conditions.


A double-blind comparison of diflunisal and aspirin in the treatment of post-operative pain after episiotomy. A double-blind randomized trial was carried out in 161 primiparous women suffering from moderate to severe post-episiotomy pain to compare the analgesic efficacy of single doses of diflunisal (125 mg, 250 mg, of 500 mg), aspirin (600 mg), and placebo. The results of pain rating assessments made before and at hourly intervals after drug administration showed that both the active drugs were more effective than placebo and produced similar pain relief over the first 4 hours. The analgesic efficacy of aspirin tailed off after 4 hours but pain relief with 500 mg diflunisal was still evident after 8 hours. Over 65% of patients in the diflunisal group had effective relief of pain at 8 hours whereas there was no significant difference between the aspirin and placebo-treated groups by the seventh and eighth hour.


Diflunisal in post-episiotomy pain: a preliminary report of a double-blind comparative study. An on-going double-blind study was carried out in women requiring pain relief after episiotomy to compare the efficacy of 500 mg diflunisal twice daily, 65 mg dextropropoxyphene plus 650 mg paracetamol 3-times daily, and placebo. Fifty-seven patients, allocated at random to receive 2-days' treatment with one or other of the trial drugs, have been studied to date. The preliminary results, as assessed by descriptive rating scales, showed that all three treatments were equally effective in relieving spontaneous pain and pain at night. Patients' overall opinion showed no difference between treatments although the investigator assessed diflunisal to be better than the combined preparation and both to be better than placebo. A visual analogue scale of assessment is to be used for the remainder of the trial.


Diflunisal in the treatment of osteoarthrosis: a double-blind study comparing diflunisal with ibuprofen. A double-blind trial was carried out in 37 patients with osteoarthrosis to compare the efficacy and tolerance of 250 mg diflunisal twice daily with that of 400 mg ibuprofen 3-times daily over an 8-week period. Rating scale assessments were made, at the end of a preceding 1-week, wash-out period on placebo and at regular fixed intervals, of weight-bearing pain, night pain, a specific functional activity, and of the duration of inactivity stiffness. Patients' and physician's overall evaluations of response, taking side-effects into account, were made on completion of the study. The data collected indicated that in 30 patients completing the trial both treatments produced similar overall results and, with the exception of weight-bearing pain which appeared to be improved more in the ibuprofen group, diflunisal provided equal therapeutic benefit with fewer side-effects.


Diflunisal compared with naproxen in the treatment of osteoarthrosis of hip or knee: a double-blind trial. A randomized double-blind trial was carried out in 20 patients with osteoarthrosis of the hip or knee to compare the efficacy and tolerance of treatment with diflunisal or naproxen. During the first 4 weeks, patients received either 250 mg diflunisal or 250 mg naproxen twice daily and this was increased by 250 mg daily in 5 patients on diflunisal and in 3 on naproxen for the second 4 weeks of the trial. The results of subjective assessments made before and at the end of Week 8 showed a trend in favour of diflunisal for improvement of symptoms, except for weight-bearing pain which was improved in only 1 patient in each group. More of the patients receiving diflunisal than naproxen considered treatment to have been satisfactory, and rated their response as equally as good as or better than previous medication. Diflunisal produced significantly high incidence of gastro-intestinal upsets, leading to the withdrawal of 2 patients at Week 4.


Two trials of diflunisal in osteoarthritis. Two double-blind inter-group trials were carried out in which diflunisal was compared for 12 weeks against aspirin in 30 patients with osteoarthritis of knees or hips, and against naproxen for 8 weeks in 20 patients with osteoarthritic knees. Diflunisal appeared to be somewhat better than aspirin in terms of both effectiveness and tolerance, whilst it was similar in both repects to naproxen.


Relationship of plasma salicylate levels to pain relief with two different salicylates. In a preliminary open study of salsalate (3 g daily for 4 weeks) in 61 patients with rheumatoid arthritis or osteoarthrosis, it was found that although the drug produced satisfactory analgesia in 64% of patients, the incidence of side-effects was high (57% of patients): most were symptoms of salicylism and probably related to the high plasma salicylate levels achieved. In a second open study, 20 patients with osteoarthrosis were treated for 4 weeks with 250 mg diflunisal twice daily and then crossed over to salsalate (3 g daily) for a further 2 weeks. The results of subjective assessments of pain relief showed that both drugs produced satisfactory analgesia, and neither was associated with a significant level of gastro-intestinal bleeding. During the diflunisal treatment period there were no reports of salicylism, and plasma salicylate levels were very much lower than those measured after salsalate. The pain relieving effects of both drugs, assessed from patient preference for one or the other treatment, were unrelated to the plasma salicylate levels and it is suggested that plasma levels may have more relationship to the incidence of side-effects than with therapeutic effects.


Diflunisal in the management of sprains. A double-blind randomized trial was carried out in 31 patients suffering from acute, minor ligamentous injuries to compare the efficacy of diflunisal in the relief of pain with that of oxyphenbutazone. Patients received either 500 mg diflunisal twice daily or 200 mg oxyphenbutazone 3-times daily for 3 days. The results of subjective assessments showed tha by Day 3 spontaneous pain had either completely resolved or markedly improved in all patients, and that diflunisal was significantly better than oxyphenbutazone on Days 1 and 3 in relieving pain on movement of the joint.


Difunisal in general practice.

Difunisal in general practice. A large-scale, double-blind comparative study was carried out in general practice to assess the relative efficacy and tolerance of difunisal and aspirin in patients suffering from acute painful conditions such as sprains and trains, osteoarthritis, etc. Patients received either 250 mg or 500 mg difunisal twice daily, or 600 mg aspirin 4-times daily for 5 days. The results of subjective assessments of pain relief from the daily records of 1902 patients (967 on diflunisal, 935 on aspirin), and the overall assessment of response by both doctors and patients, showed that diflunisal was significantly better than aspirin. Gastric side-effects were more common and more severe in patients receiving aspirin, and more often led to withdrawal of treatment.


Care of the burn wound.

Care of the burn wound. The initial therapy of thermal injuries is directed at removal of loose debris and necrotic epidermis, alleviation of pain, and prevention of infection. Following initial wound debridement, bacterial growth in the wound itself is controlled primarily through the use of tropical antibiotic agents and daily hydrotherapy to clean the wounds and remove any loose eschar. Effectiveness of topical therapy is monitored by quantitative burn wound biopsy cultures; growth of greater than 10(4) micro-organisms per gram of tissue indicates invasive burn wound sepsis. Such bacterial invasion may be further controlled through the adjunctive use of antibiotics administered into the sub-eschar space. Once eschar separation has exposed healthy granulation tissue, the burn wound must be covered with suitable biologic dressings prior to autografting. All open wounds may then be autografted with sheet grafts to the face, neck, and areas exposed to trauma or by expansion mesh grafts to cover large areas from limited donor sites. Upon completion of autografting, a vigorous physical therapy program is necessary to rehabilitate victims of massive thermal injury to a functional existence.


Rationale for topical antibiotics.

Rationale for topical antibiotics. Topical antibiotics are under attack by critics who claim that no proof of efficacy exists and that systemic administration is far more effective. In this paper, we review the existing evidence and conclude that topical antibiotics have a place in the prevention and treatment of superficial skin infections. Our own experimental studies showed that topical antibiotics promptly reduce the density of Staphylococcus aureus in secondarily infected chronic dermatoses, associated with clinical improvement. In addition, topical antibiotics were shown to be highly effective in preventing and suppressing experimental S. aureus infections in human volunteers.


Effects of drinking hot water, cold water, and chicken soup on nasal mucus velocity and nasal airflow resistance. Nasal mucus velocity and nasal airflow resistance were measured in 15 healthy subjects before and at 5 and 30 minutes after drinking hot water by sip or straw, hot chicken soup by sip or straw, and cold water by sip. A sham drinking procedure with straw was also employed. Hot water by sip increased nasal mucus velocity from 6.2 to 8.4 mm per min, hot chicken soup by sip from 6.9 to 9.2 mm per min, and chicken soup by straw from 6.4 to 7.8 mm per min five minutes after administration. These increases were statistically significant compared to cold water, hot water by straw and sham. All values returned to their baseline at 30 minutes except cold water which significantly decreased the nasal mucus velocity from 7.3 to 4.5 mm per min. There were no significant changes from baseline in nasal airflow resistance 5 and 30 minutes following the above treatments. We conclude that drinking hot fluids transiently increases nasal mucus velocity in part or totally through the nasal inhalation of water vapor. Hot chicken soup, either through the aroma sensed at the posterior nares or through a mechanism related to taste, appears to possess an additional substance for increasing nasal mucus velocity. Finally, hot liquid might be superior to cold liquids in the management of fluids in upper respiratory tract infections.


Lytic activity of a new cephalosporin, cefuroxime, against gram-negative bacteria. Cefuroxime, a new cephalosporin antibiotic, was inhibitory at low concentrations to several types of gram-negative bacteria. It was considerably more stable than cephaloridine or cephalothin to the beta-lactamases produced by Escherichia coli (RP1), Klebsiella aerogenes K1 and Enterobacter cloacae P99. Concentrations of cefuroxime much greater than the minimum inhibitory concentration (MIC) were usually necessary to induce lysis of beta-lactamase and non-beta-lactamase producers. In contrast, cephaloridine, cephalothin and ampicillin were rapidly bacteriolytic at, or near, the respective MIC against non-beta-lactamase producers, whereas the activity of these three antibiotics was considerably reduced against beta-lactamase-producing strains.


Comparison between 5-fluorocytosine, amphotericin B and the combined administration of these agents in the therapeutic effectiveness for cryptococcal meningitis. Therapeutic effectiveness of 5-fluorocytosine (5-FC), amphotericin B (Am B) and both in combined administration were retrospectively assessed and compared with one another in 28 patients with cryptococcal meningitis. Combined administration was significantly superior to Am B alone and to 5-FC alone, and these agents were suggested to afford a synergetic effect in combined administration. Adverse reactions associated with combined administration did not essentially differ from those with Am B or 5-FC alone. Combined administration was able to decrease the incidence and severity of adverse reactions by employing lower doses of Am B, and this combined administration reduced the duration of treatment. An appropriate dose for each agent in combined administration was deemed to be about 0.350 mg/kg/day Am B i.v. and 150 mg/kg/day 5-FC p. o. based on the results of this study.


Folded chromosomes in non-cycling yeast cells: evidence for a characteristic g0 form. Folded chromosomes from stationary phase or ammonia-starved yeast (Saccharomyces cerevisiae) cells can be isolated as compact structures, distinct and separable by sedimentation from the folded chromosomes of pre-replicative (G1) and post-replicative (G2) nuclei. Such cells are in a dormant or non-cycling (G0) stage. The folded genome from such cells is referred to as the g0 form and has a sedimentation velocity of about 1700S. Sedimentation analysis of mixed G0 and G1 and G2 lysates indicates that the g0 structure is not an artifactual breakdown product of the g1 or g2 structures. A comparison of the proteins from g0 versus g1 and g2 structures by gel electrophoresis has revealed differences in about 10--11 non-histone and perhaps 2 histone proteins. Entry into the G0 stage, and emergence into G1 after G0 arrest, are accompanied by an ordered transition from g2 to g1 to g0, and from g0 to g1 to g2 forms, respectively. Hence, entry into G0 and re-emergence from G0 can be considered as differentiative processes, not normally part of the cell cycle, and accompanied by specific changes in the tertiary organization of the genome.


A pepsin-revealed material possibly related to chromosomal banding. The enzymes pepsin, alpha-chymotrypsin, trypsin, RNase and DNase were applied to preparations of human metaphase chromosomes before staining to study whether dissociable materials related to the formation of G-, Q- and C-bands would be seen. Treatment with active pepsin but not the other enzymes revealed material with ribonucleo-protein properties which dissociated from the chromosomes and formed a halo.--Lateral extensions from the chromatids stretched to the rim of the halo and appeared at positions corresponding to G-bands. A G-band may be defined as a ring of stable chromatid-matrix binding at positions where the chromatids coil to form lateral extensions.


Optimal perfusion parameters in kidney preservation. The optimal pressure in the renal artery during initial perfusion with Collins' solution by spontaneous pressure in canine kidneys is 40-50 cm H2O and in human kidneys 40-60 cm H2O. An average-sized human kidney can be perfused by a full current which is limited only by the lumen of the infusion set. In smaller than average-sized human kidneys the current must be reduced to diminish the pressure in the renal artery to the optimal value. In prolonged hypothermal perfusion by means of a Gambro apparatus it will be necessary to assess the optimal pressure by direct measurement in the renal artery in intact average-sized human kidneys because the pressure reading on the manometer is not identical with the optimal pressure in the renal artery.


Miliary tuberculosis in a patient after renal transplantation. A report is presented on the first case of miliary tuberculosis in a group of 84 kidney transplant recipients treated in the Institute of Clinical and Experimental Medicine, Prague, until March 1976. The specific process was verified by bacteriological investigations of the sputum and urine. Productive specific tuberculoid-type nodules with sporadically occurring acidoresistant rods were detected in a bioptic specimen of the transplanted kidney. Also discussed are therapeutical problems in progressive renal graft insufficiency and in simultaneous chronic hepatopathy.


Renal transplantation and pregnancy.

Renal transplantation and pregnancy. Processing of data from 79 pregnancies (incl. 11 observed by the authors) in 64 women (incl. 6 of their own patients) after renal transplantation revealed that approximately in 20% of the pregnancies in chronological association with the pregnancy the function of the graft deteriorated or ceased and in four instances this participated indirectly in the mother's death within one year after delivery. The effect of immunosuppressive treatment of the pregnant mother on the development of the foetus and 57 evaluated infants resp. was manifested by a 50% incidence of prematurity, in seven neonates by clinical or post-mortem findings of adrenal hypofunction or hypoplasia resp. and by hypofunction or hypoplasia of the lymphatic apparatus. Only in one neonate and one foetus (observed by the authors) an inborn defect was revealed. In five neonates chromosomal aberrations were described. The above findings support our disapproval of pregnancy in women after renal transplantation with the exception of recipients of grafts from siblings with closely related tissue properties and with a renal function stabilized for a long period and with minimal immunosuppression.


Possibilities of dynamic scintigraphy in renal allografts. Dynamic scintigraphy, a non-invasive method, is suitable due to its sparing procedure in particular in clinical conditions where more pretentious examination methods are contraindicated or risky. Very frequently it can serve as a guide for more aimed examination methods. Its diagnostic value is great in particular where pathological conditions of the efferent urinary pathways are concerned, i.e. above all fistulae. In parenchymatous lesions it provides information on focal processes of an inflammatory and non-inflammatory nature. Investigation of both functions, of perfusion and transport of hippuran is sometimes a supplement for the differentiation of ATN and rejection nephropathies. The distribution of perfusion after administration of technetate helps to detect occlusion of the afferent arteries and minor arterioles.


Urea and ammonia excretion into gastric juice in regularly dialyzed patients and patients after renal transplantation. I. Dialyzed patients. In regularly dialyzed patients in basal gastric juice and after stimulation with pentagastrin the volume of titrable acidity, urea and ammonia were assessed. It was revealed that in relation to the plasma urea concentration in basal juice the mean urea and ammonia concentration is roughly half and in stimulation juice roughly one third. The urea concentration in gastric juice is negatively correlated to the ammonia concentration. Urea excretion into the stomach depends on the plasma urea level and on the secretory gastric activity. The decisive factor of gastric secretion is probably parietal cell secretion. From the results ensues that gastric juice of dialyzed patients contains a quantitatively significant amount of urea and ammonia. Ammonia due to its neutralizing action distorts the examination of gastric acidity assessed by titration. The findings call for a revision of hitherto known data concerning gastric secretion of uraemic patients.


[Nosocomial infection of hospitalised patients with chemotherapy-resistant strains of Klebsiella pneumoniae (author's transl)]. In a 500-bed general hospital the incidence of highly resistant strains of Klebsiella pneumonia was examined. About 20% of examined patients in the surgical and medical departments were carriers. Spread of the organism was via the hands of personnel and patients as well as various objects. The use of broad-spectrum antibiotics, especially ampicillin and cefalotin is thought to be the chief cause of the high incidence of Klebsiella emergence. About 90% of carriers had previously received antibiotics.


[Demonstration of trichinella antibodies (author's transl)]. Serum samples of humans and animals with Trichinella infection of different duration and severity were analysed for Trichinella antibodies by four different serological methods. The indirect immunofluorescence test and the indirect haemagglutination test proved to be the most sensitive ones. Complement-fixation reaction gave the poorest results. In fresh Trichinella infections the heterologous antibody against cercaria of S. mansoni was more strongly developed than the homologous antibody which is effective in the microprecision test on Trichinella larvae. Although the animals deliberately infected also had, at the beginning of infection, a marked reaction to cercaria, this test became negative earlier than the microprecipitation test. Differentiation of Trichinella from Schistosoma infections is serologically possible without difficulty by means of adult schistosomes. The cross-reaction observed between T. spiralis and various Filaria types can be differentiated with adult O. volvulus as antigen.


Mianserin: a review of its pharmacological properties and therapeutic efficacy in depressive illness. Mianserin is a tetracyclic compound advocated for the treatment of depressive illness and depression associated with anxiety. It combines antidepressant activity with a sedative effect and has an EEG and clinical activity profile similar to that of amitriptyline. It has an overall efficacy comparable with amitriptyline and imipramine in depressive illness, but at dosages which have achieved a similar overall clinical improvement, mianserin causes significantly fewer anticholinergic side effects than amitriptyline or imipramine and also appears less likely than these drugs to cause serious cardiotoxicity on overdosage. Mianserin also has anti-anxiety activity, but its role in treating patients with anxiety associated with primary depression has still to be clarified. Mianserin appears to be well tolerated by the elderly and by patients with cardiovascular disease, including those recovering from a recent myocardial infarction, and does not appear to antagonise the action of adrenergic neurone blocking antihypertensive drugs or affect the anticoagulant action of phenprocoumon.


[Intra and extracellular acid spectrum of plaque incubated in vitro]. 1. The different in the substance spectrum of incubated plaque produced by the change from glucose to sucrose is insignificant. 2. A variation in the buffer capacity, such as is typical for cariogenic plaque in vivo, markedly influences the proportional composition of the acids formed. 3. The product spectrum of a mixed bacteria population such as in plaque is time dependent. The reason for this dependence is probably the interaction of the individual types of bacteria with each other. 4. The spectrum of acid composition extracted from the plaque is different from that in the vicinity of the plaque.


[Effect of the alpha-fraction of human blood plasma on the cellular and humoral immune response in mice and rats]. Th author describes the influence of the fraction Con-I-A of human plasma on the survival of skin transplantant in mice and the influence of the same fraction as well as human ceruloplasmin (purity over 97%) on the production of hemagglutinins in rats. In the nontreated animals with alpha-fraction the transplanted skin from C57BI/10 on BIOCZH survived on the average 7,5 +/- 0,54, but in the treated animals--8,56 +/- 0,55. Titers of hemagglutinins in Wistar rats, immunized with 0, Rh--human erythrocytes was 11,6 +/- 3,5 in nontreated animals on the fifth day, but in the treated animals with alphafraction the titre was 9,5 +/- 1,35 and 5,3 +/- 1,78 in the treated animals with ceruloplasmin.


Degradation of guanosine 3'-diphosphate 5'-diphosphate in vitro by the spoT gene product of Escherichia coli. Guanosine 3'-diphosphate 5'-diphosphate (ppGpp) is rapidly degraded to guanosine 5'-diphosphate (ppG) and probably pyrophosphate by an enzyme present in the ribosomal fraction prepared from spoT+ strains of Escherichia coli. The ppGpp-degrading enzyme was released from the ribosomes during dissociation at low ionic strength. Ribosomes are not essential for degradation of ppGpp, and decay of ppGpp is strictly dependent on manganese ions. The reaction is sensitive to inhibition by tetracycline, which can be reversed by MnCl2, indicating that the inhibitory effect is due to the previously described chelating properties of the antibiotic. When the ppGpp-degrading enzyme was complemented with adenosine 5'-triphosphate (pppA) and a nucleoside diphosphate kinase, decay of ppGpp was accelerated yielding pppG and ppG as major products. In the absence of pppA we have been unable to detect the ppGpp-degrading enzyme in various spoT- mutant strains indicating that this enzyme is the spoT gene product.


Anabolic ornithine carbamoyltransferase of Escherichia coli and catabolic ornithine carbamoyltransferase of Pseudomonas putida. Steady-state kinetic analysis. The anabolic and catabolic ornithine carbamoyltransferases of Pseudomonas putida display an undirectional catalytic specialization: in citrulline synthesis for the anabolic enzyme, in citrulline phosphorolysis for the catabolic one. The irreversibility of the anabolic enzyme in vitro has been previously explained by its kinetic properties, whereas the irreversibility of the catabolic transferase in vivo was shown to be due to its allosteric behaviour. In this work a steady-state kinetic analysis has been carried out on the catabolic ornithine carbamoyltransferase at pH 6.8 in the presence of the allosteric activator, phosphate. The kinetic mechanism of Escherichia coli ornithine carbamoyltransferase serving as a reference was also determined. For the E. coli enzyme in the reverse direction, the initial velocity patterns converging on the abscissa were obtained with either citrulline or arsenate as variable substrate. The inhibition by the product ornithine was linear competitive with respect to citrulline and linear non-competitive with respect to arsenate. In the forward direction phosphate and its analogs induce an inhibition by ornithine which is partial and competitive with respect to carbamoylphosphate. Together with the results of thermo-inactivation studies in the presence of each reactant, this observation suggests a random kinetic mechanism, but with most of the reaction flux following the path where carbamoylphosphate adds before ornithine, when substrates are present at Km levels. The allosteric catabolic ornithine carbamoyltransferase of Pseudomonas displays qualitatively the same pattern as the E. coli enzyme.


Initiation factor IF-3 and the binary complex between initiation factor IF-2 and formylmethionyl-tRNA are mutually exclusive on the 30-S ribosomal subunit. The formation of 30-S initiation complexes depends strongly on initiation factor IF-3; at molar ratios of IF-3 to 30-S ribosomes up to one a stimulation is observed, whereas at ratios higher than one, initiation complex formation declines strongly. The target of the observed inhibition of fMet-tRNA binding at high concentrations of IF-3 is the 30-S initiation complex itself. On the one hand addition of IF-3 to preformed 30-S initiation complexes leads to a release of bound fMet-tRNA which is linear with the amount of factor added, whereas no effect on isolated 70-S initiation complexes is seen. The release of fMet-tRNA from preformed 30-S initiation complexes is accompanied by a release of IF-2 in a one-to-one molar ratio which is in agreement with our previous findings showing that binding of fMet-tRNA takes place via a binary complex: IF-2 . fMet-tRNA (Eur. J. Biochem. 66, 181--192 and 77, 69--75). On the other hand increasing amounts of both IF-2 and fMet-tRNA relieve the IF-3-induced inhibition of 30-S initiation complex formation. From these findings it is concluded that IF-3 and the IF-2 . fMet-tRNA complex are mutually exclusive on the 30-S ribosome. This implies that under our experimental conditions MS2 RNA binding precedes fMet-tRNA binding if one accepts that the presence of IF-3 on the 30-S subunit is obligatory for messenger binding.


Binding of labeled initiation factor IF-1 to ribosomal particles and the relationship to the mode of IF-1 action in ribosome dissociation. The binding of labeled initiation factor IF-1 to ribosomal particles has been studied in relation to the mode of action of this factor in the dissociation of 70-S ribosomes. It is demonstrated that IF-1 interacts specifically with active 70-S tight couples and free 30-S subunits. The binding of IF-1 to both 70-S and 30-S particles is not influenced by the Mg2+ concentration and the affinity of the factor for both particles is about the same. The interaction of IF-1 with these particles is highest at low Tris-HCl concentrations. Under these conditions IF-1 shows a slight dissociating activity. Using 3H-labeled IF-1 and 14C-labeled IF-3 the formation of a 30-S-subunit.IF-1 . IF-3 complex from 70-S ribosomes is demonstrated. Our studies show that IF-3 enhances the binding of IF-1 to the 30-S subunit. In contrast to IF-1, which binds about equally well to 70-S and 30-S particles in the absence of IF-3, 14C-labeled IF-3 binds predominantly to the 30-S subunit. This finding confirms the view that IF-3 acts as an anti-association factor. On the other hand, IF-1 enhances the supply of 30-S subunits in the presence of IF-3 by acting on the 30-S moiety of the 70-S ribosome.


The mechanism of codon-anticodon interaction in ribosomes. Quantitative study of codon-dependent binding of tRNA to the 30-S ribosomal subunits of Escherichia coli. The formation of a ternary complex 30-S-subunit . poly(U) . tRNAPhe is discussed and the conditions for its correct description by Langmuir's isotherm are deduced. The affinity constant of the binary complex 30-S-subunit . poly(U) is measured. The reversibility of binding of tRNAPhe to the complex 30-S-subunit . poly(U) is proved in a direct way. The main reason for the heterogeneity of ternary complexes was found to be due to the ability of high-molecular-weight poly(U) to form complicated aggregates with 30-S subunits. If a fraction of poly(U) of moderate molecular weight (30 000) is used, then the ternary complexes are homogeneous in stability and yield the same affinity constants for deacylated, aminoacylated and peptidyl-tRNAPhe (1 X 10(8) M-1 at 20 mM Mg2+, 200 mM NH+4 and 0 degrees C). Ribosomal protein S1 increases the binding constant of poly(U) with 30-S subunits but does not change the binding constant of tRNAPhe with the 30-S-subunit . poly(U) complex. All 30-S subunits, even partially stripped of S1 protein, are active in the binding of both poly(U) and tRNAPhe.


History of precordial leads in electrocardiography. Precordial leads were first used by Waller, whose capillary electroscope was too insensitive to detect the electric forces emanating from the human heart unless the electrode was placed over the precordium as near to the heart as possible. When Einthoven developed the elegant, reliable and sensitive string galvanometer, he could record the electric forces of the heart from the hands and feet of the subject without even undressing him. When Einthoven's great galvanometer became available, only the three standard limb leads were used. Thomas Lewis and others experimented with precordial direct leads and made many important discoveries in electrocardiography and cardiology. Wolferth and Wood, in 1932, introduced the first precordial lead in clinical, diagnostic cardiology. The recordings were 'upside-down', i.e. positive deflections were down and negative ones up. They called this the 4th lead (lead IV). The precordial electrode was placed on the chest over the apex of the heart, regardless of where the apex was located. This immediately opened new avenues of study in infarction, ventricular hypertrophy, bundle branch block, and all other cardiac states. Then CL, CR, CF, CB and V leads were introduced. The points considered best for placing the 'exploring' or precordial electrode became an issue, and much confusion prevailed until Wilson and his associates developed the central or isopotential terminal and until the American Heart Association and the Heart Society of Britain and Ireland met in London and published the standards for recording precordial leads in 1938. There followed, for obvious reasons, a slow settling of the confusion until the V1 through V6 precordial leads became standard procedure all over the world, as exists today. Goldberger introduced the augmented unipolar limb leads (aVR, aVL and aVF) which have resulted in the standard 12-lead electrocardiogram of routine use today. No one would consider an electrocardiographic evaluation adequate in a cardiac study at present unless the 12-lead ECG were recorded.


The macrophage, target cell of the synthetic adjuvant muramyl dipeptide. The mechanism of adjuvant activity of the synthetic glycopeptide N-acetylmuramul-L-alanyl-D-isoglutamine or muramyl dipeptide (MDP) was studied using in vitro plaque-forming cell (PFC) response to sheep erythrocytes (SRBC). Addition of MDP to DBA/2 mouse spleen cell cultures resulted regularly in a 2 to 3-fold increase of PFC numbers/10(6) recovered cells (p less than 0.01). Supernates (SPN) from MDP-stimulated cultures added to standard spleen cell + SRBC cultures brought about even more important increases of PFC numbers (p less than 0.01 to p less than 0.001). SPN from cultures supplemented with MDP alone (without SRBC) were more active than those of cell + MDP + SRBC cultures, and SPN removed on day 3 of culture were more active than those of day 5. This activity of SPN was maintained accross an H-2 histocompatibility barrier. Although pretreatment of spleen cells with anti-theta antigen serum entirely suppressed the anti-SRBC PFC response in spite of the presence of MDP, SPN from these cultures were as active as SPN from normal spleen cell MDP-stimulated cultures. In contrast, pretreatment of spleen cells with specific rabbit anti-mouse macrophage serum entirely suppressed both anti-SRBC response and SPN activity. It was concluded that the target cell for MDP is the macrophage which releases factors ultimately acting on B cells through T cell mediation.


Immune interferon. II. Different cellular site for the production of murine macrophage migration inhibitory factor and interferon. The production of macrophage migration inhibitory factor (MIF) and immune interferon (IF) by concanavalin A (Con A)-stimulated cultures of thymus, lymph node and spleen cells was investigated. It was found that all cultures produced MIF activity, whereas only spleen cells produced marked IF activity. The capacity to produce IF was found to be correlated with the macrophage content of a cell preparation as evidenced by staining for esterase-positive cells. Furthermore, column-purified spleen T cells produced MIF but no IF. Migration inhibition caused by residual mitogen could be ruled out. On the other hand, when macrophages grown from bone marrow cells were pre-exposed to supernatants of mitogen-stimulated lymphocytes, IF activity was released into freshly added medium while no significant MIF activity was found. IF was also found in supernatants of macrophage cultures after exposure to conventional inducers in vitro (polyinosinic-polycytidylic acid, Corynebacterium parvum) or in vivo (C. parvum), whereas no MIF was detected. An anti-Type I IF serum neutralized IF in supernatants from Con A-stimulated spleen cells but did not affect MIF in the same supernatants. This indicates that IF and MIF activity are associated with different molecules. It is, therefore, concluded that under the described conditions, IF and MIF are produced by different cells. T cells are the prime producers of MIF while IF is released by macrophages following induction by lymphokines.


Nuclear pores. Can they expand and contrast to regulate nucleocytoplasmic exchange? Recent evidence has revived the idea that translocations of macromolecules between nucleus and cytoplasm may be regulated via expansion and contraction of the entire diameter of the nuclear pore complex. The present investigation does not support this hypothesis.


Erythrocytes within pancreatic B-cells of corticosteroid-treated mice. An ultrastructural study of the endocrine pancreas of female ICR mice that received 21 daily injections of the synthetic glucocorticoid, Triamcinolone diacetate (8 mg/kg b.wt) revealed some examples of microhaemorrhage within islets of Langerhans, extravasation of erythrocytes, and the presence of erythrocytes within B-cells, where they undergo degradation to form myelin-like configurations.


Functional role of arginine residues in glutamic acid decarboxylase from brain and bacteria. The arginine-specific reagent phenylglyoxal rapidly inactives glutamic decarboxylase from both mouse brain and E. coli when preincubated with the enzyme at concentrations of 3 mM to 40 mM. The rate of inactivation follows pseudo-first-order kinetics and is dependent upon the concentration of phenylglyoxal. These and other data presented support the idea that arginine residues play a key role in the mechanism of action of glutamic decarboxylase.


Metabolism of vitamin K and prothrombin synthesis: anticoagulants and the vitamin K--epoxide cycle. Vitamin K is primarily located in hepatic microsomes, where the vitamin K-dependent carboxylation in prothrombin synthesis occurs. Recent evidence supports the idea that the carboxylation is linked to the metabolism of the vitamin--specifically the cyclic interconversion of vitamin K and vitamin K epoxide. The primary site of action of coumarin and indandione anticoagulants appears to be an inhibition of the epoxide-to-vitamin K conversion in this cycle. There is a correlation between the inhibition of prothrombin synthesis and the regeneration of vitamin K from the epoxide by anticoagulants. In hamsters and warfarin-resistant rats prothrombin synthesis and the epoxide-K conversion are less sensitive to warfarin than in the normal rat. The epoxide-K conversion is impaired in resistant rats, which may explain their high vitamin K requirement. There is also a correlation between vitamin K epoxidation and vitamin K-dependent carboxylation, but the apparent link may be because vitamin K hydroquinone is an intermediate in the formation of the epoxide and also the active form in carboxylation. The vitamin K-epoxide cycle is found in extrahepatic tissues such as kidney, spleen, and lung and is inhibited by warfarin.


Correction of crossbite.

Correction of crossbite. The purpose of this article is to present to the dental practitioner a better insight and understanding into the recognition, etiology, timing of treatment, differential diagnosis, and methods of treatment for the anterior and posterior crossbite conditions as seen in the developing dentition of the child. It is important to realize that early diagnosis, correction, or referral to a specialist of these occlusal irregularities may prevent the possibility of any adverse effects upon the growth and development of the child's dental-skeletal-facial complex.


Double-blind comparison of butorphanol tartrate and meperidine hydrochloride in balanced anaesthesia. Butorphanol tartrate, a synthetic morphinan which has analgesic agonist and antagonist properties, was compared with meperidine for balanced anaesthesia. The two agents were found to be comparable in efficacy, maintenance of cardiovascular stability, and incidence of side-effects. Butorphanol has the advantage of being non-narcotic and having a lower propensity for addiction. Because of its antagonist properties, there appears to be a limit to its depressant effects on respiration.


A comparative double-blind trial of the new antidepressant caroxazone and amitriptyline. On the grounds of pharmacological properties and preliminary clinical trials the efficacy of the new antidepressant caroxazone was compared to amitriptyline in the management of depression. Forty patients mostly suffering from a neurotic or anxious-neurotic depression were admitted to a double-blind trial. All patients completed the study. The Hamilton Rating Scale for Depression was used for the clinical assessment at the beginning, during and at the end of treatment. The trial lasted three weeks. A significant improvement was seen for both drugs after seven days on most symptom scores and on total symptom score. No significant differences were found either at seven days of at the end of treatment between the two drugs. There were no significant differences in the incidence and severity of side-effects. In conclusion, caroxazone appears as an effective and well tolerated drug in the treatment of depression.


Piracetam and chlormethiazole in acute alcohol withdrawal: a controlled clinical trial. Sixty in-patient alcoholics, presenting with an alcohol withdrawal syndrome after at least one week's drinking bout, were randomly allocated to fixed dose regimens of either piracetam or chlormethiazole in a one-week double-blind trial. The patients were studied in respect to physical and biochemical parameters as well as symptom reduction and side-effects. The battery of rating scales demonstrated a good symptom reduction in both drug groups. On the whole a small tendency to more symptom items being reduced on piracetam in comparison with chlormethiazole was found. But the tree items, sleep disturbances, decreased libido at the initial phase, and the staff's assessment showed statistically significant differences in favour of chlormethiazole. This study demonstrated that piracetam was just as efficient as chlormethiazole in patients not requiring sedation.


A comparison of the minimum inhibitory concentrations of sisomicin and of fourteen other antibiotics. The activities of sisomicin and of fourteen other antibiotics have been compared for their inhibitory activity on all the different strains of bacteria isolated from a 3,000 bed hospital. The antibiotic sensitivity tests were performed in liquid medium and expressed as minimum inhibitory concentrations. The tests were performed over a period of four months. The results are discussed.


Syngeneic transplantation of fetal rat pancreas. I. Effect of insulin treatment of the reversal of alloxan diabetes. Sixty-nine alloxan-diabetic male Fischer rats received syngeneic transplants of eight 18-days-postcoitum fetal pancreases at the renal subcapsular site. One half of the recipients were given 2 to 4 U. protamine-zinc insulin for seven days immediately after transplantation. This insulin-treatment regimen effectively normalized blood glucose rapidly. Forty-seven transplant recipients survived, and diabetes was reversed in all. Insulin treatment had no effect on recovery time or glucose tolerance. Those animals requiring longer periods to reach normoglycemia had impaired glucose tolerance. Some insulin-treated recipients returned to normoglycemia rapidly while others required an extended period. Those animals that showed rapid reversal exhibited elevated concentrations of plasma insulin both in the fasting state and during glucose tolerance tests. No pretransplant parameters could be identified as predictors of rapid reversal.


Syngeneic transplantation of fetal rat pancreas. II. Effect of insulin treatment on the growth and differentiation of pancreatic implants fifteen days after transplantation. Eight 18-days-postcoitum fetal pancreases were transplanted to isogenic alloxan-diabetic male rats. Some recipients were treated with insulin for seven days immediately after transplantation. Eight animals in both the insulin-treated group and control group were killed 15days after transplantation for morphologic and hormonal studies of the transplanted tissue. Using the morphometric technique of linear scanning, the insulin, glucagon, and somatostatin immunocytochemically positive, cell masses of the fetal pancreatic implants were quantitated. The beta cell mass of the implants from the control animals increased roughly eightfold from the time of transplant; insulin treatment resulted in a further two- to threefold increase. The insulin content of the implants increased more than did the beta cell mass, resulting in the fivefold increase in insulin per beta cell. The alpha cell and delta cell masses did not change during the transplant site, the mass of functional beta cells, and the cell-to-cell content of the implanted tissue. These results are discussed in relation to previous quantitative studies of pancreatic islet cell growth. The relationships of the transplant site, the mass of functional beta cell, and the cell-to-cell interaction within the islet to the maintenance of glucose homeostasis are also discussed.


The effect of E. coli L-asparaginase on oral glucose tolerance and insulin release in man. To study the effect of E. Coli L-asparaginase on glucose tolerance and insulin release, 6 patients with neoplastic disease were subjected to 3 hour oral glucose tolerance tests with simultaneous measurement of serum immunoreactive insulin (IRI) levels before and following the intravenous administration of 5000 I. U. L-asparaginase/day for 4 days. Five of the patients exhibited a significant deterioration in glucose tolerance; however, no change was noted in their fasting glucose and IRI levels. The deterioration in glucose tolerance was associated with a decrease in the amount of insulin secreted in the first 30 minutes after the oral glucose load. The total amount of insulin released during the 3 hour test remained unchanged. These studies suggest that L-asparaginase can cause a deterioration of glucose tolerance without accompanying fasting hyperglycaemia. This may be due, in part, to a decrease in glucose-induced insulin release during the first thirty minutes following oral glucose.


Insulin secretion from pancreatic islets: effect of growth hormone and related proteins. Insulin responses to clinical grade human growth hormone (hGH), intact hGH, naturally occurring diabetogenic substance (NDS), and subtilisin cleaved forms of hGH (S1 and S3) were studied using hypophysectomized rat pancreatic islets. While clinical grade hGH (200 microgram/ml) elicited a prompt and sustained release of insulin, purified intact hGH (200 microgram/ml) did not. Naturally occurring diabetogenic substance, isolated from clinical grade hGH preparations, stimulated insulin release at 200 ng/ml. Upon repeat stimulation with NDS, a significantly greater insulin release than with initial stimulation was observed. Although S3 (200 microgram/ml) elicited significant insulin release, S1 (200 microgram/ml) did not. Direct stimulation of insulin release with clinical grade hGH is not due to intact hGH but another proteins(s) such as NDS. Enzymic modification of intact hGH appears to enhance insulin stimulatory capacity.


Persistent insulin secretion, assessed by plasma C-peptide estimation in long-term juvenile diabetics with a low insulin requirement. In order to investigate whether patients with long-standing juvenile diabetes mellitus (onset of diabetes before the age of 30) and a low daily insulin requirement (less than 0.50 units/kg body weight) still have functioning B-cells, plasma C-peptide was determined after stimulation (OGTT and glucagon/tolbutamide) in 64 patients with diabetes of more than 18 years' duration (mean 31 years). Measurable endogenous insulin production was found in 24% of the patients. The prevalence of severe retinopathy was lower in the secretors than in the non-secretor group. There was no difference in insulin antibody concentration between the two groups. Furthermore, the insulin requirement in the secretor group was relatively constant during the course of diabetes. Metabolic control was similar in both groups. It is concluded that a persisting but low activity of endogenous insulin production can be found in many long-term juvenile diabetics with a low insulin requirement, while others without any residual beta-cell function develop a low insulin requirement for unknown reasons.


Metabolism of cold-stored pancreatic islets. A previous study showed that the ability of glucose to stimulate insulin release was retained in islets stored at 8 degrees C for one week provided that glucose was present in a high concentration in the storage medium. The metabolic properties of islets stored in the cold have now been further explored in an attempt to clarify the protective effect of glucose. During storage in the cold the islet formation of 3H2O from (5--3H) glucose and oxygen consumption were only a few per cent of that of fresh islets whereas the putake of 86Rb+ was 20--48%. Rewarming the cold-stored islets to 37 degrees C after one week of cold-storage restored the 86Rb+ uptake, the formation of 3H2O and 14CO2 from labelled glucose and oxygen consumption to 75, 80, 60 and 40% respectively of fresh islet levels. The results emphasize the usefulness of cold-storage for preservation of functionally intact isolated islets.


Intracellular pancreatic B cell serotonin and the dynamics of insulin release. The role of intracellular pancreatic B cell serotonin in the dynamics of insulin release was investigated in an in situ perfused rat pancreas preparation. Animals were pretreated with 5-hydroxytryptophan (5-HTP) to increase the intracellular levels of serotonin (5-HT) as shown by fluorescence histochemistry. Despite a clear induction of intracellular 5-HT fluorescence in pancreatic islets neither the pattern nor the total amount of insulin released were significantly modified after perfusion with either glucose or tolbutamide. However, the L-amino acid decarboxylase inhibitor, RO 4--4602, significantly decreased both phases of glucose-mediated insulin release in normal animals as well as in those receiving 5-HTP.


[Corrective surgery of double-outlet right ventricle and subaortic ventricular defect. Report of 12 cases surgically treated (author's transl)]. Experience with corrective surgery in 23 pts with double outlet right ventricle (DORV) and subaortic VSD is presented. The overall hospital mortality was 17%. Patients were divided into two groups: Group I includes seven cases without pulmonic stenosis and Group II sixteen cases with pulmonic stenosis. Six of Group II required a sistemic to pulmonary artery shunt earlier in life. Anatomic and clinical aspects in both groups are described as well as indication for surgery. The importance of angiocardiography for a precise diagnosis is emphasized. Problems related to management and complications are discussed; in particular how to avoid LVOTO in case of restrictive VSD and RVOTO in patients with pulmonic stenosis.


[Efficacy and tolerability of a cardioselective beta-blocking drug (atenolol) in the treatment of essential hypertension. A double blind study (author's transl)]. The antihypertensive effect of atenolol, a new beta 1 receptor blocking agent, was studied in a double blind non cross-over trial in 40 patients (pts) affected by mild to moderately severe essential hypertension with normal plasma renin activity. After a run-in period (15 days) of placebo treatment pts were assigned to two groups. The first (group A) continued placebo treatment for 30 days, the second (Group B) were given atenolol (ICI 66082) 100 mg daily for 30 days also. Atenolol significantly reduced systolic and diastolic blood pressure in recumbent and standing position and heart rate at rest. No significantly changes of the same parameters were observed in group A. Body weight and plasma renin activity was unchanged in both groups. Atenolol treatment never was discharged in order to side effects. These results seem to suggest that atenolol can be an useful drug in the treatment of systemic blood hypertension.


Pathogenesis of mucosal injury in the blind loop syndrome. Bacterial extracts were prepared from cultures originating in chronic self-filling intestinal blind loops in rats. Their ability to remove active maltase molecules from isolated brush border membranes was studied in vitro. Twelve strains in 51 tested, belonging to one of three species, Bacteroides fragilis, Clostridium perfringens, and Streptococcus fecalis, possessed maltase-releasing activity. The ability to remove maltase correlated well with the ability to hydrolyze p-nitrophenyl-tert-butyloxycarbonyl-l-alaninate (NBA), an ester substrate rapidly hydrolyzed by elastase, but not with substrated favored by tryhsin and chymotrypsin. Maltase-releasing activity from C. perfringens was strongly inhibited by soybean trypsin inhibitor and to a lesser extent by lima bean trypsin inhibitor. Of four chloromethylketone active-site directed inhibitors tested with specificities for elastase, trypsin, and chymotrypsin, inhibition was maximal with elastase-specific inhibitors. In two species, activity was shown to be heat sensitive, and to be inhibited by concentration of the extract. In one species maltase-releasing activity was shown to be due to an enzyme of molecular weight at least 66,000 with the capacity to remove lactase, sucrase, and alkaline phosphatase, as well as maltase. The results indicate that anaerobic or facultatively anaerobic species, previously identified with the pathology of of the blind loop syndrome, contain proteases which are capable of removing components of the intestinal surface membrane. These proteases appear to have elastase-like substrate specificity and may be involved in the etiology of disaccharidase deficiency in bacterial overgrowth syndromes.


Failure of atropine to inhibit gastrin-17 stimulation of the lower esophageal sphincter in man. Heptadecapeptide gastrin I (G-17) contrast the lower esophageal sphincter (LES) in man and animals. Previous studies in man found that atropine infusion (12 microgram kg-1hr-1) inhibited the effect of gastrin on the LES, suggesting that this effect of gastrin is mediated by a cholinergic mechanism. Studies in the opossum have not shown similar inhibition. To reevaluate the interaction of atropine and G-17 on the LES, 5 normal males were studied. Submaximal and maximal effective doses of G-17 were used with both atropine infusion (12 microgram kg-1hr-1) and rapid intravenous injection (1 mg). There was a small decrease in basal LES pressure with atropine infusion. However, neither atropine infusion nor rapid intravenous injection inhibited LES stimulation by submaximal and maximal doses of G-17. The results do not support the hypothesis that LES responses to gastrin are mediated by an atropine-sensitive cholinergic mechanism.


Circadian rhythm and dietary response of disaccharidase activities in isolated rat jejunum. Studies were made on the effects of intraluminal factors on the circadian rhythm and the adaptive change to diet of maltase and sucrase activities in rat small intestine. Rats given carbohydrate-free diet for 1 week showed lower specific activities of these enzymes than rats on the latter diet. Segments of jejunum, isolated as blind sacs with normal blood and nerve supplies, showed the same circadian rhythm as unligatured jejunum, but their enzyme activities were not increased by administration of carbohydrate-rich diet for 1 week. Thus it was concluded that the adaptive changes of disaccharidase activities caused by change in diet depend primarily on the presence of carbohydrate in the intestinal lumen, whereas the circadian rhythmic changes do not.


Epidermis is the site of action of tabby (Ta) in the mouse. The site of action of the sex-linked tabby (Ta) locus was analyzed by the technique of dermal-epidermal recombination grafting. Skin components from normal and tabby 14-day embryos were separated, recombined and grown 21 days in testes of histocompatible mice. Grafts of the combinations normal epidermis-normal dermis and normal epidermis-tabby dermis produced predominantly zig-zag hairs. Grafts of the combination tabby epidermis-normal dermis and tabby epidermis-tabby dermis produced hairs with a morphology similar to hairs found in tabby mice. We conclude from these results that the tabby locus acts within the epidermis, and has no effect on the dermis.


Metabolism of ribosomal RNA in mutants of Escherichia coli doubly defective in ribonuclease III and the transcription termination factor rho. To determine if proteins RNase III and rho, both of which can determine the 3' ends of RNA molecules, can complement each other, double mutants defective in these two factors were constructed. In all cases (four rho mutations tested) the double mutants were viable at lower temperatures, but were unable to grow at higher temperatures at which both of the parental strains grew. Genetic analyses suggested that the combinations of the rnc rho (RNase III-Rho-) mutations was necessary and probably sufficient to confer temperature sensitivity on carrier strains. Physiological studies showed that synthesis and maturation of rRNA, which is greatly affected by RNase III, as well as other RNAs, was indistinguishable in rnc rho strains as compared to rnc rho+ strains, thus suggesting that RNase III and rho do not complement one another in determining the 3' ends of RNA molecules. In rnc rho strains, however, the newly synthesized rRNA failed to accumulate. Thus, decay of rRNA could be the reason for the temperature sensitivity of the double mutant strains. These experiments suggest that RNase III and rho can both protect rRNA from degradation by cellular ribonucleases. They also point to the possibility that the nucleotide sequences involved in the determination of the 3' ends of RNA molecules by these two factors are not identical.


Meiotic recombination and DNA synthesis in a new cell cycle mutant of Saccharomyces cerevisiae. Vegetative cells carrying the new temperature-sensitive mutation cdc40 arrest at the restrictive temperature with a medial nuclear division phenotype. DNA replication is observed under these conditions, but most cells remain sensitive to hydroxyurea and do not complete the ongoing cell cycle if the drug is present during release from the temperature block. It is suggested that the cdc40 lesion affects an essential function in DNA synthesis. Normal meiosis is observed at the permissive temperature in cdc40 homozygotes. At the restrictive temperature, a full round of premeiotic DNA replication is observed, but neither commitment to recombination nor later meiotic events occur. Meiotic cells that are already committed to the recombination process at the permissive temperature do not complete it if transferred to the restrictive temperature before recombination is realized. These temperature shift-up experiments demonstrate that the CDC40 function is required for the completion of recombination events, as well as for the earlier stage of recombination commitment. Temperature shift-down experiments with cdc40 homozygotes suggest that meiotic segregation depends on the final events of recombination rather than on commitment to recombination.


[Population frequency of neural tube defects in the population of the city of Moscow]. A sample investigation was carried out in 14 maternity homes of Moscow during 1970--1976 in order to determine the population incidence of defects of the neural tibe. Among 282336 newborns 220 probands with these anomalies were found including 11 with syndromes of non-multifactorial etiology. The total incidence of multifactorial forms was 0.74 +/- 0.10 per 1000 newborns, the incidence of the anencephaly was 0.33 +/- 0.07% and the frequency of the spina bifida was 0.41 +/- 0.07% respectively. The sex ratio 0.61 among probands was statistically significantly different from that normal among newborns. An insignificant increase of the incidence of the defects was observed during the autumn and winter seasons. No correlation was observed between the mother's age, the birth order and the incidence of the neural tube defects.


[Coding R.M.EcoR1-plasmids derived from R-factor]. Bacteriophages P1vir and Mu-1 have been used for transductional shortening of recombinant R factor coding for R.M.EcoR1 isolated by Yoshimori et al. P1 shortening made possible the isolation of transmissive isogenic plasmids coding R.M.EcoR1 and differing in antibiotic resistances, as well as isolation of plasmids differing only in R.M.EcoR1 genes. Mu-1 mediated shortening favoured the isolation of transmissive R plasmids having lost the resistance to chloramphenicol but having all other markers of recombinant R factor intact. The data are interpreted in support of Yoshimori et al. supposition concerning the existence of R.M.EcoR1 coding recombinant R factor of Escherichia coli.