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Monoclonal antibodies have been prepared against rat liver epoxide hydrolase (EH), some of which gave precipitation lines on immunodiffusion against pure EH suggesting the presence of repetitive structural domains on the enzyme. Using ELISA, with polyclonal antibodies to rat and rabbit liver EH, reactivity and therefore structural similarities between EH of all species tested, including human, were observed. This was in contrast to immunodiffusion results demonstrating the limitations of the latter technique. Using monoclonal antibodies in ELISA, greatest structural similarity was between rat, mouse, and Syrian hamster EH and relatively little between rat and human. Two of the antibodies reacted with nearly all species tested and may be directed towards critical sites on the enzyme. This and most of the EH molecule would appear to be localised on the cytoplasmic surface of the endoplasmic reticulum.

The horizontal semicircular canals of goldfish were sinusoidally stimulated 0.07 and 63 Hz (about 3 decades). Single afferent fibre recordings showed sinusoidal modulation of discharges. Above 4 Hz the discharges became phase-locked to the stimulus. With increasing frequency the number of spikes per period decreased so that finally only one spike per period remained. At 63 Hz a stimulus of as little as 0.005 degrees was sufficient to drive the units to far above their spontaneous activity. As cupular deflection is less than the angle of body movement, the cupular deflection threshold for modulation of afferent discharges must be much less than 0.005 degrees. Transfer functions of afferent activity were determined. The simple pendulum model does not fit the data. Additional introduction of a third time constant and the low pass properties of the receptor cell membrane, the synaptic delay and the leaky integrator of the post synaptic afferent terminal improve the fit.

Ten out of 20 children with malignant diseases who received cisplatin in combination with other drugs developed hearing impairment primarily at the higher and rarely also at the lower frequencies. The CDDP-ototoxicity was found to be dose-related and irreversible. Audiometric abnormalities were symmetrical and bilateral. Two patients had symptomatic hearing impairment. Ototoxicity was more severe with higher individual and higher cumulative doses. CNS-irradiation increases the ototoxic effect of CDDP. Audiometric testing at the beginning of chemotherapy and during chemotherapy is important to find out preexisting disturbances of hearing function and to recognize early developing hearing loss.

A sodium dodecyl sulfate-gel electrophoretic procedure which allows the separation of isolated cytochrome c oxidase from different mammalian sources into 13 different polypeptides is described. Application of the silver-staining procedure results in the same protein pattern as obtained by Coomassie blue staining. From the correlation of the gel bands with 12 isolated polypeptides from which the complete amino acid sequence is known, it is concluded that mammalian cytochrome c oxidase consists of 13 different polypeptides which can all be separated by the described procedure.

Light-driven potassium ion uptake in Halobacterium halobium is mediated by bacteriorhodopsin. This uptake is charge-balanced by sodium ions and not by proton release. Light-induced shifts in concentrations of divalent cations were found to be negligible. The transient changes in extracellular pH (alkaline overshoot) can be understood by the concomitant processes of ATP synthesis, proton/sodium exchange and potassium uptake. The driving force of potassium ion uptake is the membrane potential, no ATP-dependent potassium transport process is found. Fluorescence measurements indicate a high permeability of the membrane to potassium ions compared to sodium ions. Therefore the potassium ion diffusion potential contributes to the membrane potential (about 30 mV/decade) and thereby influences the ATP level. Sudden enhancement of the diffusion potential by the potassium ionophore monactin leads to the expected transient increase in cellular ATP level. Due to the large size (up to 100-fold) of the potassium ion gradient and its high capacity (intracellular concentration up to 3 M) the potassium ion gradient can well serve the cell as a long term storage form of energy.

The number of different Legionella species is increasing at an impressive rate. In two prospective studies, one involving 110 intensive-care unit (ICU) patients with mainly nosocomial pneumonias and the other 105 patients with community-acquired pneumonias, we investigated the incidence and significance of Legionella pneumophila and non-pneumophila pneumonias on the basis of 17 different main serogroups. In the first study, 14 ICU patients had 15 (13.6%) Legionella pneumonias, which, in 5 cases (33%), were of non-pneumophila etiology. In the second study, 9 patients with community-acquired pneumonias had 10 (9.5%) Legionella pneumonias. Leading this study were 6 L. gormanii infections, followed by 2 L. dumoffii and only 1 L. pneumophila and 1 L. longbeachae pneumonia. Of the total, 22 of 23 patients with Legionnaires' disease suffered from severe basic diseases and complications (acute renal failure, respiratory insufficiency, etc.) predominant among the nosocomial pneumonias. The mortality rate was significant in these patients at 33% (5 patients) in the ICU group and 10% (1 patient) in the group with community-acquired pneumonias. We conclude that non-pneumophila Legionella species should receive more diagnostic and therapeutic consideration in patients with nosocomial or community-acquired pneumonias.

Clinical retinopathy eventually develops in the majority of insulin dependent diabetics during several decades of metabolic abnormality. Early structural lesions short of clinical significance may occasionally be detected in children much more frequently, however, after puberty. Major factors modulating the development of retinopathy are duration of diabetes, glycemic control and blood pressure.

Rat liver cytosolic epoxide hydrolase has been purified and characterized. The enzyme was purified from tiadenol-induced rat liver 540-fold with respect to trans-stilbene oxide as a substrate. Similar purification was obtained with the substrates trans-beta-ethyl styrene oxide and styrene 7,8-oxide, the specific activities decreasing in the order trans-beta-ethyl styrene oxide greater than styrene 7,8-oxide greater than trans-stilbene oxide. The enzyme exerts highest activity at pH 7.4 Km and Vmax of the pure enzyme for trans-stilbene oxide were 1.7 microM and 205 nmol x min-1 x mg protein-1 respectively. With trans-stilbene oxide as a substrate, the inhibition by organic solvents (2.5% by vol.) increased in the order ethanol less than methanol less than acetone less than isopropanol = N,N-dimethyl formamide less than acetonitrile less than tetrahydrofuran. The native enzyme, with a molecular mass of 120 kDa, consists of two 61-kDa subunits. Digestion of rat liver cytosolic and microsomal epoxide hydrolase by three proteases resulted in markedly different peptide maps. Western-blot analysis with antiserum against rat liver cytosolic epoxide hydrolase revealed a single band with the purified enzyme, and with liver cytosol from control and clofibrate-induced rats. No cross-reactivity was observed with purified rat microsomal epoxide hydrolase or microsomes. A positive reaction at the same molecular mass was obtained with liver cytosol of mouse, guinea pig, Syrian hamster and New Zealand white rabbit but not with that of green monkey.

The rate of halobacterial photophosphorylation was found to be a linear function of light intensity over a wide range (between 1 and 20 mW/cm2). At higher light intensities (above 25 mW/cm2) the ATP-synthesizing system itself limits the maximal rate of photophosphorylation. The optimal external pH range for this type of photophosphorylation is between pH 6.2 and 7.2 external. The photophosphorylation rate is directly proportional to the bacteriorhodopsin content of the cells. The quantum requirement for photophosphorylation was found to be 22 +/- 5 photons per ATP molecule synthesized. According to Mitchell's chemiosmotic hypothesis of energy coupling phosphorylation can be driven by a membrane potential or a pH gradient or a combination of both. From the results of experiments with drugs which abolish or reduce either one of the two components we conclude that the major driving force for photophosphorylation above an external pH value of 6.5 is the membrane potential, while at more acidic pH value the pH gradient becomes dominating. We did not observe a correlation between a transient alkalinization of the medium and ATP-synthesis upon illumination under certain conditions.

Lithium ions lengthen the critical dark period in short-day plants, increase the period length of circadian rhythms in Kalanchoe plants, in the rodent Meriones and influence the activity rhythm of birds. In the case of the Kalanchoe rhythm, mainly the process of the petal opening is affected.

In a cohort of 268 type I diabetic patients, aged 19.6 +/- 4.1 years (Mean +/- 1 SD), with a diabetes duration of 10.4 +/- 4.9 years, treated by the same team, using the same conventional treatment regime during the total observation period, the progression rate of early retinopathy within the first two decades of diabetes was deduced from observed transitions of the retinal status from one stage of retinopathy (as defined by fluorescein angiography) to a higher one (Malone et al., 1977) within one year. A total number of 83 such events were evaluated. After a gradual development of earliest changes within the fifth year of diabetes, the median annual rate of progression was found to be 12-13%, independent of the previous duration of diabetes and the actual retinal state.

An energy-transducing pathway in halobacteria is described. Arginine mediates substrate level phosphorylation and allows the cells to grow anaerobically. Bacteriorhodopsin plus light can function as an alternative energy source under these conditions, provided the cells contain the pigment when transferred to the anaerobic environment. Therefore the selection of mutants functionally defective in ATP synthase or bacteriorhodopsin becomes possible.

Results of the BMF study group trials ALL-REZ 83 and 85 for relapsed acute lymphoblastic leukemia (ALL) are presented. For children with late marrow relapse, remission rates of about 90% were seen in both studies. In children treated for early marrow relapse, the remission rate in study ALL-REZ 85 was superior (86% vs 62%). The probability of event-free survival for all patients and for those with early marrow relapse was also statistically significant (P less than 0.05). Children with T-cell ALL had an extremely unfavourable prognosis in both studies.

At the end of blastokinesis, serosal epitheliae of 4- to 5-day-old embryos of Locusta migratoria contain an immunohistologically detectable cytosolic protein (M r ∼240 kDa) which is related to the juvenile hormone carrier-protein in the haemolymph of the same species and which binds tritiated juvenile hormone 3 (JH3) (K d ∼10 -8 M). At this early stage of development the corpora allata of the embryo are not yet fully differentiated and do not synthesize JH3 in organ cultures. The earliest detectable JH3 production by corpora allata in isolated heads is on day 6. On the other hand, serosal epitheliae of 4- to 5-day-old embryos produce JH3 in organ cultures, as has been shown by methylation of (10- 3 H)-JH3-acid to (10- 3 H)-JH3, and by incorporation of tritiated CH 3 from L-(methyl- 3 H)-methionine into JH3. Isolated heads and abdomens of the embryos used as donors for the serosal preparations did not show methyl transferase activity responsible for JH3 biosynthesis. The serosal cells represent a hitherto unrecognized source of methyl transferase activity and of JH3 production. Degradation of JH3 to JH3-acid was also observed.

In 231 subjects with Type 1 diabetes mellitus aged 17.6 +/- 4.0 years, with a diabetes duration of 8.5 +/- 4.9 years at the end of the study, the prevalence and the development of retinopathy during a period of 5 years were studied. All patients were examined between one and six times both by ophthalmoscopy and fluorescein angiography. A total of 626 fluorescein angiographies were evaluated. By the end of the study, 109 out of 231 patients (47%) had developed retinal changes, half of which were classified as minimal (less than 5 microaneurysms). Thirty-eight patients (35% of those affected) had background (n = 28) or proliferative (n = 10) retinopathy. In subjects less than 15 years of age and diabetic for less than 5 years, retinal lesions were rare. With increasing age and duration of diabetes, both the prevalence and severity of retinal changes increased markedly. Life-table analysis was used to calculate the median individual risk for the development of early retinal changes, which was 9.1 years of diabetes duration. This risk differed in sub-groups with different ages at onset of diabetes, i.e. 12.1, 8.9 and 6.6 years (p less than 0.0001), with diabetes starting below 4, between 5 and 9, and after 10 years of age respectively. After 18 years of diabetes, every patient demonstrated at least incipient structural changes. Fluorescein angiography allowed the detection of retinopathy, on average, four years earlier than with ophthalmoscopy. The median interval between the 'onset' of retinopathy, as indicated by a few microaneurysms, and background retinopathy was 5 years.

A randomized prospective trial with 108 patients undergoing anorectal surgery was conducted comparing the use of Urecholine orally or subcutaneously to no treatment controls. There was no difference in postoperative urinary retention rates and caudal or general anesthesia, nor was there an earlier postoperative bowel movement with Urecholine. The volume of intravenous fluids significantly affected retention rates.

The effects of two cholesterol-lowering (probucol and 1-benzyl-imidazole), three triglyceride- and cholesterol-lowering (clofibrate, tiadenol and fenofibrate) and one triglyceride-lowering (acetylsalicylic acid) compounds on the specific activities of two lipid-metabolizing enzymes (cyanide-insensitive peroxisomal beta-oxidation and palmitoyl-CoA hydrolase) and two xenobiotic metabolizing enzymes (cytosolic (cEH) and microsomal epoxide hydrolase (mEHb] from the livers of male Fischer F-344 rats were investigated. With the exception of probucol and acetylsalicylic acid, all compounds tested caused a dose-dependent hepatomegaly. Taken on a weight basis fenofibrate was the most effective inducer, causing a 20-fold induction of peroxisomal beta-oxidation, a 13-fold induction of cEH activity and a 16-fold induction of palmitoyl-CoA hydrolase activity. The other compounds with triglyceride-lowering activity also induced cEH as well as peroxisomal beta-oxidation and palmitoyl-CoA hydrolase activity. The potency of each individual drug was similar for induction of cEH activity as compared with that of peroxisomal beta-oxidation and palmitoyl-CoA hydrolase activity, but very dissimilar for mEHb, which upon treatment with any of the triglyceride-lowering compounds was either not or only minimally (less than 1.5-fold) induced. 1-Benzylimidazole possessing exclusively cholesterol-lowering activity increased mEHb much more than either cEH or peroxisomal beta-oxidation. The absence of an enhancement of cEH activity in in vitro studies confirmed that the increase in enzyme activity by the test compounds is not caused by activation. cEH activity was also induced in the kidney but only about 2-fold by fenofibrate, tiadenol and acetylsalicylic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Intravenous application of 1 mg glucagon causes a significant decrease of the magnesium, calcium, and phosphate concentrations in the serum. Concerning the potassium level there is a biphasic change of concentration. Initially a significant increase of the potassium concentration is to be measured which transgresses into a longer phase of decrease of concentration. The possible causes of these changes of electrolytes after application of glucagon are discussed and it is referred to the possible clinical importance. In longer therapeutic application of glucagon a control of the serum parameters of the electrolytes metabolism appears indicated.

For the attempt to develop a cochlear prosthesis, which allows some understanding of speech, it seems--at least for the first attempts--to be appropriate to mimic natural conditions as far as possible. The auditory nerve contains about 30,000 afferent fibres. Qualitatively, their behavior is similar but quantitative measures show considerably differences (2.3). Nothing certain can be said at present however about the spiral fibres originating from the outer hair cells. The quantitative differences between single afferents concern tuning, frequency selectivity, thresholds, intensity functions and--of particular interest for electrical stimulation--differences in timing of the activity pattern, brought about by differences in travelling time along the cochlear duct (2.3). The time differences seen in the activity pattern of different fibres are in the order of several ms (2.3.6;2.3.7). Actionpotentials elicited by natural acoustic stimuli show probabilistic behavior, that is they are not strictly determined. It is obvious that with artificial electrical stimulation not every surviving single fibre can be selectively stimulated. An electrode will always stimulate a group of fibres simultaneously. With any conceivable electrical stimulation all fibres in the suprathreshold region of the electrode will be synchronously activated (3.2); a fundamental difference to the natural situation. To estimate the number of channels, necessary to stimulate the auditory nerve with sufficient accuracy to allow speech perception we consider some psychoacoustic data. These have shown that the auditory system possesses the ability to differentiate a great number of different pitches, but on the other hand it is capable of integrating different frequency areas to a so called critical bandwidth. Sound energy falling into one critical bandwidth is integrated to a uniform auditory sensation. If one is to integrate various fibres of the auditory nerve to one channel of stimulation it seems to be adequate to use the critical bandwidth as a measure (3.1). According to this criterion 15 channels would have to be introduced into the speech region of the cochlea. This would allow 1.2 mm of cochlear length for each channel. Perfect electrical separation of the channels is required. Considering the severe distortions in neuronal activity pattern, introduced by electrical stimulation in comparison to the natural conditions it is not clear even whether the number given would be sufficient. On the other hand, current spreading would appear to prohibit any higher electrode density. As far as coding of sound parameters within one channel is concerned it is proposed that full use should be made of frequency analysis according to the place principle. In respect to coding of periodicity and loudness it is proposed to approach natural conditions as far as possible (3.3). Here delay times between the individual channels and a probabilistic character of the stimuli should be introduced to avoid dominance of periodicity pitch...

Lithium administration has been shown to attenuate the leukopenia associated with systemic chemotherapy. The results of a randomized trial of lithium in 45 patients with small cell lung cancer who received combination chemotherapy and radiation therapy are reported. Patients randomized to receive lithium were started on 300 mg three times daily for 18 days of every 21 day chemotherapy cycle. Patients who received lithium experienced significantly less mid-cycle leukocyte and neutrophil count depression and spent fewer days with leukopenia and neutropenia than control patients regardless of age or extent of disease. Patients who received lithium spent fewer days hospitalized and fewer days with fever in the presence of severe neutropenia than control patients. The cumulative risk of fever with signs of infection was greater in control patients regardless of age, disease extent or the presence of marrow involvement. Patients who were given lithium received significantly more chemotherapy than control patients. Patient survival was greatest in those with limited disease, in complete responders and in those who received more than 75 percent of their induction chemotherapy although it did not differ between the two study groups. The majority of patients required either reduction or discontinuation of lithium. Those who received lithium continuously demonstrated a higher objective response rate and longer survival than either patients in whom the lithium had to be discontinued or those randomized to the control group. Infection was an important cause of death in the control group and cardiovascular event occurred frequently in the lithium group, but the major cause of death in this patient population remains progressive malignant disease.

On the basis of microscopical examination and further differentiation by special stain techniques, a new classification of defects of midpieces and tails of spermatozoa will be presented: First degree disorders i.e. abnormalities of the staining behaviour and minor structural defects, second degree disorders revealing breakes and coiling of spermatozoa tail, and finally severe third degree disorders only exhibiting a rudimentary anlage of the terminal segment of spermatozoa. The staining abnormalities of the first degree disorders are characterized by nonreactivity to the Polychrome stain of the Papanicolaou technique as well as to scarlet red stain of the Shorr technique. Although the majority of these spermatozoa do not exhibit morphological aberrations, they have to be regarded completely immotile. Considering this classification, we have observed a highly significant correlation between morphological findings of midpieces and tails and the total motility as well as the progressive motility of spermatozoa.