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Somatostatin inhibits the centrally mediated hypertensive response to clonidine in freely moving rats. The effect of somatostatin on the hypertensive response induced by intracerebroventricular (i.c.v.) injection of clonidine was investigated in freely moving rats. A 10 micrograms i.c.v. injection of clonidine produced a marked pressor response and a decrease in heart rate. No depressor response was induced by clonidine. The i.c.v. pretreatment with somatostatin (2 and 5 micrograms) dose-dependently inhibited the pressor response to i.c.v. injected clonidine (10 micrograms), and a long-lasting depressor response was observed. Systemic (i.v.) treatment with somatostatin had no such effect. These results suggest that brain somatostatin modulates the centrally-mediated pressor response to clonidine.

Somatostatin inhibits nicotinic cholinoceptor mediated-excitation in rat ambigual motoneurons in vitro. The interaction between somatostatin and acetylcholine, two putative transmitters in the nucleus ambiguus, was investigated on single ambigual neurons in a brainstem slice preparation. Somatostatin reversibly inhibited the nicotinic cholinoceptor-mediated depolarization and inward current induced by acetylcholine. This inhibition persisted in the presence of tetrodotoxin (TTX) or Mn2+. In contrast, somatostatin enhanced both the glutamate-evoked depolarization and spiking discharges generated by current injection. These results suggest that somatostatin exerts a differential action in modulating excitatory inputs to the nucleus ambiguus at the level of postsynaptic receptors.

Serotonin, but neither noradrenaline nor GABA, inhibits capsaicin-evoked release of immunoreactive somatostatin from slices of rat spinal cord. It has been suggested that somatostatin is involved in nociceptive transmission in the dorsal horn and that it is contained in small primary afferent neurons. In the present experiments, to elucidate neural systems inhibiting the release of somatostatin from the primary afferent terminals, we examined the effects of serotonin, noradrenaline and gamma-aminobutyric acid on the capsaicin-evoked, dorsal-rhizotomy-sensitive and tetrodotoxin-insensitive release of immunoreactive somatostatin, 98.7% of which was somatostatin itself, from the dorsal-half slices of lumbar and cervical enlargements of rat spinal cord. Serotonin (30-100 microM) suppressed the evoked release in a concentration-dependent manner, and the suppression was antagonized by methysergide (100 microM). The evoked release of immunoreactive somatostatin was not inhibited by noradrenaline (100 microM) or gamma-aminobutyric acid (100 microM). The present results suggest that the serotonergic systems exert an inhibitory effect on the release of somatostatin from the central terminals of primary sensory neurons.

Non-specific characteristics of intracerebral fiber elongation from the olfactory bulb transplanted into the young adult host neocortex or hippocampal formation, demonstrated immunohistochemically by the mouse Thy-1 allelic system. The olfactory bulb of an embryo (BALB/c strain mouse) was transplanted into the neocortex or hippocampal formation in a young female adult host (AKR strain mouse) and matured for at least 1 month. Projection fibers from the transplant were demonstrated immunohistochemically using the allelic form of the Thy-1 system between both mice. Fibers from the olfactory bulb transplanted into the frontal cortex showed non-specific elongation in two directions where normally there are no targets of the olfactory bulb fibers: one was toward the cortical surface among radially oriented host fiber systems and another on the corpus callosum running rostrocaudally together with the host's long association bundle. Transplants placed in the hippocampal dentate and hilar regions emit fibers mainly towards the dentate molecular layer and these fibers spread medially and laterally within the molecular layer. The results suggest that projection neurons (mitral and tufted cells) in the transplanted olfactory bulb have the potential ability of non-target-directing axon elongation into the host nerve tissue which usually prevents the penetration of newly growing fibers.

[Heart damage associated with cerebrovascular accidents]. The authors present a clinico-pathological study on 21 patients who died in acute cerebrovascular diseases. The main myocardial lesions were focal hemorrhages, contraction band necroses and myocarditis. The ECG abnormalities and the pathogenesis of the cardiopathy are discussed on the basis of their investigations and dates of references. Their conclusions is that the heart damages are modulated by catecholamines. The occurrence of this cardiopathy should be prevented by beta-blockers, so the life-expectancy of patients and the number of heart donors could increase.

Management of associated dental injuries in maxillofacial trauma. Maxillofacial trauma frequently is accompanied by significant injuries to the teeth and their supporting structures. This review of these dental injuries relates their management to other priorities of the head and neck trauma patient. The controversy over management of the tooth within the line of a mandibular fracture is discussed.

Reduction of tracheal mite parasitism of honey bees by swarming. Based on population dynamics, tracheal mite (Acarapis woodi) parasitism of colonies of honey bees (Apis mellifera) appears to be, potentially at least, regulatory and stable. Empirical and theoretical considerations suggest, however, that intracolony population dynamics of mite-honey bee worker seem to be unstable in managed situations where honey bee worker population is allowed to grow unchecked. Experimental studies showed that tracheal mite population levels increased in a managed honey bee colony but were impaired in one in which brood rearing was interrupted by loss of the queen. Mite densities but not prevalence were lowered in experimental swarms kept from rearing brood. We propose that swarming reduces mite density within a colony, therefore implicating modern techniques of hive management in the sudden historical appearance of the mite on the Isle of Wight.

Drugs, sex and HIV: a mathematical model for New York City. A data-based mathematical model was formulated to assess the epidemiological consequences of heterosexual, intravenous drug use (IVDU) and perinatal transmission in New York City (NYC). The model was analysed to clarify the relationship between heterosexual and IVDU transmission and to provide qualitative and quantitative insights into the HIV epidemic in NYC. The results demonstrated the significance of the dynamic interaction of heterosexual and IVDU transmission. Scenario analysis of the model was used to suggest a new explanation for the stabilization of the seroprevalence level that has been observed in the NYC IVDU community; the proposed explanation does not rely upon any IVDU or sexual behavioural changes. Gender-specific risks of heterosexual transmission in IVDUs were also explored by scenario analysis. The results showed that the effect of the heterosexual transmission risk factor on increasing the risk of HIV infection depends upon the level of IVDU. The model was used to predict future numbers of adult and pediatric AIDS cases; a sensitivity analysis of the model showed that the confidence intervals on these prediction estimates were extremely wide. This prediction variability was due to the uncertainty in estimating the values of the models' thirty variables (twenty biological-behavioural transmission parameters and the initial sizes of ten subgroups). However, the sensitivity analysis revealed that only a few key variables were significant in contributing to the AIDS case prediction variability; partial rank correlation coefficients were calculated and used to identify and to rank the importance of these key variables. The results suggest that long-term precise estimates of the future number of AIDS cases will only be possible once the values of these key variables have been evaluated accurately.

Ratios of template responses as the basis of semivision. The template model starts with a layer of receptors that in the case of vision are leaky detectors or counters of photons. In many animals, the ratio of the responses of a few spectral types is the basis of colour vision irrespective of intensity. Ratios of template responses are now introduced as the basis of form discrimination. In insects, the second-order neurons on the visual pathway appear to detect temporal contrast at the spatial resolution of the retina. At the next level, in the optic medulla, we find a large number of small local neurons in a column on each visual axis. The template theory is a hypothesis about how the above system functions. All possible combinations of positive, indeterminate or negative temporal contrast are considered, at two adjacent visual axes at two successive instants, giving 81 possible local templates. These templates are therefore phasic detectors of all the possible spatiotemporal contrast combinations. Some of the template responses indicate polarity of edge, flicker, or direction of motion and other abstracted features of the stimulus pattern with the maximum spatial and temporal resolution. The ratios of numbers of template responses, in higher fields at a higher level, yield quantitative measures of the qualities of edges independently of the number of edges, but taking ratios causes a corresponding loss of the spatiotemporal resolution and the pattern within each field. Templates respond to transients without computation, are readily modified or selected in evolution and can be simulated in artificial vision.

Shape from specularities: computation and psychophysics. Images of artificial and natural scenes typically contain many 'specularities' generated by mirror-like reflection from glossy surfaces. Until fairly recently computational models of visual processes have tended to regard specularities as obscuring underlying scene structure. Mathematical modelling shows that, on the contrary, they are rich in local geometric information. Recent psychophysical findings support the notion that the brain can apply that information. Our results concern the inference of 3D structure from 2D shaded images of glossy surfaces. Stereoscopically viewed highlights or 'specularities' are found to serve as cues for 3D local surface-geometry.

[Therapeutic treatment with neuroleptics. II: Subjective mechanisms of effect, compliance and consequences for treatment strategy]. The problems of subjective acceptance and reaction by the patients to the effects produced by neuroleptics, have been receiving far more less attention so far than the "objective" aspects, and have not yet been empirically tested to the same extent. However, papers have been published recently in connection with this complex within the framework of researches into concept of disease and into compliance. These papers supply proof of the tremendous significance of the patient's attitude to, and assessment of, pharmacotherapeutic measures. The following aspects are pointed out to be particularly important: The attitude and relation of the patient to his psychosis; the style of coping in the sense of integration or disintegration of the psychosis into the process of life; the dysphoric reactions to neuroleptics; and the disease pattern or disease model. Practical model examples are given to illustrate three possibilities of a more intensive connection between neuroleptic therapy and other therapeutic measures.

[Dynamics of thyrostimulating immunoglobulin levels during treatment of diffuse toxic goiter]. Twenty-five patients with diffuse toxic goiter, investigated at various time of mercazolyl therapy, demonstrated the presence of thyrostimulating immunoglobulins in 100% before treatment, in 91% after 6 months and in 50% after 12 months of treatment. Specific therapy reduced considerably not only the frequency of detection but also the activity of thyrostimulating immunoglobulins. Clinical and hormonal remission of disease did not always coincide with immunological remission.

[Therapeutic treatment with neuroleptics. I: State of research on mechanisms of action, effectiveness and compliance in treatment of psychoses]. In the management of schizophrenic psychoses, drug medication with neuroleptics occupies a central position and is in fact a first-choice treatment. The considerable side effects and late sequelae of this treatment are known to impair the quality of life of the patient and have comne to the fore once again in recent years as the starting points of controversial discussions among specialists and among those who are engaged in matters concerning psychiatric policies or "politics". The cornerstones of this debate are demonstrated and explained on the basis of the present clinico-psychiatric state of research in respect of effectivity predictors, types of mechanisms of action. Long-term courses of treatment with neuroleptics, and different dosage schedule strategies.

11C-SCH 39166, a selective ligand for visualization of dopamine-D1 receptor binding in the monkey brain using PET. The new selective D1-dopamine receptor antagonist SCH 39166 was labelled with the positron emitting isotope 11C and used as ligand for visualization of dopamine-D1 receptor binding in Cynomolgus monkeys by PET. After intravenous administration of the ligand a marked uptake of radioactivity was recorded in the D1-dopamine receptor-rich striatum and neocortex but not in the dopamine receptor-poor cerebellum. The uptake of radioactivity in striatum and neocortex was markedly displaced after the intravenous injection of a high dose of the D1-dopamine receptor antagonist SCH 23390 but not after the 5-HT2 receptor antagonist ketanserine. 11C-SCH 39166 should be a useful tool to explore D1-dopamine receptor characteristics in the living human brain by PET.

Self-injection of barbiturates, benzodiazepines and other sedative-anxiolytics in baboons. Self-injection of 12 sedative-anxiolytics was examined in baboons. Intravenous injections and initiation of a 3-h time-out were dependent upon completion of a fixed-ratio schedule requirement, permitting eight injections per day. Before testing each dose of drug, self-injection performance was established with cocaine. Subsequently, a test dose was substituted for cocaine. At some doses, all five of the benzodiazepines examined (alprazolam, bromazepam, chlordiazepoxide, lorazepam, triazolam) maintained rates (number of injections per day) of drug self-injection above vehicle control in each of the baboons tested. Maximum rates of benzodiazepine self-injection were generally submaximal. Of the benzodiazepines examined, triazolam maintained the highest rates of self-injection. Among the three barbiturates tested, methohexital generally maintained high rates of self-injection in contrast to hexobarbital and phenobarbital, which only maintained low rates. Of the four non-benzodiazepine non-barbiturate sedatives examined, both chloral hydrate and methyprylon occasionally maintained high rates of self-injection. Although there were differences within and across animals, baclofen maintained intermediate rates of self-injection. The novel anxiolytic buspirone maintained only low rates of self-injection that were not different from vehicle. This study further validates the self-injection methodology for assessing sedative-anxiolytic abuse liability and provides new information about drug elimination rate as a determinant of drug self-administration.

Place conditioning with dopamine D1 and D2 agonists injected peripherally or into nucleus accumbens. The conditioned place preference technique was used to assess the affective properties of the direct dopamine D1 agonist, SKF38393, and the direct D2 agonist, LY171555 (quinpirole). A three compartment apparatus was used: the animals' pre-experimental preference for the two choice compartments was equal and, within each experimental group, half the rats received drug pairings in each choice compartment. Intraperitoneal injections of SKF38393 produced conditioned place aversions at all doses tested (1.0-4.0 mg/kg); LY171555 produced weak conditioned place preferences at 1.0 and 2.0 mg/kg, but no reliable effect at 4.0 mg/kg. Bilateral intra-accumbens microinjections of SKF38393 produced strong preferences at all doses tested (0.5-2.0 micrograms/side); LY171555 produced strong preferences at two doses (0.5 and 1.0 micrograms/side) and no effect at a third dose (2.0 micrograms/side). These results suggest that activation of either D1 or D2 receptors in the nucleus accumbens can produce reward, and that D1 receptors (and possibly also D2 receptors) located elsewhere in the brain or in the periphery may mediate aversive effects.

Savoxepine: invalidation of an "atypical" neuroleptic response pattern predicted by animal models in an open clinical trial with schizophrenic patients. The new tetracyclic compound savoxepine exhibits potent antidopaminergic effects with preferential activity in the hippocampus as compared to striatum in rat brain. As a result of behavioural animal models and regional differences in dopamine receptor binding characteristics, it has been suggested to possess an "atypical" neuroleptic response pattern. In an open clinical trial, savoxepine was administered to 12 in-patients suffering from paranoid schizophrenia and schizophreniform disorder (DSM-III). Eight patients were treated with a stable dose of 0.5 mg per day throughout the study, while in the remaining patients higher doses up to 20 mg/day were administered. Mean total BPRS scores and subscores demonstrated a moderate improvement of mainly positive schizophrenic symptoms. In contrast to animal test results, savoxepine in a broad dose range produced typical untoward extrapyramidal symptoms in the majority of patients. Our results indicate that savoxepine may not possess the expected "atypical" neuroleptic response pattern, and that the predictive validity of the animal models in question used to separate antipsychotic effects from extrapyramidal reactions may be ill-founded.

Characteristics of benzodiazepine long-term users: investigation of benzodiazepine consumers among pharmacy customers. A sample of 171 benzodiazepine (bzd) users was investigated in the pharmacy where the patients filled in their prescriptions. Of the sample, 29.8% were males and 70.2% were females. About 60% of the patients had their current prescription from a general practitioner, the rest from different specialists. 70.8% stated to take bzds on more than 3 days of the week. The mean duration of intake of the entire sample was 4.5 years. The most frequent reasons for bzd intake were sleep disturbance followed by nervousness and somatic diseases. A total of 74.9% of the patients turned out to be well informed about the potential dependence hazards of bzd long term intake, but less than half of them had been informed by the prescribing physician. In a second step it could be demonstrated by means of multiple stepwise logistic regression analysis that certain characteristic parameters differentiate long-term users and persons with signs of potential abuse and dependence from other bzd users.

Cardiovascular reactivity to psychosocial stressors. A review of the effects of beta-blockade. Fifty-nine studies examining the effects of beta-blockers on cardiovascular reactivity to psychosocial stressors are reviewed. Across all classifications of beta-blockers, heart rate reactivity was reduced (p less than 0.0001), while there were no significant changes in either systolic or diastolic blood pressure reactivity. Nonselective beta-blockers were more often associated with a reduction in heart rate reactivity than selective blockers (p less than 0.05). There was no evidence that drug lipophilicity or intrinsic sympathomimetic activity differentially affected blood pressure or heart rate reactivity; nor was there evidence that the reactivity of hypertensive subjects was differentially affected by blockade compared to the reactivity of normotensive subjects. While beta-blockers are effective in reducing resting blood pressure, they are not effective agents in reducing blood pressure reactivity to mild psychosocial stressors.

[Psychopathological disorders before and after heart surgery]. The author describes the frequencies and characteristics of psychopathological disorders before and after open heart surgery. In addition to cognitive and anxious-depressive mood disorders in the preoperative time, anxiety and coping are prominent. Postoperatively, different mood and cognitive disorders, psychotic reactions and delirious syndromes may be found. Conditions and causes of psychopathological disorders are discussed with the aid of the literature and present results. Therapeutic possibilities are outlined.

Mechanisms of cigarette smoke-induced stimulation of rapidly adapting receptors in canine lungs. The stimulation of rapidly adapting receptors (RARs) in the lungs evoked by cigarette smoke consists of an initial and either a type I or a type II delayed response (Kou and Lee, J. Appl. Physiol. 68: 1203, 1990). In the type I response, receptor activity increased during expirations and exhibited a prominent cardiac modulation, whereas in the type II response, receptor discharge reached its peak during inspiration at peak transpulmonary pressure. To investigate the mechanisms of this stimulation, we recorded the vagal afferent activity arising from 39 RARs and delivered a single breath (120 ml) of cigarette smoke in 15 anesthetized, open-chest and artificially ventilated dogs. Studies were repeated after a pretreatment with aerosolized hexamethonium (3-8 breaths, 10%), aerosolized isoproterenol (12-15 breaths, 2%), or after the cardiac impact on the lung had been minimized by elevating the apex of the heart. The initial response of RARs was totally abolished by hexamethonium but was not affected by isoproterenol. The increase of total lung resistance induced by cigarette smoke and the concomitant type II delayed response of RARs were both abolished by isoproterenol. The type I delayed response of RARs was eliminated or largely attenuated after the apex of the heart had been elevated. Based upon these results, we conclude that a direct effect of nicotine on these receptors may be responsible for the immediate stimulation while the systemic effects of absorbed nicotine may play a part in evoking the delayed stimulation.

[Determination of the activity of urinary enzymes derived from renal tubulus]. There are several problems in measuring the activities of urinary enzymes, such as alkaline phosphatase (ALP), leucine aminopeptidase (LAP), and gamma-glutamyl transpeptidase (gamma-GTP) which are derived from renal tubulus. The purpose of the present study is to clarify the basic methodological problems in measuring these enzyme activities. Our results indicate that it is not necessary to dialyze urine when determining these three enzymes, except for alkaline phosphatase activity measured by the Kind-King method. Because of contamination of urine by bacteria and cell elements, the enzyme activity is influenced by centrifugal conditions that depend on time and speed. Our results propose that it is necessary, at least, to centrifuge at 3000 rpm for 10 minutes to obtain satisfactory data. Generally, a 24 hour urine sample instead of spot urine sample should be used for measuring the enzyme activity. However if correcting gamma-GTP activity by creatinine, even a spot urine sample may be used for clinical use.

[Fever, headache and paralysis of the left leg]. A 17 year old man was hospitalized because of fever, headache and a paresis of his left leg. Radiologic findings demonstrated a subdural interhemispheric empyema on the right side as a complication of ipsilateral pansinusitis. Streptococcus milleri was cultured as the only pathogen from maxillary sinus suppuration. Pathogenesis and therapy of subdural empyema are discussed. Cure was achieved with ceftriaxone, flucloxacilline and ornidazole during one week followed by ceftriaxone as monotherapy during further five weeks. The importance of streptococcus milleri as causing agent of purulent lesions in internal organs is stressed.

[Curable dementia and panarteritis nodosa]. A cerebral recurrence of panarteritis nodosa in a 64-year old man is reported. The patient developed lymphocytic meningitis and encephalitis resulting in dementia within 3 months. Lumbar puncture confirmed the presence of lymphocytic meningitis, and cerebral biopsy showed a lymphocytic arteritis. The neurological deficit regressed after six months of treatment with methylprednisolone and cyclophosphamide.

[Genetics and schizophrenia]. Studies of twins, adoption and familial incidence have demonstrated that heredity plays a role in the genesis of schizophrenia. Owing to recent advances in molecular biology and computerized statistical models, analyses of pedigrees and genetic linkage have made it possible to progress in the identification and mode of transmission of genetic factors in schizophrenia. The methodology and conflicting results of these studies are reviewed, together with modern hypotheses on the mode of transmission of schizophrenia. The contribution of genetic studies to the concept of schizophrenia clinical spectrum and the new strategies of research in genetics are presented.

[Biological treatments of schizophrenia]. Biological treatments of schizophrenia primarily consist of neuroleptics. These drugs can be prescribed in a relatively standardized manner (chlorpromazine equivalent), but neuroleptics will be less than effective on the type of schizophrenia with negative symptoms. Treatment can also be performed by utilizing the bipolarity of some drugs, and it is only with these drugs that resistant schizophrenia can be mobilized. Consideration is also given to other biological treatments and new prospects in chemotherapy.

Involvement of lymphocyte function-associated antigen-1 (LFA-1) in HIV infection: inhibition by monoclonal antibody. Monoclonal antibodies (MAbs) against the alpha- and beta-chain of lymphocyte-associated antigen-1 (LFA-1) were examined for inhibition of HIV-1 infection in vitro. Infection of the T cell line MT4 and the monocytic cell line U937 by isolates HTLVIIIB and SSI-002, respectively was inhibited in a concentration dependent manner by MAb against the beta-chain but not against the alpha-chain. No cross-reactivity was found between MAb against LFA-1 and against the CD4 receptor (MAb Leu3a). MAbs against the beta-chain and the CD4 receptor were found to act synergistically in inhibiting HIV infection. These data indicate that the beta-chain of LFA-1 in addition to the CD4 receptor may be involved in HIV infection in vitro.

[Over-the-counter availability of potent ulcer drugs. Study of changes in the drug use pattern and the pressure on diagnostic measures]. In spring 1989, H2-receptor blockers and sucralfate were released for sale over-the-counter in Denmark and, simultaneously, the automatic National Health Insurance subsidy for all ulcer medicine was discontinued. The consequences of these alterations for the pressure on the diagnostic measures for upper dyspepsia are assessed by analysis of the number of referrals for gastroscopy, outpatient history-taking or radiographic examination of the stomach and oesophagus. The consequences for the consumer pattern were assessed in questionnaire investigations both to the practitioners who prescribed ulcer medicine before the alterations were introduced and also to patients who bought ulcer medicine after these alterations. Only approximately 3% of ulcer medicine is sold directly over-the-counter without medical assessment or control. No problems in safety were observed as regards incorrect treatment or delayed diagnosis. The relative proportion of patients with demonstrated indications for necessary ulcer medicine has increased after the alterations primarily on account of decrease in employment of medicine in therapeutic trials. This does not appear, however, to have resulted in any marked increased in the diagnostic possibilities. Potent ulcer medicine has not become generally accepted as over-the-counter medicine. The health and health-economic consequences should, therefore, be followed up for a more prolonged period.

[Ulcer complications in the county of Funen during 1980-1990. Are there any changes in the frequency of hospitalization following the release of potent ulcer drugs for over-the-counter sale?]. With the object of investigating whether the release of H2-blockers and sucralfate for over-the-counter sale in 1989 in Denmark and the simultaneous discontinuation of the general subsidy for potent ulcer medicine have had any influence on the frequency of hospitalisation for ulcer complications, the number of these were investigated in the County of Funen during a nine-year period prior to these alterations. The number of hospitalisations on account of ulcer complications during the first year after the alterations and thereafter were assessed on the basis of the prior tendency. In addition, the characteristics of the patients were assessed by a retrospective review of the case reports for the one-year periods before and after the alterations in the dispensing rules. The number of hospitalisations on account of ulcer complications in the County of Funen rose by 45% during the period 1.4.1980-31.3.1989. No increases in the number of hospitalisations after the alterations could be demonstrated. The number of patients admitted to Odense Hospital with ulcer complications and their characteristics are, similarly, unchanged after the alterations. Three case histories are, however, registered in which the alterations may have influenced the development of the ulcer complications. There appear to be good ground to continue registration of ulcer complications with the object of investigating the long-term consequences of these alterations particularly if potent ulcer medicine is used to a greater extent as over-the-counter medicine.

[Adverse effects of ulcer drugs before and after release of cimetidine, ranitidine and sucralfate for over-the-counter sale]. During the period from the first marketing of cimetidine in 1977 and until 31 March 1990, the Danish Committee on Adverse Drug Reactions received 494 reports concerning a total of 612 suspected adverse reactions to peptic ulcer drugs (ATC group A02B). Out of these, adverse reactions to H2-receptor antagonists constituted 90%. The investigation confirms the fact that safe drugs are concerned which only rarely cause serious adverse reactions. During the first year after cimetidine, ranitidine and sucralfate became available over-the-counter (27 March 1989-31 March 1990), only one report about side effects caused by cimetidine sold over-the-counter was received. This corresponds to what might be anticipated from the usage figures, if availability over-the-counter does not result in particular adverse reaction problems. Decrease in the number of reports, alterations in the pattern of adverse reactions and under-reporting of known adverse reactions render employment of data from voluntary reports difficult.

Concomitant treatment of MBT-2 bladder tumour by tumour necrosis factor alpha and interferon alpha in conjunction with delayed type hypersensitivity immunotherapy. In our previous study [9], we reported the anti-tumour effect of TNF on mouse bladder tumour (MBT-2) both in vivo and in vitro. Inoculation of a single dose of TNF alone caused significant but transient tumour growth inhibition. Subsequent repeated doses of TNF did not sustain or augment the anti-tumour effect. The current experiments were undertaken to assess the anti-tumour activity of (i)-concomitant treatment of TNF-A and IFN-A against MBT-2 bladder tumour and (ii)-concomitant TNF + IFN-A treatment in conjunction with T-DTH (delayed-type hypersensitivity) immunotherapy. Systemic administration of multiple doses of TNF + IFN-A in vivo caused initial partial tumour regression followed by tumour growth inhibition up to 14 days following treatment. This combined treatment showed an enhanced anti-tumour effect compared to TNF-A treatment alone. Immunotherapy of MBT-2 tumour-bearing mice with T-DTH "immune" effector cells alone did not cause significant tumour growth inhibition. In contrast, concomitant administration of both T-DTH effector cells and TNF + IFN-A in MBT-2 tumour-bearing mice resulted in significant tumour growth inhibition for up to 16 days. The immune effector cells conferring immunotherapy were isolated from the spleens of tumour-immunized, "DTH-primed" animals and were characterized as Lyt 1+2- helper/DTH T cells (CD4+ phenotype). These cells mediate both DTH response to MBT-2 tumour antigens as well as anti-MBT-2 tumour protection. In vitro treatment of the "immune" cells with TNF-A resulted predominantly in the proliferation of Lyt 1+ T cells versus Lyt 2+ cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Parenteral nutrient admixtures as drug vehicles: theory and practice in the critical care setting. Parenteral nutrient (PN) admixtures are the most complex, extemporaneously compounded formulations routinely prepared for hospitalized and home-based patients. In addition, drugs are added with increasing frequency to PN admixtures, thus presenting even greater physicochemical challenges to this highly complex pharmaceutical product. The continuous infusion of selected drugs may provide pharmacokinetic and therapeutic advantages over conventional, intermittent, bolus methods of administration. Fluid conservation, cost savings, and a possible decrease in the risk of infection through reduced catheter manipulation and simplification of therapy provide additional incentives to consider the use of PN admixtures. The many advantages of PN admixtures make them an attractive approach to cost-effective care, with special clinical benefits achieved in the critical care setting. This article reviews our clinical experience using PN admixtures as drug vehicles for selected drugs and presents some theoretical as well as actual benefits associated with this practice.

[Antistressor effect of delta-sleep-inducing peptide in hypokinetic stress]. The influence of DSIP injection on the levels of neurotransmitters during hypokinetic stress was studied. It was shown that hypokinesia produced considerable changes in the levels of GABA glutamate, aspartate and homocarnosine. The injection of DSIP normalized the level of neurotransmitter amino acids. Administration of DSIP also reduced stress-induced changes in the activity of enzymes of GABA metabolism. Stress protective effect of DSIP was also demonstrated by normalising of the POL of lipids in brain.

Pattern of neuroleptic drug use in Italian mental health services. The relationship between the prescribed daily dose of neuroleptic (NL) drugs and patient-, and drug-related characteristics was explored in a cross-sectional sample of 1141 patients treated in Italian mental health services. The results of a multiple linear regression showed that the prescribed daily dose was significantly lower in women, the elderly, and those with a shorter (one to six year) psychiatric history. In contrast, being an inpatient in psychiatric wards in general and public mental hospitals was significantly associated with a higher dose; marital status, education, and diagnosis were not. The number and potency (low to moderate vs. high) of the prescribed NLs were also significantly associated with the prescribed dose, and an interaction was found between the two. Implications of these findings for improvement in NL prescription patterns are discussed.

Somatostatin levels in plasma in nonsmoking and smoking breast-feeding women. The objective of the study was to record how somatostatin levels in plasma are altered in response to breast-feeding during the lactation period and to relate somatostatin levels to the success of the lactational performance and to smoking habits. Fifty-two women were investigated 4 days post partum and 3-4 months later. Blood samples were collected and the levels of somatostatin-like immunoreactivity (below referred to as SLI) were measured with radioimmunoassay. The periods of exclusive breast-feeding and of mixed feeding were assessed as well as the milk yield. Smoking habits were noted. SLI levels were found to be significantly lower on day 4 after delivery, compared to 3-4 months later. Also the type of response to breast-feeding was different. Thus, a significant fall of SLI was seen during breast-feeding at the maternity unit, but not 3-4 months later. Smoking women breast-fed fully for a significantly shorter time than nonsmokers and had significantly higher SLI levels at onset of breast-feeding day 4 post partum. Whether the high somatostatin levels recorded in connection with breast-feeding in smokers are related to the shorter period of breast-feeding seen in this group remains to be established. In addition, the highest levels of somatostatin were seen the day after the very last breast-feeding and a possible role for somatostatin in the weaning process should be explored.

Serum mianserin concentrations in psychiatric inpatients of different ages. One hundred and sixty-nine depressive psychiatric inpatients were treated with routine therapeutic doses of mianserin. Altogether 256 serum mianserin samples were measured gas-chromatographically in 3 age groups: 17 samples in patients under 35 years, 116 samples in patients between 35 and 65 years, and 123 samples in patients over 65 years. No differences in dose-corrected (calculated as mg/kg dose basis) mean serum mianserin concentrations were found between the age classes. Neither the interindividual variation nor the number of high serum mianserin concentrations was larger among elderly subjects than in the other age groups. Concurrent neuroleptic treatment significantly increased serum mianserin levels in the oldest patient group but not in the 2 others. The results suggest that mianserin dose should not be generally reduced with advancing age.

[The polytraumatized child. Pattern of injuries, characteristics of therapeutic management and prognosis]. Accident-related injuries account for a major part of childhood morbidity and mortality. More than 25% of the patients treated at the University Clinic Aachen for severe multiple trauma are below 16 years of age. The younger the children are, the more the pattern of injuries as well as the therapeutic approach differ from the well-known standard in adults. This is due to the anatomic and physiologic differences encountered in children. A reliable and practical triage instrument is needed to overcome the problem of estimating the severity of injuries in a child. The Pediatric Trauma Score seems to fulfill these requirements.

[Hip para-articular fractures in patients over 100 years old]. Prompted by the rarity of successful treatments of patients more than 100 years of age, we report on two cases of fractures located near the hip joint. Both patients were operated urgently and discharged after a hospitalisation period of 5 and 6 weeks, respectively.

[Ender nailing for stabilization of pertrochanteric fractures in advanced age. A safe procedure?]. The postoperative course of 138 patients with a pertrochanteric fracture treated by nailing according to Ender is analysed with regard to the operative morbidity and lethality. As secondary factors associated with morbidity the specific and unspecific rate of complications, the lethality, the perioperative loss of blood and the duration of postoperative hospitalisation are evaluated. Specific complications occurred in 27%, unspecific complications in 50%, and the rate of hospital mortality was 15.2%, 60.9% of patients required a postoperative transfusion to compensate the perioperative blood loss. In contrast to other authors we cannot regard Ender nail osteosynthesis as a lowrisk procedure with a low operative morbidity. When choosing the treatment procedure alternative methods of stabilisation should be taken into account. An intensive postoperative care is of utmost importance in elderly patients.

[Ender nailing of hip para-articular fractures in advanced age]. Since the introduction of the dynamic hip screw to stabilize fractures of the coxal end of the femur Endernails are being used less and less with some teams no longer using them at all. Nevertheless, the use of Endernails appears to be advantageous when the coxal end of the femur is fractured, especially in the case of osteoporotic bones and in elderly patients. We report on 61 instances in which we used Endernails on patients whose average age was 85.5 years. The infection rate of 1.6% was very low and 50 patients were fully ambulant. 19.6% of our patients died in the postoperative phase in the hospital whereas 1/3 of the patients operated died within one year. Complications in the post-operative phase were nail-gliding which occurred in 8 cases while another patient developed a pseudarthrosis in the region of the fracture. Post-operative care check-ups revealed that 7 patients suffered from a secondary dislocation of the fracture, in 4 instances leg length remained foreshortened by more than 2 cm. In one case the final position of the operated leg remained in an outside rotation. In view of the advanced age and therefore limited mobility of all the patients mentioned, adverse post-operative consequences are irrelevant.

[Perforation of a duodenal stress ulcer in a 7-year-old polytraumatized boy]. This is a report of a seven-year-old polytraumatised boy with perforation of a duodenal stress-ulcer. Aspects of the etiology and pathogenesis were discussed. The main therapeutical efforts by stress-ulcer risk patients consist in an early sufficient shock therapy and adequate stress-ulcer prophylaxis to prevent the origin of stress-ulcers and their complications like bleeding and perforation.

[Vascular injuries as a complication of fractures, dislocations and surgical interventions]. This is a presentation of 34 patients with traumatic or intraoperative vascular injuries treated at the Rural Clinic am Plattenwald during the timeperiod from 1978 until 1988. Limb amputation was performed in three cases. Two patients died. Our goal is to show the importance in early recognition and treatment of such injuries which requires an efficient interdisciplinary cooperation between orthopedic and vascular surgeons, as well as the radiologist. The employment of angiography should be generous.

Staphylococcal pyomyositis in patients infected by the human immunodeficiency virus. We describe the manifestations of spontaneous staphylococcal pyomyositis in patients infected by the human immunodeficiency virus (HIV). We present the courses of five previously unreported patients infected by HIV who presented to our medical centers with spontaneous staphylococcal pyomyositis. Additionally, we review all previously reported cases of this entity in HIV-infected patients and discuss its possible pathogenesis and importance in the context of HIV infection. All patients presented with gradually developing fever and localized pain and swelling without accompanying leukocytosis. Often only scant evidence of local inflammation was found. None of our patients used intravenous drugs, had a history of trauma, had HIV- or zidovudine-related myositis, or had other conditions known to be associated with serious staphylococcal infections. Two patients studied had normal serum levels of all IgG subclasses. Elevated serum IgE, eosinophilic inflammatory infiltrates, or marked peripheral eosinophilia was observed in two patients. Staphylococcal pyomyositis in HIV-infected patients presents in an indolent fashion, which may delay appropriate diagnosis and treatment. Since staphylococcal pyomyositis is infrequently reported in the United States, the development of 14 such cases (five in this series and nine previously reported) among the first 140,000 cases of acquired immunodeficiency syndrome in this country implies that this patient population is predisposed to this infectious complication. The pathogenesis of this entity is uncertain, but it is notable that HIV-infected patients are commonly colonized by Staphylococcus aureus and that neutrophils from HIV-infected patients frequently manifest phagocytic, chemotactic, and oxidative defects, diminished expression of Fc tau RIII (CD16) and CR1, and impaired bactericidal activity against S. aureus.

Human immunodeficiency virus infection does not alter serum transaminases and hepatitis B virus (HBV) DNA in homosexual patients with chronic HBV infection. The influence of human immunodeficiency virus (HIV) infection on the clinical course of chronic hepatitis B virus (HBV) infection is controversial. We followed a cohort of 64 homosexual men with persistent HBs antigenemia for a median of 24 months in the hepatitis clinic of a large urban public hospital. We divided the patients into three groups according to their immune status. Group 1 (n = 13) consisted of HIV-seropositive men with evidence of immunosuppression; group 2 (n = 17), HIV-positive patients without evidence of immunosuppression; and group 3 (n = 34), HIV-negative patients. We followed serum ALT and HBV DNA determinations. There was no difference in the demographic characteristics of the three groups. Group 1 had significantly lower levels of circulating T4 lymphocytes. We found no differences in the number and severity of episodes of HBV reactivation, serum ALT levels, or HBV DNA scores among the three groups. In each group, the percentage of patients with circulating HBV DNA was the same. We conclude that HIV infection apparently does not influence the markers of liver inflammation or HBV replication in homosexual men.

Central nervous system reactions to histamine-2 receptor blockers. To review the incidence, risk factors, pharmacology, and management of central nervous system reactions to histamine-2 receptor (H2) blockers. English-language articles were identified through a search of the MEDLINE and Current Contents data-bases. Bibliographies of retrieved articles were examined for relevant articles. Case reports submitted to the Food and Drug Administration through 19 September 1989 were obtained. Studies on the association between central nervous system toxicity (psychosis, agitation, hallucinations, delirium, mental status changes, disorientation, confusion, irritability, obtundation, or hostility) and H2 blockers were analyzed. All data on the incidence of and potential predisposing factors for central nervous system reactions to H2 blockers were analyzed. Limitations of the data are discussed. Central nervous system toxicities have been associated with all H2 blockers. These reactions generally occur during the first 2 weeks of therapy and resolve within 3 days of drug withdrawal. The estimated incidence of central nervous system reactions is 0.2% or less in outpatients and 1.6% to 80% in hospitalized patients. Cimetidine is most frequently associated with these reactions; however, no clear evidence exists that one H2 blocker is more likely than another to cause a reaction. Risk factors for central nervous system reactions have been proposed, but only advanced age has some, albeit limited, data to support it as a risk factor. Studies have only infrequently established causality and there have been difficulties in establishing risk factors for an relative incidences of a phenomenon that occurs infrequently in outpatients and that can be multifactorial in origin. All H2 blockers are associated with central nervous system reactions. There is no clear evidence of a higher rate of reactions with one H2 blocker compared with another.

Pain control. There are two components to the perception of pain; the 'sensory' and the 'reactive'. Psychological factors control the latter. Pain research is rapidly advancing: the discovery of endorphins and opioid receptors, the appreciation of the psychological component of pain and the multidisciplinary approach to chronic pain are major advances. Pain can be classified as acute or chronic. Acute pain is easy to diagnose, the cause of pain obvious and the treatment logical, chronic pain has a greater psychological component, is difficult to diagnose and treatment is often empirical. Methods of pain control include drugs, injection techniques, electro stimulation, non invasive therapies, denervation procedures and palliative procedures. A multidisciplinary approach and a combination of methods is necessary to treat chronic pain. Spinal opioids, radiofrequency thermocoagulation, intrapleural bupivacaine, cryoanalgesia and patient controlled analgesia are recent advances in pain control. However, most pain can be controlled adequately with simple methods; what is essential is the interest and commitment of the physician towards achieving optimum therapeutics.

Clinical psychopharmacology of beta-adrenoceptor antagonism in treatment of anxiety. beta-adrenoceptor antagonists such as propranolol have been shown to produce improvement in the symptoms of patients with anxiety states, particularly the somatic or autonomically mediated features of their condition. It is not yet certain whether this is a central or peripheral action of beta-blocking drugs, and whether it is due to beta-adrenoceptor blockade or to another pharmacological action which these drugs possess, such as 5HT receptor blockade. There is experimental evidence that abrupt discontinuation of treatment with beta-blocking drugs is not associated with a central nervous withdrawal syndrome, but the implications are limited because of the lack of agonist models of central nervous beta-adrenoceptor function in man. The original observations on the anti-anxiety effects of propranolol were serendipitous, and illustrate the importance of designing clinical pharmacological studies so that unexpected and unsought information can be recorded.

Lymphocyte subsets in the lymph nodes of rats with autoimmune orchitis. We determined temporal variations of cell subpopulations in the immunization draining lymph nodes during the development of an experimental autoimmune orchitis (EAO) induced in Wistar rats. A phenotypic characterization of T cells and their subsets (CD4+ and CD8+), B, and Ia+ cells was performed by immunofluorescent technique. At the end of the immunization period (30 days), rats injected with testicular homogenate plus adjuvants presented a considerable increase in absolute cell number but normal lymphocyte subset percentages. Testicular damage became evident at 50 days after the first immunization and increased its severity at 80 days: animals that developed EAO presented a lower number of CD8+ cells as compared with undamaged rats. This latter group showed a low CD4/CD8 ratio due to the high proportion of CD8+ cells, which could probably have a suppressor function. At 80 days massive testicular infiltration and decreased absolute cell number in lymph nodes suggest the possible migration of specific lymphocytes to the target organ.

Isolation and partial characterization of the structural gene for human acid alpha glucosidase. Genetic deficiency of acid alpha glucosidase (GAA) results in glycogen storage disease type II. To study the disease at the molecular level, we have previously isolated and sequenced the cDNA (3.6 kb) for human GAA. We have now isolated the structural gene, mapped and determined the position and size of the exons containing the entire cDNA, and determined the sequence of the intron-exon junctions. The structural gene is approximately 28 kb and contains 20 exons. The first exon has only 5' untranslated sequence and is separated by an approximately 2.7-kb intron from the second exon that contains the initiation ATG. The second as well as the last exon are quite large (578 and 607 bp) with the remainder of the exons ranging from 85-187 bp. Additionally, two new restriction fragment length (RFLPs) for Xba I and Stu I are described at the GAA locus, one of which is most 5' of the eight RFLPs we have previously described.

Molecular genetics and human prostatic carcinoma. Advances in molecular genetic techniques have reached the point where clinical material can be reasonably well-characterized in detail. One area that is receiving increasing attention is the genetic abnormalities of tumors. Using the technique of restriction fragment length polymorphism analysis, it is possible today to build up a picture of the genome and to identify which regions are deleted or are rearranged in the tumor cells of an individual patient. Twenty years ago, experimental and theoretical findings suggested that loss of gene function could be an essential component in oncogenesis. Such genes have been named tumor suppressor genes. The significance of the consistent loss of specific regions of genetic information from the genomes of tumor cells of a particular histological type is now appreciated, as such areas may contain as yet unrecognized tumor suppressor genes. The characterization of regions consistently lost thus forms the first step in localizing such genes. We have applied this technology to the study of prostate cancer and our preliminary findings show consistent losses of genetic information from chromosomes 8, 10, and 16.

[The RFLP of LDR152/PstI in the Chinese and its application to linkage analysis in a myotonic dystrophy family]. Myotonic dystrophy (DM) is inherited as an autosomal dominant trait and is characterized by variable expressivity and late age-of-onset. In the present paper, the DNA from 61 normal individuals and a DM family with 15 members of 4 generations were collected and digested with PstI, then hybridized with the LDR152 (D19S19). The results showed that the alleles for the PstI polymorphism were 19 and 11kb in size (gene frequencies were 0.4344 and 0.5656 respectively, which are obviously different from the previous data reported). In this DM family, the carriers who had lived most of their life without knowing that they had been infected with the disease were detected by the LDR152 and the estimation of DM risk on at-risk-individuals was also calculated.

Recent advances in cancer chemoprevention. The CCPC 90 conference and workshop included presentations by basic scientists describing the key in vitro and in vivo model systems used to study epithelial carcinogenesis and its associated biochemical and molecular alterations. A major conference theme was the identification of markers identifying specific carcinogenic stages. Current work focuses on defining the biology of preneoplasia, the critical specific molecular events in multistep carcinogenesis, and the dynamic interplay between viral, behavioral, dietary, and genetic factors in human carcinogenesis. Studies of molecular epidemiology and genetic susceptibility are identifying new risk groups and contributing to preventive strategies. Another major theme of the conference was the concept of field carcinogenesis and the study of carcinogen-exposed tissue "at risk" for the development of cancer. A specific example discussed by several investigators was the issue of SPT development in head and neck and lung cancers. Novel studies of biologic markers for use in early detection and as intermediate end points were described. The latter application, if validated in human trials, may allow short-term screening of chemopreventive agents and determinations of optimal doses/schedules for phase III chemoprevention trials. These biomarker trials may serve as a bridge between preclinical work and full-scale randomized trials. The status of the major phase III clinical trials was presented. Major problems in chemoprevention trials include (1) selection of agents, doses, and schedules, (2) lack of pharmacologic and pharma quality control, (5) adherence (drop-out and drop-in), and (6) trial-specific feasibility/recruitment, issues.

The use of in vivo proton NMR to study the effects of hyperammonemia in the rat cerebral cortex. Using in vivo 1H NMR spectroscopy (1H MRS) and biochemical analysis, the effects of hyperammonemia on cerebral function were studied in three rat models: acute liver ischemia (LIS), administration of urease (UREASE) and administration of methionine sulfoximine (MSO). By means of localization in three dimensions signals were obtained exclusively from the cerebral cortex. Specially developed lineshape correction and fitting methods were used to quantitate the MRS signals. The following concentration changes were observed; a decrease in glutamate and (phospho)choline for all the models; an increase in glutamine in the LIS and UREASE model but a decrease in the MSO model; a marked increase in lactate in the LIS and UREASE group; a tendency to a decrease in N-acetylaspartate in all the models. These changes agree well with the changes in the post-mortem biochemically determined cerebral cortex glutamine and glutamate concentrations. Estimated absolute 1H MRS metabolite concentrations agree well with those obtained by other techniques; cerebral cortex glutamate, however, is underestimated by about 35% by NMR. The present data support the hypothesis that hyperammonemia is associated with a decreased availability of glutamate for neurotransmission.

Mimicking the membrane-mediated conformation of dynorphin A-(1-13)-peptide: circular dichroism and nuclear magnetic resonance studies in methanolic solution. The structural requirements for the binding of dynorphin to the kappa-opioid receptor are of profound clinical interest in the search for a powerful nonaddictive analgesic. These requirements are thought to be met by the membrane-mediated conformation of the opioid peptide dynorphin A-(1-13)-peptide, Tyr1-Gly2-Gly3-Phe4-Leu5-Arg6-Arg7-Ile8-Arg9-Pro10- Lys11-Leu12-Lys13. Schwyzer has proposed an essentially alpha-helical membrane-mediated conformation of the 13 amino acid peptide [Schwyzer, R. (1986) Biochemistry 25, 4281-4286]. In the present study, circular dichroism (CD) studies on dynorphin A-(1-13)-peptide bound to an anionic phospholipid signified negligible helical content of the peptide. CD studies also demonstrated that the aqueous-membraneous interphase may be mimicked by methanol. The 500- and 620-MHz 1H nuclear magnetic resonance (NMR) spectra of dynorphin A-(1-13)-peptide in methanolic solution were sequence-specifically assigned with the aid of correlated spectroscopy (COSY), double-quantum filtered phase-sensitive COSY (DQF-COSY), relayed COSY (RELAY), and nuclear Overhauser enhancement spectroscopy (NOESY). 2-D CAMELSPIN/ROESY experiments indicated that at least the part of the molecule from Arg7 to Arg9 was in an extended or beta-strand conformation, which agreed with deuterium-exchange and temperature-dependence studies of the amide protons and analysis of the vicinal spin-spin coupling constants 3JHN alpha. The results clearly demonstrated the absence of extensive alpha-helix formation. chi 1 rotamer analysis of the 3J alpha beta demonstrated no preferred side-chain conformations.

Purification and immunological characterization of a new form of gamma-glutamyltransferase of human semen. A new form of gamma-glutamyltransferase was purified from human seminal plasma. The purified enzyme was composed of two non-identical subunits with apparent molecular masses of 150 and 95 kDa on polyacrylamide gel electrophoresis (PAGE) in the presence of sodium dodecyl sulfate (SDS), and showed a molecular mass of 500 and 250 kDa on gel filtration in the absence and presence of 1% Triton X-100, respectively. This enzyme was different from human renal gamma-glutamyltransferase not only in apparent molecular masses, but also in amino acid compositions of both the subunits to each other. Experiments with the antisera raised against the purified enzyme revealed that the enzyme was different from the renal, hepatic and testicular enzymes in reactivity to the antibody though partially related to those enzymes. Ouchterlony double diffusion analysis indicated that both human seminal plasma and prostatic extract contained two types of gamma-glutamyltransferase, one is that we purified and the other the renal type. Hence, it is most likely that gamma-glutamyltransferase accounting for most of the enzyme activity in semen results from prostata followed by secretion to seminal plasma.

[Molecular epidemiological markers of Legionella pneumophila in the Valencian Community (II). Restriction enzyme profiles of chromosomal DNA]. Restriction enzyme profiles of chromosomal DNA obtained from 96 Legionella pneumophila strains isolated from environmental and clinical isolates and digested with Hind III have been analyzed. A method to obtain chromosomal DNA to be use in restriction studies and its electrophoretic analysis have been developed. Studying the fragments showing higher differences when comparing the profiles obtained, 5 subtypes are defined and correlated with the isolation areas. There are similar restriction profiles independent of the plasmid contents.

Human herpesvirus-6 in human lymphomas: identification of specific sequences in Hodgkin's lymphomas by polymerase chain reaction. In search of a possible involvement of the human herpesvirus type 6 (HHV-6) in human Hodgkin's and non-Hodgkin's lymphomas, we studied the levels of anti-HHV-6 antibodies in the sera of 94 cases by an immunofluorescence assay, as well as the presence of HHV-6 sequences in the affected tissues of 66 cases by polymerase chain reaction, using one set of primer oligonucleotides. Our results showed higher anti-HHV-6 antibody titers in human lymphomas than in normal blood donors, but the difference is statistically significant only when normal donors are compared with Hodgkin's lymphoma cases. HHV-6 sequences were detected in 3 of 25 Hodgkin's lymphomas and 0 of the 41 cases of non-Hodgkin's lymphomas studied. The three cases positive for HHV-6 sequences belong to the nodular sclerosis-lymphocyte depletion histologic subtype and share remarkable similarities in their clinical features. Furthermore, Southern blot analysis of total genomic DNA obtained from the neoplastic tissues of two of the three patients showed the same restriction fragment length polymorphism. Our results suggest that: (1) the high level of anti-HHV-6 antibodies in Hodgkin's disease is due to an activation of the immune system not related to the presence of HHV-6 sequences in affected lymph nodes; (2) the presence of HHV-6 sequences in human lymphoid tissues is not a frequent event, rather it is in fact a very rare event in non-Hodgkin's lymphomas, while in Hodgkin's cases it is more frequent than previously reported on the basis of Southern blot analysis; and (3) the presence of HHV-6 sequences in Hodgkin's lymphomas may have a relation with the clinical presentation of the disease.

Serotonin and proctolin modulate the response of a stretch receptor in crayfish. The modulatory effects of proctolin and a biogenic amine (5-hydroxytryptamine; 5-HT) have been investigated on a leg mechanoreceptor in the crayfish. Single afferent sensory units were recorded extra- and intracellularly during imposed sinusoidal movement to the receptor strand; all responses were facilitated by a bath application of proctolin and 5-HT at various concentrations (10(-9)-10(-6) M).

Variation in the low density lipoprotein receptor gene is associated with differences in plasma low density lipoprotein cholesterol levels in young and old normal individuals from Italy. We have used four restriction fragment length polymorphisms (RFLPs) of the human low density lipoprotein receptor (LDL-R) gene, detected by the restriction enzymes Ava II, Pvu II, and ApaLI (5' and 3'), to study the effect of variation at this gene locus in determining plasma cholesterol and LDL cholesterol levels. Two hundred eighty-nine normolipidemic individuals were studied from the Liguria region of Italy. The Pvu II RFLP was significantly associated with differences in plasma total and LDL cholesterol levels, explaining 9.6% of the sample variance in LDL cholesterol levels. The other RFLPs, which are in strong linkage disequilibrium with the Pvu II RFLP, were associated with smaller effects on LDL cholesterol. The Pvu II allele, distinguished by the presence of the variable cutting site (P2 allele), was associated with lower levels of total and LDL cholesterol, and the frequency of the P2 allele was significantly reduced in individuals with LDL cholesterol levels higher than the 75th percentile. The frequency of the P2 allele was significantly higher in the group of individuals over 65 years old, and in this group the P2 allele was also associated with a similar reduction in LDL cholesterol levels. Because of linkage disequilibrium, only four RFLP haplotypes were common in this sample. Of these, only the haplotype P2A2VI (relative frequency, 0.269) was associated with a reduction in LDL cholesterol (average excess, -11.5 mg/dl).(ABSTRACT TRUNCATED AT 250 WORDS)

Localization and ontogeny of cells expressing preprodynorphin mRNA in the rat cerebral cortex. The regional distribution of preprodynorphin (PPD) mRNA-containing cells (PPD cells) in the rat cerebral cortex was investigated by in situ hybridization histochemistry using a synthetic oligonucleotide probe. In the isocortex, PPD cells were small or medium-sized and were mainly located in layer V. While they were less numerous in the allocortex than in the isocortex. Only a few labeled cells were seen in the piriform and entorhinal cortices. In the hippocampal formation, labeled cells were observed in the granular layer of the dentate gyrus. An ontogenetic study revealed that PPD mRNA-containing cells appeared on postnatal day 7 in the isocortex and the allocortex and on day 14 in the dentate gyrus. Thereafter, they increased in number and signal intensity to reach a plateau on postnatal day 14 in both the isocortex and the allocortex and on day 35 in the dentate gyrus. The time-course of development of PPD mRNA-containing neurons in the cerebral cortex suggested that PPD-derived peptide has a neuromodulator and/or neurotransmitter role in these regions of the brain.

Screening for alcoholism in a psychiatric hospital. The prevalence of alcoholism is generally underestimated in patients in private practices, general hospitals and psychiatric institutions. Even though the World Health Organization has advocated the concurrent use of laboratory test results and questionnaires for screening, these methods are seldom used together. In this study, patients admitted consecutively to the North Bay Psychiatric Hospital were screened for alcoholism using the Michigan Alcoholism Screening Test (MAST) and gamma-glutamyl-transferase plasma level. Unexpectedly, 56.7% of the entire sample were identified as possible alcoholics; of these, 73.5% were men and 26.5% were women. When rates for men and women were looked at separately, it was found that 66.2% of the men and 40.6% of the women were alcoholic. Participants who tested positive on one or both of the screening tests were offered a more complete evaluation of their drinking behaviour. A diagnosis of alcoholism was confirmed in 88.2% of the patients who agreed to participate further. The question remains whether the high prevalence rates found are a function of the particular sample studied (i.e., patients in a hospital which typically serves a socially disadvantaged sector of the population) or reflects a feature of the general population in this catchment area. A study is currently underway in general hospitals of North Eastern Ontario in an attempt to answer this question.

Glutamate release and spreading depression in the fascia dentata in response to microdialysis with high K+: role of glia. To see electrophysiological and neurochemical events during microdialysis with high [K+], direct current (DC) and excitatory postsynaptic field potentials (fEPSPs) due to perforant path stimulation were recorded in the granule cell layer of the fascia dentata, while 3, 25, 50 or 100 mM KCl was perfused through a microdialysis probe placed 1.5 mm from the recording electrode. Glutamate and glutamine content of the dialysate was measured by high performance liquid chromatography. Raising [K+] from 3 to 25 mM reduced the efflux of glutamine, without affecting that of glutamate or the electrical activity. In about 50% of experiments, 50 mM K+ induced large (20-30 mV) negative waves of spreading depression (SD), and a suppression of fEPSPs. In the other 50%, without SD, fEPSPs did not change. Glutamate efflux increased 3-fold in both groups. SD waves were produced in all experiments with 100 mM K+ which evoked a more than 10-fold increase in glutamate release. Glutamine efflux decreased equally, by about 50%, with the 3 concentrations of K+. Microdialysis with 20 mM fluoroacetate, a glial metabolic poison, decreased the spontaneous efflux of glutamine and glutamate and increased the incidence of SD waves. Results suggest that perfusion of 50 or 100 mM K+ through a microdialysis probe causes spreading depression which blocks surrounding electrical activity. The activity of glia partly protects against spreading depression caused by high [K+].

A guide to benzodiazepine selection. Part II: Clinical aspects. To suit the specific needs of various clinical situations, selection of an appropriate benzodiazepine derivative should be based on consideration of their different pharmacokinetic and pharmacodynamic properties. Benzodiazepine derivatives that are rapidly eliminated produce the most pronounced rebound and withdrawal syndromes. Benzodiazepines that are slowly absorbed and slowly eliminated are most appropriate for the anxious patient, since these derivatives produce a gradual and sustained anxiolytic effect. Rapidly absorbed and slowly eliminated benzodiazepines are usually more appropriate for patients with sleep disturbances, since the rapid absorption induces sleep and the slower elimination rate may induce less tolerance to the sedative effect. Rational selection of a benzodiazepine for the elderly and for the suspected drug abuser is more problematic. The relevant pharmacokinetic and clinical considerations for these users are discussed. Certain derivatives may possess pharmacodynamic properties not shared by the entire benzodiazepine class; empirical studies have suggested the existence of anti-panic properties for alprazolam and clonazepam, antidepressant properties for alprazolam, and anti-manic properties for clonazepam and possibly lorazepam.

Medical therapy of the hypertensive patient with concomitant angina pectoris. Systemic hypertension and symptomatic ischemic heart disease are two common disorders that coexist in the same patient. A medical approach to the patient with both systemic hypertension and angina pectoris is presented in this article, and different treatment modalities are considered.

Medical therapy of stable angina pectoris. This article discusses the three major classes of drugs with somewhat different mechanisms of action that are available for the treatment of angina pectoris. This include nitrates, beta-adrenoreceptor blockers, and calcium-channel blockers.

Medical therapy of unstable angina pectoris. The pathophysiologic mechanisms responsible for the clinical syndrome known as unstable angina pectoris are complex but provide a framework for a rational medical approach to this ischemic condition. The combined use of nitrates, beta-blockers, calcium antagonists, antiplatelet agents, and anticoagulants has been shown to reduce recurrent ischemia, and the latter therapies have reduced the incidence of progression to myocardial infarction and death. A rational risk stratification scheme, which utilizes the presenting symptoms, electrocardiographic, and anatomic information to identify patients for whom additional revascularization procedures are warranted, is presented.

Responses of the rabbit epicardial coronary artery to acetylcholine and adrenoceptor agonists. The aim was to identify the role of the endothelium in mediating the responses to acetylcholine in the rabbit coronary artery, and to determine whether alpha or beta adrenergic stimulation may cause relaxation via endothelial receptors in the coronary arteries of this species. Responses to acetylcholine and adrenoceptor agonists were compared in isolated ring preparations with and without endothelium. The adrenoceptor agonists were examined in the presence of phentolamine or propranolol to block alpha and beta adrenoceptors, respectively. 30 New Zealand white rabbits (2.3-3.4 kg) were killed by an overdose of barbiturate and exsanguination, and the left epicardial coronary artery was dissected free. Ring preparations were suspended in organ baths under isometric tension and, where required, the tone of the preparations was raised by KC1. Concentrations of acetylcholine up to 10(-6) mol.litre-1 produced dose dependent relaxation of the preparations with endothelium intact, but no relaxation in preparations denuded of endothelium. At higher concentrations, a marked vasoconstrictor response was seen in all preparations regardless of the presence of endothelium. At basal tone, acetylcholine produced vasoconstriction which reached a maximum of 1.0 (SEM 0.14)g tension in preparations with endothelium and 1.74(0.27) g tension in those without endothelium (p less than 0.05). In coronary arteries pretreated with 50 mumol.litre-1 phenoxybenzamine to block alpha adrenoceptors, noradrenaline, isoprenaline, and salbutamol produced dose dependent relaxation of the preparations; this was unaffected by the absence of endothelium. In vessels not pretreated with phenoxybenzamine, propranolol inhibited the relaxation to noradrenaline and isoprenaline but again there was no difference between vessels with and without endothelium. In the rabbit isolated epicardial coronary artery, acetylcholine produces an endothelium dependent relaxant response over a limited concentration range; a vasoconstrictor response via smooth muscle dominates at higher concentrations. beta Adrenoceptors mediating relaxation are present on the smooth muscle, but there was no evidence for either alpha or beta adrenoceptor mediated responses via the endothelium. Important differences with coronary arteries from other species are discussed.

Clinical signs of familial hypercholesterolemia in patients with familial defective apolipoprotein B-100 and normal low density lipoprotein receptor function. In a previous study (Tybjaerg-Hansen et al, Atherosclerosis 1990;80:235-242), we identified nine patients heterozygous for the apolipoprotein B (apo B) arginine-to-glutamine (Arg3,500----Gln) mutation (familial defective apolipoprotein B-100 [FDB]). Six of these had been diagnosed clinically as familial hypercholesterolemic (FH) heterozygotes. We have since examined low density lipoprotein (LDL) receptor function in the FDB index patients and in three of their families. Skin fibroblasts from seven of seven unrelated FDB patients from whom cell lines were established exhibited normal high-affinity binding and degradation of normal LDL in vitro. In the three families, a raised plasma LDL concentration did not segregate with a haplotype of two polymorphic restriction sites at the LDL receptor locus. We conclude that the clinical and biochemical signs of classical FH can occur in the presence of the FDB mutation and a normal LDL receptor gene. In a four-generation family with 11 proven or presumed FDB heterozygotes, expression of the mutation ranged from normal plasma LDL concentrations and no clinical signs in two individuals, to hypercholesterolemia and death from myocardial infarction at age 31. Variable expression of the FDB mutation could not be explained conclusively by variation in diet, body mass index, smoking habit, apo E genotype, or plasma Lp(a) concentration.

Enhancing effect of malachite green on the development of hepatic pre-neoplastic lesions induced by N-nitrosodiethylamine in rats. The effects of malachite green (MG) and phenobarbitone (PB) were compared on the development of pre-neoplastic lesions during N-nitrosodiethylamine(DEN)-induced hepatocarcinogenesis in male Wistar rats. Rats were administered 200 p.p.m. DEN in drinking water for a period of 1 month. After an interval of 2 weeks the animals were given either MG (25 p.p.m.) or PB (500 p.p.m.) in drinking water for 2.5 months. The effects were monitored on the basis of the morphological appearance of the liver, histological pattern, gamma-glutamyltranspeptidase (GGT)-positive foci, total GGT activity and the induction of glycogen-deficient islands. Both MG and PB were found to enhance liver carcinogenesis to a significant extent when compared with either their corresponding controls or animals given DEN alone. The enhancing effect of MG at 25 p.p.m. is comparable with PB at 500 p.p.m. An enhancing effect of MG on DEN-induced hepatocarcinogenesis in the rats was demonstrated.

Radiographic assessment of nocturnal gastric juice secretion after administration of roxatidine acetate hydrochloride. Adult patients with symptoms of gastric disease were randomly assigned to a treatment group (n = 103) or untreated control group (n = 89). The treatment group received 75 mg of roxatidine acetate hydrochloride at 9 PM and 12 to 13 hours later gastric juice secretion was measured with gastric x-ray films in both groups. Mean gastric juice secretion was significantly lower in the treated group (16.1 ml/12 hrs) than in the untreated controls (49.8 ml/12 hrs). Gastric juice suppression by roxatidine was 90% in patients with gastric ulcer, 74% in patients with duodenal ulcer, 63% in patients with gastritis, and 70% in patients with no evidence of disease. It is concluded that 150 mg of roxatidine daily would be adequate to treat patients with gastric diseases.

Susceptibility to phenobarbital promotion of hepatotumorigenesis: correlation with differential expression and induction of hepatic drug metabolizing enzymes in heavy and light male (C3H x VY) F1 hybrid mice. Higher body and carcass (body - liver) weights in sodium phenobarbital (PB) treated mice correlate with formation of multiple hepatocellular adenomas in yellow Avy/A and agouti A/a (C3H x VY) F1 hybrid male mice. To assess differences in PB induction of hepatic drug metabolizing enzymes, yellow Avy/A (C3H x VY) F1 hybrid male mice were fed 0.05% sodium PB in NIH-31 diet for 7 months. Livers from the heaviest and lightest mice in the untreated and PB groups were assayed. Total cytochrome P450 content, cytochrome P450IA-selective 7-ethoxyresorufin-O-deethylase and P450IIIA-selective testosterone-6 beta-hydroxylase activities were preferentially induced in the light mice. In contrast, P450IIB-selective 7-pentoxyresorufin-O-dealkylase activity was increased only 3-fold by PB in the light mice but 6-fold in the heavy mice. Testosterone UDP-glucuronyltransferase and gamma-glutamyltranspeptidase activities were induced in the light mice but not in the heavy mice. Glutathione-S-transferase N1:1-dependent activity was induced preferentially in the heavy mice. Significant differences also occurred in constitutive expression of P450IIIA-selective testosterone-6 beta-hydroxylase, P450IA-selective 7-ethoxyresorufin-O-deethylase and testosterone UDP-glucuronyltransferase activities between the untreated weight groups. Thus, expression of constitutive and PB-inducible forms of hepatic drug metabolizing enzymes differs between heavy and light Avy/A (C3H x VY) F1 hybrid subpopulations. This suggests that differential susceptibility to PB promotion of hepatocellular adenomas among genetically identical mice is accompanied by differences in the regulation of gene expression.

Exopeptidases in human platelets: an indication for proteolytic modulation of biologically active peptides. The determination in human platelets of four exopeptidases--aminopeptidase P, dipeptidyl peptidase IV, carboxypeptidase N, and angiotensin converting enzyme--by means of fluorometric or liquid chromatography techniques was carried out. The results obtained show that the specific activities of dipeptidyl peptidase IV, carboxypeptidase N, and angiotensin converting enzyme in intact and disrupted platelets are small compared to their specific activities in serum. However, for aminopeptidase P the specific activity of this enzyme is much higher in platelets than in serum. This suggests that circulating platelets may have a significant role as scavengers for circulating peptides containing bonds susceptible for aminopeptidase P.

Cetirizine: a unique second-generation antihistamine for treatment of rhinitis and chronic urticaria. The recent development of selective H1-antagonists that minimally cross the blood-brain barrier has greatly improved the management of allergic rhinitis and chronic urticaria. These new agents have much reduced anticholinergic and sedative side effects, which were the major drawbacks of the classic H1-antihistamines. Cetirizine, a new second-generation H1-antagonist, offers several properties that may further improve the treatment of allergic rhinitis and chronic urticaria. Cetirizine is the only antihistamine known to possess activity against both the histamine-mediated early phase of the allergic response and the late-phase response of immediate hypersensitivity characterized by migration of inflammatory cells to the site of the reaction. Its efficacy has been demonstrated in clinical trials of patients with seasonal rhinitis and urticaria. The most common side effects associated with cetirizine, such as sedation, are similar to those of other second-generation antihistamines. These properties, combined with a once-daily dosage regimen, should help improve patient compliance and optimize antihistamine therapy.

Restriction fragment length polymorphisms in the Apo B gene in relation to coronary heart disease in a southern Asian population. We have examined DNA polymorphisms associated with the apolipoprotein B gene in 95 Sri Lankan males with ischaemic heart disease and 95 matched controls. For polymorphisms detected using the XbaI or MspI enzymes the allele frequency in Sri Lankans contrasted markedly from that in Caucasians. Overall, there was no significant association of any allele studied with coronary disease cases in this sample. There was, however, a significant difference observed between the XbaI allele frequency in normotriglyceridaemic or normocholesterolaemic CHD cases compared with the allele frequency in the controls.

Characterization of dipeptidyl and tripeptidyl aminopeptidases in human kidney soluble fraction. In an attempt to identify improved biochemical markers for the diagnosis of early kidney damage via urinary analysis of kidney derived enzymes, we have undertaken the systematic identification, quantification and characterization (following purification via anion exchange and gel filtration chromatography, and preparative electrophoresis) of the dipeptidyl and tripeptidyl aminopeptidases in normal human kidney soluble extract (with which the majority of the cellular activity of these enzymes is associated). Four chromatographically separable enzyme types were identified as follows (% relative activity in parentheses): dipeptidyl aminopeptidase I (EC 3.4.14.1; 24%); dipeptidyl aminopeptidase II (EC 3.4.14.2; 8%); dipeptidyl aminopeptidase IV (EC 3.4.14.5; 61%); tripeptidyl aminopeptidase (unclassified; 7%). Comparison of the levels of activity for the above enzyme types in normal and pathological urine may lead to an improvement upon existing procedures for the early detection of renal damage.

Enhanced adherence activity of OK-432-induced peritoneal neutrophils to tumor cells correlates to their increased expression of CD11b/CD18. We previously found that activated peritoneal neutrophils adhered to tumor cells and destroyed them in the cancer ascites of patients who had received intraperitoneal (ip) OK-432 injection therapy. Since tight adhesion to the tumor cell is essential for effective neutrophil-mediated tumor cell destruction, we investigated the mechanism of peritoneal neutrophil adhesion to tumor cells, using a microplate adhesion assay. An in vitro study demonstrated that the adherence activity of the peritoneal neutrophils of patients who received OK-432 injection therapy to tumor cells increased greatly compared to that of blood neutrophils. The expression of the adhesion molecules (CD11a,b,c/CD18) of peritoneal neutrophils, which was determined by an immunofluorescence study, was about four times as much in CD11b and twice as much in CD11c and CD18 compared to that in blood neutrophils. In vitro OK-432 stimulation of normal blood neutrophils increased neither the adhesion to PLC nor the CD11b expression. The enhanced adherence activity of peritoneal neutrophils to tumor cells was significantly inhibited by pretreatment of the neutrophils with anti-CD11b and anti-CD18 monoclonal antibodies (mAb), but not by pretreatment with anti CD11a or anti-CD11c mAb. These results indicated that the increased adhesiveness of OK-432-induced peritoneal neutrophils to tumor cells was due to the enhanced expression of CD11b/CD18. We concluded that CD11b/CD18 molecules on OK-432-induced peritoneal neutrophils play a crucial role in the neutrophil adherence activity against tumor cells, and these results are the first demonstration in the field of human neutrophil function.

Aminopeptidase P and dipeptidyl peptidase IV activity in human leukocytes and in stimulated lymphocytes. Human white blood cells were shown to contain high aminopeptidase P activity. The specific activities found in the high-speed supernatant of the extracts of granulocytes, lymphocytes and monocytes ranged from 30 to 70 units per mg protein. Culturing lymphocytes during 7 days in the presence of phytohaemagglutinin resulted in a 70-200% increase in the specific aminopeptidase P activity and a 200% increase in the specific activity of dipeptidyl peptidase IV. The time-course of the activity of both aminopeptidase P and dipeptidyl peptidase IV during the stimulation of human T-lymphocytes by phytohaemagglutinin indicates an involvement of these two enzymes in the proliferative process of these immunocompetent cells. Due to their substrate specificity their potential substrates must have the N-terminal Xaa-Pro sequence known to be present in several immunologically important polypeptides.

Nonorgan-specific autoantibodies in individuals infected with type 1 human immunodeficiency virus. Fifty-six human immunodeficiency virus-1-positive asymptomatic carriers were tested for the presence of a variety of nonorgan-specific autoantibodies. Antinuclear antibodies were detected in 34 sera, of which 27 were directed to the mitotic spindle apparatus and all were of the IgG isotype. Anti-Golgi complex, anti-centriole, and anti-vimentin antibodies were also present in 20.4, and 4 sera, respectively. Ten patients had less than 500 CD4-carrying T lymphocytes per cubic millimeter. Nine of them had more than one autoantibody. No correlation could be demonstrated between the number of autoantibodies and the level of serum immunoglobulins.

Roxatidine acetate as maintenance treatment for patients with peptic ulcer disease. The European Cooperative Roxatidine Study Group. The efficacy and safety of 75 mg of roxatidine acetate at night as maintenance treatment for chronic peptic ulcer disease was investigated in two double-blind randomized placebo-controlled multicenter studies. A total of 725 patients with endoscopic demonstration of a healed ulcer were recruited; 420 patients were enrolled by 28 centers in the duodenal ulcer study and 305 patients were enrolled by 24 centers in the gastric ulcer study. The duration of treatment in each study was 12 months. The primary efficacy endpoint was ulcer relapse, confirmed on scheduled endoscopy at two, four, six, nine, and 12 months or as necessitated clinically. The total ulcer recurrence rate was significantly lower in patients on active treatment: 35% and 32% of patients with a previously healed duodenal or gastric ulcer relapsed within 12 months while on roxatidine acetate, compared with 66% and 71% of patients in each study on placebo (life-table analysis, P = 0.0001). Both active and placebo treatments were well tolerated. There was no evidence of any clinically significant drug-related laboratory abnormalities, electrocardiographic changes, or changes in vital signs with either treatment. It is concluded that 75 mg of roxatidine acetate at night is a safe and effective maintenance treatment to sustain remission in patients with peptic ulcers.

Pharmacokinetic interactions between theophylline and other medication (Part I). Many drugs have been found to increase or decrease the clearance of theophylline, probably by interaction with one or more of the variants of the cytochrome P450 drug-metabolising system. Theophylline may be particularly susceptible to alteration of its clearance because of the particular form(s) of the P450 system involved, because its metabolism is saturable, and/or because 90% of its elimination is via metabolism. Its clearance has been found to be decreased (typically by around 25%, but often by far more) by erythromycin, troleandomycin (triacetyloleandomycin), roxithromycin, enoxacin, ciprofloxacin, pefloxacin, norfloxacin, ofloxacin, fluoroquinolone T-3262, pipemidic acid, cimetidine, etintidine, propranolol, verapamil, diltiazem, nifedipine, furosemide (frusemide), at least some anovulent agents, viloxazine, allopurinol, ticlopidine, idrocilamide, thiabendazole, disulfiram, influenza- and BCG-vaccination, interferon, and caffeine (half-life increase). In contrast, theophylline clearance (clearance/bioavailability) was found to be increased by isoprenaline (isoproterenol), terbutaline, some corticosteroids, phenytoin, phenobarbital, activated charcoal, felodipine moricizine, benzodiazepines and sulfinpyrazone - typically by about 25%, but sometimes by as much as 80% or more. For several of these concomitant medications, however, only some of the published studies can substantiate an influence, which may highlight the sensitivity of some interactions to particular experimental and/or clinical conditions, e.g. with terbutaline, erythromycin, ciprofloxacin, norfloxacin, ofloxacin, phenobarbital, cimetidine, verapamil, diltiazem, nifedipine, anovulents, allopurinol and influenza vaccination. Moreover, reports both of inhibition and of induction of theophylline clearance by each of rifampicin and isoniazid have appeared. Nevertheless, under investigation many medications have not been found to perceptibly influence theophylline disposition kinetics, e.g. ephedrine, orciprenaline (metaproterenol), prednisone, prednisolone, temelastine, terfenadine, mequitazine, picumast, repirinast, josamycin, midecamycin, miocamycin, spiramycin, amoxicillin, ampicillin, cefalexin, cefaclor, ceftibuten, cotrimoxazole (trimethoprim plus sulfamethoxazole), tetracycline, doxycycline, lomefloxacin, fluoroquinolones NY-198 and AM-833, nalidixic acid, lincomycin, metronidazole, certain antacids, ranitidine, roxatidine, pirenzepine, rioprostil, metoclopramide, metoprolol, atenolol, nadolol, medroxyprogesterone, dextropropoxyphene (propoxyphene), piroxicam, ozagrel, mebendazole and ascorbic acid.(ABSTRACT TRUNCATED AT 400 WORDS)

The undescended testicle. Cryptorchidism results from a complex hereditary series of incompletely understood events involving the HPG axis. The incidence is indirectly related to birth weight and dramatically decreases during the first 3 months after birth. Many nonscrotal testes are retractile and require no therapy whatsoever. True cryptorchid testes develop identifiable histologic alterations within 2 years of parturition, and endocrine abnormalities are often detectable during infancy. Hormonal therapy with hCG is effective in causing descent in only a small percent of children with cryptorchidism. GnRH nasal spray is no different from placebo in double-blind studies in which retractile testes have been excluded. The results are best in low-lying testes and in older children, but a recognized late-failure rate requires continued surveillance. HCG therapy appears to be of little use in nonpalpable cryptorchid testes. The risk of testicular cancer is increased in men with a history of cryptorchidism and even includes the contralateral descended testes. This risk may be reduced by early orchidopexy. Fertility is impaired in men with cryptorchidism and is reported to be no better than 75% and 50%, respectively, in men who have undergone successful unilateral or bilateral orchidopexy. There is unconfirmed evidence that orchidopexy carried out before the age of 2 years may improve these fertility rates. It is recommended that all children with cryptorchid testes undergo treatment by the age of 1 or 2 years. The parents of children with a nonpalpable testis should be informed of the high rate of testicular absence. If hormonal therapy is to be used, it must be initiated at 10 months of age. Treatment failures must be identified quickly to allow prompt referral of these children to a pediatric urologist or surgeon for orchidopexy.

The effect of Heparegen and D-penicillamine on the activity of some ammonia metabolizing enzymes in liver and brain of rats intoxicated with ethanol. This paper reports data on the effect of two drugs: Heparegen (thiazalidine-4-carboxylic acid) and D-penicillamine on the blood ammonia concentration and on some ammonia metabolizing enzymes in liver and brain of rats intoxicated with ethanol. It seems, that both drugs decrease ammonia concentration and simultaneously elevate liver and brain glutamine synthetase activity. The effect of D-penicillamine on the nitrogen metabolism in the damaged liver appears to be more favorable than that of Heparegen.

Memory T cells represent the predominant lymphocyte subset in acute and chronic liver inflammation. T cells can be divided into two main phenotypic subpopulations-i.e., the CD45RA-positive (2H4-positive) "naive" subset and the CD45RO-positive (UCHL1-positive) "memory" subset. In light of this recent functional reinterpretation of T-lymphocyte subpopulations, we reinvestigated the composition of the inflammatory infiltrate in liver biopsy specimens from patients with acute and chronic hepatitis. In normal liver, the few scattered mononuclear cells present in portal tracts and in the intralobular parenchyma consisted of both CD45RA-positive (2H4-positive) naive and CD45RO-positive (UCHL1-positive) memory T cells. In inflammatory liver diseases, portal tract and periportal and intralobular areas of inflammation consisted virtually only of CD45RO-positive (UCHL1-positive) memory T cells, which strongly expressed the CDw29 (4B4) antigen, and the adhesion molecules LFA-1, CD2, LFA-3, CD44 and VLA-4 and the activation marker human leukocyte antigen-DR. These results indicate that activated memory T cells represent the predominant subpopulation of lymphocytes in areas of liver inflammation. Memory T cells strongly express various homing receptors and adhesion molecules, which probably allow them to accumulate at inflammatory sites and to strengthen interaction with target cells. Furthermore, the increased number of memory T cells with enhanced interferon-gamma production in areas of liver inflammation may contribute to the maintenance and up-regulation of immune responses occurring in inflammatory liver diseases.

Effects of short-term administration of human chorionic gonadotropin on immune functions in cryptorchid children. To delineate the effects of human chorionic gonadotropin (hCG) administration on immune responsiveness, immunological parameters including serum immunoglobulins, total and differential white blood cell count T and B lymphocyte membrane phenotype, in vitro, proliferative response to phytohaemagglutinin, Concanavalin A (ConA) and pokeweed mitogen were studied in 13 prepubertal cryptorchid boys before, during, and 3 months after hCG therapy. Before treatment, all the immunological parameters were normal except for an unexpected high percentage of T suppressor-cytotoxic cells (CD8+). During therapy, the absolute number of total peripheral blood lymphocytes, and that of total T-cells, T helper-inducer cells and of CD8+ subsets were diminished. The percentage of CD8+ cells and lymphocyte response to ConA decreased significantly and returned to normal after hCG withdrawal. The possible effects of long-term hCG treatment remain to be determined.

Low arylsulphatase A activity and choreoathetotic syndrome in three siblings: differentiation of pseudodeficiency from metachromatic leukodystrophy. We report on a family with a sibship of three children for whom the diagnosis of "an unusual form of metachromatic leukodystrophy (MLD)" had been suggested earlier. The patients had choreiform movements and dystonic posturing accompanied by dysarthria since childhood. The availability of the polymerase chain reaction enabled us to show that the three siblings have a pseudodeficiency genotype (ASAp/ASAp). There was no abnormal sulphatiduria, and we propose that the neurological disease and low arylsulphatase A activity are unrelated to one another in this family. A diagnosis of MLD carries very serious implications, and we recommend that gene amplification by polymerase chain reaction and hybridization with allele-specific oligonucleotide probes should be used to corroborate the diagnosis, especially when there is no abnormal sulphatiduria and when metachromatic material cannot be demonstrated in a sural nerve biopsy.

Streptomycin and tetracycline resistance plasmids in Staphylococcus hyicus and other staphylococci. Plasmids associated with resistance to streptomycin, to streptomycin plus chloramphenicol or to tetracycline in Staphylococcus hyicus isolated from the skin of pigs have been compared, by restriction endonuclease digest patterns, with similar staphylococci from human sources and with published DNA base sequences. Several plasmids from Staph. hyicus have proved to have a very similar structure to those described from Staph. aureus but others appeared very dissimilar. This confirms the opinion that staphylococci from animal skin share a pool of plasmids with those from human skin but may also possess some of quite different structure.

Role of serotonin in therapy of depression and related disorders. Several developments in serotonin neuropharmacology have implications for psychiatric disorders and have already begun to impact their treatment. Selective inhibitors of serotonin uptake, which enhance serotonergic function by preventing the removal of serotonin from the synaptic cleft via the membrane transporter, have been introduced for the treatment of depression and may be effective in other disorders. Precursor loading can increase serotonin concentrations in the synaptic cleft, and tryptophan--which has been available in health food stores and drug stores--had become increasingly used for self-medication of depression, insomnia, and premenstrual syndrome. Conversion to serotonin is not the major metabolic pathway for tryptophan, and large increases in other tryptophan metabolites (such as quinolinic acid, a substance that is excitotoxic at high concentrations) accompany small increases in extracellular serotonin. The recent epidemic of the eosinophilia-myalgia syndrome associated with tryptophan now appears due to a trace contaminant in the product from a single manufacturer. A major advance in serotonin pharmacology has been the elucidation of serotonin receptor heterogeneity. At least seven receptor subtypes (5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-HT2, 5-HT3, 5-HT4) have been identified in brain. Direct-acting agonists and antagonists can have selective affinity for specific receptor subtypes. Selective activation of 5-HT1A receptors seems to cause anxiolytic and possibly antidepressive effects. Selective antagonists of 5-HT2 or 5-HT3 receptors may be useful in treating anxiety and schizophrenia. Drugs that enhance serotonergic function suppress aggression in animals, but the specific receptor subtypes involved are not known. The advances being made in serotonin pharmacology will help define the role of this brain neurotransmitter in psychiatric and other disorders and can be expected to lead to further therapeutic advances.

No influence of prejunctional alpha 2-adrenoceptors on the effects of nicotine and tyramine in guinea-pig atria. 1. Guinea-pig left atria were stimulated at a rate of 0.5 Hz and preloaded with 10 microCi 7-[3H]noradrenaline. In the presence of cocaine, 3 x 10(-6) mol l-1, and atropine, 10(-7) mol l-1, noradrenaline release was stimulated twice in each atrium, either by electrical field stimulation (one pulse, 0.2 ms 30 V, during each refractory period for 5 min) or by addition of either nicotine, 3 x 10(-5) mol l-1, or tyramine 10(-5) mol l-1. 2. The release of radioactivity caused by field stimulation and the associated positive inotropic effect were almost abolished by 3 x 10(-8) mol l-1 tetrodotoxin. Pretreatment with 3 x 10(-7) mol l-1 idazoxan increased the effects of field stimulation, while they were attenuated in the presence of clonidine, 3 x 10(-7) mol l-1. 3. The inotropic effect and the release of radioactivity caused by nicotine were greatly attenuated by tetrodotoxin, but were not significantly influenced by idazoxan or clonidine. 4. The release of radioactivity caused by tyramine and the inotropic effect of this drug were resistant to tetrodotoxin pretreatment and were not modified by idazoxan or clonidine. 5. It is concluded that nicotine releases noradrenaline by initiating a propagated action potential. But activation of prejunctional alpha 2-adrenoceptors does not seem to attenuate the transmitter release by limiting the spread of the action potential in the prejunctional sympathetic neuronal network.

Transection of carotid sinus nerve inhibits the turnover of dopamine and norepinephrine in long-term hypoxic carotid bodies: a biochemical and morphometric study. To assess the efferent influence of the carotid sinus nerve on the catecholamine function and the vascularity in long-term hypoxic carotid bodies, rats were exposed to hypoxia (10% O2 in nitrogen for 1 and 3 weeks) after unilateral transection of the sinus nerve. In the intact carotid bodies, long-term hypoxia elicited several biochemical and morphological alterations: increased turnover of dopamine and norepinephrine, increased volume density of blood vessels, decreased volume density of glomic tissue. Transection of the sinus nerve reduced but did not abolish the increase in turnover of dopamine and norepinephrine evoked by hypoxia without preventing the structural alterations. Immunocytochemical studies revealed the presence of nerve fibres exhibiting neuropeptide Y-like immunoreactivity which persisted after the excision of the carotid sinus nerve. Nerve fibres showing substance P-like immunoreactivity were found in the intact carotid bodies but not in the carotid bodies deprived of sinus nerve. It is concluded that the sinus nerve exerts a stimulatory efferent control on the synthesis and release of dopamine and norepinephrine in rat carotid body during long-term hypoxia, but no appreciable vasodilatory influence on the glomic vasculature. A possible role of substance P contained in the endings of the carotid sinus nerve is discussed.

Failure of phenotypic characteristics to distinguish between carrier and invasive isolates of Staphylococcus epidermidis. Thirty carrier and 29 invasive Staphylococcus epidermidis isolates were analysed for production of slime, extracellular enzymes and antibiotic resistance. Evaluation of slime production was by two methods which gave differing results, but both showed no difference between the two groups of isolates. Exoenzyme production by the two groups of isolates was also similar, and the only differences were shown in resistance to some antibiotics; carrier isolates were more resistant to novobiocin and cephalothin, but resistance to chloramphenicol, tunicamycin, teicoplanin, penicillin, ampicillin and tetracycline was similar in both groups. Cluster analysis based on exoenzyme production showed no consistent difference between invasive and carrier isolates, with the lowest similarity coefficient over 88% (except for one isolate). Consequently, none of the characteristics studied was useful in differentiating potentially invasive isolates.

Intracellular recordings from canine intracardiac ganglion cells. Stable transmembrane potentials were recorded from 60 canine intracardiac ganglion cells taken from 10 dogs, which had intact synaptic connections: mean resting membrane potential, input resistance and time constant were 61.5 mV, 70 M omega and 3.3 ms. Action potentials could be evoked by intrasomal current injection and by orthodromic and antidromic stimulation of interganglionic nerves. Orthodromic action potentials were initiated by excitatory postsynaptic potentials and mediated by nicotinic receptors. All action potentials could be blocked by tetrodotoxin. Intracellular labeling revealed large cell bodies and long dendritic and axonal processes. Thus, the functional and anatomical properties of canine cardiac ganglion cells and their synaptic connections can be elucidated using this preparation.

Theatre over-shoes do not reduce operating theatre floor bacterial counts. Occasional staff or visitors to operating theatres are usually requested to don over-shoes as this is perceived to reduce bacterial floor colony counts. However, this entails some expense and considerable inconvenience. Using disposable surface contact plates floor bacterial counts were measured four times a day at five different sites during the 5 normal working days of one 2-week period in a general operating theatre when over-shoes were worn and one 2-week period when over-shoes were not worn. There was no significant difference in the mean bacterial floor colony counts between the two periods according to sampling times or sites. As in Intensive Therapy units, over-shoes should no longer be used in general operating theatres.

Hospital green salads and the effects of washing them. Each week from April 1989 to February 1990, a plate of green salad prepared in the hospital kitchen was examined microbiologically. Of the 256 plates examined, 51% had total viable counts (TVCs) of greater than or equal to 10(5) colony forming units (cfu) g-1. Staphylococcus aureus was present in 13 samples and Escherichia coli in one sample. No Listeria monocytogenes, Clostridium perfringens or Salmonella spp. were isolated. The effect of washing mustard and cress, cucumber and the different layers of lettuce leaves was examined. Washing the salad by agitating it under running tap water in a colander for 2 min reduced the total bacterial counts by 10-fold. The inner leaves of a lettuce had TVCs less than 10(4)cfu g-1, at least 10-100-fold less than the outer leaves. Cucumber after washing had similar TVCs as after peeling. Five of six samples of mustard and cress had TVCs of at least 10(6)cfu g-1 before washing. As a consequence, mustard and cress was no longer used in our salads.

Application of Hazard Analysis Critical Control Point (HACCP) to the handling of expressed breast milk on a neonatal unit. Hazard Analysis Critical Control Point (HACCP) is a powerful procedure for ensuring quality and safety and has gained widespread use in industry. This paper describes the basic method which is a four-stage process including process analysis, hazard identification, identification of critical control points and devising effective control options. Suggestions as to how the method can be adapted to the control of hospital infection are made. A HACCP analysis, on the supply of expressed human breast milk to babies on a Special Care Baby Unit, is presented. Although only the mother's own milk was given to babies on the unit, several potential hazards were identified and suggestions have been made for their control.

Efficacy of mupirocin nasal ointment in eradicating Staphylococcus aureus nasal carriage in chronic haemodialysis patients. Topical 2% mupirocin ointment eradicated chronic Staphylococcus aureus nasal carriage immediately post-therapy in 17 (77%) of 22 haemodialysis patients. Mean time to recurrence was 3.8 weeks. Similar pre-therapy and post-therapy phage types occurred in 12 (71%) of 17 patients. Staphylococcus aureus infections developed in none of 17 successfully treated patients, two of five treatment failures (P = 0.05), and 10 of 46 untreated patients studied concurrently (P = 0.03).

Rapid screening of colonies from Listeria selective agar. A rapid method ('Liststrip', Lab M) of screening aesculin-positive colonies from Oxford selective agar was evaluated. This method relies on the ability of all Listeria spp. to hydrolyse aesculin and to have a rapid phosphatase but neither a pyroglutamic acid beta-naphthylamide amidase nor produce indole. Of 198 Listeria spp., all gave identical results (as above) in 10 min (except four isolates of L. murrayi), whereas of 112 aesculin-positive colonies from Oxford agar that were not Listeria only one gave a similar result. The method was compared with Gram stain and oxidase as a screening procedure. This strip test method is simple enough to be used by relatively unskilled staff and provides a rapid and reliable method to screen colonies from Oxford selective agar.

Wound infection under occlusive dressings. It is often supposed that occlusive dressings potentiate wound infection. However, even though heavy colonization by skin and wound flora is often seen under certain types of occlusion, clinical infection is not a frequent occurrence. Commensal wound flora consists of a variety of Gram-positive and Gram-negative organisms and fungi which do not appear to be detrimental to healing. Certain aspects of wound healing may in fact be promoted by bacterial colonization, although clinical infection can lead to wound breakdown and systemic infection. Wounds compromised by devitalized tissue, drains or sutures are more susceptible than clean wounds to clinical infection. Occlusive dressings may help prevent infection by presenting a barrier to potential pathogens, and hydrocolloid occlusive dressings have been shown to prevent dissemination of methicillin-resistant Staphylococcus aureus. The rate of clinical infection as deduced from published trials of dressings is lower under occlusion than when non-occlusive dressings are used, and this is likely to be a result of normal activity of the host defences under occlusive dressings.

Multiply antibiotic-resistant Staphylococcus epidermidis in patients, staff and environment--a one-week survey in a bone marrow transplant unit. The distribution of Staphylococcus epidermidis resistant to ciprofloxacin and/or gentamicin was studied in an isolation unit for patients undergoing bone marrow transplantation. During 1 week all such strains colonizing patients or staff members or found on the clothes of staff or in the air were investigated. Antibiograms and plasmid profiles were used for epidemiological typing. Thirty-one different antibiograms were found. A few strains were widely spread and dominated quantitatively. Staff colonization was 23%, but contamination of their clothes was 82%. Two strains which colonized three of the patients were widely spread in the air. They were found in the corridor and in every patient room, even where the patient was not colonized. The main source of the environmental contamination seems to have been patients. Possible routes of infection were direct airborne transmission as well as passive transfer via staff.

Ultraviolet B irradiation of human leukaemia HL-60 cells in vitro induces apoptosis. UV radiation is known to be a potent agent for the induction of programmed cell death (apoptosis) in human skin. However, the mechanistic aspects of UV-induced apoptosis remain ill-defined. In this study the effects of varying periods of UV-irradiation on the human leukaemia HL-60 cell line and on five other human cell lines were investigated. HL-60 cells were found to rapidly undergo apoptosis en masse after short periods of UV-irradiation, whereas prolonged exposure of these cells to this form of radiation induced a more rapid form of cell death which was suggestive of necrosis, the pathological mode of cell death. Similar effects were observed on the U937 (myelomonocytic), Molt-4 (T-lymphoblastoid), and Molt-3 (T-lymphoblastoid) cell lines, whereas the K562 (pre-erythroid) and Daudi (B-lymphoblastoid) cell lines proved to be relatively resistant to the death-inducing properties of UV-irradiation by comparison. UV-induced apoptosis in cell lines was characterized by morphological changes as well as DNA fragmentation into unit multiples of approximately 200 bp, which was indicative of endogenous endonuclease activation. This DNA fragmentation pattern was not detected in cells immediately after UV-irradiation, and was therefore not the result of direct UV-induced DNA damage. UV-induced apoptosis of the HL-60 cell line was found to require extracellular calcium and to be inhibited in a dose-dependent way by zinc added to the culture medium.

Lack of dose rate modification (0.0049 vs. 0.12 Gy/min) of fission-neutron-induced neoplastic transformation in C3H/10T1/2 cells. Clonogenic survival and neoplastic transformation of asynchronous cultures of C3H/10T1/2 cells were used to assay the effect of dose protraction of reactor-produced fission neutrons. Cells were exposed to eight neutron doses ranging from 0.05 to 0.9 Gy delivered at 11.7 or at 0.49 cGy/min. For each dose level, high and low dose rate irradiations were performed on the same day. At each dose a similar effectiveness of fission neutron irradiation at high or low dose rates was measured for both cell survival and transformation. The combined high and low dose-rate data were analysed by two- or three-parameter models. Depending on the model used, values of the effectiveness per unit dose derived as parameters of linear terms of the respective dose-response curves were 0.9-1.2 Gy-1 for clonogenic survival and 5-8 x 10(-4) Gy-1 for neoplastic transformation. It is concluded that the modification of fission neutron dose-response curves by dose rate is negligible or absent in the range of doses and dose rates examined, in contrast to results with other sources of fission or fast neutrons.