Interaction of clozapine with metformin in a schizophrenia rat model.

The low efficacy of antipsychotic drugs (e.g., clozapine) for negative symptoms and cognitive impairment has led to the introduction of adjuvant therapies. Because previous data suggest the procognitive potential of the antidiabetic drug metformin, this study aimed to assess the effects of chronic clozapine and metformin oral administration (alone and in combination) on locomotor and exploratory activities and cognitive function in a reward-based test in control and a schizophrenia-like animal model (Wisket rats). As impaired dopamine D1 receptor (D1R) function might play a role in the cognitive dysfunctions observed in patients with schizophrenia, the second goal of this study was to determine the brain-region-specific D1R-mediated signaling, ligand binding, and mRNA expression. None of the treatments affected the behavior of the control animals significantly; however, the combination treatment enhanced D1R binding and activation in the cerebral cortex. The Wisket rats exhibited impaired motivation, attention, and cognitive function, as well as a lower level of cortical D1R binding, signaling, and gene expression. Clozapine caused further deterioration of the behavioral parameters, without a significant effect on the D1R system. Metformin blunted the clozapine-induced impairments, and, similarly to that observed in the control animals, increased the functional activity of D1R. This study highlights the beneficial effects of metformin (at the behavioral and cellular levels) in blunting clozapine-induced adverse effects.

Caffeine - treat or trigger? Disparate behavioral and long-term dopaminergic changes in control and schizophrenia-like Wisket rats.

The influence of caffeine on behavioral functions in both healthy and schizophrenic subjects is controversial. Here we aimed to reveal the effects of repeated caffeine pre- and post-training treatments on motor and exploratory activities and cognitive functions in a reward-based test (Ambitus) along with a brain region-specific dopamine D2 receptor profile in control and schizophrenia-like WISKET model rats. In the control animals, pre-treatment caused temporary enhancement in motor activity, while permanent improvement in learning function was detected in the WISKET animals. Post-treatment produced significant impairments in both groups. Caffeine caused short-lasting hyperactivity followed by a rebound in the inactive phase determined in undisturbed circumstance. Caffeine treatment substantially enhanced the dopamine D2 receptor mediated G-protein activation in the prefrontal cortex and olfactory bulb of both groups, while it increased in the dorsal striatum and cerebral cortex only in the WISKET animals. Caffeine enhanced the maximal binding capacity in the hippocampus and cerebral cortex of WISKET animals, but it decreased in the prefrontal cortex of the control animals. Regarding the dopamine D2 receptor mRNA expression, caffeine treatment caused significant enhancement in the prefrontal cortex of WISKET animals, while it increased the hippocampal dopamine D2 receptor protein amount in both groups. This study highlights the disparate effects of caffeine pre- versus post-training treatments on behavioral parameters in both control and schizophrenia-like animals and the prolonged changes in the dopaminergic system. It is supposed that the delayed depressive effects of caffeine might be compensated by frequent coffee intake, as observed in schizophrenic patients.

The effect of increased NaCl intake on rat brain endogenous µ-opioid receptor signalling.

Numerous studies demonstrate the significant role of central ß-endorphin and its receptor, the µ-opioid receptor (MOR), in sodium intake regulation. The present study aimed to investigate the possible relationship between chronic high-NaCl intake and brain endogenous MOR functioning. We examined whether short-term (4 days) obligatory salt intake (2% NaCl solution) in rats induces changes in MOR mRNA expression, G-protein activity and MOR binding capacity in brain regions involved in salt intake regulation. Plasma osmolality and electrolyte concentrations after sodium overload and the initial and final body weight of the animals were also examined. After 4 days of obligatory hypertonic sodium chloride intake, there was clearly no difference in MOR mRNA expression and G-protein activity in the median preoptic nucleus (MnPO). In the brainstem, MOR binding capacity also remained unaltered, although the maximal efficacy of MOR G-protein significantly increased. Finally, no significant alterations were observed in plasma osmolality and electrolyte concentrations. Interestingly, animals that received sodium gained significantly less weight than control animals. In conclusion, we found no significant alterations in the MnPO and brainstem in the number of available cell surface MORs or de novo syntheses of MOR after hypertonic sodium intake. The increased MOR G-protein activity following acute sodium overconsumption may participate in the maintenance of normal blood pressure levels and/or in enhancing sodium taste aversion and sodium overload-induced anorexia.

Animal welfare in different human cultures, traditions and religious faiths.

Animal welfare has become a growing concern affecting acceptability of agricultural systems in many countries around the world. An earlier Judeo-Christian interpretation of the Bible (1982) that dominion over animals meant that any degree of exploitation was acceptable has changed for most people to mean that each person has responsibility for animal welfare. This view was evident in some ancient Greek writings and has parallels in Islamic teaching. A minority view of Christians, which is a widespread view of Jains, Buddhists and many Hindus, is that animals should not be used by humans as food or for other purposes. The commonest philosophical positions now, concerning how animals should be treated, are a blend of deontological and utilitarian approaches. Most people think that extremes of poor welfare in animals are unacceptable and that those who keep animals should strive for good welfare. Hence animal welfare science, which allows the evaluation of welfare, has developed rapidly.

[Incidence and invasive treatment of congenital heart diseases in Hajdu-Bihar county]. / A veleszületett szívhibák incidenciája és invazív kezelése Hajdú-Bihar megyében.

The incidence of congenital heart diseases was evaluated in the period 1994-1998. The number of those who went through therapeutic intervention and those infants dying of congenital heart disease were also assessed. Data were collected retrospectively. During the study period 26,932 live-births occurred in Hajdú-Bihar county and 421 congenital heart disease were diagnosed, 81% of whom were diagnosed under the age of one year. The most frequent diseases were secundum type atrial septal defect, ventricular septal defect and patent ductus arteriosus. 121 therapeutic procedures were performed (109 operations and 12 interventional heart catheterizations). 41 interventions occurred under the age of one and 13 before the age of 28 days. The mean age of children older than 1 year was 6 years at the time of the operation or interventional catheterization. The overall postoperative mortality within 30 days was 8.3%. During the study period 28 infants with significant heart disease died, 20 of whom also had an associated disease (most frequently prematurity). For congenital heart disease 4.5 operations or interventional heart catheterizations were required/1000 live births. The higher rate of diagnosed congenital heart disease is due to the development in diagnostic techniques, especially to Doppler-echocardiography. Owing to the operational waiting list the children's age at the time of operation is higher than optimal. The mortality among infants with heart disease is influenced by many factors, that is why stepping forward is a complex task in this field.

Acoustic rhinometry and rhinomanometry in the evaluation of nasal patency of patients with nasal septal deviation.

The aim of the present study was to assess the clinical utility of acoustic rhinometry (AR) compared with active anterior rhinomanometry (AAR) in the evaluation of nasal patency in subjects with nasal septal deviation. Fifty patients were divided into three groups based upon the part of the nasal cavity where the septal deviation was situated (anterior: up to 2.5 cm; middle: between 2.5 and 4.5 cm; posterior: between 4.5 and 8 cm measured from the columella). The control group consisted of 15 subjects with no nasal complaints and no history of nasal disease. Inspiratory and expiratory nasal airway resistance (NAR) at 75 Pa and at 150 Pa before and after decongestion were measured by AAR. Minimal Cross-sectional Area (MCA), distance of MCA, and nasal volume (Vol) were measured before and after decongestion by AR (Rhino 2000). Subjective nasal patency was assessed by Visual Analogue Score (VAS). In the statistical analysis the deviated unilateral nasal cavities were compared with the randomly chosen unilateral nasal cavities of normal subjects. Both techniques AR and AAR were sufficiently sensitive to reveal severe deviations in the anterior nasal cavity (MCA, Volant, NAR75, NAR150, p < 0.05). The techniques were less sensitive in cases of middle and posterior deviations (MCA, Volmid, Volpost, MCAmid, MCApost, NAR75, p > 0.05). The nondecongested inspiratory and expiratory NAR at 150 Pa were the only parameter that differed from normal in cases of posterior deviations. The VAS correlated better with NAR than with MCA. MCA correlated more frequently with expiratory than with inspiratory NAR.

Nasal resistance--a reliable assessment of nasal patency?

This study was undertaken to determine the distribution of nasal resistance in a healthy white population. One hundred subjects without nasal complaints were selected for the investigation. The test subjects were divided into two groups on the basis of anterior rhinoscopy. Group 1 included 60 subjects with rhinoscopically normal noses. Group 2 included 40 subjects with rhinoscopically abnormal noses. The pressure-flow data were recorded via active anterior mask rhinomanometry. The analogue pressure and flow signals were sampled and digitized by a computer system according to the time averaging method. Nasal resistance was calculated according to the recommendations of the International Committee on Standardization of Rhinomanometry. The normality of unilateral nasal resistance data distributions was assessed by the Kolmogorov-Smirnov Goodness of Fit Test at inspiratory and expiratory corresponding pressures of 50 Pa, 75 Pa, 100 Pa, and 150 Pa. The distributions of the calculated total resistance data were estimated at inspiratory and expiratory reference pressures of 75 Pa and 100 Pa. The data distributions of the two groups were compared using the Mann-Whitney U-test. Distributions for unilateral resistance were frequently found to deviate from normality. The distributions of total nasal resistance data never showed significant deviation from normality. More non-normal distributions were observed in Group 2 than in Group 1. Significant differences were determined between the two sub-groups for the non-decongested data. The entire group of subjects was homogeneous for the decongested data. The subjective assessment of nasal patency appeared not to be a sufficient criterion for the selection of subjects for normative studies in rhinomanometry. The presence of anatomical abnormalities and the influence of the nasal cycle could be responsible for the skewness of nasal resistance data in the normative studies in rhinomanometry.

The accuracy of tympanometry assessed by its sensitivity and specificity.

Tympanometry has become a widely accepted diagnostic tool for the diagnosis of otitis media with effusion (OME). The present study was conducted to assess the accuracy of the technique by calculating its sensitivity and specificity. Forty children with chronic OME and recurrent otitis media were studied. Immediate preoperative tympanograms were compared with operative findings of tympanocentesis, and sensitivity and specificity data were calculated. Approximately one third of the B type tympanograms (effusion) changed to A (effusion free) or C type (possible effusion) during the waiting period for the operation, showing resorption of fluid from the middle ear cavity. Sensitivity score was 95% bearing out the C type tympanograms. When C type tympanograms were included into the calculation, sensitivity dropped to 73%, showing liquid frequently present in cases of C type tympanograms. Tympanometry scored as more reliable in the presence of adenoid hypertrophy, when sensitivity was 83% and specificity was 90%. The absence of adenoid hypertrophy led to a drop of sensitivity to 58% and to a drop of specificity to 71%. These results may indicate that inhalant induction of anaesthesia has less effect on the middle ear in the presence of adenoidal hypertrophy and concomitant eustachian tubal dysfunction. Tympanometry proved to be a reliable diagnostic tool for the diagnosis of otitis media with effusion. Long preoperative waiting periods and the absence of adenoid hypertrophy could be responsible for the differences between preoperative tympanograms and the middle ear status observed at tympanocentesis.

Mast cell heterogeneity in higher animals: a comparison of the properties of autologous lung and intestinal mast cells from nonhuman primates.

The issue of mast cell heterogeneity has been investigated in nonhuman primates by a comparative examination of lung and intestinal mast cells. These cells were obtained in parallel from the respective tissues of individual monkeys by an identical enzymatic dispersion technique. Mast cells derived from the lungs differed from those derived from the intestine in that the majority of the former cell type could be stained with toluidine blue at pH 4 to 5, whereas the intestinal mast cells in the dispersed preparations required a more acidic pH (less than 1) to display metachromasia. In addition, the lung cells exhibited an increased content of the mast cell mediator histamine. Nonhuman primate lung mast cells were also quantitatively more responsive to an immunologic challenge than their intestinal counterparts in that they released a higher percentage of cellular histamine and generated more leukotriene C4 on stimulation. Considerable inter-animal variation was observed between the magnitude of mediator release from both mast cell types after anaphylactic activation, but evidence for the presence in nonhuman primates of the phenomenon of releasability was not obtained. The responsiveness of both cell types to a range of potential nonimmunologic secretagogues and anti-allergic agents, including compound 48/80, substance P, theophylline, and isoprenaline, was essentially similar. We conclude that mast cell heterogeneity in higher animals may be reflected more by cytochemical rather than by functional differences between mast cell classes.

The effects of aspartame on mast cells and basophils.

The artificial sweetener aspartame was studied to determine whether it had any direct effects on mast cells and basophils. Aspartame was not shown to be a direct mast cell or basophil secretagogue in vitro, or in vivo as assessed by skin testing. During an acute incubation, aspartame did not affect IgE-mediated histamine release from mast cells. However, mast cells cultured in aspartame for periods of up to 9 days showed enhanced rates of proliferation and decreased responsiveness to releasing stimuli. The effect of aspartame on proliferation of cells in culture could be ascribed to a non-specific enhancing effect of its constituent amino acids.

Activation of transglutaminase and production of protein-bound gamma-glutamylhistamine in stimulated mouse mast cells.

The identification of transglutaminase in the growth-factor-dependent mouse mast cell line PT18 was accomplished through its characteristic catalytic properties (specificity, calcium dependency, and inhibition by iodoacetamide); and by both immunoprecipitation and Western blot analysis using affinity purified antibody. The enzymatic activity in these cells increased in association with the release of histamine from the cells induced by an IgE-dependent mechanism or by exposure to the ionophores A23187 or Br-x537A. The increase in transglutaminase activity was paralleled by a marked increase in the level of protein-bound gamma-glutamylhistamine, determined in radiolabeled form in mast cells that were either metabolically labeled with [3H]histidine or incubated with [3H]histamine before degranulation. The highest level of bound gamma-glutamylhistamine was found in the immunologically stimulated cells. Enzymatic activity and the gamma-glutamyl derivative were associated primarily with the cells, both before and after stimulation. Separation of gamma-glutamylhistamine in a proteolytic digest of these cells was carried out using a combination of ion exchange chromatography and high performance liquid chromatography. The gamma-glutamyl compound was identified and quantitated through the enzymatic production of histamine with the use of gamma-glutamylamine cyclotransferase, an enzyme specific for the disassembly of gamma-glutamylamines.

[Data on artifical rearing of dual-purpose calves belonging to the dairy-beef type. 2. Effect of single or twice daily milk feeding and omission of Sunday milk feeding]. / Angaben zur künstlichen Aufzucht von Zweinutzungskälbern des Milch-Fleisch-Typs. 2. (Mitteilung) Auswirkungen von einmaligen bzw. zweimaligem Tränken sowie des Weglassens des Träukens am Sonntag

The authors carried out a 2x2 factor trial to investigate in which way different regimes of drinking and the feeding of a concentrate mixture at 2 levels of nutrition would affect the general development, food consumption and nutrient utilization of the calves or would influence their state of health and their behaviour in the period of milk feeding, and after weaning, up to the age of 6 months. No significant differences in the average liveweight were noted between th groups of calves that were milk fed once or twice daily and those milk fed once or twice daily with the exception of Sundays. The feeding of 2 types of concentrated food significantly influenced the liverweight of the calves only at the time of weaning. Significant differences in weight increases were only noticed with regal to the average daily weight increases until weaning, i.e. between the groups of animals receiving milk feeds twice daily, with the exception of Sundays, and the groups fed different types of concentrate mixtures. The different kinds of feeding did not influence the amount of solid food consumed by the animals, nor did it affect the level of nutrient utilization and the general behaviour of the animals. It was found that in the animals receiving milk once daily,except Sundays, the symptoms of diarrhea observed in the early phase of milk nutrition disappeared more slowly than in the outher animals.

[Artificial rearing of double purpose calves of the beef-dairy type. 1. Effects of the length of the milk-rearing period and of the amount of milk substitutes needed for the rearing of the calf]. / Angaben zur künstlichen Aufzucht von Zweinutzungskälbern des Milch-Fleisch-Typs

Reducing the period of Milk rearing of calves from 90 days (time of weaning) as practised today to 50 days or 70 days (and thus reducing the amount of regenerated milk which is needed to rear the calf from 400 litres to 200 litres or 300 litres) would limit the rate of weight gains of the calves in the first 3 months of age. This delay is, within certain limits, compensated for by the calf in the growth period up to 6 months of age. Therefore, the authors believe that with cattle of the Hungarian breed "Ungarische Fleckviehrasse" weaning after 50 days and rearing the calves with 200 litres of milk seems to be possible. The method of early weaning and then feeding stock mixtures of concentrates seems to be also applicable provided that the conditions of veterinary hygiene would allow this. This, in turn, would require supplementation of the food with minerals and vitamins. Due to the results obtained supplementation of concentrate mixtures with urea for calf rearing is also possible, even under practical conditions. Aromatization of the concentrate mixtures, as practised in the present series of trials, did not substantiate the favourable results obtained by the authors in previous trials with respect to the effect of aromatics on food consumption and the development of weight gains.