The influence of antibiotic treatment on the behavior and gut microbiome of adult rats neonatally insulted with lipopolysaccharide.

The present study investigated whether neonatal exposure to the proinflammatory endotoxin lipopolysaccharide (LPS) followed by an antibiotic (ATB)-induced dysbiosis in early adulthood could induce neurodevelopmental disorders-like behavioral changes in adult male rats. Combining these two stressors resulted in decreased weight gain, but no significant behavioral abnormalities were observed. LPS treatment resulted in adult rats' hypoactivity and induced anxiety-like behavior in the social recognition paradigm, but these behavioral changes were not exacerbated by ATB-induced gut dysbiosis. ATB treatment seriously disrupted the gut bacterial community, but dysbiosis did not affect locomotor activity, social recognition, and acoustic reactivity in adult rats. Fecal bacterial community analyses showed no differences between the LPS challenge exposed/unexposed rats, while the effect of ATB administration was decisive regardless of prior LPS exposure. ATB treatment resulted in significantly decreased bacterial diversity, suppression of Clostridiales and Bacteroidales, and increases in Lactobacillales, Enterobacteriales, and Burkholderiales. The persistent effect of LPS on some aspects of behavior suggests a long-term effect of early toxin exposure that was not observed in ATB-treated animals. However, an anti-inflammatory protective effect of ATB cannot be assumed because of the increased abundance of pro-inflammatory, potentially pathogenic bacteria (Proteus, Suttrella) and the elimination of the bacterial families Ruminococcaceae and Lachnospiraceae, which are generally considered beneficial for gut health.

The reduced use of invasive procedures leads to a change of frequencies of prenatally detected chromosomal aberrations: population data from the years 2012-2016.

OBJECTIVE: The aim of the study was to analyze the results of screening for chromosomal aberrations in a population with a high rate of first-trimester screening and low rate of cell-free DNA testing. METHODS: The data were obtained from the National Registry of Congenital Anomalies of the Czech Republic. We calculated and compared the proportion of autosomal trisomies (Down, Edwards, and Patau syndrome) and of other chromosomal aberrations identified during prenatal diagnostics. RESULTS: We identified 3009 prenatally diagnosed cases of chromosomal aberrations in the 2012-2016 period. The number of major autosomal trisomies has increased from 329 cases (30.86 per 10,000 live births) in 2012 to 423 cases (37.41) in 2016 (p = 0.014). The numbers of other aberrations decreased from 246 cases (23.07 per 10,000) in 2012 to 217 cases (19.19) in 2016 (p = 0.017). The usage of invasive diagnostic procedures decreased from 1099.54 in 2012 to 622.73 in 2016 (per 10,000 live births). CONCLUSIONS: Our population-based study confirmed a decrease in prenatal detection of nonmajor chromosomal aberrations wherein a decrease of invasive testing occurred. With the introduction of cell-free DNA testing, further decrease of invasive procedures and detection of nonmajor aberrations may be expected.

Interactions of 17ß-Hydroxysteroid Dehydrogenase Type 10 and Cyclophilin D in Alzheimer's Disease.

The nucleus-encoded 17ß-hydroxysteroid dehydrogenase type 10 (17ß-HSD10) regulates cyclophilin D (cypD) in the mitochondrial matrix. CypD regulates opening of mitochondrial permeability transition pores. Both mechanisms may be affected by amyloid ß peptides accumulated in mitochondria in Alzheimer's disease (AD). In order to clarify changes occurring in brain mitochondria, we evaluated interactions of both mitochondrial proteins in vitro (by surface plasmon resonance biosensor) and detected levels of various complexes of 17ß-HSD10 formed in vivo (by sandwich ELISA) in brain mitochondria isolated from the transgenic animal model of AD (homozygous McGill-R-Thy1-APP rats) and in cerebrospinal fluid samples of AD patients. By surface plasmon resonance biosensor, we observed the interaction of 17ß-HSD10 and cypD in a direct real-time manner and determined, for the first time, the kinetic parameters of the interaction (ka 2.0 × 105 M1s-1, kd 5.8 × 104 s-1, and KD 3.5 × 10-10 M). In McGill-R-Thy1-APP rats compared to controls, levels of 17ß-HSD10-cypD complexes were decreased and those of total amyloid ß increased. Moreover, the levels of 17ß-HSD10-cypD complexes were decreased in cerebrospinal fluid of individuals with AD (in mild cognitive impairment as well as dementia stages) or with Frontotemporal lobar degeneration (FTLD) compared to cognitively normal controls (the sensitivity of the complexes to AD dementia was 92.9%, that to FTLD 73.8%, the specificity to AD dementia equaled 91.7% in a comparison with the controls but only 26.2% with FTLD). Our results demonstrate the weakened ability of 17ß-HSD10 to regulate cypD in the mitochondrial matrix probably via direct effects of amyloid ß. Levels of 17ß-HSD10-cypD complexes in cerebrospinal fluid seem to be the very sensitive indicator of mitochondrial dysfunction observed in neurodegeneration but unfortunately not specific to AD pathology. We do not recommend it as the new biomarker of AD.

Acute and Chronic Sleep Deprivation-Related Changes in N-methyl-D-aspartate Receptor-Nitric Oxide Signalling in the Rat Cerebral Cortex with Reference to Aging and Brain Lateralization.

Aging and chronic sleep deprivation (SD) are well-recognized risk factors for Alzheimer's disease (AD), with N-methyl-D-aspartate receptor (NMDA) and downstream nitric oxide (NO) signalling implicated in the process. Herein, we investigate the impact of the age- and acute or chronic SD-dependent changes on the expression of NMDA receptor subunits (NR1, NR2A, and NR2B) and on the activities of NO synthase (NOS) isoforms in the cortex of Wistar rats, with reference to cerebral lateralization. In young adult controls, somewhat lateralized seasonal variations in neuronal and endothelial NOS have been observed. In aged rats, overall decreases in NR1, NR2A, and NR2B expression and reduction in neuronal and endothelial NOS activities were found. The age-dependent changes in NR1 and NR2B significantly correlated with neuronal NOS in both hemispheres. Changes evoked by chronic SD (dysfunction of endothelial NOS and the increasing role of NR2A) differed from those evoked by acute SD (increase in inducible NOS in the right side). Collectively, these results demonstrate age-dependent regulation of the level of NMDA receptor subunits and downstream NOS isoforms throughout the rat brain, which could be partly mimicked by SD. As described herein, age and SD alterations in the prevalence of NMDA receptors and NOS could contribute towards cognitive decline in the elderly, as well as in the pathobiology of AD and the neurodegenerative process.

Congenital anomalies in children born in the Czech Republic in 1994-2015.

ÚVOD Populace je v současné vystavena různým zevním vlivům, ze kterých mohou vyplývat i různá zdravotní rizika. Jedním z možných je i riziko vzniku vrozené vady (VV). Z hlediska studia zdravotního stavu populace je důležitá znalost nejen průměrných celkových incidencí VV, ale i případných změn těchto incidencí v průběhu času. Incidence VV je považována za jeden ze základních kvalitativních ukazatelů populačních i medicínských (1). Nelze opomenout ani hledání potenciálních rizik vedoucích ke zvýšené pravděpodobnosti výskytu VV. Těmito riziky mohou být nežádoucí vlivy zevního prostředí nebo faktory biologicko-sociální (věk žen, jejich onemocnění aj). Podíl jednotlivých typů VV u narozených dětí se v čase mění, obdobně jako struktura příčin úmrtí. Z hlediska epidemiologického je nutné hodnotit incidence VV a jejich změny především z pohledu jednotlivých diagnóz. Během posledních let se intenzita VV v Česku měnila. U některých typů se četnost v novorozenecké populaci snižuje díky úspěšné prenatální diagnostice, u jiných diagnóz naopak četnost u narozených dětí stoupá (2). Kromě prenatální diagnostiky se však na výsledné četnosti VV v populaci mohou uplatňovat i další vlivy. Jedním z nich může být i zlepšení, zrychlení a zkvalitnění postnatálních diagnostických možností - především zavedení a rozvoj ultrazvukové diagnostiky (3). Úspěšnost prenatální diagnostiky a četnost VV u narozených jsou rovněž významným ukazatelem prenatální a perinatální péče, přežívání dětí narozených s VV pak ukazatelem péče postnatální (především neonatální a chirurgické). Registrace vrozených vad má v České republice dlouhou tradici - Národní registr vrozených vad zahájil svou činnost již před více než půlstoletím, v roce 1964 (4).   METODIKA Retrospektivní epidemiologická studie využívá oficiální data z Národního registru vrozených vad vedeného v rámci Registru reprodukčního zdraví v Ústavu zdravotnických informací a statistiky ČR (ÚZIS). Analyzovány byly incidence jednotlivých diagnóz vrozených vad (kódy Q00-Q99) u narozených dětí z celého území České republiky za časové období 1994-2015. Incidence VV byly analyzovány pro obě pohlaví, a to jak celkově (pro celou skupinu diagnóz VV), tak i dle základních diagnostických skupin Mezinárodní klasifikace nemocí (MKN).   VÝSLEDKY V období 1994-2015 se dle údajů ÚZIS ČR narodilo v České republice celkem 87 359 dětí s vrozenou vadou zjištěnou do 1 roku života. Z tohoto celkového počtu bylo 51 315 chlapců a 36 030 dívek. U 14 případů nebylo pohlaví známé / zjištěno. Vývoj počtu diagnostikovaných případů ukazují přehledně první tři grafy (obr. 1-3), zvlášť pro chlapce, dívky a celkově. V relativních počtech to bylo za celé sledované období průměrně 385,4 na 10 000 živě narozených dětí: nejméně 242,5 v roce 1994, nejvíce pak 448,3 v roce 2011. V případě živě narozených chlapců to bylo nejméně 263,6 v roce 1994, nejvíce pak 533,3 v roce 2011; průměrná hodnota činila 440,6 na 10 000. U živě narozených dívek byla průměrná hodnota za sledované období 327,1 na 10 000 ; nejnižší hodnota 220,1 byla zaznamenána opět v roce 1994, nejvyšší hodnota 380,9 v roce 2003. Grafy na obr. 4-6 ukazují relativní počty na 10 000 živě narozených v průběhu sledovaného období, opět zvlášť pro chlapce, dívky a celkově. Další část naší analýzy se věnovala změnám v průběhu sledovaného období pro jednotlivé skupiny diagnóz dle rozdělení v Mezinárodní klasifikaci nemocí, 10. verze (tab. 1). various types of congenital anomalies are changing during the time according to different factors. Three main factors are methodical changes of the registration process, improvement of prenatal diagnostics and the real changes of incidences of selected diagnoses. While in the previous time period (till 1993) the registry included only selected diagnoses of congenital anomalies, in the new period (starting 1994) the registry includes all diagnoses of congenital anomalies from the ICD-10 classification. We can also see the difference in the incidences from 1994-1999 and 2000-2015 time period. The reason for this difference is the methodical change of registration, the Registry of congenital anomalies also receives the notifications about possible anomalies from the report of newborn (even when the report of congenital anomaly was not sent). As for the prenatal diagnostics - we may analyse possible changes of incidences - if the specific defect can be diagnosed prenatally.

Surface tension and intrinsic amyloid fluorescence of serum and cerebrospinal fluid samples in Alzheimer´s disease.

AIM: Surface tension of biological fluids can be influenced by changes in oligomerization or aggregation of surfactant peptides or proteins. Amphiphilic peptides of amyloid-ß or other amyloidogenic peptides/proteins display properties of surfactants, oligomerization and aggregation increase also their fluorescence intensity compared with native structures. Results/methodology: We estimated surface tension and native/ThioflavinT-based/intrinsic amyloid fluorescence intensity in serum and cerebrospinal fluid samples for their evalution as diagnostic biomarkers for Alzheimer´s disease (AD). DISCUSSION/CONCLUSION: Our results indicate that values of surface tension are not a suitable biomarker for AD. However, the ratio of ThioflavinT-based fluorescence to intrinsic amyloid fluorescence in cerebrospinal fluid appears to be an acceptable supportive diagnostic biomarker for AD (its sensitivity was 61.1%, and the specificity 70.8% when compared with aged controls).

Levels of 17ß-hydroxysteroid dehydrogenase type 10 in CSF are not a valuable biomarker for multiple sclerosis.

AIM: We aimed to characterize the role of mitochondrial 17ß-hydroxysteroid dehydrogenase type 10 (17ß-HSD10) overexpression in multiple sclerosis (MS) and to evaluate its use as a biomarker. Materials & methods: We estimated levels of 17ß-HSD10, amyloid ß 1-42, cyclophilin D, 17ß-HSD10-cyclophilin D complexes or 17ß-HSD10-parkin complexes in cerebrospinal fluid (CSF) samples. RESULTS: The increase in 17ß-HSD10 levels or in 17ß-HSD10-parkin complexes and links to leukocytes were found only in relapsing-remitting MS. The sensitivity of the biomarker was 64%, the specificity equaled 60-63% compared with controls. CONCLUSION: Increased CSF levels of 17ß-HSD10 in later stages of MS could be interpreted via its upregulation in demyelinated neuronal axons. CSF levels of 17ß-HSD10 are not the valuable biomarker for the early diagnosis or for the progression of MS.

Trans-generational neurochemical modulation of methamphetamine in the adult brain of the Wistar rat.

Chronic methamphetamine (METH) abuse has been shown to elicit strong neurotoxic effects. Yet, with an increasing number of children born to METH abusing mothers maturing into adulthood, one important question is how far do the neurotoxic effects of METH alter various neurotransmitter systems in the adult METH-exposed offspring. The purpose of this study was to investigate long-term trans-generational neurochemical changes, following prenatal METH exposure, in the adult Wistar rat brain. METH or saline (SAL-control animals) was administered to pregnant dams throughout the entire gestation period (G0-G22). At postnatal day 90, dopamine, serotonin, glutamate and GABA were measured in the adult brain before (baseline) and after a METH re-administration using in vivo microdialysis and liquid chromatography/mass spectrometry. The results show that METH-exposure increased basal levels of monoamines and glutamate, but decreased GABA levels in all measured brain regions. Acute challenge with METH injection in the METH-exposed group induced a lower increase in the monoamine system relative to the increase in the GABAergic and glutamatergic system. The data show that prenatal METH exposure has strong effects on the monoaminergic, GABAergic and glutamatergic system even when exposure to METH was limited to the prenatal phase. Toxicological effects of METH have therefore longer lasting effects as currently considered and seem to affect the excitatory-inhibitory balance in the brain having strong implications for cognitive and behavioral functioning.

Sex-Dependent Changes in Striatal Dopamine Transport in Preadolescent Rats Exposed Prenatally and/or Postnatally to Methamphetamine.

Methamphetamine (MA) is the most commonly used psychostimulant drug, the chronic abuse of which leads to neurodegenerative changes in the brain. The global use of MA is increasing, including in pregnant women. Since MA can cross both placental and haematoencephalic barriers and is also present in maternal milk, children of chronically abused mothers are exposed prenatally as well as postnatally. Women seem to be more vulnerable to some aspects of MA abuse than men. MA is thought to exert its effects among others via direct interactions with dopamine transporters (DATs) in the brain tissue. Sexual dimorphism of the DAT system could be a base of sex-dependent actions of MA observed in behavioural and neurochemical studies. Possible sex differences in the DATs of preadolescent offspring exposed to MA prenatally and/or postnatally have not yet been evaluated. We examined the striatal synaptosomal DATs (the activity and density of surface expressed DATs and total DAT expression) in preadolescent male and female Wistar rats (31-35-day old animals) exposed prenatally and/or postnatally to MA (daily 5 mg/kg, s.c. to mothers during pregnancy and lactation). To distinguish between specific and nonspecific effects of MA on DATs, we also evaluated the in vitro effects of lipophilic MA on the fluidity of striatal membranes isolated from preadolescent and young adult rats of both sexes. We observed similar changes in the DATs of preadolescent rats exposed prenatally or postnatally (MA-mediated drop in the reserve pool but no alterations in surface-expressed DATs). However, prenatal exposure evoked significant changes in males and postnatal exposure in females. A significant decrease in the activity of surface-expressed DATs was found only in postnatally exposed females sensitized to MA via prenatal exposure. MA applied in vitro increased the fluidity of striatal membranes of preadolescent female but not male rats. In summary, DATs of preadolescent males are more sensitive to prenatal MA exposure via changes in the reserve pool and those of preadolescent females to postnatal MA exposure via the same mechanism. The combination of prenatal and postnatal MA exposure increases the risk of dopaminergic deficits via alterations in the activity of surface-expressed DATs especially in preadolescent females. MA-mediated changes in DATs of preadolescent females could be still enhanced via nonspecific disordering actions of MA on striatal membranes.

Levels of 17ß-Hydroxysteroid Dehydrogenase Type 10 in Cerebrospinal Fluid of People with Mild Cognitive Impairment and Various Types of Dementias.

BACKGROUND: Overexpression of the mitochondrial enzyme 17ß-hydroxysteroid dehydrogenase type 10 (17ß-HSD10, which is also known as the intracellular amyloid-ß peptide (Aß) binding protein) is observed in cortical or hippocampal regions of patients with Alzheimer's disease (AD). It appears that 17ß-HSD10 may play a role in the pathogenesis of AD. OBJECTIVE: We investigated the possibility that levels of 17ß-HSD10 in cerebrospinal fluid could be a prospective biomarker of AD. METHODS: We estimated the enzyme levels in 161 people (15 non-demented controls, 52 people with mild cognitive impairment (MCI), 35 people with probable AD, or 59 people with other types of dementia) and compared them with those of Aß(1- 42), tau, and phospho-tau. RESULTS: We found significantly higher levels of 17ß-HSD10 in people with MCI due to AD (to 109.9% ), with AD (to 120.0% ), or with other types of dementia (to 110.9% ) when compared to the control group. The sensitivity of the new biomarker to AD was 80.0% , and the specificity was 73.3% (compared to controls) or 52.5-59.1% (compared to other types of dementia). Results of multiple linear regression and of correlation analysis revealed AD-mediated changes in links between 17ß-HSD10 and Mini Mental State Examination score. CONCLUSION: It seems that changes in 17ß-HSD10 start many years before symptom onset, analogous to those in Aß1 - 42, tau, or phospho-tau and that the levels are a relatively highly sensitive but unfortunately less specific biomarker of AD. A role of 17ß-HSD10 overexpression in AD is discussed.

Age-related differences in NMDA receptor subunits of prenatally methamphetamine-exposed male rats.

There is accumulating evidence that methamphetamine (MA) is a widely abused drug popular among pregnant women. MA exposure is associated with changes in the function of neurotransmitter systems, namely the dopaminergic, serotonergic and glutamatergic systems. Since N-methyl-D-aspartate receptors (NMDA) are affected by MA-induced glutamate release, we assessed the expression of NMDAR subunits (NR1, NR2A, and NR2B) and postsynaptic density protein 95 (PSD-95), which is connected with NMDAR. We measured the expression of these proteins in adolescent (30 days old) and adult (60 days old) rat males exposed to MA during the entire prenatal period and compared them with the same parameters in age matched saline-exposed rats. There was a significant increase in the NR1 and NR2B subunits in the hippocampus of adult males, but not in adolescent males. We identified a significant change in adult MA-induced rats when compared to adult controls for NR2A and NR2B, while in adolescent MA rats this change was close to the boundary of significance. In summary, our study suggests that prenatal MA exposure is connected with changes in NMDAR subunit expression in adult rats but not in adolescent rats.

Attenuated antiaggregation effects of magnetite nanoparticles in cerebrospinal fluid of people with Alzheimer's disease.

It is well known that oligomeric/aggregated amyloid ß peptides are a key player in the pathogenesis of Alzheimer's disease and that different nanoparticles influence oligomerization/aggregation processes in experiments in vitro. Our previous results demonstrated antiaggregation effects of magnetite nanoparticles in the case of protein lysozyme, however, they have yet to be supported by biological samples containing peptides/proteins preaggregated in vivo. In the study, Thioflavin T based fluorescence was evaluated on cerebrospinal fluid samples from people with Alzheimer's disease/multiple sclerosis and corresponding age-related controls using magnetite nanoparticles incubated for 24 h. Our results are as follows: (i) fluorescence of samples without nanoparticles was significantly higher in both older groups (old controls and people with Alzheimer's disease) than in those of younger (young controls and people with multiple sclerosis), (ii) nanoparticles did not markedly influence a fluorescence intensity in young people but eliminated it in both old groups; nevertheless, the effects of nanoparticles were significantly lower in patients with Alzheimer's disease then in the age-matched controls, and finally (iii) significant positive correlation was observed between fluorescence of samples without nanoparticles and levels of phospho-tau. Our results support studies reporting enhanced aggregation of different peptides/proteins occurring during normal aging and demonstrate for the first time that peptides/proteins preaggregated in vivo during Alzheimer's disease are more resistant to the antiaggregation effects of magnetite nanoparticles than those of age-matched controls. A significant correlation with phospho-tau levels indicate that the in vitro test with magnetite nanoparticles and Thioflavin T dye on cerebrospinal fluid could be sensitive to changes mediated by early Alzheimer's disease stages.

Olfactory dysfunction in narcolepsy with and without cataplexy.

BACKGROUND: Not only patients in whom REM behavior disorder (RBD) is associated with narcolepsy, but also those with narcolepsy alone are reported to have olfactory dysfunction. We investigated if hyposmia is specific to narcolepsy with cataplexy (N-C) or if narcolepsy without cataplexy (NwC) is also associated with olfactory dysfunction. METHODS: We studied olfactory function in two groups of patients: N-C group (n=66, 26 men and 40 women; mean age 41+/-18 years), and NwC group (n=17, 7 men and 10 women; mean age 46+/-20 years). As a control group we used published normative data for particular smell tests. RESULTS: Both patients with N-C and patients suffering from NwC had a significantly higher olfactory threshold (N-C group, p<0.0001; NwC group, p<0.0001) and impaired odor identification (N-C group, p<0.0001; NwC group, p<0.0001). Our results show for the first time that narcolepsy without cataplexy, where the majority of cases have normal CSF hypocretin levels, is associated with olfactory dysfunction. CONCLUSIONS: It appears that also a partial loss of hypothalamic hypocretin neurons without a clear CSF level decrease can affect smell projection.

Expression of the hippocampal NMDA receptor GluN1 subunit and its splicing isoforms in schizophrenia: postmortem study.

There is accumulating evidence that disturbances in N-methyl-D: -aspartate receptor (NMDA-R) functioning are associated with the pathogenesis of schizophrenia. To assess actual changes in the expression of the GluN1 subunit and its isoforms, we measured absolute differences in the levels of mRNA/protein for panGluN1 (eight isoforms altogether) as well as the mRNA individual isoforms in the postmortem left/right hippocampus of patients with schizophrenia in comparison with non-psychiatric subjects. There were no significant differences in the panGluN1 subunit mRNA expression, but the absolute left/right differences were much more pronounced in the patients with schizophrenia. Protein levels of the GluN1 subunit in the left hippocampus in male schizophrenic patients were lower than controls. The expression of the NR1-4b isoform was attenuated in the left, whereas the NR1-2b was reduced in the right hippocampus of schizophrenic patients. Isoforms associated with the efficiency of NMDA-induced gene expression and with phosphorylation occurred more commonly in schizophrenic hippocampi. In summary, our study suggests that NMDA-R hypofunction in schizophrenia might be selectively dependent on the dysregulation of GluN1 subunit expression, which exhibits a somewhat different expression in the left/right hippocampus of psychotic patients.

Enhanced levels of mitochondrial enzyme 17beta-hydroxysteroid dehydrogenase type 10 in patients with Alzheimer disease and multiple sclerosis.

The multifunctional mitochondrial enzyme 17beta-hydroxysteroid dehydrogenase type 10 might play a role in the development of Alzheimer disease via its high-affinity binding to amyloid beta peptides and its neuronal over-expression. It is suggested that the cerebrospinal fluid levels of the enzyme, free or bound to amyloid beta peptides, are a potential specific biomarker of Alzheimer disease. However, mitochondrial dysfunction seems to play a role in many neurological diseases including multiple sclerosis. In this study, the specificity of changes in relation to the enzyme over-expression was evaluated using enzyme-linked immunosorbent and surface plasmon resonance sensors. The data indicated pronounced increases in the enzyme levels, specifically to 179% in multiple sclerosis and to 573% in Alzheimer disease when compared to the age-matched controls. Although the differences between both diseases were statistically significant, enzyme levels do not appear to be a highly specific biomarker of Alzheimer disease. On the other hand, enhancement in levels of the enzyme bound to amyloid beta peptides was only observed in people with Alzheimer disease, which suggests that the complex should be further considered as a possible biomarker. In patients with multiple sclerosis, our results are the first to demonstrate significant changes in enzyme expression and to suggest possible alterations in amyloid beta peptides.

Lateralization of hippocampal nitric oxide mediator system in people with Alzheimer disease, multi-infarct dementia and schizophrenia.

There is evidence that brain lateralization underlying hemispheric specialization can be observed also at biochemical level. However, hemispheric differences in nitric oxide mediator system have not yet been evaluated. The hippocampus and planum temporale are highly asymmetrical regions but the degree of their laterality is altered in demented or psychotic people. In the study, l-glutamate/l-arginine/l-citrulline concentrations, nitric oxide synthase activities/expressions and nitrites/nitrates levels were estimated in autoptic hippocampi. Right/left laterality in endothelial synthase activity and in nitrites/nitrates was observed in controls. Lateral changes were estimated in patients with Alzheimer disease (a marked increase in activities of constitutive synthases and in expression of inducible enzyme in the left side) and schizophrenia (an increase in activities of all enzymes especially in the right side). Significant shifts from positive to negative correlations were found between laterality of some components of nitric oxide pathway and of planum temporale volumetry under pathological conditions. The hippocampal nitric oxide system appears to be globally right/left lateralized, especially via actions of highly asymmetrical endothelial synthase. The results suggest a specific involvement of all synthases in the development of selected diseases and show that lateral analyses are of sufficient sensitivity to reveal subtle links. The volumetric asymmetry of the planum temporale as a marker of handedness is not probably simply linked to brain laterality at biochemical level but reflects alterations due to pathological processes.

Moclobemide and cognitive behavioral therapy in the treatment of social phobia. A six-month controlled study and 24 months follow up.

The aim of the study was to assess the 6-months treatment efficacy and 24-month follow up of three different therapeutic programs (A. moclobemide and supportive guidance, B. group cognitive-behavioral therapy and pill placebo, and C. combination of moclobemide and group cognitive-behavioral therapy) in patients with a generalized form of social phobia. Eighty one patients (38 males and 43 females) were randomly assigned to three different therapeutic programs. Patients were regularly assessed on a monthly basis by an independent rater on the LSAS (Liebowitz Social Anxiety scale), CGI (Clinical Global Impression) for severity and change and BAI (Beck Anxiety Inventory). Altogether, sixty-six patients completed the six month treatment period and 15 patients dropped out. All therapeutic groups showed significant improvement. A combination of CBT and pharmacotherapy yielded the most rapid effect. Moclobemide was superior for the reduction of the subjective general anxiety (BAI) during the first 3 months of treatment, but its influence on avoidant behavior (LSAS avoidance subscale) was less pronounced. Conversely, CBT was the best choice for reduction of avoidant behavior while a reduction of subjective general anxiety appeared later than in moclobemide. After 6 months of treatment there were best results reached in groups treated with CBT and there was no advantage of the combined treatment. The relapse rate during the 24-month follow up was significantly lower in the group treated with CBT in comparison with the group A. formerly treated with moclobemide alone.

Age- and sex-dependent laterality of rat hippocampal cholinergic system in relation to animal models of neurodevelopmental and neurodegenerative disorders.

Studies suggest age- and sex-dependent structural and functional patterns of human cerebral lateralization underlie hemisphere specialization and its alterations in schizophrenia. Recent works report sexual dimorphism of neurons in the hippocampal formation and specialization of hemispheres in rats. Our experiments indicate for the first time functional lateralization of the high-affinity choline uptake (HACU) system directly associated with a synthesis of acetylcholine in the hippocampus of Wistar rats. The markedly increased HACU activity was found in the left compared to the right hippocampus of adult male but not female animals. Lineweaver-Burk plot analysis revealed a statistically significant increase of Vmax in the left hippocampus of 14-day-old when compared to 7-day-old males. It appears that laterality of HACU occurs during late postnatal maturation, and its degree is markedly enhanced after puberty and attenuated during aging. Quinolinic acid (QUIN), an endogenous agonist of N-methyl-D-aspartate type glutamate receptors, was used in this study to evaluate the neurodevelopmental hypothesis of schizophrenia. It is known that elevated levels of QUIN accompany viral infections, increasing the risk of developing schizophrenia. Bilateral intracerebroventricular application of QUIN (250 nmoles/ventricle) to pups aged 12 days significantly impaired the cholinergic hippocampal system of adolescent male and female rats and reversed lateralization of male HACU. Morphological analysis indicated marked changes in brain lesion sizes (extensive 24 h and moderate 38 days after the operation). Asymmetry of lesions was observed in the majority of cases, but the left hemisphere was not generally more vulnerable to QUIN effects than the right side. Moreover, no lateral differences were found between lesioned hippocampi in the specific binding of [3H]hemicholinium-3 (10%-15% loss of binding sites when compared to sham-operated animals). In summary, our results indicate a symmetrical drop in the number of choline carriers of lesioned male rats but a asymmetrical decrease in the activity of remaing carriers, suggesting defects in processes of sexual brain differentiation, leading under normal conditions to the higher activity of carriers in the left hippocampus. The data demonstrate viral infection-mediated alterations in normal patterns of brain asymmetry and are discussed in relation to animal models of neurodevelopmental and neurodegenerative diseases.

Age- and sex-dependent effects of ethanol on hippocampal hemicholinium-3 sensitive choline carriers during postnatal development of rats.

Vulnerability of hippocampal hemicholinium-3 (HC-3)-sensitive carriers to ethanol was evaluated in vitro during rat postnatal development. The high-affinity uptake of [3H]choline (HACU) and the specific binding of [3H]HC-3 were measured on synaptosomes from 7-, 14-, and 60-day-and 3-month-old male and female Wistar rats. Marked increases of basal (between 7 and 60 days of age) and of stimulated HACU levels via K(+)-depolarization (between 14 days and 3 months) but only a mild elevation in [3H]HC-3 binding (between 7 days and 3 months) associated with alterations in the binding site number were found. On the mature tissue, ethanol at high concentrations (5%) moderately inhibited the choline transport under basal conditions but totally eliminated depolarization effects. However, both age- and sex-dependent alterations in basal HACU mediated by high or low pharmacologically relevant alcohol concentrations (50-100 mM) were observed in the immature tissue. Namely, the dose- and incubation time-dependent inhibition of HACU associated with changes in the transport velocity was found in postnatal male but not female tissue. [3H]HC-3 binding site was not markedly sensitive to ethanol actions. Anisotropy measurements in the region of the hydrophilic heads of phospholipid bilayers and in the membrane hydrocarbon core indicated penetration of 100 mM ethanol to immature female but not male tissue. Our results suggest the noncompetitive binding of alcohol to choline carriers from immature male tissue and correspond with data reporting significant sexual dimorphism of postnatal hippocampal neurons. The direct effects of ethanol on male choline carriers can contribute to the inhibition of acetylcholine synthesis and to sex-dependent neurotoxic effects of alcohol applied in vivo during early and late postnatal period.

Bright light therapy and/or imipramine for inpatients with recurrent non-seasonal depression.

INTRODUCTION: The aim of a double-blind study was to assess the efficacy of bright light therapy and/or imipramine in the treatment of inpatients suffering with recurrent non-seasonal major depressive disorder. METHOD: 34 in-patients with DSM-III-R diagnosis of major depressive disorder, recurrent type, were randomly allocated into 3 treatment groups. After 4-day washout period with baseline assessment they underwent 3 weeks of different types of treatment: a) Group A: bright light therapy (5000 lux from 6-8 a.m.) and imipramine 150 mg/day. b) Group B: bright light therapy (5000 lux from 6-8 a.m.) and imipramine-like placebo. c) Group C: dim red light (500 lux from 6-8 a.m.) and imipramine 150 mg/day. Outcome measures included weekly Hamilton Psychiatric Rating Scale for Depression, Clinical Global Impression Scale, Montgomery and Asberg Psychiatric Rating Scale for Depression and Beck Depression Inventory. RESULTS: Patients of all three groups improved significantly. The improvement of the patients of group B treated with bright light therapy plus placebo was superior to the other two groups, but not significantly. CONCLUSION: Bright light therapy can be effective in the treatment of non-seasonal major depressive disorder.