Repeated co-treatment with mirtazapine and aripiprazole reversed the schizophrenia-like behaviors and increased the brain-derived neurotrophic factor mRNA expression in the adult Sprague-Dawley rats exposed to glutathione deficit during early postnatal brain development.

Recent studies suggest that impaired glutathione synthesis and dopaminergic transmission are important factors in the pathophysiology of schizophrenia. Moreover, some studies have suggested that antidepressants are able to increase the activity of atypical antipsychotics which may efficiently improve the treatment of negative and some cognitive symptoms of schizophrenia. In the present study, we investigated the influence of repeated co-treated with mirtazapine and aripiprazole on the schizophrenia-like behavior and brain-derived neurotrophic factor (BDNF) mRNA expression in adult rats exposed to glutathione deficit during early postnatal development. Between the postnatal days p5-p16, male pups were treated with the inhibitor of glutathione synthesis, BSO (L-buthionine-(S,R)-sulfoximine) and the dopamine uptake inhibitor, GBR 12909 alone or in combination. Mirtazapine and aripiprazole were given repeatedly, once daily for 21 days before the tests. The behavioral and biochemical tests were performed in p90-92 rats. BSO given alone and in combination with GBR 12909 induced deficits in the studied behavioral tests and decreased the expression of BDNF mRNA. Repeated aripiprazole administration at a higher dose reversed these behavioral deficits. Co-treatment with an ineffective dose of aripiprazole and mirtazapine also abolished the behavioral deficits and biochemical changes, especially in the hippocampus in these rats. The present study indicated that the inhibition of glutathione synthesis in early postnatal development induced long-term deficits corresponding to schizophrenia-like behavior and decreased the BDNF mRNA expression in adult rats, and these behavioural and biochemical deficits were reversed by repeated treatment with a higher dose of aripiprazole and also by co-treatment with an ineffective dose of aripiprazole and mirtazapine. The above data suggest that this neurodevelopment rat model of schizophrenia-induced by glutathione deficit evoked by repeated treatment with BSO alone and together with GBR 12909 in early postnatal life may be useful for studies on the pathomechanism of schizophrenia.

Pre-and postnatal exposition to fluorides induce changes in rats liver morphology by impairment of antioxidant defense mechanisms and COX induction.

INTRODUCTION: Fluorides are common in the environment and are absorbed mostly in the stomach and gut, it can easily move through cell membranes and its accumulation can cause harmful effects in skeletal and soft tissues. One of the most important F- accumulation sites is the liver. The aim of this study was to determine whether F- can cause inflammation in rat liver by affecting the activity of antioxidant enzymes and changes in the synthesis of prostaglandin E2 (PGE2) and thromboxane B2 (TXB2). MATERIALS AND METHODS: An in vivo model of prenatal and postnatal exposure to sodium fluoride (NaF) was used to carry out the experiment. Animals from control group received tap water to drink, while animals exposed to F- received drinking water containing NaF, 50 mg/L. In serum and liver we analyzed F- concentration, in liver - antioxidant enzymes activity, PGE2 and TXB2 concentration and immunolocalization of COX1 and COX2 proteins were measured. RESULTS: We observed significant changes in F- concentration only in liver. The results of this study showed that F- affects antioxidant enzymes activity, COX2 protein expression and PGE2 synthesis in liver. Also, in some regions of the liver of rats exposed to F-, the hepatocytes were diffusely altered, with changes resembling microvesicular steatosis. CONCLUSION: Chronic exposure to F- during development causes an accumulation of this element in the liver and changes in antioxidant enzymes activity and cyclooxygenase expression. Long term exposure to this element is toxic to the liver and can cause disturbances in its homeostasis.

The Influence of Fluorine on the Disturbances of Homeostasis in the Central Nervous System.

Fluorides occur naturally in the environment, the daily exposure of human organism to fluorine mainly depends on the intake of this element with drinking water and it is connected with the geographical region. In some countries, we can observe the endemic fluorosis-the damage of hard and soft tissues caused by the excessive intake of fluorine. Recent studies showed that fluorine is toxic to the central nervous system (CNS). There are several known mechanisms which lead to structural brain damage caused by the excessive intake of fluorine. This element is able to cross the blood-brain barrier, and it accumulates in neurons affecting cytological changes, cell activity and ion transport (e.g. chlorine transport). Additionally, fluorine changes the concentration of non-enzymatic advanced glycation end products (AGEs), the metabolism of neurotransmitters (influencing mainly glutamatergic neurotransmission) and the energy metabolism of neurons by the impaired glucose transporter-GLUT1. It can also change activity and lead to dysfunction of important proteins which are part of the respiratory chain. Fluorine also affects oxidative stress, glial activation and inflammation in the CNS which leads to neurodegeneration. All of those changes lead to abnormal cell differentiation and the activation of apoptosis through the changes in the expression of neural cell adhesion molecules (NCAM), glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF) and MAP kinases. Excessive exposure to this element can cause harmful effects such as permanent damage of all brain structures, impaired learning ability, memory dysfunction and behavioural problems. This paper provides an overview of the fluoride neurotoxicity in juveniles and adults.

Occurrence and seasonal variations of 25 pharmaceutical residues in wastewater and drinking water treatment plants.

Thousands of tons of pharmaceuticals are introduced into the aqueous environment due to their incomplete elimination during treatment process in wastewater treatment plants (WWTPs) and water treatment plants (WTPs). The presence of pharmacologically active compounds in the environment is of a great interest because of their potential to cause negative effects. Furthermore, drugs can undergo different processes leading to the formation of new transformation products, which may be more toxic than the parent compound. In light of these concerns, within the research a new, rapid and sensitive analytical procedure for the determination of a wide range of pharmaceuticals from different classes using solid phase extraction (SPE) and high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) technique in different water samples was developed. This methodology was applied to investigate the occurrence, removal efficiency of 25 pharmaceuticals during wastewater and drinking water treatment, and seasonal variability in the amount of selected pharmaceuticals in WWTP and WTP over a year. The most often detected analytes in water samples were carbamazepine (100 % of samples) and ibuprofen (98 % of samples), concluding that they may be considered as pollution indicators of the aqueous environment in tested area. Highly polar compound, metformin, was determined at very high concentration level of up to 8100 ng/L in analyzed water samples. Drugs concentrations were much higher in winter season, especially for non-steroidal inflammatory drugs (NSAIDs) and caffeine, probably due to the inhibited degradation related to lower temperatures and limited sunlight. Carbamazepine was found to be the most resistant drug to environmental degradation and its concentrations were at similar levels during four seasons.

Tankyrase inhibition aggravates kidney injury in the absence of CD2AP.

Inappropriate activation of the Wnt/ß-catenin pathway has been indicated in podocyte dysfunction and injury, and shown to contribute to the development and progression of nephropathy. Tankyrases, multifunctional poly(ADP-ribose) polymerase (PARP) superfamily members with features of both signaling and cytoskeletal proteins, antagonize Wnt/ß-catenin signaling. We found that tankyrases interact with CD2-associated protein (CD2AP), a protein essential for kidney ultrafiltration as CD2AP-knockout (CD2AP-/-) mice die of kidney failure at the age of 6-7 weeks. We further observed that tankyrase-mediated total poly-(ADP-ribosyl)ation (PARylation), a post-translational modification implicated in kidney injury, was increased in mouse kidneys and cultured podocytes in the absence of CD2AP. The data revealed increased activity of ß-catenin, and upregulation of lymphoid enhancer factor 1 (LEF1) (mediator of Wnt/ß-catenin pathway) and fibronectin (downstream target of Wnt/ß-catenin) in CD2AP-/- podocytes. Total PARylation and active ß-catenin were reduced in CD2AP-/- podocytes by tankyrase inhibitor XAV939 treatment. However, instead of ameliorating podocyte injury, XAV939 further upregulated LEF1, failed to downregulate fibronectin and induced plasminogen activator inhibitor-1 (PAI-1) that associates with podocyte injury. In zebrafish, administration of XAV939 to CD2AP-depleted larvae aggravated kidney injury and increased mortality. Collectively, the data reveal sustained activation of the Wnt/ß-catenin pathway in CD2AP-/- podocytes, contributing to podocyte injury. However, we observed that inhibition of the PARylation activity of tankyrases in the absence of CD2AP was deleterious to kidney function. This indicates that balance of the PARylation activity of tankyrases, maintained by CD2AP, is essential for normal kidney function. Furthermore, the data reveal that careful contemplation is required when targeting Wnt/ß-catenin pathway to treat proteinuric kidney diseases associated with impaired CD2AP.

Elucidation of transformation pathway of ketoprofen, ibuprofen, and furosemide in surface water and their occurrence in the aqueous environment using UHPLC-QTOF-MS.

The identification and determination of transformation products (TPs) of pharmaceuticals is essential nowadays, in order to track their fate in the aqueous environment and, thus, to estimate the actual pollution. However, this is a challenging task due to the necessity to apply high-resolution instruments enable to detect known and unknown compounds. This work presents the use of liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) as a powerful tool for the identification of three selected pharmaceuticals, furosemide (FUR), ibuprofen (IBP), and ketoprofen (KET), and their TPs in various water samples. Laboratory degradation experiments were performed using xenon lamp as a source of the irradiation in order to simulate phototransformation processes which may occur in the environment. Furthermore, the photodegradation kinetics of three selected compounds were assessed in a reactor equipped with xenon lamp in river water samples. Five TPs of IBP, seven of KET, and five of FUR were identified; some of them are presented here for the first time. Accurate mass measurements and fragmentation pattern obtained during an LC-QTOF-MS analysis allowed for structure elucidation of TPs followed by the creation of transformation pathway of selected pharmaceuticals. Finally, different water samples (wastewater influent and effluent, river water, untreated and treated water) were analyzed in order to estimate the presence of parent and transformed compounds. Only KET was detected in untransformed form in considered samples. Most of the TPs of selected drugs were found at least once in all water samples. Although IBP and FUR were not present in water samples as parent compounds, their different TPs occur. A great potential of LC-QTOF-MS in the identification and structural elucidation of TPs in the environment, allowing the recognition of the fate of pharmaceuticals in the environment through the determination of transformation pathway, has been presented.

WIN55,212-2 induces cytoplasmic vacuolation in apoptosis-resistant MCL cells.

Cannabinoid receptors 1 (CB1) and/or 2 (CB2) are overexpressed in many types of human malignancies including mantle cell lymphoma (MCL). Agonists to CB1 and CB2 promote ceramide de novo synthesis, p38-mitogen-activated protein kinase-dependent activation of caspase-3 and apoptotic cell death in most MCLs. However, in this report we describe that in some MCLs the response to treatment with cannabinoids decreased cell viability as assessed by metabolic activity but did not involve the caspase-3 cascade or loss of plasma membrane integrity. Both primary cells from one MCL patient and the MCL cell line Granta519 responded to treatment with cannabinoids by formation of cycloheximide-sensitive cytoplasmic vacuoles, but did not enter apoptosis. The persistent expression of mammalian homolog of Atg8 with microtubule-associated protein-1 light chain-3 II (LC3 II) and p62, as well as the lack of protection from chloroquine, indicates that lysosomal degradation is not involved in this cytoplasmic vacuolation process, distinguishing from classical autophagy. Transmission electron microscopy images and immunofluorescence staining of endoplasmic reticulum (ER) chaperone calreticulin showed that the vacuoles were of ER origin and that chromatin remained normal. These features resemble paraptosis-like cell death-a third type of a programmed cell death not previously described in response to cannabinoids.

The effect of an endogenous compound 1-methyl-1,2,3,4,-tetrahydroisoquinoline on morphine-induced analgesia, dependence and neurochemical changes in dopamine metabolism in rat brain structures.

1,2,3,4-Tetrahydroisoquinolines, among them the most interesting neuroprotective substance, an inhibitor of MAO, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), are endogenous compounds present in the central nervous system of mammals and humans. In this study, we investigated the effect of 1MeTIQ on morphine-induced analgesia, tolerance and abstinence syndrome as well as its effect on morphine-induced changes in dopamine metabolism in rat brain structures (nucleus accumbens, striatum, substantia nigra) using HPLC methodology. The experiments were carried out on male Wistar rats. Morphine analgesia was measured in the "hot-plate" test. To induce tolerance, morphine was given chronically (20 mg/kg i.p.) alone or following 1MeTIQ (50 mg/kg i.p.) injection. The development of dependence was assessed in the naloxone (2 mg/kg i.p.) precipitation test, after 10 days of morphine administration. The behavioral studies have shown that an endogenous compound, 1MeTIQ produced strong potentiation of morphine analgesia, prevented the development of morphine tolerance and inhibited expression of morphine abstinence syndrome in morphine-dependent rats. In neurochemical studies, we have demonstrated that 1MeTIQ antagonized morphine-induced changes in dopamine metabolism observed in rat brain structures. The main finding of this study was demonstration for the first time of an anti-abuse effect of an endogenous compound, 1MeTIQ, and its efficiency in counteracting morphine-induced addiction in the way useful from clinical point of view. The obtained results suggested a possibility of clinical application of 1MeTIQ in morphine addiction.

Actin dynamics in Amoeba proteus motility.

We studied the distribution of the endogenous Arp2/3 complex in Amoeba proteus and visualised the ratio of filamentous (F-actin) to total actin in living cells. The presented results show that in the highly motile Amoeba proteus, Arp2/3 complex-dependent actin polymerisation is involved in the formation of the branching network of the contractile layer, adhesive structures, and perinuclear cytoskeleton. The aggregation of the Arp2/3 complex in the cortical network, with the exception of the uroid and advancing fronts, and the spatial orientation of microfilaments at the leading edge suggest that actin polymerisation in this area is not sufficient to provide the driving force for membrane displacement. The examined proteins were enriched in the pinocytotic pseudopodia and the perinuclear cytoskeleton in pinocytotic amoebae. In migrating amoebae, the course of changes in F-actin concentration corresponded with the distribution of tension in the cell cortex. The maximum level of F-actin in migrating amoebae was observed in the middle-posterior region and in the front of retracting pseudopodia. Arp2/3 complex-dependent actin polymerisation did not seem to influence F-actin concentration. The strongly condensed state of the microfilament system could be attributed to strong isometric contraction of the cortical layer accompanied by its retraction from distal cell regions. Isotonic contraction was limited to the uroid.

Minipodia and rosette contacts are adhesive organelles present in free-living amoebae.

Using scanning electron microscopy, Amoeba proteus cells migrating on the glass have been shown to develop dense coats of minipodia, which are discrete microprotrusions up to 8 microm long and approximately 0.5 microm across. They cover the middle-anterior area of the ventral cell surface, i.e. the region previously determined as the zone of most efficient adhesion of an amoeba to its substratum. Minipodia are sparse underneath the frontal zone and lacking from the tail region. In amoebae that adhere to the glass without moving, have just started moving, or show unstable motor polarity, minipodia are grouped in rosette contacts, cauliflower-like papillae composed of supporting platforms with crowns of minipodia emerging from them. Both structures abound with cytoskeletal F-actin, as shown by staining with fluorescein-conjugated phalloidin. Amoebae experimentally prevented from adhering to the substratum neither develop discrete minipodia nor rosette contacts.

Purge-and-trap isothermal multicapillary gas chromatographic sample introduction accessory for speciation of mercury by microwave-induced plasma atomic emission spectrometry.

A compact device based on purge-and-trap multicapillary gas chromatography was developed for sensitive species-selective analysis of methylmercury and Hg2+ by atomic spectrometry. The operating mode includes in situ conversion of the analyte species to MeEtHg and HgEt2 and cryotrapping of the derivatives formed in a 0.53-mm-i.d. capillary, followed by their flash (< 30 s) isothermal low-temperature separation on a minimulticapillary (22 cm) column. The very low detection limits obtained (0.01 pg mL-1 of Hg for methylmercury) are due to the narrow injection band and reduced peak broadening in a bundle of 0.038-mm capillaries at high flow rates (> 60 mL min-1) compatible with an MIP AES detector (no dilution with a makeup gas is required). Developments regarding each of the steps of the analytical procedure and effects of operational variables (sample volume, purge flow, trap temperature, separation conditions) are discussed. The device allows speciation of MeHg+ and Hg2+ down to 5 pg g-1 in urine and, after a rapid microwave-assisted hydrolysis, down to 0.1 ng g-1 in solid biological samples with a throughput of 6 samples/h. The analytical protocols developed were validated by the analysis of DORM-1 (dogfish muscle), TORT-1 (lobster hepatopancreas), and Seronorm urine certified reference materials.

The reversibility of CT brain changes in alcohol dependence.

Control CT assessments of the brain of 15 alcohol dependent patients who showed an improvement in their clinical state were performed after a mean of 16 months. A partial decrease of the widening of cerebral sulci and the third ventrical was noticed. Also, the neuroradiological pictures of the vermis and cerebellum were seen to improve in most patients.

[Analysis of the reversibility of CT brain changes in alcohol dependent patient]. / Badania odwracalnosci zmian obrazu tomokomputerowego mózgowia chorych z zespolem uzaleznienia od alkoholu.

Control CT assessments of the brain of 15 alcohol dependent patients who showed an improvement in their clinical state were performed after a mean of 16 months. A partial decrease of the widening of cerebral sulci and the third ventrical was noticed. Also, the neuroradiological pictures of the vermis and cerebellum were seen to improve in most patients.

Hyponatremic encephalopathy: is central pontine myelinolysis a component?

PURPOSE: Severe hyponatremia is often associated with permanent brain damage. There has been substantial controversy about whether central pontine myelinolysis (CPM), a rare neurologic disorder of uncertain etiology, can complicate either hyponatremia or its therapy. This study was undertaken to determine how often hyponatremic patients with the clinical diagnosis of CPM actually have the disorder as an integral structural component of their encephalopathy. PATIENTS: Analyses were carried out in 20 patients who had severe symptomatic hyponatremia and a presumptive diagnosis of CPM, based on clinical and/or neuroradiologic findings. All had been referred for neuroradiology consultation. The mean age (+/- SD) was 47 +/- 14 years, the lowest serum sodium level was 104 +/- 8 mM, and 85% of the patients were female. The etiologies were diverse and included postoperative status, thiazide diuretics, polydipsia, infection, acute renal failure, chronic alcoholism with emesis, and beer potomania. METHODS: The original and subsequent films of 20 patients were reevaluated retrospectively by two neuroradiologists. The clinical course was also reevaluated, and in eight patients, the postmortem brain findings were reviewed. The diagnosis of CPM was made only on the basis of strict criteria relating to either (1) pathologic findings of CPM on postmortem examination; or (2) computed tomographic scan and/or magnetic resonance imaging findings diagnostic of CPM. RESULTS: No pontine lesions were present in 15 of 20 patients in whom the diagnosis of CPM had initially been made. All 15 had extrapontine demyelinating lesions but the pons was normal. Two others had only lateral pontine lesions, so that only three of 20 patients had definite CPM. All but one of the 20 hyponatremic patients had a definite hypoxic event prior to any therapy with intravenous sodium chloride. The involved brain areas included basal ganglia, thalamus, cortical gray matter, and periventricular white matter, areas often affected by hypoxia. Each of the three patients in whom unequivocal findings of CPM were present had long histories of chronic alcoholism and hepatic cirrhosis. CONCLUSIONS: These results suggest that: (1) Neither hyponatremic encephalopathy nor its therapy is commonly associated with CPM; (2) Patients with chronic alcoholism who also become hyponatremic can develop pontine demyelinating lesions; (3) Most patients with symptomatic hyponatremia who are diagnosed as having CPM in fact have diffuse cerebral demyelinating lesions with a normal pons; (4) The distribution of cerebral demyelinating lesions in patients with hyponatremic encephalopathy is compatible with hypoxic damage.

[Comparative studies of CT pictures and intraoperative findings in malignant neoplasms of the paranasal sinuses and nasopharynx]. / Konfrontacja obrazów KT z ocena sródoperacyjna nowotworów zlosliwych zatok przynosowych i nosogardla.

Five cases of malignant paranasal sinus and nasopharyngeal cancer were demonstrated. They illustrated the discrepancies in the evaluation of the extensive neoplastic process using CT scanning and intraoperative examination. The limitation of CT scanning in the diagnosis of advanced malignant cancer in this region was discussed.

Cytoplasmic streaming direction reverses in dividing Paramecium bursaria.

Using the interference-contrast videomicroscopy the speed of cytoplasmic streaming was measured during the sequence of division stages in thigmotactically settled specimens of Paramecium bursaria. The speed of cytoplasmic flow gradually decreased during the first stages of binary fission and movement became indistinguishable at stage D(3). Almost at the same time cytoplasm started to move in the opposite direction, pushing or pulling the dividing micronucleus into the prospective posterior daughter cell and eventually stopped at stage D(5)-D(6). Further cell division events proceeded without detectable movement of cytoplasmic components. Cytoplasmic streaming in the normal interphase route was gradually restored in daughter cells about 30-40 min after cell separation. During the whole period of binary fission phagocytosis was arrested. Transportation and participation in the positioning of prospective micronuclei in daughter cells seems to be the main function of cytoplasmic streaming activity in cell division of Paramecium bursaria. The possible relationship between the stages of cytoskeleton transitions and the kinetics of cytoplasmic streaming associated with cell divison is discussed.

[Evaluation of the effectiveness of electroshock therapy in patients with refractory depression]. / Ocena skutecznosci elektrowstrzasów u pacjentów z depresja oporna na leczenie.

In the group of 35 in-patients (30 female, 5 male) from the Department of Psychiatry, Medical Academy in Wroclaw with depression resistant to antidepressive pharmacotherapy, the evaluation of ES therapy was made. The high efficacy (63% of full remissions) showed combined ES therapy with tricyclic antidepressants; only in 2 female and in 1 male patient there was no effect. At the same time neither serious side-effects nor complications were found, even in older patients.