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Posterior communicating artery (PCoA) aneurysms frequently rupture in small size (<7 mm). The aim of the study is to demonstrate morphometric and hemodynamic analyses in ruptured and unruptured PCoA aneurysms to improve predictive accuracy for rupture. Geometrical models were reconstructed from rotational DSA images of 57 ruptured and 22 unruptured side-wall PCoA aneurysms, which were classified into four two-dimensional (2D) groups by a combination of H/D and H/S ratios (H: dome height, D: dome diameter, and S: semi-axis height). Surface area ratio (SAR) of low time-averaged wall shear stress (TAWSS, ≤4 dynes cm −2 ) and high oscillatory shear index (OSI, ≥0.15) were computed in aneurysms. We hypothesized that a two-step analysis method, i.e., one-dimensionally morphometric and hemodynamic analyses in each 2D group, can enhance accuracy of PCoA aneurysm rupture evaluation. There was the highest incidence of H/D > 1 and H/S ≤ 2 with the largest surface area and SAR-TAWSS, but the lowest incidence of H/D ≤ 1 and H/S > 2 with the smallest surface area and SAR-TAWSS in ruptured PCoA aneurysms. PCoA aneurysms of H/D > 1 and H/S ≤ 2 with surface area > 70 mm 2 , H/D ≤ 1 and H/S > 2 with neck diameter > 2.3 mm, H/D ≤ 1 and H/S ≤ 2 with aneurysmal height/parent diameter ratio > 1.0, and H/D > 1 and H/S > 2 with aneurysmal angle > 115° need special attention for clinical diagnosis and treatment. The study highlighted the importance of the two-step analysis method for clinical evaluation of PCoA aneurysm rupture. [ABSTRACT FROM AUTHOR]

New Findings What is the central question of this study? The present study investigated the relationship between H2S and NO in regulation of gastric fundus tension., What is the main finding and its importance? Endogenous or exogenous H2S and NO have opposite effects on fundus tension, and H2S-induced gastric fundus tension enhancements are mediated by inhibition of NO generation through the phosphoinositide 3-kinase/Akt pathway. These results are very important in exploring the mechanism of physiological accommodation and accommodation disorder., Hydrogen sulphide (H2S) is considered a new gasotransmitter, along with NO and CO. It was recently confirmed that H2S and NO play important roles in the regulation of gastrointestinal smooth muscle tension. The present study was designed to elucidate the interactions between H2S and NO with respect to the regulation of gastric fundus smooth muscle tension using Western blotting, physiological and electrochemical techniques. Real-time H2S and NO generation was detected in gastric smooth muscle tissue. NaHS, an H2S donor, enhanced fundus smooth muscle tension, whereas SNP, an NO donor, decreased fundus smooth muscle tension in a dose-dependent manner. NaHS-induced increases in fundus smooth muscle tension were suppressed by l-NAME, an NO synthase inhibitor. Aminooxyacetic acid (AOAA), a cystathionine β-synthase inhibitor, exerted inhibitory effects on fundus smooth muscle tension; these effects were also suppressed by l-NAME. Real-time NO generation was significantly potentiated by AOAA. Endothelial nitric oxide synthase (eNOS) phosphorylation at serine 1177 and Akt phosphorylation at serine 308 and threonine 473 were significantly inhibited by NaHS. LY294002, a phosphoinositide 3-kinase inhibitor, blocked these NaHS-mediated effects. However, eNOS phosphorylation at serine 1177 and Akt phosphorylation at serine 308 and threonine 473 were significantly potentiated by AOAA. Cystathionine β-synthase siRNA interference significantly increased eNOS phosphorylation at serine 1177 and Akt phosphorylation at serine 308 and threonine 473. Cystathionine β-synthase siRNA interference also increased total eNOS protein expression levels but did not significantly change total Akt kinase protein expression levels. These results suggest that H2S-induced enhancement of gastric fundus tension is mediated by inhibition of NO generation through the phosphoinositide 3-kinase/Akt pathway. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor (VEGF) is pathognomonically elevated in patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) syndrome. However, its source of overproduction is unclear. As clinical improvement is almost always associated with VEGF reduction after anti-plasma cell therapy, its increase at diagnosis has been attributed to the underlying monoclonal gammopathy, although direct evidence is still lacking. In the current study, we systemically measured VEGF levels in POEMS patients, before and after treatment. Bone marrow plasma cells showed remarkable VEGF expression, in both mRNA and protein levels, which decreased gradually in response to therapy. Of note, statistically linear correlations were observed between serum and bone marrow plasma cell VEGF levels (mRNA vs . serum, rho 0.343, p = 0.003; protein vs . serum, rho 0.644, p < 0.0001), supporting bone marrow plasma cells as the main source of circulating VEGF. Intriguingly, immunophenotyping revealed that bone marrow plasma cells were polyclonal in most patients at diagnosis. A clear monoclonal population, coexistent with polytypic cells, was only detectable in 11 cases (18%), in which comparable intracellular VEGF expression was observed between these two plasma cell populations ( p = 0.594), while monoclonal cells showed higher intracellular interleukin-6 expression ( p = 0.006). These patients had more serum monoclonal protein, less post-therapeutic complete remission, and inferior overall ( p = 0.027) and progression-free survival ( p = 0.002). Collectively, bone marrow plasma cells, mainly polyclonal population, are the major source of VEGF overproduction in POEMS patients. [ABSTRACT FROM AUTHOR]

High-fat (HF) diet modulates gut microbiota and increases plasma concentration of lipopolysaccharide (LPS) which is associated with obesity and its related low-grade inflammation and cognitive decline. Rhein is the main ingredient of the rhubarb plant which has been used as an anti-inflammatory agent for several millennia. However, the potential effects of rhein against HF diet-induced obesity and its associated alteration of gut microbiota, inflammation and cognitive decline have not been studied. In this study, C57BL/6J male mice were fed an HF diet for 8 weeks to induce obesity, and then treated with oral rhein (120 mg/kg body weight/day in HF diet) for a further 6 weeks. Chronic rhein treatment prevented the HF diet-induced recognition memory impairment assessed by the novel object recognition test, neuroinflammation and brain-derived neurotrophic factor (BDNF) deficits in the perirhinal cortex. Furthermore, rhein inhibited the HF diet-induced increased plasma LPS level and the proinflammatory macrophage accumulation in the colon and alteration of microbiota, including decreasing Bacteroides-Prevotella spp. and Desulfovibrios spp. DNA and increasing Bifidobacterium spp. and Lactobacillus spp. DNA. Moreover, rhein also reduced body weight and improved glucose tolerance in HF diet-induced obese mice. In conclusion, rhein improved recognition memory and prevented obesity in mice on a chronic HF diet. These beneficial effects occur via the modulation of microbiota, hypoendotoxinemia, inhibition of macrophage accumulation, anti-neuroinflammation and the improvement of BDNF expression. Therefore, supplementation with rhein-enriched food or herbal medicine could be beneficial as a preventive strategy for chronic HF diet-induced cognitive decline, microbiota alteration and neuroinflammation. [ABSTRACT FROM AUTHOR]

Abstract: Olanzapine is widely used in treating multiple domains of schizophrenia symptoms but induces serious metabolic side-effects. Recent evidence has showed that co-treatment of betahistine (a histaminergic H1 receptor agonist and H3 receptor antagonist) is effective for preventing olanzapine-induced weight gain/obesity, however it is not clear whether this co-treatment affects on the primary therapeutic receptor binding sites of olanzapine such as serotonergic 5-HT2A receptors (5-HT2AR) and dopaminergic D2 receptors (D2R). Therefore, this study investigated the effects of this co-treatment on 5-HT2AR, 5-HT transporter (5-HTT) and D2R bindings in various brain regions involved in antipsychotic efficacy. Female Sprague Dawley rats were administered orally (t.i.d.) with either olanzapine (1mg/kg), betahistine (2.7mg/kg), olanzapine plus betahistine (O+B), or vehicle (control) for 2weeks. Quantitative autoradiography was used to detect the density of [3H]ketanserin, [3H]paroxetine and [3H]raclopride binding site to 5-HT2AR, 5-HTT and D2R. Compared to the controls, olanzapine significantly decreased [3H]ketanserin bindings to 5-HT2AR in the prefrontal cortex, cingulate cortex, and nucleus accumbens. Similar changes in 5-HT2AR bindings in these nuclei were also observed in the O+B co-treatment group. Olanzapine also significantly decreased [3H]paroxetine binding to 5-HTT in the ventral tegmental area and substantia nigra, however, both olanzapine only and O+B co-treatment did not affect [3H]raclopride binding to D2R. The results confirmed the important role of 5-HT2AR in the efficacy of olanzapine, which is not influenced by the O+B co-treatment. Therefore, betahistine co-treatment would be an effective combination therapy to reduce olanzapine-induced weight gain side-effects without affecting olanzapine's actions on 5-HT2AR transmissions. [Copyright &y& Elsevier]

Skin wound repair is a multistage process involving multiple cellular and molecular interactions, which modulate the cell behaviors and dynamic remodeling of extracellular matrices to maximize regeneration and repair. Consequently, abnormalities in cell functions or pathways inevitably give rise to side effects, such as dysregulated inflammation, hyperplasia of nonmigratory epithelial cells, and lack of response to growth factors, which impedes angiogenesis and fibrosis. These issues may cause delayed wound healing or even non‐healing states. Current clinical therapeutic approaches are predominantly dedicated to preventing infections and alleviating topical symptoms rather than addressing the modulation of wound microenvironments to achieve targeted outcomes. Bioactive materials, relying on their chemical, physical, and biological properties or as carriers of bioactive substances, can affect wound microenvironments and promote wound healing at the molecular level. By addressing the mechanisms of wound healing from the perspective of cell behaviors, this review discusses how bioactive materials modulate the microenvironments and cell behaviors within the wounds during the stages of hemostasis, anti‐inflammation, tissue regeneration and deposition, and matrix remodeling. A deeper understanding of cell behaviors during wound healing is bound to promote the development of more targeted and efficient bioactive materials for clinical applications. [ABSTRACT FROM AUTHOR]

Purpose:This study evaluates the relationship between multiple system atrophy and α-synuclein levels in the cerebrospinal fluid, plasma and neural tissue. Method:Literature search for relevant research articles was undertaken in electronic databases and study selection was based on a priori eligibility criteria. Random-effects meta-analyses of standardized mean differences in α-synuclein levels between multiple system atrophy patients and normal controls were conducted to obtain the overall and subgroup effect sizes. Meta-regression analyses were performed to evaluate the effect of age, gender and disease severity on standardized mean differences. Results:Data were obtained from 11 studies involving 378 multiple system atrophy patients and 637 healthy controls (age: multiple system atrophy patients 64.14 [95% confidence interval 62.05, 66.23] years; controls 64.16 [60.06, 68.25] years; disease duration: 44.41 [26.44, 62.38] months). Cerebrospinal fluid α-synuclein levels were significantly lower in multiple system atrophy patients than in controls but in plasma and neural tissue, α-synuclein levels were significantly higher in multiple system atrophy patients (standardized mean difference: −0.99 [−1.65, −0.32];p= 0.001). Percentage of male multiple system atrophy patients was significantly positively associated with the standardized mean differences of cerebrospinal fluid α-synuclein levels (p= 0.029) whereas the percentage of healthy males was not associated with the standardized mean differences of cerebrospinal fluid α-synuclein levels (p= 0.920). Conclusion:In multiple system atrophy patients, α-synuclein levels were significantly lower in the cerebrospinal fluid and were positively associated with the male gender. [ABSTRACT FROM AUTHOR]

Childhood/adolescent antipsychotic drug (APD) use is exponentially increasing worldwide, despite limited knowledge of the long-term effects of early APD treatment. Whilst investigations have found that early treatment has resulted in some alterations to dopamine and serotonin neurotransmission systems (essential to APD efficacy), there have only been limited studies into potential long-term behavioural changes. This study, using an animal model for childhood/adolescent APD treatment, investigated the long-term effects of aripiprazole, olanzapine and risperidone on adult behaviours of male and female rats. Open-field/holeboard, elevated plus maze (EPM), social interaction and forced swim (FS) tests were then conducted in adult rats. Our results indicated that in the male cohort, early risperidone and olanzapine treatment elicited long-term hyper-locomotor effects (open-field/holeboard and FS tests), whilst a decrease in depressive-like behaviour (in FS test) was observed in response to olanzapine treatment. Furthermore, anxiolytic-like behaviours were found following testing in the open-field/holeboard and EPM in response to all three drug treatments. Effects in the female cohort, however, were to a far lesser extent, with behavioural attributes indicative of an increased depressive-like behaviour and hypo-locomotor activity exhibited in the FS test following early risperidone and olanzapine treatment. These results suggest that various APDs have different long-term effects on the behaviours of adult rats. [ABSTRACT FROM AUTHOR]

Summary: Based on clinical and animal studies, this review suggests a tri-phasic effect of second-generation antipsychotics (SGAs) on circulating ghrelin levels: an initial increase exerted by the acute effect of SGAs; followed by a secondary decrease possibly due to the negative feedback from the SGA-induced body weight gain or hyperphagia; and a final re-increase to reach the new equilibrium. Moreover, the results can also vary depending on individual SGAs, other hormonal states, dietary choices, and other confounding factors including medical history, co-treatments, age, gender, and ghrelin measurement techniques. Interestingly, rats treated with olanzapine, an SGA with high weight gain liabilities, are associated with increased hypothalamic ghrelin receptor (GHS-R1a) levels. In addition, expressions of downstream ghrelin signalling parameters at the hypothalamus, including neuropeptide Y (NPY)/agouti-related peptide (AgRP) and proopiomelanocortin (POMC) are also altered under SGA treatments. Thus, understanding the role of ghrelin signalling in antipsychotic drug-induced weight gain should offer potential novel pharmacological targets for tackling the obesity side-effect of SGAs and its associated metabolic syndrome. [Copyright &y& Elsevier]

• Metabolism (anabolism and catabolism) of amyloid-βeta (Aβ-peptide) occurred both in periphery and brain. • An imbalance in metabolism of Aβ-peptide results in peripheral and central abnormalities. • Different pathways involved in Aβ-peptide metabolism communicate and interlinked brain and periphery. • AD pathogenesis is closely associated with several peripheral abnormalities. • Peripheral understanding of Aβ-peptide in AD pathology might leads towards new treatments and diagnostic biomarkers. Alzheimer's disease (AD) is an age-associated, multifactorial neurodegenerative disorder that is incurable. Despite recent success in treatments that partially improve symptomatic relief, they have failed in most clinical trials. Re-holding AD for accurate diagnosis and treatment is widely known as a challenging task. Lack of knowledge of basic molecular pathogenesis might be a possible reason for ineffective AD treatment. Historically, a majority of therapy-based studies have investigated the role of amyloid-β (Aβ peptide) in the central nervous system (CNS), whereas less is known about Aβ peptide in the periphery in AD. In this review, we provide a comprehensive summary of the current understanding of Aβ peptide metabolism (anabolism and catabolism) in the brain and periphery. We show that the abnormal metabolism of Aβ peptide is significantly linked with central-brain and peripheral abnormalities; the interaction between peripheral Aβ peptide metabolism and peripheral abnormalities affects central-brain Aβ peptide metabolism, suggesting the existence of significant communication between these two pathways of Aβ peptide metabolism. This close interaction between the central brain and periphery in abnormal Aβ peptide metabolism plays a key role in the development and progression of AD. In conclusion, we need to obtain a full understanding of the dynamic roles of Aβ peptide at the molecular level in both the brain and periphery in relation to the pathology of AD. This will not only provide new information regarding the complex disease pathology, but also offer potential new clues to improve therapeutic strategies and diagnostic biomarkers for the successful treatment of AD. [ABSTRACT FROM AUTHOR]

Epidermal growth factor (EGF) plays an important role in epithelial cell proliferation and apoptosis. Our recent studies found that EGF-attenuated tumor necrosis factor-α induced HaCaT keratinocyte apoptosis, and this effect was accompanied by up-regulation of the expression of peroxisome proliferator-activated receptor β (PPARβ). However, little is known about whether PPARβ is functionally involved in the inhibition of keratinocyte apoptosis by EGF. Here, we showed that EGF up-regulated the DNA-binding and transcriptional regulation activities of PPARβ. Antisense phosphorothioate oligonucleotides against PPARβ markedly inhibited de novo synthesis of PPARβ and attenuated the protective effect of EGF on tumor necrosis factor-α–induced apoptosis. L165041, a specific PPARβ ligand, significantly enhanced the transcriptional regulation activity of PPARβ and increased the protective effect of EGF. These results suggest a molecular mechanism by which EGF protects HaCaT keratinocytes against apoptosis in a PPARβ-dependent manner. [ABSTRACT FROM AUTHOR]

Dysfunction of the glutamatergic system is believed to underlie many neurodevelopmental disorders including autism, Rett syndrome and schizophrenia. Metabotropic glutamate receptor (mGluR5) positive allosteric modulators (PAM) potentiate glutamatergic signaling, particularly indirectly via the NMDA receptor. Preclinical studies report mGluR5 PAMs can improve schizophrenia-relevant behaviours. Furthermore, adolescent administration has shown to prevent cognitive induced deficits in adult rodents. However, there is limited understanding of the short- and long-term neurochemical effects of mGluR5 PAMs, which may underlie their therapeutic effects. We examined the effect of 7-day adolescent (PN28-34) treatment with the mGluR5 PAM, CDDPB (30 mg/kg), on glutamatergic receptor expression at adolescence (PN35) and adulthood (PN96). Immunoblot analysis revealed that 7-day adolescent CDPPB treatment increased protein expression of glutamatergic receptors including the NMDA receptor subunits, NR1 and NR2A and the AMPA subunits (GluA1 and GluA2) in the adolescent hippocampus, changes that did not extend to adulthood. In contrast, there were no changes in the adolescent frontal cortex, however elevated mGluR5 protein expression was observed at adulthood following adolescent CDPPB treatment. The present study indicates adolescent CDPPB treatment may cause brain region dependent effects on the glutamatergic system, which do not persist into adulthood. These findings may have implications for the preclinical development of mGluR5 PAMs for the treatment of neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

The D2 receptor partial agonist, aripiprazole, has shown increased therapeutic efficacy for schizophrenia, autism and Tourette's syndrome compared to traditional antipsychotics such as the D2 receptor antagonist, haloperidol. Recent evidence suggests this superior profile may be associated with downstream effects on glutamatergic synapses. Group 1 metabotropic glutamate receptors (mGluRs) and their endogenous modulators, Norbin and Homer1, are regulated by D2 receptor activity, particularly within the nucleus accumbens (NAc), a target region of aripiprazole and haloperidol. This study sought to evaluate the effects of aripiprazole on Group 1 mGluRs, Norbin and Homer1 in the NAc, in comparison to haloperidol. Sprague-Dawley rats were orally administered daily doses of aripiprazole (2.25 mg/kg), haloperidol (0.3 mg/kg) or vehicle for 1 or 10-weeks. Immunoblot analyses revealed Group 1 mGluR protein levels were not altered following 1-week and 10-week aripiprazole or haloperidol treatment, compared to vehicle treated rodents. However, 1-week aripiprazole and haloperidol treatment significantly elevated Homer1a and Norbin protein expression, respectively. After 10 weeks of treatment, aripiprazole, but not haloperidol, significantly increased Norbin expression. These findings indicate the antipsychotics, aripiprazole and haloperidol, exert differential temporal effects on Norbin and Homer1 expression that may have consequences on synaptic glutamatergic transmission underlying their therapeutic profile. [ABSTRACT FROM AUTHOR]

Purpose:Neurobrucellosis (NB) is a rare complication of brucellosis. NB presents with avariety of clinical manifestations, and the symptoms are always atypical. Our aim was to analyze the demographic characteristics, clinical manifestations, laboratory findings, imaging findings, treatments and outcomes of patients with NB. Material and Method:We retrospectively reviewed the data from 17 patients with NB hospitalized at the Chinese People's Liberation Army General Hospital between 1 January 2005 and 31 October 2016. Results:The following symptoms were recorded: 10/17 (59%) patients had fever, and 9/17 (53%) patients had a disorder affecting urination and defecation. Involvement of the cranial nerves was documented in 12/17 (71%) patients. The positivity rates of the tests were as follows: serum standard tube agglutination (STA), 15/17 (88.2%); cerebrospinal fluid STA, 10/17 (59%). The radiologic findings were categorized into four types: normal, white matter changes, vascular insult and inflammatory changes. Patients were treated with different combinations of rifampicin, doxycycline, ceftriaxone sodium and sulphamethoxazole for a total of six months. Two (12%) patients deteriorated, and two (12%) patients were lost to follow-up. The remaining patients (76%) were cured, but sequelae occurred in six patients. Conclusions:NB should be kept in mind in patients with autonomic dysfunction, especially disorders of urination and defecation. Hearing loss due to vestibulocochlear nerve injury seems to be typical for NB. The high incidence of sequelae may be related to a long disease course and the involvement of the central nervous system. Early detection, diagnosis and treatment could decrease mortality and sequelae. [ABSTRACT FROM PUBLISHER]

Long-term antipsychotic treatment for schizophrenia is associated with the development of tardive dyskinesia (TD), which is involved in increased cognitive impairment. Dopamine beta-hydroxylase (DBH) gene associated with dopamine and norepinephrine systems influences cognition. Schizophrenia with TD have higher DBH activity than those without TD. This study examined whether DBH5'-insertion/deletion (-Ins/Del) polymorphism could influence cognitive function in schizophrenia with and without TD. The presence of DBH5'-Ins/Del polymorphism was determined in 345 schizophrenia with TD and 397 schizophrenia without TD. The Abnormal Involuntary Movement Scale and Repeatable Battery for Assessment of Neuropsychological Status (RBANS) were used to assess TD severity and cognition. The allele and genotype frequencies of DBH5'-Ins/Del polymorphism did not differ between patients with and without TD (both p>0.05). RBANS total score and subscales did not differ by DBH5'-Ins/Del genotype groups in patients with TD (all p>0.05). However, attention score significantly differed by DBH5'-Ins/Del genotype groups in those without TD (p<0.05). Patients without TD who were Del homozygous had significantly lower attention score than those without TD who were Ins alleles (p<0.05). Immediate memory and attention scores were lower in patients with TD than without TD (both p<0.05). This study indicated that DBH5'-Ins/Del polymorphism may not play a role in the susceptibility to TD and cognitive deficits in schizophrenia with TD, but it may influence cognitive function in schizophrenia with non-TD. Moreover, schizophrenia with TD experienced greater cognitive deficits than those with non-TD, especially in immediate memory and attention. [ABSTRACT FROM AUTHOR]

Background: Treatment of mild-moderate Alzheimer's disease (AD) subjects (N = 119) for 52 weeks with the SIRT1 activator resveratrol (up to 1 g by mouth twice daily) attenuates progressive declines in CSF Aβ40 levels and activities of daily living (ADL) scores.Methods: For this retrospective study, we examined banked CSF and plasma samples from a subset of AD subjects with CSF Aβ42 <600 ng/ml (biomarker-confirmed AD) at baseline (N = 19 resveratrol-treated and N = 19 placebo-treated). We utilized multiplex Xmap technology to measure markers of neurodegenerative disease and metalloproteinases (MMPs) in parallel in CSF and plasma samples.Results: Compared to the placebo-treated group, at 52 weeks, resveratrol markedly reduced CSF MMP9 and increased macrophage-derived chemokine (MDC), interleukin (IL)-4, and fibroblast growth factor (FGF)-2. Compared to baseline, resveratrol increased plasma MMP10 and decreased IL-12P40, IL12P70, and RANTES. In this subset analysis, resveratrol treatment attenuated declines in mini-mental status examination (MMSE) scores, change in ADL (ADCS-ADL) scores, and CSF Aβ42 levels during the 52-week trial, but did not alter tau levels.Conclusions: Collectively, these data suggest that resveratrol decreases CSF MMP9, modulates neuro-inflammation, and induces adaptive immunity. SIRT1 activation may be a viable target for treatment or prevention of neurodegenerative disorders.Trial Registration: ClinicalTrials.gov NCT01504854. [ABSTRACT FROM AUTHOR]

Aims Cannabinoid 1(CB1) receptors are closely correlated to the dopaminergic system and involved in cognitive function. Since statins have been used to regulate the progression of Parkinson's disease (PD) via its anti-inflammation and neuroprotective effects, we asked if statins affect the CB1 receptors in the 6-hydroxydopamine (6-OHDA) lesioned rat. Methods The PD rat model was established by injecting 6-OHDA into the unilateral medial forebrain bundle; while rats were orally pre-treated with simvastatin (1 or 10 mg/kg/day), or saline for 5 days before surgery, and the same treatments for each group were continued for 3 weeks post-surgery. [ 3 H] SR141716A binding autoradiography was adopted to investigate the alterations in CB1 receptor density in the brains. Findings The 6-OHDA induced a remarkable downregulation of CB1 receptor density in the prefrontal cortex, caudate putamen, nucleus accumbens, cingulate cortex, hippocampus, and substantia nigra; while simvastatin (10 mg/kg/day) significantly ameliorated this downregulation in those regions. Furthermore, simvastatin (1 mg/kg/day) reversed the 6-OHDA-induced downregulation of CB1 receptors in the substantia nigra and hippocampus. Simvastatin showed minimal changes in [ 3 H] SR141716A binding in the examined regions in sham rats, but did reveal a significant down-regulation of binding density within the striatum, prefrontal cortex and substantia nigra. Significance Alterations in the [ 3 H] SR141716A binding in the examined brain areas may represent the specific regions that mediate motor and cognitive dysfunctions in PD via the endocannabinoid system. Our data suggest a critical role of CB1 receptors in treating PD with simvastatin, and implicate CB1 receptors as a potential therapeutic target in the treatment of PD. [ABSTRACT FROM AUTHOR]

Rationale: An imbalance of excitatory and inhibitory neurotransmission underlies the glutamate hypothesis of schizophrenia. Agonists of group II metabotropic glutamate receptors, mGluR2/3, have been proposed as novel therapeutic agents to correct this imbalance. However, the influence of mGluR2/3 activity on excitatory and inhibitory neurotransmitter receptors has not been explored. Objectives: We aimed to investigate the ability of a novel mGluR2/3 agonist, LY379268, to modulate the availability of the excitatory N-methyl- d-aspartate receptor (NMDA-R) and the inhibitory gamma-aminobutyrate-A receptor (GABAA-R), in a two-hit mouse model of schizophrenia. Methods: Wild type (WT) and heterozygous neuregulin 1 transmembrane domain mutant mice (NRG1 HET) were treated daily with phencyclidine (10 mg/kg ip) or saline for 14 days. After a 14-day washout, an acute dose of the mGluR2/3 agonist LY379268 (3 mg/kg), olanzapine (antipsychotic drug comparison, 1.5 mg/kg), or saline was administered. NMDA-R and GABAA-R binding densities were examined by receptor autoradiography in several schizophrenia-relevant brain regions. Results: In both WT and NRG1 HET mice, phencyclidine treatment significantly reduced NMDA-R and GABAA-R binding density in the prefrontal cortex, hippocampus, and nucleus accumbens. Acute treatment with LY379268 restored NMDA-R and GABAA-R levels in the two-hit mouse model comparable to olanzapine. Conclusions: We demonstrate that the mGluR2/3 agonist LY379268 restores excitatory and inhibitory deficits with similar efficiency as olanzapine in our two-hit schizophrenia mouse model. This study significantly contributes to our understanding of the mechanisms underlying the therapeutic effects of LY379268 and supports the use of agents aimed at mGluR2/3. [ABSTRACT FROM AUTHOR]

There is increasing evidence that chronic noise stress impairs cognition and induces oxidative stress in the brain. Recently, orientin, a phenolic compound abundant in some fruits, millet, and herbs, has been shown to have antioxidant properties. This study investigated the potential effects of orientin against chronic noise-induced cognitive decline and its underlying mechanisms. A moderate-intensity noise exposure model was used to investigate the effects of orientin on behavior and biochemical alterations in mice. After 3 weeks of the noise exposure, the mice were treated with orientin (20 mg/kg and 40 mg/kg, oral gavage) for 3 weeks. The chronic noise exposure impaired the learning and memory in mice in the Morris water maze and step-through tests. The noise exposure also decreased exploration and interest in a novel environment in the open field test. The administration of orientin significantly reversed noise-induced alterations in these behavior tests. Moreover, the orientin treatment significantly improved the noise-induced alteration of serum corticosterone and catecholamine levels and oxidative stress in the hippocampus and prefrontal cortex. Furthermore, the orientin treatment ameliorated the noise-induced decrease in brain-derived neurotrophic factor and synapse-associated proteins (synaptophysin and postsynaptic density protein 95) in the hippocampus and prefrontal cortex. Thus, orientin exerts protective effects on noise-induced cognitive decline in mice, specifically by improving central oxidative stress, neurotransmission, and increases synapse-associated proteins. Therefore, supplementation with orientin-enriched food or fruit could be beneficial as a preventive strategy for chronic noise-induced cognitive decline. [ABSTRACT FROM AUTHOR]

Background: Cryptococcal meningitis (CM) is a relatively common opportunistic infection in patients with human immunodeficiency virus (HIV) infection and can also occur in patients with no underlying disease. The aim of this study was to evaluate the clinical manifestations, laboratory findings, diagnosis and misdiagnosis, treatment, and prognosis of CM at a tertiary care hospital. Methods: We performed a retrospective study of 55 patients at a tertiary care hospital from January 1, 1992 to December 31, 2013. All the patients had a definite diagnosis based on etiology. Results: All 55 patients had a positive cerebrospinal fluid (CSF) India ink staining result. The predominant change observed on magnetic resonance imaging (MRI) was leptomeningeal liner enhancement, which is also called 'lumbriciform-enhancing.' Only 15 patients were first diagnosed with CM, indicating a misdiagnosis rate of 72.7%. At the follow-up end point, 8 patients were cured, 33 had improved, and 14 had died. The overall response rate was 74.5%. The voriconazole group had a response rate of 100%, which was significantly higher than the other two groups. Conclusions: Most CM patients in China were previously healthy without any potential risk factors. CM was easily misdiagnosed due to the lack of specificity of early clinical symptoms. Repeated CSF India ink staining should be performed to identify the pathogen. Voriconazole could be administered to the patients with CM, especially to patients who had a treatment failure with amphotericin B alone or accompanied by fluconazole. [ABSTRACT FROM AUTHOR]

The metabolic side-effects of olanzapine have undermined drug compliance and increased concern for this otherwise-effective treatment for schizophrenia. As obesity and type 2 diabetes are associated with low-grade inflammation, and olanzapine-induced weight gain has three typical stages, the current study investigated the inflammatory effects of olanzapine in three treatment stages. Female Sprague-Dawley rats were treated orally with olanzapine (1 mg/kg three times daily) or vehicle for one week, two weeks, and five weeks. Olanzapine significantly increased body weight and white visceral fat deposition in all three treatment stages compared to control. Olanzapine enhanced average adipocyte size and level of macrophage infiltration in white adipose tissue (WAT) compared to control, with levels of macrophage infiltration increased over time. There was a high correlation between adipocyte size and macrophage infiltration rate. Olanzapine also caused increased macrophage infiltration in brown adipose tissue (BAT), but not liver. Additionally, pro-inflammatory cytokines tumor necrosis factor α (TNFα), interleukin (IL)-1β, and IL-6 were upregulated by olanzapine in the hypothalamus, WAT, and BAT compared to control, but not the liver. Finally, plasma triglycerides were elevated by olanzapine compared to control, but not total cholesterol, high density lipoprotein (HDL) or low density lipoprotein (LDL). These findings indicate that olanzapine-induced inflammation and adiposity are closely related, and that peripheral low-grade inflammation develops during olanzapine treatment. [ABSTRACT FROM PUBLISHER]

Abstract: Excessive weight gain has been identified as a serious metabolic side-effect of second-generation antipsychotics (SGAs), including olanzapine. While hyperphagia has been suggested to be the main contributor for this side-effect in the short term, reduced energy expenditure, in particular thermogenesis and locomotor activity, has been considered to contribute to the maintenance of heavy weight under long-term SGA treatments. Recent studies have identified metabolically active brown adipose tissues (BAT) in adult humans, suggesting potential clinical significance for the involvement of BAT thermogenesis in SGA-induced weight gain. However, to date there has been little research elucidating the central neuronal pathways affecting BAT thermogenesis or the morphological changes of the BAT. The present study aimed to investigate the role of BAT thermogenesis and locomotor activity in olanzapine-induced weight gain during the prolonged time courses of olanzapine treatment in an established female rat model. Although short- to mid-term olanzapine treatment had no effect on BAT temperature, we observed that long-term olanzapine treatment (from day 18 to 34) induced a significant reduction in BAT temperature, with an acute effect being observed between 45 and 150min post-treatment in the long-term cohort. Additionally, in the long-term olanzapine group, the reduced BAT temperature was accompanied by decreased UCP1 and PGC-1α expressions in the BAT. Moreover, TH mRNA expressions in both hypothalamus and brainstem were also downregulated after mid- to long-term olanzapine treatment. Further, olanzapine led to reduced percentage of brown adipocytes in BAT during mid- to long-term treatments. Finally, locomotor activity was reduced throughout the three treatment cohorts. In summary, our results suggest that the reduction of BAT thermogenesis plays an important role during the long-term of olanzapine-induced weight gain, which was accompanied by an earlier onset of BAT adipocyte morphological changes and biochemical changes in the hypothalamus and the brainstem, while locomotor activity contributes to the entire olanzapine treatment courses. [Copyright &y& Elsevier]

Background: Neuroinflammation plays an important role in the onset and progression of neurodegenerative diseases such as Alzheimer's disease. Lipopolysaccharide (LPS, endotoxin) levels are higher in the brains of Alzheimer's disease patients and are associated with neuroinflammation and cognitive decline, while neural cholinergic signaling controls inflammation. This study aimed to examine the efficacy of galantamine, a clinically approved cholinergic agent, in alleviating LPS-induced neuroinflammation and cognitive decline as well as the associated mechanism.Methods: Mice were treated with galantamine (4 mg/kg, intraperitoneal injection) for 14 days prior to LPS exposure (intracerebroventricular injection). Cognitive tests were performed, including the Morris water maze and step-through tests. mRNA expression of the microglial marker (CD11b), astrocytic marker (GFAP), and pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) were examined in the hippocampus by quantitative RT-PCR. The inflammatory signaling molecule, nuclear factor-kappa B (NF-κB p65), and synapse-associated proteins (synaptophysin, SYN, and postsynaptic density protein 95, PSD-95) were examined in the hippocampus by western blotting. Furthermore, NF-κB p65 levels in microglial cells and hippocampal neurons were examined in response to LPS and galantamine.Results: Galantamine treatment prevented LPS-induced deficits in spatial learning and memory as well as memory acquisition of the passive avoidance response. Galantamine decreased the expression of microglia and astrocyte markers (CD11b and GFAP), pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), and NF-κB p65 in the hippocampus of LPS-exposed mice. Furthermore, galantamine ameliorated LPS-induced loss of synapse-associated proteins (SYN and PSD-95) in the hippocampus. In the in vitro study, LPS increased NF-κB p65 levels in microglia (BV-2 cells); the supernatant of LPS-stimulated microglia (Mi-sup), but not LPS, decreased the viability of hippocampal neuronal cells (HT-22 cells) and increased NF-κB p65 levels as well as expression of pro-inflammatory cytokines (IL-1β, IL-6) in HT-22 cells. Importantly, galantamine reduced the inflammatory response not only in the BV-2 microglia cell line, but also in the HT-22 hippocampal neuronal cell line.Conclusions: These findings indicate that galantamine could be a promising treatment to improve endotoxin-induced cognitive decline and neuroinflammation in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]