Reduced Brain Activity in the Right Putamen as an Early Predictor for Treatment Response in Drug-Naive, First-Episode Schizophrenia

Antipsychotic medications can have a significant effect on brain function after only several days of treatment. It is unclear whether such an acute effect can serve as an early predictor for treatment response in schizophrenia. Thirty-two patients with drug-naive, first-episode schizophrenia and 32 healthy controls underwent resting-state functional magnetic resonance imaging. Patients were treated with olanzapine and were scanned at baseline and 1 week of treatment. Healthy controls were scanned once at baseline. Symptom severity was assessed within the patient group using the Positive and Negative Syndrome Scale (PANSS) at three time points (baseline, 1 week of treatment, and 8 weeks of treatment). The fractional amplitude of low frequency fluctuation (fALFF) and support vector regression (SVR) methods were used to analyze the data. Compared with the control group, the patient group showed increased levels of fALFF in the bilateral putamen at baseline. After 1 week of olanzapine treatment, the patient group showed decreased levels of fALFF in the right putamen relative to those at baseline. The SVR analysis found a significantly positive relationship between the reduction in fALFF after 1 week of treatment and the improvement in positive symptoms after 8 weeks of treatment (r = 0.431, p = 0.014). The present study provides evidence that early reduction and normalization of fALFF in the right putamen may serve as a predictor for treatment response in patients with schizophrenia

Penicillium marneffei-Stimulated Dendritic Cells Enhance HIV-1 Trans-Infection and Promote Viral Infection by Activating Primary CD4+ T Cells

Penicillium marneffei (P. marneffei) is considered an indicator pathogen of AIDS, and the endemicity and clinical features of P. marneffei have been described. While, how the co-infection of P. marneffei exacerbate deterioration of the immune response remains poorly understood. Here we isolated P. marneffei from the cutaneous lesions of AIDS patients and analyzed its effects on HIV-1-dendritic cells (DCs) interaction. We demonstrated that the monocyte-derived dendritic cells (MDDCs) could be activated by both thermally dimorphic forms of P. marneffei for significantly promoting HIV-1 trans-infection of CD4+ T cells, while these activated MDDCs were refractory to HIV-1 infection. Mechanistically, P. marneffei-activated MDDCs endocytosed large amounts of HIV-1 and sequestrated the internalized viruses into tetrapasnin CD81+ compartments potentially for proteolysis escaping. The activated MDDCs increased expression of intercellular adhesion molecule 1 and facilitated the formation of DC-T-cell conjunctions, where much more viruses were recruited. Moreover, we found that P. marneffei-stimulated MDDCs efficiently activated resting CD4+ T cells and induced more susceptible targets for viral infection. Our findings demonstrate that DC function and its interaction with HIV-1 have been modulated by opportunistic pathogens such as P. marneffei for viral dissemination and infection amplification, highlighting the importance of understanding DC-HIV-1 interaction for viral immunopathogenesis elucidation

Extraction and Analysis of Impervious Surfaces Based on a Spectral Un-Mixing Method Using Pearl River Delta of China Landsat TM/ETM+ Imagery from 1998 to 2008

Impervious surface area (ISA) is considered as an indicator of environment change and is regarded as an important input parameter for hydrological cycle simulation, water management and area pollution assessment. The Pearl River Delta (PRD), the 3rd most important economic district of China, is chosen in this paper to extract the ISA information based on Landsat images of 1998, 2003 and 2008 by using a linear spectral un-mixing method and to monitor impervious surface change by analyzing the multi-temporal Landsat-derived fractional impervious surface. Results of this study were as follows: (1) the area of ISA in the PRD increased 79.09% from 1998 to 2003 and 26.88% from 2003 to 2008 separately; (2) the spatial distribution of ISA was described according to the 1998/2003 percentage respectively. Most of middle and high percentage ISA was located in northwestern and southeastern of the whole delta, and middle percentage ISA was mainly located in the city interior, high percentage ISA was mainly located in the suburban around the city accordingly; (3) the expanding direction and trend of high percentage ISA was discussed in order to understand the change of urban in this delta; High percentage ISA moved from inner city to edge of urban area during 1998–2003 and moved to the suburban area that far from the urban area mixed with jumpily and gradually during 2003–2008. According to the discussion of high percentage ISA spatial expanded direction, it could be found out that high percentage ISA moved outward from the centre line of Pearl River of the whole delta while a high ISA percentage in both shores of the Pearl River Estuary moved toward the Pearl River; (4) combining the change of ISA with social conditions, the driving relationship was analyzed in detail. It was evident that ISA percentage change had a deep relationship with the economic development of this region in the past ten years. Contemporaneous major sport events (16th Asia Games of Guangzhou, 26th Summer Universidad of Shenzhen) and the government policies also promoted the development of the ISA. Meanwhile, topographical features like the National Nature Reserve of China restricted and affected the expansion of the ISA. Above all, this paper attempted to extract ISA in a major region of the PRD; the temporal and spatial analyses to PRD ISA demonstrated the drastic changes in developed areas of China. These results were important and valuable for land use management, ecological protection and policy establishment

The Wnt Signaling Pathway Effector TCF7L2 Mediates Olanzapine-Induced Weight Gain and Insulin Resistance

Olanzapine is a widely used atypical antipsychotic medication for treatment of schizophrenia and is often associated with serious metabolic abnormalities including weight gain and impaired glucose tolerance. These metabolic side effects are severe clinical problems but the underpinning mechanism remains poorly understood. Recently, growing evidence suggests that Wnt signaling pathway has a critical role in the pathogenesis of schizophrenia and molecular cascades of antipsychotics action, of which Wnt signaling pathway key effector TCF7L2 is strongly associated with glucose homeostasis. In this study, we aim to explore the characteristics of metabolic disturbance induced by olanzapine and to elucidate the role of TCF7L2 in this process. C57BL/6 mice were subject to olanzapine (4 mg/kg/day), or olanzapine plus metformin (150 mg/kg/day), or saline, respectively, for 8 weeks. Metabolic indices and TCF7L2 expression levels in liver, skeletal muscle, adipose, and pancreatic tissues were closely monitored. Olanzapine challenge induced remarkably increased body weight, fasting insulin, homeostasis model assessment-insulin resistance index, and TCF7L2 protein expression in liver, skeletal muscle, and adipose tissues. Notably, these effects could be effectively ameliorated by metformin. In addition, we found that olanzapine-induced body weight gain and insulin resistance actively influence the expression of TCF7L2 in liver and skeletal muscle, and elevated level of insulin determines the increased expression of TCF7L2 in adipose tissue. Our results demonstrate that TCF7L2 participates in olanzapine-induced metabolic disturbance, which presents a novel mechanism for olanzapine-induced metabolic disturbance and a potential therapeutic target to prevent the associated metabolic side effects

Risk of falls in 4 years of follow-up among Chinese adults with diabetes: findings from the China Health and Retirement Longitudinal Study

Objectives This study was to determine the incidence of falls and identify baseline factors increased risk for incident falls over time among people with diabetes.Design This study was a secondary analysis using the baseline and 4 years of follow-up data from the China Health and Retirement Longitudinal Study (CHARLS).Setting A nationally representative survey of 17 500 Chinese residents aged 45 years and older were recruited in the baseline national survey in 2011. These participants were followed up every 2 years.Participants A total of 1238 middle-aged and older adults with diabetes and no history of falls at baseline were included in the current study.Primary and secondary outcome measures Information on incidence of falls and medical treatment resulting from falls were determined by self-report.Results The findings showed that the incidence of falls was 29.4% during 4 years of follow-up. Participants with incident falls were younger, were more likely to be women, had lower education level and were less likely to be current drinkers. In addition, former drinkers were 2.22 times more likely to fall. Socially active individuals were 47% less likely to fall compared with those without social activities. Every 5 kg increase in grip strength was associated with a 13% lower risk of falls. A 10 mg/dL higher total cholesterol and 1 mg/dL higher blood urea nitrogen were associated with a 4% and 6% higher risk of falls. Finally, participants with depressive symptoms were 1.47 times more likely to fall compared with those without depressive symptoms.Conclusions These findings underscore the importance of developing a fall prevention programme for those with diabetes, and this programme should address potentially modifiable risk factors, including levels of total cholesterol, blood urea nitrogen, social activity, depressive symptoms and grip strength

Tranylcypromine Causes Neurotoxicity and Represses BHC110/LSD1 in Human-Induced Pluripotent Stem Cell-Derived Cerebral Organoids Model

Recent breakthroughs in human pluripotent stem cell-derived cerebral organoids provide a valuable platform for investigating the human brain after different drugs treatments and for understanding the complex genetic background to human pathology. Here, we identified tranylcypromine, which is used to treat refractory depression, caused human-induced pluripotent stem cell-derived brain organoids neurotoxicity, leading to decreased proliferation activity and apoptosis induction. Moreover, tranylcypromine treatment affects neurons and astrocytes, which impairs cell density and arrangement. Finally, staining of histone demethylation-related genes revealed that tranylcypromine suppresses the transcriptional activity of BHC110/LSD1-targeted genes and increases the expression of histone di-methylated K4. These results show that human brain organoids can be applied as an in vitro model for CNS drug screening to evaluate structural, cellular, and molecular changes in the normal brains or brains of patients with neuropsychiatric disorders after drug treatments

Minocycline and antipsychotics inhibit inflammatory responses in BV-2 microglia activated by LPS via regulating the MAPKs/ JAK-STAT signaling pathway

Abstract Background Abnormal activation of microglia is involved in the pathogenesis of schizophrenia. Minocycline and antipsychotics have been reported to be effective in inhibiting the activation of microglia and thus alleviating the negative symptoms of patients with schizophrenia. However, the specific molecular mechanism by which minocycline and antipsychotics inhibit microglial activation is not clear. In this study, we aimed to explore the molecular mechanism of treatment effect of minocycline and antipsychotics on schizophrenia. Methods Microglia cells were activated by lipopolysaccharide (LPS) and further treated with minocycline, haloperidol, and risperidone. Then cell morphology, specific marker, cytokines, and nitric oxide production process, and the proteins in related molecular signaling pathways in LPS-activated microglia were compared among groups. Results The study found that minocycline, risperidone, and haloperidol significantly inhibited morphological changes and reduced the expression of OX-42 protein induced by LPS. Minocycline significantly decreased the production of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1beta (IL-1β). Risperidone also showed significant decrease in the production of IL-6 and TNF-α, while haloperidol only showed significant decrease in the production of IL-6. Minocycline, risperidone, and haloperidol were found to significantly inhibit nitric oxide (NO) expression, but had no effect on inducible nitric oxide synthase (iNOS) expression. Both minocycline and risperidone were effective in decreasing the activity of c‑Jun N‑terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) in the mitogen-activated protein kinases (MAPKs) signal pathway. Additionally, minocycline and risperidone were found to increase the activity of phosphorylated-p38. In contrast, haloperidol only suppressed the activity of ERK. Minocycline also suppressed the activation of janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3), while risperidone and haloperidol only suppressed the activation of STAT3. Conclusions The results demonstrated that minocycline and risperidone exert stronger anti-inflammatory and neuroprotective effects stronger than haloperidol, through MAPKs and Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathways in BV2 cells stimulated with LPS, revealing the underlying mechanisms of minocycline and atypical antipsychotics in the treatment of negative schizophrenia symptoms

Risk factors for osteoporosis in chronic schizophrenia on long-term treatment with antipsychotics: a cross-sectional study

Abstract Background Little is known about the laboratory variable risks with bone mineral density (BMD) in patients with schizophrenia. This study was designed to fully investigate the related risk factors for decreased BMD in schizophrenia, as well as evaluate the gender difference of BMD. Method The BMD of the forearm of 211 patients (males/females = 140/71) who met the diagnostic criteria for DSM-5 schizophrenia was measured by dual-energy X-ray absorptiometry. Basic demographic information, clinical assessments, and laboratory variables (regarding nutrition, hormones, metabolism, and inflammatory markers) were comprehensively collected. Results Among 211 subjects, seventy-four (35%) patients had low BMD. Males had a significantly lower BMD T-score than females (P = 0.002). Multiple regression analyses showed that the independent risks with low BMD were lower folate, glycosylated hemoglobin levels, higher age, serum ferritin, and follicle-stimulating hormone (FSH) levels. In female patients, the BMD was mainly associated with age and serum hormones (FSH and testosterone), while the BMD of male patients was primarily related to age, microelements (serum ferritin and 25-OH-VD), and parathyroid hormone. Conclusion Our study found several meaningful correlations between osteoporosis and schizophrenia, especially regarding laboratory measures, which may provide new clues to identifying or preventing osteoporosis in clinical patients