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The aim of the present study was to evaluate the relationship of Epstein–Barr virus (EBV) infection and multiple myeloma (MM) and its impact on clinical characteristics and prognosis. Fresh peripheral blood mononuclear cells (PBMCs) from 139 MM patients who had been diagnosed and treated from January 2010 to May 2018 and 50 PBMC samples from healthy donors were obtained. PCR was carried out for detection of EBV-DNA. The results indicated a significantly higher EBV-DNA concentration among 139 MM patients compared with healthy controls (P

Drug addiction is a widespread social problem, which not only brings adverse consequences to the human body, but also causes great burden to the society. However, it's still unclear how the long-term and sustained cocaine exposure will affect clock genes’ expression in the reward related brain areas. We hypothesize that chronic cocaine exposure causes changes in the circadian rhythmic expression of clock genes in brain regions associated with reward, since previous studies have shown that cocaine use causes circadian disorders. Sprague-Dawley male rats were administrated with cocaine 20 mg/kg at ZT4 through intraperitoneal injection for 21 consecutive days. Twenty-four hours after the last cocaine administration brain samples were collected at 4-h intervals for 24 h (every 4h: ZT 0; ZT 4; ZT 8; ZT 12; ZT 16; ZT 20) to examine expression of rPer1, rPer2, rPer3, rCry, rBmal1 and rClock by quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR). We found that chronic cocaine exposure to rats resulted in significantly disturbances in expression of clock genes in reward related brain areas compared to saline - treated rats. In cocaine-treated rats, rPer1 expression in the suprachiasmatic nucleus (SCN), prefrontal cortex (PFC) and ventral tegmental area (VTA); rPer2 expression in the nucleus accumbens (NAc) shell and hippocampus; rPer3 expression in the NAc core; rCry expression in the SCN and PFC; rBmal1 expression in the SCN and NAc core showed robust circadian rhythms that were essentially identical to those in control rats. However, robust circadian rhythm in rPer1 expression in the SCN and rCry expression in the PFC was nearly completely phase - reversed in cocaine-treated rats. A blunting of circadian oscillations of rPer1 expression occurred in the NAc core and shell and hippocampus; of rPer2 expression occurred in the SCN, PFC, NAc core and hippocampus; of rPer3 expression occurred in the SCN, PFC, NAc shell, hippocampus and VTA; of rCry expression occurred in the NAc core and shell, hippocampus and VTA; of rBmal1 expression occurred in the PFC, NAc shell, hippocampus and VTA in cocaine - treated rats. These rhythm changes accompanied by significant increase in rPer1, rPer2, rPer3 and rBmal1 in the PFC, rPer1, rPer2 and rBmal1 in the hippocampus; significant decrease in rPer2, rPer3 and rCry in the SCN, rPer3, rCry, rBmal1 and rClock in the NAc core compared to control rats. rClock expression in cocaine - treated rats showed no rhythmic change, identical to control rats.These results suggest that chronic cocaine exposure results in disturbances in clock genes’ expression in reward related areas.

Anti-CD19 chimeric antigen receptor-modified T (CAR-T-19) cells have emerged as a powerful targeted immunotherapy for B-cell lineage acute lymphoblastic leukemia with a remarkable clinical response in recent trials. Nonetheless, few data are available on the subsequent clinical monitoring and treatment of the patients, especially those with disease recurrence after CAR-T-19 cell infusion. Here, we analyzed three patients who survived after our phase I clinical trial and who were studied by means of biomarkers reflecting persistence of CAR-T-19 cells in vivo and predictive factors directing further treatment. One patient achieved 9-week sustained complete remission and subsequently received an allogeneic hematopoietic stem cell transplant. Another patient who showed relapse after 20 weeks without detectable leukemia in the cerebrospinal fluid after CAR-T-19 cell treatment was able to achieve a morphological remission under the influence of stand-alone low-dose chemotherapeutic agents. The third patient gradually developed extensive extramedullary involvement in tissues with scarce immune- cell infiltration during a long period of hematopoietic remission after CAR-T-19 cell therapy. Long-term and discontinuous increases in serum cytokines (mainly interleukin 6 and C-reactive protein) were identified in two patients (Nos. 1 and 6) even though only a low copy number of CAR molecules could be detected in their peripheral blood. This finding was suggestive of persistent functional activity of CAR-T-19 cells. Combined analyses of laboratory biomarkers with their clinical manifestations before and after salvage treatment showed that the persistent immunosurveillance mediated by CAR-T-19 cells would inevitably potentiate the leukemia-killing effectiveness of subsequent chemotherapy in patients who showed relapse after CAR-T-19-induced remission.

The seasonality of depressive symptoms is prevalent in children and adolescents. However, the mechanisms that underlie such susceptibility to seasonal influences on mood disorders are unclear. We examined the effects of a short photoperiod condition on the susceptibility to subchronic unpredictable mild stress (SCUS) and rhythmic alterations of plasma corticosterone (CORT), melatonin, and neuropeptide Y (NPY) in adolescent male rats. Compared with the 12 h/12 h light/dark photoperiod control (CON) rats, the 8 h/16 h photoperiod SCUS rats exhibited significant anhedonia, a core symptom of human depression, together with a blunted diurnal rhythm and elevation of 24 h CORT, melatonin, and NPY levels. The 8 h/16 h photoperiod condition also blunted the rhythmicity of CORT, caused a phase inversion of melatonin, and caused a phase delay of NPY compared with 12 h/12 h CON rats. Such abnormalities of plasma CORT, NPY, and melatonin might cause adolescent individuals to present higher stress reactivity and greater vulnerability to stress over their lifetimes. The present study provides evidence of the susceptibility to the seasonality of stress-related disorders in adolescence.

Background Irregular circadian rhythm and some of its most characteristic symptoms are frequently observed in patients with schizophrenia. However, changes in the expression of clock genes or neuropeptides that are related to the regulation of circadian rhythm may influence the susceptibility to recurrence after antipsychotic treatment in schizophrenia, but this possibility has not been investigated. Methods Blood samples were collected from 15 healthy male controls and 13 male schizophrenia patients at 4 h intervals for 24 h before and after treatment with clozapine for 8 weeks. The outcome measures included the relative expression of clock gene mRNA PERIOD1 (PER1), PERIOD2 (PER2), PERIOD3 (PER3) and the levels of plasma cortisol, orexin, and insulin. Results Compared with healthy controls, schizophrenia patients presented disruptions in diurnal rhythms of the expression of PER1, PER3, and NPAS2 and the release of orexin, accompanied by a delayed phase in the expression of PER2, decreases in PER3 and NPAS2 expression, and an increase in cortisol levels at baseline. Several of these disruptions (i.e., in PER1 and PER3 expression) persisted after 8 weeks of clozapine treatment, similar to the decreases in the 24-h expression of PER3 and NPAS2. Clozapine treatment for 8 weeks significantly decreased the 24-h levels of PER2 and increased the 24-h levels of insulin. Conclusion These persistent neurobiological changes that occur after 8 weeks of clozapine treatment may contribute to the vulnerability to recurrence and efficacy of long-term maintenance treatment in schizophrenia.

The relationship between circadian rhythms and mood disorders has been established, circadian dysregulations are believed to exacerbate the severity of mood disorders and vice versa. Although many studies on diurnal changes of clock genes in animal model of depression have been performed from the RNA level, only a few studies have been carried out from the protein level. In this study, we investigated the diurnal changes induced by chronic unpredictable stress (CUS) using various methods, including free-running wheel test, enzyme-linked immunosorbent assay (ELISA) and Western Blotting (WB). Besides, we examined the depression-like behaviors of rats by sucrose preference test (SPT) and forced swim test (FST). We found that CUS induced significant reductions in the quantity of free-running wheel activity and the amplitude of melatonin secretion rhythm. We also found that CUS induced rhythmic disruptions of clock proteins in hippocampus. Furthermore, we found that the amplitude of PER1 in CA1 was positively related to the severity of depression-like behaviors. These results suggest that stress results in both changes in circadian rhythms and in depression-like behaviors and that it is suggested that these changes are related.

Accumulating evidence suggests that the circadian rhythm plays a critical role in mood regulation, and circadian disturbances are often found in patients with major depressive disorder (MDD). The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway is involved in mediating entrainment of the circadian system. Furthermore, the MAPK/ERK signaling pathway has been shown to be involved in the pathogenesis of MDD and the rapid onset of action of antidepressant therapies, both pharmaceutical and non-pharmaceutical. This review provides an overview of the involvement of the MAPK/ERK pathway in modulating the circadian system in the rapid action of antidepressant therapies. This pathway holds much promise for the development of novel, rapid-onset-of-action therapeutics for MDD.

Background Psychosis is a key harm associated with methamphetamine (MA) use. This study examined the relationship between the duration of MA use and risk of psychotic symptoms. Methods A cohort of 528 individuals with chronic MA use was followed for two years after leaving treatment center in Guangdong, China. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale at baseline and four follow-up visits (6, 12, 18 and 24 months after baseline). MA use during the past six months was investigated at each assessment. Generalized Estimating Equations for longitudinal panel data were developed to examine the risk of MA-associated psychotic symptoms among individuals with different durations of MA use. 340 MA users who completed at least one follow-up were included in the analysis. Results During 6-month intervals, participants who reported MA use showed a two-fold increase in the risk of psychotic symptoms compared to those with no MA use (odds ratio [OR] = 2.15, 95% confidence interval [CI] = 1.33–3.49). A dose-response effect was found between the duration of MA use and the risk of psychotic symptoms (continued 12-month MA use vs. no use: OR = 2.84, 95% CI = 1.39–5.77; continued 18-month MA use vs. no use: OR = 9.93, 95% CI = 3.58–27.57). There was no assessment for 24-month intervals due to a small sample size of the continuous use group. Conclusions Longer periods of MA use predicted a higher risk of experiencing psychotic symptoms. Early prevention of MA use could help reduce the risk of psychosis in MA users.

With the increasing use of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) in patients with advanced non-small cell lung cancer (NSCLC), acquired resistance has become a major clinical problem. A combination of different signaling pathway inhibitors is a promising strategy to overcome this. In the present study, the mitogen-activated protein kinase kinase 1/2 inhibitor, AZD6244, was used in combination with gefitinib to investigate the efficacy of this treatment in NSCLC cell lines, particularly in gefitinib-resistant cells. The EGFR-TKI-sensitive PC-9 (mutant EGFR/wild-type K-Ras) and EGFR-TKI-resistant A549 (wild-type EGFR/mutant K-Ras) human NSCLC cell lines were treated with AZD6244 alone, gefitinib alone or the combination of the two drugs, and the effects were evaluated using cell proliferation assays, with alterations in signaling pathways analyzed by western blotting. It was found that the growth inhibitory effect of combination treatment with gefitinib and AZD6244 was greater than that of gefitinib alone in the EGFR-TKI-resistant A549 cells. Treatment of A549 cells with gefitinib alone reduced the expression level of the activated form of Akt, and the combination of the two drugs showed stronger inhibition of phosphorylated-Akt and phosphorylated-extracellular signal-regulated kinases. The data showed that the combination of AZD6244 and gefitinib exhibited dose-dependent synergism in gefitinib-resistant NSCLC cells. Thus, a preclinical rationale exists for the use of AZD6244 to enhance the efficacy of gefitinib in patients with EGFR-TKI-resistant NSCLC.

The aim of this study was to investigate gender differences of periodic limb movements during sleep (PLMS) in patients with obstructive sleep apnea (OSA).This was a case-control study recruiting 364 patients with OSA (182 men, 182 women) matched for age and apnea-hypopnea index (AHI). All participants underwent overnight polysomnography (PSG), followed by the multiple sleep latency test (MSLT) and the Epworth Sleepiness Scale (ESS).Women with OSA had a significantly higher prevalence of PLMS than men (24.2 vs. 15.9 %, p 0.05). Women with OSA showed an increased prevalence of PLMS compared to men in the younger group aged ≤55 years (23.0 vs. 10.6 %, p 0.05), but not in the older groups55 years (25.3 vs. 21.6 %, p 0.05). Binary linear regression analysis in OSA patients confirmed that women were more likely to have PLMS than men (OR 1.71, 95 % CI 1.00-2.92), particularly in patients with age ≤55 years old (OR 2.48, 95 % CI 1.06-5.79), after adjusting for age, BMI, AHI, and habits of smoking and drinking.The results demonstrate that, for patients with OSA, young women had significantly increased prevalence of PLMS compared to young men, but there was no difference in prevalence of PLMS between the men and women in the older age group.

Oxidative stress may play a role in the pathogenesis of keratoconus (KC). Mitochondrial DNA (mtDNA) is closely related to mitochondrion function, and variations may affect the generation of reactive oxygen species (ROS) and be involved in the pathogenesis of KC. To test whether mtDNA background and copy number confer genetic susceptibility to KC in the Han Chinese population, we performed this association study. We analyzed mtDNA sequence variations in 210 KC patients and 309 matched individuals from China, and classified each subject by haplogroup. Mitochondrial DNA copy number was measured in a subset of these subjects (193 patients and 103 controls). Comparison of matrilineal components of the cases and control populations revealed no significant difference. However, measurement of mtDNA copy number showed that KC patients had significantly lower mtDNA copy numbers than controls (P = 0.0002), even when age, gender, and mtDNA background were considered. Our results suggest that mtDNA copy number, but not haplogroup, is associated with keratoconus, and may contribute to its pathogenesis.

Keratoconus (KC) is a complex degenerative disorder of the cornea. Genetic, environmental, and lifestyle factors may all contribute to the pathogenesis of KC. Most of the reported KC-associated SNPs have been detected in Caucasians and Australians. To investigate whether the reported associated SNPs can be found in a Chinese population, we performed a replication study of the significantly associated SNPs.A total of 210 unrelated Chinese KC patients and 191 unrelated controls were included in the present study. SNPs rs4954218 (Near RAB3GAP1 (5')), rs4894535 (FNDC3B), rs2956540 (LOX), rs3735520 (Near HGF (5')), rs1324183 (MPDZ-NF1B), rs1536482 (RXRA-COL5A1), rs7044529 (COL5A1), rs2721051 (Near FOXO1 (3')), rs9938149 (BANP-ZNF469) and rs6050307 (VSX1) were assessed for their association with KC. The genotype of each SNP was detected using the Sequenom MassARRAY-Assay.SNP rs1324183 located in MPDZ-NF1B was associated with an increased risk of KC (OR=3.108, 95% CI=1.366-7.072, p=0.005), and SNP rs2956540 in the LOX gene may confer a reduced risk of KC with a borderline p value in our population (OR=0.664, 95% CI=0.447-0.986, p=0.042). No significant difference was observed between patients and controls in the other eight SNP genotypes and allele frequencies.The replication association of rs1324183 (MPDZ-NF1B) with KC in our population and the results, which are identical to those in different populations, suggest that rs1324183 (MPDZ-NF1B) is a common genetic risk for KC and should be further investigated.

Chronic methamphetamine (MA) use is associated with psychiatric symptoms. This study explored pattern of co-occurring psychiatric symptoms in MA users and their relationship to duration of MA use. A cross-sectional study was conducted among MA users at the Shenzhen Compulsory Drug Detoxification Center from April 2012 to October 2015. The Positive and Negative Syndrome Scale, Hamilton Anxiety Scale, and Beck Depression Inventory were used to assess psychiatric symptoms. Among 1277 MA users, 57.6% participants had any type of psychiatric symptoms including depressive, anxiety and psychotic symptoms. A dose-response relationship was found between duration of MA use and risk of psychiatric symptoms. The odds ratios (OR) of depressive symptoms increased with the duration of MA use (1-5 years vs. 1 year: 1.74 [95% CI, 1.24-2.42]; ≥ 5 years vs. 1 year: 2.07 [1.19-3.61]), so did the ORs of co-occurring anxiety and depressive symptoms (1-5 years: 1.74 [1.20-2.51]; ≥ 5 years: 3.09 [1.76-5.40]). Methamphetamine-dependent individuals were four-times more likely to experience any type of psychiatric symptoms than non-dependent users. The prevalence of psychiatric symptoms was high in chronic MA users and increased with MA use duration. Early prevention and treatment strategies targeting both MA use and associated psychiatric symptoms are needed.

A survey of early stage follicular lymphoma(FL) revealed that the rigorously staged FL patients at first diagnosis had a better outcome as compared with non-rigorous staged FL patients, but there were no similar reports in China.To explore the relationship between the rigorous staging at first diagnosis and the prognosis of FL patients at different stages.The clinical data of 111 patients with newly diagnosed FL from 2008 to 2014 year were collected and analyzed. The rigorous staging included: (1) bone marrow aspiration and biopsy, (2) imaging examination of whole body including CT and ultrasounic scan, or PET/CT, either or both is defined as rigorous staging, or else as non-rigorous staging.The FL patients at I-II stages by rigorous staging showed a superior progression-free survival(PFS) compared with non-rigorous staging patients(P=0.048). For all the patients, the age, serum LDH, bone marrow lesion and more than 3 foci of diameter larger than 3 cm correlated with prognosis in univariate analysis, and multivariate analysis revealed that the age, serum LDH and bone marrow imolvement were the independent prognostic factors.Rigorous staging leads to better outcomes, suggesting that accurate and appropriate testing is important for the patients at the first treatment. The close correlation of bone marrow with prognosis indicates that the evaluation of bone marrow is very important for the daily clinical practice.

Postnatal dexamethasone (DEX) therapy has been used to treat or prevent chronic lung disease after premature births. However, there are many reports of long-term negative neurodevelopmental sequelae following this treatment. In contrast, hydrocortisone (HYD), which has fewer neurodevelopment adverse effects, is used as an alternative for DEX. In this study, we report that neonatal DEX exposure (days 1–3) caused alterations of amino acids affecting N-methyl-d-aspartate (NMDA) receptor neurotransmission in mouse brains. Neonatal DEX, but not HYD, exposure (days 1–3) significantly decreased the GluN2B subunit of NMDA receptor in the hippocampus at juvenile and adult stages. Mice treated with DEX showed cognitive deficits, as well as anxiety and depressive-like behavior at juvenile and adult stages. In contrast, mice treated with HYD (days 1–3) showed no behavioral abnormalities at these stages. In the DEX suppression test, plasma levels of corticosterone in mice exposed neonatally to DEX and HYD were significantly higher at juvenile, but not adult stages. Pretreatment with Ro 63-1908, an antagonist at GluN2B subunit, 30 min before each injection of DEX, prevented cognitive deficits, as well as anxiety and depressive-like behavior in juvenile and adult mice. Interestingly, subsequent repeated (days 29–33) administration of Ro 63-1908 or L701324, an antagonist of the glycine modulatory site on the NMDA receptor, significantly suppressed behavioral abnormalities in juvenile and adult mice after neonatal DEX exposure. These results indicate that neonatal DEX, but not HYD, exposure produced behavioral abnormalities in juvenile and adult mice by altering glutamatergic neurotransmission via the NMDA receptor. The NMDA receptor antagonists may prevent or treat these DEX-induced neonatal behavioral abnormalities in later life.

Background Chemo-resistance is one of the important causes of poor prognosis of gastric cancer patients, but the exact mechanism is still not very clear. The regulation of lncRNA and miRNA and its downstream target genes has become in focus of the field. Methods In this study, we performed lncRNA and miRNA microarray analysis of chemo-resistant cells (SGC7901/Oxaliplatin). Then, bioinformatics analysis, TaqMan real-time PCR, western blot, luciferase reporter gene assay, RNA co-immunoprecipitation, cell proliferation and apoptosis analysis were used to explicit the lncRNA-miRNA-mRNA pathway in gastric cancer chemo-resistance. Last, nude mice were used to verify the promotion of chemo-resistance in vivo. Results In this study, we identified a lncRNA-GC1, which was upregulated in chemo-resistant gastric cancer tissues and cells, and a miRNA-551b-3p, which was downregulated in chemo-resistant gastric cancer tissues and cells. Firstly, miR-551b-3p can directly bind to the non-coding region of dysbindin mRNA, thereby negatively regulating the expression of dysbindin which was involved in chemotherapy resistance in gastric cancer cells. Secondly, lncRNA-GC1 promotes chemoresistance in gastric cancer by competitively binding to miR-551b-3p to facilitate dysbindin expression in vitro and in vivo. Thirdly, the expression levels of lncRNA-GC1 were positively correlated with tumor size (P = 0.002), lymph node invasion (P = 0.001) and poor platinum response (P Conclusions LncRNA-GC1-miRNA-551b-3p-dysbindin signaling pathway may serve as a predictor for oxaliplatin response and a potential therapeutic target for gastric cancer. Legal entity responsible for the study Guo Xin. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background Adenocarcinoma of esophagogastric junction (AEG) is a special type of malignant tumor which occurs in the upper gastrointestinal tract. However, AEG is different from esophageal or gastric cancer. Its biological behavior is complicated and prognosis is poor. Even after radical resection, the overall 5-year survival rate is still very low. An in-depth analysis of the prognostic factors in patients with AEG may indicate a certain direction for clinical treatment and decision-making as well as for improving the prognosis of patients with AEG. Although some researchers have explored the factors influencing the prognosis of AEG, the independent prognostic factors are still unclear, which need to be further studied. Methods The clinical data of patients with AEG who underwent surgical treatment in PLA general hospital from January 2009 to January 2013 were collected retrospectively. According to the inclusion and exclusion criteria, a total of 343 patients with AEG were included in the study. Sex, age, basic disease, Siewert classification, tumor size (Diameter), differentiation, vascular cancer thrombus, nerve invasion, T-stage,N stage, pTNM, approach, minimally invasive surgery, resection scope, adjuvant chemotherapy, HER-2 and Ki-67 expression were analyzed comprehensively to study the independent or nonindependent prognostic factors in patients with AEG. Results The median follow-up time of the 343 patients with AEG was 50.2 months. The 5-year overall survival rate of the whole group (no IV stage) was 49.2%. Univariate analysis showed that age, basic disease, Siewert classification, tumor size (Diameter), differentiation, vascular cancer thrombus, nerve invasion, T-stage,N stage, pTNM, adjuvant chemotherapy, level of Ki-67 expression was correlated with prognosis (P Conclusions The age, tumor size (Diameter), differentiation degree, pTNM and adjuvant chemotherapy were independent prognostic factors affecting the overall survival rate of patients with AEG (P Legal entity responsible for the study Wangxinxin. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Numerous epidemiological studies have been conducted to investigate the association between Xeroderma pigmentosum complementation group D (XPD) Asp312Asn (rs1799793 G > A) and Lys751Gln (rs13181 A > C) polymorphisms and bladder cancer risk; however, the conclusions remain controversial. With this in mind, we performed this meta-analysis with 11 studies including 3,797 cases and 5,094 controls for Asp312Asn and 21 studies including 6,360 cases and 7,894 controls for Lys751Gln polymorphism. We searched available literatures from PubMed, Embase, and CBM databases. Crude odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated to assess the strength of the associations. Moreover, to validate biological plausibility of our findings, the effects of these two polymorphisms on XPD gene expression within three ethnicities was determine by gene expression analysis based on imputed genotypes from HapMap. Overall, the variant allele of Asp312Asn polymorphism was associated with an increased risk of bladder cancer (Asn/Asn vs. Asp/Asp: OR = 1.51, 95 % CI = 1.19–1.91; Asp/Asn vs. Asp/Asp: OR = 1.23, 95 % CI = 1.12–1.35; recessive model: OR = 1.33, 95 % CI = 1.10–1.61; dominant model: OR = 1.32, 95 % CI = 1.14–1.52; and allele comparing: OR = 1.26, 95 % CI = 1.11–1.42). We found the Lys751Gln was associated with increased bladder cancer risk only under the recessive model (OR = 1.14, 95 % CI = 1.01–1.29). Stratification analyses demonstrated an increased risk for Asians and hospital-based studies under all genetic models while only under the dominant model for Caucasians as to the Asp312Asn polymorphism and for Caucasians under the recessive model as to the Lys751Gln polymorphism. We also found the Asp312Asn polymorphism can significantly influence mRNA expression levels among Asians and Caucasians, and the Lys751Gln polymorphism has a similar effect for Caucasians. Despite some limitations, this meta-analysis suggests that polymorphisms in XPD gene may contribute to bladder cancer susceptibility. These findings need further validation by large well-designed prospective studies.

The present study was to investigate depression and alterations in the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axis function in methamphetamine (METH) abusers after abstinence. Depression was assessed using the 13-item Beck Depression Inventory (BDI-13) scale; blood samples from in-patients who were METH abusers and age-matched and sex-matched healthy controls were collected. The demographic characteristics and history of METH abuse also was assessed. We found that serum levels of adrenocorticotropic hormone (ACTH) and thyroxine were increased; and serum levels of cortisol, triiodothyronine, and thyroid-stimulating hormone were decreased; and the BDI score was higher in METH abusers compared with control. In addition, there was no correlation between the BDI-13 score and any of hormones of HPA and HPT axis was found. Particularly, we found abnormally higher ACTH level and mismatched with lower cortisol level in abstinent METH abusers. These results indicate that METH abusers and that their HPA and HPT functions are all altered after abstinence. Chronically using METH may destroy the regulatory function of the HPA axis, especially the feedback regulation of cortisol to ACTH.

Cocaine sensitization and reward are reported to be under the influence of diurnal rhythm. However, no previous studies have reported brain areas that play a role as modulators and underlie the mechanism of diurnal variations in cocaine reward. We examined (1) the diurnal rhythm of glycogen synthase kinase-3β (GSK-3β) activity in the suprachiasmatic nucleus (SCN) and reward-related brain areas in naive rats; (2) the effect of day and night on the acquisition of cocaine-induced conditioned place preference (CPP); (3) the influence of cocaine-induced CPP on GSK-3β activity in the SCN and reward-related brain areas; and (4) the effect of the GSK-3β inhibitor SB216763 microinjected bilaterally into the ventral tegmental area (VTA) on cocaine-induced CPP. A significant diurnal rhythm of GSK-3β activity was found in the SCN and reward-related brain areas, with diurnal variations in cocaine-induced CPP. GSK-3β activity in the SCN and reward-related brain areas exhibited marked diurnal variations in rats treated with saline. GSK-3β activity in rats treated with cocaine exhibited distinct diurnal variations only in the prefrontal cortex and VTA. Cocaine decreased the expression of phosphorylated GSK-3β (i.e. increased GSK-3β activity) only in the VTA in rats trained and tested at ZT4 and ZT16. SB216763 microinjected into the VTA bilaterally eliminated the diurnal variations in cocaine-induced CPP, but did not affect the acquisition of cocaine-induced CPP. These findings suggest that the VTA may be a critical area involved in the diurnal variations in cocaine-induced CPP, and GSK-3β may be a regulator of diurnal variations in cocaine-induced CPP.

Objective: To examine the efficacy and adverse events of recombinant human thrombopoietin (rhTPO) in the treatment of infection-associated thrombocytopenia in senile patients. Methods: The current study is a retrospective analysis of the patients receiving rhTPO for infection-associated thrombocytopenia in our hospital. Results: Forty-nine cases were included in the analysis as rhTPO group. The absolute platelet count after treatment, increase in platelet count, and the overall response rate were considerably higher in the rhTPO group than that in the control group. Improvement in bleeding score was higher in the rhTPO treatment group than that in the control group (2.1 ± 5.4 vs 0.4 ± 1.7). Bleeding event was stopped in 68.2% of the patients after rhTPO treatment and in 35% of the patients in the control group ( P = .032). A stratified analysis indicated that the therapeutic efficacy is much better in patients without organ failure. Conclusion: Recombinant human TPO is effective in alleviating infection-associated thrombocytopenia and hemorrhage in senile patients, particularly if given prior to the emergence of organ failure.

The incidence of acute myelogenous leukemia (AML) in patients over 80 years old is >20 times greater than that observed in younger patients. Previously, no standard treatment protocol for elderly patients with AML existed, however the development of hypomethylating agents, including decitabine, has brought about promising results in AML. In the present study, we report on the usage of a lower than routine dosage of decitabine in patients over 80 years old with AML. Since January 2010, 5 patients diagnosed with AML over the age of 80 years old received treatment with decitabine in our hospital. Decitabine was administered at a dose of 10–15 mg/m2 and repeated every other day for a total of 5 days. This cycle was repeated for ∼6 weeks. The 5 patients received a total of 19 cycles of treatment with decitabine. No patient achieved complete or partial remission. An antileukemic effect was observed in 25% of courses (3/12). An increase in platelet count of >20×109/l was observed in 26.3% (5/19) of cycles compared with previous treatment. An increase in hemoglobin concentration of >20 g/l was observed in 36.8% (7/19) of cycles in comparison to previous treatment, four of which achieved normal hemoglobin levels. One patient became red blood cell transfusion-independent. The median survival time was 19.8±4.8 months. Survival time from decitabine administration to mortality was 13.2±5.1 months. The main side-effect was bone marrow suppression with grade III–IV thrombocytopenia, grade III–IV leukocytopenia, grade III–IV neutropenia and anemia accounting for 94.7% (18/19), 47.4% (9/19), 89.5% (17/19) and 21.1% (4/19), respectively. Severe infection or bleeding was not observed and no patient stopped treatment due to adverse effects. In conclusion, extremely low-dose decitabine may be used safely in elderly patients and achieved longer survival times than reported previously in AML patients aged 80 and above. It is suggested that complete remission may not be the primary objective, while improvement of quality of life may be a better choice in AML patients over 80 years old. The cases observed in our study were limited, so more cases are required for further study.

Repetitive transcranial magnetic stimulation (rTMS) has been introduced as a new and effective treatment option for major depression. This paper examined the effectiveness of rTMS on first episode depressed patients when combined with antidepressant drugs. A random sample of forty-three first-episode depressed patients received active or sham rTMS to the left dorsolateral prefrontal cortex, and concomitantly took paroxetine for 4 weeks, and paroxetine monotherapy for 4 weeks afterwards. Response was defined as a ≥50% decrease on the total Hamilton Depression Rating Scale (HDRS) from the baseline, and remission was defined as an HDRS total residual score

Several preclinical studies have reported the rapid antidepressant effects of N-methyl-D-aspartate receptor (NMDAR) antagonists, although the underlying mechanisms are still unclear. Death-associated protein kinase 1 (DAPK1) couples GluN2B subunits at extrasynaptic sites to regulate NMDAR channel conductance. In the present study, we found that chronic unpredictable stress (CUS) induced extracellular glutamate accumulation, accompanied by an increase in the DAPK1-NMDAR interaction, the high expression of DAPK1 and phosphorylated GluN2B at Ser1303, a decrease in phosphorylated DAPK1 at Ser308 and synaptic protein deficits in the rat medial prefrontal cortex (mPFC). CUS also enhanced GluN2B-mediated NMDA currents and extrasynaptic responses that were induced by bursts of high-frequency stimulation, which may be associated with the loss of astrocytes and low expression of glutamate transporter-1 (GLT-1). The blockade of GLT-1 in the mPFC was sufficient to induce depressive-like behavior and cause similar molecular changes. Selective GluN2B antagonist, DAPK1 knockdown by adeno-associated virus-mediated short-hairpin RNA or a pharmacological inhibitor, and the uncoupling of DAPK1 from the NMDAR GluN2B subunit produced rapid antidepressant-like effects and reversed CUS-induced alterations in the mPFC. The inhibition of DAPK1 and its interaction with GluN2B subunit in the mPFC also rescued CUS-induced depressive-like behavior 7 days after treatment. A selective GluN2B antagonist did not have rewarding effects in the conditioned place preference paradigm. Altogether, our findings suggest that the DAPK1 interaction with the NMDAR GluN2B subunit acts as a critical component in the pathophysiology of depression and is a potential target for new antidepressant treatments.

Many clinical studies have shown that circadian rhythmic abnormalities are strongly associated with major depression. Meanwhile a large number of researches have indicated that physical exercise could effectively reduce the stress impairment and improve one’s mood, cognition and self-concept. We examined the effects of chronic unpredictable mild stress (CUMS) on rodent behaviors and the circadian rhythm of hormone and peptide levels in the plasma. We collected blood samples at 4-h intervals for 24 h to examine circadian rhythmic expression of corticosterone, melatonin and vasoactive intestinal peptide (VIP). We found that CUMS led to depressive-like behaviors and inversed rhythm in corticosterone and blunted circadian rhythms in melatonin and VIP compared to control group. Levels of corticosterone showed no differences from control group. But levels of melatonin were decreased and VIP was increased compared to control group, respectively. Swimming exercise could not alleviate the depressive-like behaviors and the blunted circadian rhythmic expression of blood hormone and peptide, also could not rescue levels of melatonin and VIP. These findings indicate that swimming exercise as a physical exercise, unexpectedly, may not act as a protect factor rather than as an additional stress in the present study. It has no effect on the depressive-like behaviors and alterations of blood hormone and peptide whether in circadian rhythm or in blood levels induced by CUMS.

Background Phospholipase C (PLC) isozymes have been implicated in schizophrenia and may play a role in the disease process. Phospholipase Ce (PLCe) isozyme is an effector of Ras and Rap small GTPases and regulates intracellular signal transduction. Little is known about its role in signaling pathways in the central nervous system that mediate higher brain functions such as learning, memory and social behavior that are disrupted in schizophrenia. Objectives To determine the effects of PLCe on social behavior, spatial memory and prepulse inhibition of acoustic (PPI) startle response in PLCe −/− mice. Methods Using a social interaction test, Morris water maze, and PPI. Results We found that PLCe − /− mice showed increased social interactions and increased novelty-seeking exploratory behavior. Interestingly, PLCe −/− mice also showed improved performance on the Morris water maze task and enhanced PPI. Conclusion These findings suggest that PLCe negatively regulates cognitive and social behaviors.

An ultrasonic device with frequency of 20 kHz was used to investigate the effect of different operational parameters such as ultrasonic power, temperature and initial molecular weight on dextran degradation. Results show that the molecular weight of dextran can be controlled by ultrasonic treatment. Higher the ultrasonic power and lower the temperature could increase the degradation rate (R).The initial molecular weight plays an important role in at the initial stage of dextran degradation (within 20 minutes). A smilar limiting molecular weight (Mw≈8.7×104) was obtained after 2 hours ultrasonic treatment for four different initial molecular weight dextrans, suggesting that the limiting molecular weight is independent on the initial molecular weight of dextran. Ultrasonic treatment can be used as a safe, simple and effective method to control the molecular weight of dextran.

Many clinical studies have shown that circadian rhythm abnormalities are strongly associated with major depression. The master clock of the circadian system in mammals is located in the suprachiasmatic nucleus (SCN) within the anterior hypothalamus, where Per1 and Per2 are essential core components of circadian rhythm oscillation. Chronic unpredictable stress (CUS) is a reliable animal model of depression with good face, predictive, and constructive validity. In the present study, we investigated the effects of CUS on the circadian expression of PER1 and PER2 in the SCN. We found that CUS led to depressive-like behavior and reduced the amplitude of PER2 oscillation in the SCN, which were blocked by 3 weeks of desipramine (DMI) treatment. 2 weeks after termination of CUS, the decreased peak of PER2 expression returned to control levels, whereas depressive-like behavior remained unchanged. Our findings suggest that the dampened amplitude of PER2 expression in the SCN may participate in the development of depressive-like behavior induced by CUS but is unlikely involved in the long-lasting effects of CUS on depressive-like behavior.

Protracted cocaine withdrawal can extend for months and contribute to cocaine seeking and relapse. However, no previous studies have reported the manifestation of protracted withdrawal from chronic cocaine in rats. Glycogen synthase kinase 3β (GSK-3β) can phosphorylate PER2, CRY2, Rev-erbα, and BMAL1 in mammals. The circadian rhythmic expression of GSK-3β in reward-related brain areas is unclear. We examined rodent behaviors and circadian disturbances of GSK-3β expression during 30 days of protracted cocaine withdrawal. The behavioral tests included open field, elevated plus maze, weight gain, and sucrose preference tests performed 3, 10, and 30 days after stopping cocaine. At these three assessment points, we collected brain samples every 4 h for 24 h to examine the circadian rhythmic expression of GSK-3β. Decreased locomotor activity, weight loss, decreased sucrose consumption on day 3, and increased time spent in the open arms of the elevated plus maze on day 10 after cocaine administration were found. Blunted circadian rhythms of phosphorylated GFK-3β (pGSK-3β) persisted for at least 30 days in all examined brain areas, with the exception of 10 days in the suprachiasmatic nucleus (SCN) and nucleus accumbens (NAc). The expression of pGSK-3β decreased in the SCN and increased in the NAc and ventral tegmental area persisted for at least 30 days, whereas in the prefrontal cortex decreased during withdrawal for 10 days but then reversed to abnormally high levels with protracted withdrawal. These long-lasting changes disrupted circadian rhythms and produced abnormal levels of phosphorylated GSK-3β protein in reward-related brain circuits, which may play a role in protracted cocaine withdrawal and contribute to relapse.

Background: We retrospectively evaluated the efficacy and safety of individualized liposomal doxorubicin-based treatment in elderly patients with non-Hodgkin’s lymphoma and poor general health. Patients and Methods: 22 patients (median age 83.5 years) were treated with liposomal doxorubicin combined with CHOP-based chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) or other individualized doxorubicin-based treatments including liposomal doxorubicin combined with rituximab. Efficacy and adverse reactions were measured. Results: Patients received a total of 80 courses of chemotherapy (mean dose 143.6 mg/patient liposomal doxorubicin). The numbers of patients achieving complete remission, uncertain complete remission, partial remission, stable disease, or progressive disease were 10 (45.5%), 4 (18.2%), 4 (18.2%), 1 (4.5%), and 3 (13.6%), respectively. The most frequently reported adverse reaction was bone marrow suppression. No serious infections were reported. 3 (13.6%) patients showed skin changes. None experienced congestive heart failure or acute myocardial infarction. There were no chemotherapyrelated deaths. Overall survival rates at 1, 3, and 5 years were 81.8, 59.1, and 40.9%, and progression-free survival rates were 83.3, 66.7, and 54.5%. Conclusions: Individualized liposomal doxorubicin-based chemotherapy is effective and safe for elderly patients with non-Hodgkin’s lymphoma.

The original English Morningness-Eveningness Questionnaire (MEQ) was translated into Chinese, and the circadian rhythmicity of 188 healthy Chinese subjects was tested using this version of the MEQ. We assessed the reliability and validity of the Chinese version and determined the cut-off points. In the Chinese version, 19 items were divided into two dimensions (i.e., sleep phase and time of greatest efficiency), and the cut-off points were determined to be the following: definitely evening type (142–46), moderately evening type (472–52), neither type (532–64), moderately morning type (652–69), and definitely morning type (702–86). Additionally, the Cronbach a coefficient was determined to be 0.769, which is satisfactory. The Chinese version of the MEQ has good psychometric properties, and its cut-off points can effectively differentiate between morningness and eveningness.

Previous studies have shown that clock genes are expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus, other brain regions, and peripheral tissues. Various peripheral oscillators can run independently of the SCN. However, no published studies have reported changes in the expression of clock genes in the rat central nervous system and peripheral blood mononuclear cells (PBMCs) after withdrawal from chronic morphine treatment. Rats were administered with morphine twice daily at progressively increasing doses for 7 days; spontaneous withdrawal signs were recorded 14 h after the last morphine administration. Then, brain and blood samples were collected at each of eight time points (every 3 h: ZT 9; ZT 12; ZT 15; ZT 18; ZT 21; ZT 0; ZT 3; ZT 6) to examine expression of rPER1 and rPER2 and rCLOCK. Rats presented obvious morphine withdrawal signs, such as teeth chattering, shaking, exploring, ptosis, and weight loss. In morphine-treated rats, rPER1 and rPER2 expression in the SCN, basolateral amygdala, and nucleus accumbens shell showed robust circadian rhythms that were essentially identical to those in control rats. However, robust circadian rhythm in rPER1 expression in the ventral tegmental area was completely phase-reversed in morphine-treated rats. A blunting of circadian oscillations of rPER1 expression occurred in the central amygdala, hippocampus, nucleus accumbens core, and PBMCs and rPER2 expression occurred in the central amygdala, prefrontal cortex, nucleus accumbens core, and PBMCs in morphine-treated rats compared with controls. rCLOCK expression in morphine-treated rats showed no rhythmic change, identical to control rats. These findings indicate that withdrawal from chronic morphine treatment resulted in desynchronization from the SCN rhythm, with blunting of rPER1 and rPER2 expression in reward-related neurocircuits and PBMCs.

Background Previous studies have shown that individuals withdrawn from chronic opiate administration undergo substantial elevations of cortisol levels with blunted corticotropin (ACTH) rhythms and that these changes persist beyond the 7–10 days of acute withdrawal symptoms. However, there are no published studies of changes in expression of clock genes or of other neuropeptides related to circadian-rhythm regulation, which may influence relapse susceptibility. Methods Blood samples were collected from 8 healthy control subjects and 16 heroin addicts during pharmacologically unassisted withdrawal on the 3rd, 10th, and 30th days of abstinence at 3-hour intervals for 24 hours. Outcome measures were the relative expression of clock gene mRNA ( hperiod1, hperiod2, hclock ) and the levels of serum cortisol, plasma ACTH, β-endorphin (β-EP), leptin, neuropeptide Y, interleukin-2 (IL-2), and tumor necrosis factor (TNF) in these subjects. Results Compared with healthy volunteers, abstinent addicts showed disruptions in diurnal rhythms of hPER1 and hPER 2 mRNA expression, along with disruptions in diurnal rhythms of cortisol, ACTH, β-endorphin, leptin, and IL-2 release. Several of these disruptions ( hPER1 , hPER2 , ACTH, β-endorphin, and IL-2) persisted for the 30-day testing period, as did elevation of 24-hour levels of cortisol and decreases in 24-hour IL-2 and TNF levels. Conclusions These prolonged neurobiological changes may play a role in protracted opiate withdrawal symptoms and contribute to relapse vulnerability.