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Invasion of carcinoma cells into surrounding tissue affects breast cancer staging, influences choice of treatment, and impacts on patient outcome. KIF21A is a member of the kinesin superfamily that has been well-studied in congenital extraocular muscle fibrosis. However, its biological relevance in breast cancer is unknown. This study investigated the functional roles of KIF21A in this malignancy and examined its expression pattern in breast cancer tissue. The function of KIF21A in breast carcinoma was studied in vitro by silencing its expression in breast cancer cells and examining the changes in cellular activities. Immunohistochemical staining of breast cancer tissue microarrays was performed to determine the expression patterns of KIF21A. Knocking down the expression of KIF21A using siRNA in MDA-MB-231 and MCF7 human breast cancer cells resulted in significant decreases in tumor cell migration and invasiveness. This was associated with reduced Patched 1 expression and F-actin microfilaments. Additionally, the number of focal adhesion kinase- and paxillin-associated focal adhesions was increased. Immunohistochemical staining of breast cancer tissue microarrays showed that KIF21A was expressed in both the cytoplasmic and nuclear compartments of carcinoma cells. Predominance of cytoplasmic KIF21A was significantly associated with larger tumors and high grade cancer, and prognostic of cause-specific overall patient survival and breast cancer recurrence. The data demonstrates that KIF21A is an important regulator of breast cancer aggressiveness and may be useful in refining prognostication of this malignant disease.

To assess the predictive value of neuropsychological tests for severe dependency in Alzheimer’s disease as defined by the Equivalent Institutional Care Rating Scale, in a multiethnic, community cohort. The sample included 146 elders from the Predictors 3 cohort. Cox proportional hazard models tested the predictive value of each neuropsychological test at baseline on relative risk of meeting severe dependency. Higher semantic processing and memory test scores at baseline were associated with lower risk of meeting severe dependency in the adjusted Cox models. The integrity of semantic processing and memory abilities in dementia appears to predict time to severe functional dependency.

Anastasiia S Boiko,1,* Ivan V Pozhidaev,1,* Diana Z Paderina,1 Anna V Bocharova,2 Irina A Mednova,1 Olga Yu Fedorenko,1 Elena G Kornetova,3,4 Anton JM Loonen,5 Arkadiy V Semke,3 Nikolay A Bokhan,6,7 Svetlana A Ivanova1,7 1Molecular Genetics and Biochemistry Laboratory, Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russian Federation; 2Laboratory of Evolutionary Genetics, Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russian Federation; 3Endogenous Disorders Department, Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russian Federation; 4University Hospital, Siberian State Medical University, Tomsk, Russian Federation; 5Unit of Pharmacotherapy, Epidemiology & Economics, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, the Netherlands; 6Addictive Disorders Department, Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russian Federation; 7Psychiatry, Addiction Psychiatry and Psychotherapy Department, Siberian State Medical University, Tomsk, Russian Federation*These authors contributed equally to this workCorrespondence: Anton JM LoonenUnit of Pharmacotherapy, Epidemiology & Economics, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen, 9713AV, the NetherlandsTel +31 50 363 7576Email a.j.m.loonen@rug.nlPurpose: Metabolic syndrome (MetS) is characterized by abdominal obesity, hyperglycaemia, dyslipidaemia and hypertension. FTO gene has been implicated in the pathogenesis of obesity, but the available scientific data concerning their relationship to antipsychotic drug-induced obesity and metabolic syndrome is still incomplete and inconsistent, which indicates that continuing the investigation of this gene’s role is necessary.Patients and Methods: In the present study, 517 patients with schizophrenia underwent antipsychotic drug treatment, and two groups were identified: patients with MetS and without MetS. Genotyping of 6 SNPs in the FTO gene was performed, and the results analyzed using R-programme.Results: We performed a statistical analysis to identify possible associations of the frequencies of genotypes and alleles of the studied polymorphisms with the presence of metabolic syndrome in schizophrenia patients, with the presence of abdominal obesity, and with an increased body mass index. The rs7185735 polymorphism did not meet the Hardy-Weinberg criterion and was excluded. After correcting for differences in age, gender and duration of illnesses, none of the variants was shown to be related to metabolic syndrome or abdominal obesity, but rs9939609, rs1421085, rs3751812 and rs8050136 were associated with body mass index.Conclusion: The present study provides additional support for these SNP’s roles as a pharmacogenetic biomarker that may become useful in the framework of the personalized medicine approach.Keywords: schizophrenia, gene polymorphism, body weight, waist circumference, fat mass and obesity associated gene

OBJECTIVE: to examine psychological factors during rehabilitation of patients with Achilles or patellar tendinopathy as well as the association between psychological factors and tendinopathy severity, sport participation, and satisfaction with activity level and tendon function.DESIGN: cross-sectional study.SETTING: online survey platform.PARTICIPANTS: 119 patients (mean age: 44 years (SD 14)) diagnosed with Achilles or patellar tendinopathy.MAIN OUTCOME MEASURES: A range of patient-reported psychological and outcome measures were recorded. Multivariate regression analyses were performed to establish the association between each psychological factor and outcome measures, adjusted for relevant confounders.RESULTS: Psychological readiness and confidence to return to sports (I-PRRS) and pain catastrophizing (PCS) were significantly associated with tendinopathy severity (modified VISA), sport participation(OSTRC-O), and satisfaction. Kinesiophobia (TSK) and the importance to patients of returning to pre-injury activity level were significantly associated with sports participation and satisfaction.CONCLUSION: The current study provides evidence of impairments in psychological factors during rehabilitation of patients with Achilles and patellar tendinopathy. Most investigated psychological factors were associated with tendinopathy severity, function, participation, and satisfaction. Physical therapists should recognize patients with lack of psychological readiness to return to sports and also patients with kinesiophobia or catastrophizing thoughts when experiencing pain.

Brain metastasis (BM) frequently occurs in patients with cutaneous melanoma, lung, and breast cancer; although, BM rarely arises from cancers of the gastrointestinal tract (GIT). The reported incidence of GIT cancer BM is less than 4%. In the last few years, effective systemic therapy has prolonged the survival of GIT patients and consequently, the incidence of developing BM is rising. Therefore, the epidemiology and biology of BM arising from GIT cancer requires a more comprehensive understanding. In spite of the development of new therapeutic agents for patients with metastatic GIT cancers, survival for patients with BM still remains poor, with a median survival after diagnosis of less than 4 months. Limited evidence suggests that early detection of isolated intra-cranial lesions will enable surgical resection plus systemic and/or radiation therapy, which may lead to an increase in overall survival. Novel diagnostic methods such as blood-based biomarker biopsies may play a crucial role in the early detection of BM. Circulating tumor cells and circulating cell-free nucleic acids are known to serve as blood biomarkers for early detection and treatment response monitoring of multiple cancers. Blood biopsy may improve early diagnosis and treatment monitoring of GIT cancers BM, thus prolonging patients’ survivals.

Background Although the incidence and mortality have decreased, gastric cancer (GC) is still a public health issue globally. An international study reported higher survival in Korea and Japan than other countries, including the United States. We examined the determinant factors of the high survival in Japan compared with the United States. Methods We analysed data on 78,648 cases from the nationwide GC registration project, the Japanese Gastric Cancer Association (JGCA), from 2004-2007 and compared them with 16,722 cases from the Surveillance, Epidemiology, and End Results Program (SEER), a United States population-based cancer registry data from 2004-2010. We estimated 5-year relative survival and applied a multivariate excess hazard model to compare the two countries, considering the effect of number of lymph nodes (LNs) examined. Results Five-year relative survival in Japan was 81.0%, compared with 45.0% in the United States. After controlling for confounding factors, we still observed significantly higher survival in Japan. Among N2 patients, a higher number of LNs examined showed better survival in both countries. Among N3 patients, the relationship between number of LNs examined and differences in survival between the two countries disappeared. Conclusion Although the wide differences in GC survival between Japan and United States can be largely explained by differences in the stage at diagnosis, the number of LNs examined may also help to explain the gaps between two countries, which is related to stage migration.

Introduction Extrapyramidal signs (EPS) are a common feature of Alzheimer's disease associated with worse outcomes in observational studies of dementia. Less research has been conducted on ethnic minority and non-clinic-based populations. Methods One hundred and forty-two multiethnic community-dwelling participants with dementia were selected. Adjusted Cox models were fitted for mortality, cognitive (Mini Mental State Examination ≤10), functional (Blessed Dementia Rating Scale ≥10), and dependency (needs full-time care) endpoints with baseline EPS as predictor. Results Thirty-seven participants (26.06%) had EPS at baseline. EPS predicted more rapid time to death (hazard ratio [HR] = 2.76, 95% confidence interval [CI] = 1.49, 5.42), and functional endpoint (HR = 3.88, 95% CI = 1.75, 8.62) but not cognitive and dependency endpoints. No evidence of interaction by ethnicity, age, sex, education, or apolipoprotein E e4 polymorphism was found. Discussion Our results partially confirm previous studies on predominantly White, clinic-based samples. Further research is needed to better understand the etiological role of EPS in AD.

Background Detailed insights in temporal evolution of high‐sensitivity cardiac troponin following acute coronary syndrome (ACS) are currently missing. We aimed to describe and compare the post‐ACS kinetics of high‐sensitivity cardiac troponin I (hs‐cTnI) and high‐sensitivity cardiac troponin T (hs‐cTnT), and to determine their intra‐ and interindividual variation in clinically stable patients. Methods and Results We determined hs‐cTnI (Abbott) and hs‐cTnT (Roche) in 1507 repeated blood samples, derived from 191 patients with ACS (median, 8/patient) who remained free from adverse cardiac events during 1‐year follow‐up. Post‐ACS kinetics were studied by linear mixed‐effect models. Using the samples collected in the 6‐ to 12‐month post‐ACS time frame, patients were then considered to have chronic coronary syndrome. We determined (differences between) the average hs‐cTnI and average hs‐cTnT concentration, and the intra‐ and interindividual variation for both biomarkers. Compared with hs‐cTnT, hs‐cTnI peaked higher (median 3506 ng/L versus 494 ng/L; P P r spearman =0.60), whereas the average hs‐cTnT concentration was 5 times more likely to be above the upper reference limit than hs‐cTnI. The intraindividual variations of hs‐cTnI and hs‐cTnT were 14.0% and 18.1%, while the interindividual variations were 94.1% and 75.9%. Conclusions Hs‐cTnI peaked higher after ACS and was quicker below the upper reference limit. In the post–6‐month samples, hs‐cTnI and hs‐cTnT were clearly not interchangeable, and average hs‐cTnT concentrations were much more often above the upper reference limit than hs‐cTnI. For both markers, the within‐patient variation fell largely below beween‐patient variation. Registration URL: https://www.trialregister.nl ; unique identifiers: NTR1698 and NTR1106.

BACKGROUND: Recent studies have shown an association in non-metastatic colorectal cancer between patient survival and immunoprofiling (expression of CD3, CD4, CD8, CD45, and FOXP3 T cells at the invasive margin (IM) and the tumor center (TC)) regardless of stage. Patients with peritoneal carcinomatosis have a dismal prognosis, but survival can be significantly improved in selected patients who undergo cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). However, current patient selection for CRS/HIPEC is suboptimal. The purpose of this study is to evaluate immune profiles of patients with peritoneal carcinomatosis and their correlation with overall survival (OS). METHODS: The study cohort included patients from a prospectively maintained database of adults with colorectal peritoneal carcinomatosis who underwent CRS/HIPEC. Immunohistochemistry (IHC) using antibodies to CD3, CD4, CD8, CD45RO, and FOXP3 T cells was performed. IHC image density was calculated using ImageJ software, and an immunoscore was determined. RESULTS: Eighty tumors were evaluated from 66 patients. These included 14 primary sites and 66 metastatic sites. R0/R1 resection was achieved in 44 (66.7%) patients. Known prognostic factors including resection status (HR 1.99, p = 0.004) and lymph node status (HR 3.49, p = 0.002) were associated with overall survival. On multivariate analysis, increased CD3/CD4 IM (HR 0.54, p = 0.03) ratio positively was associated with improved OS. DISCUSSION: This is the first study to assess the utility of subtypes of T cells as prognostic markers in patients with colorectal peritoneal carcinomatosis, which may play a role in patients with low-volume disease. Further studies into immune mechanisms may improve patient selection for cytoreductive surgery and HIPEC as well as provide novel pathways for effective immunotherapy.

Objectives Details of the biological variability of high-sensitivity C-reactive protein (hs-CRP), N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and ST2 are currently lacking in patients with acute coronary syndrome (ACS) but are crucial knowledge when aiming to use these biomarkers for personalized risk prediction. In the current study, we report post-ACS kinetics and the variability of the hs-CRP, NT-proBNP and ST2. Methods BIOMArCS is a prospective, observational study with high frequency blood sampling during 1 year post-ACS. Using 1507 blood samples from 191 patients that remained free from adverse cardiac events, we investigated post-ACS kinetics of hs-CRP, NT-proBNP and ST2. Biological variability was studied using the samples collected between 6 and 12 months after the index ACS, when patients were considered to have stable coronary artery disease. Results On average, hs-CRP rose peaked at day 2 and rose well above the reference value. ST2 peaked immediately after the ACS but never rose above the reference value. NT-proBNP level rose on average during the first 2 days post-ACS and slowly declined afterwards. The within-subject variation and relative change value (RCV) of ST2 were relatively small (13.8%, RCV 39.7%), while hs-CRP (41.9%, lognormal RCV 206.1/-67.3%) and NT-proBNP (39.0%, lognormal RCV 185.2/-64.9%) showed a considerable variation. Conclusions Variability of hs-CRP and NT-proBNP within asymptomatic and clinically stable post-ACS patients is considerable. In contrast, within-patient variability of ST2 is low. Given the low within-subject variation, ST2 might be the most useful biomarker for personalizing risk prediction in stable post-ACS patients.

Darmanastomosen bei M. Crohn sind ein kontrovers diskutiertes Thema. Im Vergleich der verschiedenen Anastomosenkonfigurationen scheint die laterolaterale Anastomose nach Kono‑S die geringste Rezidivrate zu haben. Auf die Insuffizienzrate haben weder die Anastomosenkonfiguration noch das Nahtmaterial einen Einfluss. Die Komplikationsrate kann durch Verbesserung des Ernahrungszustands, Kortisonreduktion, Pausierung von Biologika und eine orale praoperative Antibiotikaprophylaxe gesenkt werden.

NEW FINDINGS What is the topic of this review? This symposium review provides an overview of the recent work investigating whether a virtually monitored home-based high-intensity interval training (Home-HIT) intervention reduces the fear of hypoglycaemia and other common barriers to exercise in people with type 1 diabetes. What advances does it highlight? Home-HIT seems to offer a strategy to reduce fear of hypoglycaemia, while simultaneously removing other known barriers that prevent people with type 1 diabetes from taking up exercise, because it is time efficient, requires no travel time or costs associated with gym memberships, and allows people to exercise in their chosen environment. ABSTRACT People with type 1 diabetes (T1D) are recommended to engage in regular exercise for a variety of health and fitness reasons. However, many lead a sedentary lifestyle and fail to meet the physical activity guidelines, in part because of the challenge of managing blood glucose concentration and fear of hypoglycaemia. A number of strategies designed to help people with T1D to manage their blood glucose during and after exercise have been investigated. Although many of these strategies show promise in facilitating blood glucose management during and after exercise, they do not target the many other common barriers to exercise that people with T1D face, such as difficulty with cost and travel time to gyms, limited access to exercise bikes and treadmills, and a possible dislike of exercising in front of others in public places. In this symposium review, we provide an overview of ongoing research into a virtually monitored home-based high-intensity interval training (Home-HIT) programme that is designed to reduce these other common barriers to exercise. The conclusion of this review is that Home-HIT seems to offer a strategy to reduce fear of hypoglycaemia, while simultaneously removing other known barriers preventing people with T1D from taking up exercise, such as being time efficient, requiring no travel time or costs associated with gym memberships, and giving them the opportunity to exercise in their chosen environment, reducing the embarrassment experienced by some when exercising in public.

Background Previous studies have linked muscarinic M4 receptors (CHRM4) to schizophrenia. Specifically, the rs2067482 polymorphism was found to be highly associated with this disease. Purpose To test whether rs2067482 and rs72910092 are potential risk factors for schizophrenia and/or pharmacogenetic markers for antipsychotic-induced tardive dyskinesia. Patients and methods We genotyped DNA of 449 patients with schizophrenia and 134 healthy controls for rs2067482 and rs72910092 polymorphisms of the CHRM4 gene with the use of the MassARRAY® System by Agena Bioscience. Mann-Whitney test was used to compare qualitative traits and χ 2 test was used for categorical traits. Results The frequency of genotypes and alleles of rs72910092 did not differ between patients with schizophrenia and control subjects. We did not reveal any statistical differences for both rs2067482 and rs72910092 between schizophrenia patients with and without tardive dyskinesia. The frequency of the C allele of the polymorphic variant rs2067482 was significantly higher in healthy persons compared to patients with schizophrenia (OR=0.51, 95% CI [0.33-0.80]; p=0.003). Accordingly, the CC genotype was found significantly more often in healthy persons compared to patients with schizophrenia (OR=0.49, 95% CI [0.31-0.80]; p=0.010). Conclusion Our study found the presence of the minor allele (T) of rs2067482 variant being associated with schizophrenia. We argue that the association of rs2067482 with schizophrenia may be via its regulatory effect on some other gene with protein kinase C and casein Kknase substrate in neurons 3 (PACSIN3) as a possible candidate. Neither rs2067482 nor rs72910092 is associated with tardive dyskinesia.

Background: Both dehydroepiandrosterone (DHEAS) and cortisol are secreted by the adrenal glands and may modulate metabolic syndrome (MetS), which often affects the health of patients with schizophrenia. The relationship between the serum levels of these hormones and MetS has not been established. Purpose: In this pilot study, we investigated the serum levels in schizophrenia patients with and without MetS and compared them with those in healthy volunteers. Patients and Methods: After obtaining informed consent, 110 patients with acute paranoid schizophrenia were recruited directly after admission to the Mental Health Research Institute. The control group consisted of 51 persons reported on questioning to be mentally and somatically healthy. Blood samples to prepare serum were drawn after an 8-h overnight fast during one of the first days of admission. Serum cortisol and DHEAS concentrations were quantified by enzyme-linked immunosorbent assay. Results: A total of 42 patients had MetS and 68 patients were without MetS. The cortisol blood level was significantly (p = 0.012) higher in schizophrenia patients without MetS in comparison to healthy controls, while patients with schizophrenia and a MetS have significantly (p = 0.014) lower DHEAS levels than healthy volunteers. These differences could, however, exclusively be attributed to female participants. Analysis of covariance adjusted for gender and age demon-strated a significant relationship between age and DHEAS levels (F = 9.512, р =0.003). Conclusion: Lower DHEAS serum levels in relationship to MetS become evident in women, but not in men, and have age differences as a confounding factor.

Objective: To investigate the pharmacokinetics, effectiveness, and safety of subcutaneous (SC) abatacept treatment over 24 months in patients with polyarticular-course juvenile idiopathic arthritis (JIA). Methods: In this phase III, open-label, international, multicenter, single-arm study, patients with polyarticular JIA (cohort 1, ages 6–17 years and cohort 2, ages 2–5 years) in whom treatment with ≥1 disease-modifying antirheumatic drug was unsuccessful received weight-tiered SC abatacept weekly: 10 to

Background: Alcohol use disorder (AUD) not only influences individuals and families but also has a lasting social impact on communities at the national level. Dopaminergic neurotransmission is involved in excessive alcohol consumption. Phosphatidylinositol-5-phosphate-4-kinase type 2 α (PIP4K2A) plays an important role in the regulation of ascending dopamine pathways. In this study, we determined possible associations between nine polymorphisms in PIP4K2A and AUD in Russian men. Methods: 279 Russian men with AUD were investigated. The control group consisted of 222 healthy men from the general Russian population. Genotyping of DNA samples for nine polymorphic variants of PIP4K2A was carried out by the Applied Biosystems™ QuantStudio™ 5 Real-Time PCR System with use of the TaqMan1 Validated SNP Genotyping Assay (Applied Biosystems, CШA). Results: Carriage of the PIP4K2A rs2230469*TT/T genotype/allele was a relative risk factor for developing AUD in men (p = 0.026 and p = 0.0084 accordingly). Moreover, men with AUD had a higher frequency of PIP4K2A rs746203*T allele (p = 0.023) compared to healthy men. Conclusions: For the first time, we demonstrated different PIP4K2A polymorphisms to be associated with AUD presumably due to dopamine system modulation resulting from regulation of the lateral habenula.

Background: Schizophrenia is a complex mental disorder with a high heritability. Dysfunction of the N-methyl-D-aspartate (NMDA)-type glutamate receptors may be involved in the pathogenesis of schizophrenia. In this study, we examined the contribution of GRIN2A and GRIN2B (Glutamate Ionotropic Receptor NMDA Type Subunit 2A/2B) polymorphisms to the clinical features of schizophrenia, such as the leading symptoms, the type of course, and the age of onset. Methods: A population of 402 Russian patients with schizophrenia from the Siberian region was investigated. Genotyping of seventeen single-nucleotide polymorphisms (SNPs) in GRIN2A and GRIN2B was performed using QuantStudio™ 3D Digital PCR System Life Technologies amplifier using TaqMan Validated SNP Genotyping Assay kits (Applied Biosystems). The results were analyzed using Chi-square and the Fisher’s exact tests. Results: We found an association of GRIN2A rs7206256 and rs11644461 and GRIN2B rs7313149 with the early onset (before the age of 18 years old) schizophrenia. We did not reveal any associations of GRIN2A and GRIN2B polymorphisms with leading (positive vs. negative) symptoms or type of course (continuous vs. episodic) of schizophrenia. Conclusions: In the study, we confirmed the involvement of the GRIN2A and GRIN2B genes in the early onset of schizophrenia in a Russian population of the Siberian region.

Background For patients with pancreatic adenocarcinoma (PA), the optimal time interval between neoadjuvant chemoradiation (CR) to surgical resection has not been well established. Methods The National Cancer Database from 2006 to 2014 was queried for patients ≥18 y old diagnosed with PA who received neoadjuvant CR. Survival and short-term outcomes were compared between patients who had pancreaticoduodenectomy ≤12 wk and >12 wk after completion of CR. Results 1610 patients met selection criteria. Average radiation to surgery (RS) interval was 58.2 ± 39.5 d. 1419 patients had RS interval ≤12 wk (mean 47.4 d) and 191 had RS interval >12 wk (mean 138.8 d). Demographics, CA 19-9 levels, types of chemotherapy and radiation dosage were similar between the two groups. There were more patients with clinical stage III cancers in the >12 wk group than in the ≤12 wk group (33.5% versus 14%). Short-term outcomes were similar between the two groups. However, a long-term survival benefit was observed in the >12 wk group (median 25.8 versus 30.2 mo P = 0.049). An interval >12 wk was associated with significantly prolonged survival on multivariate analysis (HR: 0.80, 95% CI: 0.65-0.99; P = 0.042). Higher clinical stage and positive surgical margins were independently associated with worse survival. Conclusions Surgical resection beyond 12 wk after CR for PA did not worsen short-term outcomes. Waiting may contribute to better patient selection, especially those with locally advanced tumors. In the absence of progressive disease, patients need to be continuously evaluated for surgical resection after CR.

Objectives: Acetylcholine M (muscarinic) receptors are possibly involved in tardive dyskinesia (TD). The authors tried to verify this hypothesis by testing for possible associations between two muscarinic receptor genes (CHRM1 and CHRM2) polymorphisms and TD in patients with schizophrenia. Methods: A total of 472 patients with schizophrenia were recruited. TD was assessed cross-sectionally using the Abnormal Involuntary Movement Scale. Fourteen allelic variants of CHRM1 and CHRM2 were genotyped using Applied Biosystems amplifiers (USA) and the MassARRAY System by Agena Bioscience. Results: The prevalence of the rs1824024*GG genotype of the CHRM2 gene was lower in TD patients compared to the group without it (χ2 = 6.035, p = 0.049). This suggested that this genotype has a protective effect for the development of TD (OR = 0.4, 95% CI: 0.19–0.88). When age, gender, duration of schizophrenia and dosage of antipsychotic treatment were added as covariates in regression analysis, the results did not reach statistical significance. Conclusions: This study did identify associations between CHRM2 variations and TD; the results of logistic regression analysis with covariates suggest that the association is, however, likely to be secondary to other concomitant factors.

Background: Brain-derived neurotrophic factor (BDNF) is associated with response to antidepressant drugs in mood and anxiety disorders. Prolactin (PRL) is a pituitary hormone with behavioural effects, acting as a neurotrophic factor within the brain and may be involved in antidepressant response.Objectives: To investigate the relationship between BDNF and PRL genotypes with antidepressant drug response.Methods: Prospective inception cohort of 186 Russian treatment-free participants (28 men and 158 women) between 18 and 70 years clinically diagnosed with depressive disorder who initiated antidepressant medication. DNA polymorphisms were genotyped for PRL rs1341239, BDNF rs6265 and rs7124442. Primary outcome was measured by differences in Hamilton Depression Rating Scale (Delta HAM-D) scores between baseline/week two, week two/week four, and baseline/week four. Linear regression and independent t-test determined the significance between polymorphisms and Delta HAM-D.Results: Comparisons between genotypes did not reveal any significant differences in scores during the first two weeks of treatment. In the latter two weeks, BDNF rs7124442 homozygous C patients responded significantly worse in comparison to homozygous T patients during this period. Further analysis within women and in postmenopausal women found a similar comparison between alleles.Limitations: Study lasted four weeks, which may be considered short to associate genuine antidepressant effects.Conclusions: Patients taking tricylic antidepressants were noted to have a significant improvement in Delta HAM-D compared to patients taking SSRIs. Homozygous C BDNF rs712442 patients were found to respond significantly worse in the last two weeks of treatment.

Identifying biomarkers which can be used as a diagnostic tool is a major objective of pharmacogenetic studies. Most mental and many neurological disorders have a compiled multifaceted nature, which may be the reason why this endeavor has hitherto not been very successful. This is also true for tardive dyskinesia (TD), an involuntary movement complication of long-term treatment with antipsychotic drugs. The observed associations of specific gene variants with the prevalence and severity of a disorder can also be applied to try to elucidate the pathogenesis of the condition. In this paper, this strategy is used by combining pharmacogenetic knowledge with theories on the possible role of a dysfunction of specific cellular elements of neostriatal parts of the (dorsal) extrapyramidal circuits: various glutamatergic terminals, medium spiny neurons, striatal interneurons and ascending monoaminergic fibers. A peculiar finding is that genetic variants which would be expected to increase the neostriatal dopamine concentration are not associated with the prevalence and severity of TD. Moreover, modifying the sensitivity to glutamatergic long-term potentiation (and excitotoxicity) shows a relationship with levodopa-induced dyskinesia, but not with TD. Contrasting this, TD is associated with genetic variants that modify vulnerability to oxidative stress. Reducing the oxidative stress burden of medium spiny neurons may also be the mechanism behind the protective influence of 5-HT2 receptor antagonists. It is probably worthwhile to discriminate between neostriatal matrix and striosomal compartments when studying the mechanism of TD and between orofacial and limb-truncal components in epidemiological studies.

BACKGROUND: Adequate lymph node (LN) sampling is critical for accurate nodal staging in colon cancer (CC), particularly for T3N0 disease as current guidelines recommend considering adjuvant chemotherapy when less than 12 LNs are examined. The impact of sidedness on nodal staging accuracy in patients with T3N0 disease has not been previously studied. METHODS: Patients with pathologic T3 CC were identified from a prospective multicenter international trial of ultrastaging in CC. The probability of true nodal negativity (TNN) based on the number of LN examined was calculated for right and left CC. These results were then validated in a cohort of patients with similar inclusion criteria selected from the National Cancer Database (NCDB) between 2006 and 2014. RESULTS: Three hundred and seventy patients met the inclusion criteria in the trial cohort; 48% were LN-negative. Of 153,945 patients in the NCDB, 57% were LN-negative. The probability of TNN when 12 LNs were examined was 68% for right and 64% for left CC in the trial cohort and 77% and 72% in the NCDB. The number of LNs needed to achieve any given probability of TNN was significantly different between right and left CC in both the trial (P

See Uzquiano and Francis (doi:10.1093/brain/awz048) for a scientific commentary on this article. Mutations in RTTN, which encodes Rotatin, give rise to various brain malformations. Vandervore et al. reveal mitotic failure, aneuploidy, apoptosis and defective ciliogenesis in patient cells. Rotatin binds to myosin subunits in the leading edge of human neurons, which may explain the proliferation and migration defects observed., Recessive mutations in RTTN, encoding the protein rotatin, were originally identified as cause of polymicrogyria, a cortical malformation. With time, a wide variety of other brain malformations has been ascribed to RTTN mutations, including primary microcephaly. Rotatin is a centrosomal protein possibly involved in centriolar elongation and ciliogenesis. However, the function of rotatin in brain development is largely unknown and the molecular disease mechanism underlying cortical malformations has not yet been elucidated. We performed both clinical and cell biological studies, aimed at clarifying rotatin function and pathogenesis. Review of the 23 published and five unpublished clinical cases and genomic mutations, including the effect of novel deep intronic pathogenic mutations on RTTN transcripts, allowed us to extrapolate the core phenotype, consisting of intellectual disability, short stature, microcephaly, lissencephaly, periventricular heterotopia, polymicrogyria and other malformations. We show that the severity of the phenotype is related to residual function of the protein, not only the level of mRNA expression. Skin fibroblasts from eight affected individuals were studied by high resolution immunomicroscopy and flow cytometry, in parallel with in vitro expression of RTTN in HEK293T cells. We demonstrate that rotatin regulates different phases of the cell cycle and is mislocalized in affected individuals. Mutant cells showed consistent and severe mitotic failure with centrosome amplification and multipolar spindle formation, leading to aneuploidy and apoptosis, which could relate to depletion of neuronal progenitors often observed in microcephaly. We confirmed the role of rotatin in functional and structural maintenance of primary cilia and determined that the protein localized not only to the basal body, but also to the axoneme, proving the functional interconnectivity between ciliogenesis and cell cycle progression. Proteomics analysis of both native and exogenous rotatin uncovered that rotatin interacts with the neuronal (non-muscle) myosin heavy chain subunits, motors of nucleokinesis during neuronal migration, and in human induced pluripotent stem cell-derived bipolar mature neurons rotatin localizes at the centrosome in the leading edge. This illustrates the role of rotatin in neuronal migration. These different functions of rotatin explain why RTTN mutations can lead to heterogeneous cerebral malformations, both related to proliferation and migration defects.

Background: Motor recovery after stroke is based on neuronal plasticity and the structural reorganization of the brain. Questions are debated about the proper moment to start rehabilitation in the acute period of stroke, the significance of rehabilitation interventions during the so-called “plastic window”, and the advantages of modern and traditional programs. The aims of this study were to evaluate the role of different rehabilitation strategies and their combinations for motor recovery and the impact on functional disability by way of neurological and functional outcomes 3 months after ischemic stroke. Methods: We used three rehabilitation approaches: early rehabilitation from the first day of stroke (Phase I), traditional exercise programs (Phase II), and an author’s new method of biofeedback rehabilitation using motion sensors and augmented reality (AR) rehabilitation (Phase III). Clinical and functional outcomes were measured on the 90th day after stroke. We developed algorithms for quantifying the quality of movements during the execution of tasks in the motor domains of the AR rehabilitation program. Results: Phase I of rehabilitation led to an improvement in functional independence, and the recovery of motor functions of the extremities with an absence of mortality and clinical deterioration. AR rehabilitation led to significant improvement both with respect to clinical and functional scores on scales and to variables reflecting the quality of movements. Patients who were actively treated during Phases II and III achieved the same final level of motor recovery and functional outcomes as that of participants who had only received AR rehabilitation during Phase III. Patients who underwent outpatient observation after Phase I showed a deficit of spontaneous motor recovery on the 90th day after stroke. Conclusions: Early rehabilitation was successful but was not enough, rehabilitation programs should be carried out throughout the entire “sensitive period” of poststroke plasticity. The newly developed AR biofeedback motion training is effective and safe as a separate rehabilitation method in the early recovery period of moderately severe, hemiparalytic, and ischemic stroke. These two rehabilitation approaches must be applied together or after each other, not instead of each other, as shown in clinical practice.

Background: There is sufficient evidence that interference of dopaminergic neurotransmission contributes to the therapeutic effects of antidepressants in unipolar and bipolar depression. Methods: Hamilton depression rating scale (HAMD 17) scores of 163 at least moderately ill patients with major depressive disorders were used to establish treatment response. HAMD 17 score status was measured before initiation, after two weeks, and after four weeks of treatment with various antidepressants. The possible association between response and genotype in a total of 14 variants of dopamine neurotransmission-related proteins was investigated. Results: DRD4 rs11246226 CA heterozygous patients were found with a greater improvement of HAMD 17 score when compared to homozygous C patients during 0–2 weeks and 0–4 weeks. Patients with MAOB rs1799836 heterozygous GA and homozygous A also demonstrated improved scores during 2–4 weeks and 0–4 weeks. Conclusions: The results are preliminary due to the limited population size and the small number of variants. Further research into the involvement of habenular dopamine D4 receptors in the antidepressant response is desirable.

Proximal spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder characterized by motor neuron loss and subsequent atrophy of skeletal muscle. SMA is caused by deficiency of the essential survival motor neuron (SMN) protein, canonically responsible for the assembly of the spliceosomal small nuclear ribonucleoproteins (snRNPs). Therapeutics aimed at increasing SMN protein levels are efficacious in treating SMA. However, it remains unknown how deficiency of SMN results in motor neuron loss, resulting in many reported cellular functions of SMN and pathways affected in SMA. Herein is a perspective detailing what genetics and biochemistry have told us about SMA and SMN, from identifying the SMA determinant region of the genome, to the development of therapeutics. Furthermore, we will discuss how genetics and biochemistry have been used to understand SMN function and how we can determine which of these are critical to SMA moving forward.

Interactions between pathogens, host microbiota and the immune system influence many physiological and pathological processes. In the 20th century, widespread dermal vaccination with vaccinia virus (VACV) led to the eradication of smallpox but how VACV interacts with the microbiota and whether this influences the efficacy of vaccination are largely unknown. Here we report that intradermal vaccination with VACV induces a large increase in the number of commensal bacteria in infected tissue, which enhance recruitment of inflammatory cells, promote tissue damage and increase immunity. Treatment of vaccinated specific-pathogen-free (SPF) mice with antibiotic, or infection of genetically-matched germ-free (GF) animals caused smaller lesions without alteration in virus titre. Tissue damage correlated with enhanced neutrophil and T cell infiltration and levels of pro-inflammatory tissue cytokines and chemokines. One month after vaccination, GF mice had reduced VACV-neutralising antibodies compared to SPF mice; while numbers of VACV-specific CD8+ T cells were equal in all groups of animals. Thus, skin microbiota may provide an adjuvant-like stimulus during vaccination with VACV. This observation has implications for dermal vaccination with live vaccines.Author SummarySmallpox was caused by variola virus and was eradicated by widespread dermal vaccination with vaccinia virus (VACV), a related orthopoxvirus of unknown origin. Eradication was declared in 1980 without an understanding of the immunological correlates of protection, or knowledge of the effect of smallpox vaccination on the local microbiota. Here we demonstrate that intradermal infection of mice with VACV induces a ∼1000-fold expansion of commensal skin bacteria that influence the recruitment of inflammatory cells into the infected tissue and enhance the size of the vaccination lesion. Antibiotic treatment reduced lesion size without changing virus titres. The bacterial expansion also contributes to the level of neutralizing antibodies at one month post vaccination, because genetically matched germ-free mice developed lower neutralizing antibodies than specific pathogen free controls. Thus, dermal infection by VACV enhanced bacterial growth and these bacteria promote pathology and enhance the antibody response. This finding has implication for dermal vaccination with live vaccines.

BackgroundAnxiety disorders frequently recur in clinical populations, but the risk of recurrence of anxiety disorders is largely unknown in the general population. In this study, recurrence of anxiety and its predictors were studied in a large cohort of the adult general population.MethodsBaseline, 3-year and 6-year follow-up data were derived from the Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2). Respondents (N = 468) who had been in remission for at least a year prior to baseline were included. Recurrence was assessed at 3 and 6 years after baseline, using the Composite International Diagnostic Interview version 3.0. Cumulative recurrence rates were estimated using the number of years since remission of the last anxiety disorder. Furthermore, Cox regression analyses were conducted to investigate predictors of recurrence, using a broad range of putative predictors.ResultsThe estimated cumulative recurrence rate was 2.1% at 1 year, 6.6% at 5 years, 10.6% at 10 years, and 16.2% at 20 years. Univariate regression analyses predicted a shorter time to recurrence for several variables, of which younger age at interview, parental psychopathology, neuroticism and a current depressive disorder remained significant in the, age and gender-adjusted, multivariable regression analysis.ConclusionsRecurrence of anxiety disorders in the general population is common and the risk of recurrence extends over a lengthy period of time. In clinical practice, alertness to recurrence, monitoring of symptoms, and quick access to health care in case of recurrence are needed.

Predicting the onset and persistence of psychopathology and limited functioning might enable personalized care. Specific phobia (SP) might serve as a predictor, but this needs further evaluation. Participants of the Netherlands Mental Health Survey and Incidence Study-2 were divided into three groups: no-SP (n = 6094), history of SP (n = 204), and current SP (n = 348). Results showed that current SP was associated with a higher prevalence of other anxiety disorders, mood and substance use disorders, and lower levels of functioning. The 6-year onset of other anxiety disorders was associated with history and current SP. Current-SP was also associated with the onset of mood disorders. Neuroticism and childhood trauma only partly accounted for these associations. To conclude, SP was independently associated with presence and onset of other disorders and with limited functioning over time. The presence of SP may serve as an identifier of persons vulnerable to the development of other psychopathologies.

Vulnerability markers for onset of anxiety disorders are scarce. In depression, patients at risk tend to respond with a negative mood to ‘acute tryptophan depletion’ (ATD), while healthy volunteers and current patients do not. The serotonergic system thus provides indications for vulnerability for depression. It is unknown whether ATD reveals vulnerability in anxiety too. This study systematically reviews the effects of ATD on anxiety and assesses whether challenging anxiety modifies the response. PubMed, Embase and PsychInfo were systematically searched up to April 2019 for studies in which (1) healthy volunteers or patients with a (remitted) anxiety disorder underwent ATD and (2) levels of anxiety were reported. In total, 21 studies were included. Studies conducted in healthy volunteers (n = 13), and patients with a remitted (n = 6) or current (panic, social or generalised) anxiety disorder (n = 4). Studies were mostly of poor quality and heterogeneous regarding population, challenge test used and outcome measures. ATD did not consistently affect anxiety in any of the groups. Moreover, a challenge test after ATD (n = 17 studies) did not consistently provoke anxiety in healthy volunteers or remitted patients. A 35% CO2 challenge did consistently increase anxiety in patients with a current panic disorder (PD). To conclude, this systematic review found no clear indications that ATD provokes anxiety in those at risk for anxiety disorders. Hence, unlike in depression, ATD does not indicate vulnerability to develop an anxiety disorder. Because included studies were heterogeneous and mostly of poor quality, there is an urgent need for high quality research in homogeneous samples.

A 35-year-old woman presented seeking advice on whether to discontinue antidepressants. Several years previously she had suffered from a panic disorder that was effectively treated with cognitive behavioural therapy (CBT). A few years following remission, she began having frequent panic attacks in

Background and Aims Carcinoma associated with perianal fistula in Crohn’s disease is a pending threat for patients. This study aimed to improve understanding and facilitate development of diagnostic and therapeutic strategies. Methods A retrospective case-control study was conducted at four German hospitals. The analysis included 40 patients with proven malignancy associated with perianal Crohn’s fistulas and 40 randomly selected controls with fistulizing perianal Crohn’s disease. Differences between groups were analysed and multivariate calculations were performed to describe risk factors for oncological outcomes. Results Histology revealed adenocarcinoma in 33/40 patients and squamous cell carcinoma in 7/40 patients. Compared to fistula patients without carcinoma, patients with malignancies associated with fistula had a diagnosis of Crohn’s disease at younger age. Crohn’s disease lasted longer in patients with malignancy [25.8 ± 9.0 vs 19.6 ± 10.4; p = 0.006]. Fistula-related findings differed significantly between the two groups. Signs of complicated and severe fistulation including complex anatomy and chronic activity occurred significantly more often in patients with malignancy associated with fistula. Significant multivariate hazard ratios for overall mortality and progression-free survival were shown for histological type of cancer, metastatic disease and R1 resection. Overall survival was 45.1 ± 28.6 months and the 5-year survival rate was 65%. Conclusions In patients with adenocarcinoma or squamous cell carcinoma associated with perianal fistula in Crohn’s disease, fistula characteristics determine the risk of malignancy. Early diagnosis influences outcomes, while treatment of chronic fistula activity may be key to preventing malignancy. Expert multimodal therapy is paramount for successful treatment of perianal fistula-associated malignancies.

Background: Antipsychotic-induced metabolic syndrome (MetS) is a multifactorial disease with a genetic predisposition. Serotonin and its receptors are involved in antipsychotic-drug-induced metabolic disorders. The present study investigated the association of nine polymorphisms in the four 5-hydroxytryptamine receptor (HTR) genes HTR1A, HTR2A, HTR3A, and HTR2C and the gene encoding for the serotonin transporter SLC6A4 with MetS in patients with schizophrenia. Methods: A set of nine single-nucleotide polymorphisms of genes of the serotonergic system was investigated in a population of 475 patients from several Siberian regions (Russia) with a clinical diagnosis of schizophrenia. Genotyping was performed and the results were analyzed using chi-square tests. Results: Polymorphic variant rs521018 (HTR2C) was associated with higher body mass index in patients receiving long-term antipsychotic therapy, but not with drug-induced metabolic syndrome. Rs1150226 (HTR3A) was also associated but did not meet Hardy–Weinberg equilibrium. Conclusions: Our results indicate that allelic variants of HTR2C genes may have consequences on metabolic parameters. MetS may have too complex a mechanistic background to be studied without dissecting the syndrome into its individual (causal) components.

BACKGROUND: The C5a receptor inhibitor avacopan is being studied for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.METHODS: In this randomized, controlled trial, we assigned patients with ANCA-associated vasculitis in a 1:1 ratio to receive oral avacopan at a dose of 30 mg twice daily or oral prednisone on a tapering schedule. All the patients received either cyclophosphamide (followed by azathioprine) or rituximab. The first primary end point was remission, defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 (on a scale from 0 to 63, with higher scores indicating greater disease activity) at week 26 and no glucocorticoid use in the previous 4 weeks. The second primary end point was sustained remission, defined as remission at both weeks 26 and 52. Both end points were tested for noninferiority (by a margin of 20 percentage points) and for superiority.RESULTS: A total of 331 patients underwent randomization; 166 were assigned to receive avacopan, and 165 were assigned to receive prednisone. The mean BVAS at baseline was 16 in both groups. Remission at week 26 (the first primary end point) was observed in 120 of 166 patients (72.3%) receiving avacopan and in 115 of 164 patients (70.1%) receiving prednisone (estimated common difference, 3.4 percentage points; 95% confidence interval [CI], -6.0 to 12.8; PCONCLUSIONS: In this trial involving patients with ANCA-associated vasculitis, avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52. All the patients received cyclophosphamide or rituximab. The safety and clinical effects of avacopan beyond 52 weeks were not addressed in the trial. (Funded by ChemoCentryx; ADVOCATE ClinicalTrials.gov number, NCT02994927.).

Objective:The purpose of this study was to compare the prevalence of MetS and the associated sociodemographic, clinical, and pharmacotherapeutic characteristics of patients with schizophrenia in three psychiatric hospitals in the West Siberian region.Methods:Patients with a clinical diagnosis of schizophrenia (ICD-10: F20) and an age between 18 and 60 years were included in the study after giving informed consent. Metabolic syndrome was diagnosed according to the International Diabetes Federation criteria. This research was carried out at three Western Siberian psychiatric hospitals in Kemerovo, Tomsk, and Omsk. The study population included respectively 94, 131, and 91 inpatients with schizophrenia. We carried out schizophrenia symptoms assessment by PANSS, antipsychotic therapy evaluation, anthropometry, and biochemical analysis. Statistical Analysis included the Shapiro–Wilk test, non-parametric Kruskal–WallisH-test for independent samples, Mann–WhitneyU-test for independent samples, the chi-square test, stepwise multiple regression analyses. The level of significance wasp< 0.05.Results:The metabolic syndrome prevalence was higher among patients in Tomsk (36.6%), compared with Kemerovo (20.2%,p= 0.008) or Omsk (18.7%,p= 0.004), mainly due to the high prevalence of abdominal obesity, while men from Tomsk were more susceptible to this condition than men from other regions (p< 0.05). Patients from Omsk had the highest severity schizophrenia symptoms according to PANSS, and patients from Tomsk had the lowest severity of positive symptoms according to PANSS. Patients from Tomsk had the minimum duration of antipsychotic therapy compared with the patient from Kemerovo (p= 0.017) and from Omsk (p= 0.000019), but most patients from Tomsk received second-generation atypical antipsychotics, while patients from Omsk received mainly conventional antipsychotics (p= 0.0001). Multiple regression analysis showed that metabolic syndrome associated with schizophrenia duration and body mass index, although the association was not so strong (adjustedR2= 0.2435,p< 0.0001).Discussion:The study illustrates that in different psychiatric hospitals within the same region, the prevalence of metabolic syndrome in patients with schizophrenia can vary significantly, which dictates the need to look for opportunities to minimize the risk of its occurrence, taking into account the experience of each hospital.

Objective:Vitamin D deficiency may be a clinical problem in patients with addictions. The authors systematically searched for studies addressing vitamin D and addiction and develop a hypothesis which can direct future research of the possible mechanistic role of vitamin D in the process of addiction.Methods:Systematic review of the literature found in PubMed and EMBASE followed by narrative review combined with clinical experiences leading to hypotheses for future research.Results:Only five articles were identified about a role of vitamin D in the pathophysiology of addiction. Their results are in line with a possible influence of vitamin D in dopaminergic transmission. The cerebral vitamin D status depends on the functionality of genetic variants of vitamin D receptor and other involved genes. Routine serum calcidiol levels may not adequately reflect cerebral vitamin D status. Uncertainty exists regarding appropriate calcidiol blood levels and proper dosages for affecting the central nervous system (CNS).Conclusions:The putative pathophysiological role of vitamin D in substance abuse has been insufficiently studied which calls to more studies how to measure cerebral vitamin D status in clinical practice. Research is indicated whether vitamin D supplementation should use higher dosages and aim to reach higher calcidiol serum levels. Measuring dopaminergic functioning within the prefrontal cortex as reflected by neuropsychological tests selected as suitable could be a appropriate proxy for the cerebral vitamin D status when studying the pharmacogenomics of this functionality in patients.

Background Schizophrenia is a severe highly heritable mental disorder. The clinical heterogeneity of schizophrenia is expressed in the difference in the leading symptoms and course of the disease. Identifying the genetic variants that affect clinical heterogeneity may ultimately reveal the genetic basis of the features of schizophrenia and suggest novel treatment targets. PIP5K2A (Phosphatidylinositol-4-Phosphate 5-Kinase Type II Alpha) has been investigated as a potential susceptibility gene for schizophrenia. Methods In this work, we studied the possible association between eleven polymorphic variants of PIP5K2A and the clinical features of schizophrenia in a population of 384 white Siberian patients with schizophrenia. Genotyping was carried out on QuantStudio 5 Real-Time PCR System with a TaqMan Validate SNP Genotyping Assay (Applied Biosystems, USA). Results PIP5K2A rs8341 (χ2 = 6.559, p = 0.038) and rs946961 (χ2 = 5.976, p = 0.049) showed significant association with course of schizophrenia (continuous or episodic). The rs8341*CT (OR = 1.63, 95% CI: 1.04–2.54) and rs946961*CC (OR = 5.17, 95% CI: 1.20–22.21) genotypes were associated with a continuous type of course, while the rs8341*TT genotype (OR = 0.53, 95% CI: 0.29–0.97) was associated with an episodic type of course of schizophrenia. Therefore rs8341*TT genotype presumably has protective effect against the more severe continuous course of schizophrenia compared to the episodic one. Conclusions Our experimental data confirm that PIP5K2A is a genetic factor influencing the type of course of schizophrenia in Siberian population. Disturbances in the phosphatidylinositol pathways may be a possible reason for the transition to a more severe continuous course of schizophrenia.

Follicular lymphoma (FL) is a common indolent B-cell lymphoma that can transform into the more aggressive transformed FL (tFL). However, the molecular process driving this transformation is uncertain. In this work, we aimed to identify microRNA (miRNA)-binding sites recurrently mutated in follicular lymphoma patients, as well as in transformed FL patients. Using whole-genome sequencing data from FL tumors, we discovered 544 mutations located in bioinformatically predicted microRNA-binding sites. We then studied these specific regions using targeted sequencing in a cohort of 55 FL patients, found 16 recurrent mutations, and identified a further 69 variants. After filtering for QC, we identified 21 genes with mutated miRNA-binding sites that were also enriched for B-cell-associated genes by Gene Ontology. Over 40% of mutations identified in these genes were present exclusively in tFL patients. We validated the predicted miRNA-binding sites of five of the genes by luciferase assay and demonstrated that the identified mutations in BCL2 and EZH2 genes impaired the binding efficiency of miR-5008 and miR-144 and regulated the endogenous levels of messenger RNA (mRNA).

Background This study analysed the relationship between social support and psychological distress in Latina women in Miami-Dade County. Acculturation was examined as a modifying factor. Methods A 2005 data set from interviews of 155 Latina mothers in Miami-Dade County, from mother-daughter dyads, was analysed. Social support was measured using the Interpersonal Support Evaluation List (ISEL) score. Psychological distress was based on self-reporting symptoms of depression, anxiety, or suicidality. Acculturation was based on English proficiency and length of U.S. residency. Results Compared to those with high social support, women with low social support had greater odds of reporting psychological distress (odds ratio = 7.8 [95% CI 2.70-22.10]). Acculturation did not modify the association (p=0.74). Conclusions Social support was inversely associated with psychological distress among Latina women. Acculturation was not an effect modifier, likely due to inadequate power. The study has clinical implications for mental illness prevention in this population.

Hyperprolactinemia (HPRL) is considered to be a frequent and typical adverse drug reaction caused by antipsychotic medications first and foremost due to excessive dopamine D2 receptors blockade. The aim is to study the set of polymorphisms of genes encoding neurotransmitter synthesis and metabolism enzymes COMT, TPH1 and TPH2 in schizophrenia inpatients. A comprehensive examination of 446 schizophrenia inpatients, aged 18-75 years, was conducted. Genotyping of DNA samples in patients with or without HPRL was carried out for 14 polymorphisms of COMT, TPH1, and TPH2 genes. We revealed an association between carriership of the COMT rs165774* G allele and HPRL. As a result of the study, a regression model was designed to predict the risk of developing HPRL in schizophrenia inpatients, taking into account age, gender, and treatment duration, the dosage of drugs in chlorpromazine equivalents as independent covariates and genotypes of the studied polymorphisms.

Duchenne muscular dystrophy (DMD) is a genetic, degenerative, striated muscle disease exacerbated by chronic inflammation. Mdx mice in the genotypic DMD model poorly represent immune-mediated pathology observed in patients. Improved understanding of innate immunity in dystrophic muscles is required to develop specific anti-inflammatory treatments. Here, inflammation in mdx mice and the more fibrotic utrn(+/-);mdx Het model was comprehensively investigated. Unbiased analysis showed that mdx and Het mice contain increased levels of numerous chemokines and cytokines, with further increased in Het mice. Chemokine and chemokine receptor gene expression levels were dramatically increased in 4-week–old dystrophic quadriceps muscles, and to a lesser extent in diaphragm during the early injury phase, and had a small but consistent increase at 8 and 20 weeks. An optimized direct immune cell isolation method prevented loss of up to 90% of macrophages with density-dependent centrifugation previously used for mdx flow cytometry. Het quadriceps contain higher proportions of neutrophils and infiltrating monocytes than mdx, and higher percentages of F4/80(Hi), but lower percentages of F4/80(Lo) cells and patrolling monocytes compared with Het diaphragms. These differences may restrict regenerative potential of dystrophic diaphragms, increasing pathologic severity. Fibrotic and inflammatory gene expression levels are higher in myeloid cells isolated from Het compared with mdx quadriceps, supporting Het mice may represent an improved model for testing therapeutic manipulation of inflammation in DMD.

Dystonia is by far the most intrusive and invalidating extrapyramidal side effect of potent classical antipsychotic drugs. Antipsychotic drug-induced dystonia is classified in both acute and tardive forms. The incidence of drug-induced dystonia is associated with the affinity to inhibitory dopamine D2 receptors. Particularly acute dystonia can be treated with anticholinergic drugs, but the tardive form may also respond to such antimuscarinic treatment, which contrasts their effects in tardive dyskinesia. Combining knowledge of the pathophysiology of primary focal dystonia with the anatomical and pharmacological organization of the extrapyramidal system may shed some light on the mechanism of antipsychotic drug-induced dystonia. A suitable hypothesis is derived from the understanding that focal dystonia may be due to a faulty processing of somatosensory input, so leading to inappropriate execution of well-trained motor programmes. Neuroplastic alterations of the sensitivity of extrapyramidal medium-sized spiny projection neurons to stimulation, which are induced by the training of specific complex movements, lead to the sophisticated execution of these motor plans. The sudden and non-selective disinhibition of indirect pathway medium-sized spiny projection neurons by blocking dopamine D2 receptors may distort this process. Shutting down the widespread influence of tonically active giant cholinergic interneurons on all medium-sized spiny projection neurons by blocking muscarinic receptors may result in a reduction of the influence of extrapyramidal cortical-striatal-thalamic-cortical regulation. Furthermore, striatal cholinergic interneurons have an important role to play in integrating cerebellar input with the output of cerebral cortex, and are also targeted by dopaminergic nigrostriatal fibres affecting dopamine D2 receptors.

In this study, we aim to investigate associations between body fat parameters, glucose and lipid profiles, thyroid-stimulating hormone (TSH), and thyroid hormones (THs) levels in Tomsk-region schizophrenia patients depending upon the presence or absence of metabolic syndrome (MetS). A total of 156 psychiatric inpatients with schizophrenia who had been treated with antipsychotics for at least six months before entry were studied: 56 with and 100 without MetS. Reference groups consisted of general hospital inpatients with MetS and without schizophrenia (n = 35) and healthy individuals (n = 35). Statistical analyses were performed using the Mann&ndash, Whitney U-test, chi-square test, Spearman&rsquo, s rank correlation coefficient, multiple regression analyses, and descriptive statistics. Patients with schizophrenia and MetS had significantly higher levels of free triiodothyronine (FT3) and thyroxine (FT4) compared to schizophrenia patients without MetS (3.68 [3.25, 5.50] vs. 3.24 [2.81, 3.66], p = 0.0001, and 12.68 [10.73, 15.54] vs. 10.81 [9.76, 12.3], p = 0.0001, in pmol/L, respectively). FT3 maintained an association with MetS (p = 0.0001), sex (p = 0.0001), age (p = 0.022), and high-density lipoproteins (p = 0.033). FT4 maintained an association with MetS (p = 0.0001), sex (p = 0.001), age (p = 0.014), and glucose (p = 0.009). The data obtained showed body fat parameters, glucose and lipid profiles, and THs levels in Western-Siberian schizophrenia patients depending on MetS presence or absence.

Background: brain-derived neurotrophic factor (BDNF) may play a role during neurorehabilitation following ischemic stroke. This study aimed to elucidate the possible role of BDNF during early recovery from ischemic stroke assisted by motor training. Methods: fifty patients were included after acute recovery from ischemic stroke: 21 first received classical rehabilitation followed by &lsquo, motor rehabilitation using motion sensors and augmented reality&rsquo, (AR-rehabilitation), 14 only received AR-rehabilitation, and 15 were only observed. Serum BDNF levels were measured on the first day of stroke, on the 14th day, before AR-based rehabilitation (median, 45th day), and after the AR-based rehabilitation (median, 82nd day). Motor impairment was quantified clinically using the Fugl&ndash, Meyer scale (FMA), functional disability and activities of daily living (ADL) were measured using the Modified Rankin Scale (mRS). For comparison, serum BDNF was measured in 50 healthy individuals. Results: BDNF levels were found to significantly increase during the phase with AR-based rehabilitation. The pattern of the sequentially measured BDNF levels was similar in the treated patients. Untreated patients had significantly lower BDNF levels at the endpoint. Conclusions: the fluctuations of BDNF levels are not consistently related to motor improvement but seem to react to active treatment. Without active rehabilitation treatment, BDNF tends to decrease.

Sarcopenia, or age-related loss of muscle mass and strength, is an important contributor to loss of physical function in older adults. The pathogenesis of sarcopenia is likely multifactorial, but recently the role of neurological degeneration, such as motor unit loss, has received increased attention. Here, we investigated the longitudinal effects of muscle hypertrophy (via overexpression of human follistatin, a myostatin antagonist) on neuromuscular integrity in C57BL/6J mice between the ages of 24 and 27 months. Following follistatin overexpression (delivered via self-complementary adeno-associated virus subtype 9 injection), muscle weight and torque production were significantly improved. Follistatin treatment resulted in improvements of neuromuscular junction innervation and transmission but had no impact on age-related losses of motor units. These studies demonstrate that follistatin overexpression-induced muscle hypertrophy not only increased muscle weight and torque production but also countered age-related degeneration at the neuromuscular junction in mice.

Sarcopenia, or pathological loss of muscle mass and strength during aging, is an important contributor to loss of physical function in older adults. Sarcopenia is a multifactorial syndrome associated with intrinsic muscle and upstream neurological dysfunction. Exercise is well-established as an effective intervention for sarcopenia, but less is known about the long-term neurobiological impact of exercise. The goals of this study were to investigate the effects of exercise, alone or in combination with follistatin (FST) overexpression (antagonist of myostatin), on neuromuscular junction transmission and motor unit numbers in mice between the age of 22 and 27 months, ages at which prior studies have demonstrated that some motor unit loss is already evident. C57BL/6J mice underwent baseline assessment and were randomized to housing with or without voluntary running wheels and injection with adeno-associated virus to overexpress FST or vehicle. Groups for comparison included sedentary and running with and without FST. Longitudinal assessments showed significantly increased muscle mass and contractility in the 'running plus FST' group, but running, with and without FST, showed no effect on motor unit degeneration. In contrast, running, with and without FST, demonstrated marked improvement of neuromuscular junction transmission stability.