To better understand the mechanism(s) underlying lung cancer invasion and metastasis, a Transwell invasion chamber was used to select progressively more invasive cancer cell populations from a clonal cell line of human lung adenocarcinoma, CL1. Five sublines with progressive invasiveness, designated CL1-1, CL1-2, CL1-3, CL1-4, and CL1-5, were obtained through this in vitro selection process. Their invasive abilities through basement membrane matrix showed a 4- to 6-fold increase over that of the parental cells. Moreover, the sublines manifested an increase in their colony-forming ability on soft agar, tumorigenicity, and metastatic potency in severe combined immunodeficiency (SCID) mice. Examining the phenotypes of the cell lines revealed increased expression of 92 kD gelatinase and an increase in the cell population stained with anti-keratin-8 and -18 antibodies. Clonal isolation of anti-keratin-18-antibody-positive and -negative cell populations demonstrated a correlated enhancement of the invasiveness of these cells and their expression of keratin-18. These results support the notion that the metastatic behavior of lung cancer cells can be characterized with this in vitro system, and that the properties of these progressively invasive cancer cells can be clonally studied.

The objective of this study was to assess international trends in antipsychotic use, using a standardised methodology. A repeated cross-sectional design was applied to data extracts from the years 2005 to 2014 from 16 countries worldwide. During the study period, the overall prevalence of antipsychotic use increased in 10 of the 16 studied countries. In 2014, the overall prevalence of antipsychotic use was highest in Taiwan (78.2/1000 persons), and lowest in Colombia (3.2/1000). In children and adolescents (0-19 years), antipsychotic use ranged from 0.5/1000 (Lithuania) to 30.8/1000 (Taiwan). In adults (20-64 years), the range was 2.8/1000 (Colombia) to 78.9/1000 (publicly insured US population), and in older adults (65+ years), antipsychotic use ranged from 19.0/1000 (Colombia) to 149.0/1000 (Taiwan). Atypical antipsychotic use increased in all populations (range of atypical/typical ratio: 0.7 (Taiwan) to 6.1 (New Zealand, Australia)). Quetiapine, risperidone, and olanzapine were most frequently prescribed. Prevalence and patterns of antipsychotic use varied markedly between countries. In the majority of populations, antipsychotic utilisation and especially the use of atypical antipsychotics increased over time. The high rates of antipsychotic prescriptions in older adults and in youths in some countries merit further investigation and systematic pharmacoepidemiologic monitoring.

While clozapine use has increased in most studied countries over recent years, clozapine is still underutilised in many countries, with clozapine utilisation patterns differing significantly between countries. Future research should address the implementation of interventions designed to facilitate increased clozapine utilisation.

IMPORTANCE Previous studies suggest that depression and anxiety are common in patients with hidradenitis suppurativa (HS), more so than other dermatological conditions. Yet, to the authors' knowledge, no previous systematic review or meta-analysis has estimated the prevalence or odds ratio (OR) for those psychiatric comorbidities in this population. OBJECTIVE To assess the prevalence and odds for depression and anxiety in patients with HS. DATA SOURCES From July 25 to September 30, 2018, observational studies investigating the prevalence and odds for depression and anxiety in adults with HS were systematically searched without language restriction from the inception of each database to July 25, 2018, in PubMed/MEDLINE, Embase, and PsycINFO databases. Searches used various configurations of the terms hidradenitis suppurativa; acne inversa; depressive disorder; depression; anxiety; anxiety disorders; phobia, social; suicide; and suicide, attempted. In addition, the reference lists of included references were screened manually. STUDY SELECTION Two investigators independently screened references that measured prevalence rates and odds for depressive and anxiety symptoms in patients with HS. Of 136 unique references, 10 ultimately met inclusion criteria. DATA EXTRACTION AND SYNTHESIS Relevant data were extracted from eligible references. Authors were contacted to provide further information when necessary. Methodological quality of included studies was assessed through a modified version of the Newcastle-Ottawa Scale. Random-effects models were used to synthesize available evidence. MAIN OUTCOMES AND MEASURES Prevalence rates and ORs for depression and anxiety in adults with HS were the primary outcome measures. Heterogeneity across studies was assessed with the I 2 statistic. Sources of heterogeneity were explored through subgroup and meta-regression analyses. RESULTS Ten studies comprising 40 307 participants with HS met inclusion criteria. The overall prevalence of depression was 16.9% (95% CI, 9.9%-27.2%). Heterogeneity was large. In the subgroup of studies that considered a clinical criteria-based diagnosis of depression, the prevalence of depression was 11.9% (95% CI, 4.9%-26.2%), compared with 26.8% (95% CI, 20.4%-34.5%) in studies that used a screening instrument. The methodological quality of included studies moderated those findings. The OR for depression in individuals with HS compared with individuals without HS was 1.84 (95% CI, 1.57-2.15). The prevalence of anxiety was 4.9% (95% CI, 1.7%-13.2%); there were insufficient data to determine an odds ratio for anxiety in persons with HS because 2 studies included a comparison group. CONCLUSIONS AND RELEVANCE This systematic review and meta-analysis indicates that depression and anxiety are common comorbid conditions in patients with HS. Results suggest that the development of strategies to recognize and treat those psychiatric comorbidities in patients with HS is warranted.

Accumulation of N-terminal fragments of mutant huntingtin (mHTT) in the cytoplasm, nuclei and axons of neurons is a hallmark of Huntington's disease (HD), although how these fragments negatively impact neurons remains unclear. We followed the distribution of mHTT in the striata of transgenic R6/2-J2 HD mice as their motor function declined. The fraction of cells with diffuse, perinuclear or intranuclear mHTT changed in parallel with decreasing motor function. In transgenic mice, medium spiny neurons (MSNs) that exhibited perinuclear inclusions expressed cell-cycle markers typically not seen in the striata of normal mice, and these cells are preferentially lost as disease progresses. Electron microscopy reveals that perinuclear inclusions disrupt the nuclear envelope. The progression of perinuclear inclusions being accompanied by cell-cycle activation and culminating in cell death was also observed in 1° cortical neurons. These observations provide a strong correlation between the subcellular location of mHTT, disruption of the nucleus, re-entry into the cell-cycle and eventual neuronal death. They also highlight the fact that the subcellular distribution of mHTT is highly dynamic such that the distribution of mHTT observed depends greatly on the stage of the disease being examined.

BackgroundIt is currently unclear whether parenteral selenium supplementation should be recommended in the management of critically ill patients. Here we conducted a systematic review and meta-analysis to assess the efficacy of parenteral selenium supplementation on clinical outcomes.Methods/Principal FindingsRandomized trials investigating parenteral selenium supplementation administered in addition to standard of care to critically ill patients were included. CENTRAL, Medline, EMBASE, the Science Citation Index, and CINAHL were searched with complementary manual searches. The primary outcome was all-cause mortality. Trials published in any language were included. Two authors independently extracted data and assessed trial quality. A third author was consulted to resolve disagreements and for quality assurance. Twelve trials were included and meta-analysis was performed on nine trials that recruited critically ill septic patients. These comprised 965 participants in total. Of these, 148 patients (30.7%) in the treatment groups, and 180 patients (37.3%) in control groups died. Parenteral selenium treatment significantly reduced all-cause mortality in critically ill patients with sepsis (relative risk [RR] 0.83, 95% CI 0.70–0.99, p = 0.04, I2 = 0%). Subgroup analyses demonstrated that the administration schedule employing longer duration (RR 0.77, 95% CI 0.63–0.94, p = 0.01, I2 = 0%), loading boluses (RR 0.73, 95% CI 0.58–0.94, p = 0.01, I2 = 0%) or high-dose selenium treatment (RR 0.77, 95% CI 0.61–0.99, p = 0.04, I2 = 0%) might be associated with a lower mortality risk. There was no evidence of adverse events.Conclusions/SignificanceParenteral selenium supplementation reduces risk of mortality among critically ill patients with sepsis. Owing to the varied methodological quality of the studies, future high-quality randomized trials that directly focus on the effect of adequate-duration of parenteral selenium supplementation for severe septic patients are needed to confirm our results. Clinicians should consider these findings when treating this high-risk population.Systematic Review RegistrationPROSPERO 2011; CRD42011001768

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CISD2 is located within the chromosome 4q region frequently deleted in hepatocellular carcinoma (HCC). Mice with Cisd2 heterozygous deficiency develop a phenotype similar to the clinical manifestation of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Cisd2 haploinsufficiency causes a low incidence (20%) of spontaneous HCC and promotes HBV-associated and DEN-induced HCC; conversely, 2-fold overexpression of Cisd2 suppresses HCC in these models. Mechanistically, Cisd2 interacts with Serca2b and mediates its Ca pump activity via modulation of Serca2b oxidative modification, which regulates ER Ca uptake and maintains intracellular Ca homeostasis in the hepatocyte. CISD2 haploinsufficiency disrupts calcium homeostasis, causing ER stress and subsequent NAFLD and NASH. Hemizygous deletion and decreased expression of CISD2 are detectable in a substantial fraction of human HCC specimens. These findings substantiate CISD2 as a haploinsufficient tumor suppressor and highlights Cisd2 as a drug target when developing therapies to treat NAFLD/NASH and prevent HCC.