Citations

AbstractMany skin and skin‐related diseases affect the sexes unequally, with attendant implications for public health and resource allocation. To evaluate better the incidence of skin and skin‐related diseases affecting males vs. females, we reviewed published population‐based epidemiology studies of skin disorders performed utilizing Rochester Epidemiology Project data. Females had a higher incidence of the following diseases: connective tissue diseases (scleroderma, morphea, dermatomyositis, primary Sjögren syndrome, systemic lupus erythematosus [not in all studies]), pityriasis rosea, herpes progenitalis, condyloma acuminatum, hidradenitis suppurativa, herpes zoster (except in children), erythromelalgia, venous stasis syndrome, and venous ulcers. Males had a higher incidence of psoriasis and psoriatic arthritis, basal cell carcinoma (exception, females aged ≤40 years), squamous cell carcinoma, and lentigo maligna. Incidence rates were equal in males and females for cutaneous malignant melanoma (exception, higher in females aged 18–39 years), lower‐extremity cellulitis, cutaneous nontuberculous mycobacterial infection, Behçet disease, delusional infestation, alopecia areata, and bullous pemphigoid. Many of the population‐based sex‐specific incidence rates of skin and skin‐related diseases derived from the Rochester Epidemiology Project are strikingly different from those estimated elsewhere. In general, females are more commonly affected by skin and skin‐related diseases. The reasons for this imbalance remain to be determined and are likely multifactorial.

Abstract Background and Aims Depression and anxiety are often comorbid with alcoholism and contribute to craving and relapse. We aimed to estimate the prevalence of life‐time diagnoses of major depressive disorder (MDD), substance‐induced depression (SID), anxiety disorder (AnxD) and substance‐induced anxiety (SIA), the effects of these comorbidities on the propensity to drink in negative emotional states (negative craving), and test whether these effects differ by sex. Design Secondary analyses of baseline data collected in a single‐arm study of pharmacogenetic predictors of acamprosate response. Setting Academic medical center and affiliated community‐based treatment programs in the American upper mid‐west. Participants A total of 287 males and 156 females aged 18–80 years, meeting DSM‐IV criteria for alcohol dependence. Measurements The primary outcome measure was ‘propensity to drink in negative emotional situations’ (determined by the Inventory of Drug Taking Situations) and the key predictors/covariates were sex and psychiatric comorbidities, including MDD, SID, AnxD and SIA (determined by Psychiatric Research Interview of Substance and Mood Disorders). Findings The prevalence of the MDD, SID and AnxD was higher in females compared with males (33.1 versus 18.4%, 44.8 versus 26.4% and 42.2 versus 27.4%, respectively; P < 0.01, each), while SIA was rare (3.3%) and did not differ by sex. Increased propensity to drink in negative emotional situations was associated with comorbid MDD (β = 6.6, P = 0.013) and AnxD (β = 4.8, P = 0.042) as well as a SID × sex interaction effect ( P = 0.003), indicating that the association of SID with propensity to drink in negative emotional situations differs by sex and is stronger in males (β = 7.9, P = 0.009) compared with females (β = −6.6, P = 0.091). Conclusions There appears to be a higher prevalence of comorbid depression and anxiety disorders as well as propensity to drink in negative emotional situations in female compared with male alcoholics. Substance‐induced depression appears to have a sex‐specific effect on the increased risk for drinking in negative emotional situations in males.

Abstract Frontotemporal lobar degeneration ( FTLD ) comprises a highly heterogeneous group of disorders clinically associated with behavioral and personality changes, language impairment, and deficits in executive functioning, and pathologically associated with degeneration of frontal and temporal lobes. Some patients present with motor symptoms including amyotrophic lateral sclerosis. Genetic research over the past two decades in FTLD families led to the identification of three common FTLD genes (microtubule‐associated protein tau, progranulin, and chromosome 9 open reading frame 72) and a small number of rare FTLD genes, explaining the disease in almost all autosomal dominant FTLD families but only a minority of apparently sporadic patients or patients in whom the family history is less clear. Identification of additional FTLD (risk) genes is therefore highly anticipated, especially with the emerging use of next‐generation sequencing. Common variants in the transmembrane protein 106 B were identified as a genetic risk factor of FTLD and disease modifier in patients with known mutations. This review summarizes for each FTLD gene what we know about the type and frequency of mutations, their associated clinical and pathological features, and potential disease mechanisms. We also provide an overview of emerging disease pathways encompassing multiple FTLD genes. We further discuss how FTLD specific issues, such as disease heterogeneity, the presence of an unclear family history and the possible role of an oligogenic basis of FTLD , can pose challenges for future FTLD gene identification and risk assessment of specific variants. Finally, we highlight emerging clinical, genetic, and translational research opportunities that lie ahead. image Genetic research led to the identification of three common FTLD genes with rare variants ( MAPT , GRN , and C9orf72 ) and a small number of rare genes. Efforts are now ongoing, which aimed at the identification of rare variants with high risk and/or low frequency variants with intermediate effect. Common risk variants have also been identified, such as TMEM106B . This review discusses the current knowledge on FTLD genes and the emerging disease pathways encompassing multiple FTLD genes. This article is part of the Frontotemporal Dementia special issue .

Abstract Glioblastoma (GBM) is the most common malignant primary brain cancer. With a median survival of about a year, new approaches to treating this disease are necessary. To identify signaling molecules regulating GBM progression in a genetically engineered murine model of proneural GBM, we quantified phosphotyrosine-mediated signaling using mass spectrometry. Oncogenic signals, including phosphorylated ERK MAPK, PI3K, and PDGFR, were found to be increased in the murine tumors relative to brain. Phosphorylation of CDK1 pY15, associated with the G2 arrest checkpoint, was identified as the most differentially phosphorylated site, with a 14-fold increase in phosphorylation in the tumors. To assess the role of this checkpoint as a potential therapeutic target, syngeneic primary cell lines derived from these tumors were treated with MK-1775, an inhibitor of Wee1, the kinase responsible for CDK1 Y15 phosphorylation. MK-1775 treatment led to mitotic catastrophe, as defined by increased DNA damage and cell death by apoptosis. To assess the extensibility of targeting Wee1/CDK1 in GBM, patient-derived xenograft (PDX) cell lines were also treated with MK-1775. Although the response was more heterogeneous, on-target Wee1 inhibition led to decreased CDK1 Y15 phosphorylation and increased DNA damage and apoptosis in each line. These results were also validated in vivo, where single-agent MK-1775 demonstrated an antitumor effect on a flank PDX tumor model, increasing mouse survival by 1.74-fold. This study highlights the ability of unbiased quantitative phosphoproteomics to reveal therapeutic targets in tumor models, and the potential for Wee1 inhibition as a treatment approach in preclinical models of GBM. Mol Cancer Ther; 15(6); 1332–43. ©2016 AACR.

Hypophosphatemia has been described in patients undergoing right hepatectomy for liver cancer and in living donors for liver transplantation who also received total parenteral nutrition. At the study centre, significant hypophosphatemia (0.36 mmol/L or less) requiring intravenous replacement was seen in two of the first nine living donors for adult-to-adult liver transplantation. To determine the frequency of hypophosphatemia in living donors, the authors obtained phosphate levels on stored serum samples from postoperative days 0, 1, 3 and 7 in all nine patients, none of whom were on total parenteral nutrition. Within the first week, hypophosphatemia developed in 55.6% of patients and phosphate levels returned to normal by day 7 in all nine patients. One patient had normal phosphate levels during the first week, but had profound hypophosphatemia (0.32 mmol/L) on day 14 when he presented with a Staphylococcus aureus infection of a bile collection and significant hypoxemia. The extent of hepatectomy and the rate of liver regeneration, estimated by baseline and postoperative day 7 volumetric computed tomography scans, did not correlate with the development of hypophosphatemia. In conclusion, hypophosphatemia is common in living donors undergoing right hepatectomy and may be associated with complications. All living donors should be monitored for the development of hypophosphatemia during the first two postoperative weeks.

Not so long ago, physicians construed the irritable bowel syndrome (IBS) as being a neurotic trait: it was all in the head. Today most clinicians believe that the main abnormality lies in the brain (and spinal cord), which reacts abnormally to stimuli from the gut. Recent studies are identifying a basis for these neural changes - low grade inflammation in the gut - which may play a key role in IBS.

ROS deficiency promotes proinflammatory T cells in rheumatoid arthritis.