Dyskeratosis congenita (DC) is a genetic disorder of defective tissue maintenance and cancer predisposition caused by short telomeres and impaired stem cell function. Telomerase mutations are thought to precipitate DC by reducing either the catalytic activity or the overall levels of the telomerase complex. However, the underlying genetic mutations and the mechanisms of telomere shortening remain unknown for as many as 50% of DC patients, who lack mutations in genes controlling telomere homeostasis. Here, we show that disruption of telomerase trafficking accounts for unknown cases of DC. We identify DC patients with missense mutations in TCAB1, a telomerase holoenzyme protein that facilitates trafficking of telomerase to Cajal bodies. Compound heterozygous mutations in TCAB1 disrupt telomerase localization to Cajal bodies, resulting in misdirection of telomerase RNA to nucleoli, which prevents telomerase from elongating telomeres. Our findings establish telomerase mislocalization as a novel cause of DC, and suggest that telomerase trafficking defects may contribute more broadly to the pathogenesis of telomere-related disease.

Blockade of the Cytotoxic T Lymphocyte-associated Antigen 4 (CTLA-4), a down-regulator of T cell activation, can cause cancer regression in patients with metastatic melanoma. However, not all patients respond well to the therapy and some develop severe autoimmune reactions. We hypothesized that common genetic variation in the CTLA4 gene could contribute to response to CTLA-4 blockade and the occurrence of autoimmune reactions. We investigated seven common single-nucleotide polymorphisms, SNPs, (rs733618, rs4553808, rs11571317, rs5742909, rs231775, rs3087243 and rs7565213) in 152 Caucasian melanoma patients who received CTLA-4 blockade. Three SNPs were associated with response to therapy: proximal promoter SNPs, rs4553808 (p=0.002, OR 3.39, 95%CI:1.62–7.10) and rs11571327 (p=0.02, OR 2.89, 95%CI: 1.23–6.83) and the non-synonymous SNP rs231775 (Thr17Ala, p=0.009, OR 0.39; 95% CI 0.18–0.82). A haplotype analysis including the 7 SNPs suggested that the common haplotype, TACCGGG could be associated with no response (p=0.02) whereas the haplotype TGCCAGG (p=0.06, OR: 4.13, 95%CI: 1.17–14.5) could be associated with response to the treatment. No significant association was observed for occurrence of severe autoimmune reactions (grade III/IV) either by single SNP or haplotype analyses. Our results suggest that genetic variation in CTLA4 could influence response to CTLA-4 blockade therapy in metastatic melanoma patients, but further studies are necessary to confirm the observed associations.

Background Perinatal depression and/or anxiety disorders are undertreated pregnancy complications. This is partly due to low rates of engagement by women. This study aimed to identify barriers and facilitators to women accessing perinatal mental health services in an outer metropolitan hospital in Queensland, Australia. Methods Data was collected from pregnant women through a cross-sectional survey. Women rated the extent certain factors influenced their engagement. Respondents were separated into three groups: women who were not offered a referral to perinatal mental health services, women who were offered a referral but did not engage, and women who engaged. Results A total of 218 women participated. A response rate of 71% was achieved. 38.1% of participants did not believe themselves knowledgeable about mental illness in the perinatal period, and 14.7% did not recall being asked about their mental health during their pregnancy. Of those participants who recalled being asked about their mental health, 37.1% were offered a referral. Of these, just over a third (36.2%) accepted, and out of this group, 40% attended an appointment. Regardless of referral and engagement status, the factors identified as influencing participant engagement were time restraints, lack of childcare support, and encouragement by family and health care professionals. Stigma was not identified as a barrier. Conclusions Perinatal mental health service engagement could be improved by health services: ensuring universal screening and actively engaging women in the process: assisting with childcare; improving appointment immediacy and accessibility; and educating health care professionals about their influence on women’s engagement. Electronic supplementary material The online version of this article (10.1186/s12884-019-2320-9) contains supplementary material, which is available to authorized users.

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The phagocyte NADPH oxidase catalyzes the reduction of O2 to reactive oxygen species with microbicidal activity. It is composed of two membrane-spanning subunits, gp91-phox and p22-phox (encoded by CYBB and CYBA, respectively), and three cytoplasmic subunits, p40-phox, p47-phox, and p67-phox (encoded by NCF4, NCF1, and NCF2, respectively). Mutations in any of these genes can result in chronic granulomatous disease, a primary immunodeficiency characterized by recurrent infections. Using evolutionary mapping, we determined that episodes of adaptive natural selection have shaped the extracellular portion of gp91-phox during the evolution of mammals, which suggests that this region may have a function in host-pathogen interactions. On the basis of a resequencing analysis of approximately 35 kb of CYBB, CYBA, NCF2, and NCF4 in 102 ethnically diverse individuals (24 of African ancestry, 31 of European ancestry, 24 of Asian/Oceanians, and 23 US Hispanics), we show that the pattern of CYBA diversity is compatible with balancing natural selection, perhaps mediated by catalase-positive pathogens. NCF2 in Asian populations shows a pattern of diversity characterized by a differentiated haplotype structure. Our study provides insight into the role of pathogen-driven natural selection in an innate immune pathway and sheds light on the role of CYBA in endothelial, nonphagocytic NADPH oxidases, which are relevant in the pathogenesis of cardiovascular and other complex diseases.

Associations of FCGR3A among men with HIV/acquired immunodeficiency syndrome suggest that host responses affect the pathogenesis of Kaposi sarcoma herpesvirus (KSHV) infection and risk of acquired immunodeficiency syndrome -associated Kaposi sarcoma. Using DNA from two HIV seronegative case-control populations in Italy, we examined whether the functional FCGR3A-V158F variant was associated with risk of KSHV infection or classic Kaposi sarcoma (CKS). In population I, we examined FCGR3A variants and risk of KSHV infection in 34 KSHV latent nuclear antigen (LANA)-seropositive and 120 LANAseronegative adults from Sardinia (52% male; median age, 45 years; range, 31-60), whereas in population II, we examined risk of CKS from 133 CKS cases and 172 KSHV LANA-seropositive controls from Sicily, Rome, and Naples (70% males; median age, 74 years; range, 29-91). FCGR3A variants were determined by direct sequence analysis of a nested PCR of genomic DNA assay using allele-specific primers. KSHV LANA was determined by immunofluorescence assay. Overall, compared with the 158F allele, 158V was overrepresented among controls from both Mediterranean populations (frequency = 0.52 and 0.51, respectively). After controlling for age, 158V homozygous women were at increased risk of KSHV infection and CKS compared with 158F homozygous women [odds ratio (OR), 8.7; 95% confidence interval (95% CI), 0.8-98 and OR, 3.8; 95% CI, 1.0-14, respectively], whereas homozygous men were at decreased risk (OR, 0.4; 95% CI, 0.1-2.3 and OR, 0.4; 95% CI, 0.2-0.8, respectively). Significant gene-dose effects were observed among men and women at risk for CKS (P trend V V V 0.05). Our findings suggest that gender differences could possibly modify the effect of FCGR3A on risk of KSHV infection and CKS. Additional studies are required to confirm these relationships and determine their etiologic significance.

Although college students’ caffeine consumption has increased over the last decade, studies have not yet determined the time frame in which caffeine exerts its effects nor the impact of the vehicle by which caffeine is consumed. Sixty college students were randomly divided into one placebo (flour) and three caffeine treatment groups: 5-Hour Energy ®, Starbucks DoubleShot ®, or caffeine powder; all dosed at 3 mg caffeine/kg of body weight.  A battery of tests was performed prior to dosing and repeated 2.5 and 5 hours post treatment. Mood was self-reported on a scale of 1-100 for happiness, alertness and focus. Cognitive function was assessed by Stroop and memory tests. Reaction time, heart rate, blood glucose, and electroencephalogram were recorded. All initial measurements across groups and group baselines vs 2.5 and 5 hour results were analyzed by ANOVA followed, when indicated, by post hoc t-tests at 95% confidence levels and only significant results are reported. All caffeine groups had elevations in mood and faster reaction times at 2.5 hours (most effects sustained for 5 hours).  The 5-Hour Energy® group rated alertness higher than other caffeine treatments, and was the only group to demonstrate decreases in alpha waves, memory improvements, and impaired glucose homeostasis. All caffeine groups had improved cognition with decreased Stroop test time and the caffeine powder and 5-Hour Energy ® groups had improved Stroop test accuracy at 2.5 hours. The 5-Hour Energy shot ® had the greatest proportion of sustained caffeine effects across test parameters.

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