Citations

Background/objectives Gallstone disease and its complications are common, particularly in Western populations. Recent studies have reported a significantly increased risk of gallstones among hepatitis C virus-infected patients. However, the data on patients with hepatitis B virus (HBV) infection are still limited. This meta-analysis was carried out with the aim of summarizing all available evidence. Patients and methods A literature search was performed using MEDLINE and the EMBASE database from inception to May 2016. Studies that reported relative risks, odd ratios, or hazard ratios comparing the risk of gallstones among HBV-infected patients versus patients without HBV infection were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse-variance method. Results Nine studies fulfilled our eligibility criteria and were included in the analysis. We found no significant association between HBV infection and the risk of gallstones, with a pooled OR of 1.10 (95% CI, 0.91–1.33). The statistical heterogeneity was moderate, with an I 2 of 69%. Subgroup analysis was carried out. The pooled OR of cross-sectional studies was 1.01 (95% CI, 0.91–1.12; I 2 0%), whereas the pooled OR of case–control studies was 1.53 (95% CI, 0.85–2.74; I 2 80%). Conclusion A significant association between HBV infection and the risk of gallstones was not observed in this study.

Krabbe's disease (KD) is a fatal neurodegenerative disorder, with the early‐infantile form (EIKD) defined by onset of symptoms before age 6 months. Early and highly accurate identification of EIKD is required to maximize benefits of hematopoietic stem cell transplantation treatment. This study investigates the potential for accurate prediction of EIKD based on a novel newborn screening (NBS) tool developed from two biomarkers, galactocerebrosidase (GALC) enzyme activity and galactosylsphingosine concentration (psychosine [PSY]). Normative information about PSY and GALC, derived from distinct samples of normal newborns, was used to develop the novel diagnostic tool. Bivariate normal limits (BVNL) were constructed, assuming a multivariate normal distribution of natural logarithms of GALC and PSY of normal newborns. The (lnGALC, lnPSY) points for newborns in various “abnormal groups,” including one group of infants who subsequently suffered EIKD, were plotted on a graph of BVNL. The points for all EIKD patients fell outside of BVNL (100% sensitivity). In a simulation study to compare the false‐positive rate of existing univariate methods of diagnosis with our new BVNL‐based method, we generated 100 million normal newborn data points. All fell within BVNL (i.e., zero false positives), whereas 5,682 false positives were observed when applying a two‐tiered univariate method of the type suggested in the literature. These results suggest that (lnGALC, lnPSY) BVNLs will allow highly accurate prediction of EIKD, whereas two‐tiered univariate approaches will not. Redevelopment of the BVNL based on GALCs and PSYs measured on a common large sample of normal newborns is required for NBS use. © 2016 Wiley Periodicals, Inc.

MicroRNAs (miRNAs) regulate up to one‐third of all protein‐coding genes including genes relevant to cancer. Variants within miRNAs have been reported to be associated with prognosis, survival, response to chemotherapy across cancer types, in vitro parameters of cell growth, and altered risks for development of cancer. Five miRNA variants have been reported to be associated with risk for development of colorectal cancer (CRC). In this study, we evaluated germline genetic variation in 1,123 miRNAs in 899 individuals with CRCs categorized by clinical subtypes and in 204 controls. The role of common miRNA variation in CRC was investigated using single variant and miRNA‐level association tests. Twenty‐nine miRNAs and 30 variants exhibited some marginal association with CRC in at least one subtype of CRC. Previously reported associations were not confirmed (n = 4) or could not be evaluated (n = 1). The variants noted for the CRCs with deficient mismatch repair showed little overlap with the variants noted for CRCs with proficient mismatch repair, consistent with our evolving understanding of the distinct biology underlying these two groups. © 2016 The Authors Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.

Common fragile sites (CFS) are chromosome regions that are prone to form gaps or breaks in response to DNA replication stress. They are often found as hotspots for sister chromatid exchanges, deletions, and amplifications in different cancers. Many of the CFS regions are found to span genes whose genomic sequence is greater than 1 Mb, some of which have been demonstrated to function as important tumor suppressors. CFS regions are also hotspots for human papillomavirus (HPV) integrations in cervical cancer. We used mate‐pair sequencing to examine HPV integration events and chromosomal structural variations in 34 oropharyngeal squamous cell carcinoma (OPSCC). We used endpoint PCR and Sanger sequencing to validate each HPV integration event and found HPV integrations preferentially occurred within CFS regions similar to what is observed in cervical cancer. We also found that many of the chromosomal alterations detected also occurred at or near the cytogenetic location of CFSs. Several large genes were also found to be recurrent targets of rearrangements, independent of HPV integrations, including CSMD1 (2.1Mb), LRP1B (1.9Mb), and LARGE1 (0.7Mb). Sanger sequencing revealed that the nucleotide sequences near to identified junction sites contained repetitive and AT‐rich sequences that were shown to have the potential to form stem‐loop DNA secondary structures that might stall DNA replication fork progression during replication stress. This could then cause increased instability in these regions which could lead to cancer development in human cells. Our findings suggest that CFSs and some specific large genes appear to play important roles in OPSCC. © 2016 Wiley Periodicals, Inc.

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent, acute, and self‐limiting attacks of fever. Mutations in MEFV gene encoding pyrin account for FMF, but the high number of heterozygote patients with typical symptoms of the disease has driven a number of alternative aetiopathogenic hypotheses. The MEFV gene was knocked down in human myelomonocytic cells that express endogenous pyrin to identify deregulated microRNAs (miRNAs). Microarray analyses revealed 29 significantly differentially expressed miRNAs implicated in pathways associated with cellular integrity and survival. Implementation of in silico gene network prediction algorithms and bioinformatics analyses showed that miR‐4520a is predicted to target genes implicated in autophagy through regulation of RHEB/mTOR signaling. Differential expression levels of RHEB were confirmed by luciferase reporter gene assays providing further evidence that is directly targeted by miR‐4520a. Although the relative expression levels of miR‐4520a were variable among FMF patients, the statistical expression of miR‐4520a was different between FMF mutation carriers and controls (P = 0.0061), indicating an association between miR‐4520a expression and MEFV mutations. Comparison between FMF patients bearing the M694V mutation, associated with severe disease, and healthy controls showed a significant increase in miR‐4520a expression levels (P = 0.00545). These data suggest that RHEB, the main activator of mTOR signaling, is a valid target of miR‐4520a with the relative expression levels of the latter being significantly deregulated in FMF patients and highly dependent on the presence of pyrin mutations, especially of the M694V type. These results suggest a role of deregulated autophagy in the pathogenesis of FMF. J. Cell. Physiol. 232: 1326–1336, 2017. © 2016 Wiley Periodicals, Inc.

The newest iteration of the Diagnostic and Statistical Manual–fifth edition (DSM-5), is the first to include the diagnosis of disruptive mood dysregulation disorder (DMDD). The assessment and diagnosis of psychopathology in children are complicated, particularly for mood disorders. Practice can be guided by the use of well-validated instruments. However, as this is a new diagnosis existing instruments have not yet been evaluated for the diagnosis of DMDD. This study seeks to provide a method for using existing structured interview instruments to assess for this contemporary diagnosis. The Children’s Interview for Psychiatric Syndromes (ChIPS) and the Mini-International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) are reviewed and existing items consistent with a diagnosis of DMDD are identified. Finally, a case is presented using both measures and applying the theoretical items identified to illustrate how one might use these measures to assess DMDD. Limitations and future directions are discussed.

Context: Kisspeptin and neurokinin B (NKB) are obligate for normal gonadotropin secretion, but their hierarchy is unexplored in normal women. Objective: To investigate the interaction between kisspeptin and NKB on estrogen-regulated LH secretion. Design: Women were treated with neurokinin-3 receptor (NK3R) antagonist followed by transdermal estradiol to induce LH secretion 48 hours later, with kisspeptin-10 or vehicle infusion during estrogen administration in a 2-way crossover study. Setting: Clinical research facility. Patients or other participants: Healthy females with regular menses. Intervention(s): NK3R antagonist AZD4901 40 mg twice daily orally was taken from cycle day 4–6 for 6 days (n = 10, with 10 no treatment controls). Transdermal estradiol patches (200 μg/d) were applied after 5 days of NK3R antagonist treatment. At 24-hour estradiol treatment, women were randomized to 7-hour kisspeptin-10 (4 μg/kg/h) or vehicle iv infusion, with the alternate infusion in a subsequent cycle. Main outcome measure(s): Plasma gonadotropin and estradiol secretion. Results: After an initial suppression, LH secretion was increased 48 hours after estradiol treatment. Kisspeptin-10 increased LH secretion during the inhibitory phase, and LH remained elevated beyond the discontinuation of kisspeptin-10 infusion. NK3R antagonist decreased LH pulse frequency (0.5 ± 0.2 vs 0.7 ± 0.2 pulses/h, P < .05) and stimulated FSH response to kisspeptin-10 infusion (10.7 ± 11.0 vs 5.0 ± 3.6 IU/L, P < .05) with a nonsignificant rise in LH. The duration of LH response was blunted, with LH being lower at 48 hours (7.5 ± 4.8 vs 15.0 ± 11.4 IU/L, P < .05). Conclusions: These data demonstrate that NKB signaling regulates GnRH/LH secretion in normal women, and is predominantly proximal to kisspeptin in mediating estrogenic positive and negative feedback on LH secretion.