Hydroxychloroquine augments early virological response to pegylated interferon plus ribavirin in genotype‐4 chronic hepatitis C patients

The therapeutic effect of pegylated interferon (peg‐IFN) alfa‐2a combined with ribavirin (RBV) on chronic hepatitis C Egyptian patients is low and further efforts are required to optimize this therapy for achievement of higher rates of virological response. This study aimed to evaluate the safety and efficacy of hydroxychloroquine (HCQ) in combination with pegylated interferon plus ribavirin on early virological response (EVR) in chronic hepatitis C Egyptian patients. Naïve 120 Egyptian patients with chronic hepatitis C virus infection were divided into two groups. Group 1 have administered the standard of care therapy (pegylated interferon alfa‐2a plus ribavirin) for 12 weeks, (n = 60). Group 2 have administered hydroxychloroquine plus standard of care therapy for 12 weeks, (n = 60). Therapeutics included hydroxychloroquine (200 mg) oral twice daily, peginterferon alfa‐2a (160 μg) subcutaneous once weekly and oral weight‐based ribavirin (1000–1200 mg/day). Baseline characteristics were similar in the two groups. The percentage of early virological response was significantly more in patients given the triple therapy than in patients given the standard of care [54/60 (90%) vs. 43/60 (71.7%); P = 0.011; respectively]. Biochemical response at week 12 was also significantly higher in patients given the triple therapy compared with the standard of care [58/60 (96.7%) vs. 42/60 (70%); P < 0.001; respectively]. Along the study, the observed adverse events were mild and similar across treatment groups. Addition of hydroxychloroquine to pegylated interferon plus ribavirin improves the rate of early virological and biochemical responses in chronic hepatitis C Egyptian patients without an increase in adverse events. J. Med. Virol. 88:2170–2178, 2016. © 2016 Wiley Periodicals, Inc.

     

Relationships of sleep duration with sociodemographic and health‐related factors,psychiatric disorders and sleep disturbances in a community sample of Korean adults

The aim of this study is to examine relationships of sleep duration with sociodemographic and health‐related factors, psychiatric disorders and sleep disturbances in a nationwide sample in Korea. A total of 6510 subjects aged 18–64 years participated in this study. Logistic regression was used to calculate the odd ratios and 95% confidence intervals of the covariates, psychiatric disorders and sleep disturbances across the following sleep duration categories: 5 h or less, 6, 7, 8 and 9 h or more per day. Low levels of education, unemployment and physical illness were associated with sleeping for 5 h or less and 9 h or more. Being older and widowed/divorced/separated, high levels of physical activity, pain/discomfort, obesity and high scores on the General Health Questionnaires were associated with sleeping for 5 h or less. Female, being younger and underweight were associated with sleeping for 9 h or more. Alcohol dependence, anxiety disorder and social phobia were associated significantly with sleeping for 5 h or less and 9 h or more. Other psychiatric disorders were more common in subjects who slept for 5 h or less (e.g. alcohol use disorder, mood disorder, major depressive disorder, dysthymic disorder, obsessive‐compulsive disorder and specific phobia) or 9 h or more (e.g. post‐traumatic stress disorder). In addition, subjects who slept for 5 h or less reported more sleep disturbances than did subjects who slept for 7 h. Short or long sleep is associated with psychiatric disorders and/or sleep disturbance, therefore attention to the mental health of short or long sleepers is needed.     

Mutational analysis of hypoxia‐related genes HIF1α and CUL2 in common human cancers

Park SW, Chung NG, Hur SY, Kim HS, Yoo NJ, Lee SH. Mutational analysis of hypoxia‐related genes HIF1α and CUL2 in common human cancers. APMIS 2009; 117: 880–5. Hypoxia is a general feature of solid cancer tissues. Hypoxia upregulates hypoxia‐inducible factor 1α (HIF1α) that transactivates downstream genes and contributes to cancer pathogenesis. HIF1α is upregulated not only by hypoxia but also by genetic alterations in HIF1α‐related genes, including VHL. Cullin 2 (CUL2) interacts with the trimeric VHL‐elongin B‐elongin C complex and plays an essential role in the ubiquitinated degradation of HIF1α. The aim of this study was to explore whether HIF1α and CUL2 genes are somatically mutated, and contribute to HIF1α activation in common human cancers. For this, we have analyzed the coding region of oxygen‐dependent degradation domain of HIF1α in 47 colon, 47 gastric, 47 breast, 47 lung, and 47 hepatocellular carcinomas, and 47 acute leukemias by a single‐strand conformation polymorphism assay. In addition, we analyzed mononucleotide repeat sequences (A8) in CUL2 in 55 colorectal and 45 gastric carcinomas with microsatellite instability (MSI). We found one HIF1α mutation (p.Ala593Pro) in the hepatocellular carcinomas (1/47; 2.1%), but none in other cancers. We found two CUL2 frameshift mutations in colon cancers (p.Asn292MetfsX20), which were exclusively detected in high MSI cancers (4.9%; 2/41). Our data indicate that somatic mutation of HIF1α is rare in common cancers, and somatic mutation of CUL2 occurs in a fraction of colorectal cancers (colorectal cancers with high MSI). The data suggest that neither HIF1α nor CUL2 mutation may play a central role in HIF1α activation in gastric, colorectal, breast, lung and hepatocellular carcinomas, and acute leukemias.     

Acquired and inherited thrombophilia: implication in recurrent IVF and embryo transfer failure

BACKGROUND: The objective of this study was to determine the incidence of undiagnosed thrombophilic factors and its relation to IVF and embryo transfer failure in women who have had three or more previous IVF-embryo transfer cycles. METHODS: The study group comprised of 90 consecutive women with three or more previously failed IVF-embryo transfer cycles (group A). Two control groups were enrolled: group B (n=90) included women who have had successful pregnancy after their first IVF-embryo transfer cycle, and group C (n=100) included women who conceived spontaneously with at least one uneventful pregnancy and no previous history of miscarriage. All women were tested for the presence of inherited [factor V Leiden (FVL) mutation, prothrombin mutation, methylenetetrahydrofolate reductase (MTHFR) mutation and deficiencies in proteins S and C and antithrombin III] or acquired (lupus anticoagulant and anticardiolipin) thrombophilic factors. RESULTS: An increase in the incidences of FVL, MTHFR and antiphospholipid antibodies was found in the study group compared with the two control groups. At least one inherited or acquired thrombophilic factor was detected in 68.9% of women with repeated IVF failure compared with 25.6 and 25% in the groups B and C, respectively (P<0.01). Combined thrombophilia (two or more thrombophilic factors) was significantly higher in women who have had repeated IVF failure as compared with the two control groups (35.6 versus 4.4 and 3%) (P<0.0001). CONCLUSION: Thrombophilia has a significant role in IVF-embryo transfer implantation failure. Women with repeated IVF-embryo transfer failure should be screened for thrombophilia.     

Asynaptic feature and heterogeneous distribution of the cholinergic innervation of the globus pallidus in primates

The internal (GPi) and external (GPe) segments of the primate globus pallidus receive a significant cholinergic (ACh) innervation from the brainstem pedunculopontine tegmental nucleus. The present immunohistochemical study describes this innervation in the squirrel monkey (Saimiri sciureus), as visualized with an antibody raised against choline acetyltransferase (ChAT). At the light microscopic level, unbiased stereological quantification of ChAT positive (+) axon varicosities reveals a significantly lower density of innervation in GPi (0.26 ± 0.03 × 10⁶) than in GPe (0.47 ± 0.07 × 10⁶ varicosities/mm³ of tissue), with the anterior half of both segments more densely innervated than the posterior half. Neuronal density of GPi (3.00 ± 0.13 × 10³ neurons/mm³) and GPe (3.62 ± 0.22 × 10³ neurons/mm³) yields a mean ratio of ChAT+ axon varicosities per pallidal neuron of 74 ± 10 in the GPi and 128 ± 28 in the GPe. At the electron microscopic level, the pallidal ChAT+ axon varicosities are significantly smaller than their unlabeled counterparts, but are comparable in size and shape in the two pallidal segments. Only a minority of ChAT+ varicosities displays a synaptic specialization (12 % in the GPi and 17 % in the GPe); these scarce synaptic contacts are mostly of the symmetrical type and occur exclusively on pallidal dendrites. No ChAT+ axo-axonic synaptic contacts are observed, suggesting that ACh exerts its modulatory action on pallidal afferents through diffuse transmission, whereas pallidal neurons may be influenced by both volumic and synaptic delivery of ACh.     

Impact of HLA-C and Bw epitopes disparity on liver transplantation outcome

The occurrence of graft rejection episodes after orthotopic liver transplantation (OLT) despite the use of immunosuppressive drugs designed to suppress T lymphocyte functions, indicates the involvement of other types of cells in this process. The activity of natural killer cells and their killer immunoglobulin-like receptors (KIR) is regulated by human leukocyte antigen (HLA) class I determinants; C and Bw epitopes. Because recipient/donor pairs are usually HLA mismatched, recipient natural killer alloreactivity may be the mediating factor in rejection. In this retrospective study, we have analyzed rejection occurrence and outcome in 66 OLT recipients, 42 with and 24 without C or Bw epitope disparity in the rejection direction. Recipients transplanted from donors with no C epitope disparity had significantly fewer rejection episodes in the first year after transplantation compared with recipients transplanted across C epitope disparity (p = 0.0002). Moreover, this effect was more pronounced when the outcome was analyzed in OLT recipients across negative crossmatching for the anti-HLA class I and II antibodies. In contrast, Bw epitope disparity did not affect the outcome. In conclusion, C epitopes disparity between recipients and donors in the rejection direction appears to influence posttransplant liver outcome. This finding may be helpful in the choice of appropriate liver donor and planning immune suppression.     

Arthritis Susceptibility in Mice Expressing Human Type II Collagen in Cartilage

Collagen type II (CII) induced arthritis (CIA) in mice is an experimental model for rheumatoid arthritis. Induction with non-self (e.g. human) CII induces severe arthritis whereas the mice are less susceptible to induction with self CII (i.e. mouse). To analyse whether an autoimmune response to human CII can develop and is pathogenic the authors have established transgenic mice expressing human CII in cartilage and backcrossed them into two different gene backgrounds susceptible to CIA (DBA/1 and C3H.Q). The transgenic human CII expression was restricted to cartilage and did not disturb cartilage morphology or lead to chondrodystrophy. In addition, development of stress-induced arthritis was not affected by the transgene. The cartilage specific expression of human CII reduced, but did not eliminate, the susceptibility to CIA irrespective of the species source (human, bovine, chick, rat) of CII used for immunization. A common denominator between these heterologous CII in comparison with mouse CII is the previously defined CII 256–270 epitope. An expression level dependent T-cell tolerance was seen in this epitope as well as to the entire CII. However, all human transgenic mouse lines could still mount significant autoreactive T- and B-cell responses. Approximately 10% of the transgenic mice developed arthritis after immunization with human CII. These findings show, therefore, that cartilage-located human CII induce tolerance but can nevertheless be a target for development of arthritis.     

Relationship between cytokine concentrations (FGF, sICAM-1 and SCF) in serum, follicular fluid and ICSI outcome

OBJECTIVE: The aim of this study was (i) to investigate the existence of fibroblast growth factor (FGF), soluble intracellular adhesion molecule-1 (sICAM-1), and stem cell factor (SCF) in serum and human follicular fluid (FF) of intracytoplasmic sperm injection (ICSI) patients, and (ii) to determine the relationship between these parameters and ICSI outcome. MATERIAL AND METHOD: Seventy-five patients undergoing controlled ovarian hyperstimulation with human menopausal gonadotropin (hMG) after down-regulation with GnRHa were included in this study. The concentrations of FGF, SCF, and sICAM-1 were measured by using commercially available enzyme-linked immunosorbent assay test kits. RESULTS: The FGF, sICAM-1, and SCF concentrations in the serum of women who become pregnant (group I) were 8.5 +/- 1.5 pg/mL, 235.8 +/- 81.1 ng/mL, and 597.7 +/- 139.9 pg/mL, and the corresponding concentrations of women who did not (group II) were 6.4 +/- 3.6 pg/mL, 230.6 +/- 66.5 ng/mL, and 569.6 +/- 91.4 pg/mL respectively. No significant difference was observed between the two investigated groups with regard to the number of hMG ampoules administered for controlled ovarian hyperstimulation, estradiol concentration on the day of human chorionic gonadotropin (hCG) injection, number of retrieved oocytes and fertilization rate. CONCLUSION: The concentration of FGF, sICAM-1, and SCF did not differ significantly between the two groups in serum or in FF. Besides, the ICSI outcome was not related to their concentrations in serum or FF. Therefore, these parameters could not be used as a prognostic factor in ICSI program.     

Functional polymorphisms in the LTF gene and risk of coronary artery stenosis

Plasma lactoferrin concentrations are increased in patients with coronary artery stenosis. We investigated the effects of LTF gene polymorphisms in 305 healthy blood donors and their associations with coronary artery stenosis in 236 patients admitted for coronary angiography. Lactoferrin concentrations were determined by enzyme immunoassay. Genotyping was performed by polymerase chain reaction and DNA sequencing of LTF exons 2 and 4. In the blood donors, the deletion variant of rs10662431 and the G allele of rs1126478 were associated with higher plasma lactoferrin concentrations. The G allele of rs1126478 was more frequent in patients with significant coronary artery stenosis (p = 0.018, p value limit for significance by permutation = 0.030). The association remained significant in logistic regression with adjustment for clinical risk factors (odds ratio 2.485 [95% confidence interval 1.116-5.536], p = 0.026), but was weakened upon the inclusion of plasma lactoferrin (odds ratio 2.295 [0.949-5.550], p = 0.064). Current evidence indicates that rs1126478 affects the antibacterial effect of lactoferrin and that lactoferrin is involved in lipid metabolism. The relationships among lactoferrin genotypes, lactoferrin concentrations, and clinical factors on the risk for atherosclerosis are not fully understood, but the G allele of rs1126478 seems to have a detrimental effect in a European population.