Incidence of hepatitis C virus (HCV) antibodies and HCV-RNA in blood donors and patients with liver diseases in the Inshore Area of the Yangtze River

The Nantong area is a high risk region for primary hepatocellular carcinoma (PHC) in the inshore area of the Yangtze River. However, no detailed data are available about hepatitis C virus (HCV) infection in this area. We examined the incidences of anti-HCV and HCV-RNA in blood donors with hepatitis B surface antigen (HBsAg)- and hepatitis B core antibody (HBcAb)-negative and patients with chronic liver diseases in the Nantong area at Nantong Medical College, Jiangsu Province, the People's Republic of China. The incidences of HBV markers (HBsAg and/or HBcAb), anti-HCV (C100-3), second generation anti-HCV, HCV-RNA and any marker of HCV in the Nantong area were found to be: 0.0, 0.7, 0.4, 0.2 and 0.7% in donor bloods; 16.9, 0.0, 3.4, 15.7 and 16.9% in patients with acute hepatitis; 82.8, 2.7, 4.8, 7.5 and 10.2% in those with chronic hepatitis; 86.4, 4.5, 9.1, 4.5 and 11.4% in those with liver cirrhosis; 87.5, 6.3, 0.0, 0.0 and 6.3% in those with PHC; and 21.8, 1.3, 1.3, 0.0 and 1.3% in patients without liver diseases, respectively. Although the Nantong area is a high risk region for PHC, these data suggest that HCV infection is not an important aetiological factor for PHC in this area.     

A phase 3b study of sofosbuvir plus ribavirin in treatment‐naive and treatment‐experienced Korean patients chronically infected with genotype 2 hepatitis C virus

In Korea, patients with chronic hepatitis C virus (HCV) infection are typically treated with pegylated interferon‐alpha plus ribavirin, but interferons are contraindicated in many patients and are often poorly tolerated, particularly by the elderly and those with advanced liver disease. No interferon‐free treatment regimens are approved in Korea. Sofosbuvir is an oral nucleotide analog inhibitor of the HCV nonstructural 5B RNA polymerase. It is approved in the USA, European Union and Japan for treating a number of HCV genotypes, including genotype 2. Genotype 2 has a seroprevalence of 38–46% in Korea. This single‐arm, phase 3b study (NCT02021643) examined the efficacy and safety of sofosbuvir plus ribavirin (12‐week duration) in chronic genotype 2 HCV‐infected treatment‐naive and treatment‐experienced Korean patients with and without cirrhosis. The proportion of patients with sustained virologic response 12 weeks after treatment discontinuation (SVR12) was 97% (125/129), with 96% (101/105) of treatment‐naive and 100% (24/24) of treatment‐experienced patients achieving SVR12. Two patients experienced virologic failure (n = 1, on‐treatment failure; n = 1, relapse). No patient discontinued study treatment due to an adverse event (AE). The most common treatment‐emergent AEs were headache (18%, 23/129) and pruritus (15%, 19/129). Few patients had grade 3 AEs (5%, 6/129) or grade 3 laboratory abnormalities (12%, 15/129). No grade 4 AE was reported. These data suggest that 12 weeks of treatment with the all‐oral, interferon‐free regimen of sofosbuvir plus ribavirin is effective and well tolerated in Korean patients with chronic genotype 2 HCV infection.     

Pancreatic islets from cyclin-dependent kinase 4/R24C (Cdk4) knockin mice have significantly increased beta cell mass and are physiologically functional,indicating that Cdk4 is a potential target for pancreatic beta cell mass regeneration in Type 1 diabetes

Aims/hypothesis Cyclin-dependent kinase 4 (Cdk4) is crucial for beta cell development. A mutation in the gene encoding for Cdk4, Cdk4R24C, causes this kinase to be insensitive to INK4 cell cycle inhibitors and induces beta cell hyperplasia in Cdk4R24C knockin mice. We aimed to determine whether this Cdk4R24C mutation also affects proper islet function, and whether it promotes proliferation in human islets lentivirally transduced with Cdk4R24C cDNA.Methods Our study was conducted on wild-type and Cdk4R24C knockin mice. Pancreases were morphometrically analysed. Intraperitoneal glucose tolerance tests and intravenous insulin tolerance tests were performed on wild-type and Cdk4R24C mice. We also did in vitro islet perifusion studies and islet metabolic labelling analysis. Human islets were transduced with Cdk4R24C cDNA.Results Pancreatic islets from Cdk4R24C knockin mice exhibit a larger insulin-producing beta cell area and a higher insulin content than islets from wild-type littermates. Insulin secretion in response to glucose is faster and reaches a higher peak in Cdk4R24C mice without leading to hypoglycaemia. Conversion of proinsulin into insulin and its intermediates is similar in Cdk4R24C and wild-type mice. Glucose utilisation and oxidation measured per islet were similar in both experimental groups. Insulin secretion was faster and enhanced in Cdk4R24C islets perifused with 16.7 mmol/l glucose, with slower decay kinetics when glucose returned to 2.8 mmol/l. Moreover, human islets expressing Cdk4R24C cDNA exhibited higher beta cell proliferation.Conclusions/interpretation Despite their hyperplastic growth, Cdk4R24C insulin-producing islet cells behave like differentiated beta cells with regard to insulin production, insulin secretion in response to glucose, and islet glucose metabolism. Therefore Cdk4 could possibly be used to engineer a source of beta cell mass for islet transplantation.Abbreviations Cdk4 cyclin-dependent kinase 4 - CMV cytomegalovirus - GFP green fluorescence protein - IGTT intraperitoneal glucose tolerance test - IITT intravenous insulin tolerance test - LacZ -galactosidaseN. Marzo, C. Mora and M. E. Fabregat contributed equally to this paper.     

Two rare mutations in Turkey: IVS I.130(G–C) and IVS II.848(C–A)

β‐Thalassemia, an autosomal recessive disease, results from mutations of the β‐globin gene. More than 40 different mutations found in Turkish β‐thalassemia patients are mostly composed of point mutations, and only in very rare cases a deletion or an insertion causes β‐thalassemia phenotypes. Here, we report two patients who were clinically diagnosed with β‐thalassemia major and HbS/β‐thalassemia respectively. We performed reverse dot blot hybridizaton method and automated sequence analysis to detect the mutations. One of the patients was found to be IVS I.130 (G–C) homozygous, the other was HbS/IVS II.848 (C–A) as compound heterozygous. The aim of this study was to report hematological and clinical findings in both cases related with β‐globin gene defects that are very rare.     

Platelets at work in primary hemostasis

When platelet numbers are low or when their function is disabled, the risk of bleeding is high, which on the one hand indicates that in normal life vascular damage is a rather common event and that hence the role of platelets in maintaining a normal hemostasis is a continuously ongoing physiological process. Upon vascular injury, platelets instantly adhere to the exposed extracellular matrix resulting in platelet activation and aggregation to form a hemostatic plug. This self-amplifying mechanism nevertheless requires a tight control to prevent uncontrolled platelet aggregate formation that eventually would occlude the vessel. Therefore endothelial cells produce inhibitory compounds such as prostacyclin and nitric oxide that limit the growth of the platelet thrombus to the damaged area. With this review, we intend to give an integrated survey of the platelet response to vascular injury in normal hemostasis.     

Revisiting the evolution of gonadotropin-releasing hormones and their receptors in vertebrates: secrets hidden in genomes

Gonadotropin-releasing hormone (GnRH) and its G protein-coupled receptor, GnRHR, play a pivotal role in the control of reproduction in vertebrates. To date, many GnRH and GnRHR genes have been identified in a large variety of vertebrate species using conventional biochemical and molecular biological tools in combination with bioinformatic tools. Phylogenetic approaches, primarily based on amino acid sequence identity, make it possible to classify these multiple GnRHs and GnRHRs into several lineages. Four vertebrate GnRH lineages GnRH1, GnRH2, GnRH3, and GnRH4 (for lamprey) are well established. Four vertebrate GnRHR lineages have also been proposed—three for nonmammalian GnRHRs and mammalian GnRHR2 as well as one for mammalian GnRHR1. However, these phylogenetic analyses cannot fully explain the evolutionary origins of each lineage and the relationships among the lineages. Rapid and vast accumulation of genome sequence information for many vertebrate species, together with advances in bioinformatic tools, has allowed large-scale genome comparison to explore the origin and relationship of gene families of interest. The present review discusses the evolutionary mechanism of vertebrate GnRHs and GnRHRs based on extensive genome comparison. In this article, we focus only on vertebrate genomes because of the difficulty in comparing invertebrate and vertebrate genomes due to their marked divergence.