Beneficial effect of successful HCV treatment in patients with inherited bleeding disorders, assessed by liver stiffness measurements

Hepatitis C infection is a major comorbidity in patients with inherited bleeding disorders. Successful antiviral treatment leads to a reduction in liver fibrosis, as shown by liver biopsies. Liver stiffness measurement (LSM) is a non-invasive method of assessing liver fibrosis. The aim of this cohort study was to evaluate the long-term effect of successful antiviral treatment, using LSM, in HCV-infected patients with inherited bleeding disorders. The LSM were performed in 2005 (LSM 1) and 2009 (LSM 2) in 39 patients who were successfully treated for HCV. The change in liver fibrosis between LSM 1 and 2 was assessed. The median duration of HCV infection was 28.8 years. A total of 22 patients (56%) underwent successful antiviral treatment before LSM 1 (group 1), and 17 patients between LSM 1 and LSM 2 (group 2). The median time since antiviral treatment was 8.8 years in group 1 and 2.5 years in group 2. In group 1, the median results of LSM 1 and 2 were similar (6.0 vs. 5.6 kPa, P-value 0.36), so overall, patients remained stable. In three patients in this group, all treated more than 15 years ago, an increase of liver stiffness was shown. Group 2 showed a significant improvement in median LSM results (10.3 vs. 6.1 kPa, P-value <0.01), with decrease of liver stiffness in 82%. Even after a long HCV infection duration, successful antiviral treatment led to a significant improvement of fibrosis, measured by LSM, mainly in the first few years after completing treatment.     

Telaprevir/boceprevir era: From bench to bed and back

Hepatitis C virus (HCV) infects approximately 200 million people worldwide. Interferon-based therapies have dominated over the past two decades. However, the overall response rates remain suboptimal. Thanks to the tremendous effort from both academia and industry, two serine protease inhibitors telaprevir and boceprevir for treating chronic hepatitis C have finally reached the clinic. Although these compounds are only approved for combination use with interferon and ribavirin in genotype 1 HCV infected chronic patients, the management of HCV patients however is now evolving incredibly. Here, we overviewed a series of landmark studies, regarding the clinical development of telaprevir and boceprevir. We discussed the mechanism-of-action of telaprevir/boceprevir and their potential application in HCV-positive liver transplantation patients. We further emphasized some emerging concerns with perspective of further development in this field.     

Clinical relevance of diagnosing structural chromosome abnormalities in couples with repeated miscarriage

BACKGROUND: The annual number of parental karyotypes in cases of repeated miscarriage is increasing gradually in The Netherlands. The efficiency of offering parental karyotyping in couples with repeated miscarriage has not been evaluated before, especially not for the group with miscarriages at advanced maternal age. METHODS: A historical cohort study and nested case-control study were conducted, including couples with at least two miscarriages. Data were retrieved from medical records and telephone interviews. The obstetric follow-up was recorded for > or =2 years after the parental chromosome analysis. Data were analysed to compare ratios of carrier/non-carrier couples in whom maternal age was > or =36 or <36 years at the second, third or fourth and more miscarriage. A projected prevalence of carrier status of a structural chromosome abnormality was calculated by extrapolating the number of included patients to the original level of the total screening population. RESULTS: Forty-one couples with carrier status of a structural chromosome abnormality and 74 couples without carrier status were included. No unbalanced offspring arose after the detection of a structural chromosome abnormality. The risk of being a carrier was not significantly lower (as might be expected) when women were > or =36 years. Ascertainment after two, three, or four and more miscarriages did not change these findings. CONCLUSIONS: Karyotyping of 1324 couples ascertained for repeated miscarriage did not yield an unbalanced fetal chromosome pattern after the ascertainment of parental carrier status. In women with advanced maternal age, the frequency of carrier status was not lower than in younger women.     

Subtelomeric 6.7 Mb trisomy 10p and 5.6 Mb monosomy 21q detected by FISH and array-CGH in three related patients

Cryptic subtelomeric chromosomal aberrations are responsible for 5-10% of moderate/severe and 1% of mild intellectual disability. Unbalanced subtelomeric chromosomal rearrangements result in variable phenotypes which seem to be highly influenced by both the size of the duplication/deletion and the chromosomes involved in the translocation. We report on three related patients with moderate intellectual disability, language delay, hypotonia, facial dysmorphism, cardiac anomalies, scoliosis, and kyphosis in whom a familial (maternal) unbalanced submicroscopic translocation was found by subtelomeric fluorescence in situ hybridization (FISH). This rearrangement resulted in a partial trisomy 10pter and partial monosomy 21qter. The karyotype was 46,XY.ish der(21)t(10;21)(p14;q22.2). Confirmation of a 6.7?Mb size distal duplication of the p15.3-14 region of chromosome 10 and a 5.6?Mb distal deletion of the q22.2-22.3 region of chromosome 21 was obtained by array-CGH. To our best knowledge, such a composition of subtelomeric unbalanced translocations has not yet been published. Detection of this aberration in successive pregnancies of carrier members of the family by prenatal FISH could prevent the recurrence of the disease. Furthermore, detection of the rearrangements and identification of genes located in the chromosomal regions involved might be of interest.     

The fractionation, characterization, and subcellular localization of colony-stimulating activities released by the human monocyte-like cell line, GCT

GCT, a human monocyte-like cell line, has been shown to release biochemically distinct colony-stimulating activities (CSAs) for mouse and human marrows. These appear to be periodate-sensitive proteins with critical disulfide bonds. One, of molecular weight 145,000 daltons, stimulates macrophagic colony growth and is related to a 30,000-dalton molecule that also stimulates mouse growth. A 30,000-dalton CSA for human marrow can be separated from the 30,000-dalton mouse CSA by isoelectric focusing and gradient polyacrylamide gel electrophoresis. This distinction agrees with our previous finding of differential neutralization with anti-human urinary CSF antibody. The 30,000-dalton CSAs stimulate neutrophil, neutrophil-monocyte, and eosinophil colony growth in human marrow but only neutrophil and neutrophil-monocyte colonies in the mouse. Subcellular fractionation of GCT cells indicates that there are pools of preformed CSAs primarily associated with the cell cytosol that have similar apparent molecular weights to their secreted counterparts.