Analysis of the functional domains of the mismatch repair homologue Msh1p and its role in mitochondrial genome maintenance

Mitochondrial DNA (mtDNA) repair occurs in all eukaryotic organisms and is essential for the maintenance of mitochondrial function. Evidence from both humans and yeast suggests that mismatch repair is one of the pathways that functions in overall mtDNA stability. In the mitochondria of the yeast Saccharomyces cerevisiae, the presence of a homologue to the bacterial MutS mismatch repair protein, MSH1, has long been known to be essential for mitochondrial function. The mechanisms for which it is essential are unclear, however. Here, we analyze the effects of two point mutations, msh1-F105A and msh1-G776D, both predicted to be defective in mismatch repair; and we show that they are both able to maintain partial mitochondrial function. Moreover, there are significant differences in the severity of mitochondrial disruption between the two mutants that suggest multiple roles for Msh1p in addition to mismatch repair. Our overall findings suggest that these additional predicted functions of Msh1p, including recombination surveillance and heteroduplex rejection, may be primarily responsible for its essential role in mtDNA stability.     

Endothelial Progenitor Cells in Heart Failure: an Authentic Expectation for Potential Future Use and a Lack of Universal Definition

Congestive heart failure (CHF) is a prevalent disease (especially among the elderly) with high mortality and morbidity rates. The pathological hallmark of CHF is a loss of cardiomyocytes leading to cardiac fibrosis and dysfunctional cardiac remodeling, which culminates in organ failure. Endothelial progenitor cells (EPCs) are bone marrow-derived cells that contribute to maintenance of the integrity of endothelial wall and protect ischemic myocardium through forming new blood vessels (vasculogenesis) or proliferation of pre-existing vasculature (angiogenesis). Despite its potential, little is known about EPCs and their function in CHF. Here, we define EPC and its role in health and CHF, highlighting their contributions as a cornerstone in the maintenance of a healthy endothelium. Thereafter, we explore the behavior and relevance of EPCs in the pathophysiology of CHF, their prognostic importance, and possible utilization of EPCs as therapy for CHF. Lastly, the restrictions surrounding the use of EPCs in clinical practice will be discussed.     

Signaling pathways in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the sixth most common cancer, and its mortality rate is the third highest after lung and colon cancer. Its incidence has significantly increased in the last two decades in close relation with the ubiquitous spread of viral hepatitis. HCC has a poor prognosis since less than 30% of newly diagnosed patients will be eligible for potential curative treatment. Molecular therapies such as sorafenib, a BRAF/ VEGFR/PDGFR tyrosine kinase inhibitor, have shown to improve survival in patients with advanced HCC. This recent success has spurred intensive research aimed at identifying aberrant activation of signaling pathways. This approach will probably aid to define previously unrecognized oncogenic addiction loops in HCC and in developing more effective targeted therapies.     

HCV prevalence and co-infection with HIV among pregnant women in Saint Camille Medical Centre, Ouagadougou

Objective To determine hepatitis C virus (HCV) prevalence and the rate of HCV/human immunodeficiency virus (HIV) co‐infection in pregnant women attending Saint Camille medical centre (SCMC) in Ouagadougou. Methods A total of 607 pregnant women, 16–45 years old, with <32 weeks amenorrhoea were screened for HCV and HIV using rapid tests. The majority of the women included in the study were previously known as HIV infected, as the centre is a reference centre for the programme of prevention against mother‐to‐child HIV transmission in the country. HCV RNA was extracted and quantified using the cDNA polymerase chain reaction with the nested primers at the 5′ untranslated region. Transaminases were measured from plasma samples using spectrophotometric method. Results Of women, 62.27% were infected with HIV. The prevalence of HCV was 2.14% in the screened pregnant women: 1.75% in HIV‐negative women and 2.38% in HIV‐positive ones. This prevalence is not significantly different between HIV‐positive and HIV‐negative pregnant women (P = 0.81). HCV RNA was found in all women with anti‐HCV. A significant transaminase increase was noted in women infected with HCV (P = 0.01 and P < 0.01 for glutamic‐pyruvic transaminase and glutamic‐oxaloacetic transaminase, respectively). Risk factors significantly associated with HCV positivity in pregnant women included transfusion and genital excision. In addition, the infection was linked with the educational level of the women. Conclusion The issue of this study revealed that effort should be made to promote safe medical practices and fight against women genital excision that are found to be the main risk factors associated with the HCV infection.     

Hépatite B chronique: aspects épidémiologique, diagnostique, thérapeutique et évolutif au centre hospitalier universitaire Yalgado Ouédraogo de Ouagadougou

Abstract

The aim of this study was to describe epidemiological, diagnosis, therapeutic, and evolutionary aspects of chronic hepatitis B.

Patients and methods

It is a clinical practice study carried out from May 2005 to June 2009 in the Hepatogastroenterology Department of Yalgado-Ouédraogo Teaching Hospital in Ouagadougou. Patients with chronic hepatitis B have been followed regularly during this period. We included all patients aged over 15 with HbsAg-positive over 6 months.

Results

A total of 433 patients cohort were enrolled among 290men (66.9%). Themean age was 32 years. Circumstances of finding out chronic hepatitis B were: blood donation (53.6%), medical checkup (34.1%), asthenia, jaundice, and increased transaminases (12.5%). Duration of HBsAg carrier state varied from 1 to 23 years, with a mean age of 3.3 ± 3.6 years. In HBeAg2 384 patients (88.6%) were positive. Forty patients (23.2%) had an inactive HBsAg carrier status. In HBeAg-negative chronic hepatitis B, 70.3% of patients had persistent or intermittent elevation in transaminase levels. HBV-DNA was positive in 74.3% tested patients with a mean viral load of 1,300,646 UI/ml (6.1 log). In HBe-positive chronic hepatitis B, 71.4% of patients had persistent or intermittent elevation in transaminase levels. HBV-DNA was positive in 89.4% patients with a mean viral load of 15,000,000 UI/ml (7.1 log). We treated 62 patients: 77.7% HBeAg-negative. Sixty patients (96.7%) have been treated with lamivudine, one patient with adefovir, and another one with entecavir. In treated patients, 71.8% achieved normalization of transaminase levels. Virologic response was complete in 25 patients (40.3%) and partial in 32 patients (51.6%). In 4 of 60 lamivudine-treated patients, lamivudine resistance occurred in four cases (6.6%). A 34-year-old man presented a small hepatocellular carcinoma. Partial hepatectomy was performed. In treated patients, HBeAg loss occurred in 2 of 13 HBeAg positive patients (15.4%) and none in HBsAg. In nontreated patients, HBeAg loss occurred in 4 of 36 patients (11.1%). We observed HBsAg loss in 6 of 371 patients (1.6%) and the appearance of HBs antibody in four patients.     

H2‐M3‐restricted CD8+ T cells augment CD4+ T‐cell responses by promoting DC maturation

Infection with Listeria monocytogenes triggers the activation and expansion of nonconventional CD8⁺ T cells restricted by the MHC class Ib molecule, H2‐M3. H2‐M3‐restricted CD8⁺ T cells exhibit a memory phenotype, rapidly produce cytokines, and reach peak frequencies sooner than conventional MHC class Ia‐restricted CD8⁺ T cells. In this study, we found that simultaneous in vivo priming of H2‐M3‐restricted T cells and adoptively transferred OT‐II CD4⁺ T cells on the same DC enhances the survival of OT‐II cells. Stimulation of H2‐M3‐restricted T cells were found to induce DC maturation resulting in costimulatory molecule upregulation and production of T_H1‐type cytokines, which was dependent on both cell‐to‐cell contact and soluble factors, particularly TNF‐α, produced by activated H2‐M3‐restricted T cells. Interestingly, H2‐M3‐restricted T cells were more efficient than activated NK cells in inducing DC maturation. Furthermore, we found that OVA_323–339‐coated DC matured by coculturing with peptide‐stimulated H2‐M3‐restricted T cells were more efficient in stimulating the proliferation of Ag‐activated OT‐II cells. This study indicates that H2‐M3‐restricted T cells promote immune responses by CD4⁺ T cells by inducing DC maturation and suggests novel mechanisms for vaccine development.