hSNF5/INI1 inactivation is mainly associated with homozygous deletions and mitotic recombinations in rhabdoid tumors.

The chromatin-remodeling hSNF5/INI1 gene has recently been shown to act as a tumor suppressor gene in rhabdoid tumors (RTs). In an attempt to further characterize the main chromosomal mechanisms involved in hSNF5/INI1 inactivation in RTs, we report here the molecular cytogenetic data obtained in 12 cell lines harboring hSNF5/INI1 mutations and/or deletions in relation to the molecular genetic analysis using polymorphic markers extended to both extremities of chromosome 22q. On the whole, mitotic recombination occurring in the proximal part of chromosome 22q, as demonstrated in five cases, and nondisjunction/duplication, highly suspected in two cases (processes leading respectively to partial or complete isodisomy), appear to be major mechanisms associated with hSNF5/INI1 inactivation. Such isodisomy accompanies each of the RTs exhibiting two cytogenetically normal chromosomes 22. This results in homozygosity for the mutation at the hSNF5/INI1 locus. An alternate mechanism accounting for hSNF5/INI1 inactivation observed in these tumors is homozygous deletion in the rhabdoid consensus region. This was observed in each of the four tumors carrying a chromosome 22q abnormality and, in particular, in the three tumors with chromosomal translocations. Only one case of our series illustrates the mutation/deletion classical model proposed for the double-hit inactivation of a tumor suppressor gene.     

白血病细胞株K562和K-HHT系列P-糖蛋白功能逆转的研究

克服白血病细胞的多药耐药性是当今白血病治疗中的一个热点和难点。多药耐药的发生机制主要是ｍｄｒ１基因及其表达产物Ｐ－糖蛋白（Ｐｇｐ）的膜泵作用［１］。有证据表明一些药物能够逆转Ｐｇｐ,使细胞内药物浓度增高,从而达到杀灭白血病细胞的目的［２］。本实验运用...     

Anticipatory Pleasure Skills Training: A New Intervention to Reduce Anhedonia in Schizophrenia

PURPOSE. Anhedonia is a challenging symptom of schizophrenia and remains largely recalcitrant to current pharmacological treatments. The goal of this exploratory pilot study was to assess if a cognitive–sensory intervention could improve anticipatory pleasure. DESIGN AND METHODS. Five participants meeting the Diagnostic and Statistical Manual of Mental Disorders (4th edition, Text Revision) criteria for schizophrenia, presenting severe anhedonia and stabilized on atypical antipsychotic medication, received between 10 hours and 25 hours of training. FINDINGS. Results show that the patients improved on the anticipatory scale of the Temporal Experience of Pleasure Scale. Daily activities of the patients were also increased. PRACTICE IMPLICATIONS. These preliminary data need to be interpreted with caution given the small sample of the study, but they offer promising paths to develop new interventions to alleviate anhedonia in schizophrenia.     

NGAL,biomarqueur de lésion rénale : point d’étape en 2012

Neutrophil Gelatinase Associated Lipocalin (NGAL) is one of the most promising biomarkers for acute kidney injury (AKI). Although urinary NGAL is intuitively more appropriate to apprehend renal injury, clinical data have accumulated on the potential interest of NGAL measured indifferently in serum or urine. Diagnostic performance of NGAL greatly varies across studies according to different factors such as the type of patients (pediatric versus adult) and the clinical situations (surgery versus intensive care). Overall, NGAL is presented as a useful tool to diagnose and predict AKI outcome but several issues (the absence of a unique pertinent threshold value, the incomplete analytical validation of its measurement and, its apparent limited clinical added value as compared to traditional AKI markers) remain to be addressed in order to definitely recommend its use in clinical practice.     

Age-associated cerebral atrophy in mouse lemur primates

We assessed the regional brain atrophy in mouse lemur primates from 4.7 T T2-weighted magnetic resonance images. Thirty animals aged from 1.9 to 11.3 years were imaged. Sixty-one percent of the 23 animals older than 3 years involved in the study displayed an atrophy process. Cross-sectional analysis suggests that the atrophy follows a gradual pathway, starting in the frontal region then involving the temporal and/or the parietal part of the brain and finally the occipital region. Histological evaluation of five animals selected according to various stages of atrophy suggested that extracellular amyloid deposits and tau pathology cannot explain by themselves this atrophy and that intracellular amyloid deposition is more closely linked to this pathology. This study suggests that most of the age-related atrophy occurring in mouse lemurs is caused by one clinical, evolving, pathological process. The ability to follow this pathology non-invasively by MRI will allow to further characterize it and evaluate its relationship with neuropathological lesions that are involved in human diseases such as Alzheimer.     

Bacterial ClpB heat-shock protein,an antigen-mimetic of the anorexigenic peptide α-MSH,at the origin of eating disorders

The molecular mechanisms at the origin of eating disorders (EDs), including anorexia nervosa (AN), bulimia and binge-eating disorder (BED), are currently unknown. Previous data indicated that immunoglobulins (Igs) or autoantibodies (auto-Abs) reactive with α-melanocyte-stimulating hormone (α-MSH) are involved in regulation of feeding and emotion; however, the origin of such auto-Abs is unknown. Here, using proteomics, we identified ClpB heat-shock disaggregation chaperone protein of commensal gut bacteria Escherichia coli as a conformational antigen mimetic of α-MSH. We show that ClpB-immunized mice produce anti-ClpB IgG crossreactive with α-MSH, influencing food intake, body weight, anxiety and melanocortin receptor 4 signaling. Furthermore, chronic intragastric delivery of E. coli in mice decreased food intake and stimulated formation of ClpB- and α-MSH-reactive antibodies, while ClpB-deficient E. coli did not affect food intake or antibody levels. Finally, we show that plasma levels of anti-ClpB IgG crossreactive with α-MSH are increased in patients with AN, bulimia and BED, and that the ED Inventory-2 scores in ED patients correlate with anti-ClpB IgG and IgM, which is similar to our previous findings for α-MSH auto-Abs. In conclusion, this work shows that the bacterial ClpB protein, which is present in several commensal and pathogenic microorganisms, can be responsible for the production of auto-Abs crossreactive with α-MSH, associated with altered feeding and emotion in humans with ED. Our data suggest that ClpB-expressing gut microorganisms might be involved in the etiology of EDs.     

A Twin Study of State and Trait Anxiety in Childhood and Adolescence

Little research has addressed the relative influence of genetic and environmental factors on subclinical levels of anxiety in children. Of the two twin studies to date, one concluded that measures of adolescents' self-reported trait anxiety were best explained by shared environmental factors (Thapar & McGuffin, 1995), while the second determined that approximately half the variance was attributable to genetic effects (Topolski et al., 1997). The present study, using a sample of 547 twin pairs, reached conclusions similar to those of Topolski et al. Heritability was estimated at 45%. Measures of state anxiety conformed more closely to Thapar and McGuffin's findings, with environmental factors accounting for the variance.     

The role of interferon-gamma in murine pneumococcal pneumonia.

To determine the role of interferon (IFN)-gamma in pneumonia, IFN-gamma receptor-deficient (IFN-gamma R(-/-)) and 129/Sv (wild-type [wt]) mice were inoculated intranasally with Streptococcus pneumoniae. Although mortality did not differ between the groups 48 h after inoculation, IFN-gamma R(-/-) mice had significantly fewer pneumococci in their lungs than the wt mice. Similarly, IFN-gamma(-/-) mice had fewer colony-forming units in lungs than wt mice. The relatively increased resistance of IFN-gamma R(-/-) mice was not related to favorable effects on defense mechanisms known to contribute to antibacterial immunity-that is, the neutrophilic influx was reduced and the cytokine and nitric oxide levels were similar or lower in IFN-gamma R(-/-) mice. In contrast, mice treated with anti-IFN-gamma did not demonstrate a consistently altered bacterial outgrowth, compared with mice treated with a control antibody. These data suggest that endogenous IFN-gamma, despite its protective role in defense against intracellular pathogens, does not serve a protective role during pneumococcal pneumonia.     

Clinical impact of a real-time PCR assay for rapid identification of Staphylococcus aureus and determination of methicillin resistance from positive blood cultures

The full identification and susceptibility profile of staphylococci from positive blood cultures (BCs) generally takes 24–48 h using phenotypic methods. The aim of this prospective study was to evaluate the clinical impact of a real-time PCR strategy for rapid identification of staphylococci and determination of methicillin resistance directly from positive BCs. During a 12-month period, 250 episodes of positive BCs with organism morphology resembling staphylococci were enrolled. Two strategies were compared: conventional (n = 128) using standard phenotypic methods or rapid (n = 122) using a real-time PCR assay that is able to detect specific genes of Staphylococcus aureus (nuc and sa442) and the encoding gene for methicillin resistance (mecA). Overall, 97 episodes (39%) were clinical-significant bloodstream infections. The prevalence of methicillin resistance of S. aureus was 24%. A favorable outcome (defined as clinical cure with resolution of signs and no evidence of recurrence or relapse at 12 weeks follow-up) was observed in similar proportions of episodes with (58%) or without (60%) PCR testing (p 0.8). In multivariate analyses, age and infection due to methicillin-susceptible S. aureus (adjusted OR 0.96, 95% CI 0.93–0.99; and adjusted OR 3.11, 95% CI 1.12–8.65, respectively) were the unique factors independently associated with a favorable outcome. Among the 153 episodes of contaminated BCs, similar proportions received unjustified antibiotic therapy (PCR strategy: 17%, conventional testing: 10%; p 0.33). In a setting with a moderate level of methicillin-resistant S. aureus and relatively high contamination of BCs, real-time PCR testing was not beneficial compared to conventional methods.     

99mTc-MIBI (RP-30) to define the extent of myocardial ischemia and evaluate ventricular function

99mTc-MIBI, a new myocardial perfusion agent, is a technetium labeled isonitrile derivative. We have taken advantage of the physical characteristics of 99mTc to combine at rest, post infarction, ventricular function studies with analysis of perfusion. We have studied at rest and at stress, 22 patients with coronary artery disease selected on the basis of an abnormal coronary angiogram or on the basis of a positive exercise ECG stress test for symptomatic angina. We have also studied, at rest only, 20 patients with a previous myocardial infarction. A comparative thallium planar scintigraphy was obtained for all patients. The sensitivity of 99mTc-MIBI scintigraphy for detecting individual vessel lesions at stress was 88% as compared with 83% for 201Tl. Sensitivity was higher in patients with previous myocardial infarction (93% for the 2 isotopes) than in patients without (85% for 99mTc-MIBI versus 81% for 201Tl). Segmental myocardial correspondence between 99mTc-MIBI and 201Tl was very close (92%). The overall sensitivity for the detection of acute myocardial infarction reached respectively 91% for 99mTc MIBI and 87% for 201Tl. The specificity in the regions corresponding to arteries not involved was excellent for both tracers as we did not observe any false positive result. This is important information but it does not correspond to the specificity to detect coronary artery disease in the overall patient population. The correlation between first pass left ventricular ejection fraction obtained with 99mTc-MIBI and equilibrium left ventricular ejection fraction obtained with 99mTc red cells was excellent (r = 0.96). It was not as good but was still satisfactory for the right ventricle (r = 0.75).(ABSTRACT TRUNCATED AT 250 WORDS)