Array-based comparative genomic hybridization identifies a high frequency of copy number variations in patients with syndromic overgrowth

Overgrowth syndromes are a heterogeneous group of conditions including endocrine hormone disorders, several genetic syndromes and other disorders with unknown etiopathogenesis. Among genetic causes, chromosomal deletions and duplications such as dup(4)(p16.3), dup(15)(q26qter), del(9)(q22.32q22.33), del(22)(q13) and del(5)(q35) have been identified in patients with overgrowth. Most of them, however, remain undetectable using banding karyotype analysis. In this study, we report on the analysis using a 1-Mb resolution array-based comparative genomic hybridization (CGH) of 93 patients with either a recognizable overgrowth condition (ie, Sotos syndrome or Weaver syndrome) or an unclassified overgrowth syndrome. Five clinically relevant imbalances (three duplications and two deletions) were identified and the pathogenicity of two additional anomalies (one duplication and one deletion) is discussed. Altered segments ranged in size from 0.32 to 18.2 Mb, and no recurrent abnormality was identified. These results show that array-CGH provides a high diagnostic yield in patients with overgrowth syndromes and point to novel chromosomal regions associated with these conditions. Although chromosomal deletions are usually associated with growth retardation, we found that the majority of the imbalances detected in our patients are duplications. Besides their importance for diagnosis and genetic counseling, our results may allow to delineate new contiguous gene syndromes associated with overgrowth, pointing to new genes, the deregulation of which may be responsible for growth defect.     

Medical community preferences concerning adult living related donor liver transplantation

OBJECTIVES: To assess acceptance and acceptable estimated mortality levels for right lobe adult-to-adult living related liver transplantation for the medical and allied professions. METHODS: A paper questionnaire was sent to the physicians practicing with the French Graft Agency (Etablissement Fran?ais des Greffes) and to all nurses and ancillary staff of the Paul Brousse Hospital Hepatobiliary Center. Responses were received from surgeons: 38/73; internists specialized in hepatology: 44/120; nurses: 98/100; health care assistants: 45/86; others: 17/20. RESULTS: Acceptance of living donor transplantation is above average for all professional categories and indications may be extended including patients with cancer. Acceptable mortality for the donor was 4%, except among internists (0.7%). Currently, the real risk of mortality for the donor (1%) is lower. Acceptable mortality for the recipient was between 15 and 20%. CONCLUSIONS: Acceptance of adult living donor liver transplantation among health care professionals is clearly above average. Thus the psychological involvement of transplantation teams, which is very strong in such situations, should not hamper the development of this type of transplantation.     

Relationship between outcome and baseline blood pressure and other haemodynamic measures in acute ischaemic stroke: data from the TAIST trial

BACKGROUND: A poor outcome after stroke is associated independently with high blood pressure during the acute phase; however, relationships with other haemodynamic measures [heart rate (HR), pulse pressure (PP), rate-pressure product (RPP)] remain less clear. METHODS: The Tinzaparin in Acute Ischaemic Stroke Trial is a randomised, controlled trial assessing the safety and efficacy of tinzaparin versus aspirin in 1484 patients with acute ischaemic stroke. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and HR measurements taken immediately prior to randomization were averaged, and the mid-blood pressure (MBP), PP, mean arterial pressure (MAP), pulse pressure index, and RPP were calculated. The relationship between these haemodynamic measures and functional outcome (death or dependency, modified Rankin Scale > 2) and early recurrent stroke, were studied with adjustment for baseline prognostic factors and treatment group. Odds ratios (OR) and 95% confidence intervals (CI) refer to a change in haemodynamic measure by 10 points. RESULTS: A poor functional outcome was associated with SBP (adjusted OR; 1.11; 95% CI, 1.03-1.21), HR (adjusted OR; 1.15; 95% CI, 1.00-1.31), MBP (adjusted OR; 1.15, 95% CI, 1.03-1.29), PP (adjusted OR; 1.14; 95% CI, 1.02-1.26), MAP (adjusted OR; 1.15; 95% CI, 1.02-1.31) and RPP (adjusted OR; 1.01; 95% CI, 1.00-1.02). Early recurrent stroke was associated with SBP, DBP, MBP and MAP. CONCLUSIONS: A poor outcome is independently associated with elevations in blood pressure, HR and their derived haemodynamic variables, including PP and the RPP. Agents that modify these measures may improve functional outcome after stroke.     

Longitudinal Analysis of Gene Expression in Porcine Skeletal Muscle After Post-Injection Local Injury

Purpose The purpose of this study is to describe the time course of gene expression in a skeletal muscle local injury induced by an intramuscular (IM) injection, and to compare the dynamics of gene expression with pathological events. Materials and Methods Ten piglets received 4 IM injections of propylene glycol in the longissimus dorsi muscles 6 h, 2, 7, and 21 days before euthanasia, where control and injected muscle sites were sampled for RNA isolation and microscopic examination. The hybridization of nylon cDNA microarrays was carried out with radioactive probes obtained from the muscle RNA. Results 153 genes were found under- or over-expressed at least once among the investigated time-conditions. The eight most discriminant genes were also identified: Two genes (GTP-binding protein RAD and Ankyrin repeat domain protein) were over-expressed at 6 h and six genes between 2 and 21 days (Osteonectin, Fibronectin, Matrix metalloproteinase-2, Collagen alpha 1(I) chain, Collagen alpha 2(I) chain, and Thymosin beta-4). Necrosis, inflammation and regeneration were observed through both the dynamics of gene expression profiles and through the microscopic examinations. Conclusion Our data demonstrate that several pathways are involved in post-injection muscle injury, and that necrosis, inflammation and regeneration are not sequential but occur in parallel. PJF and LL contributed equally to this work and both should be considered as first authors.     

Molecular diagnosis of bloodstream infections caused by non-cultivable bacteria

Bloodstream infections are an important cause of morbidity and mortality in patients. Blood culture is clearly the most important diagnostic procedure for identifying micro-organisms involved in bloodstream infections except when the patient has previously received antibiotics or in the presence of slow-growing or intracellular micro-organisms. Detection of micro-organisms, mainly in blood, using pathogen-specific or broad-range PCR assays is promising. However, it is very important to emphasise that the interpretation of this molecular tool is critical because of the risk of interfering contamination, underlining the necessity to interpret the results obtained with caution. Presently, due to more widely available data and to rapid advances in biotechnology, two significant improvements allow new perspectives for molecular diagnosis. Indeed, the complete sequences of genomes have provided an important source of gene sequences for PCR-based assays. In addition, the development of real-time PCR offers several advantages in comparison to conventional PCR, including speed, simplicity, quantitative capability and low risk of contamination. Herein, we review the usefulness of molecular diagnosis of highly fastidious micro-organisms in the context of three different bloodstream infections: systemic diseases (rickettsiosis, Q fever, bartonellosis, Whipple's disease), blood-culture-negative endocarditis and bioterrorism attack.