Genetic analysis of sudden cardiac death victims: a survey of current forensic autopsy practices.

Autopsy-negative sudden cardiac deaths (SCD) seen in forensic practice are most often thought to be the result of sudden arrhythmic death syndrome. Postmortem genetic analysis is recommended in such cases, but is currently performed in only a few academic centers. In order to determine actual current practice, an on-line questionnaire was sent by e-mail to members of various forensic medical associations. The questions addressed routine procedures employed in cases of sudden cardiac death (autopsy ordering, macroscopic and microscopic cardiac examination, conduction tissue examination, immunohistochemistry and electron microscopy, biochemical markers, sampling and storage of material for genetic analyses, toxicological analyses, and molecular autopsy). Some questions concerned the legal and ethical aspects of genetic analyses in postmortem examinations, as well as any existing multidisciplinary collaborations in SCD cases. There were 97 respondents, mostly from European countries. Genetic testing in cases of sudden cardiac death is rarely practiced in routine forensic investigation. Approximately 60% of respondents reported not having the means to perform genetic postmortem testing and 40% do not collect adequate material to perform these investigations at a later date, despite working at university hospitals. The survey demonstrated that many of the problems involved in the adequate investigation of SCD cases are often financial in origin, due to the fact that activities in forensic medicine are often paid by and dependent on the judicial authorities. Problems also exist concerning the contact with family members and/or the family doctor, as well as the often-nonexistent collaboration with others clinicians with special expertise beneficial in the investigation of SCD cases, such as cardiologists and geneticists. This study highlights the importance in establishing guidelines for molecular autopsies in forensic medicine.

Activities of fosfomycin and rifampin on planktonic and adherent Enterococcus faecalis strains in an experimental foreign-body infection model.

Enterococcal implant-associated infections are difficult to treat because antibiotics generally lack activity against enterococcal biofilms. We investigated fosfomycin, rifampin, and their combinations against planktonic and adherent Enterococcus faecalis (ATCC 19433) in vitro and in a foreign-body infection model. The MIC/MBClog values were 32/>512 μg/ml for fosfomycin, 4/>64 μg/ml for rifampin, 1/2 μg/ml for ampicillin, 2/>256 μg/ml for linezolid, 16/32 μg/ml for gentamicin, 1/>64 μg/ml for vancomycin, and 1/5 μg/ml for daptomycin. In time-kill studies, fosfomycin was bactericidal at 8× and 16× MIC, but regrowth of resistant strains occurred after 24 h. With the exception of gentamicin, no complete inhibition of growth-related heat production was observed with other antimicrobials on early (3 h) or mature (24 h) biofilms. In the animal model, fosfomycin alone or in combination with daptomycin reduced planktonic counts by ≈4 log10 CFU/ml below the levels before treatment. Fosfomycin cleared planktonic bacteria from 74% of cage fluids (i.e., no growth in aspirated fluid) and eradicated biofilm bacteria from 43% of cages (i.e., no growth from removed cages). In combination with gentamicin, fosfomycin cleared 77% and cured 58% of cages; in combination with vancomycin, fosfomycin cleared 33% and cured 18% of cages; in combination with daptomycin, fosfomycin cleared 75% and cured 17% of cages. Rifampin showed no activity on planktonic or adherent E. faecalis, whereas in combination with daptomycin it cured 17% and with fosfomycin it cured 25% of cages. Emergence of fosfomycin resistance was not observed in vivo. In conclusion, fosfomycin showed activity against planktonic and adherent E. faecalis. Its role against enterococcal biofilms should be further investigated, especially in combination with rifampin and/or daptomycin treatment.

Causes and implications of overdiagnosis

Background: Overdiagnosis is defined as the diagnosis of a condition not associated with a substantial risk for health in an asymptomatic person. There are several causes of overdiagnosis. Clinical and public health implications of overdiagnosis are underappreciated. Objective: To review the causes of overdiagnosis, and its clinical and public health implications Method: Narrative review Results: Overdiagnosis results from some screening activities, increasingly sensitive diagnostic test procedures, incidental findings on routine exams, and widening diagnostic criteria to define a condition requiring an intervention. The fear of missing a diagnosis and the patients' requests for reassurance are further causes of overdiagnosis. Examples of overdiagnosis include some cases of breast and prostate cancers found by screening, pulmonary emboli identified on highly sensitive CT-scans, and kidney cancers found incidentally following abdominal CTscans. Lowering the critical levels of blood pressure, glycemia, and cholesterol to define hypertension, diabetes, and hypercholesterolemia, respectively, is also the causes of overdiagnosis. An overdiagnosed condition implies unnecessary procedures to confirm or exclude the presence of the disease and unnecessary treatments, both having potential adverse effects. Overdiagnosis also diverts health professionals from caring about other health issues and generates costs without any benefit. Measures to prevent overdiagnosis are notably 1) to increase awareness of health professionals and the population about its occurrence, 2) to account systematically for the risks and benefits of screening and diagnostic procedures using an evidence-based framework, and 3) to decide at which risk level to intervene based on the absolute risk of health events and the absolute risk reduction expected from an intervention. Conclusion: Overdiagnosis has major clinical and public health implications. Increasing awareness of its causes and implications is a step toward its prevention.

An analysis of patients' understanding of 'routine' preoperative blood tests and HIV screening. Is no news really good news?

OBJECTIVES: Many patients may believe that HIV screening is included in routine preoperative work-ups. We examined what proportion of patients undergoing preoperative blood testing believed that they had been tested for HIV. METHODS: All patients hospitalized for elective orthopaedic surgery between January and December 2007 were contacted and asked to participate in a 15-min computer-assisted telephone interview (n = 1330). The primary outcome was to determine which preoperative tests patients believed had been performed from a choice of glucose, clotting, HIV serology and cholesterol, and what percentage of patients interpreted the lack of result communication as a normal or negative test. The proportion of patients agreeable to HIV screening prior to future surgery was also determined. RESULTS: A total of 991 patients (75%) completed the questionnaire. Three hundred and seventy-five of these 991 patients (38%) believed incorrectly that they had been tested for HIV preoperatively. Younger patients were significantly more likely to believe that an HIV test had been performed (mean age 46 vs. 50 years for those who did not believe that an HIV test had been performed; P < 0.0001). Of the patients who believed that a test had been performed but received no result, 96% interpreted lack of a result as a negative HIV test. Over 80% of patients surveyed stated that they would agree to routine HIV screening prior to future surgery. A higher acceptance rate was associated with younger age (mean age 47 years for those who would agree vs. 56 years for those who would not; P < 0.0001) and male sex ( P < 0.009). CONCLUSIONS: Many patients believe that a preoperative blood test routinely screens for HIV. The incorrect assumption that a lack of result communication indicates a negative test may contribute to delays in HIV diagnoses.

Population specific and up to date cardiovascular risk charts can be efficiently obtained with record linkage of routine and observational data.

BACKGROUND: Only few countries have cohorts enabling specific and up-to-date cardiovascular disease (CVD) risk estimation. Individual risk assessment based on study samples that differ too much from the target population could jeopardize the benefit of risk charts in general practice. Our aim was to provide up-to-date and valid CVD risk estimation for a Swiss population using a novel record linkage approach. METHODS: Anonymous record linkage was used to follow-up (for mortality, until 2008) 9,853 men and women aged 25-74 years who participated in the Swiss MONICA (MONItoring of trends and determinants in CVD) study of 1983-92. The linkage success was 97.8%, loss to follow-up 1990-2000 was 4.7%. Based on the ESC SCORE methodology (Weibull regression), we used age, sex, blood pressure, smoking, and cholesterol to generate three models. We compared the 1) original SCORE model with a 2) recalibrated and a 3) new model using the Brier score (BS) and cross-validation. RESULTS: Based on the cross-validated BS, the new model (BS = 14107×10(-6)) was somewhat more appropriate for risk estimation than the original (BS = 14190×10(-6)) and the recalibrated (BS = 14172×10(-6)) model. Particularly at younger age, derived absolute risks were consistently lower than those from the original and the recalibrated model which was mainly due to a smaller impact of total cholesterol. CONCLUSION: Using record linkage of observational and routine data is an efficient procedure to obtain valid and up-to-date CVD risk estimates for a specific population.

The French adaptation of the Health of the Nation Outcome Scale for Children and Adolescents Self-Rated Form (F-HoNOSCA-SR): Validation and clinical routine use.

The current study aimed to explore the validity of an adaptation into French of the self-rated form of the Health of the Nation Outcome Scales for Children and Adolescents (F-HoNOSCA-SR) and to test its usefulness in a clinical routine use. One hundred and twenty nine patients, admitted into two inpatient units, were asked to participate in the study. One hundred and seven patients filled out the F-HoNOSCA-SR (for a subsample (N=17): at two occasions, one week apart) and the strengths and difficulties questionnaire (SDQ). In addition, the clinician rated the clinician-rated form of the HoNOSCA (HoNOSCA-CR, N=82). The reliability (assessed with split-half coefficient, item response theory (IRT) models and intraclass correlations (ICC) between the two occasions) revealed that the F-HoNSOCA-SR provides reliable measures. The concurrent validity assessed by correlating the F-HoNOSCA-SR and the SDQ revealed a good convergent validity of the instrument. The relationship analyses between the F-HoNOSCA-SR and the HoNOSCA-CR revealed weak but significant correlations. The comparison between the F-HoNOSCA-SR and the HoNOSCA-CR with paired sample t-tests revealed a higher score for the self-rated version. The F-HoNSOCA-SR was reported to provide reliable measures. In addition, it allows us to measure complementary information when used together with the HoNOSCA-CR.

Assessment of glenoid inclination on routine clinical radiographs and computed tomography examinations of the shoulder.

BACKGROUND: Accurate assessment of glenoid inclination is of interest for a variety of conditions and procedures. The purpose of this study was to develop an accurate and reproducible measurement for glenoid inclination on standardized anterior-posterior (AP) radiographs and on computed tomography (CT) images. MATERIALS AND METHODS: Three consistently identifiable angles were defined: Angle α by line AB connecting the superior and inferior glenoid tubercle (glenoid fossa) and the line identifying the scapular spine; angle β by line AB and the floor of the supraspinatus fossa; angle γ by line AB and the lateral margin of the scapula. Experimental study: these 3 angles were measured in function of the scapular position to test their resistance to rotation. Conventional AP radiographs and CT scans were acquired in extension/flexion and internal/external rotation in a range up to ±40°. Clinical study: the inter-rater reliability of all angles was assessed on AP radiographs and CT scans of 60 patients (30 with proximal humeral fractures, 30 with osteoarthritis) by 2 independent observers. RESULTS: The experimental study showed that angle α and β have a resistance to rotation of up to ±20°. The deviation from neutral position was not more than ±10°. The results for the inter-rater reliability analyzed by Bland-Altman plots for the angle β fracture group were (mean ± standard deviation) -0.1 ± 4.2 for radiographs and -0.3 ± 3.3 for CT scans; and for the osteoarthritis group were -1.2 ± 3.8 for radiographs and -3.0 ± 3.6 for CT scans. CONCLUSION: Angle β is the most reproducible measurement for glenoid inclination on conventional AP radiographs, providing a resistance to positional variability of the scapula and a good inter-rater reliability.

Novel 2-[(benzylamino)methyl]pyrrolidine-3,4-diol derivatives as alpha-mannosidase inhibitors and with antitumor activities against hematological and solid malignancies.

Novel alpha-mannosidase inhibitors of the type (2R,3R,4S)-2-({[(1R)-2-hydroxy-1-arylethyl]amino}methyl)pyrrolidine-3,4-diol have been prepared and assayed for their anticancer activities. Compound 30 with the aryl group=4-trifluoromethylbiphenyl inhibits the proliferation of primary cells and cell lines of different origins, irrespective of Bcl-2 expression levels, inducing a G2/Mcell cycle arrest and by modification of genes involved in cell cycle progression and survival.

Correlations of glycogen synthase and phosphorylase activities with glycogen concentration in human muscle biopsies. Evidence for a double-feedback mechanism regulating glycogen synthesis and breakdown.

The purpose of this study was to verify in man the relationships of muscle glycogen synthase and phosphorylase activities with glycogen concentration that were reported in animal studies. The upper level of glycogen concentration in muscle is known to be tightly controlled, and glycogen concentration was reported to have an inhibitory effect on synthase activity and a stimulatory effect on phosphorylase activity. Glycogen synthase and phosphorylase activity and glycogen concentration were measured in muscle biopsies in a group of nine normal subjects after stimulating an increase of their muscle glycogen concentration through either an intravenous glucose-insulin infusion to stimulate glycogen synthesis, or an Intralipid (Vitrum, Stockholm, Sweden) infusion in the basal state to inhibit glycogen mobilization by favoring lipid oxidation at the expense of glucose oxidation. Phosphorylase activity increased from 71.3 +/- 21.0 to 152.8 +/- 20.0 nmol/min/mg protein (P < .005) after the glucose-insulin infusion. Phosphorylase activity was positively correlated with glycogen concentration (P = .005 and P = .0001) after the glucose-insulin and Intralipid infusions, respectively. Insulin-stimulated glycogen synthase activity was significantly negatively correlated with glycogen concentration at the end of the Intralipid infusion (P < .005). In conclusion, by demonstrating a negative correlation of glycogen concentration with glycogen synthase and a positive correlation with phosphorylase, this study might confirm in man the double-feedback mechanism by which changes in glycogen concentration regulate glycogen synthase and phosphorylase activities. It suggests that this mechanism might play an important role in the regulation of glucose storage.

The importance of sonographer experience and machine quality with regards to the role of musculoskeletal ultrasound in routine care of rheumatoid arthritis patients.

OBJECTIVES: Regarding recent progress, musculoskeletal ultrasound (US) will probably soon be integrated in standard care of patient with rheumatoid arthritis (RA). However, in daily care, quality of US machines and level of experience of sonographers are varied. We conducted a study to assess reproducibility and feasibility of an US scoring for RA, including US devices of different quality and rheumatologist with various levels of expertise in US as it would be in daily care. METHODS: The Swiss Sonography in Arthritis and Rheumatism (SONAR) group has developed a semi-quantitative score using OMERACT criteria for synovitis and erosion in RA. The score was taught to 108 rheumatologists trained in US. One year after the last workshop, 19 rheumatologists participated in the study. Scans were performed on 6 US machines ranging from low to high quality, each with a different patient. Weighted kappa was calculated for each pair of readers. RESULTS: Overall, the agreement was fair to moderate. Quality of device, experience of the sonographers and practice of the score before the study improved substantially the agreement. Agreement assessed on higher quality machine, among sonographers with good experience in US increased to substantial (median kappa for B-mode and Doppler: 0.64 and 0.41 for erosion). CONCLUSIONS: This study demonstrated feasibility and reproducibility of the Swiss US SONAR score for RA. Our results confirmed importance of the quality of US machine and the training of sonographers for the implementation of US scoring in the routine daily care of RA.