Malignant hyperthermia

Malignant hyperthermia is a potentially fatal pharmacogenetic disease triggered by volatile anesthetics and/or succinylcholine. Dysregulation of intracellular calcium homeostasis is the trigger of the acute crisis. Malignant hyperthermia crisis correspond to an hypermetabolic state, which occurred acutely and interesting skeletal muscular cell. Early manifestations grouped tachycardia, tachypnea, masseter spasm, mixed acidosis and raise of the end expiratory CO2 pressure. Hyperthermia is a late sign, rhabdomyolysis is a sign of the severity of the malignant hyperthermia. The successful treatment is based on an early diagnosis, immediately interruption of triggering agents, intravenous administration of Dantrolene in sufficient dosage and starting of adequate symptomatic treatment. Prevention of this complication is based on asking the patient about genetic predisposition to malignant hyperthermia. Confirmation of the susceptibility to malignant hyperthermia can be provided by in vitro contracture test with halothane or caffeine after muscle biopsy.     

Serum ferritin levels in subjects at high risk of atherosclerosis

Serum ferritin levels were determined in a group of 148 subjects drawn from a community study who were found to be at high risk of atherosclerosis (evaluated on the basis of the following data: levels of non-HDL cholesterol, arterial pressure, smoking status, cardiovascular or cerebrovascular disease in a subject's history, diabetes mellitus, a positive family predisposition to, or accumulation of the above factors) and compared with the levels obtained in a control group of 148 examined age- and sex-matched subjects from the same community with non-significant risk factors. Mean serum ferritin levels were higher in the whole risk group and in the subgroups of risk men and postmenopausal women than in the corresponding controls (the whole risk group: 263.4 +/- 218.5 micrograms/l vs. 198.3 +/- 179.5 micrograms/l, p < 0.05; the subgroup of men 361.8 +/- 235.7 micrograms/l vs. 286.4 +/- 194.6 micrograms/l, p < 0.05 and the subgroup of postmenopausal women 184.1 +/- 143.1 vs. 126.7 +/- 108.4 micrograms/l, p < 0.05).     

Smoking intervention in subjects at risk of asbestos-related lung cancer

A smoking intervention counseling program was applied among asbestos-exposed male smokers younger than 65 years of age to examine the effect of an intervention based on risk communication. Intervention subjects (n = 431) were invited to a health status checkup combined with physician-delivered smoking intervention counseling. Control subjects (n = 141) received no intervention. After 1 year, 5% of the responders in the intervention group, versus 3.4% in the control group, had stopped smoking. Corresponding conservative estimates were 3.5% and 2.6%, respectively. The quitters had been exposed to a higher “dose” of asbestos but had smoked less, and for a shorter period, than had the continuing smokers. Counseling by a general physician increased successful quitting threefold, compared to counseling by a physician in a specialized institution. These results suggest a potential for smoking cessation among subjects at high risk of lung cancer due to asbestos exposure. General practice care may be an appropriate setting both for identification of such subjects and for intervention. Am. J. Ind. Med. 31:705–712, 1997. © 1997 Wiley-Liss, Inc.     

Improving point predictions of random effects for subjects at high risk

The prediction of random effects corresponding to subject-specific characteristics (e.g. means or rates of change) can be very useful in medical and epidemiologic research. At times, one may be most interested in obtaining accurate and/or precise predictions for subjects whose characteristic places them in a tail of the distribution. While the typical posterior mean predictor dominates others in terms of overall mean squared error of prediction (MSEP), its tendency to 'overshrink' has motivated research into alternatives emphasizing other criteria. Here, we specifically target MSEP within a certain region (e.g. above a known cut-off for high risk or a specified percentile of the random effect distribution), and we consider minimizing this quantity with and without constraints on overall MSEP efficiency. We use the normal-theory random intercept model to derive prediction methods with potential to yield markedly better performance for subjects in the specified region, given a well-controlled and (if desired) modest concession of overall MSEP. Criteria geared toward classification as well as overall and regional prediction unbiasedness are also provided. We evaluate the proposed techniques and illustrate them using repeated measures data on fasting blood glucose from type 2 diabetes patients. A simulation study verifies that theoretical properties and relative performances of the proposed predictors are essentially maintained when calculating them in practice based on estimated mixed linear model parameters. Straightforward extensions to incorporate covariates and additional random effects are briefly outlined.     

Malignant mesothelioma: attributable risk of asbestos exposure.

OBJECTIVES--To evaluate a case-control study of malignant mesothelioma through patterns of exposure to asbestos based upon information from telephone interviews with next of kin. METHODS--Potential cases, identified from medical files and death certificates, included all people diagnosed with malignant mesothelioma and registered during 1975-1980 by the Los Angeles County Cancer Surveillance Program, the New York State Cancer Registry (excluding New York City), and 39 large Veterans Administration hospitals. Cases whose diagnosis was confirmed in a special pathology review as definite or probable mesothelioma (n = 208) were included in the analysis. Controls (n = 533) had died of other causes, excluding cancer, respiratory disease, suicide, or violence. Direct exposure to asbestos was determined from responses to three types of questions: specific queries as to any exposure to asbestos; occupational or non-vocational participation in any of nine specific activities thought to entail exposure to asbestos; and analysis of life-time work histories. Indirect exposures were assessed through residential histories and reported contact with family members exposed to asbestos. RESULTS--Among men with pleural mesothelioma the attributable risk (AR) for exposure to asbestos was 88% (95% confidence interval (95% CI) 76-95%). For men, the AR of peritoneal cancer was 58% (95% CI 20-89%). For women (both sites combined), the AR was 23% (95% CI 3-72%). The large differences in AR by sex are compatible with the explanations: a lower background incidence rate in women, lower exposure to asbestos, and greater misclassification among women. CONCLUSIONS--Most of the pleural and peritoneal mesotheliomas in the men studied were attributable to exposure to asbestos. The situation in women was less definitive.     

Sampling GWAS subjects from risk populations

Power, i.e. sample size, is a crucial issue in genome-wide association studies (GWAS) on disorders generated by a multitude of weak genetic effects. Here, we examine the influence of sampling cases and/or controls from populations that are subjected to an external risk factor (such as smoking or nutritional factors). We use an additive threshold model and derive the necessary sample size as function of the external risk factor's strength and of the sampling scheme. If both cases and controls are sampled from the risk population, a loss of power must be expected. The loss of power (i.e. the increase of the necessary sample size) is even larger if only the cases are sampled from the risk population, whereas the inverse scheme (nonrisk cases and risk controls) provides a gain of power since nonrisk cases are enriched for disease-favouring alleles while risk controls are enriched for protective alleles. For small effect sizes, we derive simple approximations in analytically closed form. A strategy of GWAS sample collection from risk populations minimizing the necessary sample sizes may thus be deduced that generally applies as long as strong gene-environment interactions can be excluded.     

A brief case-finding questionnaire for common mental disorders: the CMDQ

OBJECTIVES: The aim of the study was to validate a new case-finding instrument for common mental disorders (CMDQ). METHODS: A cross-sectional, stratified, two-phase study was carried out in 28 general practices in Aarhus County, Denmark. 1785 consecutive patients, 18-65 years old, consulting 38 GPs with a new health problem participated. Patients were screened before consultation using a one-page screening questionnaire including subscales for somatisation (SCL-SOM and Whiteley-7), anxiety (SCL-ANX4), depression (SCL-DEP6) and alcohol abuse (CAGE). A stratified subsample of 701 patients was interviewed using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) interview. We tested the external validity of the scales using the SCAN interview as gold standard. All data were analysed using appropriate weighted procedures to control for the two-phase sampling design and non-response bias. RESULTS: Estimates of sensitivity and specificity for relevant ICD-10 diagnoses at theoretical optimal cut-off points on subscales: Depressive disorder: 78/86 (SCL-DEP6); Alcohol abuse or dependence: 78/97 (CAGE); Severe anxiety disorder: 77/85 (SCL-ANX4); Somatisation disorder: 83/56 (SCL-SOM); and 75/52 (Whiteley-7); any mental disorder: 72/72 (SCL-8). At the theoretical optimal cut-off points the CMDQ demonstrated higher diagnostic accuracy than GPs on any diagnosis evaluated. CONCLUSION: The study results suggest that the CMDQ has excellent external validity for use as a diagnostic aid in primary care settings.     

No evidence of HIV-2 infection in subjects at risk for aids living in North-East Italy

Sera samples from 1134 individuals (824 HIV-1 seropositive and 310 HIV-1 seronegative), collected from January 1988 to April 1990, were tested for HIV-2 antibodies by whole virus assays and synthetic peptide-based assays to determine the prevalence of HIV-2 infection in populations at risk for AIDS in North-East Italy (Veneto Region). Partial reactivities on HIV-2 Western Blot were a common finding in HIV-1 seropositive samples. None of the sera fulfilled the criteria for HIV-2 seropositivity, since only low-level reactivity was observed with an HIV-2 competitive ELISA test, and no reactivity occurred with an HIV-2 specific peptide.Therefore, there is no evidence of HIV-2 infection in this geographical area, to date.Corresponding Author