Autosomal-dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) causes sudden cardiac death and is characterized by clinical and genetic heterogeneity. Fifteen unrelated ARVC families with a disease-associated haplotype on chromosome 3p (ARVD5) were ascertained from a genetically isolated population. Identification of key recombination events reduced the disease region to a 2.36 Mb interval containing 20 annotated genes. Bidirectional resequencing showed one rare variant in transmembrane protein 43 (TMEM43 1073C-->T, S358L), was carried on all recombinant ARVD5 ancestral haplotypes from affected subjects and not found in population controls. The mutation occurs in a highly conserved transmembrane domain of TMEM43 and is predicted to be deleterious. Clinical outcomes in 257 affected and 151 unaffected subjects were compared, and penetrance was determined. We concluded that ARVC at locus ARVD5 is a lethal, fully penetrant, sex-influenced morbid disorder. Median life expectancy was 41 years in affected males compared to 71 years in affected females (relative risk 6.8, 95% CI 1.3-10.9). Heart failure was a late manifestation in survivors. Although little is known about the function of the TMEM43 gene, it contains a response element for PPAR gamma (an adipogenic transcription factor), which may explain the fibrofatty replacement of the myocardium, a characteristic pathological finding in ARVC.

To identify cancers that occur at higher rates in acquired immunodeficiency syndrome (AIDS) patients, the cancer experience of New York State (NYS) AIDS patients aged 15-69 years who were diagnosed between 1981 and 1994 was compared with that of the NYS general population. Sex and HIV risk group-specific standardized incidence ratios (SIRs), post-AIDS relative risks, and trends of relative risks were calculated to determine cancer risk. Among non-AIDS-related cancers, elevated SIRs were found for Hodgkin's disease (male, 8.0; female, 6.4; heterosexually infected males, 31.3); cancer of the rectum, rectosigmoid, and anus (male, 3.3; female, 3.0); trachea, bronchus, and lung (male, 3.3; female, 7.5); and brain and central nervous system (male, 3.1; female, 3.4; heterosexually infected females, 23.8) cancers. Moreover, significant trends of increasing relative risks from the pre-AIDS to the post-AIDS period were found for cancers of the rectum, rectosigmoid, and anus; trachea, bronchus, and lung; skin; and connective tissues (all sites, p < 0.05) among males. For AIDS-related cancers in women, invasive cervical cancer had an overall SIR of 9.1 (95% confidence interval: 6.9, 10.8) and a post-AIDS relative risk of 6.5 (95% confidence interval: 4.1, 9.7). This population-based registry linkage analysis evaluates cancer risk in AIDS patients by sex and risk factors and adds evidence that HIV-associated immunosuppression increases the risks of specific types of cancer.

To determine the phenotype and natural history of a founder genetic subtype of autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by a p.S358L mutation in TMEM43. The age of onset of cardiac symptoms, clinical events and test abnormalities were studied in 412 subjects (258 affected and 154 unaffected), all of which occurred in affected males significantly earlier and more often than unaffected males. Affected males were hospitalized four times more often than affected females (p ≤ 0.0001) and died younger (p ≤ 0.001). The temporal sequence from symptoms onset to death was prolonged in affected females by 1-2 decades. The most prevalent electrocardiogram (ECG) manifestation was poor R wave progression (PRWP), with affected males twice as likely to develop PRWP as affected females (p ≤ 0.05). Left ventricular enlargement (LVE) occurred in 43% of affected subjects, with 11% fulfilling criteria for dilated cardiomyopathy. Ventricular ectopy on Holter monitor was common and occurred early: the most diagnostically useful clinical test. No symptom or test could rule out diagnosis. This ARVC subtype is a sex-influenced lethal arrhythmogenic cardiomyopathy, with a unique ECG finding, LV dilatation, heart failure and early death, where molecular pre-symptomatic diagnosis has the greatest clinical utility.

Accidental aconitine poisoning is extremely rare in North America. This report describes the confirmation of a case of accidental aconitine poisoning using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The case involved a 25-year-old man who died suddenly following a recreational outing with friends where he consumed a number of wild berries and plants including one that was later identified as Monkshood (Aconitum napellus). Postmortem blood and urine samples were available for analysis. All routine urine and blood toxicology screens were negative. The LC-MS/MS method allowed sensitive quantification of aconitine, the main toxin in A. napellus, and showed 3.6 and 149 microg/L in blood and urine, respectively. These concentrations were similar to that reported in other aconitine-related deaths. This case illustrates the dangers of consuming unidentified plants, and documents concentrations of aconitine in blood and urine in a fatal case of A. napallus-related poisoning.