Mutant ryanodine receptors in catecholaminergic polymorphic ventricular tachycardia generate delayed afterdepolarizations due to increased propensity to Ca2+ waves.

AIMS: Mutations in cardiac ryanodine receptors (RyR2s) are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), characterized by risk of polymorphic ventricular tachyarrhythmias and sudden death during exercise. Arrhythmias are caused by gain-of-function defects in RyR2, but cellular arrhythmogenesis remains elusive. METHODS AND RESULTS: We recorded endocardial monophasic action potentials (MAPs) at right ventricular septum in 15 CPVT patients with a RyR2 mutation (P2,328S, Q4,201R, and V4,653F) and in 12 control subjects both at baseline and during epinephrine infusion (0.05 microg/kg/min). At baseline 3 and during epinephrine infusion, four CPVT patients, but none of the control subjects, showed delayed afterdepolarizations (DADs) occasionally coinciding with ventricular premature complexes. In order to study the underlying mechanisms, we expressed two types of mutant RyR2 (P2,328S and V4,653F) causing CPVT as well as wild-type RyR2 in HEK 293 cells. Confocal microscopy of Fluo-3 loaded cells transfected with any of the three RyR2s showed no spontaneous subcellular Ca(2+) release events at baseline. Membrane permeable cAMP analogue (Dioctanoyl-cAMP) triggered subcellular Ca(2+) release events as Ca(2+) sparks and waves. Cells expressing mutant RyR2s showed spontaneous Ca(2+) release events at lower concentrations of cAMP than cells transfected with wild-type RyR2. CONCLUSION: CPVT patients show DADs coinciding with premature action potentials in MAP recordings. Expression studies suggest that DADs are caused by increased propensity of abnormal RyR2s to generate spontaneous Ca(2+) waves in response to cAMP stimulation. Increased sensitivity of mutant RyR2s to cAMP may explain the occurrence of arrhythmias during exercise or emotional stress in CPVT.     

Clinical aspects of pelvic inflammatory disease

Pelvic inflammatory disease (PID) is a common and poorly managed condition. Untreated or inadequately treated, it leads to tubal infertility, ectopic pregnancy and chronic pelvic pain. Diagnostic difficulties are compounded by the wide variety of clinical presentations and the insensitivity and poor specificity of laboratory tests. Better recognition of mild and atypical disease needs a high index of suspicion whenever young, sexually active women present with gynaecological symptoms. Laparoscopy supplemented by microbiological tests and fimbrial minibiopsy should be regarded as the diagnostic 'gold standard' for research studies; new studies are required to identify techniques which might reduce under- and over-diagnosis. Early treatment reduces the risk of an adverse effect on fertility. Any therapeutic regimen selected should be effective against the common aetiological agents Chlamydia trachomatis, Neisseria gonorrhoeae, genital mycoplasmas and aerobic and anaerobic bacteria. Since at least 60% of cases of PID can be attributed to infection with a sexually transmitted organism, partner notification forms an essential part of management.      

Renal transplantations from the same kidney donor: outcome of diabetic and non-diabetic patients.

Diabetic (DM) nephropathy is an indication of renal transplantation in 30% of all cases in our hospital. We assessed retrospectively the outcome of these diabetics (DM) in comparison with their non-diabetic (NDM) controls. Each diabetic (n = 24) had a control (n = 24) receiving a kidney from the same donor. There was no difference in the stage of uraemia preoperatively. Anaesthesia and fluid therapy were standardized. Peroperative hypotension occurred more often in diabetics (NS). All operating parameters including cold ischaemia were comparable. Kidney function started immediately in 14/24 in the DM group and 13/24 in the NDM group and was delayed in 10/24 and 11/24, respectively. One diabetic patient rejected the transplant as did two non-diabetic patients. Postoperatively diuretics could be discontinued more often in the DM than in the NDM group (p < 0.05). Antihypertensives had to be started in the NDM more often (NS) than in the DM group. In conclusion, the outcome of diabetic patients after renal transplantation was comparable to their NDM controls.     

Lynestrenol induced therapeutic amenorrhea: effects of dose reduction on serum sex-hormones and lipids.

The effect of reducing the dose of peroral lynestrenol by half on serum sex-hormone, lipid and lipoprotein status was studied in 21 mentally retarded women with therapeutic amenorrhea (TA). They had previously received 5 or 10 mg peroral lynestrenol daily for periods ranging from 32 to 196 months. Dose halving of lynestrenol resulted in an increase in serum total testosterone (T) by 16% (p less than 0.05), sex-hormone binding globulin (SHBG) by 39% (p less than 0.01) and high-density lipoprotein cholesterol (HDL-C) by 28% (p less than 0.001). Both the mean serum total and free concentrations of norethisterone (NET and fNET) decreased by 60% (p less than 0.001). The serum concentrations of 17-beta-estradiol (E2), its free fractions (fE2) and free T (fT) were not significantly altered. Significant correlations were observed between the change in HDL-C and the change in T (r = 0.45, p less than 0.05), between the change in SHBG and the change in T (r = 0.62, p less than 0.01), fT (r = 0.43, p less than 0.05) and E2 (r = 0.51, p less than 0.05). The elevation of HDL-C was probably caused by the reduced serum NET concentrations. This also resulted in an increase in serum SHBG concentration, which is regarded as an indicator of the overall estrogen/androgen ratio.     

Measuring radiation exposure during percutaneous drainages: can shoulder dosemeters be used to estimate finger doses?

Some previous studies have shown remarkably high finger doses to radiologists performing percutaneous drainage under fluoroscopy. To assess the possible need for extra finger dosemeters in addition to the general dosemeter, radiologists' and assistants' radiation exposure at both shoulders and at the third fingers of both hands were recorded using thermoluminescent dosemeters during 27 interventional drainage procedures. Under couch screening was used. Mean dose rates were calculated by dividing the doses by the screening time. The dose rates for the sites measured were correlated with each other. The radiologists' bilateral finger dose rates did not correlate with each other; nor did dose rates between the left shoulder and the right hand. The radiologists' dose rates at both shoulders, however, correlated with each other, as did the shoulder dose rates with the dose rates at the ispilateral hand. The right shoulder dose rates correlated with the left hand dose rates. The assistants' dose rates at the places of measurement all showed significant correlations with each other. It is therefore concluded that radiologists involved in percutaneous drainages should use finger dosemeters on both hands; for assistants this may not be necessary.     

Cardiovascular malformations and organic solvent exposure during pregnancy in Finland

In order to investigate the possible association between cardiovascular malformations and maternal exposure to organic solvents during the first trimester of pregnancy, 569 cases and 1,052 controls were retrospectively studied. The cases represented all infants with diagnosed cardiovascular malformations born in Finland in 1982-1984, and the controls were randomly selected from all normal births in the country during the same period. All mothers were interviewed approximately 3 months after delivery by a midwife using a structured questionnaire. Exposures to organic solvents at work during the first trimester of pregnancy were slightly more prevalent among the mothers of affected infants (10.4%) than among those of controls (7.8%). Logistic regression analysis of exposure to organic solvents showed an adjusted relative odds ratio of 1.3 (95% confidence interval, 0.8-2.2). In the analysis of ventricular septal defect, exposure to organic solvents showed an adjusted relative odds ratio of 1.5 (95% confidence interval, 1.0-3.7).     

Cardiovascular malformations, work attendance, and occupational exposures during pregnancy in Finland

To explore for associations between occupational factors and cardiovascular malformations, information on the parents of 160 infants with cardiovascular malformations and 160 control parents was studied. The case infants had been reported consecutively to the Finnish Register of Congenital Malformations. All mothers were interviewed identically after delivery, using both open and pro forma questions about detailed work tasks, exposures, and leisure activities during pregnancy. The interview information was evaluated blindly. Neither parental occupational titles nor maternal working per se gave new clues to the teratogenic risk; nor did shift working, wearing of personal protective equipment, or the mother's own opinion on exposures during pregnancy. Identified occupational exposures, as categorized by an industrial hygienist, showed no remarkable associations to cardiovascular malformations. Few mothers were exposed substantially to specific occupational hazards. Comparing mothers who used medications in the first trimester with those who did not showed an odds ratio of 2.2 (95% confidence interval 1.3-3.9) when adjusted for potential confounding by multivariate logistic methods.     

Incidence and determinants of moderate COPD (GOLD II) in male smokers aged 40–65 years: 5-year follow up

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major health problem with an estimated prevalence of 10-15% among smokers. The incidence of moderate COPD, as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD), is largely unknown. AIM: To determine the cumulative incidence of moderate COPD (forced expiratory volume in 1 second/forced vital capacity ratio [FEV1/FVC] <0.7 and FEV1 <80% predicted) and its association with patient characteristics in a cohort of male smokers. DESIGN: Prospective cohort study. SETTING: The city of IJsselstein, a small town in the Netherlands. METHOD: Smokers aged 40-65 years who were registered with local GPs, participated in a study to identify undetected COPD. Baseline measurements were taken in 1998 of 399 smokers with normal spirometry (n = 292) or mild COPD (FEV1/FVC <0.7 and FEV1 >or=80% predicted, n = 107) and follow-up measurements were conducted in 2003. RESULTS: After a mean follow-up of 5.2 years, 33 participants developed moderate COPD (GOLD II). This showed an estimated cumulative incidence of 8.3% (95% CI = 5.8 to 11.4) and a mean annual incidence of 1.6%. No participant developed severe airflow obstruction. The risk of developing moderate COPD in smokers with baseline mild COPD (GOLD I) was five times higher than in those with baseline normal spirometry (one in five versus one in 25). CONCLUSIONS: In a cohort of middle-aged male smokers, the estimated cumulative incidence of moderate COPD (GOLD II) over 5 years was relatively high (8.3%). Age, childhood smoking, cough, and one or more GP contacts for lower respiratory tract problems were independently associated with incident moderate COPD.