Angiotensinogen gene T235 variant: a marker for the development of persistent microalbuminuria in children and adolescents with type 1 diabetes mellitus

AIM: We examined genetic polymorphisms in the renin-angiotensin system (RAS) coding for angiotensin I-converting enzyme (ACE) insertion/deletion (I/D) for angiotensinogen (AGT) M235T and angiotensin II receptor type 1 (AGTR1) A1166C as predictors for the development of microalbuminuria (MA) in children with type 1 diabetes mellitus (T1DM). METHODS: Four hundred fifty-three (215 males, 238 females) T1DM children [median (interquartile range): age, 16.7 years (13.9-18.3); diabetes duration, 6.9 years (3.3-10.8); age at diagnosis, 9.1 years (5.8-11.8)] were followed prospectively from diagnosis until the development of MA (two of three consecutive overnight urine samples with albumin excretion rates of > or =20 and <200 microg/min). Kaplan-Meier survival curves and Cox proportional multivariate model estimated the probability of developing MA and the relative risk for MA among different variables. RESULTS: MA developed in 41 (9.1%) subjects. The frequencies of genotypes were as follows: ACE-II 112 (25%), ACE-ID 221 (49%), and ACE-DD 117 (26%) (n=450); AGT-MM 144 (32%), AGT-MT 231 (51%), and AGT-TT 77 (17%) (n=452); AGTR1-AA 211 (47%), AGTR1-AC 204 (45%), and AGTR1-CC 37 (8%) (n=452). The cumulative risk for the development of MA was higher in ACE-DD versus ACE-ID/II groups (log-rank test, P=.05), and a trend was noticed when AGT-TT was compared to AGT-MT/MM groups (log-rank test, P=.08). AGT-TT polymorphism conferred a fourfold increased risk for MA compared to AGT-MM/MT (hazard ratio=3.8; 95% confidence interval=1.43-10.3; P=.008). INTERPRETATION: Our findings suggest that RAS gene polymorphism at AGT M235T is a strong predictor for early MA in young T1DM subjects.     

Fiessinger-Leroy-Reiter syndrome with non-obstructive cardiomyopathy treated with methotrexate]

The case of a 50 year old male with the Fiessinger-Leroy-Reiter syndrome, ankylosing spondylitis and generalised pustular psoriasis is reported. This condition wax complicated by non-obstructive cardiomyopathy, congestive cardiac failure and first-degree atrioventricular block, the site of which was localised by electrophysiological studies (nodal block with an infrahisian conduction defect). After failure of several therapeutic regimes, a spectacular improvement was obtained with Methotrexate associated with a diuretic; the signs of heart failure regressed and the cardiomyopathy stablised. A parallel improvement was seen in the skin, cardiac and articular lesions and has been maintained with an 18 months follow-up. Left ventricular performance was studied by echocardiography. The mechanism of the beneficial effect of Methotrexate is unclear; this therapeutic trial is to be extended to include other cases of primary cardiomyopathy without obstruction.     

A PKR-like eukaryotic initiation factor 2alpha kinase from zebrafish contains Z-DNA binding domains instead of dsRNA binding domains

The double-stranded RNA (dsRNA)-dependent protein kinase (PKR) is induced as part of the IFN response in mammals and acts to shut down protein synthesis by the phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha). In fish, a PKR-like kinase activity has been detected, but the enzyme responsible has eluded characterization. Here, we describe a PKR-like kinase from zebrafish. Phylogenetic analysis shows that the C-terminal kinase domain is more closely related to the kinase domain of PKR than to any of the other three known eIF2alpha kinases. Surprisingly, instead of the two dsRNA binding domains found at the N terminus of PKR, there are two Zalpha domains. Zalpha domains specifically bind dsDNA and RNA in the left-handed Z conformation, often with high affinity. They have been found previously in two other IFN-inducible proteins, the dsRNA editing enzyme, ADAR1, and Z-DNA binding protein 1 (ZBP1), as well as in the poxvirus virulence factor, E3L. This previously undescribed kinase, designated PKZ (protein kinase containing Z-DNA binding domains), is transcribed constitutively at low levels and is highly induced after injection of poly(inosinic)-poly(cytidylic) acid, which simulates viral infection. Binding of Z-DNA by the Zalpha domain of PKZ was demonstrated by circular dichroism. PKZ inhibits translation in transfected cells; site-directed mutagenesis indicates that this inhibition depends on its catalytic activity. Identification of a gene combining Zalpha domains with a PKR-like kinase domain strengthens the hypothesis that the ability to bind left-handed nucleic acid plays a role in the host response to viruses.     

Effective cryoablation of a lateral accessory pathway within the distal coronary sinus

Limited information is available on the efficacy of cryoablation in the coronary venous system in humans. A patient with a lateral accessory pathway was referred to our center after several unsuccessful endocardial and epicardial (within the coronary sinus) attempts using standard radiofrequency energy. Ablation was subsequently performed successfully by applying cryoenergy distally into the coronary sinus, using a temperature of -50 degrees C and a freezing application time of 45 s. There were no complications. Angiography of the left coronary circumflex artery and coronary venous system was performed at 12 months follow-up using cardiac multislice computed tomography, and no coronary stenosis or anatomic anomaly was found. Neither pre-excitation or any arrhythmia recurred during follow-up. This experience suggests that ablating in the distal coronary sinus can be safely performed using cryoenergy.     

Does flecainide regain its antiarrhythmic activity after electrical cardioversion of persistent atrial fibrillation?

OBJECTIVES: The purpose of this study was to evaluate the hypothesis that presumed reversion of electrical remodeling after cardioversion of atrial fibrillation (AF) restores the efficacy of flecainide. BACKGROUND: Flecainide loses its efficacy to cardiovert when AF has been present for more than 24 hours. Most probably, the loss is caused by atrial electrical remodeling. Studies suggest electrical remodeling is completely reversible within 4 days after restoration of sinus rhythm (SR). METHODS: One hundred eighty-one patients with persistent AF (median duration 3 months) were included in this prospective study. After failure of pharmacologic cardioversion by flecainide 2 mg/kg IV (maximum 150 mg in 10 minutes) and subsequent successful electrical cardioversion, we performed intense transtelephonic rhythm monitoring three times daily for 1 month. In case of AF recurrence, a second cardioversion by flecainide was attempted as soon as possible. RESULTS: AF recurred in 123 patients (68%). Successful cardioversion by flecainide occurred only when SR had been maintained for more than 4 days (7/51 patients [14%]). Failure to cardiovert was associated with a prolonged duration of the recurrent AF episode and concurrent digoxin use. Multivariate logistic regression confirmed that successful cardioversion was determined by digoxin use (odds ratio [OR] 0.093, P = .047) and by the interaction between the duration of SR and the (inverse) duration of recurrent AF (OR 6.499, P < .001). When flecainide was administered within 10 hours after AF onset and the duration of SR was greater than 4 days, the success rate was 58%. CONCLUSIONS: Flecainide recovers its antiarrhythmic action after cardioversion of AF. However, successful pharmacologic cardioversion occurs only after SR has lasted at least 4 days and is expected only for recurrences having duration of a few hours. Immediate pharmacologic cardioversion of AF recurrence may be a worthwhile strategy for management of persistent AF.     

Cost-effectiveness of ceftazidime or imipenem/cilastatin versus ceftriaxone+aminoglycoside in the treatment of febrile episodes in neutropenic cancer patients in Germany

Summary A three-pronged cost-effectivess analysis of the treatment of febrile episodes in neutropenic cancer patients was conducted. It included a review of 37 randomized, controlled studies in the MEDLINE and EMBASE databases (1980–1996). Clinical outcomes as well as costs of treatment with imipenem/cilastatin, ceftazidime and ceftriaxone+aminoglycoside were compared. Primary therapy and modification, respectively, were successful in 62 and 27% of patients treated with imipenem/cilastatin, in 56 and 31% with ceftazidime and in 41 and 13% with ceftriaxone+aminoglycoside. From the perspective of a 1,800-bed teaching hospital, the average overall cost per successfully treated patient was DM 7,475 with imipenem/cilastatin, DM 7,810 with ceftazidime and DM 8,963 with ceftriaxone+netilmicin (DM 1=USD 0.56; 7/97). The costs for the German national economy were imipenem/cilastatin DM 23,828, ceftazidime DM 24,985 and ceftriaxone+netilmicin DM 29,838.     

Effects of disulfiram on the metabolism of nitrosodiethylamine during liver carcinogenesis

Summary We have studied the effects of disulfiram (DSF) administration on the metabolism of nitrosodiethylamine (NDEA) in rats during acute and chronic administration. DSF was found to have the following effects during the course of carcinogenesis: (a) marked decrease in the exhalation of ¹⁴CO₂ derived from ¹⁴C-NDEA; (b) reduction of the total levels of DNA and RNA ethylation in the liver. In acute experiments DSF caused an incrase in the amount of NDEA in organs and in the urine. We suggest that inhibition of NDEA biotransformation and the subsequent decrease in the total level of DNA ethylation may prevent specific chemical interactions relevant to carcinogenesis.Abbreviations DSF disulfiram - NDEA N-nitrosodiethylamine     

Single or multiple dose ursodeoxycholic acid for cholestatic liver disease: biliary enrichment and biochemical response

Background: Ursodeoxycholic acid (UDCA) improves liver biochemistry in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Since UDCA acts partly by reducing the intestinal absorption of hydrophobic endogenous bile salts and is poorly absorbed from the intestine, a multiple dose regimen has been advocated. Single dose treatment, on the other hand, may improve compliance.Aim: The effects of a single or multiple dose regimen on liver enzymes and serum and biliary bile salts composition were evaluated.Methods: Twenty-seven patients (19 PSC, 8 PBC), most with early stage disease, received UDCA (10 mg kg⁻¹ day⁻¹) in a single dose at bed time (n=13) or in three divided gifts with meals (n=14) over 3 months. Five patients had both treatment regimens in random order with a 1-month wash-out period in between.Results: Liver biochemistry equally improved in both groups. Biliary enrichment (% UDCA of total bile salts, mean±SEM) was 40.1±2.4 in the single dose group vs 40.8±2.8 in the multiple dose group (p=NS) and was positively correlated with biochemical improvement (AP: r=0.47, p=0.02; GGT: r=0.58, p=0.002; ASAT: r=0.67, p=0.002; ALAT: r=0.52, p=0.01). Biochemical improvement was not correlated with the concentration or %UDCA in serum. Patients participating in the cross-over design had comparable biochemical response and biliary %UDCA during both regimens.Conclusion: Single and multiple dose UDCA have similar effects on liver biochemistry and biliary enrichment in cholestatic liver disease. Biochemical improvement appears to be related to biliary (but not serum) enrichment with UDCA.     

Trends in Alcohol-Related Mortality among New Mexico's American Indians, Hispanics, and Non-Hispanic Whites

Reduction of alcohol-related mortality is a national goal for health promotion and disease prevention. We conducted this analysis to determine whether trends in New Mexico's Hispanics, non-Hispanic Whites, and American Indians were consistent with national trends in alcohol-related mortality, and whether differences in drinking patterns could account for racial and ethnic differences in rates. Age-adjusted, race-specific, and ethnic-specific alcohol-related mortality rates and 95% confidence intervals were calculated for 5-year periods for 1958–1991 using New Mexico vital statistics data. We estimated the prevalence of acute and chronic at-risk drinking behaviors and abstinence from data collected by the Behavioral Risk Factor Surveillance System (BRFSS) for the period 1986–1992. We found that alcohol-related mortality rates varied substantially by race, ethnicity, sex, age, and calendar period. American Indians had the highest rates for both sexes. Rates increased sharply from the period 1958–1962 until the late 1970s and the early 1980s, and then began to decrease rapidly. However, during the most recent decade, the rates have followed contrasting trends in the three ethnic and racial groups. Although rates have continued to decline among non-Hispanic Whites, rates for Hispanics and American Indians have not declined, and still remain substantially higher than rates during the 1958–1962 period. Differences in at-risk drinking behaviors reported to the BRFSS do not explain the contrast in race-specific and ethnic-specific mortality rates. Although progress has been made in reducing national per capita alcohol consumption and alcohol-related mortality, certain high-risk racial and ethnic groups may not be sharing in the progress.