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.     

Effect of testosterone on lipolysis in human pre-adipocytes from different fat depots

Aim/hypothesis Regional differences in lipolysis, with higher lipolytic activity in visceral than subcutaneous fat, are important for the development of insulin resistance and might be influenced by testosterone.Methods We studied testosterone-regulated lipolysis and protein expression (by western blot) in fully differentiated pre-adipocytes from visceral (omental) and abdominal subcutaneous adipose tissue from 52 human subjects. These cells were isolated and cultured in a serum-free medium.Results Testosterone caused a specific, time- and concentration-dependent 50% reduction of catecholamine-stimulated lipolysis in the subcutaneous depot. Half of the maximum effect occurred at 10 nmol/l. The inhibitory effect was due to the inability of -adrenoceptors and cyclic AMP to stimulate the protein kinase A, hormone-sensitive lipase complex. Testosterone caused a depot-specific 50% reduction of the protein expression of hormone-sensitive lipase and ₂-adrenoceptors in differentiated subcutaneous pre-adipocytes, but no change in ₁-adrenoceptors, protein kinase A subunits or perilipin expression. In contrast, testosterone had no effect on lipolysis or protein expression in the visceral depot. However, testosterone receptors were present in both depots, and the hormone inhibited adipocyte leptin secretion. Similar effects on lipolysis were observed with dihydrotestosterone.Conclusions/interpretation Testosterone in physiological concentrations causes a depot-specific reduction of catecholamine-stimulated lipolysis in subcutaneous fat cells, probably due to reduced protein expression of ₂-adrenoceptors and hormone-sensitive lipase. This could be an important pathogenic factor underlying regional differences in lipolysis and development of insulin resistance and hyperandrogenic polycystic ovary syndrome.Abbreviations PCOS polycystic ovary syndrome - GPDH glycerol-3-phosphate dehydrogenase - AR adrenergic receptor - HSL hormone-sensitive lipase - PKA protein kinase A - OD optical density - dcAMP dibutyryl cyclic AMP     

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     

Departments of medicine and international health

There is an emerging role in international health for departments of medicine that care to accept the challenge. Supervised medical rotations in the developing world and the care of culturally distinct immigrant populations provide unique opportunities to expand the scope of medical education while emphasizing a sensitive and humanistic approach to health care. The restraints imposed by diminished laboratory support and limited availability of drugs can foster reliance on diagnostic skills and the essential elements of therapy. Medical schools may elect to become involved in international health, but they must do so without becoming exploitative. Rotations of students, residents, and faculty in both directions should lead to productive interaction at both the clinical and research levels, for all participants.     

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.