Synthesis and anti-HIV-1 integrase activities of 3-aroyl-2,3-dihydro-1,1-dioxo-1,4,2-benzodithiazines

A series of novel 3-aroyl-2,3-dihydro-1,1-dioxo-1,4,2-benzodithiazines 15-28 as potential HIV-1 integrase (IN) inhibitors have been synthesized by the reduction of 3-aroyl-1,1-dioxo-1,4,2-benzodithiazines 1-14 with benzenesulfonyl hydrazide. All the compounds 15-28 inhibited IN mediated strand transfer reaction with IC(50) values ranging from 3 to 30 microM. The 3-(4-bromobenzoyl)-6-chloro-7-methyl-2,3-dihydro-1,1-dioxo-1,4,2-benzodithiazine 17 with the IC(50) values of 4+/-1 and 3+/-1 microM for 3'-processing and strand transfer, respectively, was the most potent. Compound 17 as well its analogues were 5-20-fold less potent in Y99S and H114A mutants, implicating these residues as potential drug-binding site. This is a first report implicating Y99S and H114A of IN core domain in drug-binding interactions.     

Clinical, biochemical and hormonal characteristics of 84 patients with incidentally found adrenal tumor (incidentaloma)

In this study we have analyzed 84 patients (58 women, 26 men, mean age 57 +/- 1.1 year) hospitalized in the Department of Nephrology, Endocrinology and Metabolic Diseases of the Medical University of Silesia in Katowice from 01.01.1999 to 30.04.2003 because of incidentally discovered adrenal tumors (incidentaloma). The diameter of the tumors ranged from 8 to 86 mm (mean size 35.4 +/- 1.8 mm). Unilateral tumors were found in 74 patients and bilateral ones in 10 patients. In all patients circadian rhythm of plasma cortisol concentration and urinary cortisol excretion were measured. In 73 patients with a history of hypertension plasma renin activity was estimated in basal conditions and after stimulation by sodium restriction and upright position. Aldosteronemia and urinary metoxycatecholamines excretion were also determined. 45 patients with tumors >4 cm and/or with suspicion of malignancy or hormonal hypersecretion were qualified for surgical treatment. Thirty two patients out of the selected 45 have been operated so far. In two patients histopathological examination confirmed malignancy (adrenocortical carcinoma in one patient and metastatic cancer in the other one). The remaining 30 patients were operated because of size of the adrenal mass (16 patients) or biochemical suspicion of pheochromocytoma (12 patients, 5 of them with the mass size >4 cm) or primary aldosteronism (2 patients). The histological examination confirmed Conn syndrome in two patients and pheochromocytoma in one patient.     

Risk factors of atrial fibrillation in patients with Wolff-Parkinson-White syndrome

BACKGROUND: Atrial fibrillation (AF) in patients with WPW syndrome may be a life-threatening arrhythmia. AIM: To identify risk factors of AF and their prognostic significance in patients with WPW syndrome. METHODS: Clinical and electrophysiological parameters of 239 patients with WPW syndrome, who underwent successful RF ablation, were analysed using logistic regression and multivariate analysis. One hundred eight patients had no history of AF whereas the remaining 81 patients had previous spontaneous AF episodes. Long-term follow-up data (mean 29+/-23 months, range 1-99 months) were available in 136 patients (87 without AF and 49 with AF). RESULTS: Patients with AF were significantly older, more frequently of male gender and had more often a history of syncope than patients without AF. There were two peaks of AF occurrence - in the third and in the fifth decade of life. Fourteen patients had a history of ventricular fibrillation - 11 patients with AF vs 3 patients without AF (p=0.0016). Patients with a history of AF were more prone to AF induced during electrophysiological study and had less frequently concealed accessory pathways. CONCLUSIONS: Age, gender and a history of syncope are the independent risk factors of AF in patients with WPW syndrome. Anterograde conduction via accessory pathway is of major importance in the development of AF. RF ablation of an accessory pathway should be performed early because the risk of the procedure is small and there is an increasing risk of AF with ageing.     

Carbonate Lake Sediments in the Plastics Processing-Preliminary Polylactide Composite Case Study: Mechanical and Structural Properties

In this study, the influence of carbonate lake sediments (Polylactide/Carbonate Lake Sediments–PLA/CLS) on the mechanical and structural properties of polylactide matrix composites was investigated. Two fractions of sediments originating from 3–8 and 8–12 m were analysed for differences in particle size by distribution (Dynamic Light Scattering–DLS), phase composition (X-ray Diffraction–XRD), the presence of surface functional groups (Fourier Transform-Infrared–FT-IR), and thermal stability (Thermogravimetric Analysis–TGA). Microscopic observations of the composite fractures were also performed. The effect of the precipitate fraction on the mechanical properties of the composites before and after conditioning in the weathering chamber was verified through peel strength, flexural strength, and impact strength tests. A melt flow rate study was performed to evaluate the effect of sediment on the processing properties of the PLA/CLS composite. Hydrophobic-hydrophilic properties were also investigated, and fracture analysis was performed by optical and electron microscopy. The addition of carbon lake sediments to PLA allows for the obtention of composites resistant to environmental factors such as elevated temperature or humidity. Moreover, PLA/CLS composites show a higher flow rate and higher surface hydrophobicity in comparison with unmodified PLA.     

Steroid withdrawal at 3 months after kidney transplantation: a comparison of two tacrolimus-based regimens

The 6 month prospective, randomized study compared the steroid-sparing potential of two tacrolimus-based regimens after renal transplantation. A total of 489 patients were randomized (1:1) to receive tacrolimus/mycophenolate mofetil (MMF)/steroids (n = 243; group Tac/MMF/S) or tacrolimus/azathioprine/steroids (n = 246; group Tac/Aza/S). At 3 months, steroids were tapered off in 267 (54.6%) patients free from steroid-resistant acute rejection and with serum creatinine concentrations <160 micromol/l. The incidence of biopsy-confirmed acute rejection at month 3 was lower in group Tac/MMF/S compared with group Tac/Aza/S (18.1% vs. 26.0%,P = 0.035). Moreover, more patients in the Tac/MMF/S group met the criteria for steroid withdrawal than in the Tac/Aza/S group (60.5% vs. 48.8%; P < 0.01). The incidence of acute rejection during months 4-6 was low in all groups, both for patients on steroid-free dual therapy (Tac/MMF: 2.7%, Tac/Aza: 0.8%) and for patients who continued steroid maintenance therapy (Tac/MMF/S: 3.5%, Tac/Aza/S: 7.1%). Moreover, kidney function was well preserved in steroid-free patients with month 6 median serum creatinine levels of 119.5 micromol/l (Tac/MMF), and 115.1 micromol/l (Tac/Aza). For patients who continued to receive steroids, month 6 median creatinine levels were 130.5 micromol/l (Tac/MMF/S) and 132.8 micromol/l (Tac/Aza/S). The criteria for the selection of patients to discontinue steroids were adequate. Both tacrolimus-based regimens allowed the safe discontinuation of steroids in low-risk patients at month 3. The Tac/MMF combination was superior in the prevention of acute rejections and more patients met the chosen criteria for steroid withdrawal.     

A novel contact hypersensitivity model for rank-ordering formulated corticosteroids

Inflammation Research -     

Chronic periodontitis in hemodialysis patients with chronic kidney disease is associated with elevated serum C-reactive protein concentration and greater intima-media thickness of the carotid artery

BACKGROUND: An increasing number of papers have documented the contribution of chronic periodontitis (P) to the pathogenesis of cardiovascular disease. The aim of this study was to answer the question whether there is an association between periodontal inflammation and atherosclerotic processes in hemodialysis patients with chronic kidney disease (CKD). METHODS: Forty-four hemodialysis patients with CKD were considered. Advanced chronic periodontitis was found in 17, whereas 27 patients had no or moderate chronic periodontitis. In all patients examined, serum C-reactive protein (CRP), TNF-alfa and IL-6 concentrations, as well as intima-media thickness (IMT) of the carotid artery, were assessed. RESULTS: Patients with CKD and advanced periodontitis were characterized by a significantly higher serum CRP concentration (13.2 +/- 11.4 vs. 10.4 +/- 14.4; p<0.05) and IMT (0.742 +/- 0.028 vs. 0.656 +/- 0.019, p<0.05) than CKD patients without periodontitis. In the univariate analysis, a significant correlation between CRP and number of atherosclerotic plaques was revealed; however, it was not confirmed as an independent relationship in the multiple regression analysis. CONCLUSIONS: Inflammation of the periodontal tissue in patients with CKD is associated with increased serum CRP concentration and greater IMT. It is possible that periodontitis may induce a systemic process that may exacerbate atherosclerosis.     

Recurrent ventricular fibrillation during a febrile illness as the first manifestation of Brugada syndrome--a case report

A case of a 33-year-old male who was admitted to the hospital due to recurrent ventricular fibrillation during a febrile illness is presented. Initially, the patient was diagnosed with acute myocardial infarction and received thrombolytic treatment. Echocardiography and coronary angiography were normal. Right precordial ECG leads recorded one and two intercostal spaces higher than normal as well as ECG obtained following ajmaline administration revealed a typical Brugada pattern.     

Eleven-years long follow-up in a patient after myocardial infarction, with low ejection fraction and recurrent ventricular tachycardia. The role of implantable cardioverter defibrillator and selective ablation

The selective ablation of the recurrent ventricular tachycardia (VT) in a 75-year old patient after extensive inferior myocardial infarction (24 years ago), with low ejection fraction was performed. In 1995 the cardioverter-defibrillator was implanted due to recurrent, symptomatic VT. The coronary angiography in 1995 and in 2006 revealed the occlusion of the right coronary and the circumflex arteries. One year after implantation, he had electrical storm caused by proarrhythmic effect of amiodarone with prolongation of QT/QTc interval. During follow up episodes of VT (approximately 5/year) were successfully terminated by ATP and rarely by cardioversion. Recently, the patient was admitted to the hospital because of the very frequent (25/day) episodes of slow (500-560 ms), sustained ventricular tachycardia. The pharmacological treatment was unsuccessful. CARTO mapping and entrainment pacing revealed VT circuit around mitral annulus. A few applications at the paraseptal part of the mitral isthmus terminated VT, which was no longer inducible. During following days there were no VTs requiring ICD interventions.