Antihypertensive Effect of some Oxazolo[3,2-a]pyridines,Thiazolo[3,2-a]pyridines and Pyrido[2,1-b]oxazines in Conscious Spontaneously Hypertensive Rats

The antihypertensive activity of eighteen oxazolo[3,2-a]pyridine, fhiazolo[3,2-a]pyridine and pyrido[2,1-b]oxazine derivatives has been evaluated in conscious spontaneously hypertensive rats (SHRs), and compared with that of nifedipine, used as reference. At a dose of 50 mg kg^?1 (i.p.) eleven compounds resulted in a significant reduction in mean arterial blood pressure; four of the eleven were particularly effective, resulting in significant hypotension more than 6 h after administration and an effect that was still apparent after 24 h. The hypotension induced by nifedipine gradually decreased, disappearing 6–8 h after administration. The long-lasting activity shown by these compounds is, in general, not accompanied by reflex tachycardia. Intraperitoneal administration of two oxazolo[3,2-a]pyridine derivatives and two pyrido[2,1-b]oxazine derivatives resulted in potent and long-lasting antihypertensive action in SHRs. Further studies on the mechanism of action of these derivatives might help the determination of better structure–activity correlations and the design, synthesis and evaluation of better antihypertensive agents.     

Harlequin foetus in four siblings

Four siblings (three males, one female), affected by harlequin foetus, are presented. Genetic aspects and classification of this variety of ichthyosis are discussed.     

T-CELL SENSITIZATION TO AUTOLOGOUS THYROID CELLS AND NORMAL NON-SPECIFIC SUPPRESSOR T-CELL FUNCTION IN GRAVES'' DISEASE

We have employed a syngeneic system utilizing thyroid cell monolayers initiated following thyroid surgery co-cultured with autologous T cells to demonstrate T cell autosensitization in patients with Graves' disease. Antigen-induced blastogenesis was monitored using 24 h [3H]thymidine uptake. Control experiments with 5 d cultured normal human thyroid cells from tissue around benign adenomata showed no evidence of syngeneic T cell autosensitization. Human thyroid cells alone were unable to incorporate [3H]thymidine in the presence of bTSH. In three of four experiments with Graves' thyroid cells there was significant induction of autologous T cell blastogenesis with a mean stimulation index of 220%. In parallel experiments we explored the non-specific helper and suppressor T cell function of these and similar patients with Graves' disease. In normal controls (n = 6) increasing numbers of T cells added to a constant number of B cells (consisting of a T cell depleted peripheral mononuclear cell preparation) showed a marked helper effect measured as increasing IgG secretion. As the ratio of T:B cells increased above 4:1 there was a suppression of IgG secretion. One of two hyperthyroid Graves' patients was observed to have deficient T cell function as demonstrated by lack of IgG suppression. The remaining five patients (all but one of whom were euthyroid at the time of testing) had results similar to the controls indicating normal suppressor T cell function in this disease. Such data showed that patients with Graves' disease possessed circulating T cells which exhibited autosensitization to syngeneic thyroid cell surface antigens, a phenomenon not demonstrable in control individuals. Furthermore, this specific T cell autosensitization did not interfere with non-specific T cell function as judged by its influence on IgG secretion.     

Effects of Electrophysiologic-Guided Therapy with Class IA Antiarrhythmic Drugs on the Long-Term Outcome of Patients with Idiopathic Ventricular Fibrillation with or without the Brugada Syndrome

INTRODUCTION: Implantation of a implantable cardioverter defibrillator (ICD) is viewed universally as the "gold standard" therapy for patients with idiopathic ventricular fibrillation (VF). We sought to study the long-term value of electrophysiologic (EP)-guided therapy with Class IA antiarrhythmic drugs in patients with idiopathic VF with or without the Brugada syndrome. METHODS AND RESULTS: We performed EP studies in 34 consecutive patients who had idiopathic VF with (n = 5) or without (n = 29) the Brugada syndrome. All patients with inducible sustained polymorphic ventricular tachycardia (SPVT) or VF underwent repeated EP evaluation after oral administration of a Class IA antiarrhythmic drug (mainly quinidine). Patients rendered noninducible received this therapy on a long-term basis. SPVT/VF were induced in 27 (79.4%) patients at baseline studies. Class IA drugs effectively prevented induction of SPVT/VF in 26 (96%) patients. Of the 23 patients treated with these medications, no patient died or had a sustained ventricular arrhythmia during a mean follow-up period of 9.1 +/- 5.6 years (7 to 20 years in 15 patients). Two deaths occurred in patients without inducible SPVT/VF at baseline studies who had been treated empirically. CONCLUSION: Our results suggest that EP-guided therapy with Class IA agents is a reasonable, safe, and effective approach for the long-term management of patients with idiopathic VF. A randomized prospective study of EP-guided Class IA therapy in patients with ICDs seems warranted.     

The role of LIN28B in tumor progression and metastasis in solid tumor entities

LIN28B is an RNA-binding protein that targets a broad range of microRNAs and modulates their maturation and activity. Under normal conditions, LIN28B is exclusively expressed in embryogenic stem cells, blocking differentiation and promoting proliferation. In addition, it can play a role in epithelial-to-mesenchymal transition by repressing the biogenesis of let-7 microRNAs. In malignancies, LIN28B is frequently overexpressed, which is associated with increased tumor aggressiveness and metastatic properties. In this review, we discuss the molecular mechanisms of LIN28B in promoting tumor progression and metastasis in solid tumor entities and its potential use as a clinical therapeutic target and biomarker.