ROLES OF ENTEROBACTERIA, NITRIC OXIDE AND NEUTROPHIL IN PATHOGENESIS OF INDOMETHACIN-INDUCED SMALL INTESTINAL LESIONS IN RATS

Roles of enterobacteria, nitric oxide (NO) and neutrophil in indomethacin-induced small intestinal lesions were examined in rats. Indomethacin (10 mg kg-1), administered s.c. as a single injection, caused haemorrhagic lesions in the small intestine, mostly in the jejunum and ileum. The lesions were first observed 6 h after administration of indomethacin, the severity increasing progressively with time up to 24 h later. Following indomethacin, the enterobacterial numbers, inducible NO synthase (iNOS) activity and NO production in the intestinal mucosa were also increased with time, and changes in the former preceded those in the latter two as well as the occurrence of intestinal damage. Treatment of the animals with both NG-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine prevented intestinal lesions induced by indomethacin, with suppression of NO production. Both dexamethasone and FR167653 (an inhibitor of interleukin-1 beta/tumour necrosis factor-alpha production) also reduced the severity of intestinal lesions as well as the increase in iNOS activity following administration of indomethacin. Likewise, the occurrence of intestinal lesions was attenuated by pretreatment of the animals with anti-neutrophil serum (ANS). None of these treatments, however, affect the translocation of enterobacteria in the mucosa. By contrast, ampicillin (an anti-bacterial agent) suppressed the increase in mucosal iNOS activity as well as the enterobacterial numbers invaded in the mucosa and inhibited the occurrence of intestinal lesions after administration of indomethacin. These results strongly suggest that enterobacterial translocation in the mucosa is the first step required for activation of various factors such as iNOS/NO and neutrophils, all involved in the pathogenesis of indomethacin-induced intestinal lesions.     

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.     

Cardiac Resynchronization Therapy in Pediatric and Congenital Heart Disease

Cardiac resynchronization therapy (CRT) is an emerging option for treating dyssynchrony-associated heart failure in patients with pediatric or congenital heart disease. CRT has proved beneficial for both the acute manipulation of cardiac output after surgery for congenital heart defects and for the management of chronic systemic ventricular failure. Although there are no prospective and randomized trial data, retrospective series show that CRT is similarly effective for managing dyssynchrony-associated heart failure in this younger population as it is for treating adults with ischemic and idiopathic dilated cardiomyopathy. The heterogeneity of anatomical and functional substrates in which CRT shows efficacy calls for further studies defining the usefulness of CRT in specific subgroups of patients.     

COMMENTS

The angiotensin I-converting enzyme (ACE, kininase II, CD143) shows a broad specificity for various oligopeptides. Besides the well-known conversion of angiotensin I to II, ACE degrades efficiently kinins and the tetrapeptide AcSDKP (goralatide) and thus equally participates in the renin-angiotensin system, the kallikrein-kinin system, and the regulation of stem cell proliferation. In the mammalian testis, ACE occurs in two isoforms. The testicular isoform (tACE) is exclusively expressed during spermatogenesis and is generally thought to represent the germ cell-specific isozyme. However, we have previously demonstrated that, in addition to tACE, the somatic isoform (sACE) is also present in human germ cells. Similar to other oncofoetal markers, sACE exhibits a transient expression during foetal germ cell development and appears to be a constant feature of intratubular germ cell neoplasm, the so-called carcinoma-in-situ (CIS) and, in particular, of classic seminoma. This demands the existence of specific paracrine functions during male germ cell differentiation and development of male germ cell tumours, which are mediated by either of the two ACE isoforms. Considering the complexity of current data about ACE, a logical connection is required between (I) the precise localisation of ACE isoforms, (I) the local access to potential substrates and (II) functional data obtained by knockout mice models. The present article summarises the current knowledge about ACE and its potential substrates with special emphasis on the differentiation-restricted ACE expression during human spermatogenesis and prespermatogenesis, the latter being closely linked to the pathogenesis of human germ cell tumours.