Pharmacologic Therapy of Chronic Heart Failure

Over the past 2 decades, investigators have learned more about the pathophysiologic changes that occur in systolic and diastolic dysfunction. Ironically, in some cases, the biologic pathways that have protected the heart during acute dysfunction are the same pathways that cause progressive deleterious effects with chronic activation. In particular, it is the activation of the neurohormonal system that has a significant impact on disease progression. As a result, the neurohormonal system has provided a key target for pharmacologic therapy in patients with heart failure secondary to systolic dysfunction. These targets include the renin-angiotensin-aldosterone system as well as the sympathetic nervous system. Neurohormonal manipulation, however, is often ineffective in the pharmacologic therapy of patients with endstage heart failure, therefore other treatment strategies - including the use of inotropic agents to improve pump function and diuretics to control fluid balance are needed.     

Changes in Fos expression in the rat brain after unilateral lesions of the anterior thalamic nuclei

Activity of the immediate early gene c-fos was compared across hemispheres in rats with unilateral anterior thalamic lesions. Fos protein was quantified after rats performed a spatial working memory test in the radial-arm maze, a task that is sensitive to bilateral lesions of the anterior thalamic nuclei. Unilateral anterior thalamic lesions produced evidence of a widespread hippocampal hypoactivity, as there were significant reductions in Fos counts in a range of regions within the ipsilateral hippocampal formation (rostral CA1, rostral dentate gyrus, 'dorsal' hippocampus, presubiculum and postsubiculum). A decrease in Fos levels was also found in the rostral and caudal retrosplenial cortex but not in the parahippocampal cortices or anterior cingulate cortices. The Fos changes seem most closely linked to sites that are also required for successful task performance, supporting the notion that the anterior thalamus, retrosplenial cortex and hippocampus form key components of an interdependent neuronal network involved in spatial mnemonic processing.     

Community perceptions of dietary and environmental factors as cardiovascular diseases risk determinants

This work was carried out to assess the community's perception of the relative importance of various dietary, environmental and lifestyle factors as CVDs risk determinants and to investigate the beliefs of the community on issues related to CVDs. A household cluster sample survey was conducted in Alexandria city. The total sample was 600 persons aged > or = 18 years Results of this work revealed that public awareness of the magnitude of CVDs in the community was high. There appeared from the large percentages of incorrect or unsure responses that the community tended not to perceive the importance of different lifestyle habits specific to CVDs. 'Sociodemographic variables that were significantly associated with good perception were higher educational and occupational levels of the subjects. It was also revealed, that although the community has confidence in advice on preventive behaviours, it was reluctant to ask about screening tests. Moreover, the community is receiving some information about issues related to CVDs and, a desire for more health information from doctors and health agencies was evident. In spite of the majority of the subjects were willing to follow advice aimed to reduce their risk of getting CVDs, they were not sure what that advice might be. Studies of this type clearly have the ability to provide a range of information which ought to be available to those responsible for the planning of health promotion and education initiatives.     

Growth and heavy metals removal efficiency of Nostoc muscorum and Anabaena subcylindrica in sewage and industrial wastewater effluents

The growth of Nostoc muscorum and Anabaena subcylindrica in sterilized sewage wastewater and N. muscorum in sterilized wastewater of El-Soda Company was higher than those grown in Allen synthetic medium. Whereas, the growth of A. subcylindrica in El-Soda Company sterilized wastewater and N. muscorum as well as A. subcylindrica grown in Verta Company sterilized wastewater was slightly lower than that grown in the standard synthetic medium. The contents of chlorophyll a, carotenoids and protein of N. muscorum and A. subcylindrica grown in sterilized sewage wastewater were higher than those grown in the standard medium. Similarly, N. muscorum and the bio-mixture of N. muscorum and A. subcylindrica grown in the sterilized wastewater of El-Soda Company showed high pigments and protein contents more than those reared in Allen medium. On the other hand, the bio-mixture of N. muscorum and A. subcylindrica grown in the sterilized sewage wastewater, A. subcylindrica grown in El-Soda Company and Verta Company sterilized wastewater showed lower contents of pigments and protein compared to synthetic medium. Heavy metals, copper, cobalt, lead and manganese were removed by 12.5-81.8, 11.8-33.7, 26.4-100 and 32.7-100%, respectively, from wastewater by using cyanobacterial cultures. The metal sorption efficiency depended on the type of biosorbent, the physiological state of the cells, availability of heavy metal, concentration of heavy metal and chemical composition of wastewater. It was observed also that the single cultures in most cases was better than the mixed cultures in heavy metal removal, this may be due to the cyanobacterial competition for nutrients in mixed cultures.     

Estradiol metabolites attenuate renal and cardiovascular injury induced by chronic nitric oxide synthase inhibition

Our previous studies in rodent models of nephropathy demonstrate that 2-hydroxyestradiol (2HE), an estradiol metabolite with little estrogenic activity, exerts renoprotective effects. In vivo, 2HE is readily converted to 2-methoxyestradiol (2ME), a major estradiol metabolite with no estrogenic activity. The goal of this study was to determine whether 2ME has renal and cardiovascular protective effects in vivo. First, the acute (90 minutes) and chronic (14 days) effects of 2ME (10 microg/kg/h) on blood pressure and renal function were examined in normotensive and spontaneously hypertensive rats (SHR). Second, a rat model of cardiovascular and renal injury induced by chronic nitric oxide synthase inhibition (N-nitro-L-arginine; 40 mg/kg/d; LNNA group) was used to examine the protective effects of estradiol metabolites. Subsets of LNNA-treated rats were administered either 2HE or 2ME (10 microg/kg/h via osmotic minipump; LNNA+2ME and LNNA+2HE groups, respectively. 2-Methoxyestradiol had no acute or chronic effects on blood pressure or renal function in normotensive animals or on hypertension in SHR. Prolonged, 5-week NOS inhibition induced severe cardiovascular and renal disease and high mortality (75%, LNNA group). 2ME, but not 2HE, significantly decreased elevated blood pressure and attenuated the reduction in GFR. 2HE delayed the onset of proteinuria, whereas no proteinuria was detected in the 2-ME group. 2HE and 2ME reduced mortality rate by 66% and 83%, respectively (P < 0.001). In the kidney, 2HE and 2ME abolished LNNA-induced interstitial and glomerular inflammation, attenuated glomerular collagen IV synthesis, and inhibited glomerular and tubular cell proliferation. In the heart, 2HE and 2ME markedly reduced vascular and interstitial inflammation and reduced collagen synthesis and vascular/interstitial cell proliferation. This study provides the first evidence that, in a model of severe cardiovascular and renal injury, 2-methoxyestradiol (a major nonestrogenic estradiol metabolite) exerts renal and cardiovascular protective effects and reduces mortality.     

Mutagenesis of the epithelial polarity gene, discs large 1, perturbs nephrogenesis in the developing mouse kidney

BACKGROUND: During development of the permanent mammalian kidney (metanephros) several key epithelial events occur such as ureteric branching morphogenesis and nephrogenesis. One of the first stages of nephrogenesis involves the conversion of mesenchymal cells to epithelial cells, and thus the metanephros provides an excellent model to study epithelial polarization. The aim of this study was to investigate the role of the epithelial polarity gene, discs large 1 (dlg1), during development of the mouse kidney. METHODS: We utilized mice with a gene trap vector insertion within dlg1 (dlg(gt)) resulting in a truncated Dlg1 protein, lacking the SH3, protein 4.1 and guanylate kinase-like (GUK) domains, fused to a LacZ reporter. These mice were used to analyze the expression of Dlg1 during kidney development, the subcellular localization of Dlg1 in epithelial cells, and the ability of Dlg1 to bind to calmodulin-associated serine/threonine kinase (CASK). Metanephric organ culture was used to study branching morphogenesis and nephrogenesis in wild-type and dlg(gt) mutant mice. RESULTS: Dlg1 was expressed in ureteric and mesenchyme-derived epithelial cells during kidney development. Truncation of Dlg1 altered the normal basolateral localization of Dlg1 restricting it to the adherens junction. Due to the loss of the SH3 domain the binding capacity of Dlg1 to CASK was reduced. Nephrogenesis was altered in dlg(gt)/dlg(gt) metanephroi with a 30% decrease in nephron number. CONCLUSION: Our results indicate that the loss of the SH3, protein 4.1 and/or GUK domains of Dlg1 disrupt epithelial polarity and perturb nephrogenesis either as a secondary consequence to a defect in ureteric branching morphogenesis and/or delay in mesenchyme-to- epithelial transition.     

Five-year follow-up after clinical islet transplantation

Islet transplantation can restore endogenous beta-cell function to subjects with type 1 diabetes. Sixty-five patients received an islet transplant in Edmonton as of 1 November 2004. Their mean age was 42.9 +/- 1.2 years, their mean duration of diabetes was 27.1 +/- 1.3 years, and 57% were women. The main indication was problematic hypoglycemia. Forty-four patients completed the islet transplant as defined by insulin independence, and three further patients received >16,000 islet equivalents (IE)/kg but remained on insulin and are deemed complete. Those who became insulin independent received a total of 799,912 +/- 30,220 IE (11,910 +/- 469 IE/kg). Five subjects became insulin independent after one transplant. Fifty-two patients had two transplants, and 11 subjects had three transplants. In the completed patients, 5-year follow-up reveals that the majority ( approximately 80%) have C-peptide present post-islet transplant, but only a minority ( approximately 10%) maintain insulin independence. The median duration of insulin independence was 15 months (interquartile range 6.2-25.5). The HbA(1c) (A1C) level was well controlled in those off insulin (6.4% [6.1-6.7]) and in those back on insulin but C-peptide positive (6.7% [5.9-7.5]) and higher in those who lost all graft function (9.0% [6.7-9.3]) (P < 0.05). Those who resumed insulin therapy did not appear more insulin resistant compared with those off insulin and required half their pretransplant daily dose of insulin but had a lower increment of C-peptide to a standard meal challenge (0.44 +/- 0.06 vs. 0.76 +/- 0.06 nmol/l, P < 0.001). The Hypoglycemic score and lability index both improved significantly posttransplant. In the 128 procedures performed, bleeding occurred in 15 and branch portal vein thrombosis in 5 subjects. Complications of immunosuppressive therapy included mouth ulcers, diarrhea, anemia, and ovarian cysts. Of the 47 completed patients, 4 required retinal laser photocoagulation or vitrectomy and 5 patients with microalbuminuria developed macroproteinuria. The need for multiple antihypertensive medications increased from 6% pretransplant to 42% posttransplant, while the use of statin therapy increased from 23 to 83% posttransplant. There was no change in the neurothesiometer scores pre- versus posttransplant. In conclusion, islet transplantation can relieve glucose instability and problems with hypoglycemia. C-peptide secretion was maintained in the majority of subjects for up to 5 years, although most reverted to using some insulin. The results, though promising, still point to the need for further progress in the availability of transplantable islets, improving islet engraftment, preserving islet function, and reducing toxic immunosuppression.