cGMP and S-nitrosylation: two routes for modulation of neuronal excitability by NO

The nitric oxide (NO)-cGMP signaling cascade has been implicated in synaptic plasticity and, more broadly, in the control of many forms of electrical activity. This raises the issue of how these second messengers regulate ion channels. The field of ion-channel modulation is dominated by G proteins; NO and cGMP are often treated as poor cousins. However, recent advances surveyed here could change this perception. A surprising new dimension to NO signaling is the direct cGMP-independent action of NO on channel proteins through S-nitrosylation. The existence of two effector pathways has important functional implications, expanding and enriching the possibilities for modulating neuronal excitability.     

Coronary and systemic hemodynamic effects of sildenafil citrate: from basic science to clinical studies in patients with cardiovascular disease

Sildenafil citrate is the first oral phosphodiesterase type 5 inhibitor approved for the treatment of erectile dysfunction. The wide use of sildenafil by patients with erectile dysfunction and cardiovascular disease has resulted in a considerable number of independent studies investigating the cardiovascular safety and functional role of the phosphodiesterase type 5-cyclic guanosine monophosphate-nitric oxide pathway in the cardiovascular system. Endothelial dysfunction, defined as a reduction in the bioavailability of nitric oxide, is associated with many of the common risk factors for cardiovascular disease and erectile dysfunction. Sildenafil has been demonstrated to improve the vasomotor aspect of endothelial dysfunction in patients with heart failure and diabetes. Hemodynamic studies suggest that sildenafil is a modest vasodilator with the potential to increase coronary blood flow and coronary flow reserve. In patients with ischemic heart disease, sildenafil is associated with reductions in mean arterial and pulmonary pressure with little effect on heart rate, cardiac output, and systemic or pulmonary vascular resistance. The absence of an effect on cardiac output supports the lack of an inotropic effect of sildenafil. This is consistent with the finding that sildenafil has no effect on cyclic adenosine monophosphate levels in the vasculature. Finally, exciting reports have emerged from clinical experience with the use of phosphodiesterase type 5 inhibitors in patients with pulmonary hypertension.     

Abnormalities in the recirculation phase of contrast agent bolus passage in cerebral gliomas: comparison with relative blood volume and tumor grade

BACKGROUND AND PURPOSE: Abnormalities in the recirculation phase of the passage of a contrast agent bolus have been identified in tumors and have been suggested to represent vascular tortuosity and hypoperfusion in areas of angiogenic neovascularization. This study was performed to examine the hypothesis that these abnormalities provide information concerning the microcirculation related to tumor grade in patients with cerebral glioma. METHODS: Contrast-enhanced dynamic susceptibility MR imaging was performed in 27 patients with glioma. Residual relaxivity effects were minimized by injection of contrast agent before dynamic imaging. Maps of relative cerebral blood volume (rCBV) and relative recirculation (rR) were calculated, and values from enhancing tumor tissue were compared with tumor grade. RESULTS: Histologic grades were grade II, astrocytoma (n = 3); grade III, anaplastic astrocytoma (n = 10); and grade IV, glioblastoma multiforme (n = 14). rCBV values varied among tumor grades, with higher mean values in higher grade tumors (P <.001). Mean rR values in grade II tumors were not significantly different from those in normal gray and white matter. Mean rR values in grades III and IV tumors were similar and were significantly higher than those in grade II tumors (P <.01). The distribution of the pixel values of rR showed significant differences between grades III and IV tumors (P <.001), with low values of skewness in keeping with a normal distribution in grade III tumors and higher values in grade IV tumors. CONCLUSION: Variation in the recirculation characteristics of a contrast agent bolus is related to tumor grade in gliomas. This supports the hypothesis that abnormalities in contrast agent recirculation provide independent information concerning the microcirculation in imaging studies of angiogenesis and may be of value as surrogate markers in trials of antiangiogenic therapy.     

Hemodynamic responses to stress among black women: fitness and parental hypertension

PURPOSE: We compared hemodynamic aspects of the relationship between cardiorespiratory fitness and blood pressure changes during and after laboratory stress in young black women with or without parental history of hypertension. METHODS: Participants were 30 normotensive, black American women having low to moderate fitness levels (i.e., VO2peak) assessed by cycle ergometry who performed standard active and passive coping laboratory stressors. Blood pressure, heart rate, stroke volume, cardiac output, total peripheral resistance (TPR), calf blood flow (CBF), and calf vascular resistance (CVR) were assessed during exposure to forehead and hand cold pressors, and mental arithmetic, as well as during recovery after the tasks. RESULTS: Fitness was positively related to increases in either TPR or CVR during each stressor. In contrast, fitness was positively related to blunted blood pressure during or after passive stress (i.e., hand or forehead cold) and enhanced recovery of blood pressure and TPR after the active stressor (i.e., mental arithmetic); effects of fitness on the vascular responses during and after mental arithmetic were stronger among women having a negative history of parental hypertension. CONCLUSION: The findings confirm our previous report that fitness blunts systolic blood pressure response during the hand cold pressor in young women. They also suggest that future studies of fitness and blood pressure reactivity during stress should focus on the regulation of vascular responses and their recovery after stress. Weaker effects of VO2peak after mental arithmetic in the positive history group indicate that the level of fitness required to modify recovery from mental stress among black American women may differ according to parental history of hypertension.     

Bile decompression in children with histopathological evidence of pre-existing liver cirrhosis

Although it is agreed upon by most that adequate and timely bile decompression can preserve or even improve existing liver function much debate centers on whether pre-existing liver cirrhosis can also be reversed. To help answer this question we analyzed data on 47 children with choledochal cyst disease (CD) who underwent simultaneous liver biopsy during bile decompression surgery. We collected data on two groups of children with CD spanning two different time periods: January 1985 through November 1994 (Group A) and June 1995 through November 1999 (Group B). In Group A 37 children (16 boys and 21 girls ages 5 days to 10 years) underwent simultaneous liver biopsy during elective definitive surgery for CD. In Group B ten children (five boys and five girls age one month to 7 years) underwent liver biopsy twice: first during initial cyst decompression for acute obstruction and second during elective definitive surgery after resolution of acute disease. Degree of liver cirrhosis was based on a modified World Health Organization classification system (0-IV). In Group A 15/37 (40.5%) had significant liver cirrhosis at time of biopsy (III or IV) with altered liver function in all cases; eight of nine had normal liver function on follow-up, six were lost to follow-up. In Group B seven of ten (70%) had less liver cirrhosis on pathology at second operation with three unchanged; nine of ten (90%) regained normal liver function. We conclude that bile duct obstruction is the main cause of liver cirrhosis in children with CD. Adequate and timely bile decompression can restore normal liver function and even reverse severe cirrhosis.     

Overview of the national spinal cord injury statistical center database

OBJECTIVE: An evaluation of the history, design, and status of the database of the National Spinal Cord Injury Statistical Center (NSCISC) was undertaken to identify its continued relevance. RESEARCH DESIGN: A systematic review was conducted of goals, content, and quality control procedures, as well as its suitability and public availability for conducting future epidemiologic and health services research. RESULTS: The NSCISC database contains information on approximately 29,000 persons injured since 1973 and treated at any regional model spinal cord injury system within 1 year of injury. The NSCISC database is structured longitudinally with data collected at discharge, 1 year after injury, 5 years after injury, and every 5 years thereafter. The database includes information on demographics, injury severity, medical complications, surgical procedures, types and amounts of therapy, length of stay, charges, and both short-term and long-term treatment outcomes. Strengths include large sample size, use of valid and reliable measures, geographic and patient diversity, comprehensiveness, availability of long-term prospective follow-up information, good case identification, and rigorous quality control procedures. Limitations include lack of population basis, inclusion of only model system patients, losses to follow-up, and other missing data. Recent content additions include detailed information on each treatment phase, depression, substance abuse, environmental barriers to community integration, and patient identifying information. A process exists for researchers to gain access to the data. CONCLUSIONS: The database remains a valuable resource. Future plans include linkage to other databases to enhance research capability, a published research compendium, and development of a user's guide to facilitate database usage.     

Association between the GCG polymorphism of the selenium dependent GPX1 gene and the risk of young onset prostate cancer

Epidemiological studies have suggested an association between low selenium levels and the development of prostate cancer. Human cellular glutathione peroxidase I (hGPX1) is a selenium-dependent enzyme that protects against oxidative damage and its peroxidase activity is a plausible mechanism for cancer prevention by selenium. The GPX1 gene has a GCG repeat polymorphism in exon 1, coding for a polyalanine tract of five to seven alanine residues. To test if the GPX1 GCG repeat polymorphism associates with the risk of young-onset prostate cancer we conducted a case-control study. The GPX1Ala genotypes were determined for 267 prostate cancer cases and 260 control individuals using polymerase chain reaction (PCR) amplification with fluorescently labelled primers and an ABI 377 automated genotyper. Associations between specific genotypes and the risk of prostate cancer were examined by logistic regression. We found no significant association between the GPX1 genotypes and prostate cancer. There was however an increased frequency of the GPX1Ala6/Ala6 genotype in the prostate cancer cases compared to controls (OR: 1.67; 95% CI: 0.97-2.87). The result of this study suggests that the GPX1 genotype is unlikely to be associated with the risk of developing prostate cancer.     

Emergency care of the trauma patient in remote regions of Papua New Guinea

The purpose of this article is to discuss 'best practice' regarding the management of a trauma victim's upper airway in a remote region of Papua New Guinea (PNG). This article has been written with the trauma patient in mind; however, much of the information would be equally relevant to the acute and chronically ill patient. Therefore the management described should be of use to aid post orderlies, community health workers, nurses and doctors alike who work or patrol in remote regions of PNG. The article is designed to take the reader through a step by step approach. Commentaries to further clarify or expand the text are placed at the end of the article under specific addendum headings, so as not to disrupt the main flow of the subject matter. In addition to upper airway management, this article also details 'ideal' emergency trauma equipment and drug requirements for bush use.     

Polyarteritis nodosa presenting as a pyrexia of unknown origin

A case of an 18 year old woman is reported who presented with a pyrexia of unknown origin having returned from a trip to India. She initially had constitutional symptoms only, which rapidly progressed to a multisystem disorder. The difficulty in making the diagnosis of polyarteritis nodosa, especially with the possible differential diagnosis of infection after her recent travel, is discussed. The discussion reviews the condition of polyarteritis nodosa and analyses the diagnostic difficulties in this case.