Induction of heme oxygenase-1 is a beneficial response in a murine model of venous thrombosis.

The induction of heme oxygenase-1 (HO-1) may protect against tissue injury. The present study examines the induction of HO-1 in a murine model of venous thrombosis and explores the downstream consequences of this induction. In a model of stasis-induced thrombosis created by ligation of the inferior vena cava, HO-1 expression is markedly induced. Such expression occurs primarily in smooth muscle cells in the venous wall and in leukocytes infiltrating the venous wall and clot. To determine the significance of HO-1 induction in venous thrombosis, this model was imposed in HO-1(+/+) and HO-1(-/-) mice. The initial clot size did not differ in either group by day 2, but was significantly larger in HO-1(-/-) mice by day 10, where an exaggerated inflammatory response in the venous wall was also observed. Following ligation of the inferior vena cava, HO-1(-/-) mice exhibited increased nuclear factor kappaB activation and markedly increased up-regulation of tissue factor, selectins, inflammatory cytokines, and matrix metalloproteinase-9, the latter incriminated in both clot lysis and vascular injury. We conclude that HO-1 deficiency impairs thrombus resolution and exaggerates the inflammatory response to thrombus formation. These findings offer insight into recent observations that polymorphisms in the HO-1 gene may increase the risk for recurrent venous thrombosis and dysfunction of hemodialysis arteriovenous fistulas, the latter caused, in part, by thrombosis.

Timing of referral for vascular access placement: a systematic review.

OBJECTIVE: This review was conducted to determine the optimal timing for referring patients with end-stage renal disease to vascular surgery for access placement. METHODS: A systematic review of the electronic databases (MEDLINE, EMBASE, Current Contents, Cochrane CENTRAL and Web of Science) was conducted through March 2007. Randomized and observational studies were eligible if they compared an early referral cohort with a late referral cohort in terms of patient-important outcomes such as death, access-related sepsis, and hospitalization related to access complications. RESULTS: We found no studies that fulfilled eligibility criteria. CONCLUSION: At the present time, the optimal timing for referral to vascular surgery for vascular access placement is based on expert opinion and choices made by patients and physicians.

Autogenous versus prosthetic vascular access for hemodialysis: a systematic review and meta-analysis.

OBJECTIVES: The autogenous arteriovenous access for chronic hemodialysis is recommended over the prosthetic access because of its longer lifespan. However, more than half of the United States dialysis patients receive a prosthetic access. We conducted a systematic review to summarize the best available evidence comparing the two accesses types in terms of patient-important outcomes. METHODS: We searched electronic databases (MEDLINE, EMBASE, Cochrane CENTRAL, Web of Science and SCOPUS) and included randomized controlled trials and controlled cohort studies. We pooled data for each outcome using a random effects model to estimate the relative risk (RR) and its associated 95% confidence interval (CI). We estimated inconsistency caused by true differences between studies using the I(2) statistic. RESULTS: Eighty-three studies, of which 80 were nonrandomized, met eligibility criteria. Compared with the prosthetic access, the autogenous access was associated with a significant reduction in the risk of death (RR, 0.76; 95% CI, 0.67-0.86; I(2) = 48%, 27 studies) and access infection (RR, 0.18; 95% CI, 0.11-0.31; I(2) = 93%, 43 studies), and a nonsignificant reduction in the risk of postoperative complications (hematoma, bleeding, pseudoaneurysm and steal syndrome, RR 0.73; 95% CI, 0.48-1.16; I(2) = 65%, 31 studies) and length of hospitalization (pooled weighted mean difference -3.8 days; 95% CI, -7.8 to 0.2; P = .06). The autogenous access also had better primary and secondary patency at 12 and 36 months. CONCLUSION: Low-quality evidence from inconsistent studies with limited protection against bias shows that autogenous access for chronic hemodialysis is superior to prosthetic access.

Surveillance of arteriovenous hemodialysis access: a systematic review and meta-analysis.

OBJECTIVES: Hemodialysis centers regularly survey arteriovenous (AV) accesses for signs of dysfunction. In this review, we synthesize the available evidence to determine to what extent proactive vascular access monitoring affects the incidence of AV access thrombosis and abandonment compared with clinical monitoring. METHODS: We searched electronic databases (MEDLINE, EMBASE, Cochrane CENTRAL, Web of Science, and SCOPUS) and sought references from experts, bibliographies of included trials, and articles that cited included studies. Two reviewers independently assessed trial quality and extracted data. We used random effects meta-analysis to estimate the pooled relative risk (RR) and 95% confidence interval (CI) across studies and conducted subgroup analyses to explain heterogeneity. The I(2) statistic was used to assess heterogeneity of treatment effect among trials. RESULTS: Nine studies (1363 patients) compared a strategy of surveillance vs clinical monitoring. A vascular intervention to maintain or restore patency was provided to both groups if needed. Surveillance followed by intervention led to a nonsignificant reduction of the risk of access thrombosis (RR, 0.82; 95% CI, 0.58-1.16; I(2) = 37%) and access abandonment (RR, 0.80; 95% CI, 0.51-1.25; I(2) = 60%). Three studies (207 patients) compared the effect of vascular interventions vs observation in patients with abnormal surveillance result. Vascular interventions after an abnormal AV access surveillance led to a significant reduction of the risk of access thrombosis (RR, 0.53; 95% CI, 0.36-0.76) and a nonsignificant reduction of the risk of access abandonment (RR, 0.76; 95% CI, 0.43-1.37). CONCLUSION: Very low quality evidence yielding imprecise results suggests a potentially beneficial effect of AV access surveillance followed by interventions to restore patency. This inference, however, is weak and will require randomized trials of AV access surveillance vs clinical monitoring for rejection or confirmation.

Renal hemodynamic, inflammatory, and apoptotic responses to lipopolysaccharide in HO-1-/- mice.

Lipopolysaccharide (LPS) induces the stress-responsive gene heme oxygenase-1 (HO-1). The present study examined the significance of HO-1 in response to LPS. In HO-1(-/-) mice, as compared with HO-1(+/+) mice, LPS provoked a greater reduction in glomerular filtration rate and renal blood flow, increased renal cytokine expression, and increased activation of nuclear factor (NF)-kappaB. Conversely, HO-1-overexpressing renal epithelial cells, exposed to LPS, exhibited a blunted activation of NF-kappaB and less phosphorylation of its inhibitor, IkappaB. In HO-1(-/-) mice, as compared with HO-1(+/+) mice, LPS provoked markedly greater elevations in serum levels of Th1 cytokines, Th2 cytokines, chemokines, and cytokines that stimulate bone marrow progenitors. The liver, a major source of serum cytokines, showed an increased activation of NF-kappaB in LPS-treated HO-1(-/-) mice. In addition, LPS provoked widespread apoptosis of immune cells in the spleen and thymus in HO-1(-/-) mice but not in HO-1(+/+) mice. We conclude that HO-1 deficiency exhibits a heightened and dysregulated inflammatory response to LPS accompanied by greater impairment in renal hemodynamic response and widespread apoptosis of immune cells. Because polymorphisms in the HO-1 gene with diminished HO activity predispose to human disease, we speculate that our findings may be relevant to the clinical outcome in patients with sepsis syndromes.

Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis of randomized placebo-controlled trials.

OBJECTIVE: To conduct a systematic review and meta-analysis of randomized placebo-controlled trials to measure the effect of testosterone use on sexual function in men with sexual dysfunction and varying testosterone levels. METHODS: Librarian-designed search strategies were used to search the MEDLINE (1966 to October 2004), EMBASE (1988 to October 2004), and Cochrane CENTRAL (inception to October 2004) databases. The MEDLINE search was rerun in March 2005. We also reviewed reference lists from included studies and content expert files. We selected randomized placebo-controlled trials of testosterone vs placebo that enrolled men with sexual dysfunction and measured satisfaction with erectile function and libido and overall sexual satisfaction. RESULTS: We included 17 trials (N = 862 participants) in this review. Trials that enrolled participants with low testosterone levels showed (1) a moderate nonsignificant and inconsistent effect of testosterone use on satisfaction with erectile function (random-effects pooled effect size, 0.80; 95% confidence interval [CI], -0.10 to 1.60), (2) a large effect on libido (pooled effect size, 1.31; 95% CI, 0.40 to 2.25), and (3) no significant effect on overall sexual satisfaction. Trials that enrolled patients with low-normal and normal testosterone levels at baseline showed testosterone that caused (1) a small effect on satisfaction with erectile function (pooled effect size, 0.34; 95% CI, 0.03 to 0.65), (2) moderate nonsignificant effect on libido (pooled effect size, 0.41; 95% CI, -0.01 to 0.83), and (3) no significant effect on overall sexual satisfaction. CONCLUSION: Testosterone use in men is associated with small improvements in satisfaction with erectile function and moderate improvements in libido. Unexplained inconsistent results across trials, wide CIs, and possible reporting bias weaken these inferences.

Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials.

OBJECTIVE: To conduct a systematic review and meta-analysis of randomized trials that assessed the effect of testosterone use on cardiovascular events and risk factors in men with different degrees of androgen deficiency. METHODS: Librarian-designed search strategies were used to search the MEDLINE (1966 to October 2004), EMBASE (1988 to October 2004), and Cochrane CENTRAL (inception to October 2004) databases. The database search was performed again in March 2005. We also reviewed reference lists from included studies and content expert files. Eligible studies were randomized trials that compared any formulation of commercially available testosterone with placebo and that assessed cardiovascular risk factors (lipid fractions, blood pressure, blood glucose), cardiovascular events (cardiovascular death, nonfatal myocardial infarction, angina or claudication, revascularization, stroke), and cardiovascular surrogate end points (ie, laboratory tests indicative of cardiac or vascular disease). Using a standardized data extraction form, we collected data on participants, testosterone administration, and outcome measures. We assessed study quality with attention to allocation concealment, blinding, and loss to follow-up. RESULTS: The 30 trials included 1642 men, 808 of whom were treated with testosterone. Overall, the trials had limited reporting of methodological features that prevent biased results (only 6 trials reported allocation concealment), enrolled few patients, and were of brief duration (only 4 trials followed up patients for > 1 year). The median loss to follow-up across all 30 trials was 9%. Testosterone use in men with low testosterone levels led to inconsequential changes in blood pressure and glycemia and in all lipid fractions (total cholesterol: odds ratio [OR], -0.22; 95% confidence interval [CI], -0.71 to 0.27; high-density lipoprotein cholesterol: OR, -0.04; 95% CI, -0.39 to 0.30; low-density lipoprotein cholesterol: OR, 0.06; 95% CI, -0.30 to 0.42; and triglycerides: OR, -0.27; 95% CI, -0.61 to 0.08); results were similar in patients with low-normal to normal testosterone levels. The OR between testosterone use and any cardiovascular event pooled across trials that reported these events (n = 6) was 1.82 (95% CI, 0.78 to 4.23). Several trials failed to report data on measured outcomes. For reasons we could not explain statistically, the results were inconsistent across trials. CONCLUSION: Currently available evidence weakly supports the inference that testosterone use in men is not associated with important cardiovascular effects. Patients and clinicians need large randomized trials of men at risk for cardiovascular disease to better inform the safety of long-term testosterone use.

Physiology and pathophysiology of heme: implications for kidney disease.

An iron-containing, tetrapyrrole ring, heme is an essential prosthetic group in an array of proteins that comprehensively affect cellular function and metabolism; yet "free" heme in sufficient amounts can be damaging to the kidney and other organs because of its bioreactivity and pro-oxidant effects. This review discusses the cellular metabolism of heme in health and disease and covers such areas as the synthesis of heme and its utilization in heme proteins; mechanisms underlying the toxicity of heme; and the extent to which pathophysiologic processes, such as renal incorporation of heme proteins or destabilization of intracellular heme proteins, increase intracellular levels of heme and provoke renal injury. The main catabolic process that degrades heme, the heme oxygenase (HO) system, is reviewed, and evidence for the protective effects of HO-1 against acute and chronic heme/heme protein-induced renal injury is summarized. Finally, current views regarding the molecular basis for heme-induced upregulation of HO-1 are discussed.

Testosterone use in men and its effects on bone health. A systematic review and meta-analysis of randomized placebo-controlled trials.

CONTEXT: Androgen-deficient men are at increased risk of osteoporosis. The extent to which testosterone can prevent and treat osteoporosis in men remains unclear. OBJECTIVE AND DESIGN: We performed a systematic review and meta-analysis of randomized placebo-controlled trials in men to estimate the effect of testosterone use on bone health outcomes. DATA SOURCES: The review encompassed librarian-designed search strategies using MEDLINE (1966 to March 2005), EMBASE (1988 to March 2005), and Cochrane CENTRAL (inception to March 2005); a review of reference lists from included studies; and content expert files. DATA COLLECTION: Independently and in duplicate, we assessed the methodological quality of the eligible trials and collected data on bone mineral density and bone fractures at the longest point of complete follow-up. DATA SYNTHESIS: We included eight trials enrolling 365 patients. Two trials followed patients for more than 1 yr. Meta-analysis of these trials showed that, compared with placebo, im testosterone was associated with an 8% (95% confidence interval, 4%, 13%) gain in lumbar bone mineral density and transdermal testosterone had no significant impact. Testosterone use was associated with a nonsignificant 4% (95% confidence interval, -2%, 9%) gain in femoral neck bone mineral density with unexplained differences in results across trials (26% of these differences were not explained by chance alone). No trials measured or reported the effect of testosterone on fractures. CONCLUSIONS: Intramuscular testosterone moderately increased lumbar bone density in men; the results on femoral neck bone density are inconclusive. Without bone fracture data, the available trials offer weak and indirect inferences about the clinical efficacy of testosterone on osteoporosis prevention and treatment in men.

Circulating plasma cells detected by flow cytometry as a predictor of survival in 302 patients with newly diagnosed multiple myeloma.

We detected circulating plasma cells (PCs) by flow cytometry in 302 patients with newly diagnosed multiple myeloma (MM) by gating on CD38+CD45- cells. The number of circulating PCs per 50 000 mononuclear cells was reported. In 80 (27%) patients, no circulating PC were seen; 106 (35%) patients had 1 to 10 and 115 (38%) patients had more than 10 circulating PCs. Median overall survival for the 302 patients was 47 months. Patients with 10 or fewer circulating PCs had a median survival of 58.7 months, whereas patients with more than 10 circulating PCs had a median survival of 37.3 months (P = .001). On multivariate analysis, the prognostic value of circulating PCs was independent of beta2-microglobulin, albumin, and C-reactive protein. There was only a weak correlation between tumor mass and circulating PCs, suggesting that the appearance of circulating PCs may be a reflection of tumor biology. We conclude that the number of circulating PCs measured by flow cytometry in patients with newly diagnosed MM is an independent predictor of survival.