Efficacy of tolvaptan on advanced chronic kidney disease with heart failure: a randomized controlled trial

Clinical and Experimental Nephrology - Tolvaptan (TLV) is reported to improve diuretic effects in patients with chronic kidney disease (CKD) when furosemide (FUR) is not sufficiently effective....     

Transrectal ultrasound biopsy of the prostate: does it still have a role in prostate cancer diagnosis?

Transrectal ultrasound (TRUS) guided biopsy of the prostate has been a standard diagnostic approach for prostate cancer over the past thirty years. Today, the role of TRUS biopsy is being challenged by transperineal (TP) prostate biopsy due to concerns over the safety and diagnostic yield of TRUS biopsy. TRUS biopsy still offers a convenient, reliable and accessible tool for diagnosing prostate cancer in the majority of patients. It continues to play a role in prostate cancer diagnosis, especially where hospital resource allocation is limited, including the public sector. TRUS biopsy has low rates of severe complications, although there remains room for improvement in current practice to improve the tolerability and reduce the incidence of post-biopsy infection.     

HIF-2alpha regulates murine hematopoietic development in an erythropoietin-dependent manner

Erythropoiesis in the adult mammal depends critically on erythropoietin, an inducible cytokine with pluripotent effects. Erythropoietin gene expression increases under conditions associated with lowered oxygen content such as anemia and hypoxia. HIF-1alpha, the founding member of the hypoxia-inducible factor (HIF) alpha class, was identified by its ability to bind and activate the hypoxia-responsive enhancer in the erythropoietin regulatory region in vitro. The existence of multiple HIF alpha members raises the question of which HIF alpha member or members regulates erythropoietin expression in vivo. We previously reported that mice lacking wild-type HIF-2alpha, encoded by the EPAS1 gene, exhibit pancytopenia. In this study, we have characterized the etiology of this hematopoietic phenotype. Molecular studies of EPAS1-null kidneys reveal dramatically decreased erythropoietin gene expression. EPAS1-null as well as heterozygous mice have impaired renal erythropoietin induction in response to hypoxia. Treatment of EPAS1-null mice with exogenous erythropoietin reverses the hematopoietic and other defects. We propose that HIF-2alpha is an essential regulator of murine erythropoietin production. Impairments in HIF signaling, involving either HIF-1alpha or HIF-2alpha, may play a prominent role in conditions involving altered hematopoietic or erythropoietin homeostasis.     

Neurohormonal activation in severe heart failure: relations to patient death and the effect of treatment with flosequinan

BACKGROUND: Flosequinan is a direct-acting vasodilator that exerts beneficial hemodynamic effects and improves the exercise tolerance of patients with heart failure. However, a multicenter trial has demonstrated that long-term administration of flosequinan is associated with increased mortality rate. To explore a possible role of neurohormonal activation on this adverse outcome, we conducted a substudy to examine the plasma levels of 3 neurohormonal systems known to have prognostic implications in heart failure. METHODS: At 20 participating Canadian centers, paired plasma samples at baseline and 1 month after randomization for the measurement of N-terminal atrial natriuretic peptide (N-ANP), angiotensin II, and norepinephrine were obtained in 234 patients (114 receiving flosequinan and 120 receiving placebo). RESULTS: Treatment with flosequinan was associated with a decline in median plasma N-ANP levels (2139 pmol/L at baseline to 1625 pmol/L at 1 month [P =. 0001]), unchanged plasma angiotensin II levels (40 to 50 pmol/L [P =. 2700]), and a modest increase in plasma norepinephrine levels (391 to 439 pg/mL [P =.002]). These changes were not observed in the placebo group. Multivariate analysis of baseline variables revealed that plasma norepinephrine level predicted patients' death whereas analysis incorporating both baseline and 1-month variables indicated that plasma N-ANP level predicted patients' death. Furthermore, in the flosequinan group, a significant decline in plasma N-ANP level was observed in the survivors only. On multivariate analysis of baseline and 1-month data, the increase in plasma norepinephrine level did not predict the increase in heart rate associated with the use of flosequinan, suggesting that the 2 effects might be mediated by separate mechanisms. CONCLUSIONS: Results of our study demonstrate that in patients with severe heart failure, baseline norepinephrine level predicts death. Flosequinan increases plasma norepinephrine level and heart rate in these patients through mechanisms that override its beneficial hemodynamic effects. Our study reinforces the concept that the direct actions of a pharmacologic agent may have a more profound impact on the prognosis of these patients than the hemodynamic effects.     

Increased soluble (pro)renin receptor protein by autophagy inhibition in cultured cancer cells

(Pro)renin receptor ((P)RR) regulates the renin–angiotensin system and functions as an essential accessory subunit of vacuolar H⁺‐ATPase. There is accumulating evidence that shows close relationship between (P)RR and autophagy. Soluble (P)RR consisting of the extracellular domain of (P)RR is generated from (P)RR by proteolytic enzymes. The aim of the present study was to clarify the influence of autophagy inhibition on soluble (P)RR expression in cancer cells. Autophagy was inhibited by treatment of bafilomycin A1 or chloroquine in MCF‐7 and A549 cells for 72 hr. Western blot analysis showed that protein levels of soluble (P)RR were markedly elevated by autophagy inhibition, whereas no noticeable increases were observed in full‐length (P)RR. Secretion of soluble (P)RR into the medium was increased dose‐dependently by bafilomycin A1 or chloroquine. Autophagy inhibition was confirmed by enhanced accumulation of autophagy‐related proteins, LC3, p62 and LAMP1 in intracellular vesicles. Increased amount of soluble (P)RR by autophagy inhibition was decreased by site‐1 protease inhibitor, whereas no noticeable increase in site‐1 protease immunoreactivity was observed in cells with autophagy inhibition by immunocytochemistry. These findings suggest that soluble (P)RR protein accumulates by autophagy inhibition, possibly because of the reduced degradation of soluble (P)RR in the intracellular vesicles during autophagy inhibition.     

PEER umbrella systematic review of systematic reviews: Management of osteoarthritis in primary care

ObjectiveTo determine how many patients with chronic osteoarthritis pain respond to various non-surgical treatments.Data sourcesPubMed and the Cochrane Library.Study selection Published systematic reviews of randomized controlled trials (RCTs) that included meta-analysis of responder outcomes for at least 1 of the following interventions were included: acetaminophen, oral nonsteroidal anti-inflammatory drugs (NSAIDs), topical NSAIDs, serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, cannabinoids, counseling, exercise, platelet-rich plasma, viscosupplementation, glucosamine, chondroitin, intra-articular corticosteroids, rubefacients, or opioids.Synthesis In total, 235 systematic reviews were included. Owing to limited reporting of responder meta-analyses, a post hoc decision was made to evaluate individual RCTs with responder analysis within the included systematic reviews. New meta-analyses were performed where possible. A total of 155 RCTs were included. Interventions that led to more patients attaining meaningful pain relief compared with control included exercise (risk ratio [RR] of 2.36; 95% CI 1.79 to 3.12), intra-articular corticosteroids (RR = 1.74; 95% CI 1.15 to 2.62), SNRIs (RR = 1.53; 95% CI 1.25 to 1.87), oral NSAIDs (RR = 1.44; 95% CI 1.36 to 1.52), glucosamine (RR = 1.33; 95% CI 1.02 to 1.74), topical NSAIDs (RR = 1.27; 95% CI 1.16 to 1.38), chondroitin (RR = 1.26; 95% CI 1.13 to 1.41), viscosupplementation (RR = 1.22; 95% CI 1.12 to 1.33), and opioids (RR = 1.16; 95% CI 1.02 to 1.32). Preplanned subgroup analysis demonstrated no effect with glucosamine, chondroitin, or viscosupplementation in studies that were only publicly funded. When trials longer than 4 weeks were analyzed, the benefits of opioids were not statistically significant.ConclusionInterventions that provide meaningful relief for chronic osteoarthritis pain might include exercise, intra-articular corticosteroids, SNRIs, oral and topical NSAIDs, glucosamine, chondroitin, viscosupplementation, and opioids. However, funding of studies and length of treatment are important considerations in interpreting these data.