The mortality rate of patients who develop acute kidney injury during sepsis nearly doubles. The effectiveness of therapy is hampered because it is usually initiated only after the onset of symptoms. As renal microvascular failure during sepsis is correlated with the generation of reactive nitrogen species, the therapeutic potential of resveratrol, a polyphenol vasodilator that is also capable of scavenging reactive nitrogen species, was investigated using the cecal ligation and puncture (CLP) murine model of sepsis-induced acute kidney injury. Resveratrol when given at 5.5 h following CLP reversed the decline in cortical capillary perfusion, assessed by intravital microscopy, at 6 h in a dose-dependent manner. Resveratrol produced the greatest improvement in capillary perfusion and increased renal blood flow and the glomerular filtration rate without raising systemic pressure. A single dose at 6 h after CLP was unable to improve renal microcirculation assessed at 18 h; however, a second dose at 12 h significantly improved microcirculation and decreased the levels of reactive nitrogen species in tubules, while improving renal function. Moreover, resveratrol given at 6, 12, and 18 h significantly improved survival. Hence, resveratrol may have a dual mechanism of action to restore the renal microcirculation and scavenge reactive nitrogen species, thus protecting the tubular epithelium even when administered after the onset of sepsis.

No abstract

Administration of sodium selenite in septic shock has been associated with apparently conflicting results that may be related to different dosing schedules. Bolus administration, leading to a transient pro-oxidative effect, could limit the inflammatory reaction and improve outcomes. We studied 21 anesthetized, mechanically ventilated, invasively monitored, and fluid-resuscitated sheep. Nine hours after inducing peritonitis by injection of autologous feces, the animals were randomized into three groups: (i) bolus injection (2 mg selenium as selenite, followed by 0.06 microg . kg-1 . h-1, n = 7); (ii) continuous infusion (4 microg . kg-1 . h-1 selenium, n = 7), or (iii) control (n = 7). No vasopressors or antibiotics were administered. All animals were monitored until spontaneous death. Peak plasma selenium values reached 4 to 14 micromol . L-1. Compared with the other groups, sheep given a bolus of sodium selenite had delayed hypotension with better maintained cardiac index, delayed hyperlactatemia, fewer sepsis-induced microvascular alterations, and a prolonged survival time (21.9 [bolus group] vs. 18.4 [continuous group] and 18.3 h [control group], P< 0.05). Hence, in this model of septic shock, the administration of a large bolus of sodium selenite (rather than a continuous administration) resulted in beneficial effects, probably by a transient oxidative effect.

Polycystic ovary syndrome (PCOS) represents an endocrine disorder, which is closely related with gut microbiota. Inulin, a kind of probiotics, has been proven to alleviate gut microbiota dysbiosis. Metformin, a biguanide agent, shows beneficial effects on chronic metabolic diseases. Our objective was to assess the effects and associated mechanisms of inulin and metforin on attenuation of PCOS in mice. Mice were divided into 4 groups: control group (CON), model group (MOD), inulin group (INU), metformin group (MET). The last three groups were fed 6 mg of dehydroepiandrosterone (DHEA) per 100 g body weight and 60% high-fat diet to generate mice model. After 21 days of intervention, mice were euthanized and associated indications were investigated. Body weight (BW) and testosterone (T) levels were significantly decreased, but estradiol (E2) levels were increased in INU or MET group, respectively. Ovary HE staining demonstrated that inulin or metformin ameliorated PCOS morphology. Inflammatory indicators from plasma and ovary including TNF-α, IL-6, and IL-17A were decreased in INU or MET group. Moreover, IL-10 in ovary of INU or MET group was increased. Sequencing and analysis of gut microbiota showed that compared to MOD group, Bifidobacterium was increased, but Proteobacteria, Helicobacter and Parasutterella were decreased in INU group. Helicobacter was decreased in MET group. Correlation analysis showed that gut microbiota was correlated with inflammatory factors. Our results revealed that inulin and metformin alleviated PCOS via anti-inflammation and modulating gut microbiota, which may contribute to potential clinical therapy for the disease.

Microcirculatory dysfunction is correlated with increased mortality among septic patients and is believed to be a major contributor to the development of acute kidney injury (AKI). Rolipram, a selective phosphodiesterase 4 (PDE4) inhibitor, has been shown to reduce microvascular permeability and in the kidney, increase renal blood flow (RBF). This led us to investigate its potential to improve the renal microcirculation and preserve renal function during sepsis using a murine cecal ligation and puncture (CLP) model to induce sepsis. Rolipram, tested at doses of 0.3-10 mg/kg i.p., acutely restored capillary perfusion in a bell-shaped dose-response effect with 1 mg/kg being the lowest most efficacious dose. This dose also acutely increased RBF despite transiently decreasing mean arterial pressure. Rolipram also reduced renal microvascular permeability. It is noteworthy that delayed treatment with rolipram at 6 hours after CLP restored the renal microcirculation, reduced blood urea nitrogen and serum creatinine, and increased glomerular filtration rate at 18 hours. However, delayed treatment with rolipram did not reduce serum nitrate/nitrite levels, a marker of nitric oxide production, nor reactive nitrogen species generation in renal tubules. These data show that restoring the microcirculation with rolipram, even with delayed treatment, is enough to improve renal function during sepsis despite the generation of oxidants and suggest that PDE4 inhibitors should be evaluated further for their ability to treat septic-induced AKI.

In this clinically relevant ovine model of septic shock, hypercapnia had similar effects to dobutamine on hemodynamic variables and lactic acidosis. Hypercapnia improved tissue oxygenation and reduced lung edema formation more than dobutamine administration.

Objectives: To assess off-treatment virological relapse rates and to determine the role of hepatitis B surface antigen (HBsAg) quantification in predicting virological relapse after stopping entecavir (ETV) treatment in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB). Methods: One hundred and twelve CHB patients for whom ETV was stopped in accordance with the Asian Pacific Association for the Study of the Liver guidelines stopping rules were enrolled. Patient HBsAg and HBV DNA levels were monitored every 4-12 weeks during ETV treatment and after ETV cessation. Post-treatment virological relapse was defined as a serum HBV DNA level of >10 000 copies/ml after stopping ETV treatment. Results: The virological relapse rate at 52 weeks after stopping ETV was 48.2%. The post-treatment virological relapse rate was significantly higher in patients aged >50 years than in those aged <50 years (p < 0.001), and the virological relapse rate was significantly lower in patients with an HBsAg level <2.0 log 10 IU /ml than in those with a level !2.0 log 10 IU /ml at ETV cessation (p = 0.005). An HBsAg level of 2.5 log 10 IU/ml at HBeAg seroconversion was the optimal cut-off value for predicting post-treatment virological relapse (p < 0.001). In those aged <50 years and with HBsAg 2.5 log 10 IU/ml at HBeAg seroconversion, the relapse rate was only 5%. In patients with HBsAg 2.5 log 10 IU/ml at HBeAg seroconversion, 52.4% achieved HBsAg levels 2.0 log 10 IU/ml at ETV cessation, while in those with HBsAg >2.5 log 10 IU/ml at HBeAg seroconversion, only 4.4% achieved this criterion. Conclusions: HBsAg levels can help guide the timing of cessation of ETV treatment. HBsAg levels of 2.5 log 10 IU/ml at HBeAg seroconversion may be a useful marker to predict virological relapse after the cessation of ETV treatment in HBeAg-positive CHB patients.

Excess weight gain is the most significant, preventable cause of increased blood pressure (BP) in patients with primary (essential) hypertension and increases the risk for cardiovascular and renal diseases. In this review, we discuss the role of the brain melanocortin system in causing increased sympathetic activity in obesity and other forms of hypertension. In addition, we highlight potential mechanisms by which the brain melanocortin system modulates metabolic and cardiovascular functions.