Dexmedetomidine Protects Against Multi-Organ Dysfunction Induced by Heatstroke via Sustaining The Intestinal Integrity.

Previous studies have indicated that gut-derived endotoxin played a pivotal role for aggravating systemic inflammatory response to multi-organ dysfunction under heatstroke. Dexmedetomidine (DEX) could protect against inflammation and multi-organ injury in various scenarios. The aim of this study was to explore the protective effect of DEX on heatstroke and the mechanism involved. Male C57BL/6 mice were placed in a controlled climate chamber (40 ±â€Š1°C) until the maximum core temperature (Tc, Max) of 42.7°C, the received criterion of heatstroke, was attained, DEX (25 µg/kg) or 0.9% saline was injected intraperitoneally immediately. The results showed that DEX could significantly attenuate multi-organ injury induced by heatstroke, simultaneously decrease levels of serum inflammatory cytokines through inhibiting the intestinal nuclear factor-κB activation. Furthermore, to assess the effects of DEX on intestine mucosal barrier under heatstroke, the levels of plasma endotoxin, FD4, and D-lactate were detected and the expression of tight junction proteins occludin and ZO-1 was analyzed by western blot and immunohistochemistry. Meanwhile, transmission electron microscopy was employed to confirm the ultrastructure of intestine. Interestingly, we found that DEX decreased the intestinal permeability and sustained the integrity of intestinal barrier. Finally, to evaluate the anti-apoptosis effect of DEX, the pro-apoptotic protein Bax and anti-apoptotic protein Bcl-2 were analyzed by western blot, and terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling (TUNEL) staining was conducted. The results showed that DEX decreased TUNEL-positive cells induced by heatstroke in a Bax/Bcl-2-related manner. Taken together, our results indicate that DEX could protect against inflammation and multi-organ injury induced by heatstroke via sustaining the intestinal integrity.

NLRP3 inflammasome activation mediates radiation-induced pyroptosis in bone marrow-derived macrophages.

A limit to the clinical benefit of radiotherapy is not an incapacity to eliminate tumor cells but rather a limit on its capacity to do so without destroying normal tissue and inducing inflammation. Recent evidence reveals that the inflammasome is essential for mediating radiation-induced cell and tissue damage. In this study, using primary cultured bone marrow-derived macrophages (BMDM) and a mouse radiation model, we explored the role of NLRP3 inflammasome activation and the secondary pyroptosis underlying radiation-induced immune cell death. We observed an increasing proportion of pyroptosis and elevating Caspase-1 activation in 10 and 20 Gy radiation groups. Nlrp3 knock out significantly diminished the quantity of cleaved-Caspase-1 (p10) and IL-1ß as well as the proportion of pyroptosis. Additionally, in vivo research shows that 9.5 Gy of radiation promotes Caspase-1 activation in marginal zone cells and induces death in mice, both of which can be significantly inhibited by knocking out Nlrp3. Thus, based on these findings, we conclude that the NLRP3 inflammasome activation mediates radiation-induced pyroptosis in BMDMs. Targeting NLRP3 inflammasome and pyroptosis may serve as effective strategies to diminish injury caused by radiation.

NLRP3 gene knockout blocks NF-κB and MAPK signaling pathway in CUMS-induced depression mouse model.

BACKGROUND: Abundant researches indicate that neuroinflammation has important roles in the pathophysiology of depression. Our previous study found that the NLRP3 inflammasome mediated stress-induced depression-like behavior in mice via regulating neuroinflammation. However, it still remains unclear that how the NLRP3 inflammasome influences related inflammatory signaling pathway to contribute to neuroinflammation in depression. METHODS: We used wild-type mice and NLRP3 gene knockout mice to explore the role of NLRP3 inflammasome and related inflammatory signaling pathways in chronic unpredictable mild stress (CUMS) induced depression mouse model. RESULTS: Both wild-type and NLRP3 knockout stress group mice gained less weight than control group mice after 4 weeks CUMS exposure. The wild-type mice subjected to 4 weeks CUMS displayed depression-like behaviors, including decreased sucrose preference and increased immobility time in the tail suspension test. The NLRP3 knockout stress group mice didn't demonstrate depression-like behaviors. The levels of interleukin-1ß protein in serum and hippocampi of CUMS exposed wild-type mice were significantly higher, while the NLRP3 knockout stress group mice didn't show an elevation of interleukin-1ß levels. Similarly to early researches, we found that CUMS led to promoted NLRP3 expression in hippocampi. In addition, the hippocampi in CUMS exposed wild-type mice had higher p-JNK and p-p38 protein expression, which indicated activation of the mitogen-activated protein kinases (MAPK) pathway. The knockout of NLRP3 gene inhibited CUMS-induced activation of the MAPK pathway. The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) protein complex was activated in the hippocampi of wild-type mice after CUMS exposure, while knockout of NLRP3 gene hindered its activation. CONCLUSIONS: These data further proved that the NLRP3 inflammasome mediated CUMS-induced depression-like behavior. The NLRP3 inflammasome regulated CUMS-induced MAPK pathway and NF-κB protein complex activation in depression mouse model. Further researches targeting the NLRP3 inflammasome-signaling pathway might be under a promising future in the prevention and treatment of depression.

Chronic preclinical safety evaluation of EPO-018B, a pegylated peptidic erythropoiesis-stimulating agent in monkeys and rats.

EPO-018B, a synthetic peptide-based erythropoiesis stimulating agent (ESA), is mainly designed for treatment of anemia caused by chronic renal failure and chemotherapy against cancer. It overcomes the deficiencies of currently approved ESA, including the frequent administration of temperature-sensitive recombinant protein and anti-EPO antibody-mediated pure red cell aplasia (PRCA). This study was designed to evaluate the potential chronic toxicity of EPO-018B. Subcutaneous administration doses were designed as 0, 0.2, 1 and 10mg/kg for six months for 160 rats (20/gender/group) and 0, 0.3, 3 and 20mg/kg for nine months for 32 monkeys (4/gender/group) once every three weeks. The vehicles received the same volume of physiological saline injection. All animals survived to the scheduled necropsies after six weeks (for rats) and fourteen weeks (for monkeys) recovery period, except for the two high-dose female rats and two high-dose male monkeys, which were considered related to the increased RBCs, chronic blood hyperviscosity and chronic cardiac injury. EPO-018B is supposed to be subcutaneously injected once every month and the intended human therapeutic dose is 0.025mg/kg. The study findings at 0.2mg/kg for rats and 0.3mg/kg for monkeys were considered to be the study NOAEL (the no observed adverse effect level), which were more than ten times the intended human therapeutic dose. Higher doses caused adverse effects related to the liver toxicity, cardiotoxicity, appearance of neutralizing antibodies of EPO-018B and the decrease of serum glucose and cholesterol. Most treatment-induced effects were reversible or revealed ongoing recovery upon the discontinuation of treatment. The sequelae occurred in rats and monkeys were considered secondary to exaggerated pharmacology and would less likely occur in the intended patient population. As to the differences between human beings and animals, the safety of EPO-018B need to be further confirmed in the future clinical studies.

Activation of the NLRP3 inflammasome in lipopolysaccharide-induced mouse fatigue and its relevance to chronic fatigue syndrome.

BACKGROUND: The NLRP3 inflammasome (NOD-like receptor family, pyrin domain containing 3) is an intracellular protein complex that plays an important role in innate immune sensing. Its activation leads to the maturation of caspase-1 and regulates the cleavage of interleukin (IL)-1ß and IL-18. Various studies have shown that activation of the immune system plays a pivotal role in the development of fatigue. However, the mechanisms underlying the association between immune activation and fatigue remained elusive, and few reports have described the involvement of NLRP3 inflammasome activation in fatigue. METHODS: We established a mouse fatigue model with lipopolysaccharide (LPS, 3 mg/kg) challenge combined with swim stress. Both behavioural and biochemical parameters were measured to illustrate the characteristics of this model. We also assessed NLRP3 inflammasome activation in the mouse diencephalon, which is the brain region that has been suggested to be responsible for fatigue sensation. To further identify the role of NLRP3 inflammasome activation in the pathogenesis of chronic fatigue syndrome (CFS), NLRP3 KO mice were also subjected to LPS treatment and swim stress, and the same parameters were evaluated. RESULTS: Mice challenged with LPS and subjected to the swim stress test showed decreased locomotor activity, decreased fall-off time in a rota-rod test and increased serum levels of IL-1ß and IL-6 compared with untreated mice. Serum levels of lactic acid and malondialdehyde (MDA) were not significantly altered in the treated mice. We demonstrated increased NLRP3 expression, IL-1ß production and caspase-1 activation in the diencephalons of the treated mice. In NLRP3 KO mice, we found remarkably increased locomotor activity with longer fall-off times and decreased serum IL-1ß levels compared with those of wild-type (WT) mice after LPS challenge and the swim stress test. IL-1ß levels in the diencephalon were also significantly decreased in the NLRP3 KO mice. By contrast, IL-6 levels were not significantly altered. CONCLUSIONS: These findings suggest that LPS-induced fatigue is an IL-1ß-dependent process and that the NLRP3/caspase-1 pathway is involved in the mechanisms of LPS-induced fatigue behaviours. NLRP3/caspase-1 inhibition may be a promising therapy for fatigue treatment.

Anti-vascular endothelial growth factor for control of wound healing in glaucoma surgery.

BACKGROUND: Trabeculectomy is performed as a treatment for glaucoma to lower intraocular pressure (IOP). The surgical procedure involves creating a channel through the wall of the eye. However scarring during wound healing can block this channel which will lead to the operation failing. Anti-vascular endothelial growth factor (VEGF) agents have been proposed to slow down healing response and scar formation. OBJECTIVES: To assess the effectiveness of anti-VEGF therapies administered by subconjunctival injection for the outcome of trabeculectomy at 12 months follow-up and to examine the balance of benefit and harms when compared to any other anti-scarring agents or no additional anti-scarring agents. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2015, Issue 10), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2015), EMBASE (January 1980 to November 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 12 November 2015. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of anti-VEGF therapies administered by subconjunctival injection compared to any other anti-scarring agents or no additional anti-scarring agents (no treatment or placebo) in trabeculectomy surgery. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcome was successful trabeculectomy at 12 months after surgery which was defined as achieving a target IOP (usually no more than 21 mm Hg) without any additional intervention. Other outcomes included: qualified success (achieving target IOP with or without additional intervention), mean IOP and adverse events. MAIN RESULTS: We included five RCTs (175 participants, 177 eyes) that met the inclusion criteria in this review.One trial conducted in Iran (37 participants, 37 eyes) compared anti-VEGF (bevacizumab 0.2 mg) versus control (sham injection) in people with refractory glaucoma. We judged this study to be at low risk of bias.The primary outcome of this review was not reported; mean IOP at three months was 15.1 mm Hg (standard deviation 1.0) in both anti-VEGF and control groups.Four trials compared anti-VEGF to mitomycin C (MMC) (138 particpants, 140 eyes). These studies were conducted in India, Iran, Turkey and the USA. The anti-VEGF agent used in these four trials was bevacizumab 2.5 mg (two trials), bevacizumab 1.25 mg three times and ranibizumab 0.5 mg. Two trials were at high risk of bias in two domains and one trial was at high risk of bias in four domains.Only one of these trials reported the primary outcome of this review (42 participants, 42 eyes). Low quality evidence from this trial showed that people receiving bevacizumab 2.5 mg during primary trabeculectomy were less likely to achieve complete success at 12 months compared to people receiving MMC but the confidence interval (CI) was wide and compatible with increased chance of complete success for anti-VEGF (risk ratio (RR) 0.71, 95% CI 0.46 to 1.08), Assuming that approximately 81% of people receiving MMC achieve complete success, the anticipated success using anti-VEGF agents would be between 37.2% and 87.4%. The same trial suggested no evidence for any difference in qualified success between bevacizumab and MMC (RR 1.00, 95% CI 0.87 to 1.14, moderate quality evidence). Two trials of primary trabeculectomy provided data on mean IOP at 12 months; one trial of bevacizumab 2.5 mg and one trial of ranibizumab 0.5 mg. Mean IOP was 1.86 mm Hg higher (95% CI 0.15 to 3.57) in the anti-VEGF groups compared to the MMC groups (66 people, low quality evidence). Data were reported on wound leak, hypotony, shallow anterior chamber and endophthalmitis, but these events occurred rarely and currently there are not enough data available to detect any differences, if any, between the two treatments. AUTHORS' CONCLUSIONS: The evidence is currently of low quality which is insufficient to refute or support anti-VEGF subconjunctival injection for control of wound healing in glaucoma surgery. The effect on IOP control of anti-VEGF agents in glaucoma patients undergoing trabeculectomy is still uncertain, compared to MMC.Further RCTs of anti-VEGF subconjunctival injection in glaucoma surgery are required, particularly compared to sham treatment with at least 12 months follow-up.

Is the CARD8 rs2043211 polymorphism associated with susceptibility to Crohn's disease? A meta-analysis.

Many studies have reported the association between the CARD8 gene polymorphism rs2043211 and the susceptibility to Crohn's disease (CD), but the results have remained quite contradictory. Therefore, the aim of the meta-analysis was to explore whether the CARD8 rs2043211 polymorphism has an effect on CD risk. We performed a systematic literature search for related articles published up to July 2014 in multiple databases. Six eligible articles containing eight studies were selected. Odds ratios (ORs) as well as their corresponding 95% confidence intervals (CIs) were used to estimate the association between the CARD8 polymorphism and CD risk in different genotypic models. Heterogeneity analysis was also performed and publication bias was taken into account. Subgroup analyses were conducted according to different ethnicities, as well as different types of CD. In the pooled analyses, no statistical significant association was found between the CARD8 polymorphism and CD risk in the overall population or Caucasian subgroup in the additive model (overall population: OR = 0.93, 95% CI = 0.87-1.01; Caucasian: OR = 0.93, 95% CI = 0.83-1.05). However, subgroup analysis based on different CD types showed a significant association between the CARD8 polymorphism and CD risk in the additive model (ileal CD: OR = 0.83, 95% CI = 0.70-0.98; stenotic or fistulizing CD: OR = 0.81, 95% CI = 0.72-0.92). Our results indicated that CD may involve different types of pathogenesis and have variable clinical manifestations. In patients with ileal, stenotic or fistulizing CD, the mutant-type rs2043211 polymorphism may generate a potentially protective effect.

Association between vitamin D receptor gene polymorphisms and susceptibility to Parkinson's disease: a meta-analysis.

Previous studies have reported an association between vitamin D receptor (VDR) gene polymorphisms and Parkinson's disease (PD), but the results were controversial. To explore whether VDR gene polymorphisms have an effect on PD risk, we performed this meta-analysis to evaluate the association between three VDR gene polymorphisms (Bsml, Apal, Taql) and PD susceptibility. We performed a systematic literature search for articles published up to February 2014 in multiple databases and selected seven eligible studies. Four studies were included for each polymorphism. Odds ratios (ORs) as well as their corresponding 95% confidence intervals (CIs) were used to estimate the association between VDR gene polymorphisms and PD risk in four phenotype models. Subgroup analysis and publication bias were also performed. Heterogeneity analysis and sensitivity analysis were performed if necessary. We failed to detect any association between Apal, Bsml, Taql polymorphisms and PD susceptibility in all four genetic models. In subgroup analysis grouped by ethnicity, no significant association was detected. The present meta-analysis indicates that the VDR genetic polymorphisms Bsml, Apal and Taql are not associated with susceptibility to PD. Because of the limited number of included studies, the results should be cautiously interpreted. More carefully designed studies are needed to verify our results.

Subchronic safety evaluation of CMS-1 (a botanical antihypertensive product derived from Semen Cnidium monnieri) in Sprague-Dawley rats and beagle dogs.

CMS-1, mainly composed of imperatorin as its active compound, is a partially purified fraction of a Chinese herbal medicine, Semen Cnidium monnieri. CMS-1 has the potential to be further developed as a new treatment for hypertension. Thus, we studied its toxicity in both Sprague-Dawley rats and beagle dogs. Rats (0-900mg/kg/day) and dogs (0-450mg/kg/day) received CMS-1 orally for 30 consecutive days, followed by a 15-day recovery period. The major target organs of CMS-1 toxicity are the GI (inappetence), liver (hepatocellular necrosis, enzyme elevation), thymus (atrophy), cardiovascular (hypotension), changes in ECG T and P waveforms, elevation of nitrous oxide levels and hematological (RBC parameters disturbances) systems. Most treatment-induced adverse effects were reversible or showed a progressive recovery upon discontinuation of the treatment. The No Observed Adverse Effect Level (NOAEL) was 100mg/kg/day for rats and 50mg/kg/day for dogs. This non-clinical study suggests that clinical monitoring of CMS-1 in patients should focus on the gastrointestinal system, blood tests for liver functions, electrolytes, and blood homeostasis, cardiovascular functions, and immune functions.

Subchronic safety evaluation of EPO-018B, a pegylated peptidic erythropoiesis stimulating agent, after 5-week subcutaneous injection in Cynomolgus monkeys and Sprague-Dawley rats.

EPO-018B, a synthetic peptide-based erythropoiesis stimulating agent (ESA), is coupled to polyethylene glycol (PEG) and designed to specifically bind and activate the erythropoietin (EPO) receptor to result in production of red blood cells. This study was designed to evaluate the potential subchronic toxicity of EPO-018B for Cynomolgus monkeys and Sprague-Dawley rats both at 0, 0.5, 5 and 50 mg/kg every week for 5 weeks, followed by 6-week recovery for rats and 12-week recovery for monkeys. The No Observed Adverse Effect Level (NOAEL) for rats and monkeys were both considered to be at least 0.5 mg/kg/day, the minimum toxic dose to be 5.0 mg/kg/day and the severe toxic dose to be more than 50.0 mg/kg/day. The toxicological effects included the exaggerated pharmacology and secondary sequelae that resulted from an erythropoiesis-stimulating agent treatment to healthy animals. Most treatment induced effects were reversible or showed ongoing recovery upon discontinuation of treatment. The anticipated patient population for EPO-018B treatment is targeted to be the anemia patients caused by chronic renal failure or chemotherapy against to cancer and is expected to have an ideal clinical application prospect.

Intraocular pressure-lowering effects of commonly used fixed-combination drugs with timolol: a systematic review and meta-analysis.

BACKGROUND: The first goal of medical therapy in glaucoma is to reduce intraocular pressure (IOP), and the fixed-combination medications are needed to achieve sufficiently low target IOP. The aim of this systematic review and meta-analysis is to evaluate IOP-lowering effect of the commonly used fixed-combination drugs containing 0.5% timolol. METHODS: Pertinent publications were identified through systematic searches. Over 85% of the patients had to be diagnosed with primary open-angle glaucoma (POAG) or ocular hypertension (OHT). Forty-one randomized clinical trials were included in the meta-analysis. The main efficacy measures were the absolute and relative values of mean diurnal IOP reduction, and the highest and lowest IOP reductions on the diurnal IOP curve. The pooled 1- to 3-month IOP-lowering effects after a medicine-free washout period was calculated by performing meta-analysis using the random effects model, and relative treatment effects among different fixed combinations were assessed using a mixed-effects meta-regression model. RESULTS: The relative reductions for mean diurnal IOP were 34.9% for travoprost/timolol, 34.3% for bimatoprost/timolol, 33.9% for latanoprost/timolol, 32.7% for brinzolamide/timolol, 29.9% for dorzolamide/timolol, and 28.1% for brimonidine/timolol. For the highest IOP decrease, relative reductions ranged from 31.3% for dorzolamide/timolol to 35.5% for travoprost/timolol; for the lowest IOP decrease, those varied from 25.9% for dorzolamide/timolol to 33.1% for bimatoprost/timolol. Both latanoprost/timolol and travoprost/timolol were more effective in lowering mean diurnal IOP than brimonidine/timolol (WMD: 5.9 and 7.0) and dorzolamide/timolol (WMD: 3.8 and 3.3). CONCLUSIONS: All six commonly used fixed-combination drugs containing timolol can effectively lower IOP in patients with POAG and OHT, and both latanoprost/timolol and travoprost/timolol might achieve better IOP-lowering effects among the six fixed-combination agents.

Myocilin polymorphisms and primary open-angle glaucoma: a systematic review and meta-analysis.

BACKGROUND: Glaucoma is the leading cause of irreversible blindness in the world. Recent evidence indicates a role for genetic susceptibility to primary open-angle glaucoma (POAG). The relation between myocilin polymorphisms and POAG susceptibility has been studied in different populations. METHODS: A meta-analysis of 32 published genetic association case-control studies, which examined the relation between POAG and the R46X, R76K, Y347Y, T353I, and Q368X polymorphisms of the myocilin gene, was carried out. RESULTS: In meta-analysis, significant associations were observed between POAG risk and two myocilin polymorphisms with summarized odds ratio of 4.68 (95%CI, 2.02-10.85) for Q368X and 2.17 (95% CI, 1.32-3.57) for T353I. Both Q368X and T353I were significantly associated with high-tension glaucoma, with summarized odds ratio of 4.26 (1.69, 10.73) and 2.26 (1.37-3.72). In Westerners, significant association was observed for Q368X mutation (odds ratio, 5.17; 95% CI, 2.16-12.40). However, in Asians it was for T353I (odds ratio, 2.17; 95% CI, 1.32-3.57). CONCLUSIONS: There is strong evidence that myocilin polymorphisms are associated with POAG susceptibility, and the prevalence of myocilin mutations might be ethnicity-dependent in Caucasians for Q368X and in Asians for T353I.

E-selectin deficiency attenuates brain ischemia in mice.

AIMS: To determine whether E-selectin deficiency can attenuate brain ischemia in a mouse model of focal cerebral ischemia. METHODS: E-selectin was determined in spontaneously hypertensive rats (SHRs) and stroke-prone spontaneously hypertensive rats (SHR-SPs). E-selectin knockout (Es(-/-) ) mice and wild-type control (WT) mice underwent permanent distal middle cerebral artery occlusion (MCAO). Behavioral analyses were performed followed by the measurement of infarct areas. Myeloperoxidase (MPO) protein was determined by Western blot. IL-6, IL-1ß, and TNF-α were detected by ELISA. In situ detection of apoptotic cells was performed by TUNEL staining. RESULTS: The brain and serum E-selectin levels were higher in SHR-SPs than in SHRs (P < 0.05) after salt intake. E-selectin deficiency improved neurological function and reduced infarct area in cerebral ischemic mice. MPO and IL-1ß were lower in Es(-/-) mice than in WT mice. In addition, the number of apoptotic cells in Es(-/-) mice was significantly less than in WT mice after MCAO. CONCLUSIONS: E-selectin deficiency presents protective effect on cerebral ischemia. This protective effect is likely achieved by the inhibition of inflammation and apoptosis.

Effect of intravitreal anti-vascular endothelial growth factor therapy on the risk of arterial thromboembolic events: a meta-analysis.

BACKGROUND: Intravitreal anti-vascular endothelial growth factor (VEGF) monoclonal antibodies are used in ocular neovascular diseases. A consensus has emerged that intravenous anti-VEGF can increase the risk of arterial thromboembolic events. However, the role of intravitreal anti-VEGF in arterial thromboembolism is controversial. Therefore, we did a systematic review and meta-analysis to investigate the effects of intravitreal anti-VEGF on the risk of arterial thromboembolic events. METHODS: Electronic databases were searched to identify relevant randomized clinical trials comparing intravitreal anti-VEGF with controls. Criteria for inclusion in our meta-analysis included a study duration of no less than 12 months, the use of a randomized control group not receiving any intravitreal active agent, and the availability of outcome data for arterial thromboembolic events, myocardial infarction, cerebrovascular accidents, and vascular death. The risk ratios and 95% CIs were calculated using a fixed-effects or random-effects model, depending on the heterogeneity of the included studies. RESULTS: A total of 4942 patients with a variety of ocular neovascular diseases from 13 randomized controlled trials were identified and included for analysis. There was no significant difference between intravitreal anti-VEGF and control in the risk of all events, with risk ratios of 0.87 (95% CI, 0.64 to 1.19) for arterial thromboembolic events, 0.96 (95% CI, 0.55-1.68) for cerebrovascular accidents, 0.69 (95% CI 0.40-1.21) for myocardial infarctions, and 0.68 (95% CI, 0.37-1.27) for vascular death. CONCLUSIONS: The strength evidence suggests that the intravitreal use of anti-VEGF antibodies is not associated with an increased risk of arterial thromboembolic events.

Meta-analysis of α2-adrenergic agonists versus carbonic anhydrase inhibitors as adjunctive therapy.

OBJECTIVE: To evaluate the efficacy of α2-adrenergic agonist (AA) brimonidine and topical carbonic anhydrase inhibitors (CAIs) dorzolamide and brinzolamide in reducing intraocular pressure (IOP) when used as adjunctive therapy to ß-blockers (BBs) or prostaglandin analogs (PGAs). RESEARCH DESIGN AND METHODS: Pertinent publications were identified through systematic searches of PubMed, EMBASE, and the Cochrane Controlled Trials Register. Randomized controlled trials comparing AA with CAIs in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT) who had inadequate IOP control with monotherapy of a BB or PGA. The weighted mean differences (WMD) of IOP-lowering efficacy were calculated by performing meta-analysis. MAIN OUTCOME MEASURES: The main efficacy measures were the reduction from baseline to end of treatment in IOP at peak, trough, and diurnal curve. RESULTS: Eleven published randomized clinical trials involving 1493 patients were included in the meta-analysis. As adjunctive therapy, the IOP reduction was greater in the brimonidine group than in the CAI group at peak (WMD: 0.99 mmHg [95% confidence interval, 0.45 to 1.53]) and diurnal curve (WMD: 0.62 mmHg [0.07 to 1.18]). As adjunctive therapy to BBs, brimonidine was more effective than CAIs in reducing IOP at peak (WMD: 0.85 mmHg [0.42 to 1.29]) and trough (WMD: 0.47 mmHg [0.12 to 0.83]). As adjunctive therapy to PGAs, brimonidine resulted greater reduction in peak IOP than CAIs (WMD: 1.04 mmHg [0.08 to 2.00]). CONCLUSIONS: Brimonidine provides greater IOP-lowering efficacy than topical carbonic anhydrase inhibitors as adjunctive therapy to BBs or PGAs.

Hepatoprotective effects and mechanisms of dehydrocavidine in rats with carbon tetrachloride-induced hepatic fibrosis.

AIM OF THE STUDY: The current study was designed to examine the effects and possible mechanisms of dehydrocavidine (DC) on carbon tetrachloride (CCl4)-induced hepatic fibrosis in male Sprague-Dawley (SD) rats. MATERIALS AND METHODS: Hepatic fibrosis was induced in male rats with CCl4 administration for 12 weeks. Liver histopathological study was performed, and the liver function was examined by determining the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and total bilirubin (TBIL) for evaluating the effect of DC on hepatic fibrosis. The possible mechanisms were investigated by measuring hepatic collagen metabolism and oxidative stress level. Furthermore, oligo microarray analysis of 263 genes was performed, and quantitative real-time RT-PCR was used to verify 4 of the abnormally expressed genes (Bcl2, Cyp3a13, IL18 and Rad50). RESULTS: DC treatment significantly inhibited the loss of body weight and the increase of liver weight induced by CCl4. DC also improved the liver function of rats as indicated by decreased serum enzymatic activities of ALT, AST, ALP and TBIL. Histopathological results indicated that DC alleviated liver damage and reduced the formation of fibrous septa. Moreover, DC significantly decreased liver hydroxyproline (Hyp) and increased urine Hyp. It also decreased liver malondialdehyde concentration, increased activities of liver superoxide dismutase, catalase and glutathione peroxidase. Microarray analysis revealed that DC altered the expression of genes related to apoptosis, cytokines and other proteins involved in tissue repair. CONCLUSIONS: Our findings indicate that DC can protect rats from CCl4-induced hepatic fibrosis through reducing oxidative stress, promoting collagenolysis, and regulating fibrosis-related genes.

The features of reserpine-induced gastric mucosal lesions.

AIM: To reinvestigate the characteristics of reserpine-induced gastric mucosal lesions (GMLs). METHODS: The GML-inducing effect of reserpine and the time-course of recovery from reserpine-induced GMLs were examined in Sprague-Dawley (SD) rats. The GML-inducing and blood pressure-decreasing effects of Compound Hypotensive Tablets (CHTs) were investigated in spontaneously hypertensive rats (SHRs). Intracerebroventricular (icv) injection and vagotomy were performed to verify the central vagal mechanism in reserpine-induced GMLs. RESULTS: Single intraperitoneal (ip) injections of reserpine (0.25, 0.5, 1, 2, 4, and 6 mg/kg) dose-dependently induced GMLs in SD rats. Both single and repeated (2 weeks) oral administrations of reserpine led to slight GMLs at doses of 24 mg/kg and 10 mg/kg, respectively. Blood pressure was significantly decreased in SHRs after 2 months of CHT administration (0.01 and 0.03 mg/kg; doses were expressed as the amount of reserpine in the CHT). CHT doses of 0.3 mg/kg induced GMLs, but 0.1 mg/kg did not. Examining the time course of recovery from GMLs, severe GMLs occurred 18 h after ip reserpine (4 mg/kg), obviously lessened at 1 week and healed spontaneously at 3 weeks. Intracerebroventricular injections of reserpine caused GMLs at much lower doses (0.08 and 0.4 mg/kg), and reserpine-induced GMLs were greatly inhibited by vagotomy, suggesting the involvement of a central vagal mechanism. CONCLUSION: Reserpine-induced GMLs were dose-dependent, and the lesions healed spontaneously within 3 weeks. Long-term treatment with CHT at doses adequate to decrease blood pressure will not induce GMLs. A central vagal mechanism was involved in reserpine-induced GMLs.