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Disease modifying anti-rheumatic drugs (DMARDs) were developed to treat joint inflammation. There is growing evidence that anti-inflammatory drugs prevent major cardiovascular events (MACE). The aim of this systematic review and meta-analysis was to examine whether DMARDs reduce the risk of MACE. A systematic literature search was performed to identify randomized controlled trials (RCTs) testing the effect of DMARDs on cardiovascular events. The primary outcome was MACE defined as the first occurrence of non-fatal myocardial infarction (MI), non-fatal stroke or cardiovascular death. Secondary outcomes were myocardial infarction or stroke alone and all-cause mortality. Safety was assessed by fatal or life threatening infection. Meta-analyses were performed using random effect models and reported as risk ratios (RR) and 95% confidence intervals (CI). Study quality and publication bias were assessed using the Cochrane Collaboration’s tool for assessing risk of bias and funnel plots. Twelve RCTs involving 18,056 participants testing three different DMARDs subclasses (Tumor Necrosis Factor inhibitors—4 trials; Janus Kinase inhibitors—5 trials; Interleukin inhibitors—3 trials) were included. Meta-analysis suggested that none of the DMARD subclasses had any effect on MACE, MI alone, stroke alone, risk of fatal or life threatening infection or death. Risk of bias was high, low and unclear in five, six and one studies respectively. Funnel plots suggested a low possibility of publication bias. This meta-analysis suggests that DMARDs do not affect the incidence of MACE. More trials are needed for firm conclusions.

Proteins from parasitic worms have been posed as novel therapies for rheumatoid arthritis (RA) and other auto-inflammatory diseases. However, with so many potential therapeutics, it is important that drug discovery be based on the specific phyla or species which show the most promising effects. Therefore, the aim of this systematic review and meta-analysis was to evaluate the reported effects of helminthic secretory proteins and derivative therapy on RA in an animal model. Medline, Scopus and Web of Science were searched to identify studies evaluating helminthic therapy in the collagen-induced arthritis model of RA. A meta-analysis was undertaken to determine the overall effect of the proteins. Subgroup analyses were also undertaken to investigate individual treatments. Seven articles were included in the analysis. Overall, helminthic therapy significantly reduced arthritis score (SMD −1.193, 95% CI −1.525, −0.860). Subgroup analyses found a significant reduction in arthritis score following treatment with helminth protein ES-62 (SMD −1.186, 95% CI −1.633, −0.738) and phosphorylcholine-based treatment (SMD −0.997, 95% CI −1.423, −0.571). Subgroup analyses found ES-62 treatment significantly decreased IFN-γ levels (SMD −1.611, 95% CI −2.734, −0.487) and significantly increased levels of IL-10 (SMD 0.946, 95% CI 0.127, 1.765). Therapeutics from parasitic worms are a promising avenue for drug discovery, especially with all included studies reporting a significant improvement in arthritis score. Based on pooled data presented in this study, the nematode Acanthocheilonema viteae seems to be of particular interest for therapeutics.

Background No network meta‐analysis has considered the relative efficacy of cilostazol, home exercise therapy, supervised exercise therapy (SET), endovascular revascularization (ER), and ER plus SET (ER+SET) in improving maximum walking distance (MWD) over short‐ ( Methods and Results A systematic literature search was performed to identify randomized controlled trials testing 1 or more of these 5 treatments according to Preferred Reporting Items for Systematic Review and Meta‐Analysis guidelines. The primary outcome was improvement in MWD assessed by a standardized treadmill test. Secondary outcomes were adverse events and health‐related quality of life. Network meta‐analysis was performed using the gemtc R statistical package. The Cochrane collaborative tool was used to assess risk of bias. Forty‐six trials involving 4256 patients were included. At short‐term follow‐up, home exercise therapy (mean difference [MD], 89.4 m; 95% credible interval [CrI], 20.9–157.7), SET (MD, 186.8 m; 95% CrI, 136.4–237.6), and ER+SET (MD, 326.3 m; 95% CrI, 222.6–430.6), but not ER (MD, 82.5 m; 95% CrI, −2.4 to 168.2) and cilostazol (MD, 71.1 m; 95% CrI, −24.6 to 167.9), significantly improved MWD (in meters) compared with controls. At moderate‐term follow‐up, SET (MD, 201.1; 95% CrI, 89.8–318.3) and ER+SET (MD, 368.5; 95% CrI, 195.3–546.9), but not home exercise therapy (MD, 99.4; 95% CrI, −174.0 to 374.9) or ER (MD, 84.2; 95% CrI, −35.3 to 206.4), significantly improved MWD (in meters) compared to controls. At long‐term follow‐up, none of the tested treatments significantly improved MWD compared to controls. Adverse events and quality of life were reported inconsistently and could not be meta‐analyzed. Risk of bias was low, moderate, and high in 4, 24, and 18 trials respectively. Conclusions This network meta‐analysis suggested that SET and ER+SET are effective at improving MWD over the moderate term (

Background There are currently few effective drugs to treat the leg symptoms of peripheral arterial disease (PAD). Previous studies have suggested that the nutraceutical, quercetin, can improve exercise performance and reduce pain sensitivity in healthy mice and improve blood supply in a rodent model of acute hind-limb ischaemia. These models may not be relevant to people with PAD. The aim of this study was to examine the effect of quercetin on exercise performance, physical activity and blood supply in a novel mouse model of sustained hind-limb ischaemia. Methods Hind-limb ischaemia was induced in 6-month-old male apolipoprotein E-deficient mice using a novel two-stage surgical procedure. Five days after induction of ischaemia, mice were allocated to commence dietary quercetin or a control diet for 4 weeks. The primary outcome was exercise performance evaluated using a treadmill test. Other outcomes included physical activity, estimated by an open field test, and hind-limb blood supply, assessed by laser Doppler monitoring. Results A sustained reduction in relative limb blood supply (P, The dietary flavonoid quercetin has been reported to improve exercise performance in healthy mice and people, and increase limb perfusion in models of acute hind limb ischemia. Acute hind limb ischemia models may not be representative of human peripheral artery disease.We report that quercetin does not improve exercise performance or limb perfusion in a newly developed two stage mouse model of sustained hind limb ischemia. Our findings suggest that quercetin may not be beneficial for patients with sustained limb ischemia due to peripheral artery disease. little evidence of efficacy

The aims of this systematic review were to assess the clinical relevance and quality of previously published animal models of ischemic ulceration and examine the available evidence for interventions improving ulcer healing in these models. Publicly available databases were searched for original studies investigating the effect of limb ischemia on wound healing in animal models. The quality of studies was assessed using two tools based on the Animal research: Reporting of In Vivo Experiments (ARRIVE) guidelines and the clinical relevance of the models. A total of 640 wounds (ischemic=314; non-ischemic=326) were assessed in 252 animals (92 mice, 140 rats, 20 rabbits) from 7 studies. Meta-analyses showed that wound healing was consistently delayed by ischemia at all time-points examined (day-7 standard median difference (SMD) 5.36, 95% CI 3.67 to 7.05; day-14 SMD 4.50, 95% CI 2.90 to 6.10 and day-21 SMD 2.53, 95% CI 1.25 to 3.80). No significant difference in wound healing was observed between 32 diabetic and 32 non-diabetic animals with ischemic wounds. Many studies lacked methods to reduce bias, such as outcome assessors blinded to group allocation and sample size calculations and clinically relevant model characteristics, such as use of older animals and a peripheral location of the wound. Five different interventions were reported to improve wound healing in these models. The impaired wound healing associated with limb ischemia can be modeled in a variety of different animals. Improvements in study design could increase clinical relevance, reduce bias and aid the discovery of translatable therapies.

A volume-pressure sensor and tail-cuff method for monitoring blood pressure is non-invasive and inexpensive. This method requires animals to be restrained or subjected to anesthesia, but comparative effects of these manipulations on hemodynamic parameters have not been documented.Using a volume-pressure sensor and tail-cuff, we serially measured blood pressure and heart rate in normotensive adult male Lewis rats after light isoflurane-induced anesthesia (5% induction, 1% maintenance) and, following untrained restraint. Blood pressure was recorded until the acquisition of three complete measurements without the range of replicate mean arterial pressures exceeding 15 mmHg (steady-state).Averages for the entire series of consecutive measurements indicated that restraint yielded significantly higher systolic and diastolic blood pressure than anesthesia (P .05), but heart rate was not affected. Following stabilization at steady-state, there were no significant differences in intra- or inter-day hemodynamic values between the restraint and isoflurane groups. The inter-day coefficient of variation for systolic pressure was 13-23% for isoflurane and 9-14% for restraint. Bland-Altman analysis showed wide limits of agreement (±59 mmHg systolic; ±49 mmHg diastolic pressure) between restraint and isoflurane measurements.Isoflurane caused more variability but there was agreement in BP evaluation by the isoflurane and restraint methods. Using the VPR system, light isoflurane-induced anesthesia and restraint could effectively be used to screen and quantify overt changes in hemodynamic parameters for cardiovascular research utilizing laboratory rodents.

Background and aims Diets enriched with tree nuts have been demonstrated to reduce the risk of atherosclerosis-related cardiovascular events. Abdominal aortic aneurysm (AAA) shares common risk factors with atherosclerosis and AAA patients commonly have atherosclerosis related cardiovascular events. AAA has some distinct pathological and clinical characteristics to those of atherosclerosis. No previous study has examined the effect of a diet enriched with tree nuts on experimental or clinical AAA. This study investigated the effect of a diet enriched with tree nuts on the development and severity of AAA within an experimental rodent model. Methods Male apolipoprotein E deficient mice were allocated to a diet enriched with tree nuts or control diet for 56 days (n = 17 per group). After 28 days, all mice were infused with angiotensin II whilst being maintained on their respective diets. The primary outcome was AAA severity assessed by the supra-renal aortic diameter, measured by ultrasound and ex vivo morphometric analysis. The severity of atherosclerosis was assessed by computer-aided analysis of Sudan IV stained aortic arches and sections of brachiocephalic arteries prepared with Van Gieson's stain. Results The diet enriched with tree nuts did not influence aortic diameter or aortic rupture incidence. Mice receiving the diet enriched with tree nuts had significantly less atherosclerosis within the brachiocephalic artery (p = 0.033) but not in the aortic arch. Conclusions This experimental study suggests that a diet enriched with tree nuts does not reduce the severity of AAA, but does reduce the severity of atherosclerosis within the brachiocephalic artery. The study was not powered to identify a moderate effect of the diet on the primary outcome and therefore this cannot be excluded.

Diets rich in flavonoids have been reported to have beneficial effects in the primary prevention of cardiovascular events. There are limited data, however, on the cardiovascular benefits of purified flavonoids. The aim of this systematic review and meta-analysis was to examine the reported effects of isolated flavonoids on aortic atherosclerosis in a mouse model. Medline, Pubmed, Science direct and Web of Science were searched to identify studies which examined the effect of isolated flavonoids on aortic atherosclerosis in apolipoprotein E deficient mice. A meta-analysis was performed to determine the overall effect of the flavonoids, and sub-analyses were performed to compare the effects of the flavonols and flavan-3-ols. Eleven studies, which examined a total of 208 mice receiving a flavonoid and 126 control mice, were included. Overall the flavonoids significantly reduced aortic atherosclerosis (SMD 1.10, 95% CI 0.69, 1.51). Of the 18 flavonoid interventions examined 12 were flavonols and 3 were flavan-3-ols. Sub-analyses suggested that the flavonols (SMD 1.31, 95% CI 0.66, 1.91) but not the flavan-3-ols (SMD 0.33, 95% CI -0.19, 0.85) significantly decreased atherosclerosis area. Of the eleven studies, only one examined histological markers of atherosclerosis plaque stability. Most studies did not report blinding of outcome assessors or reproducibility of the primary outcome, and did not justify the sample size used and flavonoid dose administered. Based on the included studies, the flavonols appear to be the most effective flavonoids for reducing aortic atherosclerotic lesion area in apolipoprotein E deficient mice.