Fetal and post-natal outcomes in offspring after intrauterine metformin exposure: A systematic review and meta-analysis of animal experiments.

AIMS: The impact of maternal metformin use during pregnancy on fetal, infant, childhood and adolescent growth, development, and health remains unclear. Our objective was to systematically review the available evidence from animal experiments on the effects of intrauterine metformin exposure on offspring's anthropometric, cardiovascular and metabolic outcomes. METHODS: A systematic search was conducted in PUBMED and EMBASE from inception (searched on 12th April 2023). We extracted original, controlled animal studies that investigated the effects of maternal metformin use during pregnancy on offspring anthropometric, cardiovascular and metabolic measurements. Subsequently, risk of bias was assessed and meta-analyses using the standardized mean difference and a random effects model were conducted for all outcomes containing data from 3 or more studies. Subgroup analyses were planned for species, strain, sex and type of model in the case of 10 comparisons or more per subgroup. RESULTS: We included 37 articles (n = 3133 offspring from n = 716 litters, containing n = 51 comparisons) in this review, mostly (95%) on rodent models and 5% pig models. Follow-up of offspring ranged from birth to 2 years of age. Thirty four of the included articles could be included in the meta-analysis. No significant effects in the overall meta-analysis of metformin on any of the anthropometric, cardiovascular and metabolic offspring outcome measures were identified. Between-studies heterogeneity was high, and risk of bias was unclear in most studies as a consequence of poor reporting of essential methodological details. CONCLUSION: This systematic review was unable to establish effects of metformin treatment during pregnancy on anthropometric, cardiovascular and metabolic outcomes in non-human offspring. Heterogeneity between studies was high and reporting of methodological details often limited. This highlights a need for additional high-quality research both in humans and model systems to allow firm conclusions to be established. Future research should include focus on the effects of metformin in older offspring age groups, and on outcomes which have gone uninvestigated to date.

Pulmonary valve tissue engineering strategies in large animal models.

In the last 25 years, numerous tissue engineered heart valve (TEHV) strategies have been studied in large animal models. To evaluate, qualify and summarize all available publications, we conducted a systematic review and meta-analysis. We identified 80 reports that studied TEHVs of synthetic or natural scaffolds in pulmonary position (n = 693 animals). We identified substantial heterogeneity in study designs, methods and outcomes. Most importantly, the quality assessment showed poor reporting in randomization and blinding strategies. Meta-analysis showed no differences in mortality and rate of valve regurgitation between different scaffolds or strategies. However, it revealed a higher transvalvular pressure gradient in synthetic scaffolds (11.6 mmHg; 95% CI, [7.31-15.89]) compared to natural scaffolds (4,67 mmHg; 95% CI, [3,94-5.39]; p = 0.003). These results should be interpreted with caution due to lack of a standardized control group, substantial study heterogeneity, and relatively low number of comparable studies in subgroup analyses. Based on this review, the most adequate scaffold model is still undefined. This review endorses that, to move the TEHV field forward and enable reliable comparisons, it is essential to define standardized methods and ways of reporting. This would greatly enhance the value of individual large animal studies.

Maternal obesity in pregnancy impacts offspring cardiometabolic health: Systematic review and meta-analysis of animal studies.

Obesity before and during pregnancy leads to reduced offspring cardiometabolic health. Here, we systematically reviewed animal experimental evidence of maternal obesity before and during pregnancy and offspring anthropometry and cardiometabolic health. We systematically searched Embase and Medline from inception until January 2018. Eligible publications compared offspring of mothers with obesity to mothers with a normal weight. We performed meta-analyses and subgroup analyses. We also examined methodological quality and publication bias. We screened 2543 publications and included 145 publications (N = 21 048 animals, five species). Essential methodological details were not reported in the majority of studies. We found evidence of publication bias for birth weight. Offspring of mothers with obesity had higher body weight (standardized mean difference (SMD) 0.76 [95% CI 0.60;0.93]), fat percentage (0.99 [0.64;1.35]), systolic blood pressure (1.33 [0.75;1.91]), triglycerides (0.64 [0.42;0.86], total cholesterol (0.46 [0.18;0.73]), glucose level (0.43 [0.24;0.63]), and insulin level (0.81 [0.61;1.02]) than offspring of control mothers, but similar birth weight. Sex, age, or species did not influence the effect of maternal obesity on offspring's cardiometabolic health. Obesity before and during pregnancy reduces offspring cardiometabolic health in animals. Future intervention studies should investigate whether reducing obesity prior to conception could prevent these detrimental programming effects and improve cardiometabolic health of future generations.

The protective effect of anterior cruciate ligament reconstruction on articular cartilage: a systematic review of animal studies.

OBJECTIVE: It is unclear if anterior cruciate ligament (ACL) reconstruction can prevent the onset of degenerative changes in the knee. Previous studies were inconclusive on this subject. The aim of this study was to systematically review all studies on the effect of ACL reconstruction on articular cartilage in animals. DESIGN: Pubmed and Embase were searched to identify all original articles concerning the effect of ACL reconstruction on articular cartilage compared with both its positive (ACL transection) and negative (sham and/or non-operated) control in animals. Subsequently a Risk of bias and meta analysis was conducted based on five outcomes (gross macroscopic assessment, medical imaging, histological histochemical grading, histomophometrics and biomechanical characterization) related to articular cartilage. RESULTS: From the 19 included studies, 29 independent comparisons could be identified which underwent ACL reconstruction with an average timing of data collection of 23 weeks (range 1-104 weeks). Due to limited data availability meta-analysis could only be conducted for gross macroscopic damage. ACL reconstruction caused significant gross macroscopic damage compared with intact controls (SMD 2.0 [0.88; 3.13]). These findings were supported by individual studies reporting on histomorphometrics, histology and imaging. No significant gross macroscopic damage was found when ACL reconstruction was compared with ACL transection (SMD -0.64 [-1.85; 0.57]). CONCLUSION: This systematic review with an average follow up of included studies of 23 weeks (range 1-104 weeks) demonstrates that, in animals, ACL reconstruction does not protect articular cartilage from degenerative changes. The consistency of the direction of effect, provides some reassurance that the direction of effect in humans might be the same.

Efficacy of Soiled Bedding Transfer for Transmission of Mouse and Rat Infections to Sentinels: A Systematic Review.

PURPOSE: This systematic review was conducted to gain insight into the efficacy of transmission of infectious agents to colony sentinels by soiled bedding transfer based on publications studying this subject in mice and rats. This information is essential to establish recommendations for the design of health monitoring programs which use sentinels to determine the microbiological status of laboratory animal colonies. RESULTS: Fifteen original articles retrieved from PubMed, Embase, and CAB abstracts met the inclusion criteria. The design of the studies varied substantially per infectious agent with regard to dose of soiled bedding, exposure time, and sentinel strains used. CONCLUSION: With our conservative criteria for effectiveness, soiled bedding transfer appeared to be effective for MHV, MPV, TMEV, Helicobacter spp., and fur mite infections and ineffective for Sendai virus. For other infectious agents, such as MNV, EDIM, MVM, SDAV, Clostridium piliforme, and pinworms, too few data were available to be able to draw robust conclusions on the efficacy of soiled bedding transfer. RECOMMENDATION: The identified evidence only pertains to a portion of the infectious organisms included in the FELASA 2014 guidelines. As many animal facilities design their health monitoring program according to these recommendations, additional studies are warranted to draw comprehensive conclusions on the effective transmission of the infectious agents listed in these guidelines by soiled bedding transfer.

Ibogaine and addiction in the animal model, a systematic review and meta-analysis.

Ibogaine is a naturally occurring substance which has been increasingly used in the lay-scene to reduce craving and relapse in patients with substance use disorders (SUDs). Although human clinical trials on the safety and efficacy of ibogaine are lacking, animal studies do support the efficacy of ibogaine. In this systematic review and meta-analysis (MA), we summarise these animal findings, addressing three questions: (1) does ibogaine reduce addictive behaviour in animal models of SUDs?; (2) what are the toxic effects of ibogaine on motor functioning, cerebellum and heart rhythm?; (3) what are neuropharmacological working mechanisms of ibogaine treatment in animal models of SUDs? MA of 27 studies showed that ibogaine reduced drug self-administration, particularly during the first 24 h after administration. Ibogaine had no effect on drug-induced conditioned place preference. Ibogaine administration resulted in motor impairment in the first 24 h after supplementation, and cerebral cell loss even weeks after administration. Data on ibogaines effect on cardiac rhythm, as well as on its neuropharmacological working mechanisms are limited. Our results warrant further studies into the clinical efficacy of ibogaine in SUD patients in reducing craving and substance use, but close monitoring of the patients is recommended because of the possible toxic effects. In addition, more work is needed to unravel the neuropharmacological working mechanisms of ibogaine and to investigate its effects on heart rhythm.

The protective effect of meniscus allograft transplantation on articular cartilage: a systematic review of animal studies.

Despite widespread reporting on clinical results, the effect of meniscus allograft transplantation on the development of osteoarthritis is still unclear. The aim of this study was to systematically review all studies on the effect of meniscus allograft transplantation on articular cartilage in animals. Pubmed and Embase were searched for original articles concerning the effect of meniscus allograft transplantation on articular cartilage compared with both its positive (meniscectomy) and negative (either sham or non-operated) control in healthy animals. Outcome measures related to assessment of damage to articular cartilage were divided in five principal outcome categories. Standardized mean differences (SMD) were calculated and pooled to obtain an overall SMD and 95% confidence interval. 17 articles were identified, representing 14 original animal cohorts with an average timing of data collection of 24 weeks [range 4 weeks; 30 months]. Compared to a negative control, meniscus allograft transplantation caused gross macroscopic (1.45 [0.95; 1.95]), histological (3.43 [2.25; 4.61]) damage to articular cartilage, and osteoarthritic changes on radiographs (3.12 [1.42; 4.82]). Moreover, results on histomorphometrics and cartilage biomechanics are supportive of this detrimental effect on cartilage. On the other hand, meniscus allograft transplantation caused significantly less gross macroscopic (-1.19 [-1.84; -0.54]) and histological (-1.70 [-2.67; -0.74]) damage to articular cartilage when compared to meniscectomy. However, there was no difference in osteoarthritic changes on plain radiographs (0.04 [-0.48; 0.57]), and results on histomorphometrics and biomechanics did neither show a difference in effect between meniscus allograft transplantation and meniscectomy. In conclusion, although meniscus allograft transplantation does not protect articular cartilage from damage, it reduces the extent of it when compared with meniscectomy.

DHA and cholesterol containing diets influence Alzheimer-like pathology, cognition and cerebral vasculature in APPswe/PS1dE9 mice.

Cholesterol and docosahexenoic acid (DHA) may affect degenerative processes in Alzheimer's Disease (AD) by influencing Abeta metabolism indirectly via the vasculature. We investigated whether DHA-enriched diets or cholesterol-containing Typical Western Diets (TWD) alter behavior and cognition, cerebral hemodynamics (relative cerebral blood volume (rCBV)) and Abeta deposition in 8- and 15-month-old APP(swe)/PS1(dE9) mice. In addition we investigated whether changes in rCBV precede changes in Abeta deposition or vice versa. Mice were fed regular rodent chow, a TWD-, or a DHA-containing diet. Behavior, learning and memory were investigated, and rCBV was measured using contrast-enhanced MRI. The Abeta load was visualized immunohistochemically. We demonstrate that DHA altered rCBV in 8-month-old APP/PS1 and wild type mice[AU1]. In 15-month-old APP/PS1 mice DHA supplementation improved spatial memory, decreased Abeta deposition and slightly increased rCBV, indicating that a DHA-enriched diet can diminish AD-like pathology. In contrast, TWD diets decreased rCBV in 15-month-old mice. The present data indicate that long-term dietary interventions change AD-like pathology in APP/PS1 mice. Additionally, effects of the tested diets on vascular parameters were observed before effects on Abeta load were noted. These data underline the importance of vascular factors in the APP/PS1 mouse model of AD pathology.

Changes in cerebral blood volume and amyloid pathology in aged Alzheimer APP/PS1 mice on a docosahexaenoic acid (DHA) diet or cholesterol enriched Typical Western Diet (TWD).

High dietary cholesterol and low dietary docosahexaenoic acid (DHA) intake are risk factors for Alzheimer's disease (AD). However, it is unclear how these components influence the course of the disease. We investigated the effects of dietary lipids on beta-amyloid deposition and blood circulation in the brains of 18-month-old APP/PS1 mice. Starting at 6 months of age, mice were fed a regular rodent chow, a Typical Western Diet (TWD) containing 1% cholesterol, or a diet with a high (0.5%) level of DHA for 12 months. Relative cerebral blood volume (rCBV) and flow (CBF) were determined with (2)H MR spectroscopy and gradient echo contrast enhanced MRI. Deposition of beta-amyloid was visualized in fixed brain tissue with immunohistochemistry. The TWD diet increased plaque burden in the dentate gyrus of the hippocampus, but did not significantly reduce rCBV. In contrast, the DHA-enriched diet increased rCBV without changing blood flow indicating a larger circulation in the brain probably due to vasodilatation and decreased the amount of vascular beta-amyloid deposition. Together, our results indicate that the long-term intake of dietary lipids can impact both brain circulation and beta-amyloid deposition, and support the involvement of hemodynamic changes in the development of AD.