Kara Cashman

Beta-Oxidation Is Essential for Mouse Oocyte Developmental Competence and Early Embryo Development

Oocyte and embryo metabolism are closely linked with their subsequent developmental capacity. Lipids are a potent source of cellular energy, yet little is known about lipid metabolism during oocyte maturation and early embryo development. Generation of ATP from lipids occurs within mitochondria via beta-oxidation of fatty acids, with the rate-limiting step catalyzed by carnitine palmitoyl transferase I (CPT1B), a process also requiring carnitine. We sought to investigate the regulation and role of beta-oxidation during oocyte maturation and preimplantation development. Expression of Cpt1b mRNA, assessed by real-time RT-PCR in murine cumulus-oocyte complexes (COCs), increased following hormonal induction of oocyte maturation and ovulation in vivo with human chorionic gonadotropin (5 IU) and in embryos reaching the blastocyst stage. Beta-oxidation, measured by the production of 3H2O from [3H]palmitic acid, was significantly increased over that in immature COCs following induction of maturation in vitro with epidermal growth factor (3 ng/ml) and follicle-stimulating hormone (50 mIU/ml). The importance of lipid metabolism for oocyte developmental competence and early embryo development was demonstrated by assessing the rate of embryo development following inhibition or upregulation of beta-oxidation with etomoxir (an inhibitor of CPT1B) or l-carnitine, respectively. Inhibition of beta-oxidation during oocyte maturation or zygote cleavage impaired subsequent blastocyst development. In contrast, l-carnitine supplementation during oocyte maturation significantly increased beta-oxidation, improved developmental competence, and in the absence of a carbohydrate energy supply, significantly increased 2-cell cleavage. Thus, carnitine is an important cofactor for developing oocytes, and fatty acids are an important energy source for oocyte and embryo development.

Disruption of Mitochondrial Malate-Aspartate Shuttle Activity in Mouse Blastocysts Impairs Viability and Fetal Growth

Abstract The nutrient requirements and metabolic pathways used by the developing embryo transition from predominantly pyruvate during early cleavage stages to glucose at the blastocyst; however, the complexities involved in the regulation of metabolism at different developmental stages are not clear. The aims of this study were to examine the role of the malate-aspartate shuttle (MAS) in nutrient metabolism pathways in the developing mouse blastocyst and the consequences of impaired metabolism on embryo viability and fetal and placental growth. Eight-cell-stage mouse embryos were cultured in the presence of the MAS inhibitor amino-oxyacetate, with or without pyruvate as an energy substrate in the media. When the MAS was inhibited, the rate of glycolysis and lactate production was significantly elevated and glucose uptake reduced, relative to control cultured embryos in the presence of pyruvate. Despite these changes in embryo metabolism, this did not influence development to the blastocyst stage, but it did reduce the number of inner cell mass and trophectoderm cells. When these embryos were transferred to psuedopregnant females, inhibition of the MAS significantly reduced the proportion of embryos that implanted and developed into fetuses on Day 18 of pregnancy. Finally, fetal growth was reduced while placental weight was maintained, leading to a decreased fetal:placental weight ratio relative to control embryos. These results suggest that impaired metabolism of glucose in the blastocyst via the MAS alters the ability of the embryos to implant and form a pregnancy and leads to reduced fetal weight, likely via altered placental development and function.

What is the benefit of introducing new hip and knee prostheses

BACKGROUND New joint replacement prostheses are being continually introduced into the market. The underlying purpose of the introduction of new devices is to improve patient outcomes. This study was undertaken to determine how many new prostheses were associated with improved patient outcomes. BACKGROUND Data were obtained from a comprehensive national database. Outcome analysis was performed on all new hip and knee prostheses introduced into the market between January 1, 2003, and December 31, 2007, and used on at least 100 occasions. The findings were compared with the combined results of the three best performing established hip and knee prostheses with a minimum duration of follow-up of five years. The principal outcome measures were the rate of revision per observed component years and the time to first revision, with use of Kaplan-Meier estimates of implant survivorship. RESULTS Most prostheses introduced into the market during the study period were used on fewer than 100 occasions. Analysis of those that had been used in a sufficient number of procedures showed that 27% (nine of thirty-three) of the hip replacements and 29% (eight of twenty-eight) of the knee replacements had a significantly higher rate of revision than the established prostheses. None of the newer prostheses had a lower rate of revision than the established prostheses. CONCLUSION This study indicates that there was no benefit to the introduction of new prostheses into this national market during the five-year study period. Importantly, 30% of the new prostheses were associated with a significantly worse outcome compared with the prostheses with a minimal duration of follow-up of five years.

Common mental disorders associated with 2-year diabetes incidence: The Netherlands Study of Depression and Anxiety (NESDA)

BACKGROUND Few prospective cohort studies describe the risk of type 2 diabetes mellitus associated with depression or anxiety. The aim of this study was to determine the 2-year diabetes incidence and pattern of explanatory factors associated with depressive and/or anxiety disorders. METHODS A prospective cohort of 2981 participants (aged 18-65 years, 66% women) recruited in the Netherlands Study of Depression and Anxiety (NESDA) from community, primary care and outpatient psychiatric clinics were followed-up for two years. Complete data were analyzed from 2460 participants without baseline diabetes. Lifetime or current (past 6-month) depressive and/or anxiety disorders at baseline were assessed using the Composite Interview Diagnostic Instrument (CIDI) and classified by the DSM-IV. Diabetes was classified by either self-report, medications, or fasting plasma glucose ≥ 7.0 mmol/L. Baseline covariates included age, gender, lifestyle factors, and medical conditions. Odds ratios (OR [95% confidence intervals]) for diabetes were determined using exact logistic regression. RESULTS The unadjusted 2-year diabetes incidence was 0.2% (1/571), 1.1% (6/548), and 1.8% (24/1340) for no, remitted, and current depressive and/or anxiety disorders, respectively. In comparison to those without psychopathology, current depressive and/or anxiety disorders was associated with diabetes incidence in unadjusted (OR 10.4 [1.7, 429.0]) and age-adjusted (OR 11.9 (1.9, 423.0]) analyses. The strength of this association (beta coefficient) was slightly changed after further adjustments for impaired fasting glucose (11.4%), high triglycerides (-7.8%), and lifestyle cumulative risk score (-5.0%), in contrast to other covariates when assessed in separate models. LIMITATIONS The low incidence of diabetes resulted in considerable uncertainty for the odds ratios and low statistical power that limited covariate adjustments. CONCLUSIONS The relative odds of developing diabetes within two years was increased for persons with current depressive and/or anxiety disorders, which was partially explained by, but remained independent of, lifestyle cumulative risk factors.

Glucose deprivation, oxidative stress and peroxisome proliferator-activated receptor-α (PPARA) cause peroxisome proliferation in preimplantation mouse embryos

Ex vivo two-cell mouse embryos deprived of glucose in vitro can develop to blastocysts by increasing their pyruvate consumption; however, zygotes when glucose-deprived cannot adapt this metabolic profile and degenerate as morulae. Prior to their death, these glucose-deprived morulae exhibit upregulation of the H+-monocarboxylate co-transporter SLC16A7 and catalase, which partly co-localize in peroxisomes. SLC16A7 has been linked to redox shuttling for peroxisomal beta-oxidation. Peroxisomal function is unclear during preimplantation development, but as a peroxisomal transporter in embryos, SLC16A7 may be involved and influenced by peroxisome proliferators such as peroxisome proliferator-activated receptor-alpha (PPARA). PCR confirmed Ppara mRNA expression in mouse embryos. Zygotes were cultured with or without glucose and with the PPARA-selective agonist WY14643 and the developing embryos assessed for expression of PPARA and phospho-PPARA in relation to the upregulation of SLC16A7 and catalase driven by glucose deprivation, indicative of peroxisomal proliferation. Reactive oxygen species (ROS) production and relationship to PPARA expression were also analysed. In glucose-deprived zygotes, ROS was elevated within 2 h, as were PPARA expression within 8 h and catalase and SLC16A7 after 12-24 h compared with glucose-supplied embryos. Inhibition of ROS production prevented this induction of PPARA and SLC16A7. Selective PPARA agonism with WY14643 also induced SLC16A7 and catalase expression in the presence of glucose. These data suggest that glucose-deprived cleavage stage embryos, although supplied with sufficient monocarboxylate-derived energy, undergo oxidative stress and exhibit elevated ROS, which in turn upregulates PPARA, catalase and SLC16A7 in a classical peroxisomal proliferation response.

Large diameter metal on metal articulations. Comparison of total hip arthroplasty and hip resurfacing arthroplasty.

The use of large diameter metal bearing total hip arthroplasty (THA) and hip resurfacing arthroplasty (HRA) increased in popularity in the last decade. More recent literature has highlighted the effect of head size in patient outcomes. Data was obtained from the Australian Orthopaedic Association National Joint Replacement Registry (AOA-NJRR) to evaluate the Birmingham (MoM) bearing surface when used with THA and HRA. There is no difference in the overall rate of revision between the THA and HRA but head size has a significant effect on revision rate. The data show that small diameter metal bearings in HRA (below 50mm) have a higher rate of revision than large diameter metal bearings in HRA (equal to and above 50mm) (P<.001). Conversely the large diameter metal bearings in THA have a higher rate of revision than the small diameter metal bearings in THA (P=.027). The revision rate for large diameter HRA compared to small diameter THA is not significantly different P=.670. We recommend caution when choosing either a large diameter (≥50mm) metal on metal THA or small diameter (<50mm) HRA.

Exeter short stems compared with standard length exeter stems : experience from the Australian orthopaedic association national joint replacement registry

The standard Exeter stem has a length of 150 mm with offsets 37.5 to 56 mm. Shorter stems of lengths 95, 115 and 125 mm with offsets 35.5 mm or less are available for patients with smaller femurs. Concern has been raised regarding the behavior of the smaller implants. This paper analyzed data from the Australian Orthopaedic Association National Joint Replacement Registry comparing survivorship of stems of offset 35.5 mm or less with the standard stems of 37.5 mm offset or greater. At 7 years, there was no significant difference in the cumulative percent revision rate in the short stems (3.4%, 95% CI 2.4-4.8%) compared with the standard length stems (3.5%, 95% CI 3.3-3.8%) despite its use in a greater proportion of potentially more difficult developmental dysplasia of the hip cases.

The use of femoral stems with exchangeable necks in primary total hip arthroplasty increases the rate of revision

Aims Femoral stems with exchangeable (modular) necks were introduced to offer surgeons an increased choice when determining the version, offset and length of the femoral neck during total hip arthroplasty (THA). It was hoped that this would improve outcomes and reduce complications, particularly dislocation. In 2010, the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) first reported an increased rate of revision after primary THA using femoral stems with an exchangeable neck. The aim of this study was to provide a more comprehensive up‐to‐date analysis of primary THA using femoral stems with exchangeable and fixed necks. Materials and Methods The data included all primary THA procedures performed for osteoarthritis (OA), reported to the AOANJRR between 01 September 1999 and 31 December 2014. There were 9289 femoral stems with an exchangeable neck and 253 165 femoral stems with a fixed neck. The characteristics of the patients and prostheses including the bearing surface and stem/neck metal combinations were examined using Cox proportional hazard ratios (HRs) and Kaplan‐Meier estimates of survivorship. Results It was found that prostheses with an exchangeable neck had a higher rate of revision and this was evident regardless of the bearing surface or the size of the femoral head. Exchangeable neck prostheses with a titanium stem and a cobalt‐chromium neck had a significantly higher rate of revision compared with titanium stem/titanium neck combinations (HR 1.83, 95% confidence interval 1.49 to 2.23, p < 0.001). Revisions were higher for these combinations compared with femoral stems with a fixed neck. Conclusion There appears to be little evidence to support the continued use of prostheses with an exchangeable neck in primary THA undertaken for OA.

Is sudden death random or is it in the weather

It has been suggested that the weather may promote some types of death; this study sought to determine if types of death in the region around Adelaide, South Australia, occur in non-random clusters and in relationship to the weather. A Poisson model was used to determine if the occurrence of types of death were random. An exploratory analysis was performed for each death type to see if there was a relationship to weather variables using data supplied by the Bureau of Meteorology. Cases examined at Forensic Science South Australia from 1 January 2008 to 31 December 2009 were reviewed. It was ascertained that cardiovascular deaths were distributed non-randomly; there was statistical evidence to suggest that deaths from ischemic heart disease, pulmonary embolus and drug toxicity had non-random occurrence. Maximum temperatures and increases in temperatures correlated with deaths from natural causes, cardiovascular disease, ischemic heart disease and pulmonary thromboembolus; lower hours of sunlight were statistically significant for deaths due to pulmonary thromboembolus. The distribution pattern of deaths resulting from motor vehicle collision did not fit the Poisson (random) model with variation through the week also being present. Non-random clusters of deaths do occur and weather events, such as increase in temperature, are associated with some types of death. However, analysis indicates that the weather is not responsible for all clustering. With regards to motor vehicle collision deaths temporal variation may be related to social factors, such as holiday periods. Further investigation may assist with health resource planning.

Patellofemoral crepitus in high flexion rotating platform knee arthroplasty

Recently, implant manufacturers have made modifications to currently available implants in an attempt to improve postoperative flexion. The Low Contact Stress (LCS) RPS (DePuy Orthopaedics Inc., Warsaw, IN, USA) is one such prosthesis which is a modification of the established LCS RP design. Satisfactory results have been obtained without patella resurfacing in the original LCS RP design.