The corticotrophin-releasing factor/urocortin system regulates white fat browning in mice through paracrine mechanisms

Objectives: The corticotrophin-releasing factor (CRF)/urocortin system is expressed in the adipose tissue of mammals, but its functional role in this tissue remains unknown. Methods: Pharmacological manipulation of the activity of CRF receptors, CRF1 and CRF2, was performed in 3T3L1 white pre-adipocytes and T37i brown pre-adipocytes during in vitro differentiation. The expression of genes of the CRF/urocortin system and of markers of white and brown adipocytes was evaluated along with mitochondrial biogenesis and cellular oxygen consumption. Metabolic evaluation of corticosterone-deficient or supplemented Crhr1-null (Crhr1−/−) mice and their wild-type controls was performed along with gene expression analysis carried out in white (WAT) and brown (BAT) adipose tissues. Results: Peptides of the CRF/urocortin system and their cognate receptors were expressed in both pre-adipocyte cell lines. In vitro pharmacological studies showed an inhibition of the expression of the CRF2 pathway by the constitutive activity of the CRF1 pathway. Pharmacological activation of CRF2 and, to a lesser extent, inhibition of CRF1 signaling induced molecular and functional changes indicating transdifferentiation of white pre-adipocytes and differentiation of brown pre-adipocytes. Crhr1−/− mice showed increased expression of CRF2 and its agonist Urocortin 2 in adipocytes that was associated to brown conversion of WAT and activation of BAT. Crhr1−/− mice were resistant to diet-induced obesity and glucose intolerance. Restoring physiological circulating corticosterone levels abrogated molecular changes in adipocytes and the favorable phenotype of Crhr1−/− mice. Conclusions: Our findings suggest the importance of the CRF2 pathway in the control of adipocyte plasticity. Increased CRF2 activity in adipocytes induces browning of WAT, differentiation of BAT and is associated with a favorable metabolic phenotype in mice lacking CRF1. Circulating corticosterone represses CRF2 activity in adipocytes and may thus regulate adipocyte physiology through the modulation of the local CRF/urocortin system. Targeting CRF receptor signaling specifically in the adipose tissue may represent a novel approach to tackle obesity

Synthesis of N4-aryl-β-d-glucopyranosylcytosines: a methodology study

A number of leaving groups, including arylsulfonates, triazoles, 3-nitrotriazoles, and tetrazoles, have been studied for the substitution reaction by aryl and alkyl amines at the 4-position of β-d-glucopyranosyluracils. Examination of the stability, ease of purification and reactivity in the substitution reaction led to a number of optimized conditions with the most convenient involving substitution of triazole derivatives under microwave conditions in the presence of silica gel. Under these conditions, a number of N4-aryl-substituted β-d-glucopyranosylcytosines were prepared as potential inhibitors of glycogen phosphorylase, a molecular target for type-2 diabetes mellitus

The effect of orientation of the acetabular component on outcome following total hip arthroplasty with small diameter hard-on-soft bearings

We assessed the orientation of the acetabular component in 1070 primary total hip arthroplasties with hard-on-soft, small diameter bearings, aiming to determine the size and site of the target zone that optimises outcome. Outcome measures included complications, dislocations, revisions and ΔOHS (the difference between the Oxford Hip Scores pre-operatively and five years post-operatively). A wide scatter of orientation was observed (2sd 15°). Placing the component within Lewinnek’s zone was not associated withimproved outcome. Of the different zone sizes tested (± 5°, ± 10° and ± 15°), only ± 15° was associated with a decreased rate of dislocation. The dislocation rate with acetabular components inside an inclination/anteversion zone of 40°/15° ± 15° was four times lower than those outside. The only zone size associated with statistically significant and clinically important improvement in OHS was ± 5°. The best outcomes (ΔOHS &gt; 26) were achieved with a 45°/25° ± 5° zone. This study demonstrated that with traditional technology surgeons can only reliably achieve a target zone of ±15°. As the optimal zone to diminish the risk of dislocation is also ±15°, surgeons should be able to achieve this. This is the first study to demonstrate that optimal orientation of the acetabular component improves the functional outcome. However, the target zone is small (± 5°) and cannot, with current technology, be consistently achieved. Cite this article: Bone Joint J 2015;97-B:164–72. </jats:p

Angiotensin type 1 receptor antagonist losartan, reduces MPTP-induced degeneration of dopaminergic neurons in substantia nigra

BACKGROUND: Recent attention has focused on understanding the role of the brain-renin-angiotensin-system (RAS) in stroke and neurodegenerative diseases. Direct evidence of a role for the brain-RAS in Parkinson's disease (PD) comes from studies demonstrating the neuroprotective effect of RAS inhibitors in several neurotoxin based PD models. In this study, we show that an antagonist of the angiotensin II (Ang II) type 1 (AT(1)) receptor, losartan, protects dopaminergic (DA) neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity both in primary ventral mesencephalic (VM) cultures as well as in the substantia nigra pars compacta (SNpc) of C57BL/6 mice (Fig. 1). RESULTS: In the presence of exogenous Ang II, losartan reduced MPP(+ )(5 μM) induced DA neuronal loss by 72% in vitro. Mice challenged with MPTP showed a 62% reduction in the number of DA neurons in the SNpc and a 71% decrease in tyrosine hydroxylase (TH) immunostaining of the striatum, whereas daily treatment with losartan lessened MPTP-induced loss of DA neurons to 25% and reduced the decrease in striatal TH(+ )immunostaining to 34% of control. CONCLUSION: Our study demonstrates that the brain-RAS plays an important neuroprotective role in the MPTP model of PD and points to AT(1 )receptor as a potential novel target for neuroprotection

Involvement of the Endocrine-Disrupting Chemical Bisphenol A (BPA) in Human Placentation

Background: Endocrine-disrupting chemicals (EDCs) are environmental chemicals/toxicants that humans are exposed to, interfering with the action of multiple hormones. Bisphenol A (BPA) is classified as an EDC with xenoestrogenic activity with potentially adverse effects in reproduction. Currently, a significant knowledge gap remains regarding the complete spectrum of BPA-induced effects on the human placenta. As such, the present study examined the effects of physiologically relevant doses of BPA in vitro. Methods: qRT-PCR, Western blotting, immunofluorescence, ELISA, microarray analyses, and bioinformatics have been employed to study the effects of BPA using nonsyncytialised (non-ST) and syncytialised (ST) BeWo cells. Results: Treatment with 3 nM BPA led to an increase in cell number and altered the phosphorylation status of p38, an effect mediated primarily via the membrane-bound estrogen receptor (GPR30). Nonbiased microarray analysis identified 1195 and 477 genes that were differentially regulated in non-ST BeWo cells, whereas in ST BeWo cells, 309 and 158 genes had altered expression when treated with 3 and 10 nM, respectively. Enriched pathway analyses in non-ST BeWo identified a leptin and insulin overlap (3 nM), methylation pathways (10 nM), and differentiation of white and brown adipocytes (common). In the ST model, most significantly enriched were the nuclear factor erythroid 2-related factor 2 (NRF2) pathway (3 nM) and mir-124 predicted interactions with cell cycle and differentiation (10 nM). Conclusion: Collectively, our data offer a new insight regarding BPA effects at the placental level, and provide a potential link with metabolic changes that can have an impact on the developing fetus.Isambard PhD Scholarship, Brunel University Londo

Pelvic position and movement during hip replacement

The orientation of the acetabular component is influenced not only by the orientation at which the surgeon implants the component, but also the orientation of the pelvis at the time of implantation. Hence, the orientation of the pelvis at set-up and its movement during the operation, are important. During 67 hip replacements, using a validated photogrammetric technique, we measured how three surgeons orientated the patient's pelvis, how much the pelvis moved during surgery, and what effect these had on the final orientation of the acetabular component. Pelvic orientation at set-up, varied widely (mean (± 2, standard deviation (sd))): tilt 8° (2sd ± 32), obliquity -4° (2sd ± 12), rotation -8° (2sd ± 14). Significant differences in pelvic positioning were detected between surgeons (p &lt; 0.001). The mean angular movement of the pelvis between set-up and component implantation was 9° (sd 6). Factors influencing pelvic movement included surgeon, approach (posterior &gt; lateral), procedure (hip resurfacing &gt; total hip replacement) and type of support (p &lt; 0.001). Although, on average, surgeons achieved their desired acetabular component orientation, there was considerable variability (2sd ± 16) in component orientation. We conclude that inconsistency in positioning the patient at set-up and movement of the pelvis during the operation account for much of the variation in acetabular component orientation. Improved methods of positioning and holding the pelvis are required

Pelvic position and movement during hip replacement

The orientation of the acetabular component is influenced not only by the orientation at which the surgeon implants the component, but also the orientation of the pelvis at the time of implantation. Hence, the orientation of the pelvis at set-up and its movement during the operation, are important. During 67 hip replacements, using a validated photogrammetric technique, we measured how three surgeons orientated the patient's pelvis, how much the pelvis moved during surgery, and what effect these had on the final orientation of the acetabular component. Pelvic orientation at set-up, varied widely (mean (± 2, standard deviation (sd))): tilt 8° (2sd ± 32), obliquity -4° (2sd ± 12), rotation -8° (2sd ± 14). Significant differences in pelvic positioning were detected between surgeons (p lateral), procedure (hip resurfacing > total hip replacement) and type of support (p < 0.001). Although, on average, surgeons achieved their desired acetabular component orientation, there was considerable variability (2sd ± 16) in component orientation. We conclude that inconsistency in positioning the patient at set-up and movement of the pelvis during the operation account for much of the variation in acetabular component orientation. Improved methods of positioning and holding the pelvis are required

Idiopathic radiographic apical root resorption in wind instrument players

Root resorption of the permanent teeth involves an elaborate interaction among inflammatory cells resulting in loss of dental hard tissues. This report describes three clinical cases where idiopathic root resorption occurred in wind instrument playing patients. These patients produce adequate non-orthodontic forces, while playing their instruments, to expose their teeth to root resorbing force. Careful clinical monitoring of patients' teeth should be undertaken, as the additive effects of orthodontic treatment and musical habits are unknown

Oxidative Inactivation of Mitochondrial Aconitase Results in Iron and H2O2-Mediated Neurotoxicity in Rat Primary Mesencephalic Cultures

BACKGROUND:Mitochondrial oxidative stress is a contributing factor in the etiology of numerous neuronal disorders. However, the precise mechanism(s) by which mitochondrial reactive oxygen species (ROS) modify cellular targets to induce the death of neurons remains unknown. The goal of this study was to determine if oxidative inactivation of mitochondrial aconitase (m-aconitase) resulted in the release of redox-active iron (Fe2+) and hydrogen peroxide (H2O2) and whether this contributes to cell death. METHODOLOGY/PRINCIPAL FINDINGS:Incubation of rat primary mesencephalic cultures with the redox cycling herbicide paraquat (PQ2+) resulted in increased production of H2O2 and Fe2+ at times preceding cell death. To confirm the role of m-aconitase as a source of Fenton reagents and death, we overexpressed m-aconitase using an adenoviral construct thereby increasing the target available for inactivation by ROS. Co-labeling studies identified astrocytes as the predominant cell type expressing transduced m-aconitase although neurons were identified as the primary cell type dying. Oxidative inactivation of m-aconitase overexpressing cultures resulted in exacerbation of H2O2 production, Fe2+ accumulation and increased neuronal death. Increased cell death in m-aconitase overexpressing cultures was attenuated by addition of catalase and/or a cell permeable iron chelator suggesting that neuronal death occurred in part via astrocyte-derived H2O2. CONCLUSIONS:These results suggest a role of ROS-sensitive m-aconitase as a source of Fe2+ and H2O2 and as a contributing factor to neurotoxicity

The effect of type of femoral component fixation on mortality and morbidity after hip hemiarthroplasty:A systematic review and meta-analysis

Background: Hip hemiarthroplasty is a well-established treatment of displaced femoral neck fracture, although debate exists over whether cemented or uncemented fixation is superior. Uncemented prostheses have typically been used in younger, healthier patients and cemented prostheses in older patients with less-stable bone. Also, earlier research has suggested that bone cement has cytotoxic effects and may trigger cardiovascular and respiratory adverse events. Questions/Purposes: The aim of this systematic review and meta-analysis was to compare morbidity and mortality rates after cemented and uncemented hemiarthroplasty for the treatment of displaced femoral neck fractures in elderly patients. Methods: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched seven medical databases for randomized clinical trials and observational studies. We compared cemented and uncemented hemiarthroplasty using the Harris Hip Score (HHS), as well as measures of postoperative pain, mortality, and complications. Data were extracted and pooled as risk ratios or standardized mean difference with their corresponding 95% confidence intervals in a meta-analysis model. Results: The meta-analysis included 34 studies (12 randomized trials and 22 observational studies), with a total of 42,411 patients. In the pooled estimate, cemented hemiarthroplasty was associated with less risk of postoperative pain than uncemented hemiarthroplasty. There were no significant differences between groups regarding HHS or rates of postoperative mortality, pulmonary embolism, cardiac arrest, myocardial infarction, acute cardiac arrhythmia, or deep venous thrombosis. Conclusions: While we found that cemented hemiarthroplasty results in less postoperative pain than uncemented hemiarthroplasty in older patients with femoral neck fracture, the lack of significant differences in functional hip scores, mortality, and complications was surprising. Further high-level research is needed