Genomic variants within chromosome 14q32.32 regulate bone mass through MARK3 signaling in osteoblasts

Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. GWAS have identified hundreds of loci influencing BMD, but few have been functionally analyzed. In this study, we show that SNPs within a BMD locus on chromosome 14q32.32 alter splicing and expression of PAR-1a/microtubule affinity regulating kinase 3 (MARK3), a conserved serine/threonine kinase known to regulate bioenergetics, cell division, and polarity. Mice lacking Mark3 either globally or selectively in osteoblasts have increased bone mass at maturity. RNA profiling from Mark3-deficient osteoblasts suggested changes in the expression of components of the Notch signaling pathway. Mark3-deficient osteoblasts exhibited greater matrix mineralization compared with controls that was accompanied by reduced Jag1/Hes1 expression and diminished downstream JNK signaling. Overexpression of Jag1 in Mark3-deficient osteoblasts both in vitro and in vivo normalized mineralization capacity and bone mass, respectively. Together, these findings reveal a mechanism whereby genetically regulated alterations in Mark3 expression perturb cell signaling in osteoblasts to influence bone mass.     

Bilateral optic nerve edema presenting as initial manifestation of thyroid eye disease

A 48-year-old smoker with a history of hyperthyroidism treated 10 years prior to presentation with radioactive iodine ablation of the thyroid gland presented to his ophthalmologist with a 2-week history of transient loss of vision in the right eye occurring for 1 to 2 hours each morning. He denied ocular pain, diplopia or change in the prominence of one or both eyes. Examination revealed 2 mm of relative proptosis on the right, bilateral temporal flare and lower lid retraction. There was minimal upper lid retraction and no evidence of lid lag. Ocular motility was full. Dilated fundoscopic examination revealed bilateral optic nerve edema, right more than left. CT of the orbit demonstrated enlargement of the extraocular muscles bilaterally with marked enlargement of the right medial rectus and left inferior rectus muscles resulting in crowding at the orbital apex bilaterally. Laboratory testing revealed the patient to be hyperthyroid. The patient was treated with high dose oral steroids followed by orbital radiation. Hyperthyroidism was managed by the patient’s primary care physician. Visual symptoms rapidly improved with oral steroids and orbital radiation. Optic nerve edema completely resolved. Repeat CT imaging demonstrated a reduction in the enlargement of the extraocular muscles with relief of bilateral optic nerve compression.     

Assessment of the reporting of quality and outcome measures in hepatic resections: a call for 90-day reporting in all hepatectomy series

BackgroundThe aim of this paper is to assess the current state of quality and outcomes measures being reported for hepatic resections in the recent literature.MethodsMedline and PubMed databases were searched for English language articles published between 1 January 2002 and 30 April 2013. Two examiners reviewed each article and relevant citations for appropriateness of inclusion, which excluded papers of liver donor hepatic resections, repeat hepatectomies or meta-analyses. Data were extracted and summarized by two examiners for analysis.ResultsFifty-five studies were identified with suitable reporting to assess peri-operative mortality in hepatic resections. In only 35% (19/55) of the studies was the follow-up time explicitly stated, and in 47% (26/55) of studies peri-operative mortality was limited to in-hospital or 30 days. The time period in which complications were captured was not explicitly stated in 19 out of 28 studies. The remaining studies only captured complications within 30 days of the index operation (8/28). There was a paucity of quality literature addressing truly patient-centred outcomes.ConclusionQuality outcomes after a hepatic resection are inconsistently reported in the literature. Quality outcome studies for a hepatectomy should report mortality and morbidity at a minimum of 90 days after surgery.     

Lipoprotein Lipase Overexpression in Skeletal Muscle Attenuates Weight Regain by Potentiating Energy Expenditure

Moderate weight loss improves numerous risk factors for cardiometabolic disease; however, long-term weight loss maintenance (WLM) is often thwarted by metabolic adaptations that suppress energy expenditure and facilitate weight regain. Skeletal muscle has a prominent role in energy homeostasis; therefore, we investigated the effect of WLM and weight regain on skeletal muscle in rodents. In skeletal muscle of obesity-prone rats, WLM reduced fat oxidative capacity and downregulated genes involved in fat metabolism. Interestingly, even after weight was regained, genes involved in fat metabolism were also reduced. We then subjected mice with skeletal muscle lipoprotein lipase overexpression (mCK-hLPL), which augments fat metabolism, to WLM and weight regain and found that mCK-hLPL attenuates weight regain by potentiating energy expenditure. Irrespective of genotype, weight regain suppressed dietary fat oxidation and downregulated genes involved in fat metabolism in skeletal muscle. However, mCK-hLPL mice oxidized more fat throughout weight regain and had greater expression of genes involved in fat metabolism and lower expression of genes involved in carbohydrate metabolism during WLM and regain. In summary, these results suggest that skeletal muscle fat oxidation is reduced during WLM and regain, and therapies that improve skeletal muscle fat metabolism may attenuate rapid weight regain.     

Incidence of dementia after age 90 in a multiracial cohort

Introduction

Little is known about dementia incidence in diverse populations of oldest-old, the age group with highest dementia incidence.