Genome sequence of an Australian kangaroo, Macropus eugenii, provides insight into the evolution of mammalian reproduction and development.

BACKGROUND: We present the genome sequence of the tammar wallaby, Macropus eugenii, which is a member of the kangaroo family and the first representative of the iconic hopping mammals that symbolize Australia to be sequenced. The tammar has many unusual biological characteristics, including the longest period of embryonic diapause of any mammal, extremely synchronized seasonal breeding and prolonged and sophisticated lactation within a well-defined pouch. Like other marsupials, it gives birth to highly altricial young, and has a small number of very large chromosomes, making it a valuable model for genomics, reproduction and development. RESULTS: The genome has been sequenced to 2 × coverage using Sanger sequencing, enhanced with additional next generation sequencing and the integration of extensive physical and linkage maps to build the genome assembly. We also sequenced the tammar transcriptome across many tissues and developmental time points. Our analyses of these data shed light on mammalian reproduction, development and genome evolution: there is innovation in reproductive and lactational genes, rapid evolution of germ cell genes, and incomplete, locus-specific X inactivation. We also observe novel retrotransposons and a highly rearranged major histocompatibility complex, with many class I genes located outside the complex. Novel microRNAs in the tammar HOX clusters uncover new potential mammalian HOX regulatory elements. CONCLUSIONS: Analyses of these resources enhance our understanding of marsupial gene evolution, identify marsupial-specific conserved non-coding elements and critical genes across a range of biological systems, including reproduction, development and immunity, and provide new insight into marsupial and mammalian biology and genome evolution

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Long-term follow-up of multi-disciplinary outpatient treatment for chronic fatigue syndrome/myalgic encephalopathy

Aims: The current study evaluated the long-term effectiveness of a multi-disciplinary approach to chronic fatigue syndrome/myalgic encephalopathy (CFS/ME) in a UK outpatient service. Methods: A longitudinal questionnaire survey was posted to 300 patients, incorporating measures of fatigue, physical functioning, mental health, and pain. Outcome measures administered at baseline (prior to service use) were compared to assessments at discharge, and at follow-up (average 34 months post-intervention). Results: Linear mixed modelling showed that fatigue, physical functioning, and depression significantly improved, although the improvement was reduced for fatigue, physical functioning, and pain at follow-up. Gainful employment had a significant positive association with most measures. Conclusions: The targeted multi-disciplinary service appeared to be at least somewhat effective long-term, and highly acceptable to patients. Patients appeared to benefit from individual and group approaches that combined cognitive behavioural therapy, graded exercise therapy, and pacing

Efficacy and Safety of a Novel Oral Inducer of Apolipoprotein A-I Synthesis in Statin-Treated Patients With Stable Coronary Artery Disease A Randomized Controlled Trial

OBJECTIVES: The purpose of this study was to investigate the safety, tolerability, and efficacy of RVX-208, the first oral agent designed to enhance apolipoprotein A-I (apoA-I) synthesis. BACKGROUND: No agent that selectively induces synthesis of apoA-I has reached an advanced stage of clinical development. METHODS: A total of 299 statin-treated patients with coronary artery disease were treated with placebo, or RVX-208 at a dose of 50 mg, 100 mg, or 150 mg twice daily for 12 weeks. Changes in lipid-related biomarkers, in addition to safety and tolerability, of RVX-208 were investigated. RESULTS: For each dose of RVX-208, individual pairwise comparisons of apoA-I changes with placebo, the primary end point, did not achieve statistical significance. However, treatment with RVX-208 was associated with a dose-dependent increase in apoA-I levels by up to 5.6% (p = 0.035 for trend). Administration of RVX-208 resulted in significant increases in levels of high-density lipoprotein cholesterol (HDL-C) ranging from 3.2% to 8.3% (p = 0.02), and large HDL particles increased by 11.1% to 21.1% (p = 0.003). ApoA-I levels increased rapidly from 8 to 12 weeks, suggesting that peak pharmacological effect has not been achieved by the end of the 12-week study. Transient and reversible elevations in liver transaminases >3 times the upper limit of normal were observed in 18 patients treated with RVX-208, with no associated increase in bilirubin levels. CONCLUSIONS: Administration of RVX-208 for 12 weeks was associated with increases in apoA-I, HDL-C, and concentration of large HDL particles, consistent with facilitation of cholesterol mobilization. Maximal increases in apoA-I may require longer exposure. An increase in liver enzymes was observed with active treatment. (Clinical Trial for Dose Finding and Safety of RVX000222 in Subjects With Stable Coronary Artery Disease; NCT01058018

Impact of PCSK9 inhibition on coronary atheroma progression: Rationale and design of Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV)

Statin-mediated low-density lipoprotein cholesterol (LDL-C) lowering fails to prevent more than half of cardiovascular events in clinical trials. Serial plaque imaging studies have highlighted the benefits of aggressive LDL-C lowering, with plaque regression evident in up to two-thirds of patients with achieved LDL-C levels <70 mg/dL. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors permit LDL-C-lowering by a further 54% to 75% in statin-treated patients. The impact of achieving very low LDL-C levels with PCSK9 inhibitors on coronary atherosclerosis has not been investigated. To test the hypothesis that incremental LDL-C lowering with the PCSK9 inhibitor, evolocumab, will result in a significantly greater change from baseline in coronary atheroma volume than placebo in subjects receiving maximally tolerated statin therapy. A phase 3, multicenter, double-blind, randomized, placebo-controlled trial evaluating the impact of evolocumab on coronary atheroma volume as assessed by serial coronary intravascular ultrasound at baseline in patients undergoing a clinically indicated coronary angiogram with angiographic evidence of coronary atheroma, and after 78 weeks of treatment. Subjects (n = 968) were randomized 1:1 into 2 groups to receive monthly either evolocumab 420 mg or placebo subcutaneous injections. The GLAGOV trial will explore whether greater degrees of plaque regression are achievable with ultrahigh-intensity LDL-C lowering after combination statin-PCSK9 inhibitor therapy. GLAGOV will provide important mechanistic, safety, and efficacy data prior to the eagerly anticipated clinical outcomes trials testing the PCSK9 inhibitor hypothesis (www.clinicaltrials.gov identifier NCT01813422

Effect of infusion of high-density lipoprotein mimetic containing recombinant apolipoprotein A-I Milano on coronary disease in patients with an acute coronary syndrome in the MILANO-PILOT trial: A randomized clinical trial

IMPORTANCE Infusing a high-density lipoprotein mimetic containing apolipoprotein A-I Milano demonstrated potential atheroma regression in patients following an acute coronary syndrome. To our knowledge, the effect of infusing a new mimetic preparation (MDCO-216) with contemporary statin therapy is unknown. OBJECTIVE To determine the effect of infusingMDCO-216 on coronary atherosclerosis progression. DESIGN, SETTING, AND PARTICIPANTS This double-blind, randomized clinical trial conducted in 22 hospitals in Canada and Europe compared the effects of 5 weekly intravenous infusions of MDCO-216 at a dose of 20mg/kg weekly (n = 59) with placebo (n = 67) in statin-treated patients with an acute coronary syndrome. MAIN OUTCOMES AND MEASURES The primary efficacy measurewas the nominal change in percent atheroma volume (PAV) from baseline to day 36 as measured by serial intravascular ultrasonography. The secondary efficacy measureswere the nominal changes in normalized total atheroma volume (TAV), atheroma volume in the most diseased 10-mm segment, and the percentage of patientswhodemonstrated plaque regression. Safety and tolerabilitywere also evaluated. RESULTS Among 122 randomized patients (mean [SD] age, 61.8 [10.4] years; 93men[76.2%]; 61 [50.0%] with prior statin use; and a mean [SD] low-density lipoprotein cholesterol [LDL-C] level of 87.6 [40.5]mg/dL [to convert to millimoles per liter, multiply by0.0259]), 113 (92.6%) had evaluable imaging results at follow-up. The receiving-treatment LDL-C levelswere comparable with the placebo andMDCO-216 (68.6 vs 70.5mg/dL; difference, -2.5mg/dL; 95%CI, -10.1 to 5.0; P = .51).Areduction in high-density lipoprotein cholesterol levelswas observed inMDCO, but not placebo patients (-3.3 vs 3.0mg/dL [to convert to millimoles per liter, multiply by0.0259]; difference, -6.3mg/dL; 95%CI, -8.5 to -4.1; P < .001). Percent atheroma volume, whichwas adjusted for baseline values, decreased0.94%with the placebo and0.21% withMDCO-216 (difference,0.73%; 95%CI, -0.07 to 1.52; P = .07). Normalized TAVdecreased 7.9mm3 with the placebo and 6.4mm3 withMDCO-216 (difference, 1.6mm3; 95%CI, -5.6 to 8.7; P = .67), and atheroma volume in the most diseased segment decreased 1.8mm3 with the placebo and 2.2mm3 with MDCO-216 (difference0.4mm3; 95%CI, -4.4 to 3.5; P = .83).Asimilar percentage of patients demonstrated a regression of PAV(67.2%vs 55.8%; P = .21) and TAV(68.9%vs 71.2%; P = .79) in the placebo andMDCO-216 groups, respectively. CONCLUSIONS AND RELEVANCE Among patients with an acute coronary syndrome, infusing MDCO-216 did not produce an incremental plaque regression in the setting of contemporary statin therapy