Different dietary fat and energy subtypes have an impact on both the metabolic health and the intestinal microbiota population of the host. The present study assessed the impact of dietary fat ...quality, with a focus on dietary fatty acid compositions of varying saturation, on the metabolic health status and the intestinal microbiota composition of the host. C57BL/6J mice (n 9–10 mice per group) were fed high-fat (HF) diets containing either (1) palm oil, (2) olive oil, (3) safflower oil or (4) flaxseed/fish oil for 16 weeks and compared with mice fed low-fat (LF) diets supplemented with either high maize starch or high sucrose. Tissue fatty acid compositions were assessed by GLC, and the impact of the diet on host intestinal microbiota populations was investigated using high-throughput 16S rRNA sequencing. Compositional sequencing analysis revealed that dietary palm oil supplementation resulted in significantly lower populations of Bacteroidetes at the phylum level compared with dietary olive oil supplementation (P< 0·05). Dietary supplementation with olive oil was associated with an increase in the population of the family Bacteroidaceae compared with dietary supplementation of palm oil, flaxseed/fish oil and high sucrose (P< 0·05). Ingestion of the HF-flaxseed/fish oil diet for 16 weeks led to significantly increased tissue concentrations of EPA, docosapentaenoic acid and DHA compared with ingestion of all the other diets (P< 0·05); furthermore, the diet significantly increased the intestinal population of Bifidobacterium at the genus level compared with the LF-high-maize starch diet (P< 0·05). These data indicate that both the quantity and quality of fat have an impact on host physiology with further downstream alterations to the intestinal microbiota population, with a HF diet supplemented with flaxseed/fish oil positively shaping the host microbial ecosystem.
Systemic hyperuricemia (HyUA) in obesity/type 2 diabetes facilitated by elevated activity of xanthine oxidoreductase (XOR), which is the sole source of uric acid (UA) in mammals, has been proposed to ...contribute to the pathogenesis of insulin resistance/dyslipidemia in obesity. Here, the effects of hepatocyte-specific ablation of
, the gene encoding XOR (HXO), and whole-body pharmacologic inhibition of XOR (febuxostat) on obesity-induced insulin resistance/dyslipidemia were assessed. Deletion of hepatocyte
substantially lowered liver and plasma UA concentration. When exposed to an obesogenic diet, HXO and control floxed (FLX) mice became equally obese, but systemic HyUA was absent in HXO mice. Despite this, obese HXO mice became as insulin resistant and dyslipidemic as obese FLX mice. Similarly, febuxostat dramatically lowered plasma and tissue UA and XOR activity in obese wild-type mice without altering obesity-associated insulin resistance/dyslipidemia. These data demonstrate that hepatocyte XOR activity is a critical determinant of systemic UA homeostasis, that deletion of hepatocyte
is sufficient to prevent systemic HyUA of obesity, and that neither prevention nor correction of HyUA improves insulin resistance/dyslipidemia in obesity. Thus, systemic HyUA, although clearly a biomarker of the metabolic abnormalities of obesity, does not appear to be causative.
Summary Background Post-partum depression is a serious mood disorder in women that might be triggered by peripartum fluctuations in reproductive hormones. This phase 2 study investigated brexanolone ...(USAN; formerly SAGE-547 injection), an intravenous formulation of allopregnanolone, a positive allosteric modulator of γ-aminobutyric acid (GABAA ) receptors, for the treatment of post-partum depression. Methods For this double-blind, randomised, placebo-controlled trial, we enrolled self-referred or physician-referred female inpatients (≤6 months post partum) with severe post-partum depression (Hamilton Rating Scale for Depression HAM-D total score ≥26) in four hospitals in the USA. Eligible women were randomly assigned (1:1), via a computer-generated randomisation program, to receive either a single, continuous intravenous dose of brexanolone or placebo for 60 h. Patients and investigators were masked to treatment assignments. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all randomised patients who started infusion of study drug or placebo and who had a completed baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Patients were followed up until day 30. This trial is registered with ClinicalTrials.gov , number NCT02614547. Findings This trial was done between Dec 15, 2015 (first enrolment), and May 19, 2016 (final visit of the last enrolled patient). 21 women were randomly assigned to the brexanolone (n=10) and placebo (n=11) groups. At 60 h, mean reduction in HAM-D total score from baseline was 21·0 points (SE 2·9) in the brexanolone group compared with 8·8 points (SE 2·8) in the placebo group (difference −12·2, 95% CI −20·77 to −3·67; p=0·0075; effect size 1·2). No deaths, serious adverse events, or discontinuations because of adverse events were reported in either group. Four of ten patients in the brexanolone group had adverse events compared with eight of 11 in the placebo group. The most frequently reported adverse events in the brexanolone group were dizziness (two patients in the brexanolone group vs three patients in the placebo group) and somnolence (two vs none). Moderate treatment-emergent adverse events were reported in two patients in the brexanolone group (sinus tachycardia, n=1; somnolence, n=1) and in two patients in the placebo group (infusion site pain, n=1; tension headache, n=1); one patient in the placebo group had a severe treatment-emergent adverse event (insomnia). Interpretation In women with severe post-partum depression, infusion of brexanolone resulted in a significant and clinically meaningful reduction in HAM-D total score, compared with placebo. Our results support the rationale for targeting synaptic and extrasynaptic GABAA receptors in the development of therapies for patients with post-partum depression. A pivotal clinical programme for the investigation of brexanolone in patients with post-partum depression is in progress. Funding Sage Therapeutics, Inc.
A series of novel 4-oxopyrimidine TRPV1 antagonists was evaluated in assays measuring the blockade of capsaicin or acid-induced influx of calcium into CHO cells expressing TRPV1. The investigation of ...the structure−activity relationships in the heterocyclic A-region revealed the optimum pharmacophoric elements required for activity in this series and resulted in the identification of subnanomolar TRPV1 antagonists. The most potent of these antagonists were thoroughly profiled in pharmacokinetic assays. Optimization of the heterocyclic A-region led to the design and synthesis of 23, a compound that potently blocked multiple modes of TRPV1 activation. Compound 23 was shown to be effective in a rodent “on-target” biochemical challenge model (capsaicin-induced flinch, ED50 = 0.33 mg/kg p.o.) and was antihyperalgesic in a model of inflammatory pain (CFA-induced thermal hyperalgesia, MED = 0.83 mg/kg, p.o.). Based on its in vivo efficacy and pharmacokinetic profile, compound 23 (N-{4-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy-benzothiazol-2-yl}-acetamide; AMG 517) was selected for further evaluation in human clinical trials.
ILC2 numbers positively correlated with mean eosinophils per hpf (r = 0.7; P < .0001; CI, 0.45-0.84; Pearson r correlation) enumerated by independent pathologic analysis of hematoxylin and eosin ...sections (Fig 2, B). ...esophageal ILC2s correlated strongly with eosinophilia and were increased in samples from patients with active EoE compared with patients with inactive EoE, PPI-REE, and control non-EoE tissue.
The vanilloid receptor-1 (VR1 or TRPV1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role as an integrator of multiple pain-producing stimuli. From a ...high-throughput screening assay, measuring calcium uptake in TRPV1-expressing cells, we identified an N-aryl trans-cinnamide (AMG9810, compound 9) that acts as a potent TRPV1 antagonist. We have demonstrated the antihyperalgesic properties of 9 in vivo and have also reported the discovery of novel, orally bioavailable cinnamides derived from this lead. Herein, we expand our investigations and describe the synthesis and biological evaluation of a series of conformationally constrained analogues of the s-cis conformer of compound 9. These investigations resulted in the identification of 4-amino- and 4-oxopyrimidine cores as suitable isosteric replacements for the trans-acrylamide moiety. The best examples from this series, pyrimidines 79 and 74, were orally bioavailable and exhibited potent antagonism of both rat (IC50 = 4.5 and 0.6 nM, respectively) and human TRPV1 (IC50 = 7.4 and 3.7 nM, respectively). In addition, compound 74 was shown to be efficacious at blocking a TRPV1-mediated physiological response in vivo in the capsaicin-induced hypothermia model in rats; however, it was ineffective at preventing thermal hyperalgesia induced by complete Freund's adjuvant in rats.
At war with the weather Kunreuther, Howard; Michel-Kerjan, Erwann; Doherty, Neil A
2009, 20110819, 20090605, 2013-06-26, 20090101, Letnik:
1
eBook, Book
The United States and other nations are facing large-scale risks at an accelerating rhythm. In 2005, three major hurricanes--Katrina, Rita, and Wilma--made landfall along the U.S. Gulf Coast within a ...six-week period. The damage caused by these storms led to insurance reimbursements and federal disaster relief of more than $180 billion--a record sum. Today we are more vulnerable to catastrophic losses because of the increasing concentration of population and activities in high-risk coastal regions of the country. The question is not whether but when, and how frequently, future catastrophes will strike and the extent of damages they will cause. Who should pay the costs associated with catastrophic losses suffered by homeowners in hazard-prone areas? In At War with the Weather, Howard Kunreuther and Erwann Michel-Kerjan with their colleagues deliver a groundbreaking analysis of how we currently mitigate, insure against, and finance recovery from natural disasters in the United States. They offer innovative, long-term solutions for reducing losses and providing financial support for disaster victims that define a coherent strategy to assure sustainable recovery from future large-scale disasters. The amount of data collected and analyzed and innovations proposed make this the most comprehensive book written on these critical issues in the past thirty years.
Ubiquitin specific peptidase 7 (USP7) is a deubiquitinating enzyme (DUB) that removes ubiquitin tags from specific protein substrates in order to alter their degradation rate and sub-cellular ...localization. USP7 has been proposed as a therapeutic target in several cancers because it has many reported substrates with a role in cancer progression, including FOXO4, MDM2, N-Myc, and PTEN. The multi-substrate nature of USP7, combined with the modest potency and selectivity of early generation USP7 inhibitors, has presented a challenge in defining predictors of response to USP7 and potential patient populations that would benefit most from USP7-targeted drugs. Here, we describe the structure-guided development of XL177A, which irreversibly inhibits USP7 with sub-nM potency and selectivity across the human proteome. Evaluation of the cellular effects of XL177A reveals that selective USP7 inhibition suppresses cancer cell growth predominantly through a p53-dependent mechanism: XL177A specifically upregulates p53 transcriptional targets transcriptome-wide, hotspot mutations in TP53 but not any other genes predict response to XL177A across a panel of ~500 cancer cell lines, and TP53 knockout rescues XL177A-mediated growth suppression of TP53 wild-type (WT) cells. Together, these findings suggest TP53 mutational status as a biomarker for response to USP7 inhibition. We find that Ewing sarcoma and malignant rhabdoid tumor (MRT), two pediatric cancers that are sensitive to other p53-dependent cytotoxic drugs, also display increased sensitivity to XL177A.
Since there are no specific cut-offs established for B-type natriuretic peptide (BNP) and clinical risk/outcomes, BNP has been included with a qualitative description (normal versus elevated) that ...likely still provides useful information in these scenarios. ...in settings in which syncope could be fatal for the patient and/or others and there might be limited access to medical care for surveillance of LV function and/or AVR, should symptoms develop, AVR was considered Appropriate in the low-surgical-risk patient and medical management as a May Be Appropriate alternative. In scenarios addressing patients at high surgical risk, raters were influenced by whether symptoms were felt to be the result of the comorbid conditions versus AS and by the anticipated life expectancy imposed by the comorbidities. ...there was mostly an Appropriate rating for TAVR in patients with anticipated life expectancy >1 year, and mostly Rarely Appropriate for those with life expectancy <1 year. The group was also cognizant of the fact that the risk profile of different patients presenting with the same concomitant valvular conditions may dictate different management. ...we have listed 6 possible treatment options in this table, with not all options as viable alternatives for each clinical scenario.
Purpose
Etomidate and ketamine are hemodynamically stable induction agents often used to sedate critically ill patients during emergency endotracheal intubation. In 2015, quality improvement data ...from our hospital suggested a survival benefit at Day 7 from avoidance of etomidate in critically ill patients during emergency intubation. In this clinical trial, we hypothesized that randomization to ketamine instead of etomidate would be associated with Day 7 survival after emergency endotracheal intubation.
Methods
A prospective, randomized, open-label, parallel assignment, single-center clinical trial performed by an anesthesiology-based Airway Team under emergent circumstances at one high-volume medical center in the United States. 801 critically ill patients requiring emergency intubation were randomly assigned 1:1 by computer-generated, pre-randomized sealed envelopes to receive etomidate (0.2–0.3 mg/kg,
n
= 400) or ketamine (1–2 mg/kg,
n
= 401) for sedation prior to intubation. The pre-specified primary endpoint of the trial was Day 7 survival. Secondary endpoints included Day 28 survival.
Results
Of the 801 enrolled patients, 396 were analyzed in the etomidate arm, and 395 in the ketamine arm. Day 7 survival was significantly lower in the etomidate arm than in the ketamine arm (77.3% versus 85.1%, difference − 7.8, 95% confidence interval − 13, − 2.4,
p
= 0.005). Day 28 survival rates for the two groups were not significantly different (etomidate 64.1%, ketamine 66.8%, difference − 2.7, 95% confidence interval − 9.3, 3.9,
p
= 0.294).
Conclusion
While the primary outcome of Day 7 survival was greater in patients randomized to ketamine, there was no significant difference in survival by Day 28.
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