Background Diabetes mellitus and high platelet reactivity (HPR) on clopidogrel are both associated with increased risk of ischemic events after percutaneous coronary intervention, but whether the ...HPR-associated risk of adverse ischemic events differs by diabetes mellitus status is unknown. Methods and Results ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) was a prospective, multicenter registry of patients treated with coronary drug-eluting stents. HPR was defined as P2Y12 reaction units >208 by the VerifyNow point-of-care assay. Cox multivariable analysis was used to assess whether HPR-associated risk of major adverse cardiac events (MACE; cardiac death, myocardial infarction, or stent thrombosis) varied for patients with insulin-treated diabetes mellitus (ITDM), non-ITDM, and no diabetes mellitus. Diabetes mellitus and HPR were included in an interaction analysis. Of 8582 patients enrolled, 2429 (28.3%) had diabetes mellitus, of whom 998 (41.1%) had ITDM. Mean P2Y12 reaction units were higher in patients with diabetes mellitus versus without diabetes mellitus, and HPR was more frequent in patients with diabetes mellitus. HPR was associated with consistently increased 2-year rates of MACE in patients with and without diabetes mellitus (
=0.36). A significant interaction was present between HPR and non-insulin-treated diabetes mellitus versus ITDM for 2-year MACE (adjusted hazard ratio HR for non-ITDM, 2.28 95% CI, 1.39-3.73 versus adjusted HR for ITDM, 1.02 95% CI, 0.70-1.50;
=0.01). Conclusions HPR was more common in patients with diabetes mellitus and was associated with an increased risk of MACE in both patients with and without diabetes mellitus. In patients with diabetes mellitus, a more pronounced effect of HPR on MACE was present in lower-risk non-ITDM patients than in higher-risk patients with ITDM. Registration URL: https://clinicaltrials.gov/ct2/show/NCT00638794; Unique identifier: NCT00638794. ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents).
Objective To determine: 1) placental eNOS mRNA concentration across gestation in normal ovine pregnancy and in an ovine model of intrauterine growth restriction (IUGR), and 2) placental eNOS protein ...concentration in early ovine pregnancy. Study Design A total of 24 sheep were studied with 12 ewes placed in hyperthermic (HT) conditions to induce IUGR and 12 were kept in control conditions. HT and control animals underwent euthanasia at 3 developmental time points (55, 95, & 130 days gestational age; dGA) in ovine placental & fetal development. Results Compared to controls, HT pregnancies showed 1) no differences in fetal weights at 55 dGA and 95dGA with significant reductions at 130 dGA, 2) significantly smaller placentae at 95 and 130 dGA with a trend for a reduction at 55 dGA, 3) significant decreases in cotyledon eNOS mRNA at 95 and 130 dGA, 4) a significant increase in caruncle eNOS mRNA expression at 130 dGA, 5) significant increase in eNOS protein in the caruncle, but not in the cotyledon at 55 dGA. Conclusion Placental eNOS concentration is transcriptionally regulated at mid-gestation, while additional post-transcriptional regulation is also involved during early and late gestation in this model of placental and fetal growth restriction.
Neutrophils respond to chemotactic stimuli by increasing the nucleation and polymerization of actin filaments, but the location and regulation of these processes are not well understood. Here, using ...a permeabilized-cell assay, we show that chemotactic stimuli cause neutrophils to organize many discrete sites of actin polymerization, the distribution of which is biased by external chemotactic gradients. Furthermore, the Arp2/3 complex, which can nucleate actin polymerization, dynamically redistributes to the region of living neutrophils that receives maximal chemotactic stimulation, and the least-extractable pool of the Arp2/3 complex co-localizes with sites of actin polymerization. Our observations indicate that chemoattractant-stimulated neutrophils may establish discrete foci of actin polymerization that are similar to those generated at the posterior surface of the intracellular bacterium Listeria monocytogenes. We propose that asymmetrical establishment and/or maintenance of sites of actin polymerization produces directional migration of neutrophils in response to chemotactic gradients.
Vitamin D3 up-regulated protein 1 (VDUP1) is a key mediator of oxidative stress on various cellular processes via downstream effects on apoptosis signaling kinase 1 (ASK1) and p38 mitogen-activated ...protein kinase (MAPK). Here, we report that VDUP1 expression is significantly increased in rat hearts following acute myocardial ischemia, suggesting it may have important regulatory effects on cardiac physiological processes during periods of oxidative stress. Transfection of H9C2 cardiomyoblasts with a sequence-specific VDUP1 DNA enzyme to down-regulate VDUP1 mRNA expression significantly reduced apoptosis and enhanced cell survival under conditions of H2O2 stress, and these effects involved inhibition of ASK1 activity. Direct intracardiac injection of the DNA enzyme at the time of acute myocardial infarction reduced myocardial VDUP1 mRNA expression and resulted in prolonged reduction in cardiomyocyte apoptosis and ASK1 activity. Moreover, down-regulation of VDUP1 was accompanied by significant reduction in cardiac expression of pro-collagen type I α2 mRNA level, as well as marked reduction in myocardial scar formation. These features were accompanied by significant improvement in cardiac function. Together, these results suggest a direct role for VDUP1 in the adverse effects of ischemia and oxidative stress on cardiomyocyte survival, left ventricular collagen deposition, and cardiac function. Strategies to inhibit VDUP1 expression and/or function during acute ischemic events may be beneficial to cardiac functional recovery and prevention of left ventricular remodeling.
Summary
Background/Aims
The evolution of Le Fort III and Monobloc procedures with utilization of distraction devices has resulted in shortened surgical times, greater facial advancements, and ...decreased transfusion requirements. The aim of this observational study was to utilize data from the multicenter Pediatric Craniofacial Surgery Perioperative Registry to present and compare patient characteristics and outcomes in children undergoing midface advancement with distraction osteogenesis.
Methods
We queried the Pediatric Craniofacial Surgery Perioperative Registry for children undergoing midface advancement involving distractor application from June 2012 to September 2016. Data extracted included demographics, perioperative management, complications, fluid and transfusion volumes, and length of stay. The extracted patient characteristics and perioperative variables were summarized and compared.
Results
The query yielded 72 cases from 11 institutions: 49 children undergoing Le Fort III and 23 undergoing Monobloc procedures. Monobloc patients were younger, weighed less, and more likely to have tracheostomies along with elevated intracranial pressure. Greater transfusion was observed in the Monobloc group for nearly all of the transfusion outcomes evaluated. Median ICU and hospital length of stay were 2 and 3 days longer, respectively, in the Monobloc group. Perioperative complications were not uncommon, occurring in 18% of patients in the Le Fort III group and 30% in the Monobloc group.
Conclusion
Monobloc procedures were associated with greater transfusion and longer ICU and hospital length of stay. Perioperative complications were more prevalent in the Monobloc group.
A validated disease severity scoring system (DS3) for Gaucher disease type 1 (GD1) is needed to standardize patient monitoring and to define patient cohorts in clinical studies.
DS3 domains were ...established by an expert physician group using the nominal group technique of consensus formation. Items were selected by 36 GD1 physicians. The expert group determined appropriate measurement techniques for each item. Measurements were weighted considering contributions to GD1 morbidity and mortality. Consensus Clinical Global Impression Severity scores for sample cases were compared with average DS3 scores. A minimal clinically important difference in GD1 DS3 score was calculated.
The GD1 DS3 includes bone (42% of score), hematologic (32%), and visceral domains (26%); individual items use routine assessments, including medical history, blood chemistry, organ volume measurements, and bone evaluations (magnetic resonance imaging and dual x-ray absorptiometry). The maximum score is 19. Interrater reliability was 0.97 (Cohen's kappa). DS3 scores were highly correlated with Clinical Global Impression Severity scores (r2 = 0.89). The minimal clinically important difference was −3.2 improvement and +3.9 deterioration.
This DS3 accurately quantifies GD1 status and intrapatient change over time. Testing of reliability and validity will continue to allow eventual implementation of the DS3 in clinical studies and routine practice.
Melanin-concentrating hormone (MCH) is a cyclic, nonadecapeptide expressed in the CNS of all vertebrates that regulates feeding behavior and energy homeostasis via interaction with the central ...melanocortin system. Regulation of this interaction results in modulation of food intake and body weight gain, demonstrating significant therapeutic potential for the treatment of obesity. The MCH-1 receptor (MCH-R1) has been identified as a key target in MCH regulation, as small molecule antagonists of MCH-R1 have demonstrated activity in vivo. Herein, we document our research in a bicyclo3.1.0hexyl urea series with particular emphasis on structure-activity relationships and optimization of receptor occupancy, measured both in vitro and via an ex vivo binding assay following an oral dosing regimen. Several compounds have been tested in vivo and exhibit oral efficacy in relevant acute rodent feeding models. In particular, 24u has proven efficacious in chronic rodent models of obesity, showing a statistically significant reduction in food intake and body weight over a 28 day study.
Specific retinoid X receptor (RXR) agonists, such as LG100268 (LG268), and the thiazolidinedione (TZD) PPARγ agonists, such as rosiglitazone, produce insulin sensitization in rodent models of insulin ...resistance and type 2 diabetes. In sharp contrast to the TZDs that produce significant increases in body weight gain, RXR agonists reduce body weight gain and food consumption. Unfortunately, RXR agonists also suppress the thyroid hormone axis and generally produce hypertriglyceridemia. Heterodimer-selective RXR modulators have been identified that, in rodents, retain the metabolic benefits of RXR agonists with reduced side effects. These modulators bind specifically to RXR with high affinity and are RXR homodimer partial agonists. Although RXR agonists activate many heterodimer partners, these modulators selectively activate RXR:PPARα and RXR:PPARγ, but not RXR:RARα, RXR:LXRα, RXR:LXRβ, or RXR:FXRα. We report the in vivo characterization of one RXR modulator, LG101506 (LG1506). In Zucker fatty (fa/fa) rats, LG1506 is a potent insulin sensitizer that also enhances the insulin-sensitizing activities of rosiglitazone. Administration of LG1506 reduces both body weight gain and food consumption and blocks the TZD-induced weight gain when coadministered with rosiglitazone. LG1506 does not significantly suppress the thyroid hormone axis in rats, nor does it elevate triglycerides in Sprague Dawley rats. However, LG1506 produces a unique pattern of triglycerides elevation in Zucker rats. LG1506 elevates high-density lipoprotein cholesterol in humanized apolipoprotein A-1-transgenic mice. Therefore, selective RXR modulators are a promising approach for developing improved therapies for type 2 diabetes, although additional studies are needed to understand the strain-specific effects on triglycerides.
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