Search

Introduction: Most individuals make healthcare visits before suicide, but many do not have a diagnosed mental health condition. This study seeks to investigate suicide risk among patients with a range of physical health conditions in a U.S. general population sample and whether risk persists after adjustment for mental health and substance use diagnoses., Methods: This study included 2,674 individuals who died by suicide between 2000 and 2013 along with 267,400 controls matched on year and location in a case-control study conducted in 2016 across eight Mental Health Research Network healthcare systems. A total of 19 physical health conditions were identified using diagnostic codes within the healthcare systems' Virtual Data Warehouse, including electronic health record and insurance claims data, during the year before index date., Results: Seventeen physical health conditions were associated with increased suicide risk after adjustment for age and sex (p<0.001); nine associations persisted after additional adjustment for mental health and substance use diagnoses. Three conditions had a more than twofold increased suicide risk: traumatic brain injury (AOR=8.80, p<0.001); sleep disorders; and HIV/AIDS. Multimorbidity was present in 38% of cases versus 15.5% of controls, and represented nearly a twofold increased risk for suicide., Conclusions: Although several individual conditions, for example, traumatic brain injury, were associated with high risk of suicide, nearly all physical health conditions increased suicide risk, even after adjustment for potential confounders. In addition, having multiple physical health conditions increased suicide risk substantially. These data support suicide prevention based on the overall burden of physical health., (Copyright © 2017 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Study Objectives: To examine and compare the arousability threshold and fall risk upon awakening of doxepin (6 mg) versus zolpidem (10 mg)., Methods: A total of 52 healthy adult males were included in a double-blind, placebo-controlled, four-way crossover study. The experimental procedure included four nights with polysomnography in the lab (zolpidem, doxepin, and their respective placebo conditions). Arousability was measured using an auditory awakening threshold delivered at the peak-plasma concentration for the active hypnotics and at matched times for the respective placebo conditions. Fall risk during the night was measured following awakening using the Berg Balance Scale and the Tandem Walk Task., Results: Both arousability and fall risk were lower in the doxepin condition compared to the zolpidem condition. Furthermore, arousability and fall risk for doxepin did not differ significantly from the placebo conditions. A significantly greater proportion of participants in the zolpidem condition (63.5%) did not wake until receiving the loudest tone (110 dB) as compared to the doxepin (17.6%) and placebo conditions (17.3%, 5.8%)., Conclusions: Results suggest that zolpidem has greater risks for balance and awakening threshold compared with low-dose doxepin. Future prospective studies should extend results to clinical samples with population-level risk of injury and arousability., (© Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Study Objectives: To examine the real-world effectiveness of benzodiazepine receptor agonists (BzRAs) by quantifying response and remission rates in a clinical sample receiving chronic BzRA treatment for insomnia., Methods: Participants were outpatients (N = 193; 72% female; 55.2 ± 11.1 year) who had an insomnia diagnosis per medical records, and who were taking a therapeutic dose of BzRA for their insomnia. Endpoints were nocturnal sleep disturbance and Insomnia Severity Index (ISI) scores. A reduction meeting the criterion for the minimally important difference in ISI scores (change ≥ 6) constituted "response"; "remission" was inferred when symptoms fell below the clinical cutoff (ISI < 11)., Results: Most participants (71%) used BzRAs at least 5 nights per week. Mean ISI scores were significantly lower (t = 22.31; p < .01) while on BzRAs than when untreated, but remained in the clinical range (mean = 11.0; standard deviation = 5.7). Although 76.7% responded to treatment, only 47.7% remitted. The majority (68.9%) of participants had a sleep-onset latency > 30 minutes and/or wake-time after sleep onset > 60 minutes while on BzRAs. After controlling for gender and insomnia severity when untreated, odds of insomnia persistence despite BzRA use were 2 times higher in patients with comorbid medical [odds ratio (OR) = 2.39; 95% confidence interval (CI) = 1.20% to 4.77%; p < .05] and psychiatric disorders (OR = 2.24; 95% CI = 1.21% to 4.13%; p < .05)., Conclusions: This is the first study to distinguish between response and remission in insomnia patients taking BzRAs. Findings suggest that while many insomnia patients respond to chronic BzRA treatment, most do not remit. Remission rates are particularly low for comorbid insomnia, the most prevalent phenotype of the disorder., (© Sleep Research Society 2016. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Background: Current US guidelines recommend the Asthma Control Test (ACT) for assessing disease control and selecting treatment., Objective: The goal of this study was to prospectively assess the ACT and its component questions for their utility in predicting the risk of severe asthma exacerbations., Methods: Individuals were participants in the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity, and those included in the current analysis had the following characteristics: age 18 years or more, physician-diagnosed asthma, and longitudinal care received at a large health system in southeastern Michigan. Study participants underwent a baseline evaluation, which included answering the ACT. A severe asthma exacerbation was defined as one requiring oral steroids, an emergency department visit, or inpatient admission. Receiver-operator characteristic curves were used to measure and compare the predictive utility of the ACT and its component questions for severe asthma exacerbations., Results: Of 1180 participants, 354 (30.0%) experienced a severe asthma exacerbation within 6 months of their baseline evaluation. When compared with the individual questions that composed the ACT, the composite score was significantly better at predicting severe exacerbations with 1 exception; the composite ACT score and the question assessing rescue medication use were not significantly different (P = .580). Pharmacy-based records of metered-dose inhaler short-acting beta-agonist use and asthma severity were also not significantly different from the composite ACT score., Conclusions: Our study demonstrates that although the ACT is modestly predictive for exacerbations, the composite score may not be superior to assessing rescue medication use alone for predicting the risk of severe asthma exacerbations., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Systemic lupus erythematosus (SLE) is an autoimmune disease with a high prevalence of hypertension. NZBWF1 (SLE-Hyp) mice develop hypertension that can be prevented by modulating T cells. The peptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) decreases renal damage and improves renal function in a model of SLE without hypertension (MRL/lpr). However, it is not known whether Ac-SDKP prevents hypertension in NZBWF1 mice. We hypothesized that in SLE-Hyp, Ac-SDKP prevents hypertension and renal damage by modulating T cells. Animals were divided into four groups: (1) control + vehicle, (2) control + Ac-SDKP, (3) SLE + vehicle, and (4) SLE + Ac-SDKP Systolic blood pressure (SBP), albuminuria, renal fibrosis, and T-cell phenotype were analyzed. SBP was higher in SLE compared to control mice and was not decreased by Ac-SDKP treatment. Half of SLE mice developed an acute and severe form of hypertension accompanied by albuminuria followed by death. Ac-SDKP delayed development of severe hypertension, albuminuria, and early mortality, but this delay did not reach statistical significance. Ac-SDKP prevented glomerulosclerosis, but not interstitial fibrosis in SLE-Hyp mice. SLE-Hyp mice showed a decrease in helper and cytotoxic T cells as well as an increase in double negative lymphocytes and T helper 17 cells, but these cells were unaffected by Ac-SDKP In conclusion, Ac-SDKP prevents kidney damage, without affecting blood pressure in an SLE animal model. However, during the acute relapse of SLE, Ac-SDKP might also delay the manifestation of an acute and severe form of hypertension leading to early mortality. Ac-SDKP is a potential tool to treat renal damage in SLE-Hyp mice., (© 2017 Henry Ford Health System. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Objective: This exploratory study assessed health literacy among urban African-American high school students to improve understanding of the association between adolescent health literacy and asthma., Methods: We conducted a secondary data analysis of the control group (n = 181) of the Puff City randomized controlled trial (2006-2010), a web-based intervention to promote asthma management among students, grades 9 through 12. A validated self-report 3-item health literacy screening instrument was completed at final online follow-up survey. Logistic regression was used to explore the association between health literacy, demographic characteristics, quality of life, asthma management, and health care utilization., Results: Multivariate analysis revealed that an overall inadequate health literacy score was associated with students who were more likely to be younger (OR 0.61; 95% CI 0.44-0.84), not on Medicaid (OR 0.36; 95% CI 0.17-0.76), have at least one hospitalization (OR 1.29; 95% CI 1.07-1.56); and a lower overall quality of life (OR 0.75; 95% CI 0.59-0.95). Those lacking confidence in filling out medical forms, needing help reading hospital materials, and having difficulty understanding written information were more likely to not have a rescue inhaler (OR 0.49; 95% CI 0.25-0.94), have one or more emergency visits (OR 1.21 95% CI 1.02-1.43), and one or more hospitalizations (OR 1.19; 95% CI 1.01-1.41), respectively., Conclusions: The findings indicate a significant association between inadequate health literary and suboptimal asthma management. It is important to advance understanding of adolescent health literacy, especially those at-risk, as they assume asthma self-management tasks and move toward independent adult self-care., Competing Interests: Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Connecting tubule glomerular feedback (CTGF) is a mechanism where an increase in sodium (Na) concentration in the connecting tubule (CNT) causes the afferent arteriole (Af-Art) to dilate. We recently reported that aldosterone within the CNT lumen enhances CTGF via a nongenomic effect involving GPR30 receptors and sodium/hydrogen exchanger (NHE), but the signaling pathways of this mechanism are unknown. We hypothesize that aldosterone enhances CTGF via cAMP/protein kinase A (PKA) pathway that activates protein kinase C (PKC) and stimulates superoxide (O 2 - ) production. Rabbit Af-Arts and their adherent CNTs were microdissected and simultaneously perfused. Two consecutive CTGF curves were elicited by increasing the CNT luminal NaCl. We found that the main effect of aldosterone was to sensitize CTGF and we analyzed data by comparing NaCl concentration in the CNT perfusate needed to achieve half of the maximal response (EC 50 ). During the control period, the NaCl concentration that elicited a half-maximal response (EC 50 ) was 37.0 ± 2.0 mmol/l; addition of aldosterone (10 -8 mol/l) to the CNT lumen decreased EC 50 to 19.3 ± 1.3 mmol/l (P ≤ 0.001 vs. Control). The specific adenylyl cyclase inhibitor 2',3'-dideoxyadenosine (ddA; 2 × 10 -4 mol/l) and the PKA inhibitor H-89 dihydrochloride hydrate (H-89; 2 × 10 -6 mol/l) prevented the aldosterone effect. The selective PKC inhibitor GF109203X (10 -8 mol/l) also prevented EC 50 reduction caused by aldosterone. CNT intraluminal addition of O 2 - scavenger tempol (10 -4 mol/l) blocked the aldosterone effect. We conclude that aldosterone inside the CNT lumen enhances CTGF via a cAMP/PKA/PKC pathway and stimulates O 2 - generation and this process may contribute to renal damage by increasing glomerular capillary pressure., (Copyright © 2016 the American Physiological Society.)

Galectin-3 (Gal-3), a member of the β-galactoside lectin family, has an important role in immune regulation. In hypertensive rats and heart failure patients, Gal-3 is considered a marker for an unfavorable prognosis. Nevertheless, the role and mechanism of Gal-3 action in hypertension-induced target organ damage are unknown. We hypothesized that, in angiotensin II (ANG II)-induced hypertension, genetic deletion of Gal-3 prevents left ventricular (LV) adverse remodeling and LV dysfunction by reducing the innate immune responses and myocardial fibrosis. To induce hypertension, male C57BL/6J and Gal-3 knockout (KO) mice were infused with ANG II (3 μg·min -1 ·kg -1 sc) for 8 wk. We assessed: 1) systolic blood pressure by plethysmography, 2) LV function and remodeling by echocardiography, 3) myocardial fibrosis by histology, 4) cardiac CD68 + macrophage infiltration by histology, 5) ICAM-1 and VCAM-1 expression by Western blotting, 6) plasma cytokines, including interleukin-6 (IL-6), by enzyme-linked immunosorbent assay, and 7) regulatory T (T reg ) cells by flow cytometry as detected by their combined expression of CD4, CD25, and FOXP3. Systolic blood pressure and cardiac hypertrophy increased similarly in both mouse strains when infused with ANG II. However, hypertensive C57BL/6J mice suffered impaired ejection and shortening fractions. In these mice, the extent of myocardial fibrosis and macrophage infiltration was greater in histological sections, and cardiac ICAM-1, as well as plasma IL-6, expression was higher as assessed by Western blotting. However, all these parameters were blunted in Gal-3 KO mice. Hypertensive Gal-3 KO mice also had a higher number of splenic T reg lymphocytes. In conclusion, in ANG II-induced hypertension, genetic deletion of Gal-3 prevented LV dysfunction without affecting blood pressure or LV hypertrophy. This study indicates that the ANG II effects are, in part, mediated or triggered by Gal-3 together with the related intercellular signaling (ICAM-1 and IL-6), leading to cardiac inflammation and fibrosis., (Copyright © 2016 the American Physiological Society.)

Background: Breast cancer sentinel lymph nodes (SLNs) with metastases (mets) are often palpably enlarged. We hypothesized that the volume of the SLN and the size of mets are directly related. SLNs harboring mets are often firm, with increased intra-nodal pressure (INP), and we hypothesized that SLN volume, as well as INP, would correlate directly with SLN metastasis size., Methods: The SLN volume, INP and met size were measured in 296 SLNs and compared using linear regression analysis. The SLNs were subsequently grouped based upon pN stage. SLN INP and volume were compared between these resultant groups., Results: Increased SLN volume significantly predicted increased SLN met size on univariate and multivariate analysis (p = 0.001 and p = 0.011, respectively). SLN met size predicted increased SLN INP on both univariate and multivariate analysis (both p = 0.001). SLN volume only significantly correlated with increased SLN INP on univariate analysis (p = 0.001). On subgroup analysis of nodal disease, pN1/2/3 nodes (SLN met sizes >2 mm) were significantly larger (p = 0.039 and p = 0.003, respectively) than pN0 and pN1(mi) nodes, and had significantly increased INP (all p = 0.001) as compared to pN0, pN0(i+), and pN1(mi) nodes., Conclusions: SLN volume and INP increased with increasing SLN met size. The threshold met size for this increase was >2 mm (pN1 disease)., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Complete ophthalmic examinations were performed on 160 Macaroni penguins ( Eudyptes chrysolophus ) and 90 Rockhopper penguins ( Eudyptes chrysocome ) at eight North American zoological institutions. Cataract prevalence in the Macaroni population was 46.5% (n = 74) of penguins and 42.3% (135/319) of eyes. Cataract prevalence in the Rockhopper population was 45.5% (n = 40) of penguins and 40.6% (73/180) of eyes. The mean age of Macaroni penguins without ocular disease was 7.4 ± 5.8 yr, while that of Rockhoppers was 9.8 ± 6.4 yr. Risk factors for cataract were examined through husbandry surveys completed by each institution and by evaluation of light intensity and ultraviolet (UV) light measurements acquired in each penguin exhibit. Risk factors associated with cataract in Macaroni penguins included age, dietary smelt, hand-feeding, and fluorescent exhibit lighting. Risk factors associated with cataract in Rockhopper penguins included age, dietary capelin, increasing population density, and increasing length of minimum photoperiod. Factors associated with decreased odds of cataract in Macaroni penguins included saltwater pool, monitoring of water quality for salinity, pH, and alkalinity; use of water additives; presence of pool filtration and sterilization systems; use of metal halide lightbulbs; increasing light intensity; and UV spectrum lighting. Factors associated with decreased odds of cataract in Rockhoppers included dietary herring and krill, increasing exhibit land area, pool temperature monitoring, increasing maximum photoperiod, and increasing minimum UV light.

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural tetrapeptide with anti-inflammatory and antifibrotic properties. Previously, we have shown that prolyl oligopeptidase (POP) is involved in the Ac-SDKP release from thymosin-β4 (Tβ4). However, POP can only hydrolyze peptides shorter than 30 amino acids, and Tβ4 is 43 amino acids long. This indicates that before POP hydrolysis takes place, Tβ4 is hydrolyzed by another peptidase that releases NH2-terminal intermediate peptide(s) with fewer than 30 amino acids. Our peptidase database search pointed out meprin-α metalloprotease as a potential candidate. Therefore, we hypothesized that, prior to POP hydrolysis, Tβ4 is hydrolyzed by meprin-α. In vitro, we found that the incubation of Tβ4 with both meprin-α and POP released Ac-SDKP, whereas no Ac-SDKP was released when Tβ4 was incubated with either meprin-α or POP alone. Incubation of Tβ4 with rat kidney homogenates significantly released Ac-SDKP, which was blocked by the meprin-α inhibitor actinonin. In addition, kidneys from meprin-α knockout (KO) mice showed significantly lower basal Ac-SDKP amount, compared with wild-type mice. Kidney homogenates from meprin-α KO mice failed to release Ac-SDKP from Tβ4. In vivo, we observed that rats treated with the ACE inhibitor captopril increased plasma concentrations of Ac-SDKP, which was inhibited by the coadministration of actinonin (vehicle, 3.1 ± 0.2 nmol/l; captopril, 15.1 ± 0.7 nmol/l; captopril + actinonin, 6.1 ± 0.3 nmol/l; P < 0.005). Similar results were obtained with urinary Ac-SDKP after actinonin treatment. We conclude that release of Ac-SDKP from Tβ4 is mediated by successive hydrolysis involving meprin-α and POP., (Copyright © 2016 the American Physiological Society.)

Background: Inhaled corticosteroids (ICSs) are the preferred treatment for achieving asthma control. However, little is known regarding the factors contributing to treatment response and whether treatment response differs by population group., Objective: We sought to assess behavioral, sociodemographic, and genetic factors related to ICS response among African American and European American subjects with asthma., Methods: Study participants were part of the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). The analytic sample included asthmatic subjects aged 12 to 56 years with greater than 12% bronchodilator reversibility and percent predicted FEV1 of between 40% and 90%. Participants received 6 weeks of inhaled beclomethasone dipropionate. The primary measure of ICS response was a change in Asthma Control Test (ACT) score; the secondary measure was a change in prebronchodilator FEV1. Adherence was measured with electronic monitors. Genetic ancestry was estimated for African American participants by using genome-wide genotype data., Results: There were 339 study participants; 242 self-identified as African American and 97 as European American. Baseline ACT score, percent predicted FEV1, degree of bronchodilator response, and ICS adherence were significantly associated with ICS response. A baseline ACT score of 19 or less was useful in identifying those who would respond, as evidenced by the significant dose-response relationship with ICS adherence. Neither self-reported race-ethnicity among all participants nor proportion of African ancestry among African American participants was associated with ICS responsiveness., Conclusions: Our findings suggest that baseline lung function measures and self-reported asthma control predict ICS response, whereas self-reported race-ethnicity and genetic ancestry do not., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring tetrapeptide that prevents inflammation and fibrosis in hypertension and other cardiovascular diseases. We previously showed that, in angiotensin II-induced hypertension, Ac-SDKP decreased the activation of nuclear transcription factor NF-κB, whereas, in experimental autoimmune myocarditis and hypertension animal models, it also reduced the expression of endothelial leukocyte adhesion molecule ICAM-1. However, the mechanisms by which Ac-SDKP downregulated ICAM-1 expression are still unclear. TNF-α is a proinflammatory cytokine that induces ICAM-1 expression in various cell types via TNF receptor 1 and activation of the classical NF-κB pathway. We hypothesized that in endothelial cells Ac-SDKP suppresses TNF-α-induced ICAM-1 expression by decreasing IKK phosphorylation that as a consequence leads to a decrease of IκB phosphorylation and NF-κB activation. To test this hypothesis, human coronary artery endothelial cells were treated with Ac-SDKP and then stimulated with TNF-α. We found that TNF-α-induced ICAM-1 expression was significantly decreased by Ac-SDKP in a dose-dependent manner. Ac-SDKP also decreased TNF-α-induced NF-κB translocation from cytosol to nucleus, as assessed by electrophoretic mobility shift assay, which correlated with a decrease in IκB phosphorylation. In addition, we found that Ac-SDKP decreased TNF-α-induced IKK phosphorylation and IKK-β expression. However, Ac-SDKP had no effect on TNF-α-induced phosphorylation of p38 MAP kinase or ERK. Thus we conclude that Ac-SDKP inhibition of TNF-α activation of canonical, i.e., IKK-β-dependent, NF-κB pathway and subsequent decrease in ICAM-1 expression is achieved via inhibition of IKK-β., (Copyright © 2016 the American Physiological Society.)

Ophthalmic examinations were performed on 160 macaroni penguins (Eudyptes chrysolophus) and 90 southern rockhopper penguins (Eudyptes chrysocome) at eight North American zoos and aquaria. Intraocular pressure (IOP) was measured using rebound tonometry while penguins were held in two different body positions. Correlations between IOP and factors including age, body position, eye pathology, and housing parameters were evaluated. Normal macaroni penguins had a mean IOP of 42.0 ± 9.7 mm Hg. Normal rockhopper penguins had a mean IOP of 32.9 ± 6.2 mm Hg. Neither species had significantly different IOP between sexes or between left and right eyes of the same penguin. In both species, there was a negative linear correlation between age and IOP. In the macaroni population, IOP was significantly higher when IOP measurement was performed before ophthalmic exam; this was not true in rockhoppers. In both species, IOP measured in a horizontal body position was significantly higher than IOP measured in a vertical body position. In both species, eyes with corneal lesions had significantly lower IOP than normal eyes. In the macaroni penguin, eyes with rubeosis iridis had significantly lower IOP than normal eyes. In macaroni penguins, eyes with cataracts had significantly lower mean IOP than normal eyes; this was not true for rockhoppers.

Unlabelled: The American College of Sports Medicine currently recommends the HR reserve (HRR) method to guide exercise in individuals who have heart failure with reduced ejection fraction. This recommendation is based on the known association between %HRR and percentage of V˙O2 reserve (%V˙O2R) in this population. However, to our knowledge, no studies exist regarding this relation in individuals with a left ventricular assist device (LVAD)., Purpose: This article aimed to describe the relation between V˙O2 and surrogate markers of exercise intensity among patients with LVAD., Methods: Patients with continuous-flow LVAD (n = 24, seven females) completed a symptom-limited graded exercise test on a treadmill. HR and V˙O2 were measured continuously and averaged every 20 s. Regression equations were determined using a generalized estimating equation to predict %V˙O2R from %HRR, Borg RPE, and LVAD flow, overall and stratified by presence of pacing., Results: Although the association between %HRR and %V˙O2R was good (R = 0.75), the slope and y-intercept for %HRR versus %V˙O2R was different from the line of identity (P = 0.002). However, when paced subjects were excluded (n = 8) from the analysis, there was no significant difference between the slope and y-intercept (= 0.036 + 0.937 × %HRR; SEE, 2%; P = 0.052). RPE showed a strong association with %V˙O2R (R = 0.84), whereas LVAD flow showed a weak (albeit statistically significant) association (R = 0.05). Both had slopes and y-intercepts that were different from the line of identity (P < 0.05)., Conclusions: In patients with LVAD who are not paced during exercise, the use of %HRR is a good predictor of %V˙O2R. However, for patients in this population who are also paced during exercise, RPE is a suitable surrogate measure of exercise intensity.

Objective: Clinical utility and cost-effectiveness of carotid duplex examination prior to cardiac surgery have been questioned by the multidisciplinary committee creating the 2012 Appropriate Use Criteria for Peripheral Vascular Laboratory Testing. We report the clinical outcomes and postoperative neurologic symptoms in patients who underwent carotid duplex ultrasound prior to open heart surgery at a tertiary institution., Methods: Using the combined databases from our clinical vascular laboratory and the Society of Thoracic Surgery, a retrospective analysis of all patients who underwent carotid duplex ultrasound within 13 months prior to open heart surgery from March 2005 to March 2013 was performed. The outcomes between those who underwent carotid duplex scanning (group A) and those who did not (group B) were compared., Results: Among 3233 patients in the cohort who underwent cardiac surgery, 515 (15.9%) patients underwent a carotid duplex ultrasound preoperatively, and 2718 patients did not (84.1%). Among the patients who underwent carotid screening vs no screening, there was no statistically significant difference in the risk factors of cerebrovascular disease (10.9% vs 12.7%; P = .26), prior stroke (8.2% vs 7.2%; P = .41), and prior transient ischemic attack (2.9% vs 3.3%; P = .24). For those undergoing isolated coronary artery bypass grafting (CABG), 306 (17.8%) of 1723 patients underwent preoperative carotid duplex ultrasound. Among patients who had carotid screening prior to CABG, the incidence of carotid disease was low: 249 (81.4%) had minimal or mild stenosis (<50%); 25 (8.2%) had unilateral moderate stenosis (50%-69%); 10 (3.3%) had bilateral moderate stenosis; 9 (2.9%) had unilateral severe stenosis (70%-99%); 5 (1.6%) had contralateral moderate stenosis; 2 (0.7%) had bilateral severe stenosis; 4 (1.3%) had unilateral occluded with contralateral less than 50% stenosis, 1 (0.3%) had unilateral occluded with contralateral (70%-99%) stenosis; and 1 had bilateral occluded carotid arteries. Primary outcomes of patients who underwent isolated CABG showed no difference in the perioperative mortality (2.9% vs 4.3%; P = .27) and stroke (2.9% vs 2.6%; P = .70) between patients undergoing preoperative duplex scanning and those who did not. Primary outcomes of patients who underwent open heart surgery also showed no difference in the perioperative mortality (5.1% vs 6.9%; P = .14) and stroke (2.6% vs 2.4%; P = .85) between patients undergoing preoperative duplex scanning and those who did not. Operative intervention of severe carotid stenosis prior to isolated CABG occurred in 2 of the 17 patients (11.8%) identified who underwent carotid endarterectomy with CABG., Conclusions: In this study, the correlation between preoperative duplex-documented high-grade carotid stenosis and postoperative stroke was low. Prudent use of preoperative carotid duplex ultrasound should be based on the presence of cerebrovascular symptoms and the type of open heart surgery., (Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Hypertension is associated with cardiovascular disease, stroke, and a range of other medical sequelae. Accurate blood pressure (BP) readings, which depend on the integrity and calibration of the measuring device, are essential to identifying suboptimal BP. This study describes calibration rates of aneroid BP devices (a) utilized in home healthcare (HHC) and (b) having the needle resting within the zero accuracy indicator. BP devices from one branch of a home care agency were inspected and checked for calibration according to the protocol set forth by the European Society of Hypertension. Of the 125 devices measured, 78.4% were in calibration. Of the 94 devices with the gauge needle resting in the zero accuracy indicator, 11.7% were not in calibration; whereas, 51.6% of the 31 devices with the gauge needle resting outside the zero accuracy indicator were found not in calibration. Twenty-one devices were not checked for calibration due to inflation bulb malfunction, tubing tears, or excessive wear. Furthermore, visual inspection of the needle placement did not confirm a device as being in or out of calibration. Proper maintenance and routine calibration of BP equipment is foundational to assuring accuracy of BP readings obtained by HHC providers.

Background: The clinical course of patients with omphalocele is challenging to predict. There is no standard method to characterize omphalocele size. Previous studies suggest that the ratio of abdominal circumference to omphalocele defect in-utero is indicative of postnatal outcomes. We hypothesize that omphalocele ratio correlates with outcomes of primary closure versus staged closure., Methods: A retrospective chart review of all neonates diagnosed with omphalocele from 2002 to 2013 with prenatal ultrasounds available (n=30) was conducted. Omphalocele ratio was defined as omphalocele diameter/abdominal circumference (OD/AC). Data collected included primary versus staged closure, time to full feeds, duration of mechanical ventilation, and length of stay (LOS). Long-term outcomes and quality of life were also reported., Results: ROC curve analysis generated optimal OD/AC ratio of 0.26. Twenty of 30 patients had a ratio less than this cutoff. Sixty percent (12/20) in the low-ratio group achieved primary closure versus zero (0/10) in the high-ratio group (p=0.001). Time on mechanical ventilation was 15.8 days (low-ratio) versus 79 days (high-ratio) (p=0.05). LOS was 33.8 days (low-ratio) versus 85.6 days (high-ratio) (p=0.119). PedsQL™ mean score was 85.5 ± 11.0 (n=20) at long-term follow-up. Readmission rates yielded no difference., Conclusions: The omphalocele ratio is a promising predictor of postnatal outcomes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural tetrapeptide with anti-inflammatory and antifibrotic properties. Its effect on salt-sensitive (SS) hypertension is unknown. We hypothesized that in Dahl SS rats on high-salt (HS) diet, Ac-SDKP prevents loss of nephrin expression and renal immune cell infiltration, leading to a decrease in albuminuria, renal inflammation, fibrosis, and glomerulosclerosis. To test this, Dahl SS rats and consomic SS13BN controls were fed either a low-salt (0.23% NaCl) or HS (4% NaCl) diet and treated for 6 weeks with vehicle or Ac-SDKP at either low or high dose (800 or 1600 μg/kg per day, respectively). HS increased systolic blood pressure in SS rats (HS+vehicle, 186±5 versus low salt+vehicle, 141±3 mm Hg; P<0.005) but not in SS13BN rats. Ac-SDKP did not affect blood pressure. Compared with low salt, HS-induced albuminuria, renal inflammation, fibrosis, and glomerulosclerosis in both strains, but the damages were higher in SS than in SS13BN. Interestingly, in SS13BN rats, Ac-SDKP prevented albuminuria induced by HS (HS+vehicle, 44±8 versus HS+low Ac-SDKP, 24±3 or HS+high Ac-SDKP, 8±1 mg/24 h; P<0.05), whereas in SS rats, only high Ac-SDKP dose significantly attenuated albuminuria (HS+vehicle, 94±10 versus HS+high Ac-SDKP, 57±7 mg/24 h; P<0.05). In both strains, Ac-SDKP prevented HS-induced inflammation, interstitial fibrosis, and glomerulosclerosis. In summary, in SS rats on HS diet, at low and high doses, Ac-SDKP prevented renal damage without affecting the blood pressure. Only the high dose of Ac-SDKP attenuated HS-induced albuminuria. Conversely, in SS13BN rats, both doses of Ac-SDKP prevented HS-induced renal damage and albuminuria.

Elevated interleukin-4 (IL-4) levels are associated with cardiac fibrosis in hypertension and heart failure in both patients and experimental animals. We hypothesized that chronically elevated IL-4 induces cardiac fibrosis, resulting in a predisposition of the heart to angiotensin II-induced damage. Wild-type Balb/c (WT, high circulating IL-4) and IL-4-deficient Balb/c mice (IL-4(-/-)) were used. WT mice exhibited cardiac fibrosis (evidenced by an increase in expression of procollagen genes/interstitial collagen fraction), enlarged left ventricle chamber, and declined cardiac function associated with a greater number of mast cells and macrophages in the heart compared with IL-4(-/-). In contrast, IL-4(-/-) mice had normal cardiac architecture/function while showing a 57.9% reduction in heart interstitial collagen compared with WT, despite elevated proinflammatory cytokines in heart tissue. In response to angiotensin II administration, IL-4(-/-) had reduced interstitial myocardial fibrosis and were protected from developing dilated cardiomyopathy, which was seen in WT mice. This was associated with increased macrophage infiltration into the hearts of WT mice, despite a similar degree of hypertension and increased cardiac transforming growth factor-β1 in both groups. In vitro data demonstrated that IL-4 upregulates procollagen genes and stimulates collagen production in mouse cardiac fibroblasts. This process is mediated by signal transducer and activator of transcription 6 signaling pathway via IL-4 receptor alpha. This study not only establishes a causal relationship between IL-4 and cardiac fibrosis/dysfunction, but also reveals a critical role for IL-4 in angiotensin II-induced cardiac damage. IL-4 could serve as an additional target for the treatment of cardiac fibrosis., (© 2015 American Heart Association, Inc.)

Purpose: Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been established as a mainstay of heart failure treatment. Current data are limited and conflicting regarding the consistency of ACE/ARB benefit across race groups in heart failure. This study aims to clarify this point., Methods: This was a retrospective study of insured patients with a documented ejection fraction of less than 50%, hospitalized for heart failure between January 2000 and June 2008. Pharmacy claims data were used to estimate ACE/ARB exposure over 6-month rolling windows. The association between ACE/ARB exposure and all-cause hospitalization or death was assessed by proportional hazards regression, with adjustment for baseline covariates and β-blocker exposure. Further analyses were stratified by race, and included an ACE/ARB × Race interaction term., Results: A total of 1095 patients met inclusion criteria (619 African-American individuals). Median follow-up was 2.1 years. In adjusted models, ACE/ARB exposure was associated with lower risk of death or hospitalization in both groups (African-Americans hazard ratio 0.47, P < 0.001; whites hazard ratio 0.55, P < 0.001). A formal test for interaction was consistent with similar effects in each group (P = 0.861, β = 0.04)., Conclusion: ACE/ARB exposure was equally associated with a protective effect in preventing death or rehospitalization among heart failure patients with systolic dysfunction in both African-American patients and whites.

Peer-assisted learning (PAL) as an educational philosophy benefits both the peer-teacher and peer-learner. The changing role of paramedicine towards autonomous and professional practice demands future paramedics to be effective educators. Yet PAL is not formally integrated in undergraduate paramedic programs. We aimed to examine the effects of an educational intervention on students' PAL experiences as peer-teachers. Two one-hour workshops were provided prior to PAL teaching sessions including small group activities, individual reflections, role-plays and material notes. Peer-teachers completed the Teaching Style Survey, which uses a five-point Likert scale to measure participants' perceptions and confidence before and after PAL involvement. Thirty-eight students were involved in an average of 3.7 PAL sessions. The cohort was predominated by males (68.4%) aged ≤ 25 (73.7%). Following PAL, students reported feeling more confident in facilitating tutorial groups (p = 0.02). After the PAL project peer-teachers were also more likely to set high standards for their learners (p = 0.009). This PAL project yielded important information for the continual development of paramedic education. Although PAL increases students' confidence, the full role of PAL in education remains unexplored. The role of the university in this must also be clearly clarified., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Systemic lupus erythematosus is an autoimmune disease characterized by the development of auto antibodies against a variety of self-antigens and deposition of immune complexes that lead to inflammation, fibrosis, and end-organ damage. Up to 60% of lupus patients develop nephritis and renal dysfunction leading to kidney failure. N-acetyl-seryl-aspartyl-lysyl-proline, i.e., Ac-SDKP, is a natural tetrapeptide that in hypertension prevents inflammation and fibrosis in heart, kidney, and vasculature. In experimental autoimmune myocarditis, Ac-SDKP prevents cardiac dysfunction by decreasing innate and adaptive immunity. It has also been reported that Ac-SDKP ameliorates lupus nephritis in mice. We hypothesize that Ac-SDKP prevents lupus nephritis in mice by decreasing complement C5-9, proinflammatory cytokines, and immune cell infiltration. Lupus mice treated with Ac-SDKP for 20 wk had significantly lower renal levels of macrophage and T cell infiltration and proinflammatory chemokine/cytokines. In addition, our data demonstrate for the first time that in lupus mouse Ac-SDKP prevented the increase in complement C5-9, RANTES, MCP-5, and ICAM-1 kidney expression and it prevented the decline of glomerular filtration rate. Ac-SDKP-treated lupus mice had a significant improvement in renal function and lower levels of glomerular damage. Ac-SDKP had no effect on the production of autoantibodies. The protective Ac-SDKP effect is most likely achieved by targeting the expression of proinflammatory chemokines/cytokines, ICAM-1, and immune cell infiltration in the kidney, either directly or via C5-9 proinflammatory arm of complement system., (Copyright © 2015 the American Physiological Society.)

Afferent (Af-Art) and efferent arterioles resistance regulate glomerular capillary pressure. The nephron regulates Af-Art resistance via: 1) vasoconstrictor tubuloglomerular feedback (TGF), initiated in the macula densa via Na-K-2Cl cotransporters (NKCC2) and 2) vasodilator connecting tubuloglomerular feedback (CTGF), initiated in connecting tubules via epithelial Na channels (ENaC). Furosemide inhibits NKCC2 and TGF. Benzamil inhibits ENaC and CTGF. In vitro, CTGF dilates preconstricted Af-Arts. In vivo, benzamil decreases stop-flow pressure (PSF), suggesting that CTGF antagonizes TGF; however, even when TGF is blocked, CTGF does not increase PSF, suggesting there is another mechanism antagonizing CTGF. We hypothesize that in addition to NKCC2, activation of Na/H exchanger (NHE) antagonizes CTGF, and when both are blocked CTGF dilates Af-Arts and this effect is blocked by a CTGF inhibitor benzamil. Using micropuncture, we studied the effects of transport inhibitors on TGF responses by measuring PSF while increasing nephron perfusion from 0 to 40 nl/min. Control TGF response (-7.9 ± 0.2 mmHg) was blocked by furosemide (-0.4 ± 0.2 mmHg; P < 0.001). Benzamil restored TGF in the presence of furosemide (furosemide: -0.2 ± 0.1 vs. furosemide+benzamil: -4.3 ± 0.3 mmHg; P < 0.001). With furosemide and NHE inhibitor, dimethylamiloride (DMA), increase in tubular flow increased PSF (furosemide+DMA: 2.7 ± 0.5 mmHg, n = 6), and benzamil blocked this (furosemide+DMA+benzamil: -1.1 ± 0.2 mmHg; P < 0.01, n = 6). We conclude that NHE in the nephron decreases PSF (Af-Art constriction) when NKCC2 and ENaC are inhibited, suggesting that in the absence of NKCC2, NHE causes a TGF response and that CTGF dilates the Af-Art when TGF is blocked with NKCC2 and NHE inhibitors., (Copyright © 2015 the American Physiological Society.)

Background: Detecting occult bleeding can be challenging and may delay resuscitation. The Shock Index (SI) defined as heart rate divided by systolic blood pressure has attracted attention. Prediction models using combinations of pre-hospital SI (phSI) and the trauma centre SI (tcSI) values may be effective in identifying patients requiring massive blood transfusions (MT)., Aim: To explore whether combinations of the phSI and the tcSI augment MT prediction., Methods: The scores were retrospectively developed using all major trauma patients that presented to The Alfred Hospital between 2006 and 2012. The first PH and TC observations were used. To avoid exclusion of the 'sickest' patients, the SI was imputed to 2 where SBP was missing, but HR was present. We developed 4 models. (i) 'Dichotomised', defined as positive when both phSI and tcSI were ≥1. (ii) 'Formulaic', defined by logistic regression analysis. (iii) 'Combination', defined pragmatically based on the logistic regression. (iv) 'Trending', defined as: tcSI minus phSI., Results: There were 6990 major trauma patients and 360 (5.2%) received MT. There were 1371 cases with either phSI or tcSI missing and were thus excluded from the analysis. The 'Dichotomised' had higher positive predictive value than the tcSI with a further 5 per 100 patients identified. The 'Formulaic' model, defined as: log Odds (MT)=2.16×tcSI+0.89×phSI-5.42, and the 'Combination' model, defined as: phSI×0.5+tcSI, performed equally (AUROC 0.83 versus 0.83, χ(2)=0.86, p=0.35). The 'Formulaic' performed marginally, but statistically significantly, more accurate than the tcSI alone (AUROC 0.83 versus 0.82, χ(2)=6.89, p<0.01). An 'Upward Trending' SI was observed in 1758 patients, revealing a 4.6-fold univariate association with MT (OR 4.55; 95%CI 2.64-7.83), and an AUROC of 0.79 (95%CI 0.74-0.83). The 'Downward Trending' SI was protective against MT (OR 0.44; 95%CI 0.34-0.57)., Conclusion: The initial pre-hospital SI is associated with MT. However, this relationship did not clinically augment MT decision when combined with the in-hospital SI. The simplicity of the SI makes it a favourable option to explore further. Computer-assisted technology in data capturing, analysis and prognostication presents avenues for further research., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The prevalence of medication use among Americans is reported at 48% with significant linear increases with advancing age. A link between specific medication use and fall risk has been established. The purposes of this study are to describe (a) medication categories and (b) medication prevalence associated with fall risk prescribed to individuals case-managed by physical therapists (PTs) in home healthcare (HHC). Descriptive retrospective chart reviews of age, gender, ethnicity, diagnosis, and prescribed medication profiles were obtained from electronic health records (EHRs) of individuals case-managed by PTs at one HHC agency. Descriptive statistics of patient characteristics and medications were analyzed. The chi-square test compared difference by age, gender, and ethnicity. Ninety-five EHRs met criteria for inclusion. Eight hundred and nineteen total medications, comprising 403 medications and 34 medication categories were identified. The highest medication categories prescribed were pain relief (70.5%); cardiovascular agents (65.3%); vitamins, minerals, therapeutic nutrients, and electrolytes (60.0%); gastrointestinal (53.7%); and heart and cholesterol agents (45.3%). Fall risk indicators were identified including medication from a fall risk category (4.2%) and polypharmacy (90.5%). Individuals case-managed by PTs in the HHC setting are prescribed medications from a variety of medication categories including fall risk indicators. This study emphasizes the importance of PTs' review of medications during an initial examination to identify potential adverse events, including falls, which may occur as a result of medication usage.

Objective: Inflammation has been proposed as a key component in the development of hypertension and cardiac remodeling associated with different cardiovascular diseases. However, the role of the proinflammatory cytokine interleukin-6 in the chronic stage of hypertension is not well defined. Here, we tested the hypothesis that deletion of interleukin-6 protects against the development of hypertension, cardiac inflammation, fibrosis, remodeling and dysfunction induced by high salt diet and angiotensin II (Ang II)., Methods: Male C57BL/6J and interleukin-6-knock out (KO) mice were implanted with telemetry devices for blood pressure (BP) measurements, fed a 4% NaCl diet, and infused with either vehicle or Ang II (90 ng/min per mouse subcutaneously) for 8 weeks. We studied BP and cardiac function by echocardiography at baseline, 4 and 8 weeks., Results: Myocyte cross-sectional area (MCSA), macrophage infiltration, and myocardial fibrosis were also assessed. BP increased similarly in both strains when treated with Ang II and high salt (Ang II-high salt); however, C57BL/6J mice developed a more severe decrease in left ventricle ejection fraction, fibrosis, and macrophage infiltration compared with interleukin-6-KO mice. No differences between strains were observed in MCSA, capillary density and MCSA to capillary density ratio., Conclusion: In conclusion, absence of interleukin -6 did not alter the development of Ang II-high salt-induced hypertension and cardiac hypertrophy, but it prevented the development of cardiac dysfunction, myocardial inflammation, and fibrosis. This indicates that interleukin-6 plays an important role in hypertensive heart damage but not in the development of hypertension.

Background: Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors (GLP-1 agents) may be protective in heart failure (HF). We set out to determine whether GLP-1 agent use is associated with HF risk in diabetics., Methods and Results: In this retrospective cohort study of members of a large health system, we identified >19,000 adult diabetics from January 1, 2000, to July 1, 2012. GLP-1 agent users were matched 1:2 to control subjects with the use of propensity matching based on age, race, sex, coronary disease, HF, diabetes duration, and number of antidiabetic medications. The association of GLP-1 agents with time to HF hospitalization was tested with multivariable Cox regression. All-cause hospitalization and mortality were secondary end points. We identified 1,426 users of GLP-1 agents and 2,798 control subjects. Both were similar except for angiotensin-converting enzyme inhibitors/angiotensin receptor blocker use, number of antidiabetic medications, and age. There were 199 hospitalizations, of which 128 were for HF, and 114 deaths. GLP-1 agents were associated with reduced risk of HF hospitalization (adjusted hazard ratio [aHR] 0.51, 95% confidence interval [CI] 0.34-0.77; P = .002), all-cause hospitalization (aHR 0.54, 95% CI 0.38-0.74; P = .001), and death (aHR 0.31, 95% CI 0.18-0.53; P = .001)., Conclusions: GLP-1 agents may reduce the risk of HF events in diabetics., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Low birth weight (LBW) has been shown to be an independent risk factor for asthma. We hypothesized that LBW would have its greatest impact on early onset disease., Methods: A racially diverse cohort of children born from 1983 to 1985 at two hospitals, one urban and one suburban in the same metropolitan area, and oversampled for babies weighing ≤2500 g, was identified retrospectively when the children were 6 years of age and followed periodically. At the age 17 years study visit, cohort members and their parent/guardians were separately interviewed face-to-face regarding the subject's history of asthma using the standardized ISAAC questionnaire. We measured the cumulative incidence of asthma from birth through adolescence defined by age of diagnosis and persistence/remittance., Results: Six-hundred and eighty teens (82.6% of the original cohort) were included in the analyses, 387 with LBW and 293 of normal birth weight. The prevalence of physician-diagnosed "Current Asthma" was associated with LBW (p = 0.003 for trend), with patterns stronger in males and whites. LBW was associated most strongly with Late Onset Persistent asthma (current asthma that was diagnosed after 8 years); p for trend 0.032. This trend was again most evident in males and whites. None of the asthma categories classified as "remittent" were statistically associated with LBW., Conclusions: LBW was not associated with diagnosed asthma that remitted before age 17 years. LBW was associated with asthma diagnosis in mid-childhood that persisted through adolescence, suggesting that the asthmagenic effects of LBW can become evident post the early years of childhood and persist into adulthood.

Background: Characteristic features of hypokinetic dysarthria develop in Parkinson disease (PD). We hypothesized that quantified acoustic changes of voice might provide a correlate of disease severity., Objective: To determine if there are significant differences in acoustic measures of voice between mild and moderate PD; 2) To evaluate correlations between acoustic parameters of voice and subtests of the UPDRS in mild and moderate PD., Methods: Twenty six participants with PD underwent vocal acoustic testing while off PD medication, for comparison to 22 healthy controls. Participants with PD were divided into two groups based upon UPDRS activities of daily living (ADL) ratings: summed scores were used to define mild and moderate PD. Participants voiced /i/ ("ee") at comfort, high, and low pitch (3 trials/pitch). The CSpeech Waveform Analysis Program was used to analyze cycle-to-cycle frequency ("jitter") and amplitude ("shimmer") irregularities of the vocal signal, signal-to-noise ratio, and maximum phonation frequency range converted to semitones. Sections of UPDRS scores were correlated to acoustic variables of voice., Results: Key findings included a significant difference between the semitone range of the control subjects and the moderate PD group (p = 0.036). Further analyses revealed significant differences in semitone range for males between the controls vs. mild PD (p = 0.014), and controls vs. moderate PD (p = 0.005). Significant correlations were also found between acoustic findings and both the ADL and motor portions of the UPDRS., Conclusions: Acoustic analysis of voice, particularly frequency range, may provide a quantifiable correlate of disease progression in PD.

Injuries to the fingertips are among the most common injuries to the hand and result in approximately 4.8 million emergency department visits per year. Most injuries are lacerations or crushes; amputations represent a small but complex spectrum of injury. Treatments available cover a broad range of techniques with no single recommended reference standard for treatment. Although there is no consensus on how these injuries should be treated, the goals of treatment should include minimization of pain, optimization of healing time, preservation of sensibility and length, prevention of painful neuromas, avoidance or limiting of nail deformity, minimization of time lost from work, and provision of an acceptable cosmetic appearance. In this review we present a variety of options in caring for these injuries to help achieve these goals, and the available data that support the various treatment plans., (Copyright © 2014 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Thymosin-β4 (Tβ4) promotes cell survival, angiogenesis, and tissue regeneration and reduces inflammation. Cardiac rupture after myocardial infarction (MI) is mainly the consequence of excessive regional inflammation, whereas cardiac dysfunction after MI results from a massive cardiomyocyte loss and cardiac fibrosis. It is possible that Tβ4 reduces the incidence of cardiac rupture post-MI via anti-inflammatory actions and that it decreases adverse cardiac remodeling and improves cardiac function by promoting cardiac cell survival and cardiac repair. C57BL/6 mice were subjected to MI and treated with either vehicle or Tβ4 (1.6 mg·kg(-1)·day(-1) ip via osmotic minipump) for 7 days or 5 wk. Mice were assessed for 1) cardiac remodeling and function by echocardiography; 2) inflammatory cell infiltration, capillary density, myocyte apoptosis, and interstitial collagen fraction histopathologically; 3) gelatinolytic activity by in situ zymography; and 4) expression of ICAM-1 and p53 by immunoblot analysis. Tβ4 reduced cardiac rupture that was associated with a decrease in the numbers of infiltrating inflammatory cells and apoptotic myocytes, a decrease in gelatinolytic activity and ICAM-1 and p53 expression, and an increase in the numbers of CD31-positive cells. Five-week treatment with Tβ4 ameliorated left ventricular dilation, improved cardiac function, markedly reduced interstitial collagen fraction, and increased capillary density. In a murine model of acute MI, Tβ4 not only decreased mortality rate as a result of cardiac rupture but also significantly improved cardiac function after MI. Thus, the use of Tβ4 could be explored as an alternative therapy in preventing cardiac rupture and restoring cardiac function in patients with MI., (Copyright © 2014 the American Physiological Society.)

Context: Metformin is considered first-line treatment for type 2 diabetes mellitus. However, little is known about its effects in African American individuals., Objective: The objective of the study was to assess whether metformin's effect on glycemic control differs by race-ethnicity Design: Electronic health records were used to identify adults who had a diagnosis of diabetes, two or more fills of metformin, and two or more glycated hemoglobin (HbA1c) measurements. Pharmacy claims were used to estimate metformin exposure based on fill frequency and dose dispensed. Regression analyses modeled the relationship between metformin exposure and HbA1c levels. Analyses were stratified by race-ethnicity and baseline HbA1c values., Setting: The study was conducted at a large health system in southeast Michigan., Main Outcome Measure: Differences in HbA1c levels while on metformin were measured., Results: We identified 19 672 patients with diabetes taking metformin; 7429 were African American and 8783 were European American. Baseline HbA1c values in these two groups were 7.81% (61.8 mmol/mol) and 7.38% (57.1 mmol/mol), respectively. Compared with no use, metformin was associated with a 0.62% (6.8 mmol/mol) reduction in HbA1c; however, there was a significant difference by race-ethnicity (P < .001). Among African American individuals, metformin use was associated with a 0.90% (9.8 mmol/mol) reduction in HbA1c levels, whereas among European Americans, metformin was associated with a 0.42% (4.6 mmol/mol) reduction. Irrespective of baseline HbA1c, metformin use was associated with lower HbA1c levels in African American individuals., Conclusions: African American individuals appear to have a better glycemic response to metformin when compared with European Americans. Further studies are needed to determine whether this translates to commensurate reductions in diabetes complications.

The afferent arteriole (Af-Art) controls glomerular capillary pressure, an important determinant of glomerular injury. Af-Art myogenic response is mediated by ATP, and ATP signaling is in turn mediated by 20-HETE. Dahl salt-sensitive rats (Dahl SS) have decreased renal 20-HETE production. We hypothesized that Dahl SS have an impaired myogenic response and constrictor response to ATP, due to decreased 20-HETE. Af-Arts from Dahl SS or Dahl salt-resistant rats (Dahl SR) were microdissected and perfused. When myogenic response was induced by increasing Af-Art perfusion pressure from 60 to 140 mmHg, luminal Af-Art diameter decreased in Dahl SR but not in Dahl SS (-3.1 ± 0.8 vs. 0.5 ± 0.8 μm, P < 0.01). The 20-HETE antagonist 20-HEDE (10(-6) M) blocked the myogenic response in Dahl SR but had no effect in Dahl SS. Addition of a subconstrictor concentration of 20-HETE (but not a subconstrictor concentration of norepinephrine) restored the myogenic response in Dahl SS. We then perfused Af-Arts at 60 mmHg and tested the effects of the ATP analog α,β-methylene-ATP (10(-6) M). Maximum ATP-induced constriction was attenuated in Dahl SS compared with Dahl SR (1.5 ± 0.5 vs. 7.4 ± 0.8 μm, P < 0.001). 20-HEDE attenuated ATP-induced Af-Art constriction in Dahl SR but not in Dahl SS, and consequently, ATP-induced constriction was no longer different between strains. In conclusion, Dahl SS have an impaired myogenic response and ATP-induced Af-Art constriction due to a decrease in Af-Art 20-HETE. The impaired myogenic responses may contribute to the nephrosclerosis that develops in Dahl SS., (Copyright © 2014 the American Physiological Society.)

Increasing Na delivery to epithelial Na channels (ENaC) in the connecting tubule (CNT) dilates the afferent arteriole (Af-Art), a process we call connecting tubule glomerular feedback (CTGF). We hypothesize that aldosterone sensitizes CTGF via a nongenomic mechanism that stimulates CNT ENaC via the aldosterone receptor GPR30. Rabbit Af-Arts and their adherent CNTs were microdissected and simultaneously perfused. Two consecutive CTGF curves were elicited by increasing luminal NaCl in the CNT. During the control period, the concentration of NaCl that elicited a half-maximal response (EC50) was 37.0 ± 2.0 mmol/l; addition of aldosterone 10(-8) mol/l to the CNT lumen caused a left-shift (decrease) in EC50 to 19.3 ± 1.3 mmol/l (P = 0.001 vs. control; n = 6). Neither the transcription inhibitor actinomycin D nor the translation inhibitor cycloheximide prevented the effect of aldosterone (control EC50 = 34.7 ± 1.9 mmol/l; aldosterone+actinomycin D EC50 = 22.6 ± 1.6 mmol/l; P < 0.001 and control EC50 = 32.4 ± 4.3 mmol/l; aldosterone+cycloheximide EC50 = 17.4 ± 3.3 mmol/l; P < 0.001). The aldosterone antagonist eplerenone prevented the sensitization of CTGF by aldosterone (control EC50 = 33.2 ± 1.7 mmol/l; aldosterone+eplerenone EC50 = 33.5 ± 1.3 mmol/l; n = 7). The GPR30 receptor blocker G-36 blocked the sensitization of CTGF by aldosterone (aldosterone EC50 = 16.5 ± 1.9 mmol/l; aldosterone+G-36 EC50 = 29.0 ± 2.1 mmol/l; n = 7; P < 0.001). Finally, we found that the sensitization of CTGF by aldosterone was mediated, at least in part, by the sodium/hydrogen exchanger (NHE). We conclude that aldosterone in the CNT lumen sensitizes CTGF via a nongenomic effect involving GPR30 receptors and NHE. Sensitized CTGF induced by aldosterone may contribute to renal damage by increasing Af-Art dilation and glomerular capillary pressure (glomerular barotrauma)., (Copyright © 2014 the American Physiological Society.)

Background and Objectives: Infection is the second leading cause of death in hemodialysis patients. Catheter-related bloodstream infection and infection-related mortality have not improved in this population over the past two decades. This study evaluated the impact of a prophylactic antibiotic lock solution on the incidence of catheter-related bloodstream infection and mortality., Design, Setting, Participants, & Measurements: This prospective, multicenter, observational cohort study compared the effectiveness of two catheter locking solutions (gentamicin/citrate versus heparin) in 555 hemodialysis patients dialyzing with a tunneled cuffed catheter between 2008 and 2011. The groups were not mutually exclusive. Rates of catheter-related bloodstream infection and mortality hazards were compared between groups., Results: The study population (n=555 and 1350 catheters) had a median age of 62 years (interquartile range=41-83 years), with 50% men and 71% black. There were 427 patients evaluable in the heparin period (84,326 days) and 322 patients evaluable in the antibiotic lock period (71,192 days). Catheter-related bloodstream infection in the antibiotic lock period (0.45/1000 catheter days) was 73% lower than the heparin period (1.68/1000 catheter days; P=0.001). Antibiotic lock use was associated with a decreased risk of catheter-related bloodstream infection compared with heparin (risk ratio, 0.23; 95% confidence interval, 0.13 to 0.38 after multivariate adjustment). Cox proportional hazards modeling found that antibiotic lock was associated with a reduction in mortality (hazard ratio, 0.36; 95% confidence interval, 0.22 to 0.58 in unadjusted analyses; hazard ratio, 0.32; 95% confidence interval, 0.14 to 0.75 after multivariate adjustment). The rate of gentamicin-resistant organisms decreased (0.40/1000 person-years to 0.22/1000 person-years) in the antibiotic lock period (P=0.01)., Conclusions: The results of this study show that the use of a prophylactic, gentamicin/citrate lock was associated with a substantial reduction in catheter-related bloodstream infection and is the first to report a survival advantage of antibiotic lock in a population at high risk of infection-related morbidity and mortality., (Copyright © 2014 by the American Society of Nephrology.)

Purpose: To describe a transabdominal, transuterine Seldinger-based percutaneous approach to create a shunt for treatment of fetal thoracic abnormalities., Materials and Methods: Five fetuses presented with nonimmune fetal hydrops secondary to fetal thoracic abnormalities causing severe mass effect. Under direct ultrasound guidance, an 18-gauge needle was used to access the malformation. Through a peel-away sheath, a customized pediatric transplant 4.5-F double J ureteral stent was advanced; the leading loop was placed in the fetal thorax, and the trailing end was left outside the fetal thorax within the amniotic cavity., Results: Seven thoracoamniotic shunts were successfully placed in five fetuses; one shunt was immediately replaced because of displacement during the procedure, and another shunt was not functioning at follow-up requiring insertion of a second shunt. All fetuses had successful decompression of the thoracic malformation, allowing lung reexpansion and resolution of hydrops. Three of five mothers had meaningful (> 7 d) prolongation of their pregnancies. All pregnancies were maintained to > 30 weeks (range, 30 weeks 1 d-37 weeks 2 d). There were no maternal complications., Conclusions: A Seldinger-based percutaneous approach to draining fetal thoracic abnormalities is feasible and can allow for prolongation of pregnancy and antenatal lung development and ultimately result in fetal survival., (Copyright © 2014 SIR. Published by Elsevier Inc. All rights reserved.)

Background: Rising prescription opioid use and abuse have prompted widespread concern. However, to date there have been few rigorous investigations into the policies and events which may have contributed to these trends., Objective: This study investigates trends in opioid use and related adverse events among individuals with non-cancer pain before and after implementation of major national policies., Study Design: The study used a longitudinal prospective study design. The analysis was limited to adults (age = 18 years) without a recorded cancer diagnosis. Pharmacy claims were used to assess rates of prescription opioid use, the strength of opioids dispensed, the proportion using opioids chronically, and related adverse events. Time trend analysis was used to identify changes in these rates over time. The study was Institutional Review Board approved., Setting: Study patients were members of a large, health maintenance organization in southeast Michigan, with longitudinal records of prescription opioid use., Results: The analysis comprised 523,623 individuals and 1,066,700 opioid pharmacy fills from January 1, 1997, to December 31, 2011. Contemporaneous with the implementation of health organization accreditation criteria requiring assessment and treatment of pain in all patients beginning January 2001, we observed a consistent and unabated increase in the rate of opioid fills and the proportion of chronic use. A parallel increase in the annual rate of adverse events was also observed. Similarly, we observed a continuous rise in the average strength of opioid fills following January 2001 with the exception of a single drop in December 2010, which was attributable to the withdrawal of propoxyphene from the U.S. market., Limitations: This was an observational study and not a trial. Other long-term opioid-related benefits or harms, including functional status, quality of life, and substance use disorder, were not assessed., Conclusions: This study provides temporal evidence for a rise in prescription opioid use after implementation of health organization accreditation criteria requiring standardized management of all individuals with pain.

Background: Nonadherence to inhaled corticosteroids (ICSs) for asthma maintenance therapy is common and is associated with poor asthma outcomes. Simplifying dosing regimens for some chronic disease conditions has resulted in better adherence; however, little is known regarding the effect of ICS dosing on adherence for the treatment of asthma., Objective: To determine whether once daily dosing is associated with higher adherence to ICS therapy when compared with 2 or more times daily dosing among patients with asthma., Methods: Six years of pharmacy claims data were linked with prescription information to estimate ICS therapy adherence for patients with asthma 12 to 56 years of age who were members of a large health maintenance organization. Patient follow-up continued from the initial ICS fill until one of the following: the last ICS fill in the observation period, a switch of ICS dosing regimen, or the initiation of ICS and long-acting β-agonist combination therapy. Adherence was estimated by calculating a continuous multiple-interval measure of medication availability. Regression models were used to assess the relationship between adherence in patients treated with once daily vs 2 or more times daily ICS therapy., Results: Among the 1,302 patients who met the inclusion criteria, 17% were prescribed once daily therapy, and 83% were prescribed 2 or more times daily therapy. Models comparing ICS adherence among individuals following once daily and 2 or more times daily ICS regimens suggested that once daily dosing was associated with an approximately 20% increase in adherence. This significant difference persisted among subgroups defined by sex, race/ethnicity, age, and asthma severity., Conclusion: Once daily dosing was associated with higher adherence to ICS therapy; this included clinically relevant subgroups., (Copyright © 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objectives/hypothesis: To determine the added cost of care and analyze risk factors in patients who suffered vocal fold paralysis (VFP) after thyroid surgery., Study Design: Retrospective cohort study., Methods: Seventy-six patients who developed unilateral or bilateral VFP after thyroidectomy from 2005 through 2009, and a control group of 238 patients who underwent the same surgery without developing VFP, were compared on hospital charges, hospital and intensive care unit (ICU) length of stay (LOS), unplanned intubation, tracheotomies, respiratory failure, readmission, death, pathology, body mass index (BMI), gland weight, swallowing studies, and need for indwelling feeding tube. Differences between outcomes for unilateral VFP patients versus bilateral VFP patients were analyzed. Rate of recovery of VFP and need for further surgery after thyroidectomy were described., Results: Patients who developed VFP after thyroidectomy had significantly greater rates of all the parameters listed above. BMI, gland weight, and pathology (malignant vs. benign) were not significantly different between the two groups. VFP group underwent additional surgeries after thyroidectomy related to the VFP. Thirty-three% of unilateral VFP patients with long-term follow-up recovered fully. Patients with bilateral VFP with long-term follow-up, had recovery of one vocal fold in 50% and both in 23% of cases., Conclusions: Patients with unilateral or bilateral VFP after thyroidectomy experience significantly more morbidity and incurred significantly more health care charges after surgery than similar patients who do not have VFP after thyroidectomy. The likelihood of VFP was not related to malignancy, BMI, or thyroid gland weight in this series., (Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.)

Unlabelled: Previous studies have suggested that exposure to cats and dogs during early childhood reduces the risk of allergic disease, possibly by increasing home endotoxin exposure. This study asked the question of whether cats and dogs are the dominant influence on dust endotoxin concentrations in homes after considering other variables reportedly associated with endotoxin. The presence of cats or dogs in homes, household and home characteristics, and dust endotoxin concentrations from 5 locations were assessed in 966 urban and suburban homes. Whether considered together as pets or as cats and dogs separately, the presence of cats and dogs significantly contributed to living room and bedroom floor endotoxin concentrations, but not to bed endotoxin concentrations. However, the two variables consistently related to endotoxin in all home sites were the home occupant density (occupants/room) and cleanliness of the home. Our data suggest that reducing occupant density and improving home cleanliness would reduce home endotoxin concentrations more than removing pet cats or dogs from the home., Practical Implications: Many studies have shown that early childhood exposure to indoor cats or dogs is associated with a reduced risk of later allergic disease and asthma. An important question is whether alteration in allergic risk associated with cat and dog exposure results from increased endotoxin exposure or from some other associated exposure. Our findings show that cats and dogs are not the dominant source of endotoxin in homes; rather, the density of human occupation and poor cleaning contribute more consistently to higher home endotoxin concentrations especially in the beds., (© 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.)

Background: Although depression has been linked with asthma, its relationship with asthma exacerbations, including emergency department (ED) visits and oral steroid (OS) use, has not been well documented. The aim is to investigate whether depression increases exacerbations among patients with asthma., Method: The study included 568 participants with asthma who were between 18 and 56 years old, were taking an inhaled corticosteroid, and participated in baseline and follow-up surveys. Surveys and medical records from a large, health system were collected as part of the Adherence Feedback for Improving Respiratory Medication Use trial. Number of ED visits and OS prescription fills for asthma were calculated for 12-month periods before and after the follow-up survey. Depression was measured using a standardized two-item instrument. Negative binomial regression and modified proportional hazards models were used., Results: Among patients with asthma, those who had depression (n = 187; 32.9%) were at increased risk for an asthma-related ED visit (adjusted relative risk = 1.96, 95% confidence interval [CI] = 1.02-3.75), but not an OS fill (adjusted relative risk = 0.98; 95% CI = 0.72-1.32). Participants with depression and asthma who received psychiatric treatment via antidepressant medication (n = 126; 22.2%) or psychotherapy (n = 39; 6.9%) were more likely to have an ED visit (medication hazard ratio = 2.09, 95% CI = 1.35-3.25; psychotherapy hazard ratio = 2.07, 95% CI = 1.38-3.22)., Conclusions: This study suggests a temporal relationship between depression and asthma-related ED visits. Research and practice must consider the importance of these comorbid conditions. Trial Registration ClinicalTrials.gov identifier: NCT00459368.

Background: There are large and persisting disparities in severe asthma exacerbations by race-ethnicity, and African American subjects are among those at greatest risk. It is unclear whether this increased risk solely represents differences in environmental exposures and health care or whether there is a predisposing genetic component., Objective: We sought to assess the relationship between genetic ancestry and severe exacerbations among African American subjects with asthma., Methods: Participants were part of the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). These subjects were 12 to 56 years of age, received care from a single large health system, and had a physician's diagnosis of asthma. Genetic ancestry was estimated by using a set of validated ancestry informative markers. Severe exacerbations (ie, asthma-related emergency department visits, hospitalizations, and burst oral steroid use) were prospectively identified from health care claims., Results: We assessed genetic ancestry in 392 African American subjects with asthma. The average proportion of African ancestry was 76.1%. A significant interaction was identified between ancestry and sex on severe exacerbations, such that the risk was significantly higher with increasing African ancestry among male but not female subjects. The association among male subjects persisted after adjusting for potential confounders (relative rate, 4.30 for every 20% increase in African ancestry; P = .029)., Conclusions: African ancestry was significantly and positively associated with severe exacerbations among male African American subjects. These findings suggest that a portion of the risk of asthma exacerbations in this high-risk group is attributable to a genetic risk factor that partitions with ancestry., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Myocarditis is commonly associated with cardiotropic infections and has been linked to development of autoimmunity. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring tetrapeptide that prevents inflammation and fibrosis in hypertension and other cardiovascular diseases; however, its effect on autoimmune-mediated cardiac diseases remains unknown. We studied the effects of Ac-SDKP in experimental autoimmune myocarditis (EAM), a model of T cell-mediated autoimmune disease. This study was conducted to test the hypothesis that Ac-SDKP prevents autoimmune myocardial injury by modulating the immune responses. Lewis rats were immunized with porcine cardiac myosin and treated with Ac-SDKP or vehicle. In EAM, Ac-SDKP prevented both systolic and diastolic cardiac dysfunction, remodeling as shown by hypertrophy and fibrosis, and cell-mediated immune responses without affecting myosin-specific autoantibodies or antigen-specific T cell responses. In addition, Ac-SDKP reduced cardiac infiltration by macrophages, dendritic cells, and T cells, pro-inflammatory cytokines [interleukin (IL)-1α, tumor necrosis factor-α, IL-2, IL-17] and chemokines (cytokine-induced neutrophil chemoattractant-1, interferon-γ-induced protein 10), cell adhesion molecules (intercellular adhesion molecule-1, L-selectin), and matrix metalloproteinases (MMP). Ac-SDKP prevents autoimmune cardiac dysfunction and remodeling without reducing the production of autoantibodies or T cell responses to cardiac myosin. The protective effects of Ac-SDKP in autoimmune myocardial injury are most likely mediated by inhibition of 1) innate and adaptive immune cell infiltration and 2) expression of proinflammatory mediators such as cytokines, chemokines, adhesion molecules, and MMPs.

Parathyroid hormone (PTH) is positively coupled to the generation of cAMP via its actions on the PTH1R and PTH2R receptors. Renin secretion from juxtaglomerular (JG) cells is stimulated by elevated intracellular cAMP, and every stimulus that increases renin secretion is thought to do so via increasing cAMP. Thus we hypothesized that PTH increases renin release from primary cultures of mouse JG cells by elevating intracellular cAMP via the PTH1R receptor. We found PTH1R, but not PTH2R, mRNA expressed in JG cells. While PTH increased JG cell cAMP content from (log(10) means ± SE) 3.27 ± 0.06 to 3.92 ± 0.12 fmol/mg protein (P < 0.001), it did not affect renin release. The PTH1R-specific agonist, parathyroid hormone-related protein (PTHrP), also increased JG cell cAMP from 3.13 ± 0.09 to 3.93 ± 0.09 fmol/mg protein (P < 0.001), again without effect on renin release. PTH2R receptor agonists had no effect on cAMP or renin release. PTHrP increased cAMP in the presence of both low and high extracellular calcium from 3.31 ± 0.17 to 3.83 ± 0.20 fmol/mg protein (P < 0.01) and from 3.29 ± 0.18 to 3.63 ± 0.22 fmol/mg protein (P < 0.05), respectively, with no effect on renin release. PTHrP increased JG cell cAMP in the presence of adenylyl cyclase-V inhibition from 2.85 ± 0.17 to 3.44 ± 0.14 fmol/mg protein (P < 0.001) without affecting renin release. As a positive control, forskolin increased JG cell cAMP from 3.39 ± 0.13 to 4.48 ± 0.07 fmol/mg protein (P < 0.01) and renin release from 2.96 ± 0.10 to 3.29 ± 0.08 ng ANG I·mg prot(-1)·h(-1) (P < 0.01). Thus PTH increases JG cell cAMP via non-calcium-sensitive adenylate cyclases without affecting renin release. These data suggest compartmentalization of cAMP signaling in JG cells.

N-Acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) inhibits endothelin-1 (ET-1)-induced activation of p44/42 mitogen-activated protein kinase (p44/42 MAPK) and collagen production in cultured rat cardiac fibroblasts (RCFs). However, we do not know whether its inhibitory effect on p44/42 MAPK is due to the altered activity of protein tyrosine phosphatases (PTPs), which in turn downregulate the p44/42 MAPK signaling pathway. The activity of Src homology 2-containing protein tyrosine phosphatase-2 (SHP-2) is downregulated by ET-1 in RCFs; thus, we hypothesized that Ac-SDKP inhibits ET-1-stimulated collagen production in part by preserving SHP-2 activity and thereby inhibiting p44/42 MAPK phosphorylation. When we stimulated RCFs with ET-1 in the presence or absence of Ac-SDKP, we found that (a) PTP activity was reduced by ET-1 and (b) this effect was counteracted by Ac-SDKP in a dose-dependent fashion. Next, we extracted SHP-2 from RCF lysates by immunoprecipitation and determined that (a) ET-1 inhibited SHP-2 by 40 % and (b) this effect was prevented by Ac-SDKP. However, Ac-SDKP failed to inhibit ET-1-induced p44/42 MAPK phosphorylation in RCFs treated with SHP-2 short hairpin RNA (shRNA); in contrast, in cells transfected with control shRNA, Ac-SDKP's inhibitory effect on ET-1-induced p44/42 MAPK activation remained intact. Moreover, the inhibitory effect of Ac-SDKP on ET-1-stimulated collagen production was blunted in cells treated with the SHP-1/2 inhibitor NSC-87877. Thus, we concluded that the inhibitory effect of Ac-SDKP on ET-1-stimulated collagen production by RCFs is mediated in part by preserving SHP-2 activity and thereby preventing p44/42 MAPK activation. Ac-SDKP or its analogs could represent a new therapeutic tool to treat fibrotic diseases in the cardiovascular system.