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δ-Opioid receptor (DOR) signaling and reactive oxygen species (ROS) mediate intermittent hypoxia induced protection of canine myocardium.

Recent Research Articles from UNTHSC - Thu, 02/18/2016 - 07:30
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δ-Opioid receptor (DOR) signaling and reactive oxygen species (ROS) mediate intermittent hypoxia induced protection of canine myocardium.

Basic Res Cardiol. 2016 Mar;111(2):17

Authors: Estrada JA, Williams AG, Sun J, Gonzalez L, Downey HF, Caffrey JL, Mallet RT

Abstract
Intermittent, normobaric hypoxia confers robust cardioprotection against ischemia-induced myocardial infarction and lethal ventricular arrhythmias. δ-Opioid receptor (DOR) signaling and reactive oxygen species (ROS) have been implicated in cardioprotective phenomena, but their roles in intermittent hypoxia are unknown. This study examined the contributions of DOR and ROS in mediating intermittent hypoxia-induced cardioprotection. Mongrel dogs completed a 20 day program consisting of 5-8 daily, 5-10 min cycles of moderate, normobaric hypoxia (FIO2 0.095-0.10), with intervening 4 min room air exposures. Subsets of dogs received the DOR antagonist naltrindole (200 μg/kg, sc) or antioxidant N-acetylcysteine (250 mg/kg, po) before each hypoxia session. Twenty-four hours after the last session, the left anterior descending coronary artery was occluded for 60 min and then reperfused for 5 h. Arrhythmias detected by electrocardiography were scored according to the Lambeth II conventions. Left ventricles were sectioned and stained with 2,3,5-triphenyl-tetrazolium-chloride, and infarct sizes were expressed as percentages of the area at risk (IS/AAR). Intermittent hypoxia sharply decreased IS/AAR from 41 ± 5 % (n = 12) to 1.8 ± 0.9 % (n = 9; P < 0.001) and arrhythmia score from 4.1 ± 0.3 to 0.7 ± 0.2 (P < 0.001) vs. non-hypoxic controls. Naltrindole (n = 6) abrogated the cardioprotection with IS/AAR 35 ± 5 % and arrhythmia score 3.7 ± 0.7 (P < 0.001 vs. untreated intermittent hypoxia). N-acetylcysteine (n = 6) interfered to a similar degree, with IS/AAR 42 ± 3 % and arrhythmia score 4.7 ± 0.3 (P < 0.001 vs. untreated intermittent hypoxia). Without the intervening reoxygenations, hypoxia (n = 4) was not cardioprotective (IS/AAR 50 ± 8 %; arrhythmia score 4.5 ± 0.5; P < 0.001 vs. intermittent hypoxia). Thus DOR, ROS and cyclic reoxygenation were obligatory participants in the gradually evolving cardioprotection produced by intermittent hypoxia.

PMID: 26879900 [PubMed - in process]

Mitochondrial Dihydrolipoamide Dehydrogenase is Upregulated in Response to Intermittent Hypoxic Preconditioning.

Recent Research Articles from UNTHSC - Thu, 02/18/2016 - 07:30
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Mitochondrial Dihydrolipoamide Dehydrogenase is Upregulated in Response to Intermittent Hypoxic Preconditioning.

Int J Med Sci. 2015;12(5):432-40

Authors: Li R, Luo X, Wu J, Thangthaeng N, Jung ME, Jing S, Li L, Ellis DZ, Liu L, Ding Z, Forster MJ, Yan LJ

Abstract
Intermittent hypoxia preconditioning (IHP) has been shown to protect neurons against ischemic stroke injury. Studying how proteins respond to IHP may identify targets that can help fight stroke. The objective of the present study was to investigate whether mitochondrial dihydrolipoamide dehydrogenase (DLDH) would respond to IHP and if so, whether such a response could be linked to neuroprotection in ischemic stroke injury. To do this, we subjected male rats to IHP for 20 days and measured the content and activity of DLDH as well as the three α-keto acid dehydrogenase complexes that contain DLDH. We also measured mitochondrial electron transport chain enzyme activities. Results show that DLDH content was indeed upregulated by IHP and this upregulation did not alter the activities of the three α-keto acid dehydrogenase complexes. Results also show that the activities of the five mitochondrial complexes (I-V) were not altered either by IHP. To investigate whether IHP-induced DLDH upregulation is linked to neuroprotection against ischemic stroke injury, we subjected both DLDH deficient mouse and DLDH transgenic mouse to stroke surgery followed by measurement of brain infarction volume. Results indicate that while mouse deficient in DLDH had exacerbated brain injury after stroke, mouse overexpressing human DLDH also showed increased brain injury after stroke. Therefore, the physiological significance of IHP-induced DLDH upregulation remains to be further investigated.

PMID: 26078703 [PubMed - indexed for MEDLINE]

Δ(9)-Tetrahydrocannabinol-like effects of novel synthetic cannabinoids in mice and rats.

Recent Research Articles from UNTHSC - Tue, 02/16/2016 - 07:30

Δ(9)-Tetrahydrocannabinol-like effects of novel synthetic cannabinoids in mice and rats.

Psychopharmacology (Berl). 2016 Feb 15;

Authors: Gatch MB, Forster MJ

Abstract
RATIONALE: Novel cannabinoid compounds continue to be marketed as "legal" marijuana substitutes, even though little is known about their molecular and behavioral effects.
OBJECTIVES: Six of these compounds (ADBICA, ADB-PINACA, THJ-2201, RCS-4, JWH-122, JWH-210) were tested for in vitro and in vivo cannabinoid-like effects to determine their abuse liability.
METHODS: Binding to and functional activity at CB1 cannabinoid receptors was tested. Locomotor activity in mice was tested to screen for behavioral activity and to identify behaviorally active dose ranges and times of peak effect. Discriminative stimulus effects of the six compounds were tested in rats trained to discriminate Δ(9)-tetrahydrocannabinol (Δ(9)-THC).
RESULTS: ADBICA, ADB-PINACA, THJ-2201, RCS-4, JWH-122, and JWH-210 showed high affinity binding at the CB1 receptor at nanomolar affinities (0.59 to 22.5 nM), and all acted as full agonists with nanomolar potencies (0.024 to 111 nM) when compared to the CB1 receptor full agonist CP 55940. All compounds depressed locomotor activity below 50 % of vehicle responding, with depressant effects lasting 1.5 to nearly 4 h. All compounds fully substituted (<80 % Δ(9)-THC-appropriate responding) for the discriminative stimulus effects of Δ(9)-THC. 3,4-Methylenedioxy-methamphetamine (MDMA) was tested as a negative control and did not substitute for Δ(9)-THC (11 % Δ(9)-THC-appropriate responding).
CONCLUSIONS: All six of the compounds acted at the CB1 receptor and produced behavioral effects common to abused cannabinoid compounds, which suggest that these compounds have substantial abuse liability common to controlled synthetic cannabinoid compounds.

PMID: 26875756 [PubMed - as supplied by publisher]

Exposure to Stimulatory CpG Oligonucleotides During Gestation induces Maternal Hypertension and Excess Vasoconstriction in Pregnant Rats.

Recent Research Articles from UNTHSC - Sun, 02/14/2016 - 07:29

Exposure to Stimulatory CpG Oligonucleotides During Gestation induces Maternal Hypertension and Excess Vasoconstriction in Pregnant Rats.

Am J Physiol Heart Circ Physiol. 2016 Feb 12;:ajpheart.00834.2015

Authors: Goulopoulou S, Wenceslau CF, McCarthy CG, Matsumoto T, Webb RC

Abstract
Bacterial infections increase risk for pregnancy complications, such as preeclampsia and pre-term birth. Unmethylated CpG DNA sequences are present in bacterial DNA and have immunostimulatory effects. Maternal exposure to CpG DNA induces fetal demise and craniofacial malformations; however, the effects of CpG DNA on maternal cardiovascular health have not been examined. We tested the hypothesis that exposure to synthetic CpG oligonucleotides (ODN) during gestation would increase blood pressure and cause vascular dysfunction in pregnant rats. Pregnant and non-pregnant female rats were treated with CpG ODN (ODN 2395) or saline (Veh) starting on gestational day 14 or corresponding day for the non-pregnant groups. Exposure to CpG ODN increased systolic blood pressure in pregnant (Veh: 121 ± 2 mmHg vs. ODN 2395: 134 ± 2 mmHg, p<0.05) but not in non-pregnant rats (Veh: 111 ± 2 mmHg vs. ODN 2395: 108 ± 5 mmHg, p>0.05). Mesenteric resistance arteries from pregnant CpG ODN-treated rats had increased contractile responses to U46619 [thromboxane A2(TxA2) mimetic] compared to arteries from vehicle-treated rats [Emax (%KCl), Veh: 87 ± 4 vs. ODN 2395: 104 ± 4, p<0.05)]. Nitric oxide synthase (NOS) inhibition increased contractile responses to U46619 and CpG ODN treatment abolished this effect in arteries from pregnant ODN 2395-treated rats. CpG ODN potentiated the involvement of cyclooxygenase (COX) to U46619-induced contractions. In conclusion, exposure to CpG ODN during gestation induces maternal hypertension, augments resistance artery contraction, increases the involvement of COX-dependent mechanisms and reduces the contribution of NOS-dependent mechanisms to TxA2-induced contractions in mesenteric resistance arteries.

PMID: 26873968 [PubMed - as supplied by publisher]

Assessment of direct gating and allosteric modulatory effects of meprobamate in recombinant GABAA receptors.

Recent Research Articles from UNTHSC - Sun, 02/14/2016 - 07:29

Assessment of direct gating and allosteric modulatory effects of meprobamate in recombinant GABAA receptors.

Eur J Pharmacol. 2016 Feb 9;

Authors: Kumar M, Dillon GH

Abstract
Meprobamate is a schedule II anxiolytic and the primary metabolite of the muscle relaxant carisoprodol. Meprobamate modulates GABAA (γ-aminobutyric acid type A) receptors, and has barbiturate-like activity. To gain insight into its actions, we have conducted a series of studies using recombinant GABAA receptors. In αxβzγ2 GABAA receptors (where x=1-6 and z=1-3), the ability to enhance GABA-mediated current was evident for all α subunit isoforms, with the largest effect observed in α5-expressing receptors. Direct gating was present with all α subunits, although attenuated in α3-expressing receptors. Allosteric and direct effects were comparable in α1β1γ2 and α1β2γ2 receptors, whereas allosteric effects were enhanced in α1β2 compared to α1β2γ2 receptors. In "extrasynaptic" (α1β3δ and α4β3δ) receptors, meprobamate enhanced EC20 and saturating GABA currents, and directly activated these receptors. The barbiturate antagonist bemegride attenuated direct effects of meprobamate. Whereas pentobarbital directly gated homomeric β3 receptors, meprobamate did not, and instead blocked the spontaneously open current present in these receptors. In wild type homomeric ρ1 receptors, pentobarbital and meprobamate were ineffective in direct gating; a mutation known to confer sensitivity to pentobarbital did not confer sensitivity to meprobamate. Our results provide insight into the actions of meprobamate and parent therapeutic agents such as carisoprodol. Whereas in general actions of meprobamate were comparable to those of carisoprodol, differential effects of meprobamate at some receptor subtypes suggest potential advantages of meprobamate may be exploited. A re-assessment of previously synthesized meprobamate-related carbamate molecules for myorelaxant and other therapeutic indications is warranted.

PMID: 26872987 [PubMed - as supplied by publisher]

Analogs of microgravity: head-down tilt and water immersion.

Recent Research Articles from UNTHSC - Sat, 02/13/2016 - 07:32

Analogs of microgravity: head-down tilt and water immersion.

J Appl Physiol (1985). 2016 Feb 11;:jap.00986.2015

Authors: Watenpaugh DE

Abstract
This article briefly reviews the fidelity of ground-based methods used to simulate human existence in weightlessness (spaceflight). These methods include horizontal bed rest (BR), head-down tilt bed rest (HDT), head-out water immersion (WI), and head-out dry immersion (DI; immersion with an impermeable elastic cloth barrier between subject and water). Among these, HDT has become by far the most commonly used method, especially for longer studies. DI is less common but well-accepted for long-duration studies. Very few studies exist that attempt to validate a specific simulation mode against actual microgravity. Many fundamental physical and thus physiological differences exist between microgravity and our methods to simulate it, and between the different methods. Also, although weightlessness is the salient feature of spaceflight, several ancillary factors of space travel complicate Earth-based simulation. In spite of these discrepancies and complications, the analogs duplicate many responses to 0 G reasonably well. As we learn more about responses to microgravity and spaceflight, investigators will continue to fine-tune simulation methods to optimize accuracy and applicability.

PMID: 26869710 [PubMed - as supplied by publisher]

Involvement of AMPA Receptor and Its Flip and Flop Isoforms in Retinal Ganglion Cell Death Following Oxygen/Glucose Deprivation.

Recent Research Articles from UNTHSC - Sat, 02/13/2016 - 07:32

Involvement of AMPA Receptor and Its Flip and Flop Isoforms in Retinal Ganglion Cell Death Following Oxygen/Glucose Deprivation.

Invest Ophthalmol Vis Sci. 2016 Feb 1;57(2):508-26

Authors: Park YH, Broyles HV, He S, McGrady NR, Li L, Yorio T

Abstract
PURPOSE: The α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptors (AMPAR) subunits can be posttranscriptionally modified by alternative splicing forming flip and flop isoforms. We determined if an ischemia-like insult to retinal ganglion cells (RGCs) increases AMPAR susceptibility to s-AMPA-mediated excitotoxicity through changes in posttranscriptional modified isoforms.
METHODS: Purified neonatal rat RGCs were subjected to either glucose deprivation (GD) or oxygen/glucose deprivation (OGD) conditions followed by treatment with either 100 μM s-AMPA or Kainic acid. A live-dead assay and caspase 3 assay was used to assess cell viability and apoptotic changes, respectively. We used JC-1 dye and dihydroethidium to measure mitochondria depolarization and reactive oxygen species (ROS), respectively. Calcium imaging with fura-2AM was used to determine intracellular calcium, while the fluorescently-labeled probe, Nanoprobe1, was used to detect calcium-permeable AMPARs. Quantitative PCR (qPCR) analysis was done to determine RNA editing sites AMPAR isoforms.
RESULTS: Glucose deprivation, as well as an OGD insult followed by AMPAR stimulation, produced a significant increase in RGC death. Retinal ganglion cell death was independent of caspase 3/7 activity, but was accompanied by increased mitochondrial depolarization and increased ROS production. This was associated with an elevated intracellular Ca2+ and calcium permeable-AMPARs. The mRNA expression of GLUA2 and GLUA3 flop isoform decreased significantly, while no appreciable changes were found in the corresponding flip isoforms. There were no changes in the Q/R editing of GLUA2, while R/G editing of GLUA2 flop declined under these conditions.
CONCLUSIONS: Following oxidative injury, RGCs become more susceptible to AMPAR-mediated excitotoxicity. RNA editing and changes in alternative spliced flip and flop isoforms of AMPAR subunits may contribute to increased RGC death.

PMID: 26868754 [PubMed - in process]

Two blinking mechanisms in highly confined AgInS2 and AgInS2/ZnS quantum dots evaluated by single particle spectroscopy.

Recent Research Articles from UNTHSC - Sat, 02/13/2016 - 07:32
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Two blinking mechanisms in highly confined AgInS2 and AgInS2/ZnS quantum dots evaluated by single particle spectroscopy.

Nanoscale. 2016 Feb 11;8(7):4151-9

Authors: Cichy B, Rich R, Olejniczak A, Gryczynski Z, Strek W

Abstract
Ternary AgInS2 quantum dots (QDs) have been found as promising cadmium-free, red-shifted, and tunable luminescent bio-probes with efficient Stokes and anti-Stokes excitations and luminescence lifetimes (ca. 100 ns) convenient for time resolved techniques like fluorescence life-time imaging. Although the spectral properties of the AgInS2 QDs are encouraging, the complex recombination kinetics in the QDs being still far from understood, limits their full utility. In this paper we report on a model describing the recombination pathways responsible for large deviations from the first-order decay law observed commonly in the ternary chalcogenides. The presented results were evaluated by means of individual AgInS2 QD spectroscopy aided by first principles calculations including the electronic structure and structural reconstruction of the QDs. Special attention was devoted to study the impact of the surface charge state on the excited state relaxation and effect of its passivation by Zn(2+) ion alloying. Two different blinking mechanisms related to defect-assisted charge imbalance in the QD responsible for fast non-radiative relaxation of the excited states as well as surface recharging of the QD were found as the major causes of deviations from the first-order decay law. Careful optimization of the AgInS2 QDs would help to fabricate new red-shifted and tunable fluorescent bio-probes characterized by low-toxicity, high quantum yield, long luminescence lifetime, and time stability, leading to many novel in vitro and in vivo applications based on fluorescence lifetime imaging (FLIM) and time-gated detection.

PMID: 26866468 [PubMed - in process]

Cholinergic Neurons in the Basal Forebrain Promote Wakefulness by Actions on Neighboring Non-Cholinergic Neurons: An Opto-Dialysis Study.

Recent Research Articles from UNTHSC - Sat, 02/13/2016 - 07:32
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Cholinergic Neurons in the Basal Forebrain Promote Wakefulness by Actions on Neighboring Non-Cholinergic Neurons: An Opto-Dialysis Study.

J Neurosci. 2016 Feb 10;36(6):2057-67

Authors: Zant JC, Kim T, Prokai L, Szarka S, McNally J, McKenna JT, Shukla C, Yang C, Kalinchuk AV, McCarley RW, Brown RE, Basheer R

Abstract
UNLABELLED: Understanding the control of sleep-wake states by the basal forebrain (BF) poses a challenge due to the intermingled presence of cholinergic, GABAergic, and glutamatergic neurons. All three BF neuronal subtypes project to the cortex and are implicated in cortical arousal and sleep-wake control. Thus, nonspecific stimulation or inhibition studies do not reveal the roles of these different neuronal types. Recent studies using optogenetics have shown that "selective" stimulation of BF cholinergic neurons increases transitions between NREM sleep and wakefulness, implicating cholinergic projections to cortex in wake promotion. However, the interpretation of these optogenetic experiments is complicated by interactions that may occur within the BF. For instance, a recent in vitro study from our group found that cholinergic neurons strongly excite neighboring GABAergic neurons, including the subset of cortically projecting neurons, which contain the calcium-binding protein, parvalbumin (PV) (Yang et al., 2014). Thus, the wake-promoting effect of "selective" optogenetic stimulation of BF cholinergic neurons could be mediated by local excitation of GABA/PV or other non-cholinergic BF neurons. In this study, using a newly designed opto-dialysis probe to couple selective optical stimulation with simultaneous in vivo microdialysis, we demonstrated that optical stimulation of cholinergic neurons locally increased acetylcholine levels and increased wakefulness in mice. Surprisingly, the enhanced wakefulness caused by cholinergic stimulation was abolished by simultaneous reverse microdialysis of cholinergic receptor antagonists into BF. Thus, our data suggest that the wake-promoting effect of cholinergic stimulation requires local release of acetylcholine in the basal forebrain and activation of cortically projecting, non-cholinergic neurons, including the GABAergic/PV neurons.
SIGNIFICANCE STATEMENT: Optogenetics is a revolutionary tool to assess the roles of particular groups of neurons in behavioral functions, such as control of sleep and wakefulness. However, the interpretation of optogenetic experiments requires knowledge of the effects of stimulation on local neurotransmitter levels and effects on neighboring neurons. Here, using a novel "opto-dialysis" probe to couple optogenetics and in vivo microdialysis, we report that optical stimulation of basal forebrain (BF) cholinergic neurons in mice increases local acetylcholine levels and wakefulness. Reverse microdialysis of cholinergic antagonists within BF prevents the wake-promoting effect. This important result challenges the prevailing dictum that BF cholinergic projections to cortex directly control wakefulness and illustrates the utility of "opto-dialysis" for dissecting the complex brain circuitry underlying behavior.

PMID: 26865627 [PubMed - in process]

Different Angiotensin-converting enzyme inhibitors and the associations with overall and cause-specific mortalities in patients with hypertension.

Recent Research Articles from UNTHSC - Sat, 02/13/2016 - 07:32
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Different Angiotensin-converting enzyme inhibitors and the associations with overall and cause-specific mortalities in patients with hypertension.

Am J Hypertens. 2015 Jun;28(6):823-30

Authors: Chang CH, Lin JW, Caffrey JL, Wu LC, Lai MS

Abstract
BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors have been widely used in the treatment of hypertension, but the comparative effectiveness in reducing mortality among different drugs is seldom reported.
METHODS: We identified hypertensive patients who started captopril, enalapril, lisinopril, fosinopril, perindopril, ramipril, or imidapril therapy from Taiwan's National Health Insurance database between 1 January 2004 and 31 December 2009. Overall and cause-specific mortalities were ascertained through a linkage to Taiwan's National Death Registry. Patients were followed from the initiation of ACE inhibitors to death, disenrollment, or study termination (31 December 2010). A Cox proportional hazard regression model was used to calculate the hazard ratio (HR) and 95% confidence interval (CI), using ramipril as the reference group.
RESULTS: A total of 989,489 hypertensive patients were included, with a mean follow-up ranging from 3.5 years for imidapril to 4.5 years for enalapril. Captopril initiators had the highest overall mortality rate (117.8 per 1,000,000 person-days) as compared to other ACE inhibitors (54.3-79.4 per 1,000,000 person-days). Patients who started captopril therapy had a significantly increased risk of overall mortality (HR: 1.28, 95% CI: 1.24-1.31) when compared with ramipril. Enalapril (HR: 1.08, 95% CI: 1.05-1.11) and fosinopril (HR: 1.08, 95% CI: 1.05-1.12) were also associated with a modestly increased risk. No difference in mortality was found for lisinopril, perindopril, and imidapril, as compared with ramipril.
CONCLUSIONS: There are differences in the mortality risk associated with different ACE inhibitors. However, potential residual confounding effects might still exist.

PMID: 25498540 [PubMed - indexed for MEDLINE]

Teacher and Friend Social Support: Association with Body Weight in African-American Adolescent Females.

Recent Research Articles from UNTHSC - Thu, 02/11/2016 - 07:29

Teacher and Friend Social Support: Association with Body Weight in African-American Adolescent Females.

J Racial Ethn Health Disparities. 2015 Sep;2(3):358-364

Authors: Stanford J, Khubchandani J, Webb FJ, Lee J, Doldren M, Rathore M

Abstract
The purpose of this study was to examine the direct and indirect ecological influences of teacher and friend social support on body weight and diet behaviors in African-American adolescent females. Using a quantitative, cross-sectional research design, a convenience sample of 182 urban African-American adolescent females (12-17 years old) completed a 39-item questionnaire. The questionnaire assessed perceived teacher social support, friend social support, nutrition self-efficacy, and diet behaviors (with internal reliability values of scale items: alpha = 0.74, 0.81, 0.77, and 0.69 respectively). Anthropometric assessments were conducted to measure height and weight to compute BMI. Majority of the participants were in middle or early high school (65 %) and were overweight or obese (57.7 %). Both teacher social support and friend social support demonstrated a positive, indirect influence on child weight status through nutrition self-efficacy and diet behaviors following two different and specific paths of influence. Diet behaviors, in turn, demonstrated a positive, direct effect on child weight status. In the structural model, teacher social support had the greatest effect on diet behaviors, demonstrating a direct, positive influence on diet behaviors (B = 0.421, p < 0.05), but its direct effect on nutrition self-efficacy was not significant. Friend social support demonstrated a positive, direct effect on nutrition self-efficacy (B = 0.227, p < 0.05), but its direct effect on diet behaviors was not statistically significant. The study's findings call for actively addressing the childhood obesity epidemic in the school environment by implementing health behavior change strategies at various social and ecological environmental levels.

PMID: 26863465 [PubMed - as supplied by publisher]

Intensive Care Unit Admission With Community-Acquired Pneumonia.

Recent Research Articles from UNTHSC - Tue, 02/09/2016 - 07:29
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Intensive Care Unit Admission With Community-Acquired Pneumonia.

Am J Med Sci. 2015 Nov;350(5):380-6

Authors: Vohra AS, Tak HJ, Shah MB, Meltzer DO, Ruhnke GW

Abstract
BACKGROUND: There has been a dramatic increase in the use of intensive care units (ICUs) over the past 25 years. Greater use of validated measures of illness severity may better inform ICU admission decisions in patients with community-acquired pneumonia. This article examined predictors of ICU admission and hospitalization costs, including the pneumonia severity index (PSI) and CURB-65 (confusion, uremia, respiratory rate, blood pressure, age ≥65 years) scores.
METHODS: The study identified 422 patients hospitalized for community-acquired pneumonia, ascertaining patient characteristics by chart review and extraction of administrative data. Multivariate logistic regression was performed to quantify the association of the PSI, CURB-65 and comorbidities with ICU admission. The predictors of cost were estimated using a generalized linear model.
RESULTS: Compared to 194 general medicine patients, certain clinical and radiographic findings were more common among 228 ICU patients. Compared to PSI reference group I/II/III, ICU admission was strongly associated with risk class IV (odds ratio [OR], 3.06; 95% confidence interval [CI], 1.63-5.72) and V (OR, 4.84; CI, 2.44-9.62), and also CURB-65 ≥3 (OR, 2.90; CI, 1.51-5.56). The relative increase in mortality among PSI risk class V (compared to IV) patients was 2.68 times higher in general medicine, compared with the ICU. Among ICU admissions, risk class V was associated with an additional cost of $14,548 (95% CI, $4,232 to $24,864).
CONCLUSIONS: Illness severity and chronic pulmonary disease are strong predictors of ICU admission. More extensive use of the PSI may optimize site-of-care decisions, thereby minimizing mortality and unnecessary resource utilization.

PMID: 26445305 [PubMed - indexed for MEDLINE]

Randomized trial of a dry-powder, fibrin sealant in vascular procedures.

Recent Research Articles from UNTHSC - Tue, 02/09/2016 - 07:29
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Randomized trial of a dry-powder, fibrin sealant in vascular procedures.

J Vasc Surg. 2015 Nov;62(5):1288-95

Authors: Gupta N, Chetter I, Hayes P, O-Yurvati AH, Moneta GL, Shenoy S, Pribble JP, Zuckerman LA

Abstract
OBJECTIVE: Topical hemostats are important adjuncts for stopping surgical bleeding. The safety and efficacy of Fibrocaps, a dry-powder, fibrin sealant containing human plasma-derived thrombin and fibrinogen, was evaluated in patients undergoing vascular surgical procedures.
METHODS: In this single-blind trial (clinicaltrials.gov: NCT01527357), adult patients were randomized 2:1 to Fibrocaps plus gelatin sponge (Fibrocaps) vs gelatin sponge alone. Results are presented for the patient subset undergoing vascular procedures with suture hole bleeding. The primary efficacy endpoint compared time to hemostasis (TTH) over 5 minutes. Safety follow-up continued to day 29.
RESULTS: A total of 175 patients were randomized and treated (Fibrocaps, 117; gelatin sponge, 58). Patients were predominately male (69%) and underwent arterial bypass (81%), arteriovenous graft formation (9%), or carotid endarterectomy (9%). Fibrocaps significantly reduced TTH compared with gelatin sponge (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.5-3.1; median TTH, 2 minutes; 95% CI, 1.5-2.5 vs 4 minutes; 95% CI, 3.0-5.0; P < .002). Significant reductions were also observed in patients receiving concomitant antiplatelet agents alone (HR, 2.8; 95% CI, 1.0-7.4; P = .03; n = 33), anticoagulants alone (HR, 2.0; 95% CI, 1.0-4.0; P = .04; n = 43), or both antiplatelet agents and anticoagulants (Fibrocaps vs gelatin sponge, HR, 2.3; 95% CI, 1.2-4.3; P = .008; n = 65). Incidences of common adverse events (procedural pain, nausea, constipation) were generally comparable between treatment arms. Anti-thrombin antibodies developed in 2% of Fibrocaps-treated patients and no-gelatin-sponge patients.
CONCLUSIONS: Fibrocaps, a ready-to-use, dry-powder fibrin sealant, was well-tolerated and reduced TTH in patients undergoing vascular procedures, including those receiving antiplatelet agents and/or anticoagulants, demonstrating its safety and usefulness as an adjunct to hemostasis.

PMID: 26254451 [PubMed - indexed for MEDLINE]

An impaired neuroimmune pathway promotes the development of hypertension in systemic lupus erythematosus.

Recent Research Articles from UNTHSC - Tue, 02/09/2016 - 07:29
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An impaired neuroimmune pathway promotes the development of hypertension in systemic lupus erythematosus.

Am J Physiol Regul Integr Comp Physiol. 2015 Nov 1;309(9):R1074-7

Authors: Mathis KW

Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disorder that affects nearly 2 million people in the United States. The majority of SLE cases occur in women at an age in which the prevalence of hypertension and cardiovascular disease is typically low. However, women with SLE have a high prevalence of hypertension for reasons that remain unclear. Because immune cells and chronic inflammation have been implicated in the pathogenesis of both hypertension and SLE and because inflammation has been shown to be regulated by the autonomic nervous system, studies investigating neuroimmune mechanisms of hypertension could have direct and significant clinical implications. The purpose of this review is to introduce a recently described neuroimmune pathway and discuss its potential importance in the development of hypertension and renal injury during SLE.

PMID: 26084696 [PubMed - indexed for MEDLINE]

Elevation of intraocular pressure in rodents using viral vectors targeting the trabecular meshwork.

Recent Research Articles from UNTHSC - Tue, 02/09/2016 - 07:29
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Elevation of intraocular pressure in rodents using viral vectors targeting the trabecular meshwork.

Exp Eye Res. 2015 Dec;141:33-41

Authors: Pang IH, Millar JC, Clark AF

Abstract
Rodents are increasingly being used as glaucoma models to study ocular hypertension, optic neuropathy, and retinopathy. A number of different techniques are used to elevate intraocular pressure in rodent eyes by artificially obstructing the aqueous outflow pathway. Another successful technique to induce ocular hypertension is to transduce the trabecular meshwork of rodent eyes with viral vectors expressing glaucoma associated transgenes to provide more relevant models of glaucomatous damage to the trabecular meshwork. This technique has been used to validate newly discovered glaucoma pathogenesis pathways as well as to develop rodent models of primary open angle glaucoma. Ocular hypertension has successfully been induced by adenovirus 5 mediated delivery of mutant MYOC, bioactivated TGFβ2, SFRP1, DKK1, GREM1, and CD44. Advantages of this approach are: selective tropism for the trabecular meshwork, the ability to use numerous mouse strains, and the relatively rapid onset of IOP elevation. Disadvantages include mild-to-moderate ocular inflammation induced by the Ad5 vector and sometimes transient transgene expression. Current efforts are focused at discovering less immunogenic viral vectors that have tropism for the trabecular meshwork and drive sufficient transgene expression to induce ocular hypertension. This viral vector approach allows rapid proof of concept studies to study glaucomatous damage to the trabecular meshwork without the expensive and time-consuming generation of transgenic mouse lines.

PMID: 26025608 [PubMed - indexed for MEDLINE]

Non-continuous measurement of intraocular pressure in laboratory animals.

Recent Research Articles from UNTHSC - Tue, 02/09/2016 - 07:29
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Non-continuous measurement of intraocular pressure in laboratory animals.

Exp Eye Res. 2015 Dec;141:74-90

Authors: Millar JC, Pang IH

Abstract
Glaucoma is a leading cause of blindness, which is treatable but currently incurable. Numerous animal models therefore have both been and continue to be utilized in the study of numerous aspects of this condition. One important facet associated with the use of such models is the ability to accurately and reproducibly measure (by cannulation) or estimate (by tonometry) intraocular pressure (IOP). At this juncture there are several different approaches to IOP measurement in different experimental animal species, and the list continues to grow. We feel therefore that a review of this subject matter is timely and should prove useful to others who wish to perform similar measurements. The general principles underlying various types of tonometric and non-tonometric techniques for non-continuous determination of IOP are considered. There follows discussion of specific details as to how these techniques are applied to experimental animal species involved in the research of this disease. Specific comments regarding anesthesia, circadian rhythm, and animal handling are also included, especially in the case of rodents. Brief consideration is also given to possible future developments.

PMID: 25933714 [PubMed - indexed for MEDLINE]

Development and in vivo evaluation of child-friendly lopinavir/ritonavir pediatric granules utilizing novel in situ self-assembly nanoparticles.

Recent Research Articles from UNTHSC - Sun, 02/07/2016 - 07:29

Development and in vivo evaluation of child-friendly lopinavir/ritonavir pediatric granules utilizing novel in situ self-assembly nanoparticles.

J Control Release. 2016 Feb 2;

Authors: Pham K, Li D, Guo S, Penzak S, Dong X

Abstract
The aim of this study was to develop a nanotechnology to formulate a fixed-dose combination of poorly water-soluble drugs in a children-friendly, flexible solid dosage form. For diseases like HIV, pediatric patients are taking multiple drugs for effective treatments. Fixed-dose combinations could reduce pill burdens and costs as well as improving patient adherence. However, development of fixed-dose combinations of poorly water-soluble drugs for pediatric formulations is very challenging. We discovered a novel nanotechnology that produced in situ self-assembly nanoparticles (ISNPs) when the ISNP granules were introduced to water. In this study, antiretroviral drug granules, including lopinavir (LPV) ISNP granules and a fixed-dose combination of LPV/ritonavir (RTV) ISNP granules, were prepared using the ISNP nanotechnology, which spontaneously produced drug-loaded ISNPs in contact with water. Drug-loaded ISNPs had particle size less than 158nm with mono-dispersed distribution, over 95% entrapment efficiency for both LPV and RTV and stability over 8h in simulated physiological conditions. Drug-loaded ISNP granules with about 16% of LPV and 4% of RTV were palatable and stable at room temperature over 6months. Furthermore, LPV/RTV ISNP granules displayed a 2.56-fold increase in bioavailability and significantly increased LPV concentrations in tested tissues, especially in HIV sanctuary sites, as compared to the commercial LPV/RTV tablet (Kaletra®) in rats. Overall, the results demonstrated that the novel ISNP nanotechnology is a promising platform to manufacture palatable, "heat" stable, and flexible pediatric granules for fixed-dose combinations that can be used as sachets and sprinkles. To the best of our knowledge, this is the first report on this kind of novel nanotechnology for pediatric fixed-dose combinations of poorly water-soluble drugs.

PMID: 26849919 [PubMed - as supplied by publisher]

Massively parallel sequencing of forensic STRs: Considerations of the DNA commission of the International Society for Forensic Genetics (ISFG) on minimal nomenclature requirements.

Recent Research Articles from UNTHSC - Fri, 02/05/2016 - 07:29

Massively parallel sequencing of forensic STRs: Considerations of the DNA commission of the International Society for Forensic Genetics (ISFG) on minimal nomenclature requirements.

Forensic Sci Int Genet. 2016 Jan 21;22:54-63

Authors: Parson W, Ballard D, Budowle B, Butler JM, Gettings KB, Gill P, Gusmão L, Hares DR, Irwin JA, King JL, Knijff P, Morling N, Prinz M, Schneider PM, Neste CV, Willuweit S, Phillips C

Abstract
The DNA Commission of the International Society for Forensic Genetics (ISFG) is reviewing factors that need to be considered ahead of the adoption by the forensic community of short tandem repeat (STR) genotyping by massively parallel sequencing (MPS) technologies. MPS produces sequence data that provide a precise description of the repeat allele structure of a STR marker and variants that may reside in the flanking areas of the repeat region. When a STR contains a complex arrangement of repeat motifs, the level of genetic polymorphism revealed by the sequence data can increase substantially. As repeat structures can be complex and include substitutions, insertions, deletions, variable tandem repeat arrangements of multiple nucleotide motifs, and flanking region SNPs, established capillary electrophoresis (CE) allele descriptions must be supplemented by a new system of STR allele nomenclature, which retains backward compatibility with the CE data that currently populate national DNA databases and that will continue to be produced for the coming years. Thus, there is a pressing need to produce a standardized framework for describing complex sequences that enable comparison with currently used repeat allele nomenclature derived from conventional CE systems. It is important to discern three levels of information in hierarchical order (i) the sequence, (ii) the alignment, and (iii) the nomenclature of STR sequence data. We propose a sequence (text) string format the minimal requirement of data storage that laboratories should follow when adopting MPS of STRs. We further discuss the variant annotation and sequence comparison framework necessary to maintain compatibility among established and future data. This system must be easy to use and interpret by the DNA specialist, based on a universally accessible genome assembly, and in place before the uptake of MPS by the general forensic community starts to generate sequence data on a large scale. While the established nomenclature for CE-based STR analysis will remain unchanged in the future, the nomenclature of sequence-based STR genotypes will need to follow updated rules and be generated by expert systems that translate MPS sequences to match CE conventions in order to guarantee compatibility between the different generations of STR data.

PMID: 26844919 [PubMed - as supplied by publisher]

Evaluation of Xpert MTB/RIF to identify pulmonary tuberculosis in tuberculosis suspects from low and higher prevalence settings compared to acid fast smear and culture.

Recent Research Articles from UNTHSC - Thu, 02/04/2016 - 07:29

Evaluation of Xpert MTB/RIF to identify pulmonary tuberculosis in tuberculosis suspects from low and higher prevalence settings compared to acid fast smear and culture.

Clin Infect Dis. 2016 Feb 2;

Authors: Firnhaber C, Kendall MA, Wu X, Mazurek GH, Benator DA, Tuberculosis Trials Consortium, Arduino R, Fernandez M, Guy E, Johnson P, Metchock B, Sattler F, Telzak E, Wang YF, Weiner M, Swindells S, Sanne IM, Havlir DV, Grinsztejn B, Alland D, ACTG A5295 and TBTC Study 34 teams

Abstract
BACKGROUND:  Xpert MTB/RIF(Xpert) is a rapid nucleic acid amplification test widely used in high tuberculosis(TB) prevalence settings to detect tuberculosis as well as rpoB mutations associated with rifampin resistance. Data are needed on the diagnostic performance of Xpert in lower prevalence settings to inform appropriate use for both tuberculosis detection and the need for respiratory isolation.
METHODS:  Xpert was compared to two sputa, each evaluated with AFB smear and mycobacterial culture using liquid and solid culture media, from participants with suspected pulmonary TB from the US, Brazil, and South Africa.
RESULTS:  Of 992 participants enrolled with evaluable results, 22% had culture-confirmed TB. In 638(64%) US participants, one Xpert demonstrated sensitivity of 85.2%(96.7% in participants with AFB smear-positive(AFB+) sputum, 59.3% with AFB- sputum),specificity of 99.2%, NPV 97.6%, and PPV 94.9%. Results did not differ between higher and low prevalence settings. A second Xpert increased overall sensitivity to 91.1%(100% if AFB+, 71.4% if AFB-), with specificity of 98.9%. In US participants, a single negative Xpert predicted the absence of AFB+/culture+ tuberculosis with an NPV of 99.7%; NPV of two Xperts was 100%, suggesting a role in removing patients from airborne infection isolation. Xpert detected TB DNA and mutations associated with rifampin resistance in five of seven participants with rifampin-resistant, culture+ tuberculosis. Specificity for rifampin resistance was 99.5%,NPV was 98.9%.
CONCLUSIONS:  In the US, Xpert testing performed comparably to two higher TB prevalence settings. These data support the use of Xpert in the initial evaluation of TB suspects and in algorithms assessing need for respiratory isolation.

PMID: 26839383 [PubMed - as supplied by publisher]

Neural Control of Blood Pressure in Chronic Intermittent Hypoxia.

Recent Research Articles from UNTHSC - Thu, 02/04/2016 - 07:29

Neural Control of Blood Pressure in Chronic Intermittent Hypoxia.

Curr Hypertens Rep. 2016 Mar;18(3):19

Authors: Shell B, Faulk K, Cunningham JT

Abstract
Sleep apnea (SA) is increasing in prevalence and is commonly comorbid with hypertension. Chronic intermittent hypoxia is used to model the arterial hypoxemia seen in SA, and through this paradigm, the mechanisms that underlie SA-induced hypertension are becoming clear. Cyclic hypoxic exposure during sleep chronically stimulates the carotid chemoreflexes, inducing sensory long-term facilitation, and drives sympathetic outflow from the hindbrain. The elevated sympathetic tone drives hypertension and renal sympathetic activity to the kidneys resulting in increased plasma renin activity and eventually angiotensin II (Ang II) peripherally. Upon waking, when respiration is normalized, the sympathetic activity does not diminish. This is partially because of adaptations leading to overactivation of the hindbrain regions controlling sympathetic outflow such as the nucleus tractus solitarius (NTS), and rostral ventrolateral medulla (RVLM). The sustained sympathetic activity is also due to enhanced synaptic signaling from the forebrain through the paraventricular nucleus (PVN). During the waking hours, when the chemoreceptors are not exposed to hypoxia, the forebrain circumventricular organs (CVOs) are stimulated by peripherally circulating Ang II from the elevated plasma renin activity. The CVOs and median preoptic nucleus chronically activate the PVN due to the Ang II signaling. All together, this leads to elevated nocturnal mean arterial pressure (MAP) as a response to hypoxemia, as well as inappropriately elevated diurnal MAP in response to maladaptations.

PMID: 26838032 [PubMed - in process]

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