Recent Research Articles from UNTHSC

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NCBI: db=pubmed; Term="University of North Texas Health Science Center"[All Fields] OR "Univ. of North Texas Health Science Center"[All Fields] OR "UNT Health Science Center"[All Fields] OR "Osteopathic Research Center"[All Fields] OR "University of North Texas System College of Pharmacy"[All Fields] OR "UNT System College of Pharmacy"[All Fields] OR "College of Pharmacy, University of North Texas System"[All Fields]
Updated: 1 hour 14 min ago

Rationalizing the use of functionalized poly-lactic-co-glycolic acid nanoparticles for dendritic cell-based targeted anticancer therapy.

Sat, 02/20/2016 - 07:32

Rationalizing the use of functionalized poly-lactic-co-glycolic acid nanoparticles for dendritic cell-based targeted anticancer therapy.

Nanomedicine (Lond). 2016 Feb 19;

Authors: Kokate RA, Chaudhary P, Sun X, Thamake SI, Maji S, Chib R, Vishwanatha JK, Jones HP

Abstract
BACKGROUND: Delivery of PLGA (poly [D, L-lactide-co-glycolide])-based biodegradable nanoparticles (NPs) to antigen presenting cells, particularly dendritic cells, has potential for cancer immunotherapy.
MATERIALS & METHODS: Using a PLGA NP vaccine construct CpG-NP-Tag (CpG-ODN-coated tumor antigen [Tag] encapsulating NP) prepared using solvent evaporation technique we tested the efficacy of ex vivo and in vivo use of this construct as a feasible platform for immune-based therapy.
RESULTS: CpG-NP-Tag NPs were avidly endocytosed and localized in the endosomal compartment of bone marrow-derived dendritic cells. Bone marrow-derived dendritic cells exposed to CpG-NP-Tag NPs exhibited an increased maturation (higher CD80/86 expression) and activation status (enhanced IL-12 secretion levels). In vivo results demonstrated attenuation of tumor growth and angiogenesis as well as induction of potent cytotoxic T-lymphocyte responses.
CONCLUSION: Collectively, results validate dendritic cells stimulatory response to CpG-NP-Tag NPs (ex vivo) and CpG-NP-Tag NPs' tumor inhibitory potential (in vivo) for therapeutic applications, respectively.

PMID: 26892440 [PubMed - as supplied by publisher]

Exercise, but not antioxidants, reversed ApoE4-associated motor impairments in adult GFAP-ApoE mice.

Sat, 02/20/2016 - 07:32

Exercise, but not antioxidants, reversed ApoE4-associated motor impairments in adult GFAP-ApoE mice.

Behav Brain Res. 2016 Feb 15;

Authors: Chaudhari K, Wong JM, Vann PH, Sumien N

Abstract
Motor dysfunction has been found to be predictive of cognitive dysfunction in Alzheimer's disease and to occur earlier than cognitive impairments. While apolipoprotein(Apo) E4 has been associated with cognitive impairments, it remains unclear whether it also increases risk for motor dysfunction. Exercise and antioxidants are often recommended to reduce cognitive declines, however it is unclear whether they can successfully improve motor impairments. This study was designed to determine the extent of the impact of apolipoprotein genotype on motor function, and whether interventions such as exercise and antioxidant intake can improve motor function. This study will be the first to identify the nature of the interaction between antioxidant intake and exercise using a mouse model expressing either the human ApoE3 or ApoE4 isoforms under glial fibrillary acid protein promoter (GFAP-ApoE3 and GFAP-ApoE4 mice). The mice were fed either a control diet or the control diet supplemented with vitamins E and C (1.12 IU/g diet α-tocopheryl acetate and 1.65mg/g ascorbic acid). Each genotype/diet group was further divided into a sedentary group or a group that followed a 6days a week exercise regimen. After 8 weeks on their respective treatment, the mice were administered a battery of motor tests to measure reflexes, strength, coordination and balance. GFAP-ApoE4 exhibited impaired motor learning and diminished strength compared to the GFAP-ApoE3 mice. Exercise alone was more efficient at improving motor function and reversing ApoE4-associated impairments than antioxidants alone, even though improvements were rather subtle. Contrarily to expected outcomes, combination of antioxidants and exercise did not yield further improvements of motor function. Interestingly, antioxidants antagonized the beneficial effects of exercise on strength. These data suggest that environmental and genetic factors influence the outcome of interventions on motor function and should be investigated more thoroughly and taken into consideration when implementing changes in lifestyles.

PMID: 26892275 [PubMed - as supplied by publisher]

Alcohol mixed with energy drink: Use may be a consequence of heavy drinking.

Fri, 02/19/2016 - 07:29

Alcohol mixed with energy drink: Use may be a consequence of heavy drinking.

Addict Behav. 2016 Feb 10;57:55-61

Authors: Rossheim ME, Thombs DL, Weiler RM, Barry AE, Suzuki S, Walters ST, Barnett TE, Paxton RJ, Pealer LN, Cannell B

Abstract
AIMS: In recent years, studies have indicated that consumers of alcohol mixed with energy drink (AmED) are more likely to drink heavily and experience more negative consequences than consumers who avoid these beverages. Although researchers have identified a number of plausible hypotheses that explain how alcohol-energy drink co-ingestion could cause greater alcohol consumption, there has been no postulation about reverse causal relations. This paper identifies several plausible hypotheses for the observed associations between AmED consumption and greater alcohol consumption, and provides initial evidence for one such hypothesis suggesting that heavy drinking may be a determinant of AmED use.
METHOD: Data collected from 511bar patrons were used to examine the plausibility of one of the proposed hypotheses, i.e., AmED is an artifact of heavy drinking. Associations between the consumption of an assortment of alcoholic beverage types and total alcohol consumption were examined at the event-level, to assess whether AmED is uniquely related with greater alcohol consumption.
RESULTS: Increased alcohol consumption was associated with greater odds of consuming most alcoholic beverage types; this association was not unique to AmED.
CONCLUSIONS: Results support the overlooked hypothesis that AmED use is an artifact of heavy drinking. Thus, AmED consumption may be a consequence or marker of heavier drinking. Much of the existing research on alcoholic beverage types is limited in its ability to implicate any specific type of drink, including AmED, as a cause of increased alcohol consumption and related harm. More rigorous study designs are needed to examine causal relationships.

PMID: 26890245 [PubMed - as supplied by publisher]

Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors.

Thu, 02/18/2016 - 07:30
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Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors.

Chem Rev. 2016 Feb 16;

Authors: Lindsley CW, Emmitte KA, Hopkins CR, Bridges TM, Gregory KJ, Niswender CM, Conn PJ

Abstract
Allosteric modulation of GPCRs has initiated a new era of basic and translational discovery, filled with therapeutic promise yet fraught with caveats. Allosteric ligands stabilize unique conformations of the GPCR that afford fundamentally new receptors, capable of novel pharmacology, unprecedented subtype selectivity, and unique signal bias. This review provides a comprehensive overview of the basics of GPCR allosteric pharmacology, medicinal chemistry, drug metabolism, and validated approaches to address each of the major challenges and caveats. Then, the review narrows focus to highlight recent advances in the discovery of allosteric ligands for metabotropic glutamate receptor subtypes 1-5 and 7 (mGlu1-5,7) highlighting key concepts ("molecular switches", signal bias, heterodimers) and practical solutions to enable the development of tool compounds and clinical candidates. The review closes with a section on late-breaking new advances with allosteric ligands for other GPCRs and emerging data for endogenous allosteric modulators.

PMID: 26882314 [PubMed - as supplied by publisher]

Ictal Coprolalia: A Case Report and Review of Ictal Speech as a Localizing Feature in Epilepsy.

Thu, 02/18/2016 - 07:30
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Ictal Coprolalia: A Case Report and Review of Ictal Speech as a Localizing Feature in Epilepsy.

Pediatr Neurol. 2016 Jan 19;

Authors: Daniel C, Perry MS

Abstract
BACKGROUND: Recognizing ictal semiology is an essential component to localization of seizure onset, especially in intractable epilepsy where surgical therapies may be beneficial. Ictal speech can be a common component of seizure semiology, but the various forms of ictal speech may have different lateralizing and localizing value. Coprolalia is a very rare form of ictal speech.
METHODS: We present the case of a 15 year old with seizures characterized by agitation and coprolalia which was medically intractable.
RESULTS: The patient underwent surgical evaluation including video EEG, MRI, and functional neuroimaging. Data indicated onset within the dominant frontal lobe which was further localized using stereo-electroencephalography prior to focal cortical resection.
CONCLUSIONS: Ictal coprolalia is a rare presentation of ictal speech. We review the various forms of ictal speech and their value in localizing seizure onset.

PMID: 26880529 [PubMed - as supplied by publisher]

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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]

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