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Exaggerated sympathoexcitatory reflexes develop with changes in the rostral ventrolateral medulla in obese Zucker rats.

Recent Research Articles from UNTHSC - Fri, 06/10/2016 - 06:36

Exaggerated sympathoexcitatory reflexes develop with changes in the rostral ventrolateral medulla in obese Zucker rats.

Am J Physiol Regul Integr Comp Physiol. 2016 Jun 8;:ajpregu.00085.2016

Authors: Huber DA, Schreihofer AM

Abstract
Obesity leads to altered autonomic reflexes that reduce stability of mean arterial pressure (MAP). Sympathoinhibitory reflexes such as baroreflexes are impaired, but reflexes that raise MAP appear to be augmented. In obese Zucker rats (OZR) sciatic nerve stimulation evokes larger increases in MAP by unknown mechanisms. We sought to determine the autonomic underpinnings of this enhanced somatic pressor reflex, and whether other sympathoexcitatory reflexes are augmented. We also determined whether their final common pathway, glutamatergic activation of the rostral ventrolateral medulla (RVLM), was enhanced in male OZR compared to lean Zucker rats (LZR). Sciatic nerve stimulation or activation of the nasopharyngeal reflex evoked larger rises in splanchnic SNA (79% and 45% larger in OZR respectively, P<0.05) and MAP in urethane-anesthetized, ventilated, paralyzed adult OZR compared to LZR. After elimination of baroreflex feedback by pharmacological prevention of changes in MAP and heart rate, these two sympathoexcitatory reflexes were still exaggerated in OZR (167% and 69% larger respectively, P<0.05). In adult OZR microinjections of glutamate, AMPA, or NMDA into the RVLM produced larger rises in SNA (~61% larger in OZR, P<0.05 for each drug) and MAP, but stimulation of axonal fibers in the upper thoracic spinal cord yielded equivalent responses in OZR and LZR. In juvenile OZR and LZR, sympathoexcitatory reflexes and physiological responses to RVLM activation were comparable. These data suggest the ability of glutamate to activate the RVLM becomes enhanced in adult OZR and may contribute to the development of exaggerated sympathoexcitatory responses independent of impaired baroreflexes.

PMID: 27280427 [PubMed - as supplied by publisher]

The Role of Presenilin-1 in the Excitatory Stress of Ethanol Withdrawal.

Recent Research Articles from UNTHSC - Fri, 06/10/2016 - 06:36

The Role of Presenilin-1 in the Excitatory Stress of Ethanol Withdrawal.

J Pharmacol Exp Ther. 2016 Jun 8;

Authors: Jung ME, Metzger DB, Das HK

Abstract
Presenilin-1 (PS1) is a core component of γ-secretase that is involved in neurodegeneration. We have previously shown that PS1 interacts with a MAPK (JNK), and another MAPK (p38) is activated by ethanol withdrawal (EW), abrupt termination from chronic ethanol-exposure. EW is excitotoxic in nature, induces glutamate upregulation, and provokes neuronal damage. Here, we explored a potential mechanistic pathway involving glutamate, p38 (p38α isozyme), and PS1 that may mediate EW-induced excitotoxic stress. We used the prefrontal cortex of male rats withdrawn from a chronic ethanol diet. Additionally, we used ethanol withdrawn HT22 cells (mouse hippocampal) treated with the inhibitor of glutamate receptors (MK-801), p38α (SB203580), or γ-secretase (DAPT) during EW. Separately, ethanol-free HT22 cells were exposed to glutamate with or without SB203580 or DAPT. Protein levels, mRNA levels, and cell viability were assessed using immunoblotting, q-PCR, and Calcein assay, respectively. The prefrontal cortex of ethanol withdrawn rats or HT22 cells showed an increase in PS1 and p38α, which was attenuated by MK-801 and SB203580, but mimicked by glutamate treatment to ethanol-free HT22 cells. DAPT attenuated the toxic effect of EW or glutamate on HT22 cells. These results suggest that PS1 expression is triggered by glutamate through p38α, contributing to the excitotoxic stimulus of EW.

PMID: 27278235 [PubMed - as supplied by publisher]

HIV-1 and alcohol abuse promote astrocyte inflammation: A mechanistic synergy via the cytosolic phospholipase A2 pathway.

Recent Research Articles from UNTHSC - Fri, 06/10/2016 - 06:36
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HIV-1 and alcohol abuse promote astrocyte inflammation: A mechanistic synergy via the cytosolic phospholipase A2 pathway.

Cell Death Dis. 2015;6:e2017

Authors: Pandey R, Ghorpade A

PMID: 26658191 [PubMed - indexed for MEDLINE]

Interaction of astrocytes and T cells in physiological and pathological conditions.

Recent Research Articles from UNTHSC - Fri, 06/10/2016 - 06:36
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Interaction of astrocytes and T cells in physiological and pathological conditions.

Brain Res. 2015 Oct 14;1623:63-73

Authors: Xie L, Yang SH

Abstract
The central nervous system (CNS) has long been recognized as a site of 'immune privilege' because of the existence of the blood brain barrier (BBB) which presumably isolates CNS from the peripheral immunosurveillance. Different from the peripheral organs, CNS is unique in response to all forms of CNS injury and disease which is mainly mediated by resident microglia and astrocyte. There is increasing evidence that immune cells are not only involved in neuroinflammation process but also the maintenance of CNS homeostasis. T cells, an important immune cell population, are involved in the pathogenesis of some neurological diseases by inducing either innate or adaptive immune responses. Astrocytes, which are the most abundant cell type in the CNS, maintain the integrity of BBB and actively participate in the initiation and progression of neurological diseases. Surprisingly, how astrocytes and T cells interact and the consequences of their interaction are not clear. In this review we briefly summarized T cells diversity and astrocyte function. Then, we examined the evidence for the astrocytes and T cells interaction under physiological and pathological conditions including ischemic stroke, multiple sclerosis, viral infection, and Alzheimer's disease. This article is part of a Special Issue entitled SI: Cell Interactions In Stroke.

PMID: 25813828 [PubMed - indexed for MEDLINE]

Coupling of neurogenesis and angiogenesis after ischemic stroke.

Recent Research Articles from UNTHSC - Fri, 06/10/2016 - 06:36
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Coupling of neurogenesis and angiogenesis after ischemic stroke.

Brain Res. 2015 Oct 14;1623:166-73

Authors: Ruan L, Wang B, ZhuGe Q, Jin K

Abstract
Stroke is a leading cause of mortality and severe long-term disability worldwide. Development of effective treatment or new therapeutic strategies for ischemic stroke patients is therefore crucial. Ischemic stroke promotes neurogenesis by several growth factors including FGF-2, IGF-1, BDNF, VEGF and chemokines including SDF-1, MCP-1. Stroke-induced angiogenesis is similarly regulated by many factors most notably, eNOS and CSE, VEGF/VEGFR2, and Ang-1/Tie2. Important findings in the last decade have revealed that neurogenesis is not the stand-alone consideration in the fight for full functional recovery from stroke. Angiogenesis has been also shown to be critical in improving post-stroke neurological functional recovery. More than that, recent evidence has shown a highly possible interplay or dependence between stroke-induced neurogenesis and angiogenesis. Moving forward, elucidating the underlying mechanisms of this coupling between stroke-induced neurogenesis and angiogenesis will be of great importance, which will provide the basis for neurorestorative therapy. This article is part of a Special Issue entitled SI: Cell Interactions In Stroke.

PMID: 25736182 [PubMed - indexed for MEDLINE]

Postmortem medicolegal genetic diagnostics also require reporting guidance.

Recent Research Articles from UNTHSC - Fri, 06/10/2016 - 06:36
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Postmortem medicolegal genetic diagnostics also require reporting guidance.

Eur J Hum Genet. 2016 Mar;24(3):329-30

Authors: Sajantila A, Budowle B

PMID: 25469540 [PubMed - indexed for MEDLINE]

Exfoliative Excrement.

Recent Research Articles from UNTHSC - Thu, 06/09/2016 - 14:33

Exfoliative Excrement.

JAMA Dermatol. 2016 Jun 1;152(6):701

Authors: Roman J, Reynolds SD

PMID: 27276354 [PubMed - as supplied by publisher]

Sources and implications of NADH/NAD(+) redox imbalance in diabetes and its complications.

Recent Research Articles from UNTHSC - Thu, 06/09/2016 - 14:33

Sources and implications of NADH/NAD(+) redox imbalance in diabetes and its complications.

Diabetes Metab Syndr Obes. 2016;9:145-153

Authors: Wu J, Jin Z, Zheng H, Yan LJ

Abstract
NAD(+) is a fundamental molecule in metabolism and redox signaling. In diabetes and its complications, the balance between NADH and NAD(+) can be severely perturbed. On one hand, NADH is overproduced due to influx of hyperglycemia to the glycolytic and Krebs cycle pathways and activation of the polyol pathway. On the other hand, NAD(+) can be diminished or depleted by overactivation of poly ADP ribose polymerase that uses NAD(+) as its substrate. Moreover, sirtuins, another class of enzymes that also use NAD(+) as their substrate for catalyzing protein deacetylation reactions, can also affect cellular content of NAD(+). Impairment of NAD(+) regeneration enzymes such as lactate dehydrogenase in erythrocytes and complex I in mitochondria can also contribute to NADH accumulation and NAD(+) deficiency. The consequence of NADH/NAD(+) redox imbalance is initially reductive stress that eventually leads to oxidative stress and oxidative damage to macromolecules, including DNA, lipids, and proteins. Accordingly, redox imbalance-triggered oxidative damage has been thought to be a major factor contributing to the development of diabetes and its complications. Future studies on restoring NADH/NAD(+) redox balance could provide further insights into design of novel antidiabetic strategies.

PMID: 27274295 [PubMed - as supplied by publisher]

Depressive symptoms as a cause and effect of job loss in men and women: evidence in the context of organisational downsizing from the Swedish Longitudinal Occupational Survey of Health.

Recent Research Articles from UNTHSC - Thu, 06/09/2016 - 14:33
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Depressive symptoms as a cause and effect of job loss in men and women: evidence in the context of organisational downsizing from the Swedish Longitudinal Occupational Survey of Health.

BMC Public Health. 2015;15:1045

Authors: Andreeva E, Magnusson Hanson LL, Westerlund H, Theorell T, Brenner MH

Abstract
BACKGROUND: Few studies have examined depression as both a cause and effect of unemployment, but no prior work investigated these relationships in the context of organisational downsizing. We explored whether the exposure to downsizing is associated with subsequent depression (social causation), and whether pre-existing depression increases the risk of being laid off when organisations downsize (health selection).
METHODS: Two successive waves of the nationally representative Swedish Longitudinal Occupational Survey of Health represented the baseline (2008) and follow-up (2010) of this study. Analyses included 196 workers who lost their jobs through downsizing, 1462 layoff survivors remaining in downsized organisations and 1845 employees of non-downsized workplaces. The main outcomes were: (1) Depressive symptoms at follow-up, assessed with a brief subscale from the Symptom Checklist 90, categorised by severity levels ("major depression", "less severe symptoms" and "no depression") and analysed in relation to earlier downsizing exposure; (2) Job loss in persons with downsizing in relation to earlier depressive symptoms. The associations were assessed by means of multinomial logistic regression.
RESULTS: Job loss consistently predicted subsequent major depression among men and women, with a somewhat greater effect size in men. Surviving a layoff was significantly associated with subsequent major depression in women but not in men. Women with major depression have increased risks of exclusion from employment when organisations downsize, whereas job loss in men was not significantly influenced by their health.
CONCLUSIONS: The evidence from this study suggests that the relative importance of social causation and health selection varies by gender in the context of organisational downsizing. Strategies for handling depression among employees should be sensitive to gender-specific risks during layoffs. Policies preventing social exclusion can be important for female workers at higher risk of depression.

PMID: 26458894 [PubMed - indexed for MEDLINE]

Universal cholesterol screening of children in community-based ambulatory pediatric clinics.

Recent Research Articles from UNTHSC - Thu, 06/09/2016 - 14:33
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Universal cholesterol screening of children in community-based ambulatory pediatric clinics.

J Clin Lipidol. 2015 Sep-Oct;9(5 Suppl):S88-92

Authors: Wilson DP, Davis S, Matches S, Shah D, Leung-Pineda V, Mou M, Hamilton L, McNeal CJ, Bowman WP

Abstract
BACKGROUND: Early identification and treatment of individuals with elevated levels of atherogenic cholesterol have been shown to be effective and safe in reducing morbidity and mortality, especially in familial hypercholesterolemia. To better inform providers and identify children and adolescents at risk of premature cardiovascular disease, in November 2011, the National Heart, Lung, and Blood Institute (NHLBI) published guidelines recommending cholesterol screening of all children aged between 9 to 11 and 17 to 21 years regardless of the child's general health or the presence or the absence of cardiovascular disease risk factors.
OBJECTIVE: To compare the number of 9- to 11-year-old children screened for hypercholesterolemia in 5 community-based ambulatory pediatric clinics before and after publication of the NHLBI's guidelines.
METHODS: Practice demographics, screening frequency, and test results for each clinic were collected before and after publication of the NHLBI's recommendation. Provider education was provided between measures.
RESULTS: Of all eligible 9- to 11-year-old children, 489 (17.1%) were screened before and 686 (20.1%) after the NHLBI's guidelines and provider education.
CONCLUSIONS: Baseline rates of lipid screening for the 5 community-based ambulatory pediatric clinics were higher than those previously reported and increased significantly after publication of the NHLBI's recommendations and provider education. However, overall screening rates remained low. Given the high prevalence of premature cardiovascular disease associated with atherogenic cholesterol, especially familial hypercholesterolemia, additional strategies are needed to improve screening rates.

PMID: 26343216 [PubMed - indexed for MEDLINE]

Fetal Growth, Obesity, and Atopic Disorders in Adolescence: a Retrospective Birth Cohort Study.

Recent Research Articles from UNTHSC - Thu, 06/09/2016 - 14:33
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Fetal Growth, Obesity, and Atopic Disorders in Adolescence: a Retrospective Birth Cohort Study.

Paediatr Perinat Epidemiol. 2015 Sep;29(5):472-9

Authors: Lin MH, Hsieh CJ, Caffrey JL, Lin YS, Wang IJ, Ho WC, Chen PC, Wu TN, Lin RS

Abstract
BACKGROUND: Developmental status at birth and subsequent obesity have been implicated in the development of childhood atopic dermatitis (AD) and allergic rhinitis (AR).
METHODS: The current study analysed the cohort data of 74 688 junior high school students from a national retrospective birth cohort study in Taiwan. A random 10% sample was selected from singleton livebirths with complete data on the analytical variables of interest. Atopic disorders, including AD and AR, were assessed by questionnaires (International Study of Asthma and Allergies in Childhood). Logistic regression analyses were applied with adjustments for related risk factors.
RESULTS: Among subjects mainly 13-15 years of age, the estimated prevalence was 7.6% for AD and 22.4% for AR. While the role of fetal growth in allergic disorders was less evident, the risk of developing AD and AR were both influenced by a combination of fetal growth status and adolescent body mass index (BMI). Compared with those with normal fetal growth and school-aged BMI, the risk of developing AD increased 64% among adolescents with both restricted fetal growth and high BMI (odds ratio 1.64, 95% confidence interval 1.37, 1.97). The risk for this combination was higher than that for either restricted fetal growth or high BMI alone. Nevertheless, the overall interaction between BMI and fetal growth status on atopic disorders did not reach statistical significance.
CONCLUSIONS: Excessive weight gain could be an important risk factor related to developing atopic dermatitis and allergic rhinitis during adolescence, especially among infants born small for gestational age.

PMID: 26218618 [PubMed - indexed for MEDLINE]

Efficacy of a Telehealth Intervention on Colonoscopy Uptake When Cost Is a Barrier: The Family CARE Cluster Randomized Controlled Trial.

Recent Research Articles from UNTHSC - Thu, 06/09/2016 - 14:33
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Efficacy of a Telehealth Intervention on Colonoscopy Uptake When Cost Is a Barrier: The Family CARE Cluster Randomized Controlled Trial.

Cancer Epidemiol Biomarkers Prev. 2015 Sep;24(9):1311-8

Authors: Steffen LE, Boucher KM, Damron BH, Pappas LM, Walters ST, Flores KG, Boonyasiriwat W, Vernon SW, Stroup AM, Schwartz MD, Edwards SL, Kohlmann WK, Lowery JT, Wiggins CL, Hill DA, Higginbotham JC, Burt R, Simmons RG, Kinney AY

Abstract
BACKGROUND: We tested the efficacy of a remote tailored intervention Tele-Cancer Risk Assessment and Evaluation (TeleCARE) compared with a mailed educational brochure for improving colonoscopy uptake among at-risk relatives of colorectal cancer patients and examined subgroup differences based on participant reported cost barriers.
METHODS: Family members of colorectal cancer patients who were not up-to-date with colonoscopy were randomly assigned as family units to TeleCARE (N = 232) or an educational brochure (N = 249). At the 9-month follow-up, a cost resource letter listing resources for free or reduced-cost colonoscopy was mailed to participants who had reported cost barriers and remained nonadherent. Rates of medically verified colonoscopy at the 15-month follow-up were compared on the basis of group assignment and within group stratification by cost barriers.
RESULTS: In intent-to-treat analysis, 42.7% of participants in TeleCARE and 24.1% of participants in the educational brochure group had a medically verified colonoscopy [OR, 2.37; 95% confidence interval (CI) 1.59-3.52]. Cost was identified as a barrier in both groups (TeleCARE = 62.5%; educational brochure = 57.0%). When cost was not a barrier, the TeleCARE group was almost four times as likely as the comparison to have a colonoscopy (OR, 3.66; 95% CI, 1.85-7.24). The intervention was efficacious among those who reported cost barriers; the TeleCARE group was nearly twice as likely to have a colonoscopy (OR, 1.99; 95% CI, 1.12-3.52).
CONCLUSIONS: TeleCARE increased colonoscopy regardless of cost barriers.
IMPACT: Remote interventions may bolster screening colonoscopy regardless of cost barriers and be more efficacious when cost barriers are absent.

PMID: 26101306 [PubMed - indexed for MEDLINE]

The association between comorbid anxiety disorders and the risk of stroke among patients with diabetes: An 11-year population-based retrospective cohort study.

Recent Research Articles from UNTHSC - Mon, 06/06/2016 - 06:33

The association between comorbid anxiety disorders and the risk of stroke among patients with diabetes: An 11-year population-based retrospective cohort study.

J Affect Disord. 2016 May 26;202:178-186

Authors: Tsai MT, Erickson SR, Cohen LJ, Wu CH

Abstract
BACKGROUND: Diabetes and anxiety disorders are independent risk factors for stroke. However, it remains unclear whether the risk of stroke is higher among diabetic patients with comorbid anxiety than without comorbid anxiety. Therefore, the purpose of this study was to investigate the association between comorbid anxiety and the risk of stroke among patients with diabetes.
METHODS: This is a retrospective cohort study. We used the National Health Insurance Research Database in Taiwan to identify a diabetes cohort with a new diagnosis of an anxiety disorder but without a history of stroke. The enrollment period was 2001-2006 with up to 11 years of follow-up data. Comorbid anxiety was defined by both a clinical diagnosis of the DSM-IV (ICD-9-CM) and prescriptions for anxiolytic medications. Propensity score matching was performed to balance the selected confounders between the anxiety-exposed group and anxiety non-exposed group. Cox-propositional hazard regression models were used to evaluate the association between comorbid anxiety and the risk of stroke.
RESULTS: Among patients with diabetes (N=40,846), an estimated 5.8% (N=2374) of patients had comorbid anxiety disorders. Diabetic patients with comorbid anxiety were significantly associated with a higher risk of stroke compared to patients without comorbid anxiety (hazard ratio: 1.33, 95% confidence interval: 1.02-1.72).
LIMITATIONS: The severity of anxiety or diabetes could not be measured from the claims data. Residual confounding may still exist.
CONCLUSION: A significantly elevated risk of stroke was observed in association with comorbid anxiety among patients with diabetes. Psychiatrists should consider routine screening for anxiety disorders to prevent a stroke event among patients with diabetes.

PMID: 27262640 [PubMed - as supplied by publisher]

Radiotherapeutic bandage for the treatment of squamous cell carcinoma of the skin.

Recent Research Articles from UNTHSC - Sun, 06/05/2016 - 06:30

Radiotherapeutic bandage for the treatment of squamous cell carcinoma of the skin.

Nucl Med Biol. 2016 Jun;43(6):333-8

Authors: Koneru B, Shi Y, Munaweera I, Wight-Carter M, Kadara H, Yuan H, Di Pasqua AJ, Balkus KJ

Abstract
INTRODUCTION: Squamous cell carcinoma (SCC) is the second most common form of skin cancer in the United States. The efficacy of a pharmaceutically elegant radiotherapeutic bandage, previously described by us for application against SCC of the skin, was tested for the first time in vivo using a subcutaneous SCC mouse model and a therapeutically relevant radiation dose.
METHODS: Female athymic nude mice were injected with human Colo-16 SCC cells subcutaneously and after eight days (average tumor volume: 35±8.6mm(3)) received no treatment, or were exposed to non-radioactive or radioactive (92.5±18.5MBq) bandages for approximately 1h (n=10 per group). After treatment, tumors were measured over fifteen days, tumor volume ratios (TVRs) compared and histopathology performed.
RESULTS: Fifteen days after treatment, the TVR of the radioactive bandage treatment group was 3.3±4.5, while TVRs of the non-radioactive bandage treatment and no treatment control groups were 33.2±14.7 and 26.9±12.6, respectively. At the time of necropsy, there was mild focal epidermal hyperplasia surrounding a small area of epidermal ulceration in the radioactive bandage group. No other examined tissue (i.e., muscle, liver, kidney, lung, spleen and heart) showed significant lesions.
CONCLUSIONS: Our radiotherapeutic bandage exhibits promising efficacy against SCC of the skin in a mouse model. It can be individually tailored for easy application on tumor lesions of all shapes and sizes, and could complement or possibly replace surgery in the clinic.

PMID: 27260774 [PubMed - in process]

Exposure to common respiratory bacteria alters the airway epithelial response to subsequent viral infection.

Recent Research Articles from UNTHSC - Sun, 06/05/2016 - 06:30

Exposure to common respiratory bacteria alters the airway epithelial response to subsequent viral infection.

Respir Res. 2016;17(1):68

Authors: Bellinghausen C, Gulraiz F, Heinzmann AC, Dentener MA, Savelkoul PH, Wouters EF, Rohde GG, Stassen FR

Abstract
BACKGROUND: Colonization of the airways with potential pathogenic bacteria is observed in a number of chronic respiratory diseases, such as COPD or cystic fibrosis. Infections with respiratory viruses are known triggers of exacerbations of these diseases. We here investigated if pre-exposure to bacteria alters the response of lung epithelial cells to subsequent viral infection.
METHODS: Bronchial epithelial cells (BEAS-2B cells and primary bronchial epithelial cells) were exposed to heat-inactivated Haemophilus influenzae, Pseudomonas aeruginosa or Streptococcus pneumoniae and subsequently infected with respiratory syncytial virus (RSV), type 2 human adenovirus or influenza B. Levels of pro-inflammatory cytokines, viral replication and expression of pattern recognition receptors were determined in culture supernatants and/or cell lysates.
RESULTS: Exposure of BEAS-2B cells to H. influenzae before and during RSV-infection synergistically increased the release of IL-6 (increase above calculated additive effect at 72 h: 56 % ± 3 %, mean ± SEM) and IL-8 (53 % ± 12 %). This effect was sustained even when bacteria were washed away before viral infection and was neither associated with enhanced viral replication, nor linked to increased expression of key pattern recognition receptors. P. aeruginosa enhanced the release of inflammatory cytokines to a similar extent, yet only if bacteria were also present during viral infection. S. pneumoniae did not enhance RSV-induced cytokine release. Surprisingly, adenovirus infection significantly reduced IL-6 release in cells exposed to either of the three tested bacterial strains by on average more than 50 %. Infection with influenza B on the other hand did not affect cytokine production in BEAS-2B cells exposed to the different bacterial strains.
CONCLUSION: Pre-exposure of epithelial cells to bacteria alters the response to subsequent viral infection depending on the types of pathogen involved. These findings highlight the complexity of microbiome interactions in the airways, possibly contributing to the susceptibility to exacerbations and the natural course of airway diseases.

PMID: 27259950 [PubMed - as supplied by publisher]

Bitropic D3 Dopamine Receptor Selective Compounds as Potential Antipsychotics.

Recent Research Articles from UNTHSC - Sat, 06/04/2016 - 06:34
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Bitropic D3 Dopamine Receptor Selective Compounds as Potential Antipsychotics.

Curr Pharm Des. 2015;21(26):3700-24

Authors: Luedtke RR, Rangel-Barajas C, Malik M, Reichert DE, Mach RH

Abstract
Neuropsychiatric disorders represent a substantial social and health care issue. The National Institutes of Health estimates that greater than 2 million adults suffer from neuropsychiatric disorders in the USA. These individuals experience symptoms that can include auditory hallucinations, delusions, unrealistic beliefs and cognitive dysfunction. Although antipsychotic medications are available, suboptimal therapeutic responses are observed for approximately one-third of patients. Therefore, there is still a need to explore new pharmacotherapeutic strategies for the treatment of neuropsychiatric disorders. Many of the medications that are used clinically to treat neuropsychiatric disorders have a pharmacological profile that includes being an antagonist at D2-like (D2, D3 and D4) dopamine receptor subtypes. However, dopamine receptor subtypes are involved in a variety of neuronal circuits that include movement coordination, cognition, emotion, affect, memory and the regulation of prolactin. Consequently, antagonism at D2-like receptors can also contribute to some of the adverse side effects associated with the long-term use of antipsychotics including the a) adverse extrapyramidal symptoms associated with the use of typical antipsychotics and b) metabolic side effects (weight gain, hyperglycemia, increased risk of diabetes mellitus, dyslipidemia and gynecomastia) associated with atypical antipsychotic use. Preclinical studies suggest that D3 versus D2 dopamine receptor selective compounds might represent an alternative strategy for the treatment of the symptoms of schizophrenia. In this review we discuss a) how bitropic Nphenylpiperazine D3 dopamine receptor selective compounds have been developed by modification of the primary (orthosteric) and secondary (allosteric or modulatory) pharmacophores to optimize D3 receptor affinity and D2/D3 binding selectivity ratios and b) the functional selectivity of these compounds. Examples of how these compounds might be modified to develop bivalent ligands capable of interacting with receptor dimers or oligomers are also provided. Preclinical studies using bitropic D3 dopamine receptor selective ligands are also discussed as strategy to pharmacologically dissect the role of the D2 and D3 dopamine receptor subtypes in animal models of neuropsychiatric, neurological and substance abuse disorders. This research has the potential to a) advance the understanding of the role of the D2 and D3 dopamine receptor subtypes in neuropsychiatric disorders and b) lead to new treatment strategies for neuropsychiatric disorders.

PMID: 26205291 [PubMed - indexed for MEDLINE]

Allostery: An Overview of Its History, Concepts, Methods, and Applications.

Recent Research Articles from UNTHSC - Fri, 06/03/2016 - 06:36

Allostery: An Overview of Its History, Concepts, Methods, and Applications.

PLoS Comput Biol. 2016 Jun;12(6):e1004966

Authors: Liu J, Nussinov R

Abstract
The concept of allostery has evolved in the past century. In this Editorial, we briefly overview the history of allostery, from the pre-allostery nomenclature era starting with the Bohr effect (1904) to the birth of allostery by Monod and Jacob (1961). We describe the evolution of the allostery concept, from a conformational change in a two-state model (1965, 1966) to dynamic allostery in the ensemble model (1999); from multi-subunit (1965) proteins to all proteins (2004). We highlight the current available methods to study allostery and their applications in studies of conformational mechanisms, disease, and allosteric drug discovery. We outline the challenges and future directions that we foresee. Altogether, this Editorial narrates the history of this fundamental concept in the life sciences, its significance, methodologies to detect and predict it, and its application in a broad range of living systems.

PMID: 27253437 [PubMed - as supplied by publisher]

Towards the development of a screening tool to enhance the detection of elder abuse and neglect by emergency medical technicians (EMTs): a qualitative study.

Recent Research Articles from UNTHSC - Fri, 06/03/2016 - 06:36

Towards the development of a screening tool to enhance the detection of elder abuse and neglect by emergency medical technicians (EMTs): a qualitative study.

BMC Emerg Med. 2016;16(1):19

Authors: Cannell MB, Jetelina KK, Zavadsky M, Gonzalez JM

Abstract
BACKGROUND: To develop a screening tool to enhance elder abuse and neglect detection and reporting rates among emergency medical technicians (EMTs). Our primary aim was to identify the most salient indicators of elder abuse and neglect for potential inclusion on a screening tool. We also sought to identify practical elements of the tool that would optimize EMT uptake and use in the field, such as format, length and number of items, and types of response options available.
METHODS: Qualitative data were collected from 23 EMTs and Adult Protective Services (APS) caseworkers that participated in one of five semi-structured focus groups. Focus group data were iteratively coded by two coders using inductive thematic identification and data reduction. Findings were subject to interpretation by the research team.
RESULTS: EMTs and APS caseworks identified eight domains of items that might be included on a screening tool: (1) exterior home condition; (2) interior living conditions; (3) social support; (4) medical history; (5) caregiving quality; (6) physical condition of the older adult; (7) older adult's behavior; and, (8) EMTs instincts. The screening tool should be based on observable cues in the physical or social environment, be very brief, easily integrated into electronic charting systems, and provide a decision rule for reporting guidance to optimize utility for EMTs in the field.
CONCLUSIONS: We described characteristics of a screening tool for EMTs to enhance detection and reporting of elder abuse and neglect to APS. Future research should narrow identified items and evaluate how these domains positively predict confirmed cases of elder abuse and neglect.

PMID: 27250247 [PubMed - in process]

Curcumin Mimics the Neurocognitive and Anti-Inflammatory Effects of Caloric Restriction in a Mouse Model of Midlife Obesity.

Recent Research Articles from UNTHSC - Fri, 06/03/2016 - 06:36
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Curcumin Mimics the Neurocognitive and Anti-Inflammatory Effects of Caloric Restriction in a Mouse Model of Midlife Obesity.

PLoS One. 2015;10(10):e0140431

Authors: Sarker MR, Franks S, Sumien N, Thangthaeng N, Filipetto F, Forster M

Abstract
Dietary curcumin was studied for its potential to decrease adiposity and reverse obesity- associated cognitive impairment in a mouse model of midlife sedentary obesity. We hypothesized that curcumin intake, by decreasing adiposity, would improve cognitive function in a manner comparable to caloric restriction (CR), a weight loss regimen. 15-month-old male C57BL/6 mice were assigned in groups to receive the following dietary regimens for 12 weeks: (i) a base diet (Ain93M) fed ad libitum (AL), (ii) the base diet restricted to 70% of ad libitum (CR) or (iii) the base diet containing curcumin fed AL (1000 mg/kg diet, CURAL). Blood markers of inflammation, interleukin 6 (IL-6) and C-reactive protein (CRP), as well as an indicator of redox stress (GSH: GSSG ratio), were determined at different time points during the treatments, and visceral and subcutaneous adipose tissue were measured upon completion of the experiment. After 8 weeks of dietary treatment, the mice were tested for spatial cognition (Morris water maze) and cognitive flexibility (discriminated active avoidance). The CR group showed significant weight loss and reduced adiposity, whereas CURAL mice had stable weight throughout the experiment, consumed more food than the AL group, with no reduction of adiposity. However, both CR and CURAL groups took fewer trials than AL to reach criterion during the reversal sessions of the active avoidance task, suggesting an improvement in cognitive flexibility. The AL mice had higher levels of CRP compared to CURAL and CR, and GSH as well as the GSH: GSSG ratio were increased during curcumin intake, suggesting a reducing shift in the redox state. The results suggest that, independent of their effects on adiposity; dietary curcumin and caloric restriction have positive effects on frontal cortical functions that could be linked to anti-inflammatory or antioxidant actions.

PMID: 26473740 [PubMed - indexed for MEDLINE]

Interactive effects of hypoxia, hypercapnia and lung volume on sympathetic nerve activity in humans.

Recent Research Articles from UNTHSC - Fri, 06/03/2016 - 06:36
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Interactive effects of hypoxia, hypercapnia and lung volume on sympathetic nerve activity in humans.

Exp Physiol. 2015 Sep;100(9):1018-29

Authors: Jouett NP, Watenpaugh DE, Dunlap ME, Smith ML

Abstract
NEW FINDINGS: What is the central question of this study? The central question of this study was to investigate the interaction of mild exposures to O2 and CO2 on chemoreflex control of SNA and the modulation of lung volume and respiratory phase on this interaction. What is the main finding and its importance? We demonstrate that the synergistic interaction of oxygen- and carbon dioxide-chemosensitive control of the sympathetic nervous system with hypoxia and hypercapnia exists at very mild excitatory stimuli, is significantly overridden by lung inflation and does not extend to inhibitory modulation by hypocapnia in healthy subjects. These findings demonstrate the important inhibitory modulation of sympathetic nerve activity by lung inflation mechanisms in healthy individuals even in the presence of strong sympathoexcitatory stimuli. We hypothesized that simultaneous stimulation of O2 - and CO2 -sensitive chemoreflexes produces synergistic activation of the sympathetic nervous system and that this effect would be most apparent at low lung volume (expiratory) phases of respiration. Each subject (n = 11) breathed 16 gas mixtures in random order: a 4 × 4 matrix of normoxic to hypoxic (8, 12, 16 and 21% O2 ) combined with normocapnic to hypercapnic gases (0, 2, 4 and 6% CO2). Tidal volume, arterial pressure, heart rate and muscle sympathetic nerve activity (MSNA) were measured continuously before and while breathing each gas mixture for 2 min. Changes in MSNA were determined for each gas mixture. The MSNA was subdivided into low and high lung volume and respiratory phases to investigate further modulation by components of normal respiratory phase. Both hypoxia and hypercapnia increased mean MSNA independently. Mean and low lung volume MSNA increased exponentially with increasing levels of combined hypoxia and hypercapnia and resulted in a significant interaction (P < 0.01). In contrast, MSNA during the high lung volume phase of respiration never increased significantly (P > 0.4). Similar but less pronounced effects were found for expiratory and inspiratory phases of respiration. These effects created marked respiratory periodicity in MSNA at higher levels of combined hypoxia and hypercapnia. Finally, the response to hypoxia was not affected by hypocapnia, suggesting that the interaction occurs only during excitatory chemosensitive stimuli. These data indicate that hypoxia and hypercapnia interact to elicit synergistic sympathoexcitation and that withdrawal of sympathoinhibitory effects of lung inflation exaggerates this chemoreflex interaction.

PMID: 26132990 [PubMed - indexed for MEDLINE]

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