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: 3 hours 16 min ago

A genetic overview of 23Y-STR markers in UAE population.

Fri, 04/29/2016 - 06:30

A genetic overview of 23Y-STR markers in UAE population.

Forensic Sci Int Genet. 2016 Apr 19;23:150-152

Authors: Nazir M, Alhaddad H, Alenizi M, Alenizi H, Taqi Z, Sanqoor S, Alrazouqi A, Hassan A, Alfalasi R, Gaur S, Al Jaber J, Ziab J, Al-Harbi E, Moura-Neto RS, Budowle B

PMID: 27124011 [PubMed - as supplied by publisher]

Reducing the burden of suicide in the U.S.: the aspirational research goals of the National Action Alliance for Suicide Prevention Research Prioritization Task Force.

Thu, 04/28/2016 - 06:32
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Reducing the burden of suicide in the U.S.: the aspirational research goals of the National Action Alliance for Suicide Prevention Research Prioritization Task Force.

Am J Prev Med. 2014 Sep;47(3):309-14

Authors: Claassen CA, Pearson JL, Khodyakov D, Satow PM, Gebbia R, Berman AL, Reidenberg DJ, Feldman S, Molock S, Carras MC, Lento RM, Sherrill J, Pringle B, Dalal S, Insel TR

Abstract
BACKGROUND: The National Action Alliance for Suicide Prevention Research Prioritization Task Force (RPTF) has created a prioritized national research agenda with the potential to rapidly and substantially reduce the suicide burden in the U.S. if fully funded and implemented.
PURPOSE: Viable, sustainable scientific research agendas addressing challenging public health issues such as suicide often need to incorporate perspectives from multiple stakeholder groups (e.g., researchers, policymakers, and other end-users of new knowledge) during an agenda-setting process. The Stakeholder Survey was a web-based survey conducted and analyzed in 2011-2012 to inform the goal-setting step in the RPTF agenda development process. The survey process, and the final list of "aspirational" research goals it produced, are presented here.
METHODS: Using a modified Delphi process, diverse constituent groups generated and evaluated candidate research goals addressing pressing suicide prevention research needs.
RESULTS: A total of 716 respondents representing 49 U.S. states and 18 foreign countries provided input that ultimately produced 12 overarching, research-informed aspirational goals aimed at reducing the U.S. suicide burden. Highest-rated goals addressed prevention of subsequent suicidal behavior after an initial attempt, strategies to retain patients in care, improved healthcare provider training, and generating care models that would ensure accessible treatment.
CONCLUSIONS: The Stakeholder Survey yielded widely valued research targets. Findings were diverse in focus, type, and current phase of research development but tended to prioritize practical solutions over theoretical advancement. Other complex public health problems requiring input from a broad-based constituency might benefit from web-based tools that facilitate such community input.

PMID: 24750971 [PubMed - indexed for MEDLINE]

Rigid Residue Scan Simulations Systematically Reveal Residue Entropic Roles in Protein Allostery.

Wed, 04/27/2016 - 06:31

Rigid Residue Scan Simulations Systematically Reveal Residue Entropic Roles in Protein Allostery.

PLoS Comput Biol. 2016 Apr;12(4):e1004893

Authors: Kalescky R, Zhou H, Liu J, Tao P

Abstract
Intra-protein information is transmitted over distances via allosteric processes. This ubiquitous protein process allows for protein function changes due to ligand binding events. Understanding protein allostery is essential to understanding protein functions. In this study, allostery in the second PDZ domain (PDZ2) in the human PTP1E protein is examined as model system to advance a recently developed rigid residue scan method combining with configurational entropy calculation and principal component analysis. The contributions from individual residues to whole-protein dynamics and allostery were systematically assessed via rigid body simulations of both unbound and ligand-bound states of the protein. The entropic contributions of individual residues to whole-protein dynamics were evaluated based on covariance-based correlation analysis of all simulations. The changes of overall protein entropy when individual residues being held rigid support that the rigidity/flexibility equilibrium in protein structure is governed by the La Châtelier's principle of chemical equilibrium. Key residues of PDZ2 allostery were identified with good agreement with NMR studies of the same protein bound to the same peptide. On the other hand, the change of entropic contribution from each residue upon perturbation revealed intrinsic differences among all the residues. The quasi-harmonic and principal component analyses of simulations without rigid residue perturbation showed a coherent allosteric mode from unbound and bound states, respectively. The projection of simulations with rigid residue perturbation onto coherent allosteric modes demonstrated the intrinsic shifting of ensemble distributions supporting the population-shift theory of protein allostery. Overall, the study presented here provides a robust and systematic approach to estimate the contribution of individual residue internal motion to overall protein dynamics and allostery.

PMID: 27115535 [PubMed - as supplied by publisher]

Peripheral retinal telangiectasia and ischemia in Takayasu's arteritis.

Tue, 04/26/2016 - 06:30

Peripheral retinal telangiectasia and ischemia in Takayasu's arteritis.

Arthritis Rheumatol. 2016 Apr 25;

Authors: Batliwala SY, Perez M, Aston W, Chavala SH

PMID: 27110659 [PubMed - as supplied by publisher]

Novel in situ self-assembly nanoparticles for formulating a poorly water-soluble drug in oral solid granules, improving stability, palatability, and bioavailability.

Sat, 04/23/2016 - 06:42

Novel in situ self-assembly nanoparticles for formulating a poorly water-soluble drug in oral solid granules, improving stability, palatability, and bioavailability.

Int J Nanomedicine. 2016;11:1451-60

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

Abstract
PURPOSE: The purpose of this study was to develop a novel lipid-based nanotechnology to formulate poorly water-soluble drugs in oral solid granules to improve stability, palatability, and bioavailability.
MATERIALS AND METHODS: In one method, we prepared ritonavir (RTV) nanoparticles (NPs) by a microemulsion-precursor method and then converted the RTV NPs to solid granules by wet granulation to produce RTV NP-containing granules. In the other innovative method, we did not use water in the formulation preparation, and discovered novel in situ self-assembly nanoparticles (ISNPs). We prepared RTV ISNP granules that did not initially contain NPs, but spontaneously produced RTV ISNPs when the granules were introduced to water with gentle agitation. We fully characterized these RTV nanoformulations. We also used rats to test the bioavailability of RTV ISNP granules. Finally, an Astree electronic tongue was used to assess the taste of the RTV ISNP granules.
RESULTS: RTV NP-containing granules only had about 1% drug loading of RTV in the solid granules. In contrast, RTV ISNP granules achieved over 16% drug loading and were stable at room temperature over 24 weeks. RTV ISNPs had particle size between 160 nm and 300 nm with narrow size distribution. RTV ISNPs were stable in simulated gastric fluid for 2 hours and in simulated intestinal fluid for another 6 hours. The data from the electronic tongue showed that the RTV ISNP granules were similar in taste to blank ISNP granules, but were much different from RTV solution. RTV ISNP granules increased RTV bioavailability over 2.5-fold compared to RTV solution.
CONCLUSION: We successfully discovered and developed novel ISNPs to manufacture RTV ISNP granules that were reconstitutable, stable, and palatable, and improved RTV bioavailability. The novel ISNP nanotechnology is a platform to manufacture oral solid dosage forms for poorly water-soluble drugs, especially for pediatric formulation development.

PMID: 27103803 [PubMed - in process]

Authors' Response to Letter Regarding Alcohol Sales Tax and Sexually Transmitted Infections.

Sat, 04/23/2016 - 06:42

Authors' Response to Letter Regarding Alcohol Sales Tax and Sexually Transmitted Infections.

Am J Prev Med. 2016 May;50(5):e161

Authors: Staras SA, Livingston MD, Wagenaar AC

PMID: 27102644 [PubMed - in process]

Breath-based meditation: A mechanism to restore the physiological and cognitive reserves for optimal human performance.

Fri, 04/22/2016 - 10:37
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Breath-based meditation: A mechanism to restore the physiological and cognitive reserves for optimal human performance.

World J Clin Cases. 2016 Apr 16;4(4):99-102

Authors: Carter KS, Carter Iii R

Abstract
Stress can be associated with many physiological changes resulting in significant decrements in human performance. Due to growing interests in alternative and complementary medicine by Westerners, many of the traditions and holistic yogic breathing practices today are being utilized as a measure for healthier lifestyles. These state-of-the-art practices can have a significant impact on common mental health conditions such as depression and generalized anxiety disorder. However, the potential of yogic breathing on optimizing human performance and overall well-being is not well known. Breathing techniques such as alternate nostril, Sudarshan Kriya and bhastrika utilizes rhythmic breathing to guide practitioners into a deep meditative state of relaxation and promote self-awareness. Furthermore, yogic breathing is physiologically stimulating and can be described as a natural "technological" solution to optimize human performance which can be categorized into: (1) cognitive function (i.e., mind, vigilance); and (2) physical performance (i.e., cardiorespiratory, metabolism, exercise, whole body). Based on previous studies, we postulate that daily practice of breathing meditation techniques play a significant role in preserving the compensatory mechanisms available to sustain physiological function. This preservation of physiological function may help to offset the time associated with reaching a threshold for clinical expression of chronic state (i.e., hypertension, depression, dementia) or acute state (i.e., massive hemorrhage, panic attic) of medical conditions. However, additional rigorous biomedical research is needed to evaluate the physiological mechanisms of various forms of meditation (i.e., breath-based, mantra, mindfulness) on human performance. These efforts will help to define how compensatory reserve mechanisms of cardiovascular and immune systems are modulated by breath-based meditation. While it has been suggested that breath-based meditation is easier for beginning practitioners when compared to other forms of meditation more research is needed to elucidate these observations. A breath-based meditation sequence such as Sudarshan Kriya has the potential to help develop an individual's self-awareness and support better integration of the brain (i.e., mind) with other organ systems (i.e., body) for enhanced human performance.

PMID: 27099859 [PubMed]

In vitro and in vivo neuroprotective effects of cJun N-terminal kinase inhibitors on retinal ganglion cells.

Fri, 04/22/2016 - 10:37
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In vitro and in vivo neuroprotective effects of cJun N-terminal kinase inhibitors on retinal ganglion cells.

Mol Neurodegener. 2016;11(1):30

Authors: Kim BJ, Silverman SM, Liu Y, Wordinger RJ, Pang IH, Clark AF

Abstract
BACKGROUND: The c-Jun N-terminal kinase (JNK) signaling pathway plays an important role in neuronal pathophysiology. Using JNK inhibitors, we examined involvement of the JNK pathway in cultured rat retinal ganglion cell (RGC) death and in mouse retinal ischemia/reperfusion (I/R) injury of the visual axis. The in vitro effects of JNK inhibitors were evaluated in cultured adult rat retinal cells enriched in RGCs. Retinal I/R was induced in C57BL/6J mice through elevation of intraocular pressure to 120 mmHg for 60 min followed by reperfusion. SP600125 was administered intraperitoneally once daily for 28 days. Phosphorylation of JNK and c-Jun in the retina was examined by immunoblotting and immunohistochemistry. The thickness of retinal layers and cell numbers in the ganglion cell layer (GCL) were examined using H&E stained retinal cross sections and spectral domain optical coherence tomography (SD-OCT). Retinal function was measured by scotopic flash electroretinography (ERG). Volumetric measurement of the superior colliculus (SC) as well as VGLUT2 and PSD95 expression were studied.
RESULTS: JNK inhibitors SP600125 and TAT-JNK-III, dose-dependently and significantly (p < 0.05) protected against glutamate excitotoxicity and trophic factor withdrawal induced RGC death in culture. In the I/R model, phosphorylation of JNK (pJNK) in the retina was significantly (p < 0.05) increased after injury. I/R injury significantly (p < 0.05) decreased the thickness of retinal layers, including the whole retina, inner plexiform layer, and inner nuclear layer and cell numbers in the GCL. Administration of SP600125 for 28 days protected against all these degenerative morphological changes (p < 0.05). In addition, SP600125 significantly (p < 0.05) protected against I/R-induced reduction in scotopic ERG b-wave amplitude at 3, 7, 14, 21 and 28 days after injury. SP600125 also protected against the I/R-induced losses in volume and levels of synaptic markers in the SC. Moreover, the protective effects of SP600125 in the retina and SC were also detected even with only 7 days (Days 1-7 after I/R) of SP600125 treatment.
CONCLUSIONS: Our results demonstrate the important role the JNK pathway plays in retinal degeneration in both in vitro and in vivo models and suggest that JNK inhibitors may be a useful therapeutic strategy for neuroprotection of RGCs in the retina.

PMID: 27098079 [PubMed - in process]

Flu-like and Other Systemic Drug Reactions Among Persons Receiving Weekly Rifapentine Plus Isoniazid or Daily Isoniazid for Treatment of Latent Tuberculosis Infection in the PREVENT Tuberculosis Study.

Fri, 04/22/2016 - 10:37
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Flu-like and Other Systemic Drug Reactions Among Persons Receiving Weekly Rifapentine Plus Isoniazid or Daily Isoniazid for Treatment of Latent Tuberculosis Infection in the PREVENT Tuberculosis Study.

Clin Infect Dis. 2015 Aug 15;61(4):527-35

Authors: Sterling TR, Moro RN, Borisov AS, Phillips E, Shepherd G, Adkinson NF, Weis S, Ho C, Villarino ME, Tuberculosis Trials Consortium

Abstract
BACKGROUND: Weekly rifapentine plus isoniazid for 3 months (3HP) is as effective as daily isoniazid for 9 months (9H) for latent tuberculosis infection in high-risk persons, but there have been reports of possible flu-like syndrome.
METHODS: We identified clinically significant systemic drug reactions (SDR) and evaluated risk factors in patients who did not complete treatment in the PREVENT Tuberculosis study.
RESULTS: Among 7552 persons who received ≥ 1 dose of study drug, 153 had a SDR: 138/3893 (3.5%) with 3HP vs 15/3659 (0.4%) with 9H (P < .001). In the 3HP arm, 87 (63%) had flu-like syndrome and 23 (17%) had cutaneous reactions; 13/3893 (0.3%) had severe reactions (6 were hypotensive) and 6 reported syncope. Symptoms occurred after a median of 3 doses, and 4 hours after the dose; median time to resolution was 24 hours. There were no deaths. In multivariate logistic regression analysis, factors independently associated with SDR included receipt of 3HP (adjusted odds ratio [aOR] 9.4; 95% confidence interval [CI], 5.5, 16.2), white non-Hispanic race/ethnicity (aOR 3.3; 95% CI, 2.3, 4.7), female sex (aOR 2.0; 95% CI, 1.4, 2.9), age ≥ 35 years (aOR 2.0; 95% CI, 1.4, 2.9), and lower body mass index (body mass index [BMI]; P = .009). In a separate multivariate analysis among persons who received 3HP, severe SDR were associated with white non-Hispanic race/ethnicity (aOR 5.4; 95% CI, 1.8, 16.3), and receipt of concomitant non-study medications (aOR 5.9; 95% CI, 1.3, 27.1).
CONCLUSIONS: SDR were more common with 3HP, and mostly flu-like. Persons of white race, female sex, older age, and lower BMI were at increased risk. Severe reactions were rare and associated with 3HP, concomitant medication, and white race. The underlying mechanism is unclear.
CLINICAL TRIALS REGISTRATION: NCT00023452.

PMID: 25904367 [PubMed - indexed for MEDLINE]

Transcription Factor Brn-3b Overexpression Enhances Neurite Outgrowth in PC12 Cells Under Condition of Hypoxia.

Thu, 04/21/2016 - 06:30
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Transcription Factor Brn-3b Overexpression Enhances Neurite Outgrowth in PC12 Cells Under Condition of Hypoxia.

Cell Mol Neurobiol. 2015 Aug;35(6):769-83

Authors: Phatak NR, Stankowska DL, Krishnamoorthy RR

Abstract
Transcription factor Brn-3b plays a key role in retinal ganglion cell differentiation, survival, and axon outgrowth during development. However, the precise role of Brn-3b in the normal adult retina as well as during neurodegeneration is unclear. In the current study, the effect of overexpression of Brn-3b was assessed in vitro, in PC12 cells under conditions of normoxia and hypoxia. Immunoblot analysis showed that overexpression of Brn-3b in PC12 cells as well as 661W cells produced significant increase in the growth cone marker, growth-associated protein-43 (GAP-43), and acetylated-tubulin (ac-TUBA). In addition, an increased immunostaining for GAP-43 and ac-TUBA was observed in PC12 cells overexpressing Brn-3b, which was accompanied by a marked increase in neurite outgrowth, compared to PC12 cells overexpressing the empty vector. In separate experiments, one set of PC12 cells transfected either with a Brn-3b expression vector or an empty vector was subjected to conditions of hypoxia for 2 h, while another set of similarly transfected PC12 cells was maintained in normoxic conditions. It was found that the upregulation of GAP-43 and ac-TUBA in PC12 cells overexpressing Brn-3b under conditions of normoxia was sustained under conditions of hypoxia. Immunocytochemical analysis revealed not only an upregulation of GAP-43 and ac-TUBA, but also increased neurite outgrowth in PC12 cells transfected with Brn-3b as compared to PC12 cells transfected with empty vector in both normoxia and hypoxia. The findings have implications for a potential role of Brn-3b in neurodegenerative diseases in which hypoxia/ischemia contribute to pathophysiology of the disease.

PMID: 25786379 [PubMed - indexed for MEDLINE]

A Novel Luciferase Assay For Sensitively Monitoring Myocilin Variants in Cell Culture.

Wed, 04/20/2016 - 06:33

A Novel Luciferase Assay For Sensitively Monitoring Myocilin Variants in Cell Culture.

Invest Ophthalmol Vis Sci. 2016 Apr 1;57(4):1939-1950

Authors: Zadoo S, Nguyen A, Zode G, Hulleman JD

Abstract
Purpose: Primary open angle glaucoma-associated mutations in myocilin (MYOC) cause protein "nonsecretion," rendering secreted MYOC difficult to detect using conventional techniques. This study focused on developing and using an assay that can quickly and easily detect mutant MYOC secretion.
Methods: We fused Gaussia luciferase (eGLuc2) to MYOC variants and expressed the constructs in HEK-293T and NTM-5 cells. Secreted and intracellular levels of MYOC eGLuc2 variants were evaluated by Western blotting and compared to untagged and FLAG-tagged MYOC constructs. Secreted and soluble intracellular MYOC eGLuc2 were measured by a GLuc assay. The secretion of nine additional MYOC mutants was assayed in conditioned media from transfected cells to test the applicability of the assay for monitoring other MYOC variants.
Results: Myocilin eGLuc2 behaved similarly to untagged and FLAG-tagged MYOC with respect to secretion, soluble intracellular levels, and in response to drug treatment. The GLuc assay could sensitively detect Y437H MYOC secretion 30 minutes after media change. Gaussia luciferase fused variants followed anticipated trends; nonpathogenic variants (D208E, G244V) were secreted at wild-type (WT) levels, whereas predicted disease-causing variants (C245Y, G246R, E300K, Y437H, I477N) demonstrated substantial secretion defects. Secretion defects caused by the C245Y, G246R, and Y437H mutations were partially rescued by permissive growth temperature. Interestingly, however, this increase in secretion was independent of newly synthesized protein.
Conclusions: Fusion of eGLuc2 to MYOC does not significantly change the behavior of MYOC. This newly developed MYOC reporter system can be used to study engineered MYOC variants and potentially to identify modulators of MYOC secretion and function.

PMID: 27092720 [PubMed - as supplied by publisher]

Crosstalk between TGFβ and Wnt signaling pathways in the human trabecular meshwork.

Wed, 04/20/2016 - 06:33

Crosstalk between TGFβ and Wnt signaling pathways in the human trabecular meshwork.

Exp Eye Res. 2016 Apr 14;

Authors: Webber HC, Bermudez JY, Sethi A, Clark AF, Mao W

Abstract
Primary Open Angle Glaucoma (POAG) is an irreversible, vision-threatening disease that affects millions worldwide. The principal risk factor of POAG is increased intraocular pressure (IOP) due to pathological changes in the trabecular meshwork (TM). The TGFβ signaling pathway activator TGFβ2 and the Wnt signaling pathway inhibitor secreted frizzled-related protein 1 (SFRP1) are elevated in the POAG TM. In this study, we determined whether there is a crosstalk between the TGFβ/Smad pathway and the canonical Wnt pathway using luciferase reporter assays. Lentiviral luciferase reporter vectors for studying the TGFβ/Smad pathway or the canonical Wnt pathway were transduced into primary human non-glaucomatous TM (NTM) cells. Cells were treated with or without a combination of 5 μg/ml TGFβ2 and/or 100 ng/ml Wnt3a recombinant proteins, and luciferase levels were measured using a plate reader. We found that TGFβ2 inhibited Wnt3a-induced canonical Wnt pathway activation, while Wnt3a inhibited TGFβ2-induced TGFβ/Smad pathway activation (n = 6, p < 0.05) in 3 NTM cell strains. We also found that knocking down of Smad4 or β-catenin using siRNA in HTM5 cells transfected with similar luciferase reporter plasmids abolished the inhibitory effect of TGFβ2 and/or Wnt3a on the other pathway (n = 6). Our results suggest the existence of a cross-inhibition between the TGFβ/Smad and canonical Wnt pathways in the TM, and this cross-inhibition may be mediated by Smad4 and β-catenin.

PMID: 27091054 [PubMed - as supplied by publisher]

Astrocyte Elevated Gene-1 (AEG-1) and the A(E)Ging HIV/AIDS-HAND.

Wed, 04/20/2016 - 06:33

Astrocyte Elevated Gene-1 (AEG-1) and the A(E)Ging HIV/AIDS-HAND.

Prog Neurobiol. 2016 Apr 14;

Authors: Vartak-Sharma N, Nooka S, Ghorpade A

Abstract
Recent attempts to analyze human immunodeficiency virus (HIV)-1-induced gene expression changes in astrocytes uncovered a multifunctional oncogene, astrocyte elevated gene-1 (AEG-1). Our previous studies revealed that AEG-1 regulates reactive astrocytes proliferation, migration and inflammation, all hallmarks of aging and CNS injury. Moreover, the involvement of AEG-1 in neurodegenerative disorders, such as Huntington's disease and migraine, and its induction in the aged brain suggest a plausible role in regulating overall CNS homeostasis and aging. Therefore, it is important to investigate AEG-1 specifically in aging-associated cognitive decline. In this study, we decipher the common mechanistic links in cancer, aging and HIV-1-associated neurocognitive disorders that likely contribute to AEG-1-based regulation of astrocyte responses and function. Despite AEG-1 incorporation into HIV-1 virions and its induction by HIV-1, tumor necrosis factor-α and interleukin-1β, the specific role(s) of AEG-1 in astrocyte-driven HIV-1 neuropathogenesis are incompletely defined. We propose that AEG-1 plays a central role in a multitude of cellular stress responses involving mitochondria, endoplasmic reticulum and the nucleolus. It is thus important to further investigate AEG-1-based cellular and molecular regulation in order to successfully develop better therapeutic approaches that target AEG-1 to combat cancer, HIV-1 and aging.

PMID: 27090750 [PubMed - as supplied by publisher]

Pyruvate stabilizes electrocardiographic and hemodynamic function in pigs recovering from cardiac arrest.

Wed, 04/20/2016 - 06:33
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Pyruvate stabilizes electrocardiographic and hemodynamic function in pigs recovering from cardiac arrest.

Exp Biol Med (Maywood). 2015 Dec;240(12):1774-84

Authors: Cherry BH, Nguyen AQ, Hollrah RA, Williams AG, Hoxha B, Olivencia-Yurvati AH, Mallet RT

Abstract
Cardiac electromechanical dysfunction may compromise recovery of patients who are initially resuscitated from cardiac arrest, and effective treatments remain elusive. Pyruvate, a natural intermediary metabolite, energy substrate, and antioxidant, has been found to protect the heart from ischemia-reperfusion injury. This study tested the hypothesis that pyruvate-enriched resuscitation restores hemodynamic, metabolic, and electrolyte homeostasis following cardiac arrest. Forty-two Yorkshire swine underwent pacing-induced ventricular fibrillation and, after 6 min pre-intervention arrest, 4 min precordial compressions followed by transthoracic countershocks. After defibrillation and recovery of spontaneous circulation, the pigs were monitored for another 4 h. Sodium pyruvate or NaCl were infused i.v. (0.1 mmol·kg(-1)·min(-1)) throughout precordial compressions and the first 60 min recovery. In 8 of the 24 NaCl-infused swine, the first countershock converted ventricular fibrillation to pulseless electrical activity unresponsive to subsequent countershocks, but only 1 of 18 pyruvate-treated swine developed pulseless electrical activity (relative risk 0.17; 95% confidence interval 0.13-0.22). Pyruvate treatment also lowered the dosage of vasoconstrictor phenylephrine required to maintain systemic arterial pressure at 15-60 min recovery, hastened clearance of excess glucose, elevated arterial bicarbonate, and raised arterial pH; these statistically significant effects persisted up to 3 h after sodium pyruvate infusion, while infusion-induced hypernatremia subsided. These results demonstrate that pyruvate-enriched resuscitation achieves electrocardiographic and hemodynamic stability in swine during the initial recovery from cardiac arrest. Such metabolically based treatment may offer an effective strategy to support cardiac electromechanical recovery immediately after cardiac arrest.

PMID: 26088865 [PubMed - indexed for MEDLINE]

Challenges in the Development of Therapy for Dry Age-Related Macular Degeneration.

Tue, 04/19/2016 - 06:31
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Challenges in the Development of Therapy for Dry Age-Related Macular Degeneration.

Adv Exp Med Biol. 2016;854:103-9

Authors: Wei CX, Sun A, Yu Y, Liu Q, Tan YQ, Tachibana I, Zeng H, Wei JY

Abstract
Dry age-related macular degeneration (AMD), a multifactorial progressive degenerative disease of the retinal photoreceptors, pigmented epithelium and Bruch's membrane/choroid in central retina, causes visual impairment in millions of elderly people worldwide. The only available therapy for this disease is the over-the-counter (OTC) multi-vitamins plus macular xanthophyll (lutein/zeaxanthin) which attempts to block the damages of oxidative stress and ionizing blue light. Therefore development of dry AMD prescribed treatment is a pressing unmet medical need. However, this effort is currently hindered by many challenges, including an incomplete understanding of the mechanism of pathogenesis that leads to uncertain targets, confounded by not yet validated preclinical models and the difficulty to deliver the drugs to the posterior segment of the eye. Additionally, with slow disease progression and a less than ideal endpoint measurement method, clinical trials are necessarily large, lengthy and expensive. Increased commitment to research and development is an essential foundation for dealing with these problems. Innovations in clinical trials with novel endpoints, nontraditional study designs and the use of surrogate diseases might shorten the study time, reduce the patient sample size and consequently lower the budget for the development of the new therapies for the dry AMD.

PMID: 26427400 [PubMed - indexed for MEDLINE]

Introduction to EER Special Issue on ocular fibrosis.

Tue, 04/19/2016 - 06:31
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Introduction to EER Special Issue on ocular fibrosis.

Exp Eye Res. 2016 Jan;142:1

Authors: O'Brien C, Clark AF

PMID: 26253011 [PubMed - indexed for MEDLINE]

The prodrug DHED selectively delivers 17β-estradiol to the brain for treating estrogen-responsive disorders.

Tue, 04/19/2016 - 06:31
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The prodrug DHED selectively delivers 17β-estradiol to the brain for treating estrogen-responsive disorders.

Sci Transl Med. 2015 Jul 22;7(297):297ra113

Authors: Prokai L, Nguyen V, Szarka S, Garg P, Sabnis G, Bimonte-Nelson HA, McLaughlin KJ, Talboom JS, Conrad CD, Shughrue PJ, Gould TD, Brodie A, Merchenthaler I, Koulen P, Prokai-Tatrai K

Abstract
Many neurological and psychiatric maladies originate from the deprivation of the human brain from estrogens. However, current hormone therapies cannot be used safely to treat these conditions commonly associated with menopause because of detrimental side effects in the periphery. The latter also prevents the use of the hormone for neuroprotection. We show that a small-molecule bioprecursor prodrug, 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), converts to 17β-estradiol in the brain after systemic administration but remains inert in the rest of the body. The localized and rapid formation of estrogen from the prodrug was revealed by a series of in vivo bioanalytical assays and through in vivo imaging in rodents. DHED treatment efficiently alleviated symptoms that originated from brain estrogen deficiency in animal models of surgical menopause and provided neuroprotection in a rat stroke model. Concomitantly, we determined that 17β-estradiol formed in the brain from DHED elicited changes in gene expression and neuronal morphology identical to those obtained after direct 17β-estradiol treatment. Together, complementary functional and mechanistic data show that our approach is highly relevant therapeutically, because administration of the prodrug selectively produces estrogen in the brain independently from the route of administration and treatment regimen. Therefore, peripheral responses associated with the use of systemic estrogens, such as stimulation of the uterus and estrogen-responsive tumor growth, were absent. Collectively, our brain-selective prodrug approach may safely provide estrogen neuroprotection and medicate neurological and psychiatric symptoms developing from estrogen deficiency, particularly those encountered after surgical menopause, without the adverse side effects of current hormone therapies.

PMID: 26203081 [PubMed - indexed for MEDLINE]

Methylene blue-induced neuronal protective mechanism against hypoxia-reoxygenation stress.

Tue, 04/19/2016 - 06:31
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Methylene blue-induced neuronal protective mechanism against hypoxia-reoxygenation stress.

Neuroscience. 2015 Aug 20;301:193-203

Authors: Ryou MG, Choudhury GR, Li W, Winters A, Yuan F, Liu R, Yang SH

Abstract
UNLABELLED: Brain ischemia and reperfusion (I/R) injury occurs in various pathological conditions, but there is no effective treatment currently available in clinical practice. Methylene blue (MB) is a century-old drug with a newly discovered protective function in the ischemic stroke model. In the current investigation we studied the MB-induced neuroprotective mechanism focusing on stabilization and activation of hypoxia-inducible factor-1α (HIF-1α) in an in vitro oxygen and glucose deprivation (OGD)-reoxygenation model.
METHODS: HT22 cells were exposed to OGD (0.1% O2, 6h) and reoxygenation (21% O2, 24h). Cell viability was determined with the calcein AM assay. The dynamic change of intracellular O2 concentration was monitored by fluorescence lifetime imaging microscopy (FLTIM). Glucose uptake was quantified using the 2-[N-(7-Nitrobenz-2-Oxa-1,3-Diazol-4-yl)Amino]-2-Deoxy-d-Glucose (2-NBDG) assay. ATP concentration and glycolytic enzyme activity were examined by spectrophotometry. Protein content changes were measured by immunoblot: HIF-1α, prolyl hydroxylase 2 (PHD2), erythropoietin (EPO), Akt, mTOR, and PIP5K. The contribution of HIF-1α activation in the MB-induced neuroprotective mechanism was confirmed by blocking HIF-1α activation with 2-methoxyestradiol-2 (2-MeOE2) and by transiently transfecting constitutively active HIF-1α.
RESULTS: MB increases cell viability by about 50% vs. OGD control. Compared to the corresponding control, MB increases intracellular O2 concentration and glucose uptake as well as the activities of hexokinase and G-6-PDH, and ATP concentration. MB activates the EPO signaling pathway with a corresponding increase in HIF-1α. Phosphorylation of Akt was significantly increased with MB treatment followed by activation of the mTOR pathway. Importantly, we observed, MB increased nuclear translocation of HIF-1α vs. control (about three folds), which was shown by a ratio of nuclear:cytoplasmic HIF-1α protein content.
CONCLUSION: We conclude that MB protects the hippocampus-derived neuronal cells against OGD-reoxygenation injury by enhancing energy metabolism and increasing HIF-1α protein content accompanied by an activation of the EPO signaling pathway.

PMID: 26047733 [PubMed - indexed for MEDLINE]

Changes in biomechanical dysfunction and low back pain reduction with osteopathic manual treatment: results from the OSTEOPATHIC Trial.

Tue, 04/19/2016 - 06:31
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Changes in biomechanical dysfunction and low back pain reduction with osteopathic manual treatment: results from the OSTEOPATHIC Trial.

Man Ther. 2014 Aug;19(4):324-30

Authors: Licciardone JC, Kearns CM, Crow WT

Abstract
The purpose of this study was to measure changes in biomechanical dysfunction following osteopathic manual treatment (OMT) and to assess how such changes predict subsequent low back pain (LBP) outcomes. Secondary analyses were performed with data collected during the OSTEOPATHIC Trial wherein a randomized, double-blind, sham-controlled, 2 × 2 factorial design was used to study OMT for chronic LBP. At baseline, prevalence rates of non-neutral lumbar dysfunction, pubic shear, innominate shear, restricted sacral nutation, and psoas syndrome were determined in 230 patients who received OMT. Five OMT sessions were provided at weeks 0, 1, 2, 4, and 6, and the prevalence of each biomechanical dysfunction was again measured at week 8 immediately before the final OMT session. Moderate pain improvement (≥30% reduction on a 100-mm visual analogue scale) at week 12 defined a successful LBP response to treatment. Prevalence rates at baseline were: non-neutral lumbar dysfunction, 124 (54%); pubic shear, 191 (83%); innominate shear, 69 (30%); restricted sacral nutation, 87 (38%), and psoas syndrome, 117 (51%). Significant improvements in each biomechanical dysfunction were observed with OMT; however, only psoas syndrome remission occurred more frequently in LBP responders than non-responders (P for interaction = 0.002). Remission of psoas syndrome was the only change in biomechanical dysfunction that predicted subsequent LBP response after controlling for the other biomechanical dysfunctions and potential confounders (odds ratio, 5.11; 95% confidence interval, 1.54-16.96). These findings suggest that remission of psoas syndrome may be an important and previously unrecognized mechanism explaining clinical improvement in patients with chronic LBP following OMT.

PMID: 24704126 [PubMed - indexed for MEDLINE]

HIV/neuroAIDS biomarkers.

Sun, 04/17/2016 - 06:33

HIV/neuroAIDS biomarkers.

Prog Neurobiol. 2016 Apr 12;

Authors: Rahimian P, He JJ

Abstract
HIV infection often causes neurological symptoms including cognitive and motor dysfunction, which have been collectively termed HIV/neuroAIDS. Neuropsychological assessment and clinical symptoms have been the primary diagnostic criteria for HIV/neuroAIDS, even for the mild cognitive and motor disorder, the most prevalent form of HIV/neuroAIDS in the era of combination antiretroviral therapy. Those performance-based assessments and symptoms are generally descriptive and do not have the sensitivity and specificity to monitor the diagnosis, progression, and treatment response of the disease when compared to objective and quantitative laboratory-based biological markers, or biomarkers. In addition, effects of demographics and comorbidities such as substance abuse, psychiatric disease, nutritional deficiencies, and co-infection on HIV/neuroAIDS could be more readily determined using biomarkers than using neuropsychological assessment and clinical symptoms. Thus, there have been great efforts in identification of HIV/neuroAIDS biomarkers over the past two decades. The need for reliable biomarkers of HIV/neuroAIDS is expected to increase as the HIV-infected population ages and their vulnerability to neurodegenerative diseases, particularly Alzheimer's disease increases. Currently, three classes of HIV/neuroAIDS biomarkers are being pursued to establish objective laboratory-based definitions of HIV-associated neurologic injury: cerebrospinal fluid biomarkers, blood biomarkers, and neuroimaging biomarkers. In this review, we will focus on the current knowledge in the field of HIV/neuroAIDS biomarker discovery.

PMID: 27084354 [PubMed - as supplied by publisher]

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