Recent Research Articles from UNTHSC

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Boosting Endogenous Resistance of Brain to Ischemia.

Fri, 02/26/2016 - 07:00
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Boosting Endogenous Resistance of Brain to Ischemia.

Mol Neurobiol. 2016 Feb 24;

Authors: Sun F, Johnson SR, Jin K, Uteshev VV

Abstract
Most survivors of ischemic stroke remain physically disabled and require prolonged rehabilitation. However, some stroke victims achieve a full neurological recovery suggesting that the human brain can defend itself against ischemic injury, but the protective mechanisms are unknown. This study used selective pharmacological agents and a rat model of cerebral ischemic stroke to detect endogenous brain protective mechanisms that require activation of α7 nicotinic acetylcholine receptors (nAChRs). This endogenous protection was found to be (1) limited to less severe injuries; (2) significantly augmented by intranasal administration of a positive allosteric modulator of α7 nAChRs, significantly reducing brain injury and neurological deficits after more severe ischemic injuries; and (3) reduced by inhibition of calcium/calmodulin-dependent kinase-II. The physiological role of α7 nAChRs remains largely unknown. The therapeutic activation of α7 nAChRs after cerebral ischemia may serve as an important physiological responsibility of these ubiquitous receptors and holds a significant translational potential.

PMID: 26910820 [PubMed - as supplied by publisher]

Rhabdomyomatous mesenchymal hamartoma of the face causing trigeminal neuralgia.

Fri, 02/26/2016 - 07:00
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Rhabdomyomatous mesenchymal hamartoma of the face causing trigeminal neuralgia.

Am J Case Rep. 2015;16:338-40

Authors: White LR, Agrawal V, Sutton L, Balbosa AC

Abstract
BACKGROUND: Rhabdomyomatous mesenchymal hamartoma (RMH) is a benign, potentially pigmented lesion that occurs in the head and neck region. It generally consists of haphazardly arranged skeletal muscle with adipose tissue, blood vessels, collagen and nerve fibers and is largely asymptomatic. Trigeminal neuralgia is pain due to compression of the trigeminal nerve. TN may be idiopathic or associated with lesion-mediated compression.
CASE REPORT: We describe the case of a 14-year-old female presenting with trigeminal neuralgia (TN) associated with RMH. On initial consultation, the patient presented with a history of right-sided lower facial swelling, numbness, and pain. Evaluation by various specialists confirmed TN. Surgical resection of the lesion resolved the condition and pathology confirmed RMH.
CONCLUSIONS: This is the first case report demonstrating RMH-mediated TN. Surgical resection of the RMH is a safe management approach for this diagnosis.

PMID: 26037964 [PubMed - indexed for MEDLINE]

Joseon funerary texts tested using ancient DNA analysis of a Korean mummy.

Fri, 02/26/2016 - 07:00
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Joseon funerary texts tested using ancient DNA analysis of a Korean mummy.

Anat Rec (Hoboken). 2015 Jun;298(6):1191-207

Authors: Oh CS, Koh BJ, Yoo DS, Park JB, Min SR, Kim YS, Lee SS, Ge J, Seo SB, Shin DH

Abstract
In Korea, ancient DNA (aDNA) analysis has been applied to investigations into the genetic affiliations of mummies found in Joseon Dynasty tombs (1392-1910 CE), becoming now indispensable tool for researches studying human remains from archaeological sites. In the course of our recent examinations on a Korean mummy of Joseon Dynasty, we discovered many teeth contained in a pouch. And in fact, the historical literature on the topic of Joseon funerals contain general accounts of pouches in which an individual's lost teeth were collected over the course of a lifetime and, after death, placed in the coffin with the body. To test the veracity of the historical texts, the present study undertook aDNA analyses and compared the results between specifically questioned (Q) samples (teeth) and known (K) samples (brain and bone) from the mummy to ensure that they came from the same individual. Although the Q-K comparison of autosomal short tandem repeat results did not show full concordance due to allelic drop-outs in some loci, our statistical calculation indicated that the teeth in the pouch are highly likely those of the mummy. Additionally, Q-K comparison of mitochondrial DNA sequence results showed 100% matches between samples. There results, in short, could not gainsay the conjecture that the teeth samples originated from the person buried in the tomb; and if so, he must have kept his teeth for a long time after their loss. As the application of aDNA analysis to Korean mummy studies develops, there will be other opportunities to test historical documents, particularly those referring to funerary rites.

PMID: 25998652 [PubMed - indexed for MEDLINE]

An overview of the Families Improving Together (FIT) for weight loss randomized controlled trial in African American families.

Fri, 02/26/2016 - 07:00
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An overview of the Families Improving Together (FIT) for weight loss randomized controlled trial in African American families.

Contemp Clin Trials. 2015 May;42:145-57

Authors: Wilson DK, Kitzman-Ulrich H, Resnicow K, Van Horn ML, St George SM, Siceloff ER, Alia KA, McDaniel T, Heatley V, Huffman L, Coulon S, Prinz R

Abstract
BACKGROUND: The Families Improving Together (FIT) randomized controlled trial tests the efficacy of integrating cultural tailoring, positive parenting, and motivational strategies into a comprehensive curriculum for weight loss in African American adolescents. The overall goal of the FIT trial is to test the effects of an integrated intervention curriculum and the added effects of a tailored web-based intervention on reducing z-BMI in overweight African American adolescents.
DESIGN AND SETTING: The FIT trial is a randomized group cohort design the will involve 520 African American families with an overweight adolescent between the ages of 11-16 years. The trial tests the efficacy of an 8-week face-to-face group randomized program comparing M + FWL (Motivational Plus Family Weight Loss) to a comprehensive health education program (CHE) and re-randomizes participants to either an 8-week on-line tailored intervention or control on-line program resulting in a 2 (M + FWL vs. CHE group) × 2 (on-line intervention vs. control on-line program) factorial design to test the effects of the intervention on reducing z-BMI at post-treatment and at 6-month follow-up.
INTERVENTION: The interventions for this trial are based on a theoretical framework that is novel and integrates elements from cultural tailoring, Family Systems Theory, Self-Determination Theory and Social Cognitive Theory. The intervention targets positive parenting skills (parenting style, monitoring, communication); cultural values; teaching parents to increase youth motivation by encouraging youth to have input and choice (autonomy-support); and provides a framework for building skills and self-efficacy through developing weight loss action plans that target goal setting, monitoring, and positive feedback.

PMID: 25835731 [PubMed - indexed for MEDLINE]

Store-Operated Ca2+ Channels in Mesangial Cells Inhibit Matrix Protein Expression.

Fri, 02/26/2016 - 07:00
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Store-Operated Ca2+ Channels in Mesangial Cells Inhibit Matrix Protein Expression.

J Am Soc Nephrol. 2015 Nov;26(11):2691-702

Authors: Wu P, Wang Y, Davis ME, Zuckerman JE, Chaudhari S, Begg M, Ma R

Abstract
Accumulation of extracellular matrix derived from glomerular mesangial cells is an early feature of diabetic nephropathy. Ca(2+) signals mediated by store-operated Ca(2+) channels regulate protein production in a variety of cell types. The aim of this study was to determine the effect of store-operated Ca(2+) channels in mesangial cells on extracellular matrix protein expression. In cultured human mesangial cells, activation of store-operated Ca(2+) channels by thapsigargin significantly decreased fibronectin protein expression and collagen IV mRNA expression in a dose-dependent manner. Conversely, inhibition of the channels by 2-aminoethyl diphenylborinate significantly increased the expression of fibronectin and collagen IV. Similarly, overexpression of stromal interacting molecule 1 reduced, but knockdown of calcium release-activated calcium channel protein 1 (Orai1) increased fibronectin protein expression. Furthermore, 2-aminoethyl diphenylborinate significantly augmented angiotensin II-induced fibronectin protein expression, whereas thapsigargin abrogated high glucose- and TGF-β1-stimulated matrix protein expression. In vivo knockdown of Orai1 in mesangial cells of mice using a targeted nanoparticle siRNA delivery system resulted in increased expression of glomerular fibronectin and collagen IV, and mice showed significant mesangial expansion compared with controls. Similarly, in vivo knockdown of stromal interacting molecule 1 in mesangial cells by recombinant adeno-associated virus-encoded shRNA markedly increased collagen IV protein expression in renal cortex and caused mesangial expansion in rats. These results suggest that store-operated Ca(2+) channels in mesangial cells negatively regulate extracellular matrix protein expression in the kidney, which may serve as an endogenous renoprotective mechanism in diabetes.

PMID: 25788524 [PubMed - indexed for MEDLINE]

An attachment-based description of the medial collateral and spring ligament complexes.

Fri, 02/26/2016 - 07:00
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An attachment-based description of the medial collateral and spring ligament complexes.

Foot Ankle Int. 2015 Jun;36(6):710-21

Authors: Cromeens BP, Kirchhoff CA, Patterson RM, Motley T, Stewart D, Fisher C, Reeves RE

Abstract
BACKGROUND: Anatomy of the medial collateral and spring ligament complexes has been the cause of confusion. The anatomic description is highly dependent on the source studied and little agreement exists between texts. In addition, inconsistent nomenclature has been used to describe the components. This study attempted to clarify confusion through the creation of a 3D ligament map using attachment-based dissection.
METHODS: Nine fresh foot and ankle specimens were observed. The medial collateral ligament and spring ligament complexes were dissected using their attachment sites as a guide to define individual components. Each component's perimeter and thickness was measured and each bony attachment was mapped using a microscribe 3D digitizer.
RESULTS: Five components were identified contributing to the ligament complexes of interest: the tibiocalcaneonavicular, superficial posterior tibiotalar, deep posterior tibiotalar, deep anterior tibiotalar, and inferoplantar longitudinal ligaments. The largest component by total attachment area was the tibiocalcaneonavicular ligament followed by the deep posterior tibiotalar ligament. The largest ligament surface area of attachment to the tibia and talus was the deep posterior tibiotalar ligament. The largest attachment to the navicular and calcaneus was the tibiocalcaneonavicular ligament, which appeared to function in holding these bones in proximity while supporting the head of the talus.
CONCLUSION: By defining complex components by their attachment sites, a novel, more functional and reproducible description of the medial collateral and spring ligament complexes was created.
CLINICAL RELEVANCE: The linear measurements and 3D maps may prove useful when attempting more anatomically accurate reconstructions.

PMID: 25712121 [PubMed - indexed for MEDLINE]

High sensitivity multiplex short tandem repeat loci analyses with massively parallel sequencing.

Fri, 02/26/2016 - 07:00
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High sensitivity multiplex short tandem repeat loci analyses with massively parallel sequencing.

Forensic Sci Int Genet. 2015 May;16:38-47

Authors: Zeng X, King JL, Stoljarova M, Warshauer DH, LaRue BL, Sajantila A, Patel J, Storts DR, Budowle B

Abstract
STR typing in forensic genetics has been performed traditionally using capillary electrophoresis (CE). However, CE-based method has some limitations: a small number of STR loci can be used; stutter products, dye artifacts and low level alleles. Massively parallel sequencing (MPS) has been considered a viable technology in recent years allowing high-throughput coverage at a relatively affordable price. Some of the CE-based limitations may be overcome with the application of MPS. In this study, a prototype multiplex STR System (Promega) was amplified and prepared using the TruSeq DNA LT Sample Preparation Kit (Illumina) in 24 samples. Results showed that the MinElute PCR Purification Kit (Qiagen) was a better size selection method compared with recommended diluted bead mixtures. The library input sensitivity study showed that a wide range of amplicon product (6-200ng) could be used for library preparation without apparent differences in the STR profile. PCR sensitivity study indicated that 62pg may be minimum input amount for generating complete profiles. Reliability study results on 24 different individuals showed that high depth of coverage (DoC) and balanced heterozygote allele coverage ratios (ACRs) could be obtained with 250pg of input DNA, and 62pg could generate complete or nearly complete profiles. These studies indicate that this STR multiplex system and the Illumina MiSeq can generate reliable STR profiles at a sensitivity level that competes with current widely used CE-based method.

PMID: 25528025 [PubMed - indexed for MEDLINE]

Effect of adenovirus-mediated RNA interference of IL-1β expression on spinal cord injury in rats.

Wed, 02/24/2016 - 07:29

Effect of adenovirus-mediated RNA interference of IL-1β expression on spinal cord injury in rats.

Spinal Cord. 2016 Feb 23;

Authors: Lin WP, Lin JH, Cai B, Shi JX, Li WJ, Choudhury GR, Wu SQ, Wu JZ, Wu HP, Ke QF

Abstract
STUDY DESIGN: We introduced an adenoviral vector expressing interleukin-1β (IL-1β) small-hairpin RNA (shRNA) into the injured spinal cords to evaluate the therapeutic potential of IL-1β downregulation in a rat model of spinal cord injury (SCI).
OBJECTIVES: The purpose of this study was to investigate the possible protective effects of the IL-1β downregulation on traumatic SCI in rats.
SETTING: Department of Orthopedic Surgery, The Second Affiliated Hospital, Fujian Medical University, Quanzhou, People's Republic of China.
METHODS: An adenoviral shRNA targeting IL-1β was constructed and injected at the T12 section 7 days before SCI. The rats' motor functions were evaluated by the Basso-Beattie-Bresnahan (BBB) rating scale. Immunofluorescence, enzyme-linked immunosorbent assay, flow-cytometric analysis and western blots were also performed.
RESULTS: Animals downregulating IL-1β had significantly better recovery of locomotor function and less neuronal loss after SCI. In addition, IL-1β downregulation significantly decreased tumor necrosis factor-alpha (TNF-α) level and Bax expression, reduced the activity of caspase-3 and increased Bcl-2 expression after SCI.
CONCLUSION: This study demonstrated that the IL-1β downregulation may have potential therapeutic benefits for both reducing secondary damages and improving the outcomes after traumatic SCI.Spinal Cord advance online publication, 23 February 2016; doi:10.1038/sc.2016.20.

PMID: 26902461 [PubMed - as supplied by publisher]

Tip110: Physical properties, primary structure, and biological functions.

Sun, 02/21/2016 - 07:29

Tip110: Physical properties, primary structure, and biological functions.

Life Sci. 2016 Feb 16;

Authors: Whitmill A, Timani KA, Liu Y, He JJ

Abstract
HIV-1 Tat-interacting protein of 110kDa (Tip110), also referred to as squamous cell carcinoma antigen recognized by T cells 3 (Sart3), p110 or p110(nrb), was initially identified as a cDNA clone (KIAA0156) without annotated functions. Over the past twenty years, several functions have been attributed to this protein. The proposed biological functions include roles for Tip110 in pre-mRNA splicing, gene transcription, stem cell biology, and development. Dysregulation of Tip110 is also a contributing factor in the development of cancer and other human diseases. It is clear that our understanding of this protein is rapidly evolving. In this review, we aimed to provide a summary of all the existing literature on this gene/protein and its proposed biological functions.

PMID: 26896687 [PubMed - as supplied by publisher]

Racial and Ethnic Disparities in Health and Health Care: an Assessment and Analysis of the Awareness and Perceptions of Public Health Workers Implementing a Statewide Community Transformation Grant in Texas.

Sun, 02/21/2016 - 07:29

Racial and Ethnic Disparities in Health and Health Care: an Assessment and Analysis of the Awareness and Perceptions of Public Health Workers Implementing a Statewide Community Transformation Grant in Texas.

J Racial Ethn Health Disparities. 2016 Mar;3(1):46-54

Authors: Akinboro O, Ottenbacher A, Martin M, Harrison R, James T, Martin E, Murdoch J, Linnear K, Cardarelli K

Abstract
INTRODUCTION: Little is known about the awareness of public health professionals regarding racial and ethnic disparities in health in the United States of America (USA). Our study objective was to assess the awareness and perceptions of a group of public health workers in Texas regarding racial health disparities and their chief contributing causes.
METHODS: We surveyed public health professionals working on a statewide grant in Texas, who were participants at health disparities' training workshops. Multivariable logistic regression was employed in examining the association between the participants' characteristics and their perceptions of the social determinants of health as principal causes of health disparities.
RESULTS: There were 106 respondents, of whom 38 and 35 % worked in health departments and non-profit organizations, respectively. The racial/ethnic groups with the highest incidence of HIV/AIDS and hypertension were correctly identified by 63 and 50 % of respondents, respectively, but only 17, and 32 % were knowledgeable regarding diabetes and cancer, respectively. Seventy-one percent of respondents perceived that health disparities are driven by the major axes of the social determinants of health. Exposure to information about racial/ethnic health disparities within the prior year was associated with a higher odds of perceiving that social determinants of health were causes of health disparities (OR 9.62; 95 % CI 2.77, 33.41).
CONCLUSION: Among public health workers, recent exposure to information regarding health disparities may be associated with their perceptions of health disparities. Further research is needed to investigate the impact of such exposure on their long-term perception of disparities, as well as the equity of services and programs they administer.

PMID: 26896104 [PubMed - in process]

WISE 2005: Aerobic and resistive countermeasures prevent paraspinal muscle deconditioning during 60-days bed rest in women.

Sat, 02/20/2016 - 07:32

WISE 2005: Aerobic and resistive countermeasures prevent paraspinal muscle deconditioning during 60-days bed rest in women.

J Appl Physiol (1985). 2016 Feb 18;:jap.00532.2015

Authors: Holt JA, Macias BR, Schneider SM, Watenpaugh DE, Lee SM, Chang DG, Hargens AR

Abstract
Microgravity-induced lumbar paraspinal muscle deconditioning may contribute to back pain commonly experienced by astronauts, and may increase the risk of postflight injury. We hypothesized that a combined resistance and aerobic exercise countermeasure protocol that included spinal loading would mitigate lumbar paraspinal muscle deconditioning during 60-days of bed rest in women.
METHODS: Sixteen women underwent 60-day, 6° head-down-tilt bed rest and were randomized into control and exercise groups. During bed rest, the control group performed no exercise. The exercise group performed supine treadmill exercise within lower body negative pressure (LBNP) for 3-4 d/wk and flywheel resistive exercise for 2-3 d/wk. Paraspinal muscle cross-sectional area (CSA) was measured using a lumbar spine MRI sequence before and after bed rest (BR). In addition, isokinetic spinal flexion and extension strengths were measured before and after BR. Data are presented as mean ± SD.
RESULTS: Total lumbar paraspinal muscle CSA decreased significantly more in controls (10.9 ± 3.4%) than in exercisers (4.3 ± 3.4%; p <0.05). The erector spinae was the primary contributor (76%) to total lumbar paraspinal muscle loss. Moreover, exercise attenuated isokinetic spinal extension loss (-4.3 ± 4.5%), as compared to controls (-16.6 ± 11.2%; p <0.05).
CONCLUSIONS: LBNP treadmill and flywheel resistive exercises during simulated microgravity mitigates decrements in lumbar paraspinal muscle structure and spine function. Therefore, space flight exercise countermeasures that attempt to reproduce spinal loads experienced on Earth may mitigate spinal deconditioning during long-duration space travel.

PMID: 26893030 [PubMed - as supplied by publisher]

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]

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