Recent Research Articles from UNTHSC

Recent research articles indexed in PubMed from authors affiliated with the UNT Health Science Center.

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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]
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Resolving the etiology of atopic disorders by using genetic analysis of racial ancestry.

Thu, 06/29/2017 - 07:39
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Resolving the etiology of atopic disorders by using genetic analysis of racial ancestry.

J Allergy Clin Immunol. 2016 Sep;138(3):676-99

Authors: Gupta J, Johansson E, Bernstein JA, Chakraborty R, Khurana Hershey GK, Rothenberg ME, Mersha TB

Abstract
Atopic dermatitis (AD), food allergy, allergic rhinitis, and asthma are common atopic disorders of complex etiology. The frequently observed atopic march from early AD to asthma, allergic rhinitis, or both later in life and the extensive comorbidity of atopic disorders suggest common causal mechanisms in addition to distinct ones. Indeed, both disease-specific and shared genomic regions exist for atopic disorders. Their prevalence also varies among races; for example, AD and asthma have a higher prevalence in African Americans when compared with European Americans. Whether this disparity stems from true genetic or race-specific environmental risk factors or both is unknown. Thus far, the majority of the genetic studies on atopic diseases have used populations of European ancestry, limiting their generalizability. Large-cohort initiatives and new analytic methods, such as admixture mapping, are currently being used to address this knowledge gap. Here we discuss the unique and shared genetic risk factors for atopic disorders in the context of ancestry variations and the promise of high-throughput "-omics"-based systems biology approach in providing greater insight to deconstruct their genetic and nongenetic etiologies. Future research will also focus on deep phenotyping and genotyping of diverse racial ancestry, gene-environment, and gene-gene interactions.

PMID: 27297995 [PubMed - indexed for MEDLINE]

Social support for physical activity: Comparison of family, friends, and coworkers.

Wed, 06/28/2017 - 07:35
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Social support for physical activity: Comparison of family, friends, and coworkers.

Work. 2016;55(4):893-899

Authors: Sarkar S, Taylor WC, Lai D, Shegog R, Paxton RJ

Abstract
BACKGROUND: Few studies have examined the associations among family, friend, and coworker social support for physical activity. It is important to know the sources of social support that facilitate and promote physical activity among fulltime working adults.
OBJECTIVE: We analyzed the associations among family, friend, and coworker social support for physical activity and moderate-to-vigorous physical activity among participants in a worksite study.
METHODS: This study was a cross-sectional analysis of baseline data from 144 participants from four worksites in a large, southwestern city in the United States. The intervention for the worksite study was Booster Breaks (a physical activity routine of 15 minutes) practiced daily to break-up prolonged sitting time. Descriptive statistics and multiple linear regressions were conducted using SPSS version 20.
RESULTS: Age was inversely associated (p = 0.001), and social support from friends (p = 0.04) and coworkers (p = 0.003) were positively associated with physical activity in the unadjusted model. After controlling for all the covariates (age, sex, marital status, BMI, education, and income) in the model, only coworker social support was positively (p = 0.027) associated with physical activity among participants in the workplace study.
CONCLUSIONS: Coworker social support is an important correlate of physical activity and should be incorporated in workplace health promotion programs.

PMID: 28059824 [PubMed - indexed for MEDLINE]

Population and performance analyses of four major populations with Illumina's FGx Forensic Genomics System.

Tue, 06/27/2017 - 07:41

Population and performance analyses of four major populations with Illumina's FGx Forensic Genomics System.

Forensic Sci Int Genet. 2017 Jun 17;30:81-92

Authors: Churchill JD, Novroski NMM, King JL, Seah LH, Budowle B

Abstract
The MiSeq FGx Forensic Genomics System (Illumina) enables amplification and massively parallel sequencing of 59 STRs, 94 identity informative SNPs, 54 ancestry informative SNPs, and 24 phenotypic informative SNPs. Allele frequency and population statistics data were generated for the 172 SNP loci included in this panel on four major population groups (Chinese, African Americans, US Caucasians, and Southwest Hispanics). Single-locus and combined random match probability values were generated for the identity informative SNPs. The average combined STR and identity informative SNP random match probabilities (assuming independence) across all four populations were 1.75E-67 and 2.30E-71 with length-based and sequence-based STR alleles, respectively. Ancestry and phenotype predictions were obtained using the ForenSeq™ Universal Analysis System (UAS; Illumina) based on the ancestry informative and phenotype informative SNP profiles generated for each sample. Additionally, performance metrics, including profile completeness, read depth, relative locus performance, and allele coverage ratios, were evaluated and detailed for the 725 samples included in this study. While some genetic markers included in this panel performed notably better than others, performance across populations was generally consistent. The performance and population data included in this study support that accurate and reliable profiles were generated and provide valuable background information for laboratories considering internal validation studies and implementation.

PMID: 28651097 [PubMed - as supplied by publisher]

Role of angiotensin-converting enzyme 1 within the median preoptic nucleus following chronic intermittent hypoxia.

Tue, 06/27/2017 - 07:41
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Role of angiotensin-converting enzyme 1 within the median preoptic nucleus following chronic intermittent hypoxia.

Am J Physiol Regul Integr Comp Physiol. 2017 Feb 01;312(2):R245-R252

Authors: Faulk K, Shell B, Nedungadi TP, Cunningham JT

Abstract
Sustained hypertension is an important consequence of obstructive sleep apnea. An animal model of the hypoxemia associated with sleep apnea, chronic intermittent hypoxia (CIH), produces increased sympathetic nerve activity (SNA) and sustained increases in blood pressure. Many mechanisms have been implicated in the hypertension associated with CIH, including the role of ΔFosB within the median preoptic nucleus (MnPO). Also, the renin-angiotensin system (RAS) has been associated with CIH hypertension. We conducted experiments to determine the possible association of FosB/ΔFosB with a RAS component, angiotensin-converting enzyme 1 (ACE1), within the MnPO following 7 days of CIH. Retrograde tract tracing from the paraventricular nucleus (PVN), a downstream region of the MnPO, was used to establish a potential pathway for FosB/ΔFosB activation of MnPO ACE1 neurons. After CIH, ACE1 cells with FosB/ΔFosB expression increased colocalization with a retrograde tracer that was injected unilaterally within the PVN. Also, Western blot examination showed ACE1 protein expression increasing within the MnPO following CIH. Chromatin immunoprecipitation (ChIP) assays demonstrated an increase in FosB/ΔFosB association with the ACE1 gene within the MnPO following CIH. FosB/ΔFosB may transcriptionally target ACE1 within the MnPO following CIH to affect the downstream PVN region, which may influence SNA and blood pressure.

PMID: 28003214 [PubMed - indexed for MEDLINE]

Retention in care and reasons for discontinuation of lifelong antiretroviral therapy in a cohort of Cameroonian pregnant and breastfeeding HIV-positive women initiating 'Option B+' in the South West Region.

Tue, 06/27/2017 - 07:41
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Retention in care and reasons for discontinuation of lifelong antiretroviral therapy in a cohort of Cameroonian pregnant and breastfeeding HIV-positive women initiating 'Option B+' in the South West Region.

Trop Med Int Health. 2017 Feb;22(2):161-170

Authors: Atanga PN, Ndetan HT, Achidi EA, Meriki HD, Hoelscher M, Kroidl A

Abstract
OBJECTIVE: To assess linkage and retention in care along the PMTCT cascade in HIV-positive pregnant and breastfeeding women initiating Option B+ in Cameroon.
METHODS: We prospectively determined uptake of HIV testing and counselling (HTC), uptake of ART and retention in care after Option B+ initiation between October 2013 and December 2014 in pregnant and breastfeeding women from five sites within the Kumba Health District. Retention in care was assessed over at least 12 months follow-up and estimated by Kaplan-Meier analysis. During follow-up, tracing outcomes and reasons for discontinuing treatment were documented.
RESULTS: The uptake of HTC of 5813 women with unknown HIV status was 98.5%, 251 (4.4%) were newly diagnosed HIV positive, and ART uptake in women eligible to start Option B+ was 96.8%. We enrolled 268 women initiating lifelong ART in the follow-up. Overall, 65 (24.3%) discontinued treatment, either defined by loss to follow-up (44.6%) or actively stopped treatment (55.8%). Retention in care was 88.0% and 81.1% at 6 and 12 months, respectively. Discontinuation was significantly associated in multivariate analysis with small sites and high staff turnover [aOR 2.5 (95% CI 1.6, 3.9), P < 0.001]. Main reasons for stopping treatment were HIV status denial and stigma (52.8%), religious reasons (25.0%) and lack of transport fare (11.1%).
CONCLUSION: We observed good uptake of HTC, ART and retention in care, which declined over time. Discontinuation of Option B+ was highest at small sites with a high staff turnover. Improved staffing, adequate task shifting and community interventions to track defaulters including reducing stigma and religious beliefs may improve Option B+ retention.

PMID: 27865052 [PubMed - indexed for MEDLINE]

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

Tue, 06/27/2017 - 07:41
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Exaggerated sympathoexcitatory reflexes develop with changes in the rostral ventrolateral medulla in obese Zucker rats.

Am J Physiol Regul Integr Comp Physiol. 2016 Aug 01;311(2):R243-53

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 with lean Zucker rats (LZR). Sciatic nerve stimulation or activation of the nasopharyngeal reflex evoked larger rises in splanchnic sympathetic nerve activity (SNA) (79% and 45% larger in OZR, respectively; P < 0.05) and MAP in urethane-anesthetized, ventilated, paralyzed adult OZR compared with 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 that 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 - indexed for MEDLINE]

AMBULATORY BLOOD PRESSURE PATTERNS IN PATIENTS WITH RETINAL VEIN OCCLUSION.

Tue, 06/27/2017 - 07:41
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AMBULATORY BLOOD PRESSURE PATTERNS IN PATIENTS WITH RETINAL VEIN OCCLUSION.

Retina. 2016 Dec;36(12):2304-2310

Authors: Rao VN, Ulrich JN, Viera AJ, Parlin A, Fekrat S, Chavala SH

Abstract
PURPOSE: Failure of blood pressure (BP) to dip during sleep (nondipper pattern) is associated with cardiovascular disease and stroke. The prevalence and degree of nondipping and masked hypertension in patients with retinal vein occlusion (RVO), which is associated with stroke, has not been previously examined.
METHODS: We measured clinic and 24-hour ambulatory BPs in 22 patients with RVO and 20 control participants without known eye disease matched by age and sex. Mean BP dipping, defined as the ratio of difference in mean awake and sleep systolic BPs to mean awake systolic BP, and masked and nocturnal hypertension were compared between groups.
RESULTS: Mean 24-hour ambulatory BP was 144/79 mmHg among those with RVO and 136/77 mmHg among controls. Patients with RVO had an almost 2-fold higher prevalence of nondipping pattern (80.8% [95% confidence interval, 52.8-94.1] vs. 50.4% [95% confidence interval, 26.1-74.5]; P = 0.008). Average sleep systolic BP dip in patients with RVO was 6.1% versus 11.9% in controls (P = 0.004). More patients with RVO had masked hypertension by ambulatory BPs than controls (71% vs. 50%), but this difference was not statistically significant.
CONCLUSION: Our data suggest an association between RVO and nondipper BP pattern. Ambulatory BP monitoring may be useful in the evaluation of patients with RVO by identifying those who may benefit from more aggressive BP control.

PMID: 27205892 [PubMed - indexed for MEDLINE]

Racial Disparities in Menu-Labeling Usage: Analysis of the 2012 Behavioral Risk Factor Surveillance System (BRFSS) Sugar-Sweetened Beverage and Menu-Labeling Module.

Sun, 06/25/2017 - 07:35
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Racial Disparities in Menu-Labeling Usage: Analysis of the 2012 Behavioral Risk Factor Surveillance System (BRFSS) Sugar-Sweetened Beverage and Menu-Labeling Module.

J Racial Ethn Health Disparities. 2017 Jun 23;:

Authors: Shikdar S, Suzuki S

Abstract
OBJECTIVES: Race/ethnic disparities in obesity are widely reported and are often attributed to diet-related factors, such as menu-labeling usage. We aimed to determine whether racial difference exists in menu-labeling usage.
METHODS: Data from the 2012 Behavioral Risk Factor Surveillance System were used. Menu labeling was measured from the Sugar-Sweetened Beverages and Menu Labeling module administered in 18 states. We stratified the population into four race/ethnic categories: non-Hispanic whites (reference, n = 66,019, 63%), non-Hispanic blacks (n = 13,623, 13%), Hispanics (n = 14,671, 14%), and others (n = 7336, 7%). Logistic regression was used to examine the racial/ethnic differences in menu-labeling usage. Analyses were conducted adjusting for sociodemographic characteristics, sugar-sweetened beverage intake, and exercise.
RESULTS: The prevalence of menu-labeling usage was approximately 55% overall. Hispanics (adjusted odds ratio [AOR], 1.35; 95% confidence interval [CI], 1.14-1.60) and other race/ethnic groups (AOR, 1.39; 95% CI, 1.18-1.64) used menu labeling more compared to non-Hispanic whites. After stratification by race/ethnicity, menu-labeling usage was not associated with exercise or soda consumption among Hispanics, but significant associations were observed among the other three race/ethnic groups.
CONCLUSIONS: The findings suggest that participation in healthy behaviors was associated with the higher usage of menu labeling across all racial/ethnic groups except Hispanics. Future studies are needed to explore this mechanism among individuals engaging in unhealthier behavior as well as how it affects Hispanics.

PMID: 28646355 [PubMed - as supplied by publisher]

Increased glomerular filtration rate and impaired contractile function of mesangial cells in TRPC6 knockout mice.

Sun, 06/25/2017 - 07:35
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Increased glomerular filtration rate and impaired contractile function of mesangial cells in TRPC6 knockout mice.

Sci Rep. 2017 Jun 23;7(1):4145

Authors: Li W, Ding Y, Smedley C, Wang Y, Chaudhari S, Birnbaumer L, Ma R

Abstract
The present study was conducted to determine if TRPC6 regulates glomerular filtration rate (GFR) and the contractile function of glomerular mesangial cells (MCs). GFR was assessed in conscious TRPC6 wild type and knockout mice, and in anesthetized rats with and without in vivo knockdown of TRPC6 in kidneys. We found that GFR was significantly greater, and serum creatinine level was significantly lower in TRPC6 deficient mice. Consistently, local knockdown of TRPC6 in kidney using TRPC6 specific shRNA construct significantly attenuated Ang II-induced GFR decline in rats. Furthermore, Ang II-stimulated contraction and Ca(2+) entry were significantly suppressed in primary MCs isolated from TRPC6 deficient mice, and the Ca(2+) response could be rescued by re-introducing TRPC6. Moreover, inhibition of reverse mode of Na(+)-Ca(2+) exchange by KB-R7943 significantly reduced Ca(2+) entry response in TRPC6-expressing, but not in TRPC6-knocked down MCs. Ca(2+) entry response was also significantly attenuated in Na(+) free solution. Single knockdown of TRPC6 and TRPC1 resulted in a comparable suppression on Ca(2+) entry with double knockdown of both. These results suggest that TRPC6 may regulate GFR by modulating MC contractile function through multiple Ca(2+) signaling pathways.

PMID: 28646178 [PubMed - in process]

A Single amino acid residue at transmembrane domain 4 of the alpha subunit influences carisoprodol direct gating efficacy at GABAA receptors.

Sat, 06/24/2017 - 07:41
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A Single amino acid residue at transmembrane domain 4 of the alpha subunit influences carisoprodol direct gating efficacy at GABAA receptors.

J Pharmacol Exp Ther. 2017 Jun 22;:

Authors: Kumar M, Kumar M, Freund J, Dillon GH

Abstract
The muscle relaxant carisoprodol (CSP, trade name Soma) has recently been controlled at the federal level as a Schedule IV drug due to its high abuse potential and consequences of misuse, such as withdrawal syndrome, delusions, seizures and even death. Recent work has shown that carisoprodol can directly gate and allosterically modulate the GABAA receptor. These actions are subunit-dependent; compared to other GABAA receptors, carisoprodol has nominal direct gating effects in α3β2γ2receptors. Here, using site-directed-mutagenesis and whole cell patch clamp electrophysiology in transiently transfected HEK293 cells, we examined the role of GABAA receptor α subunit transmembrane domain 4 (TM4) amino acids in direct gating and allosteric modulatory actions of carisoprodol. Mutation of α3 valine at position 440 to leucine (present in the equivalent position in the α1 subunit) significantly increased the direct gating effects of carisoprodol, without affecting allosteric modulatory effects. The corresponding reverse mutation, α1(L415V), decreased carisoprodol direct gating potency and efficacy. Analysis of a series of amino acid mutations at the 415 position demonstrated amino acid volume correlated positively with CSP efficacy, while polarity inversely correlated with CSP efficacy. We conclude α1(415) of TM4 is involved in the direct gating, but not allosteric modulatory, actions of carisoprodol. Also, orientation of alkyl or hydroxyl groups at this position influence direct gating effects. These findings support the likelihood that direct gating and allosteric modulatory effects of carisoprodol are mediated via distinct binding sites.

PMID: 28642232 [PubMed - as supplied by publisher]

Phosphorylation at serine 31 targets tyrosine hydroxylase to vesicles for transport along microtubules.

Sat, 06/24/2017 - 07:41
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Phosphorylation at serine 31 targets tyrosine hydroxylase to vesicles for transport along microtubules.

J Biol Chem. 2017 Jun 21;:

Authors: Jorge-Finnigan A, Kleppe R, Jung-Kc K, Ying M, Marie M, Rios-Mondragon I, Salvatore MF, Saraste J, Martinez A

Abstract
Tyrosine hydroxylase (TH) catalyzes the conversion of L-tyrosine into L-Dopa, which is the rate-limiting step in the synthesis of catecholamines, particularly dopamine in dopaminergergic neurons. Low dopamine levels and death of the dopaminergic neurons are hallmarks of Parkinson's disease (PD), where α-synuclein is also a key player. TH is highly regulated, notably by phosphorylation of several Ser/Thr residues in the N-terminal tail. However, the functional role of TH phosphorylation at the Ser31 site (THpSer31) remains unclear. Here, we report that THpSer31 co-distributes with the Golgi complex and synaptic-like vesicles in rat and human dopaminergic cells. We also found that the TH microsomal fraction content decreases after inhibition of cyclin dependent kinase 5 (Cdk5) and ERK1/2. The cellular distribution of an overexpressed phospho-null mutant, TH1-S31A, was restricted to the soma of neuroblastoma cells, with decreased association to the microsomal fraction, whereas a phospho-mimic mutant, TH1-S31E, was distributed throughout the soma and neurites. TH1-S31E associated with vesicular monoamine transporter 2 (VMAT2) and α-synuclein in neuroblastoma cells, and endogenous TH-pSer31 was detected in VMAT2- and α-synuclein-immunoprecipitated mouse brain samples. Microtubule disruption or co-transfection with α-synuclein A53T, a PD associated mutation, caused TH1-S31E accumulation in the cell soma. Our results indicate that Ser31 phosphorylation may regulate TH subcellular localization by enabling its transport along microtubules, notably towards the projection terminals. These findings disclose a new mechanism of TH regulation by phosphorylation and reveal its interaction with key players in PD, opening up new research avenues for better understanding dopamine synthesis in physiological and pathological states.

PMID: 28637871 [PubMed - as supplied by publisher]

STORE OPERATED CALCIUM ENTRY SUPPRESSED TGFβ1-SMAD3 SIGNALING PATHWAY IN GLOMERULAR MESANGIAL CELLS.

Sat, 06/24/2017 - 07:41
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STORE OPERATED CALCIUM ENTRY SUPPRESSED TGFβ1-SMAD3 SIGNALING PATHWAY IN GLOMERULAR MESANGIAL CELLS.

Am J Physiol Renal Physiol. 2017 Jun 21;:ajprenal.00483.2016

Authors: Chaudhari S, Li W, Wang Y, Jiang H, Ma Y, Davis ME, Zuckerman JE, Ma R

Abstract
Our previous study demonstrated that the abundance of extracellular matrix proteins was suppressed by store-operated Ca2+ entry in mesangial cells (MCs). The present study was conducted to investigate the underlying mechanism focused on the transforming growth factor beta 1 (TGFβ1) - Smad3 pathway, a critical pathway for ECM expansion in diabetic kidneys. We hypothesized that SOCE suppressed ECM protein expression by inhibiting this pathway in MCs. In cultured human MCs, we observed that TGFβ1 (5 ng/ml for 15 hours) significantly increased Smad3 phosphorylation as evaluated by immunoblot. However, this response was markedly inhibited by thapsigargin (1 µM), a classical activator of store-operated Ca2+ channel. Consistently, both immunocytochemistry and immunoblot showed that TGFβ1 significantly increased nuclear translocation of Smad3 which was prevented by pre-treatment with thapsigargin. Importantly, the thapsigargin effect was reversed by Lanthanum (La3+) (5 µM) and GSK-7975A (10 µM), both of which are selective blockers of store-operated Ca2+ channel. Furthermore, knockdown of Orai1, the pore-forming subunit of store-operated Ca2+ channel, significantly augmented TGFβ1-induced Smad3 phosphorylation. Overexpression of Orai1 augmented the inhibitory effect of thapsigargin on TGFβ1-induced phosphorylation of Smad3. In agreement with the data from cultured MCs, in vivo knockdown of Orai1 specific to MCs using a targeted nanoparticle siRNA delivery system resulted in marked increase in abundance of phosphorylated Smad3 and in nuclear translocation of Smad3 in glomerulus of mice. Taken together, our results indicate that store-operated Ca2+ entry in MCs negatively regulates the TGFβ1-Smad3 signaling pathway.

PMID: 28637791 [PubMed - as supplied by publisher]

Dissociation of striatal dopamine and tyrosine hydroxylase expression from aging-related motor decline: evidence from calorie restriction intervention.

Sat, 06/24/2017 - 07:41
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Dissociation of striatal dopamine and tyrosine hydroxylase expression from aging-related motor decline: evidence from calorie restriction intervention.

J Gerontol A Biol Sci Med Sci. 2017 Jun 20;:

Authors: Salvatore MF, Terrebonne J, Cantu MA, McInnis TR, Venable K, Kelley P, Kasanga EA, Latimer B, Owens CL, Pruett BS, Yu Y, Luedtke R, Forster MJ, Sumien N, Ingram DK

Abstract
The escalating increase in retirees living beyond their 8th decade brings increased prevalence of aging-related impairments, including locomotor impairment (Parkinsonism) which may affect ~50% of those reaching age 80, but has no confirmed neurobiological mechanism. Lifestyle strategies that attenuate motor decline, and its allied mechanisms, must be identified. Aging studies report little to moderate loss of striatal dopamine (DA) or tyrosine hydroxylase (TH) in nigrostriatal terminals, in contrast to ~70-80% loss associated with bradykinesia onset in Parkinson's disease. These studies evaluated the effect of ~6 months 30% calorie restriction (CR) on nigrostriatal DA regulation and aging-related locomotor decline initiated at 12 months of age in Brown-Norway Fischer F1 hybrid rats. Aging-related decline in locomotor activity was prevented by CR. However, striatal DA or TH expression were decreased in the CR group, but increased in substantia nigra versus the ad libitum group or 12 mo old cohort. In a 4- 6-month old cohort, pharmacological TH inhibition reduced striatal DA ~30%, comparable to decreases reported in aged rats and the CR group, without affecting locomotor activity. The dissociation of moderate striatal DA reduction from locomotor activity seen in both studies suggest that aging-related decreases in striatal DA are dissociated from locomotor decline.

PMID: 28637176 [PubMed - as supplied by publisher]

Control of cerebral ischemia with magnetic nanoparticles.

Sat, 06/24/2017 - 07:41
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Control of cerebral ischemia with magnetic nanoparticles.

Nat Methods. 2017 Feb;14(2):160-166

Authors: Jia JM, Chowdary PD, Gao X, Ci B, Li W, Mulgaonkar A, Plautz EJ, Hassan G, Kumar A, Stowe AM, Yang SH, Zhou W, Sun X, Cui B, Ge WP

Abstract
The precise manipulation of microcirculation in mice can facilitate mechanistic studies of brain injury and repair after ischemia, but this manipulation remains a technical challenge, particularly in conscious mice. We developed a technology that uses micromagnets to induce aggregation of magnetic nanoparticles to reversibly occlude blood flow in microvessels. This allowed induction of ischemia in a specific cortical region of conscious mice of any postnatal age, including perinatal and neonatal stages, with precise spatiotemporal control but without surgical intervention of the skull or artery. When combined with longitudinal live-imaging approaches, this technology facilitated the discovery of a feature of the ischemic cascade: selective loss of smooth muscle cells in juveniles but not adults shortly after onset of ischemia and during blood reperfusion.

PMID: 27941784 [PubMed - indexed for MEDLINE]

Ecogeographic variation across morphofunctional units of the human nose.

Sat, 06/24/2017 - 07:41
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Ecogeographic variation across morphofunctional units of the human nose.

Am J Phys Anthropol. 2017 Jan;162(1):103-119

Authors: Maddux SD, Butaric LN, Yokley TR, Franciscus RG

Abstract
OBJECTIVES: Although the internal nose is overwhelmingly responsible for heat and moisture exchange during respiration, external nasal morphology is more commonly cited as evincing climatic adaptation in humans. Here, we assess variation across all four morphofunctional units of the complete nasorespiratory tract (external pyramid, nasal aperture, internal nasal fossa, and nasopharynx) to determine which units provide the strongest evidence of climatic adaptation.
MATERIALS AND METHODS: We employ 20 linear measurements collected on 837 modern human crania from major geographic (Arctic Circle, Asia, Australia, Europe, Africa) and climatic (polar, temperate, hot-arid, tropical) zones. In conjunction with associated climatic and geographic data, these morphological data are employed in multivariate analyses to evaluate the associations between each of these functional nasal units and climate.
RESULTS: The external pyramid and nasopharynx exhibit virtually no evidence of climate-mediated morphology across the regional samples, while apparent associations between climate and nasal aperture morphology appear influenced by the geographic (and likely genetic) proximities of certain populations. Only the internal nasal fossa exhibits an ecogeographic distribution consistent with climatic adaptation, with crania from colder and/or drier environments displaying internal nasal fossae that are longer, taller, and narrower (especially superiorly) compared to those from hotter and more humid environments.
CONCLUSIONS: Our study indicates that the internal nasal fossa exhibits a stronger association with climate compared to other aspects of the human nose. Further, our study supports suggestions that regional variation in internal nasal fossa morphology reflects demands for heat and moisture exchange via adjustment of internal nasal airway dimensions. Our study thus provides empirical support for theoretical assertions related to nasorespiratory function, with important implications for understanding human nasal evolution.

PMID: 27670377 [PubMed - indexed for MEDLINE]

Retinal vascular injuries and intravitreal human embryonic stem cell-derived haemangioblasts.

Thu, 06/22/2017 - 07:40

Retinal vascular injuries and intravitreal human embryonic stem cell-derived haemangioblasts.

Acta Ophthalmol. 2017 Jun 21;:

Authors: Wang JD, An Y, Zhang JS, Wan XH, Zhang W, Lanza R, Lu SJ, Jonas JB, Xu L

Abstract
OBJECTIVE: To investigate whether intravitreally applied haemangioblasts (HB) derived from human embryonic stem cells (hESCs) are helpful for the repair of vascular damage caused in animals by an oxygen-induced retinopathy (OIR), by an induced diabetic retinopathy (DR) or by an induced retinal ischaemia with subsequent reperfusion.
METHODS: Human embryonic stem cell-derived HBs were transplanted intravitreally into C57BL/6J mice (OIR model), into male Wistar rats with an induced DR and into male Wistar rats undergoing induced retinal ischaemia with subsequent reperfusion. Control groups of animals received an intravitreal injection of endothelial cells (ECs) or phosphate-buffered saline (PBS). We examined the vasculature integrity in the mice with OIR, the blood-retina barrier in the rats with induced DR, and retinal thickness and retinal ganglion cell density in retina flat mounts of the rats with the retinal ischaemic-reperfusion retinopathy.
RESULTS: In the OIR model, the study group versus control groups showed a significantly (p < 0.001) smaller retinal avascular area [5.1 ± 2.7%;n = 18 animals versus 12.2 ± 2.8% (PBS group; n = 10 animals) and versus 11.8 ± 3.7% (EC group; n = 8 animals)] and less retinal neovascularization [6.3 ± 2.5%;n = 18 versus 15.2 ± 6.3% (n = 10; PBS group) and versus 15.8 ± 3.3% (n = 8; EC group)]. On retinal flat mounts, hESC-HBs were integrated into damaged retinal vessels and stained positive for PECAM (CD31) as EC marker. In the DR model, the study group versus the EC control group showed a significantly (p = 0.001) better blood-retina barrier function as measured at 2 days after the intravitreal injections [study group: 20.2 ± 12.8 μl/(g × hr); n = 6; versus EC control group: 52.9 ± 9.9 μl/(g × hr; n = 6)]. In the retinal ischaemia-reperfusion model, the groups did not differ significantly in retinal thickness and retinal ganglion cell density at 2, 5 and 7 days after baseline.
CONCLUSION: By integrating into damaged retinal vessels and differentiating into ECs, intravitreally administered hESC-HBs may have partially repaired a retinal vascular injury caused by OIR model and DR.

PMID: 28636206 [PubMed - as supplied by publisher]

Interposition Ankle Arthroplasty Using Acellular Dermal Matrix: A Small Series.

Thu, 06/22/2017 - 07:40
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Interposition Ankle Arthroplasty Using Acellular Dermal Matrix: A Small Series.

J Foot Ankle Surg. 2017 Jul - Aug;56(4):894-897

Authors: Carpenter B, Duncan K, Ernst J, Ryba D, Suzuki S

Abstract
Although ankle arthrodesis is the reference standard for end-stage ankle arthritis, loss of mobility and adjacent joint arthritis are consequences that alternatives to arthrodesis attempt to avoid. The purpose of the present study was to report the clinical results of interpositional arthroplasty using acellular dermal matrix in 4 patients (age 32 to 42 years) for the treatment of advanced ankle osteoarthritis. The primary findings included relief of pain, with improvement in tibiotalar joint range of motion from a mean of 16.5° (range 0° to 24°) preoperatively to a mean of 31° (range 25° to 40°) postoperatively. All 4 patients underwent open arthrotomy of the anterior and posterior tibiotalar capsule with plafond exostectomy and debridement of all deleterious tissue within the ankle capsule. The articular surface of the talar dome was denuded down to smooth subchondral bone, and microfracture was performed. Autologous calcaneal bone marrow aspirate was applied, and talar resurfacing was achieved using an acellular dermal matrix. Knotless anchors placed medially and laterally within the anterior and posterior dome were used to affix the dermal matrix. The follow-up period ranged from 12 to 18 (mean 14) months. The mean pre- and 12-month postoperative Association of Orthopaedic Foot and Ankle Society hindfoot-ankle scale scores were 35 and 88.5, respectively. These outcomes suggest that interpositional tibiotalar arthroplasty using an acellular dermal matrix is successful in improving function and range of motion and decreasing pain. As an alternative to tibiotalar arthrodesis, interpositional tibiotalar arthroplasty might be the procedure of choice for young patients with end-stage ankle arthritis. Longer follow-up periods, histologic testing, and arthroscopic evaluations would be advantageous to further assess the durability of this procedure.

PMID: 28633799 [PubMed - in process]

Ceftriaxone reduces L-dopa-induced dyskinesia severity in 6-hydroxydopamine parkinson's disease model.

Wed, 06/21/2017 - 16:51

Ceftriaxone reduces L-dopa-induced dyskinesia severity in 6-hydroxydopamine parkinson's disease model.

Mov Disord. 2017 Jun 20;:

Authors: Chotibut T, Meadows S, Kasanga EA, McInnis T, Cantu MA, Bishop C, Salvatore MF

Abstract
BACKGROUND: Increased extracellular glutamate may contribute to l-dopa induced dyskinesia, a debilitating side effect faced by Parkinson's disease patients 5 to 10 years after l-dopa treatment. Therapeutic strategies targeting postsynaptic glutamate receptors to mitigate dyskinesia may have limited success because of significant side effects. Increasing glutamate uptake may be another approach to attenuate excess glutamatergic neurotransmission to mitigate dyskinesia severity or prolong the time prior to onset. Initiation of a ceftriaxone regimen at the time of nigrostriatal lesion can attenuate tyrosine hydroxylase loss in conjunction with increased glutamate uptake and glutamate transporter GLT-1 expression in a rat 6-hydroxydopamine model. In this article, we examined if a ceftriaxone regimen initiated 1 week after nigrostriatal lesion, but prior to l-dopa, could reduce l-dopa-induced dyskinesia in an established dyskinesia model.
METHODS: Ceftriaxone (200 mg/kg, intraperitoneal, once daily, 7 consecutive days) was initiated 7 days post-6-hydroxydopamine lesion (days 7-13) and continued every other week (days 21-27, 35-39) until the end of the study (day 39 postlesion, 20 days of l-dopa).
RESULTS: Ceftriaxone significantly reduced abnormal involuntary movements at 5 time points examined during chronic l-dopa treatment. Partial recovery of motor impairment from nigrostriatal lesion by l-dopa was unaffected by ceftriaxone. The ceftriaxone-treated l-dopa group had significantly increased striatal GLT-1 expression and glutamate uptake. Striatal tyrosine hydroxylase loss in this group was not significantly different when compared with the l-dopa alone group.
CONCLUSIONS: Initiation of ceftriaxone after nigrostriatal lesion, but prior to and during l-dopa, may reduce dyskinesia severity without affecting l-dopa efficacy or the reduction of striatal tyrosine hydroxylase loss. © 2017 International Parkinson and Movement Disorder Society.

PMID: 28631864 [PubMed - as supplied by publisher]

Increasing the reach of forensic genetics with massively parallel sequencing.

Wed, 06/21/2017 - 16:51
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Increasing the reach of forensic genetics with massively parallel sequencing.

Forensic Sci Med Pathol. 2017 Jun 19;:

Authors: Budowle B, Schmedes SE, Wendt FR

Abstract
The field of forensic genetics has made great strides in the analysis of biological evidence related to criminal and civil matters. More so, the discipline has set a standard of performance and quality in the forensic sciences. The advent of massively parallel sequencing will allow the field to expand its capabilities substantially. This review describes the salient features of massively parallel sequencing and how it can impact forensic genetics. The features of this technology offer increased number and types of genetic markers that can be analyzed, higher throughput of samples, and the capability of targeting different organisms, all by one unifying methodology. While there are many applications, three are described where massively parallel sequencing will have immediate impact: molecular autopsy, microbial forensics and differentiation of monozygotic twins. The intent of this review is to expose the forensic science community to the potential enhancements that have or are soon to arrive and demonstrate the continued expansion the field of forensic genetics and its service in the investigation of legal matters.

PMID: 28631109 [PubMed - as supplied by publisher]

Erythropoietin: Endogenous Protection of Ischemic Brain.

Wed, 06/21/2017 - 16:51
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Erythropoietin: Endogenous Protection of Ischemic Brain.

Vitam Horm. 2017;105:197-232

Authors: Mallet RT, Ryou MG

Abstract
The human brain requires uninterrupted delivery of blood-borne oxygen and nutrients to sustain its function. Focal ischemia, particularly, ischemic stroke, and global ischemia imposed by cardiac arrest disrupt the brain's fuel supply. The resultant ATP depletion initiates a complex injury cascade encompassing intracellular Ca(2+) overload, glutamate excitotoxicity, oxido-nitrosative stress, extracellular matrix degradation, and inflammation, culminating in neuronal and astroglial necrosis and apoptosis, neurocognitive deficits, and even death. Unfortunately, brain ischemia has proven refractory to pharmacological intervention. Many promising treatments afforded brain protection in animal models of focal and global ischemia, but failed to improve survival and neurocognitive recovery of stroke and cardiac arrest patients in randomized clinical trials. The culprits are the blood-brain barrier (BBB) that limits transferral of medications to the brain parenchyma, and the sheer complexity of the injury cascade, which presents a daunting array of targets unlikely to respond to monotherapies. Erythropoietin is a powerful neuroprotectant capable of interrupting multiple aspects of the brain injury cascade. Preclinical research demonstrates erythropoietin's ability to suppress glutamate excitotoxicity and intracellular Ca(2+) overload, dampen oxidative stress and inflammation, interrupt the apoptotic cascade, and preserve BBB integrity. However, the erythropoietin dosages required to traverse the BBB and achieve therapeutically effective concentrations in the brain parenchyma impose untoward side effects. Recent discoveries that hypoxia induces erythropoietin production within the brain and that neurons, astroglia, and cerebrovascular endothelium harbor membrane erythropoietin receptors, raise the exciting prospect of harnessing endogenous erythropoietin to protect the brain from the ravages of ischemia-reperfusion.

PMID: 28629519 [PubMed - in process]

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