Recent Research Articles from UNTHSC

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

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Updated: 8 min 55 sec ago

The refined biomimetic NeuroDigm GEL™ ( )Model of neuropathic pain in the mature rat.

Sun, 06/18/2017 - 07:36
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The refined biomimetic NeuroDigm GEL™ ( )Model of neuropathic pain in the mature rat.

F1000Res. 2016;5:2516

Authors: Hannaman MR, Fitts DA, Doss RM, Weinstein DE, Bryant JL

Abstract
Background: Many humans suffering with chronic pain have no clinical evidence of a lesion or disease. They are managed with a morass of drugs and invasive procedures. Opiates usually become less effective over time. In many, their persistent pain occurs after the healing of a soft tissue injury. Current animal models of neuropathic pain typically create direct neural damage with open surgeries using ligatures, neurectomies, chemicals or other forms of deliberate trauma. However, we have observed clinically that after an injury in humans, the naturally occurring process of tissue repair can cause chronic neural pain. Methods: We demonstrate how the refined biomimetic NeuroDigm GEL™ Model, in the mature male rat, gradually induces neuropathic pain behavior with a nonsurgical percutaneous implant of tissue-derived hydrogel in the musculo-fascial tunnel of the distal tibial nerve. Morphine, Celecoxib, Gabapentin and Duloxetine were each screened in the model three times each over 5 months after pain behaviors developed. A pilot study followed in which recombinant human erythropoietin was applied to the GEL neural procedure site. Results: The GEL Model gradually developed neuropathic pain behavior lasting months. Morphine, initially effective, had less analgesia over time. Celecoxib produced no analgesia, while gabapentin and duloxetine at low doses had profound analgesia at all times tested. The injected erythropoietin markedly decreased bilateral pain behavior that had been present for over 4 months. Histology revealed a site of focal neural remodeling, with neural regeneration, as in human biopsies. Conclusion: The refined NeuroDigm GEL™ Model induces localized neural remodeling resulting in robust neuropathic pain behavior. The analgesics responses in this model reflect known responses of humans with neuropathic pain. The targeted recombinant human erythropoietin appears to heal the ectopic focal neural site, as demonstrated by the extinguishing of neuropathic pain behavior present for over 4 months.

PMID: 28620451 [PubMed - in process]

Beyond Body Mass Index: Are Weight-loss Programs the Best Way to Improve the Health of African American Women?

Fri, 06/16/2017 - 07:35

Beyond Body Mass Index: Are Weight-loss Programs the Best Way to Improve the Health of African American Women?

Prev Chronic Dis. 2017 Jun 15;14:E48

Authors: Dodgen L, Spence-Almaguer E

Abstract
African American women have higher prevalence (82%) of overweight (body mass index [BMI] 25-29) and obesity (BMI ≥30) than white women (63.2%) or Hispanic women (77.2%), and weight-loss programs yield minimal results in this population. We examine the concept of BMI as a measure of health for African American women and suggests a more holistic, multifaceted approach to preventing chronic disease.

PMID: 28617664 [PubMed - in process]

Preterm birth and air pollution: Critical windows of exposure for women with asthma.

Fri, 06/16/2017 - 07:35
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Preterm birth and air pollution: Critical windows of exposure for women with asthma.

J Allergy Clin Immunol. 2016 Aug;138(2):432-440.e5

Authors: Mendola P, Wallace M, Hwang BS, Liu D, Robledo C, Männistö T, Sundaram R, Sherman S, Ying Q, Grantz KL

Abstract
BACKGROUND: Ambient air pollutants may increase preterm birth (PTB) risk, but critical exposure windows are uncertain. The interaction of asthma and pollutant exposure is rarely studied.
OBJECTIVE: We sought to assess the interaction of maternal asthma and air pollutant exposures in relation to PTB risk.
METHODS: Electronic medical records for 223,502 US deliveries were linked with modified Community Multiscale Air Quality model outputs. Logistic regression with generalized estimating equations estimated the odds ratio and 95% CIs for PTB on the basis of the interaction of maternal asthma and particulate matter with aerodynamic diameter of less than 2.5 microns and particulate matter with aerodynamic diameter of less than 10 microns, ozone (O3), nitrogen oxides (NOx), sulfur dioxide (SO2), and carbon monoxide (CO) per interquartile range. For each gestational week 23 to 36, exposures among women who delivered were compared with those remaining pregnant. Three-month preconception, whole pregnancy, weeks 1 to 28, and the last 6 weeks of gestation averages were also evaluated.
RESULTS: On assessing PTB by gestational week, we found that significant asthma interactions were sporadic before 30 weeks but more common during weeks 34 to 36, with higher risk among mothers with asthma for NOx, CO, and SO2 exposure and an inverse association with O3 in week 34. Odds of PTB were significantly higher among women with asthma for CO and NOx exposure preconception and early in pregnancy. In the last 6 weeks of pregnancy, PTB risk associated with particulate matter with aerodynamic diameter of less than 10 microns was higher among women with asthma.
CONCLUSIONS: Mothers with asthma may experience a higher risk for PTB after exposure to traffic-related pollutants such as CO and NOx, particularly for exposures 3-months preconception and in the early weeks of pregnancy.

PMID: 26944405 [PubMed - indexed for MEDLINE]

Investigation of the STR loci noise distributions of PowerSeq™ Auto System.

Thu, 06/15/2017 - 10:35

Investigation of the STR loci noise distributions of PowerSeq™ Auto System.

Croat Med J. 2017 Jun 14;58(3):214-221

Authors: Zeng X, King JL, Budowle B

Abstract
AIM: To characterize the noise and stutter distribution of 23 short tandem repeats (STRs) included in the PowerSeqTM Auto System.
METHODS: Raw FASTQ files were analyzed using STRait Razor v2s to display alleles and coverage. The sequence noise was divided into several categories: noise at allele position, noise at -1 repeat position, and artifact. The average relative percentages of locus coverage for each noise, stutter, and allele were calculated from the samples used for this locus noise analysis.
RESULTS: Stutter products could be routinely observed at the -2 repeat position, -1 repeat position, and +1 repeat position of alleles. Sequence noise at the allele position ranged from 10.22% to 28.81% of the total locus coverage. At the allele position, individual noise reads were relatively low.
CONCLUSION: The data indicate that noise generally will be low. In addition, the PowerSeqTM Auto System could capture nine flanking region single nucleotide polymorphisms (SNPs) that would not be observed by other current kits for massively parallel sequencing (MPS) of STRs.

PMID: 28613038 [PubMed - in process]

Cullin neddylation may allosterically tune polyubiquitin chain length and topology.

Thu, 06/15/2017 - 10:35
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Cullin neddylation may allosterically tune polyubiquitin chain length and topology.

Biochem J. 2017 Feb 20;474(5):781-795

Authors: Onel M, Sumbul F, Liu J, Nussinov R, Haliloglu T

Abstract
Conjugation of Nedd8 (neddylation) to Cullins (Cul) in Cul-RING E3 ligases (CRLs) stimulates ubiquitination and polyubiquitination of protein substrates. CRL is made up of two Cul-flanked arms: one consists of the substrate-binding and adaptor proteins and the other consists of E2 and Ring-box protein (Rbx). Polyubiquitin chain length and topology determine the substrate fate. Here, we ask how polyubiquitin chains are accommodated in the limited space available between the two arms and what determines the polyubiquitin linkage topology. We focus on Cul5 and Rbx1 in three states: before Cul5 neddylation (closed state), after neddylation (open state), and after deneddylation, exploiting molecular dynamics simulations and the Gaussian Network Model. We observe that regulation of substrate ubiquitination and polyubiquitination takes place through Rbx1 rotations, which are controlled by Nedd8-Rbx1 allosteric communication. Allosteric propagation proceeds from Nedd8 via Cul5 dynamic hinges and hydrogen bonds between the C-terminal domain of Cul5 (Cul5(CTD)) and Rbx1 (Cul5(CTD) residues R538/R569 and Rbx1 residue E67, or Cul5(CTD) E474/E478/N491 and Rbx1 K105). Importantly, at each ubiquitination step (homogeneous or heterogeneous, linear or branched), the polyubiquitin linkages fit into the distances between the two arms, and these match the inherent CRL conformational tendencies. Hinge sites may constitute drug targets.

PMID: 28082425 [PubMed - indexed for MEDLINE]

Characterization of genetic sequence variation of 58 STR loci in four major population groups.

Thu, 06/15/2017 - 10:35
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Characterization of genetic sequence variation of 58 STR loci in four major population groups.

Forensic Sci Int Genet. 2016 Nov;25:214-226

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

Abstract
Massively parallel sequencing (MPS) can identify sequence variation within short tandem repeat (STR) alleles as well as their nominal allele lengths that traditionally have been obtained by capillary electrophoresis. Using the MiSeq FGx Forensic Genomics System (Illumina), STRait Razor, and in-house excel workbooks, genetic variation was characterized within STR repeat and flanking regions of 27 autosomal, 7 X-chromosome and 24 Y-chromosome STR markers in 777 unrelated individuals from four population groups. Seven hundred and forty six autosomal, 227 X-chromosome, and 324 Y-chromosome STR alleles were identified by sequence compared with 357 autosomal, 107 X-chromosome, and 189 Y-chromosome STR alleles that were identified by length. Within the observed sequence variation, 227 autosomal, 156 X-chromosome, and 112 Y-chromosome novel alleles were identified and described. One hundred and seventy six autosomal, 123 X-chromosome, and 93 Y-chromosome sequence variants resided within STR repeat regions, and 86 autosomal, 39 X-chromosome, and 20 Y-chromosome variants were located in STR flanking regions. Three markers, D18S51, DXS10135, and DYS385a-b had 1, 4, and 1 alleles, respectively, which contained both a novel repeat region variant and a flanking sequence variant in the same nucleotide sequence. There were 50 markers that demonstrated a relative increase in diversity with the variant sequence alleles compared with those of traditional nominal length alleles. These population data illustrate the genetic variation that exists in the commonly used STR markers in the selected population samples and provide allele frequencies for statistical calculations related to STR profiling with MPS data.

PMID: 27697609 [PubMed - indexed for MEDLINE]

Massively parallel sequencing of 68 insertion/deletion markers identifies novel microhaplotypes for utility in human identity testing.

Thu, 06/15/2017 - 10:35
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Massively parallel sequencing of 68 insertion/deletion markers identifies novel microhaplotypes for utility in human identity testing.

Forensic Sci Int Genet. 2016 Nov;25:198-209

Authors: Wendt FR, Warshauer DH, Zeng X, Churchill JD, Novroski NM, Song B, King JL, LaRue BL, Budowle B

Abstract
Short tandem repeat (STR) loci are the traditional markers used for kinship, missing persons, and direct comparison human identity testing. These markers hold considerable value due to their highly polymorphic nature, amplicon size, and ability to be multiplexed. However, many STRs are still too large for use in analysis of highly degraded DNA. Small bi-allelic polymorphisms, such as insertions/deletions (INDELs), may be better suited for analyzing compromised samples, and their allele size differences are amenable to analysis by capillary electrophoresis. The INDEL marker allelic states range in size from 2 to 6 base pairs, enabling small amplicon size. In addition, heterozygote balance may be increased by minimizing preferential amplification of the smaller allele, as is more common with STR markers. Multiplexing a large number of INDELs allows for generating panels with high discrimination power. The Nextera™ Rapid Capture Custom Enrichment Kit (Illumina, Inc., San Diego, CA) and massively parallel sequencing (MPS) on the Illumina MiSeq were used to sequence 68 well-characterized INDELs in four major US population groups. In addition, the STR Allele Identification Tool: Razor (STRait Razor) was used in a novel way to analyze INDEL sequences and detect adjacent single nucleotide polymorphisms (SNPs) and other polymorphisms. This application enabled the discovery of unique allelic variants, which increased the discrimination power and decreased the single-locus random match probabilities (RMPs) of 22 of these well-characterized INDELs which can be considered as microhaplotypes. These findings suggest that additional microhaplotypes containing human identification (HID) INDELs may exist elsewhere in the genome.

PMID: 27685342 [PubMed - indexed for MEDLINE]

Native American population data based on the Globalfiler(®) autosomal STR loci.

Thu, 06/15/2017 - 10:35
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Native American population data based on the Globalfiler(®) autosomal STR loci.

Forensic Sci Int Genet. 2016 Sep;24:e12-3

Authors: Ng J, Oldt RF, McCulloh KL, Weise JA, Viray J, Budowle B, Smith DG, Kanthaswamy S

Abstract
Native American population data are limited and thus impact computing accurate statistical parameters for forensic investigations. Thus, additional information should be generated from geographically representative tribes in North America, particularly from those that are not included in existing population databases for forensic use. The Globafiler(®) PCR Amplification kit was used to produce STR genotypic data for 533 individuals who represent 31 Native American tribal populations derived from eight geographically diverse regions in North America. Population genetic estimates from 21 autosomal STRs are reported.

PMID: 27421760 [PubMed - indexed for MEDLINE]

Genetic analysis of the Yavapai Native Americans from West-Central Arizona using the Illumina MiSeq FGx™ forensic genomics system.

Thu, 06/15/2017 - 10:35
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Genetic analysis of the Yavapai Native Americans from West-Central Arizona using the Illumina MiSeq FGx™ forensic genomics system.

Forensic Sci Int Genet. 2016 Sep;24:18-23

Authors: Wendt FR, Churchill JD, Novroski NM, King JL, Ng J, Oldt RF, McCulloh KL, Weise JA, Smith DG, Kanthaswamy S, Budowle B

Abstract
Forensically-relevant genetic markers were typed for sixty-two Yavapai Native Americans using the ForenSeq™ DNA Signature Prep Kit.These data are invaluable to the human identity community due to the greater genetic differentiation among Native American tribes than among other subdivisions within major populations of the United States. Autosomal, X-chromosomal, and Y-chromosomal short tandem repeat (STR) and identity-informative (iSNPs), ancestry-informative (aSNPs), and phenotype-informative (pSNPs) single nucleotide polymorphism (SNP) allele frequencies are reported. Sequence-based allelic variants were observed in 13 autosomal, 3 X, and 3 Y STRs. These observations increased observed and expected heterozygosities for autosomal STRs by 0.081±0.068 and 0.073±0.063, respectively, and decreased single-locus random match probabilities by 0.051±0.043 for 13 autosomal STRs. The autosomal random match probabilities (RMPs) were 2.37×10-26 and 2.81×10-29 for length-based and sequence-based alleles, respectively. There were 22 and 25 unique Y-STR haplotypes among 26 males, generating haplotype diversities of 0.95 and 0.96, for length-based and sequencebased alleles, respectively. Of the 26 haplotypes generated, 17 were assigned to haplogroup Q, three to haplogroup R1b, two each to haplogroups E1b1b and L, and one each to haplogroups R1a and I1. Male and female sequence-based X-STR random match probabilities were 3.28×10-7 and 1.22×10-6, respectively. The average observed and expected heterozygosities for 94 iSNPs were 0.39±0.12 and 0.39±0.13, respectively, and the combined iSNP RMP was 1.08×10-32. The combined STR and iSNP RMPs were 2.55×10-58 and 3.02×10-61 for length-based and sequence-based STR alleles, respectively. Ancestry and phenotypic SNP information, performed using the ForenSeq™ Universal Analysis Software, predicted black hair, brown eyes, and some probability of East Asian ancestry for all but one sample that clustered between European and Admixed American ancestry on a principal components analysis. These data serve as the first population assessment using the ForenSeq™ panel and highlight the value of employing sequence-based alleles for forensic DNA typing to increase heterozygosity, which is beneficial for identity testing in populations with reduced genetic diversity.

PMID: 27243782 [PubMed - indexed for MEDLINE]

D5S2500 is an ambiguously characterized STR: Identification and description of forensic microsatellites in the genomics age.

Thu, 06/15/2017 - 10:35
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D5S2500 is an ambiguously characterized STR: Identification and description of forensic microsatellites in the genomics age.

Forensic Sci Int Genet. 2016 Jul;23:19-24

Authors: Phillips C, Parson W, Amigo J, King JL, Coble MD, Steffen CR, Vallone PM, Gettings KB, Butler JM, Budowle B

Abstract
In the process of establishing short tandem repeat (STR) sequence variant nomenclature guidelines in anticipation of expanded forensic multiplexes for massively parallel sequencing (MPS), it was discovered that the STR D5S2500 has multiple positions and genomic characteristics reported. This ambiguity is because the marker named D5S2500 consists of two different microsatellites forming separate components in the capillary electrophoresis multiplexes of Qiagen's HDplex (Hilden, Germany) and AGCU ScienTech's non-CODIS STR 21plex (Wuxi, Jiangsu, China). This study outlines the genomic details used to identify each microsatellite and reveals the D5S2500 marker in HDplex has the correctly assigned STR name, while the D5S2500 marker in the AGCU 21plex, closely positioned a further 1643 nucleotides in the human reference sequence, is an unnamed microsatellite. The fact that the D5S2500 marker has existed as two distinct STR loci undetected for almost ten years, even with reported discordant genotypes for the standard control DNA, underlines the need for careful scrutiny of the genomic properties of forensic STRs, as they become adapted for sequence analysis with MPS systems. We make the recommendation that precise chromosome location data must be reported for any forensic marker under development but not in common use, so that the genomic characteristics of the locus are validated to the same level of accuracy as its allelic variation and forensic performance. To clearly differentiate each microsatellite, we propose the name D5S2800 be used to identify the Chromosome-5 STR in the AGCU 21plex.

PMID: 26974236 [PubMed - indexed for MEDLINE]

Absolute humidity and the human nose: A reanalysis of climate zones and their influence on nasal form and function.

Wed, 06/14/2017 - 07:35
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Absolute humidity and the human nose: A reanalysis of climate zones and their influence on nasal form and function.

Am J Phys Anthropol. 2016 Oct;161(2):309-20

Authors: Maddux SD, Yokley TR, Svoma BM, Franciscus RG

Abstract
OBJECTIVES: Investigations into the selective role of climate on human nasal variation commonly divide climates into four broad adaptive zones (hot-dry, hot-wet, cold-dry, and cold-wet) based on temperature and relative humidity. Yet, absolute humidity-not relative humidity-is physiologically more important during respiration. Here, we investigate the global distribution of absolute humidity to better clarify ecogeographic demands on nasal physiology.
METHODS: We use monthly observations from the Climatic Research Unit Timeseries 3 (CRU TS3) database to construct global maps of average annual temperature, relative humidity and absolute humidity. Further, using data collected by Thomson and Buxton (1923) for over 15,000 globally-distributed individuals, we calculate the actual amount of heat and water that must be transferred to inspired air in different climatic regimes to maintain homeostasis, and investigate the influence of these factors on the nasal index.
RESULTS: Our results show that absolute humidity, like temperature, generally decreases with latitude. Furthermore, our results demonstrate that environments typically characterized as "cold-wet" actually exhibit low absolute humidities, with values virtually identical to cold-dry environments and significantly lower than hot-wet and even hot-dry environments. Our results also indicate that strong associations between the nasal index and absolute humidity are, potentially erroneously, predicated on individuals from hot-dry environments possessing intermediate (mesorrhine) nasal indices.
DISCUSSION: We suggest that differentially allocating populations to cold-dry or cold-wet climates is unlikely to reflect different selective pressures on respiratory physiology and nasal morphology-it is cold-dry, and to a lesser degree hot-dry environments, that stress respiratory function. Our study also supports assertions that demands for inspiratory modification are reduced in hot-wet environments, and that expiratory heat elimination for thermoregulation is a greater selective pressure in such environments.

PMID: 27374937 [PubMed - indexed for MEDLINE]

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

Wed, 06/14/2017 - 07:35
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Allostery: An Overview of Its History, Concepts, Methods, and Applications.

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

Authors: Liu J, Nussinov R

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

PMID: 27253437 [PubMed - indexed for MEDLINE]

Fast STR allele identification with STRait Razor 3.0.

Tue, 06/13/2017 - 07:37

Fast STR allele identification with STRait Razor 3.0.

Forensic Sci Int Genet. 2017 Jun 01;30:18-23

Authors: Woerner AE, King JL, Budowle B

Abstract
The short tandem repeat allele identification tool (STRait Razor), a program used to characterize the haplotypes of short tandem repeats (STRs) in massively parallel sequencing (MPS) data, was redesigned. STRait Razor v3.0 performs ∼660× faster allele identification than its previous version (v2s), a speedup that is largely due to a novel indexing strategy used to perform "fuzzy" (approximate) string matching of anchor sequences. Written in a portable compiled language, C++, STRait Razor v3.0 functions on all major operating systems including Microsoft Windows, and it has cross-platform multithreading support. In silico estimates of precision and accuracy of STRait Razor v3.0 were 100% in this evaluation and results were highly concordant with those of Strait Razor v2s. STRait Razor v3.0 adds several key features that simplify the haplotype reporting process, including simple filters to remove low frequency haplotypes as well as merging haplotypes within a locus encoded on opposite strands of the DNA molecule.

PMID: 28605651 [PubMed - as supplied by publisher]

Estimated blood alcohol concentrations achieved by consuming supersized alcopops.

Tue, 06/13/2017 - 07:37

Estimated blood alcohol concentrations achieved by consuming supersized alcopops.

Am J Drug Alcohol Abuse. 2017 Jun 12;:1-4

Authors: Rossheim ME, Thombs DL

Abstract
BACKGROUND: Producers of supersized alcopops have ignored requests from a number of state attorneys general to reduce the alcohol concentration in these products. To the contrary, new flavor options have since been released that contain even greater alcohol content so that some alcopop products now contain 5.5 standard alcoholic drinks in a single-serving can. Though alcohol content of supersized alcopops has risen, little attention has been paid to the blood alcohol concentration (BAC) level consumers can expect to achieve from drinking these products.
OBJECTIVES: To estimate BAC levels expected from consuming one or two cans of supersized alcopop, relative to beer.
METHODS: Median weight data from the National Health and Nutrition Examination Survey were used in Matthews and Miller's (1979) BAC estimation formula.
RESULTS: Consuming a single supersized alcopop over the course of 2 hours can put youth and young adults well over the legal per se driving limit of 0.08 g/dL. Consuming two cans puts them at risk of alcohol poisoning.
CONCLUSIONS: Estimates provided here show that supersized alcopop consumers obtain dangerously high BAC levels. Reductions in the alcohol content of supersized alcopops should be an urgent priority for public health policy and law.

PMID: 28605266 [PubMed - as supplied by publisher]

Rapid repeatable in vivo detection of retinal reactive oxygen species.

Tue, 06/13/2017 - 07:37
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Rapid repeatable in vivo detection of retinal reactive oxygen species.

Exp Eye Res. 2017 Jun 08;:

Authors: Fan N, Silverman SM, Liu Y, Wang X, Kim BJ, Tang L, Clark AF, Liu X, Pang IH

Abstract
Oxidative injuries, such as those related to reactive oxygen species (ROS), have been implicated in various retinal and optic nerve disorders. Many ROS detection methods have been developed. Although widely utilized, many of these methods are useful only in post mortem tissues, or require relatively expensive equipment, or involve intraocular injection. In the present study, we demonstrated and characterized a chemiluminescent probe L-012 as a noninvasive, in vivo ROS detection agent in the mouse retina. Using optic nerve crush (ONC) and retinal ischemia/reperfusion (I/R) as mouse injury models, we show that L-012 produced intensive luminescent signals specifically in the injured eyes. Histological examination showed that L-012 administration was safe to the retina. Additionally, compounds that reduce tissue superoxide levels, apocynin and TEMPOL, decreased injury-induced L-012 chemiluminescence. The decrease in L-012 signals correlated with their protective effects against retinal I/R-induced morphological and functional changes in the retina. Together, these data demonstrate the feasibility of a fast, simple, reproducible, and non-invasive detection method to monitor in vivo ROS in the retina. Furthermore, the results also show that reduction of ROS is a potential therapeutic approach for protection from these retinal injuries.

PMID: 28603016 [PubMed - as supplied by publisher]

The efficacy of novel anatomical sites for the assessment of muscle oxygenation during central hypovolemia.

Fri, 06/09/2017 - 07:35
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The efficacy of novel anatomical sites for the assessment of muscle oxygenation during central hypovolemia.

Exp Biol Med (Maywood). 2016 Nov;241(17):2007-2013

Authors: Sprick JD, Soller BR, Rickards CA

Abstract
Muscle tissue oxygenation (SmO2) can track central blood volume loss associated with hemorrhage. Traditional peripheral measurement sites (e.g., forearm) may not be practical due to excessive movement or injury (e.g., amputation). The aim of this study was to evaluate the efficacy of three novel anatomical sites for the assessment of SmO2 under progressive central hypovolemia. 10 male volunteers were exposed to stepwise prone lower body negative pressure to decrease central blood volume, while SmO2 was assessed at four sites-the traditional site of the flexor carpi ulnaris (ARM), and three novel sites not previously investigated during lower body negative pressure, the deltoid, latissimus dorsi, and trapezius. SmO2 at the novel sites was compared to the ARM sensor and to stroke volume responses. A reduction in SmO2 was detected by the ARM sensor at the first level of lower body negative pressure (-15 mmHg; P = 0.007), and at -30 (the deltoid), -45 (latissimus dorsi), and -60 mmHg lower body negative pressure (trapezius) at the novel sites (P ≤ 0.04). SmO2 responses at all novel sites were correlated with responses at the ARM (R ≥ 0.89), and tracked the reduction in stroke volume (R ≥ 0.87); the latissimus dorsi site exhibited the strongest linear correlations (R ≥ 0.96). Of the novel sensor sites, the latissimus dorsi exhibited the strongest linear associations with SmO2 at the ARM, and with reductions in central blood volume. These findings have important implications for detection of hemorrhage in austere environments (e.g., combat) when use of a peripheral sensor may not be ideal, and may facilitate incorporation of these sensors into uniforms.

PMID: 27439541 [PubMed - indexed for MEDLINE]

Using an exercise program to improve activity tolerance in a female with postural orthostatic tachycardia syndrome: A case report.

Thu, 06/08/2017 - 07:43
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Using an exercise program to improve activity tolerance in a female with postural orthostatic tachycardia syndrome: A case report.

Physiother Theory Pract. 2017 Jun 07;:1-10

Authors: Richardson MV, Nordon-Craft A, Carrothers L

Abstract
INTRODUCTION: The incidence of postural orthostatic tachycardia syndrome (POTS) is estimated to be at least 500,000 in the United States and is most commonly found in premenopausal females. This syndrome shares clinical features with orthostatic hypotension (OH); however, the inclusion criteria and clinical features for POTS are not well known. The purposes of this case report are to: 1) describe the common clinical features of POTS and highlight the differences to orthostatic hypotension and 2) discuss physical therapy management of patients with POTS using exercise.
CASE PRESENTATION: A 34-year-old female with a POTS exacerbation completed a 4-week physical therapy endurance and strengthening 'reconditioning' program. Initial symptoms included the following: dyspnea with mild exertion, light-headedness, fatigue, leg "heaviness," and the inability to perform normal work duties.
OUTCOMES: One-mile track walk test (1-MWT) estimated VO2max improved from the 45-50th percentile to the 65-70th percentile at 8 weeks post-discharge. She returned to work full-time and resumed all previous fitness activities.
CONCLUSION: The patient demonstrated clinically meaningful improvements in estimated VO2max after the "reconditioning" training. Physical therapists should be able to recognize the clinical features and inclusion criteria for POTS as part of a differential diagnosing process for patients complaining of orthostatic symptoms.

PMID: 28590791 [PubMed - as supplied by publisher]

Intermittent hypoxia training protects cerebrovascular function in Alzheimer's disease.

Wed, 06/07/2017 - 07:34
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Intermittent hypoxia training protects cerebrovascular function in Alzheimer's disease.

Exp Biol Med (Maywood). 2016 Jun;241(12):1351-63

Authors: Manukhina EB, Downey HF, Shi X, Mallet RT

Abstract
Alzheimer's disease (AD) is a leading cause of death and disability among older adults. Modifiable vascular risk factors for AD (VRF) include obesity, hypertension, type 2 diabetes mellitus, sleep apnea, and metabolic syndrome. Here, interactions between cerebrovascular function and development of AD are reviewed, as are interventions to improve cerebral blood flow and reduce VRF. Atherosclerosis and small vessel cerebral disease impair metabolic regulation of cerebral blood flow and, along with microvascular rarefaction and altered trans-capillary exchange, create conditions favoring AD development. Although currently there are no definitive therapies for treatment or prevention of AD, reduction of VRFs lowers the risk for cognitive decline. There is increasing evidence that brief repeated exposures to moderate hypoxia, i.e. intermittent hypoxic training (IHT), improve cerebral vascular function and reduce VRFs including systemic hypertension, cardiac arrhythmias, and mental stress. In experimental AD, IHT nearly prevented endothelial dysfunction of both cerebral and extra-cerebral blood vessels, rarefaction of the brain vascular network, and the loss of neurons in the brain cortex. Associated with these vasoprotective effects, IHT improved memory and lessened AD pathology. IHT increases endothelial production of nitric oxide (NO), thereby increasing regional cerebral blood flow and augmenting the vaso- and neuroprotective effects of endothelial NO. On the other hand, in AD excessive production of NO in microglia, astrocytes, and cortical neurons generates neurotoxic peroxynitrite. IHT enhances storage of excessive NO in the form of S-nitrosothiols and dinitrosyl iron complexes. Oxidative stress plays a pivotal role in the pathogenesis of AD, and IHT reduces oxidative stress in a number of experimental pathologies. Beneficial effects of IHT in experimental neuropathologies other than AD, including dyscirculatory encephalopathy, ischemic stroke injury, audiogenic epilepsy, spinal cord injury, and alcohol withdrawal stress have also been reported. Further research on the potential benefits of IHT in AD and other brain pathologies is warranted.

PMID: 27190276 [PubMed - indexed for MEDLINE]

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

Wed, 06/07/2017 - 07:34
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Crosstalk between TGFβ and Wnt signaling pathways in the human trabecular meshwork.

Exp Eye Res. 2016 Jul;148:97-102

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 - indexed for MEDLINE]

A Fine-Tune Role of Mir-125a-5p on Foxn1 During Age-Associated Changes in the Thymus.

Tue, 06/06/2017 - 13:37

A Fine-Tune Role of Mir-125a-5p on Foxn1 During Age-Associated Changes in the Thymus.

Aging Dis. 2017 May;8(3):277-286

Authors: Xu M, Sizova O, Wang L, Su DM

Abstract
Decline of transcription factor FoxN1, which predominantly regulates thymic epithelial cell (TEC) differentiation and homeostasis lifelong, is demonstrated to be casually related to age-related thymic involution. Whereas, a global role of microRNAs (miRNAs) has also been demonstrated to control and maintain TEC-constituting thymic microenvironment and to be changed in expression profile in the aged thymus. Therefore, it is urgently necessary to build knowledge regarding whether and which miRNAs regulate FoxN1 gene in the aged thymus. We primarily compared changes in miRNA expression profile between young and aged murine TECs with Mus musculus miRBase-V20 arrays (containing 1892 unique probes), and clearly identified and validated that at least one miRNA, miR-125a-5p, was increased in aged thymus. Applying miR-125a-5p mimics was able to inhibit FoxN1 3'UTR luciferase activity in a 293T cell line and to suppress FoxN1 expression in murine TEC Z210 cells. Since a single miRNA can play a fine-tuning role to regulate expression of multiple genes and a single gene can be regulated by multiple miRNAs, our result adds a single miRNA, miR-125a-5p, into the panel of FoxN1-regulating miRNAs associated with thymic aging.

PMID: 28580184 [PubMed]

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