Recent Research Articles from UNTHSC

Subscribe to Recent Research Articles from UNTHSC  feed Recent Research Articles from UNTHSC
NCBI: db=pubmed; Term="University of North Texas Health Science Center"[All Fields] OR "Univ. of North Texas Health Science Center"[All Fields] OR "UNT Health Science Center"[All Fields] OR "Osteopathic Research Center"[All Fields] OR "University of North Texas System College of Pharmacy"[All Fields] OR "UNT System College of Pharmacy"[All Fields] OR "College of Pharmacy, University of North Texas System"[All Fields]
Updated: 3 hours 42 min ago

A method for identifying discriminative isoform-specific peptides for clinical proteomics application.

15 hours 46 min ago

A method for identifying discriminative isoform-specific peptides for clinical proteomics application.

BMC Genomics. 2016;17(Suppl 7):522

Authors: Zhang F, Chen JY

Abstract
BACKGROUND: Clinical proteomics application aims at solving a specific clinical problem within the context of a clinical study. It has been growing rapidly in the field of biomarker discovery, especially in the area of cancer diagnostics. Until recently, protein isoform has not been viewed as a new class of early diagnostic biomarkers for clinical proteomics. A protein isoform is one of different forms of the same protein. Different forms of a protein may be produced from single-nucleotide polymorphisms (SNPs), alternative splicing, or post-translational modifications (PTMs). Previous studies have shown that protein isoforms play critical roles in tumorigenesis, disease diagnosis, and prognosis. Identifying and characterizing protein isoforms are essential to the study of molecular mechanisms and early detection of complex diseases such as breast cancer. However, there are limitations with traditional methods such as EST sequencing, Microarray profiling (exon array, Exon-exon junction array), mRNA next-generation sequencing used for protein isoform determination: 1) not in the protein level, 2) no connectivity about connection of nonadjacent exons, 3) no SNPs and PTMs, and 4) low reproducibility. Moreover, there exist the computational challenges of clinical proteomics studies: 1) low sensitivity of instruments, 2) high data noise, and 3) high variability and low repeatability, although recent advances in clinical proteomics technology, LC-MS/MS proteomics, have been used to identify candidate molecular biomarkers in diverse range of samples, including cells, tissues, serum/plasma, and other types of body fluids.
RESULTS: Therefore, in the paper, we presented a peptidomics method for identifying cancer-related and isoform-specific peptide for clinical proteomics application from LC-MS/MS. First, we built a Peptidomic Database of Human Protein Isoforms, then created a peptidomics approach to perform large-scale screen of breast cancer-associated alternative splicing isoform markers in clinical proteomics, and lastly performed four kinds of validations: biological validation (explainable index), exon array, statistical validation of independent samples, and extensive pathway analysis.
CONCLUSIONS: Our results showed that alternative splicing isoform makers can act as independent markers of breast cancer and that the method for identifying cancer-specific protein isoform biomarkers from clinical proteomics application is an effective one for increasing the number of identified alternative splicing isoform markers in clinical proteomics.

PMID: 27557076 [PubMed - as supplied by publisher]

IL-7 and Depression: The importance of gender and blood fraction.

15 hours 46 min ago

IL-7 and Depression: The importance of gender and blood fraction.

Behav Brain Res. 2016 Aug 20;

Authors: Hall JR, Wiechmann A, Edwards M, Johnson LA, O'Bryant SE

Abstract
Interleukin 7 (IL-7) is involved in B and T cell development and differentiation. Recent work suggests IL-7 may be altered in depression; however, we have previously shown that gender and blood fraction oftentimes impacts putative biomarker relationships among those with and without Alzheimer's disease (AD). The current study examined the impact of blood fraction (serum versus plasma) and gender on the IL7 depression link in a sample of elders with and without AD. Non-fasting serum (150 AD cases 150 controls) and plasma (100 AD cases, 100 controls) IL-7 levels were assayed via electrochemiluminescence. The correlation between serum and plasma for IL-7 was 0.34. In the total sample, serum (r(2)=0.16, p=0.006) and plasma (r(2)=-0.20, p=0.007) IL-7 levels were significantly, but inversely, correlated with GDS-30 scores. When split by gender, serum IL-7 levels were significantly positively associated with GDS scores among men (r(2)=0.34, p=0.001) whereas plasma IL-7 levels (r(2)=-0.23, p=0.008) were significantly negatively associated with GDS scores among women. A logistic regression model predicting depression status (GDS30>=10) included age, gender, education, plasma, and serum IL-7 levels, found both significantly associated with depression status, but in opposite directions. Our findings support a significant link between IL-7 and depression; however, we further highlight the importance of blood fraction and gender when examining this relationship. Additionally, these findings further support the need for additional work that could lead to targeted therapeutic interventions utilizing anti-inflammatory medications for individuals with depression.

PMID: 27555535 [PubMed - as supplied by publisher]

The Essential Role of Neutrophils during Infection with the Intracellular Bacterial Pathogen Listeria monocytogenes.

Sun, 08/21/2016 - 06:33

The Essential Role of Neutrophils during Infection with the Intracellular Bacterial Pathogen Listeria monocytogenes.

J Immunol. 2016 Sep 1;197(5):1557-65

Authors: Witter AR, Okunnu BM, Berg RE

Abstract
Neutrophils have historically been characterized as first responder cells vital to host survival because of their ability to contain and eliminate bacterial and fungal pathogens. However, recent studies have shown that neutrophils participate in both protective and detrimental responses to a diverse array of inflammatory and infectious diseases. Although the contribution of neutrophils to extracellular infections has been investigated for decades, their specific role during intracellular bacterial infections has only recently been appreciated. During infection with the Gram-positive intracellular pathogen Listeria monocytogenes, neutrophils are recruited from the bone marrow to sites of infection where they use novel bacterial-sensing pathways leading to phagocytosis and production of bactericidal factors. This review summarizes the requirement of neutrophils during L. monocytogenes infection by examining both neutrophil trafficking and function during primary and secondary infection.

PMID: 27543669 [PubMed - in process]

Tetracycline-Containing MCM-41 Mesoporous Silica Nanoparticles for the Treatment of Escherichia coli.

Sat, 08/20/2016 - 06:29
Related Articles

Tetracycline-Containing MCM-41 Mesoporous Silica Nanoparticles for the Treatment of Escherichia coli.

Molecules. 2015;20(11):19690-8

Authors: Koneru B, Shi Y, Wang YC, Chavala SH, Miller ML, Holbert B, Conson M, Ni A, Di Pasqua AJ

Abstract
Tetracycline (TC) is a well-known broad spectrum antibiotic, which is effective against many Gram positive and Gram negative bacteria. Controlled release nanoparticle formulations of TC have been reported, and could be beneficial for application in the treatment of periodontitis and dental bone infections. Furthermore, TC-controlled transcriptional regulation systems (Tet-on and Tet-off) are useful for controlling transgene expression in vitro and in vivo for biomedical research purposes; controlled TC release systems could be useful here, as well. Mesoporous silica nanomaterials (MSNs) are widely studied for drug delivery applications; Mobile crystalline material 41 (MCM-41), a type of MSN, has a mesoporous structure with pores forming channels in a hexagonal fashion. We prepared 41 ± 4 and 406 ± 55 nm MCM-41 mesoporous silica nanoparticles and loaded TC for controlled dug release; TC content in the TC-MCM-41 nanoparticles was 18.7% and 17.7% w/w, respectively. Release of TC from TC-MCM-41 nanoparticles was then measured in phosphate-buffered saline (PBS), pH 7.2, at 37 °C over a period of 5 h. Most antibiotic was released from both over this observation period; however, the majority of TC was released over the first hour. Efficacy of the TC-MCM-41 nanoparticles was then shown to be superior to free TC against Escherichia coli (E. coli) in culture over a 24 h period, while blank nanoparticles had no effect.

PMID: 26528964 [PubMed - indexed for MEDLINE]

Effects of age and acute muscle fatigue on reactive postural control in healthy adults.

Fri, 08/19/2016 - 06:29
Related Articles

Effects of age and acute muscle fatigue on reactive postural control in healthy adults.

Clin Biomech (Bristol, Avon). 2015 Dec;30(10):1108-13

Authors: Papa EV, Foreman KB, Dibble LE

Abstract
BACKGROUND: Falls can cause moderate to severe injuries such as hip fractures and head trauma in older adults. While declines in muscle strength and sensory function contribute to increased falls in older adults, skeletal muscle fatigue is often overlooked as an additional contributor to fall risk. The purpose of this investigation was to examine the effects of acute lower extremity muscle fatigue and age on reactive postural control in healthy adults.
METHODS: A sample of 16 individuals participated in this study (8 healthy older adults and 8 healthy young persons). Whole body kinematic and kinetic data were collected during anterior and posterior reproducible fall tests before (T0) and immediately after (T1) eccentric muscle fatiguing exercise, as well as after 15-min (T15) and 30-min (T30) of rest.
FINDINGS: Lower extremity joint kinematics of the stepping limb during the support (landing) phase of the anterior fall were significantly altered by the presence of acute muscle fatigue. Step velocity was significantly decreased during the anterior falls. Statistically significant main effects of age were found for step length in both fall directions. Effect sizes for all outcomes were small. No statistically significant interaction effects were found.
INTERPRETATION: Muscle fatigue has a measurable effect on lower extremity joint kinematics during simulated falls. These alterations appear to resolve within 15 min of recovery. The above deficits, coupled with a reduced step length, may help explain the increased fall risk in older adults.

PMID: 26351001 [PubMed - indexed for MEDLINE]

Mindfulness-Based Stress Reduction vs Cognitive Behavioral Therapy for Chronic Low Back Pain.

Thu, 08/18/2016 - 06:29

Mindfulness-Based Stress Reduction vs Cognitive Behavioral Therapy for Chronic Low Back Pain.

JAMA. 2016 Aug 9;316(6):663

Authors: Gatchel RJ, Licciardone JC

PMID: 27532923 [PubMed - as supplied by publisher]

Development of novel HDL-mimicking α-tocopherol-coated nanoparticles to encapsulate nerve growth factor and evaluation of biodistribution.

Thu, 08/18/2016 - 06:29

Development of novel HDL-mimicking α-tocopherol-coated nanoparticles to encapsulate nerve growth factor and evaluation of biodistribution.

Eur J Pharm Biopharm. 2016 Aug 12;

Authors: Prathipati P, Zhu J, Dong X

Abstract
Nerve Growth Factor (NGF) is one of the members of the neurotrophin family with multifaceted functions. However, clinic application of NGF is hurdled by the challenge on formulation development. The objective of this study was to develop novel high-density lipoproteins (HDL)-mimicking nanoparticles (NPs) coated with α-tocopherol to incorporate NGF by a self-assembly approach. The NPs were prepared by an optimized self-assembly method that is simple and scalable. The composition of HDL-mimicking NPs was optimized. The prototype of the HDL-mimicking α-tocopherol-coated NPs contained phosphatidylserine (a negative charged phospholipid) and D- α-Tocopheryl polyethylene glycol succinate (a source of vitamin E) to enhance the entrapment efficiency of apolipoprotein A-I in the NPs. The entrapment efficiency of apolipoprotein A-I was about 30%. The NPs had particle size about 200 nm with a relatively narrow size distribution. Finally, cationic ion-pair agents were optimized to form ion-pairs with NGF to facilitate the incorporation of NGF into the NPs. Protamine sodium salt USP formed an optimal ion-pair complex with NGF. The results showed that the novel HDL-mimicking α-tocopherol-coated NPs successfully encapsulated NGF with over 65% entrapment efficiency by using this ion-pair strategy. In vitro release studies demonstrated a slow release of NGF from NGF NPs in PBS containing 5% BSA at 37°C for 72 hours. Further biodistribution studies showed that intravenously injected NGF NPs significantly increased NGF concentration in plasma and decreased the uptake in liver, spleen and kidney, compared to free NGF in mice.

PMID: 27531623 [PubMed - as supplied by publisher]

Immune senescence: Significance of the stromal microenvironment.

Wed, 08/17/2016 - 14:30

Immune senescence: Significance of the stromal microenvironment.

Clin Exp Immunol. 2016 Aug 16;

Authors: Masters AR, Haynes L, Su DM, Palmer DB

Abstract
The immune system undergoes age-associated changes known as immunosenescence, resulting in increased susceptibility to infections, cancers and autoimmunity in the aged. The basis of our understanding of immunosenescence has been primarily derived from studies examining intrinsic defects within many of the cells of the immune system. While these studies have provided insight into the mechanisms of immunosenescence, a picture is now emerging that the stromal microenvironment within lymphoid organs also contributes significantly to the age-associated decline of immune function. These extrinsic defects appear to impact the functional activity of immune cells and may offer a potential target to recover immune activity. Indeed, rejuvenation studies which have targeted the stromal niche have successfully restored immune function in the aged, highlighting the impact of the microenvironment towards the aetiology of immunosenescence. This article is protected by copyright. All rights reserved.

PMID: 27529161 [PubMed - as supplied by publisher]

Blimp-1/PRDM1 regulates the transcription of human CS1 (SLAMF7) gene in NK and B cells.

Wed, 08/17/2016 - 14:30
Related Articles

Blimp-1/PRDM1 regulates the transcription of human CS1 (SLAMF7) gene in NK and B cells.

Immunobiology. 2016 Jan;221(1):31-9

Authors: Kim JR, Mathew SO, Mathew PA

Abstract
CS1 (CRACC/CD319/SLAMF7) is a member of SLAM (Signaling Lymphocyte Activation Molecule) family receptors and is expressed on NK cells, a subset of CD8(+) T lymphocytes, activated monocytes, mature dendritic cells and activated B cells. In NK cells, CS1 signaling induces cytolytic function of NK cells against targets whereas in B cells CS1 induces proliferation and autocrine cytokine production. CS1 is upregulated in multiple myeloma cells and contributes to clonogenic growth and tumorigenicity. However, the mechanism of CS1 upregulation is unknown. In this study, we analyzed the transcriptional regulation of human CS1 gene in NK and B cells. The promoter region of CS1 contains a Blimp-1/PRDM1 binding site and relative luciferase activities of successive deletion mutants of CS1 promoter were different between Blimp-1/PRDM1-positive and Blimp-1/PRDM1-negative cells. Proximal region of CS1 promoter contains a CAAT box and atypical TATA-box that might result in common transcription initiation at -29 nucleotides upstream of the ATG translation start codon. Electrophoretic Mobility Shift Assay (EMSA) and Chromatin Immunoprecipitation (ChIP) assays revealed Blimp-1/PRDM1 binds to the CS1 promoter region. Mutating the Blimp-1/PRDM1 site at -750 to -746 decreased the transcriptional activity of CS1 promoter implicating a trans-activating function of Blimp-1/PRDM1 in human CS1 gene regulation. The finding that Blimp-1/PRDM1 enhances transcription of CS1 gene in multiple myeloma cells may help in developing novel strategies for therapeutic intervention in multiple myeloma.

PMID: 26310579 [PubMed - indexed for MEDLINE]

The Impact of Race and Neighborhood Racial Composition on Preventable Readmissions for Diabetic Medicare Home Health Beneficiaries.

Tue, 08/16/2016 - 10:32
Related Articles

The Impact of Race and Neighborhood Racial Composition on Preventable Readmissions for Diabetic Medicare Home Health Beneficiaries.

J Racial Ethn Health Disparities. 2016 Aug 11;

Authors: Chen HF, Homan S, Carlson E, Popoola T, Radhakrishnan K

Abstract
BACKGROUND: The recommended home health financial penalty program for preventable readmission does not factor race/ethnicity and neighborhood racial compositions into the determination of preventable readmission rates. Home health agencies may avoid beneficiaries from certain racial/ethnic groups and neighborhoods if these two factors have an effect on preventable readmissions. We examined the association between preventable readmissions with race/ethnicity and neighborhood racial composition.
METHODS: Several 2009 national data were used, such as the Master Beneficiary Summary File, Medicare Provider Analysis and Review File, and Outcome Assessment Information Set. Our sample consisted of diabetic Medicare home health beneficiaries (African-Americans and Whites only). We analyzed predictors of time-to-first 30-day preventable readmission, including short/long-term diabetic complications, chronic obstructive pulmonary disease/asthma, bacterial pneumonia, dehydration, urinary tract infection, hypertension, heart failure, angina without procedure, uncontrolled diabetes, and lower-extremity amputation.
RESULTS: There were 86,567, 17,262, and 11,392 observations in neighborhoods with low (6 % African-Americans), moderate (35 % African-Americans), and high (76 % African-Americans) density of African-Americans, respectively. Using Cox regression models, we found that in neighborhoods with moderate and high density of African-Americans, African-Americans had 21 % (hazard ratio (HR) 1.21; 95 % confidence interval (CI) 1.04-1.39) and 24 % (HR 1.24; 95 % CI 1.01-1.52) significantly higher hazards of 30-day preventable readmissions than Whites, respectively.
CONCLUSION: Race and neighborhood racial compositions are beyond home health providers' control. These two factors should be considered as covariates for the preventable readmissions in the recommended home health financial penalty program.

PMID: 27514389 [PubMed - as supplied by publisher]

Increased Partner Risk Characteristic Among Adolescents Using Alcohol In the Moment.

Fri, 08/12/2016 - 10:31

Increased Partner Risk Characteristic Among Adolescents Using Alcohol In the Moment.

Sex Transm Dis. 2016 Sep;43(9):537-541

Authors: Staras SA, Livingston MD, Komro KA

Abstract
BACKGROUND: Alcohol is a recognized risk factor for sexually transmitted diseases acquisition, but the mechanism is unclear. Potentially, adolescents using alcohol in the 2 hours before sex (in-the-moment use) have riskier sexual partners.
METHODS: We used multivariable logistic regression to examine the association between in-the-moment alcohol use and partner risk characteristics reported for the most recent sex among primarily 17- to 18-year-old adolescents originally recruited from a representative sample of Chicago public elementary schools. We created 3 composite partner risk profiles: partner familiarity risk (casual and unexpected), partner context risk (age discordance and met in public), and overall risk using all measures except partner alcohol use.
RESULTS: Teens who reported any in-the-moment alcohol use were more likely than nondrinking teens to report casual (adjusted odds ratio [AOR], 3.2; 95% confidence interval [95% CI], 2.1-4.9), unexpected (AOR, 1.6; 95% CI, 1.0-2.5), age discordant (AOR, 3.0; 95% CI, 2.0-4.6), or met in public partners (AOR, 1.4; 95% CI, 1.0 to 2.1). For each composite measure, the number of partner risk characteristics reported increased linearly with the percent of teens drinking in the moment (Cochran-Armitage trend, P < 0.0001). Compared with zero characteristics, in-the-moment alcohol use was associated with increased odds of reporting 1 (AOR, 2.8; 95% CI, 1.7-4.5), 2 (AOR, 4.6; 95% CI, 2.7, 7.6), or 3 to 4 characteristics (AOR, 7.1; 95% CI, 3.3-15.3).
CONCLUSIONS: Our findings expand the link between in-the-moment alcohol use and partner risk reported in prior studies to encompass adolescents' general sexual experiences and additional partner characteristics including the highly associated composite characteristics.

PMID: 27513378 [PubMed - as supplied by publisher]

Patient-centered medical home features and expenditures by medicare beneficiaries.

Fri, 08/12/2016 - 10:31
Related Articles

Patient-centered medical home features and expenditures by medicare beneficiaries.

Am J Manag Care. 2014 May;20(5):379-85

Authors: Stockbridge EL, Philpot LM, Pagán JA

Abstract
OBJECTIVES: To determine the impact of individual features of the patient-centered medical home (PCMH) care model on next-year healthcare expenditures including outpatient, inpatient, emergency department, pharmacy, and total healthcare expenditures among Medicare beneficiaries 65 years and older.
STUDY DESIGN: Analysis of retrospective longitudinal survey data. Methods Longitudinal files from the Medical Expenditure Panel Survey were analyzed. Differences in expenditures for individuals whose usual sources of care did or did not have different PCMH features were estimated using recycled predictions from generalized linear regression models.
RESULTS: Having little to no difficulty contacting the regular source of care over the telephone during regular business hours was associated with significantly lower total and inpatient expenditures over the next year (differences of $2867 and $3736, respectively). Having a regular source of care with office hours at night or on weekends was associated with significantly lower outpatient, emergency department, and other expenditures (differences of $535, $103, and $328, respectively). Pharmacy expenditures were significantly higher for individuals whose usual source of care inquired about medications and treatments prescribed by other doctors (difference of $362).
CONCLUSIONS: This study points out the need to identify how individual PCMH features impact healthcare expenditures across different policy-relevant categories. Practices that have not fully adopted a PCMH model can still make progress in improving quality and controlling costs by adopting even some modest features of the PCMH model.

PMID: 25181567 [PubMed - indexed for MEDLINE]

A sex difference in oxidative stress and behavioral suppression induced by ethanol withdrawal in rats.

Wed, 08/10/2016 - 06:30

A sex difference in oxidative stress and behavioral suppression induced by ethanol withdrawal in rats.

Behav Brain Res. 2016 Aug 5;

Authors: Jung ME, Metzger DB

Abstract
Ethanol withdrawal (EW) is referred to the abrupt termination of long-term heavy drinking, and provokes oxidative brain damage. Here, we investigated whether the cerebellum and hippocampus of female rats are less affected by prooxidant EW than male rats due to the antioxidant effect of 17β-estradiol (E2). Female and male rats received a four-week ethanol diet and three-week withdrawal per cycle for two cycles. Some female rats were ovariectomized with E2 or antioxidant (Vitamin E+Co-Q10) treatment. Measurements were cerebellum (Rotarod) and hippocampus (water-maze)-related behaviors, oxidative markers (O2•-, malondialdehyde, protein carbonyls), mitochondrial membrane swelling, and a key mitochondrial enzyme, cytochrome c oxidase (CcO). Separately, HT22 (hippocampal) cells were subjected to ethanol-exposure and withdrawal for two cycles to assess the effect of a CcO inhibitor on E2's protection for mitochondrial respiration and cell viability. Ethanol-withdrawn female rats showed a smaller increase in oxidative markers in cerebellum and hippocampus than male rats, and E2 treatment decreased the oxidative markers. Compared to male counterparts, ethanol-withdrawn female rats showed better Rotarod but poorer water-maze performance, accompanied by more severe mitochondrial membrane swelling and CcO suppression in hippocampus. E2 or antioxidant treatment improved Rotarod but not water-maze performance. In the presence of a CcO inhibitor, E2 treatment failed to protect mitochondrial respiration and cell viability from EW. These data suggest that antioxidant E2 contributes to smaller oxidative stress in ethanol-withdrawn female than male rats. They also suggest that EW-induced severe mitochondrial damage in hippocampus may blunt E2's antioxidant protection for hippocampus-related behavior.

PMID: 27503149 [PubMed - as supplied by publisher]

δ-Opioid receptors: Pivotal role in intermittent hypoxia-augmentation of cardiac parasympathetic control and plasticity.

Tue, 08/09/2016 - 06:31
Related Articles

δ-Opioid receptors: Pivotal role in intermittent hypoxia-augmentation of cardiac parasympathetic control and plasticity.

Auton Neurosci. 2016 Jul 25;

Authors: Estrada JA, Barlow MA, Yoshishige D, Williams AG, Downey HF, Mallet RT, Caffrey JL

Abstract
BACKGROUND: Intermittent hypoxia training (IHT) produces robust myocardial protection against ischemia-reperfusion induced infarction and arrhythmias. Blockade of this cardioprotection by antagonism of either β1-adrenergic or δ-opioid receptors (δ-OR) suggests autonomic and/or opioidergic adaptations.
PURPOSE: To test the hypothesis that IHT shifts cardiac autonomic balance toward greater cholinergic and opioidergic influence.
METHODS: Mongrel dogs completed 20d IHT, non-hypoxic sham training, or IHT with the δ-OR antagonist naltrindole (200μg/kgsc). The vagolytic effect of the δ-OR agonist met-enkephalin-arg-phe delivered by sinoatrial microdialysis was evaluated following IHT. Sinoatrial, atrial and left ventricular biopsies were analyzed for changes in δ-OR, the neurotrophic monosialoganglioside, GM-1, and cholinergic and adrenergic markers.
RESULTS: IHT enhanced vagal bradycardia vs. sham dogs (P<0.05), and blunted the δ2-OR mediated vagolytic effect of met-enkephalin-arg-phe. The GM-1 labeled fibers overlapped strongly with cholinergic markers, and IHT increased the intensity of both signals (P<0.05). IHT increased low and high intensity vesicular acetylcholine transporter labeling of sinoatrial nodal fibers (P<0.05) suggesting an increase in parasympathetic arborization. IHT reduced select δ-OR labeled fibers in both the atria and sinoatrial node (P<0.05) consistent with moderation of the vagolytic δ2-OR signaling described above. Furthermore, blockade of δ-OR signaling with naltrindole during IHT increased the protein content of δ-OR (atria and ventricle) and vesicular acetylcholine transporter (atria) vs. sham and untreated IHT groups. IHT also reduced the sympathetic marker, tyrosine hydroxylase in ventricle (P<0.05).
SUMMARY: IHT shifts cardiac autonomic balance in favor of parasympathetic control via adaptations in opioidergic, ganglioside, and adrenergic systems.

PMID: 27498137 [PubMed - as supplied by publisher]

Phase 3 Evaluation of HP802-247 in the Treatment of Chronic Venous Leg Ulcers.

Tue, 08/09/2016 - 06:31
Related Articles

Phase 3 Evaluation of HP802-247 in the Treatment of Chronic Venous Leg Ulcers.

Wound Repair Regen. 2016 Aug 6;

Authors: Kirsner RS, Vanscheidt W, Keast DH, Lantis JC, Dove CR, Cazzell SM, Vartivarian M, Augustin M, Marston WA, McCoy ND, Cargill DI, Lee TD, Dickerson JE, Slade HB, HP802-247 Study Group

Abstract
In 2012 we reported promising results from a Phase 2 clinical trial of HP802-247, a novel spray-applied investigational treatment for chronic venous leg ulcers (VLU) consisting of human, allogeneic fibroblasts and keratinocytes. We now describe Phase 3 clinical testing of HP802-247, its failure to detect efficacy, and subsequent investigation into the root causes of the failure. Two randomized, controlled trials enrolled a total of 673 adult outpatients at 96 centers in North America and Europe. The primary endpoint was the proportion of ulcers with confirmed closure at the end of 12 weeks of treatment. An investigation into the root cause for the failure of HP802-247 to show efficacy in these two Phase 3 trials was initiated immediately following the initial review of the North American trial results. 421 patients were enrolled in the North American (HP802-247, 211; Vehicle 210) and 252 in the European (HP802-247, 131; Vehicle 121) trials. No difference in proportion of closed ulcers at week 12 was observed between treatment groups for either the North American (HP802-247, 61.1%; Vehicle 60.0%; P=0.5896) or the European (HP802-247, 47.0%; Vehicle 50.0%; P=0.5348) trials. Thorough investigation found no likelihood that design or execution of the trials contributed to the failure. Variability over time during the trials in the clinical response implicated the quality of the cells comprising HP802-247. Concordance between the two separate, randomized, controlled trials with distinct, non-overlapping investigative sites and independent monitoring teams renders the possibility of a Type II error vanishingly small and provides strong credibility for the unexpected lack of efficacy observed. The most likely causative factors for the efficacy failure in Phase 3 was phenotypic change in the cells (primarily keratinocytes) leading to batch to batch variability due to the age of the cell banks. This article is protected by copyright. All rights reserved.

PMID: 27495869 [PubMed - as supplied by publisher]

Treadmill exercise within lower body negative pressure protects leg lean tissue mass and extensor strength and endurance during bed rest.

Tue, 08/09/2016 - 06:31
Related Articles

Treadmill exercise within lower body negative pressure protects leg lean tissue mass and extensor strength and endurance during bed rest.

Physiol Rep. 2016 Aug;4(15)

Authors: Schneider SM, Lee SM, Feiveson AH, Watenpaugh DE, Macias BR, Hargens AR

Abstract
Leg muscle mass and strength are decreased during reduced activity and non-weight-bearing conditions such as bed rest (BR) and spaceflight. Supine treadmill exercise within lower body negative pressure (LBNPEX) provides full-body weight loading during BR and may prevent muscle deconditioning. We hypothesized that a 40-min interval exercise protocol performed against LBNPEX 6 days week(-1) would attenuate losses in leg lean mass (LLM), strength, and endurance during 6° head-down tilt BR, with similar benefits for men and women. Fifteen pairs of healthy monozygous twins (8 male and 7 female pairs) completed 30 days of BR with one sibling of each twin pair assigned randomly as the non-exercise control (CON) and the other twin as the exercise subject (EX). Before and after BR, LLM and isokinetic leg strength and endurance were measured. Mean knee and ankle extensor and flexor strength and endurance and LLM decreased from pre- to post-BR in the male CON subjects (P < 0.01), but knee extensor strength and endurance, ankle extensor strength, and LLM were maintained in the male EX subjects. In contrast, no pre- to post-BR changes were significant in the female subjects, either CON or EX, likely due to their lower pre-BR values. Importantly, the LBNPEX countermeasure prevents or attenuates declines in LLM as well as extensor leg strength and endurance. Individuals who are stronger, have higher levels of muscular endurance, and/or have greater LLM are likely to experience greater losses during BR than those who are less fit.

PMID: 27495299 [PubMed - in process]

Ischemia-induced Angiogenesis is Attenuated in Aged Rats.

Sun, 08/07/2016 - 10:33
Related Articles

Ischemia-induced Angiogenesis is Attenuated in Aged Rats.

Aging Dis. 2016 Aug;7(4):326-35

Authors: Tang Y, Wang L, Wang J, Lin X, Wang Y, Jin K, Yang GY

Abstract
To study whether focal angiogenesis is induced in aged rodents after permanent distal middle cerebral artery occlusion (MCAO), young adult (3-month-old) and aged (24-month-old) Fisher 344 rats underwent MCAO and sacrificed up to two months after MCAO. Immunohistochemistry and synchrotron radiation microangiography were performed to examine the number of newly formed blood vessels in both young adult and aged rats post-ischemia. We found that the number of capillaries and small arteries in aged brain was the same as young adult brain. In addition, we found that after MCAO, the number of blood vessels in the peri-infarct region of ipsilateral hemisphere in aged ischemic rats was significantly increased compared to the aged sham rats (p<0.05). We also confirmed that ischemia-induced focal angiogenesis occurred in young adult rat brain while the blood vessel density in young adult ischemic brain was significantly higher than that in the aged ischemic brain (p<0.05). Our data suggests that focal angiogenesis in aged rat brain can be induced in response to ischemic brain injury, and that aging impedes brain repairing and remodeling after ischemic stroke, possible due to the limited response of angiogenesis.

PMID: 27493831 [PubMed]

Fully Threaded Versus Partially Threaded Screws: Determining Shear in Cancellous Bone Fixation.

Sun, 08/07/2016 - 10:33
Related Articles

Fully Threaded Versus Partially Threaded Screws: Determining Shear in Cancellous Bone Fixation.

J Foot Ankle Surg. 2015 Nov-Dec;54(6):1021-4

Authors: Downey MW, Kosmopoulos V, Carpenter BB

Abstract
Many researchers have studied and compared various forms of intraosseous fixation. No studies have examined the effects of shear through stiffness and failure strength of a fully threaded versus a partially threaded screw. Our hypothesis was that the fully threaded lag screw technique would provide greater shear strength and resistance. Thirty-six synthetic sawbone blocks were used to test screw fixation. In group 1 (n = 9), 2 blocks were fixed together using a fully threaded 4.0-mm stainless steel cancellous bone screw and the lag technique. In group 2 (n = 8), 2 blocks were fixed together using the standard manufacturer-recommended method for inserting 4.0-mm partially threaded stainless steel cancellous bone screws. The constructs were then mechanically tested. Shear was applied by compressing each construct at an axial displacement rate of 0.5 mm/s until failure. The fully threaded screw had a significantly greater (p = .026) initial stiffness (106.4 ± 15.8 N/mm) than the partially threaded screw (80.1 ± 27.5 N/mm). The yield load and displacement for the fully threaded group (429.4 ± 11.7 N and 7.2 ± 0.35 mm) were 64% and 67% greater than those for the partially threaded screw group (261.4 ± 26.1 N and 4.3 ± 1.03 mm), respectively. The results of the present study have demonstrated the importance of a full-thread construct to prevent shear and to decrease strain at the fracture. The confirmation of our hypothesis questions the future need and use of partially threaded screws for cancellous bone fixation.

PMID: 26210079 [PubMed - indexed for MEDLINE]

Treatment with an orally bioavailable prodrug of 17β-estradiol alleviates hot flushes without hormonal effects in the periphery.

Tue, 08/02/2016 - 10:30

Treatment with an orally bioavailable prodrug of 17β-estradiol alleviates hot flushes without hormonal effects in the periphery.

Sci Rep. 2016;6:30721

Authors: Merchenthaler I, Lane M, Sabnis G, Brodie A, Nguyen V, Prokai L, Prokai-Tatrai K

Abstract
Estrogen deprivation has a profound effect on the female brain. One of the most obvious examples of this condition is hot flushes. Although estrogens relieve these typical climacteric symptoms, many women do not want to take them owing to unwanted side-effects impacting, for example, the uterus, breast and blood. Therefore, there is a need for developing safer estrogen therapies. We show here that treatment with 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), a novel brain-targeting bioprecursor prodrug of the main human estrogen, 17β-estradiol, alleviates hot flushes in rat models of thermoregulatory dysfunction of the brain. Oral administration of DHED elicits a significant reduction of tail skin temperature (TST) rise representing hot flushes in the morphine-dependent ovariectomized rat model and results in the restoration of estrogen deprivation-induced loss of diurnal rhythm in TST. These beneficial effects occur without detrimental peripheral hormonal exposure; thus, the treatment avoids potentially harmful stimulation of estrogen-sensitive peripheral organs, including the uterus and the anterior pituitary, or the proliferation of MCF-7a breast cancer cell xenografts. Our promising preclinical assessments warrant further considerations of DHED for the development of a brain-selective 17β-estradiol therapy to relieve hot flushes without undesirable peripheral side-effects.

PMID: 27477453 [PubMed - in process]

A Depressive Endophenotype for Predicting Cognitive Decline among Mexican American Adults and Elders.

Sat, 07/30/2016 - 06:32

A Depressive Endophenotype for Predicting Cognitive Decline among Mexican American Adults and Elders.

J Alzheimers Dis. 2016 Jul 25;

Authors: Johnson LA, Gamboa A, Vintimilla R, Edwards M, Hall J, Weiser B, Yadav M, Dickensheets T, O'Bryant SE

Abstract
BACKGROUND: Late life depression is a prodromal feature and a risk factor for Alzheimer's disease (AD) and mild cognitive impairment (MCI). We identified five items in the Geriatric Depression scale (DepE) that are important as a risk for MCI and AD: memory problems, feeling blue, crying, feeling worthless, and trouble concentrating.
OBJECTIVE: Our goal was to examine the relationship between DepE and cognition in a cohort of Mexican Americans.
METHODS: Data from 317 Mexican Americans from the HABLE study were analyzed. DepE scores were dichotomized into two groups: endorsement of 1 item or less, and endorsement of 2 or more items. Cognition was assessed via neuropsychological tests, and diagnosis was based on consensus review. We utilized linear regression to examine the association between DepE and cognitive performance, and logistic regression to examine the utility of DepE in predicting MCI. To examine the impact of DepE on memory over 12 months, we performed ANOVA analysis.
RESULTS: Elevated DepE scores were associated with poorer performance on various measures of memory and cognition, but not executive or visual spatial skills. Over 12 months, we found a decline in immediate memory among women but not men. Those with high scores were 4 times more likely to have MCI. ANOVA of total scores revealed differences between groups on immediate memory (p < 0.05) in women, with no significant differences on delay recall in either gender.
CONCLUSION: DepE can be utilized in Mexican Americans to identify those at risk of memory related cognitive decline.

PMID: 27472872 [PubMed - as supplied by publisher]

Pages