Recent Research Articles from UNTHSC

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Updated: 52 min 17 sec ago

CRH promotes S. pneumoniae growth in vitro and increases lung carriage in mice.

52 min 17 sec ago

CRH promotes S. pneumoniae growth in vitro and increases lung carriage in mice.

Front Microbiol. 2015;6:279

Authors: Ndjom CG, Jones HP

Abstract
Streptococcus pneumoniae (S. pneumoniae), a commensal across the nasal passages, is responsible for the majority of infectious pneumonia cases worldwide. Previous studies have shown that hormonal factors may be influential in regulating S. pneumoniae's transition from a non-pathogen to a pathogenic state. The current study investigated the effects of corticotropin-releasing hormone (CRH), a peptide hormone involved in stress, on the pathogenicity of S. pneumoniae. Mice were infected with CRH-treated S. pneumoniae via intranasal route, showing an increase in pulmonary bacterial burden. We also quantified S. pneumoniae's response to CRH through limited serial dilutions and growth curve analysis. We demonstrated that CRH promotes S. pneumoniae titer-dependent proliferation, as well as accelerates log-phase growth. Results also showed an increase in pneumococcal-associated virulence protein A virulence gene expression in response to CRH. These results demonstrate a role for CRH in S. pneumoniae pathogenicity, thus implicating CRH in mediating the transition of S. pneumoniae into a pathogenic state.

PMID: 25904910 [PubMed]

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

52 min 17 sec ago

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

Clin Infect Dis. 2015 Apr 22;

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

Abstract
BACKGROUND:  Weekly rifapentine plus isoniazid for 3 months (3HP) is as effective as daily isoniazid (9H) for 9 months for latent tuberculosis infection in high-risk persons, but there have been reports of possible flu-like syndrome.
METHODS:  We identified clinically significant systemic drug reactions (SDR) and evaluated risk factors in patients who did not complete treatment in the PREVENT TB study.
RESULTS:  Among 7,552 persons who received >1 dose of study drug, 153 had a SDR: 138/3,893(3.5%) with 3HP vs. 15/3,659(0.4%) with 9H(P<0.001). In the 3HP arm, 87(63%) had flu-like syndrome and 23(17%) had cutaneous reactions; 13/3,893(0.3%) had severe reactions (6 were hypotensive) and 6 reported syncope. Symptoms occurred after a median of 3 doses, and 4 hours after the dose; median time to resolution was 24 hours. There were no deaths. In multivariate logistic regression analysis, factors independently associated with SDR included receipt of 3HP (aOR 9.4;95%CI:5.5, 16.2), white non-Hispanic race/ethnicity (aOR 3.3;95%CI:2.3, 4.7), female sex (aOR 2.0;95% CI:1.4, 2.9), age >35 years (aOR 2.0;95% CI:1.4, 2.9), and lower body mass index (BMI; P=0.009). In a separate multivariate analysis among persons who received 3HP, severe SDR were associated with white non-Hispanic race/ethnicity (aOR 5.4;95% CI:1.8, 16.3), and receipt of concomitant non-study medications (aOR 5.9;95% CI:1.3, 27.1).
CONCLUSIONS:  SDR were more common with 3HP, and mostly flu-like. Persons of white race, female sex, older age, and lower BMI were at increased risk. Severe reactions were rare and associated with 3HP, concomitant medication, and white race. The underlying mechanism is unclear.

PMID: 25904367 [PubMed - as supplied by publisher]

A weighted U-statistic for genetic association analyses of sequencing data.

52 min 17 sec ago
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A weighted U-statistic for genetic association analyses of sequencing data.

Genet Epidemiol. 2014 Dec;38(8):699-708

Authors: Wei C, Li M, He Z, Vsevolozhskaya O, Schaid DJ, Lu Q

Abstract
With advancements in next-generation sequencing technology, a massive amount of sequencing data is generated, which offers a great opportunity to comprehensively investigate the role of rare variants in the genetic etiology of complex diseases. Nevertheless, the high-dimensional sequencing data poses a great challenge for statistical analysis. The association analyses based on traditional statistical methods suffer substantial power loss because of the low frequency of genetic variants and the extremely high dimensionality of the data. We developed a Weighted U Sequencing test, referred to as WU-SEQ, for the high-dimensional association analysis of sequencing data. Based on a nonparametric U-statistic, WU-SEQ makes no assumption of the underlying disease model and phenotype distribution, and can be applied to a variety of phenotypes. Through simulation studies and an empirical study, we showed that WU-SEQ outperformed a commonly used sequence kernel association test (SKAT) method when the underlying assumptions were violated (e.g., the phenotype followed a heavy-tailed distribution). Even when the assumptions were satisfied, WU-SEQ still attained comparable performance to SKAT. Finally, we applied WU-SEQ to sequencing data from the Dallas Heart Study (DHS), and detected an association between ANGPTL 4 and very low density lipoprotein cholesterol.

PMID: 25331574 [PubMed - indexed for MEDLINE]

Stress induces p38 MAPK-mediated phosphorylation and inhibition of Drosha-dependent cell survival.

52 min 17 sec ago
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Stress induces p38 MAPK-mediated phosphorylation and inhibition of Drosha-dependent cell survival.

Mol Cell. 2015 Feb 19;57(4):721-34

Authors: Yang Q, Li W, She H, Dou J, Duong DM, Du Y, Yang SH, Seyfried NT, Fu H, Gao G, Mao Z

Abstract
MicroRNAs (miRNAs) regulate the translational potential of their mRNA targets and control many cellular processes. The key step in canonical miRNA biogenesis is the cleavage of the primary transcripts by the nuclear RNase III enzyme Drosha. Emerging evidence suggests that the miRNA biogenic cascade is tightly controlled. However, little is known whether Drosha is regulated. Here, we show that Drosha is targeted by stress. Under stress, p38 MAPK directly phosphorylates Drosha at its N terminus. This reduces its interaction with DiGeorge syndrome critical region gene 8 and promotes its nuclear export and degradation by calpain. This regulatory mechanism mediates stress-induced inhibition of Drosha function. Reduction of Drosha sensitizes cells to stress and increases death. In contrast, increase in Drosha attenuates stress-induced death. These findings reveal a critical regulatory mechanism by which stress engages p38 MAPK pathway to destabilize Drosha and inhibit Drosha-mediated cellular survival.

PMID: 25699712 [PubMed - indexed for MEDLINE]

A nanotherapy strategy significantly enhances anticryptosporidial activity of an inhibitor of bifunctional thymidylate synthase-dihydrofolate reductase from Cryptosporidium.

Fri, 04/24/2015 - 7:29am

A nanotherapy strategy significantly enhances anticryptosporidial activity of an inhibitor of bifunctional thymidylate synthase-dihydrofolate reductase from Cryptosporidium.

Bioorg Med Chem Lett. 2015 Apr 4;

Authors: Mukerjee A, Iyidogan P, Castellanos-Gonzalez A, Cisneros JA, Czyzyk D, Ranjan AP, Jorgensen WL, White AC, Vishwanatha JK, Anderson KS

Abstract
Cryptosporidiosis, a gastrointestinal disease caused by protozoans of the genus Cryptosporidium, is a common cause of diarrheal diseases and often fatal in immunocompromised individuals. Bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) from Cryptosporidium hominis (C. hominis) has been a molecular target for inhibitor design. C. hominis TS-DHFR inhibitors with nM potency at a biochemical level have been developed however drug delivery to achieve comparable antiparasitic activity in Cryptosporidium infected cell culture has been a major hurdle for designing effective therapies. Previous mechanistic and structural studies have identified compound 906 as a nM C. hominis TS-DHFR inhibitor in vitro, having μM antiparasitic activity in cell culture. In this work, proof of concept studies are presented using a nanotherapy approach to improve drug delivery and the antiparasitic activity of 906 in cell culture. We utilized PLGA nanoparticles that were loaded with 906 (NP-906) and conjugated with antibodies to the Cryptosporidium specific protein, CP2, on the nanoparticle surface in order to specifically target the parasite. Our results indicate that CP2 labeled NP-906 (CP2-NP-906) reduces the level of parasites by 200-fold in cell culture, while NP-906 resulted in 4.4-fold decrease. Moreover, the anticryptosporidial potency of 906 improved 15 to 78-fold confirming the utility of the antibody conjugated nanoparticles as an effective drug delivery strategy.

PMID: 25900220 [PubMed - as supplied by publisher]

Streptozotocin-induced type 1 diabetes in rodents as a model for studying mitochondrial mechanisms of diabetic β cell glucotoxicity.

Thu, 04/23/2015 - 3:29am

Streptozotocin-induced type 1 diabetes in rodents as a model for studying mitochondrial mechanisms of diabetic β cell glucotoxicity.

Diabetes Metab Syndr Obes. 2015;8:181-8

Authors: Wu J, Yan LJ

Abstract
Chronic hyperglycemia and the corresponding glucotoxicity are the main pathogenic mechanisms of diabetes and its complications. Streptozotocin (STZ)-induced diabetic animal models are useful platforms for the understanding of β cell glucotoxicity in diabetes. As diabetes induced by a single STZ injection is often referred to as type 1 diabetes that is caused by STZ's partial destruction of pancreas, one question often being asked is whether the STZ type 1 diabetes animal model is a good model for studying the mitochondrial mechanisms of β cell glucotoxicity. In this mini review, we provide evidence garnered from the literature that the STZ type 1 diabetes is indeed a suitable model for studying mitochondrial mechanisms of diabetic β cell glucotoxicity. Evidence presented includes: 1) continued β cell derangement is due to chronic hyperglycemia after STZ is completely eliminated out of the body; 2) STZ diabetes can be reversed by insulin treatment, which indicates that β cell responds to treatment and shows ability to regenerate; and 3) STZ diabetes can be ameliorated or alleviated by administration of phytochemicals. In addition, mechanisms of STZ action and fundamental gaps in understanding mitochondrial mechanisms of β cell dysfunction are also discussed.

PMID: 25897251 [PubMed]

Assessment of subunit-dependent direct gating and allosteric modulatory effects of carisoprodol at GABAA receptors.

Thu, 04/23/2015 - 3:29am

Assessment of subunit-dependent direct gating and allosteric modulatory effects of carisoprodol at GABAA receptors.

Neuropharmacology. 2015 Apr 17;

Authors: Kumar M, González LA, Dillon GH

Abstract
Carisoprodol is a widely prescribed muscle relaxant, abuse of which has grown considerably in recent years. It directly activates and allosterically modulates α1β2γ2 GABAARs, although the site(s) of action are unknown. To gain insight into the actions of carisoprodol, subunit-dependent effects of this drug were assessed. Whole-cell patch clamp recordings were obtained from HEK293 cells expressing α1β2, α1β3 or αxβzγ2 (where x = 1-6 and z = 1-3) GABAARs, and in receptors incorporating the δ subunit (modeling extrasynaptic receptors). The ability to directly gate and allosterically potentiate GABA-gated currents was observed for all configurations. Presence or absence of the γ2 subunit did not affect the ability of carisoprodol to directly gate or allosterically modulate the receptor. Presence of the β1 subunit conferred highest efficacy for direct activation relative to maximum GABA currents, while presence of the β2 subunit conferred highest efficacy for allosteric modulation of the GABA response. With regard to α subunits, carisoprodol was most efficacious at enhancing the actions of GABA in receptors incorporating the α1 subunit. The ability to directly gate the receptor was generally comparable regardless of the α subunit isoform, although receptors incorporating the α3 subunit showed significantly reduced direct gating efficacy and affinity. In extrasynaptic (α1β3δ and α4β3δ) receptors, carisoprodol had greater efficacy than GABA as a direct gating agonist. In addition, carisoprodol allosterically potentiated both EC20 and saturating GABA concentrations in these receptors. In assessing voltage-dependence, we found direct gating and inhibitory effects were insensitive to membrane voltage, whereas allosteric modulatory effects were affected by membrane voltage. Our findings demonstrate direct and allosteric effects of carisoprodol at synaptic and extrasynpatic GABAARs and that subunit isoform influences these effects.

PMID: 25896767 [PubMed - as supplied by publisher]

Orthopedic Emergencies: A Practical Emergency Department Classification (US-VAGON) in Pelvic Fractures.

Thu, 04/23/2015 - 3:29am
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Orthopedic Emergencies: A Practical Emergency Department Classification (US-VAGON) in Pelvic Fractures.

Emerg Med Clin North Am. 2015 May;33(2):451-473

Authors: Wang H, Coppola PT, Coppola M

Abstract
Trauma is one of the leading causes of death before the age of 40 years and approximately 5% of patients with trauma who require hospital admission have pelvic fractures. This article updates the emergency department classification of pelvic fractures first described in 2000. This information is of practical value to emergency physicians in identifying the potential vascular, genitourinary, gastrointestinal, orthopedic, and neurologic complications and further assists them in the initial evaluation and treatment of patients with pelvic fractures.

PMID: 25892731 [PubMed - as supplied by publisher]

Risk factors for and assessment of symptomatic pseudarthrosis after lumbar pedicle subtraction osteotomy in adult spinal deformity.

Thu, 04/23/2015 - 3:29am
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Risk factors for and assessment of symptomatic pseudarthrosis after lumbar pedicle subtraction osteotomy in adult spinal deformity.

Spine (Phila Pa 1976). 2014 Jul 1;39(15):1190-5

Authors: Dickson DD, Lenke LG, Bridwell KH, Koester LA

Abstract
STUDY DESIGN: Retrospective review of prospectively collected data.
OBJECTIVE: To assess the prevalence, risk factors, and clinical outcomes for pseudarthrosis after a lumbar pedicle subtraction osteotomy (PSO).
SUMMARY OF BACKGROUND DATA: There exists no large series that examines pseudarthrosis rates of PSOs.
METHODS: Data of 171 consecutive patients with adult deformity who underwent a lumbar PSO by 2 surgeons at a single institution with a minimum 2-year follow-up were analyzed. Pseudarthrosis diagnosed through sagittal malalignment and instrumentation failure noted on radiograph was confirmed intraoperatively.
RESULTS: Eighteen (10.5%) of 171 patients developed pseudarthrosis after a PSO. Eleven of the 18 patients (6.4% of all patients, 61.1% of the 18 patients with pseudarthrosis) had pseudarthrosis at the PSO site, L3 being the most common; other locations included the lumbosacral junction (4/18), thoracolumbar junction (2/18), and upper thoracic spine (1/18). Preoperative pseudarthrosis level was a predictor of the postoperative level of pseudarthrosis (93%). Fifteen of the 18 patients (83%) had no interbody fusion directly above or below the PSO site, 16 (88%) had a history of pseudarthrosis at the time of PSO surgery and 2 of 3 patients who had prior radiation to the lumbar region developed pseudarthrosis. Most pseudarthroses occurred within the first 2 years (n = 13/18), between 2 and 5 years (n = 3/18), and more than 5 years (n = 2/18) postoperatively. Prior pseudarthrosis (P < 0.0001), pseudarthrosis at the PSO site (P < 0.0001), prior decompression in the lumbar region (P = 0.0037), prior radiation to the lumbar region (P < 0.0001), and presence of inflammatory/neurological disorders (P < 0.0036) were identified as risk factors. All 18 patients with pseudarthroses required revision surgery (posterior-only surgery, n = 12; anteroposterior surgery, n = 6) due to loss of sagittal alignment and pain. The mean pre-revision Scoliosis Research Society score was 85, post-revision score was 95 (P = 0.0166), and the mean pre-revision Oswestry Disability Index score was 42.5, post-revision score was 34.5 (P = 0.0203).
CONCLUSION: The overall prevalence of pseudarthrosis was 10.5% of which 61% occurred at the actual PSO site and Scoliosis Research Society and Oswestry Disability Index scores improved significantly after pseudarthrosis repair.
LEVEL OF EVIDENCE: 4.

PMID: 25171067 [PubMed - indexed for MEDLINE]

Detergent screening of the human voltage-gated proton channel using fluorescence-detection size-exclusion chromatography.

Thu, 04/23/2015 - 3:29am
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Detergent screening of the human voltage-gated proton channel using fluorescence-detection size-exclusion chromatography.

Protein Sci. 2014 Aug;23(8):1136-47

Authors: Agharkar A, Rzadkowolski J, McBroom M, Gonzales EB

Abstract
The human voltage-gated proton channel (Hv1) is a membrane protein consisting of four transmembrane domains and intracellular amino- and carboxy-termini. The protein is activated by membrane depolarization, similar to other voltage-sensitive proteins. However, the Hv1 proton channel lacks a traditional ion pore. The human Hv1 proton channel has been implicated in mediating sperm capacitance, stroke, and most recently as a biomarker/mediator of cancer metastasis. Recently, the three-dimensional structures for homologues of this voltage-gated proton channel were reported. However, it is not clear what artificial environment is needed to facilitate the isolation and purification of the human Hv1 proton channel for structural study. In the present study, we generated a chimeric protein that placed an enhanced green fluorescent protein (EGFP) to the amino-terminus of the human Hv1 proton channel (termed EGFP-Hv1). The chimeric protein was expressed in a baculovirus expression system using Sf9 cells and subjected to detergent screening using fluorescence-detection size-exclusion chromatography. The EGFP-Hv1 proton channel can be solubilized in the zwitterionic detergent Anzergent 3-12 and the nonionic n-dodecyl-β-d-maltoside (DDM) with little protein aggregation and a prominent monomeric protein peak at 48 h postinfection. Furthermore, we demonstrate that the chimeric protein exhibits a monomeric protein peak, which is distinguishable from protein aggregates, at the final size-exclusion chromatography purification step. Taken together, we can conclude that solubilization in DDM will provide a useable final product for further structural characterization of the full-length human Hv1 proton channel.

PMID: 24863684 [PubMed - indexed for MEDLINE]

Neonatal Variables, Altitude of Residence and Aymara Ancestry in Northern Chile.

Wed, 04/22/2015 - 3:29am

Neonatal Variables, Altitude of Residence and Aymara Ancestry in Northern Chile.

PLoS One. 2015;10(4):e0121834

Authors: Rothhammer F, Fuentes-Guajardo M, Chakraborty R, Lorenzo Bermejo J, Dittmar M

Abstract
Studies performed in the Andean plateau, one of the highest inhabited areas in the world, have reported that reduced availability of oxygen is associated to fetal growth retardation and lower birth weight, which are established predictors of morbidity and mortality during the first year of life. To test this hypothesis, perinatal variables of neonates born at the Juan Noé Hospital of Arica, Chile, were analyzed in relation to altitude of residence and Aymara ancestry of their mothers. The study population comprised the offspring of 5,295 mothers born between February 2004 and August 2010. Information included birth weight, height, head circumference, gestational age, altitude of residence and socioeconomic status, and was obtained from medical records. Mother´s ancestry was assessed based on surnames which were linked to percentages of Aymara admixture estimates relying on 40 selected ancestry informative markers. After correcting for the effect of multicollinearity among predictor variables, neonates born to mothers with an increased component of Aymara ancestry showed significantly higher birth weight and height at sea level, a marginally significant (p-value 0.06) decrease of birth weight and a significant decrease of height with altitude in comparison with the offspring of mothers with low Aymara ancestry. Since observed tendencies are suggestive of a possible genetic adaptation to hypoxia of the Chilean Aymara, we discuss briefly preliminary evidence related to fetal oxygen transport, particularly polymorphisms in the promoters of the HBG1 and HBG2 genes that are modulators of HbF synthesis, obtained in this ethnic group.

PMID: 25885573 [PubMed - as supplied by publisher]

Inhibition of triple-negative and Herceptin-resistant breast cancer cell proliferation and migration by Annexin A2 antibodies.

Sat, 04/18/2015 - 3:31am
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Inhibition of triple-negative and Herceptin-resistant breast cancer cell proliferation and migration by Annexin A2 antibodies.

Br J Cancer. 2014 Dec 9;111(12):2328-41

Authors: Chaudhary P, Thamake SI, Shetty P, Vishwanatha JK

Abstract
BACKGROUND: Annexin A2 (AnxA2), a calcium-dependent phospholipid binding protein, is abundantly present at the surface of triple-negative and Herceptin-resistant breast cancer cells. Interactions between cell-surface AnxA2 and tyrosine kinase receptors have an important role in the tumour microenvironment and act together to enhance tumour growth. The mechanism supporting this role is still unknown.
METHODS: The membrane function of AnxA2 was blocked by incubating cells with anti-AnxA2 antibodies. Western blotting, immunoprecipitation, immunofluorescence, 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), flow cytometry, Clonogenic, and wound-healing assays were performed in this study.
RESULTS: We demonstrate that AnxA2 interacts with epidermal growth factor receptor (EGFR) at the cell surface and has an important role in cancer cell proliferation and migration by modulating EGFR functions. Blocking AnxA2 function at the cell surface by anti-AnxA2 antibody suppressed the EGF-induced EGFR tyrosine phosphorylation and internalisation by blocking its homodimerisation. Furthermore, addition of AnxA2 antibody significantly inhibited the EGFR-dependent PI3K-AKT and Raf-MEK-ERK downstream pathways under both EGF-induced and basal growth conditions, resulting in lower cell proliferation and migration.
CONCLUSIONS: These findings suggest that cell-surface AnxA2 has an important regulatory role in EGFR-mediated oncogenic processes by keeping EGFR signalling events in an activated state. Therefore, AnxA2 could potentially be used as a therapeutic target in triple-negative and Herceptin-resistant breast cancers.

PMID: 25321192 [PubMed - indexed for MEDLINE]

Diversity of piroplasms detected in blood-fed and questing ticks from several states in the United States.

Sat, 04/18/2015 - 3:31am
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Diversity of piroplasms detected in blood-fed and questing ticks from several states in the United States.

Ticks Tick Borne Dis. 2014 Jun;5(4):373-80

Authors: Shock BC, Moncayo A, Cohen S, Mitchell EA, Williamson PC, Lopez G, Garrison LE, Yabsley MJ

Abstract
Piroplasms in the genera Babesia, Theileria, and Cytauxzoon are tick-borne parasites that may be animal and human pathogens. Most piroplasms with known life cycles are transmitted by ixodid ticks; however, for many species, the vector is unknown. This study was conducted to determine the prevalence and diversity of piroplasms in ticks from several US states. Piroplasm-specific polymerase chain reaction (PCR) assays were used to test 1631 ticks from Georgia (n=486), Kentucky (n=103), Pennsylvania (n=1), Tennessee (n=626), and Texas (n=414). Ticks were either questing (n=42) or collected from animals (n=627) or humans (n=962). The 2 primary species tested were Dermacentor variabilis (n=702) and Amblyomma americanum (n=743), but Amblyomma cajennense (n=99), Amblyomma maculatum (n=16), Ixodes scapularis (n=4), I. woodi (n=1), and unidentified Amblyomma spp. nymphs (n=64) were also tested. A low prevalence of piroplasms was detected with 37 (2.3%), 35 (2.1%), and 9 (0.6%) ticks positive for Theileria spp., Babesia spp., or Cytauxzoon felis, respectively. Based on sequence analysis, at least 6 Babesia spp. were detected and 15 of the 35 (41%) Babesia-positive ticks were A. americanum, 19 (56%) were D. variabilis, and one (3%) was an I. scapularis. Nine Babesia-positive ticks were removed from humans from Kentucky (n=1), Georgia (n=2), Texas (n=5), and Pennsylvania (n=1). Three Babesia-positive ticks were questing A. americanum which represents the first report of Babesia-infected questing Amblyomma in the US. Theileria infections were only detected in A. americanum, and all sequences were similar to white-tailed deer associated Theileria spp. C. felis was only detected in D. variabilis. These data suggest that A. americanum may be a vector of Babesia spp., although experimental studies are needed to confirm vector competence. Finally, these data demonstrate a high diversity of piroplasms in both questing and partially fed ticks in the US; although, host-blood meals can be present in non-questing ticks.

PMID: 24709338 [PubMed - indexed for MEDLINE]

Limb remote ischemic per-conditioning in combination with post-conditioning reduces brain damage and promotes neuroglobin expression in the rat brain after ischemic stroke.

Fri, 04/17/2015 - 3:30am

Limb remote ischemic per-conditioning in combination with post-conditioning reduces brain damage and promotes neuroglobin expression in the rat brain after ischemic stroke.

Restor Neurol Neurosci. 2015 Apr 13;

Authors: Ren C, Wang P, Wang B, Li N, Li W, Zhang C, Jin K, Ji X

Abstract
PURPOSE: Limb remote ischemic per-conditioning or post-conditioning has been shown to be neuroprotective after cerebral ischemic stroke. However, the effect of combining remote per-conditioning with post-conditioning on ischemic/reperfusion injury as well as the underlying mechanisms are largely unexplored.
METHODS: Here, adult male Sprague Dawley rats were subjected to middle cerebral artery occlusion (MCAO). The limb ischemic stimulus was immediately applied after onset of focal ischemia (per-conditioning), followed by repeated short episodes of remote ischemia 24 hr after reperfusion (post-conditioning). The infarct volume, motor function, and the expression of neuroglobin (Ngb) were measured at different durations after reperfusion.
RESULTS: We found that a single episode of limb remote per-conditioning afforded short-term protection, but combining repeated remote post-conditioning during the 14 days after reperfusion significantly ameliorated cerebral ischemia/reperfusion injury. Interestingly, we also found that ischemic per- and post-conditioning significantly increased expression of Ngb, an oxygen-binding globin protein that has been demonstrated to be neuroprotective against stroke, at peri-infarct regions from day 1 to day 14 following ischemia/reperfusion.
CONCLUSION: Our results suggest that the conventional per-conditioning combined with post-conditioning may be used as a novel neuroprotective strategy against ischemia-reperfusion injury, and Ngb seems to be one of the important players in limb remote ischemia-mediated neuroprotection.

PMID: 25868435 [PubMed - as supplied by publisher]

Glutaredoxin 2 (Grx2) gene deletion induces early onset of age-dependent cataracts in mice.

Fri, 04/17/2015 - 3:30am
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Glutaredoxin 2 (Grx2) gene deletion induces early onset of age-dependent cataracts in mice.

J Biol Chem. 2014 Dec 26;289(52):36125-39

Authors: Wu H, Yu Y, David L, Ho YS, Lou MF

Abstract
Glutaredoxin 2 (Grx2) is an isozyme of glutaredoxin1 (thioltransferase) present in the mitochondria and nucleus with disulfide reductase and peroxidase activities, and it controls thiol/disulfide balance in cells. In this study, we investigated whether Grx2 gene deletion could induce faster age-related cataract formation and elucidated the biochemical changes effected by Grx2 gene deletion that may contribute to lens opacity. Slit lamp was used to examine the lenses in Grx2 knock-out (KO) mice and age-matched wild-type (WT) mice ages 1 to 16 months. In the Grx2 null mice, the lens nuclear opacity began at 5 months, 3 months sooner than that of the control mice, and the progression of cataracts was also much faster than the age-matched controls. Lenses of KO mice contained lower levels of protein thiols and GSH with a significant accumulation of S-glutathionylated proteins. Actin, αA-crystallin, and βB2-crystallin were identified by Western blot and mass spectroscopy as the major S-glutathionylated proteins in the lenses of 16-month-old Grx2 KO mice. Compared with the WT control, the lens of Grx2 KO mice had only 50% of the activity in complex I and complex IV and less than 10% of the ATP pool. It was concluded that Grx2 gene deletion altered the function of lens structural proteins through S-glutathionylation and also caused severe disturbance in mitochondrial function. These combined alterations affected lens transparency.

PMID: 25362663 [PubMed - indexed for MEDLINE]

HIV-1 Tat alters neuronal autophagy by modulating autophagosome fusion to the lysosome: implications for HIV-associated neurocognitive disorders.

Fri, 04/17/2015 - 3:30am
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HIV-1 Tat alters neuronal autophagy by modulating autophagosome fusion to the lysosome: implications for HIV-associated neurocognitive disorders.

J Neurosci. 2015 Feb 4;35(5):1921-38

Authors: Fields J, Dumaop W, Elueteri S, Campos S, Serger E, Trejo M, Kosberg K, Adame A, Spencer B, Rockenstein E, He JJ, Masliah E

Abstract
Antiretroviral therapy has increased the life span of HIV+ individuals; however, HIV-associated neurocognitive disorder (HAND) occurrence is increasing in aging HIV patients. Previous studies suggest HIV infection alters autophagy function in the aging CNS and HIV-1 proteins affect autophagy in monocyte-derived cells. Despite these findings, the mechanisms leading to dysregulated autophagy in the CNS remain unclear. Here we sought to determine how HIV Tat dysregulates autophagy in neurons. Tat caused a dose-dependent decrease in autophagosome markers, microtubule-associated protein-1 light chain β II (LC3II), and sequestosome 1(SQSTM1), in a membrane-enriched fraction, suggesting Tat increases autophagic degradation. Bafilomycin A1 increased autophagosome number, LC3II, and SQSTM1 accumulation; Tat cotreatment diminished this effect. Tat had no effect when 3-methyladenine or knockdown of beclin 1 blocked early stages of autophagy. Tat increased numbers of LC3 puncta and resulted in the formation of abnormal autophagosomes in vitro. Likewise, in vivo studies in GFAP-Tat tg mice showed increased autophagosome accumulation in neurons, altered LC3II levels, and neurodegeneration. These effects were reversed by rapamycin treatment. Tat colocalized with autophagosome and lysosomal markers and enhanced the colocalization of autophagosome with lysosome markers. Furthermore, co-IP studies showed that Tat interacts with lysosomal-associated membrane protein 2A (LAMP2A) in vitro and in vivo, and LAMP2A overexpression reduces Tat-induced neurotoxicity. Hence, Tat protein may induce autophagosome and lysosome fusion through interaction with LAMP2A leading to abnormal neuronal autophagy function and dysregulated degradation of critical intracellular components. Therapies targeting Tat-mediated autophagy alterations may decrease neurodegeneration in aging patients with HAND.

PMID: 25653352 [PubMed - indexed for MEDLINE]

Enhancement of anti-tumor effect of particulate vaccine delivery system by 'bacteriomimetic' CpG functionalization of poly-lactic-co-glycolic acid nanoparticles.

Wed, 04/15/2015 - 3:29am

Enhancement of anti-tumor effect of particulate vaccine delivery system by 'bacteriomimetic' CpG functionalization of poly-lactic-co-glycolic acid nanoparticles.

Nanomedicine (Lond). 2015 Mar;10(6):915-929

Authors: Kokate RA, Thamake SI, Chaudhary P, Mott B, Raut S, Vishwanatha JK, Jones HP

Abstract
AIM: Low immunogenicity remains a major obstacle in realizing the full potential of cancer vaccines. In this study, we evaluated CpG-coated tumor antigen (Tag)-encapsulating 'bacteriomimetic' nanoparticles (CpG-nanoparticle [NP]-Tag NPs) as an approach to enhance anti-tumor immunity.
MATERIALS & METHODS: CpG-NP-Tag NPs were synthesized, characterized for their physicochemical properties and tested in vivo.
RESULTS: We found CpG predosing followed by intraperitoneal (IP) immunization with CpG-NP-Tag NPs significantly attenuated tumor growth in female BALB/c mice compared with respective controls. Histopathological and Immunofluorescence data revealed CpG-NP-Tag tumors had lower proliferation, higher apoptotic activity, greater CD4(+) and CD8(+) T cell infiltration as well as higher IFN-γ levels as compared with control groups.
CONCLUSION: Our findings suggest CpG-NP-Tag NPs can enhance anti-tumor effect of nanoparticulate tumor vaccination system.

PMID: 25867857 [PubMed - as supplied by publisher]

Clinical Outcomes Associated With Serial Sharp Debridement of Diabetic Foot Ulcers With and Without Clostridial Collagenase Ointment.

Tue, 04/14/2015 - 3:29am

Clinical Outcomes Associated With Serial Sharp Debridement of Diabetic Foot Ulcers With and Without Clostridial Collagenase Ointment.

Wounds. 2014 Mar;26(3):57-64

Authors: Motley TA, Lange DL, Dickerson JE, Slade HB

Abstract
OBJECTIVE: Fifty-five subjects with diabetes mellitus type 1 or 2 and a neuropathic, nonischemic foot ulcer were enrolled into this randomized, controlled, multicenter trial designed to examine the effects of debridement with clostridial collagenase ointment (CCO) used in conjunction with serial sharp debridement for a period of 6 weeks.
METHODS: Serial sharp debridement without adjunctive CCO was used in the control group. Various standard care therapies thought to support debridement by endogenous proteases were selected at the discretion of the investigators for use in the control group. The primary outcome measure of this trial was the percent change in ulcer area from baseline at the end of the debridement/treatment period (EOT) and at the end of an additional 6 weeks of follow-up (EOS). Secondary objectives were to assess wound status at EOT and EOS using a standardized wound assessment tool, and to compare the average time to closure for ulcers debrided with serial sharp debridement with and without adjunctive CCO.
RESULTS: Wound area decreased relative to baseline for both the CCO group (-68%, -61%) and the control group (-36%, -46%) at EOT and EOS, respectively. While the inter-group differences did not reach statistical significance, wound area was significantly decreased from baseline at both EOT and EOS for the CCO (P < 0.001) but not for the control group. Wound status scores (scale range 8 to 40) improved for both groups during treatment (CCO: -3.5, control: -3.2) and follow-up (CCO: -5.3, control: -6.4). No differences were observed in the number of sharp debridements (CCO: 3.7, control: 4.0). Median time to closure for wounds that healed was 6 weeks for CCO and 8 weeks for control. On average, ulcers treated with serial sharp debridement plus adjunctive CCO decreased in size more rapidly than ulcers treated without adjunctive CCO debridement. No safety issues were identified based on a review of reported adverse events.
CONCLUSION: These results suggest there is more to wound debridement than meets the eye, and establish a foundation for larger, confirmatory studies.

PMID: 25860329 [PubMed - as supplied by publisher]

Two dimensional blue native/SDS-PAGE to identify mitochondrial complex I subunits modified by 4-hydroxynonenal (HNE).

Tue, 04/14/2015 - 3:29am

Two dimensional blue native/SDS-PAGE to identify mitochondrial complex I subunits modified by 4-hydroxynonenal (HNE).

Front Physiol. 2015;6:98

Authors: Wu J, Luo X, Yan LJ

Abstract
The lipid peroxidation product 4-hydroxynonenal (HNE) can form protein-linked HNE adducts, thereby impacting protein structure and function. Mitochondrial complex I (NADH-ubiquinone oxidoreductase), containing at least 45 subunits in mammalian cells, sits in a lipid-rich environment and is thus very susceptible to HNE modifications. In this paper, a procedure for the identification of HNE-modified complex I subunits is described. Complex I was isolated by first dimensional non-gradient blue native polyacrylamide gel electrophoresis (BN-PAGE). The isolated complex I band, visualized by either Coomassie blue staining or silver staining, was further analyzed by second dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). HNE-modified proteins were visualized by Western blotting probed with anti-HNE antibodies. HNE-positive bands were then excised and the proteins contained in them were identified by mass spectrometric peptide sequencing. The method was successfully applied for the identification of two complex I subunits that showed enhanced HNE-modifications in diabetic kidney mitochondria.

PMID: 25859224 [PubMed]

Risk of Intracranial Hemorrhage from Statin Use in Asians: A Nationwide Cohort Study.

Tue, 04/14/2015 - 3:29am

Risk of Intracranial Hemorrhage from Statin Use in Asians: A Nationwide Cohort Study.

Circulation. 2015 Apr 9;

Authors: Chang CH, Lin CH, Caffrey JL, Lee YC, Liu YC, Lin JW, Lai MS

Abstract
BACKGROUND: -Reports of statin usage and increased risk of intracranial hemorrhage (ICH) have been inconsistent. This study examined potential associations between statin usage and the risk of ICH in subjects without a prior history of stroke.
METHODS AND RESULTS: -Patients initiating statin therapy between 2005 and 2009 without a prior history of ischemic or hemorrhagic stroke were identified from Taiwan's National Health Insurance database. Participants were stratified by advanced age (≥ 70 years), sex, and diagnosed hypertension. The outcome of interest was hospital admission for ICH (ICD-9-CM codes 430, 431, 432). Cox regression models were applied to estimate the hazard ratio (HR) of ICH. The cumulative statin dosage stratified by quartile and adjusted for baseline disease risk score served as the primary variable using the lowest quartile of cumulative dosage as a reference. There were 1,096,547 statin initiators with an average follow-up of 3.3 years. The adjusted HR for ICH between the highest the lowest quartile was non-significant at 1.06 with a 95% confidence interval [CI] spanning 1.00 (0.94-1.19). Similar non-significant results were found in sensitivity analyses using different outcome definitions or model adjustments, reinforcing the robustness of the study findings. Subgroup analysis identified an excess of ICH frequency in patients without diagnosed hypertension (adjusted HR 1.36 [1.11-1.67]).
CONCLUSIONS: -Generally, no association was observed between cumulative statin use and risk of ICH among subjects without a prior history of stroke. An increased risk was identified among the non-hypertensive cohort, but this finding should be interpreted with caution.

PMID: 25858194 [PubMed - as supplied by publisher]

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