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Recent Research Articles from UNTHSC

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Introduction to the Suicide Prevention Research Prioritization Task Force special supplement: the topic experts.

Wed, 05/20/2015 - 3:29am
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Introduction to the Suicide Prevention Research Prioritization Task Force special supplement: the topic experts.

Am J Prev Med. 2014 Sep;47(3 Suppl 2):S102-5

Authors: Pearson JL, Claassen CA, Booth CL, Research Prioritization Task Force of the National Action Alliance for Suicide Prevention

PMID: 25145726 [PubMed - indexed for MEDLINE]

Shortening femoral osteotomy with stemmed resurfacing total knee arthroplasty for severe flexion contracture in Juvenile Rheumatoid Arthritis.

Sat, 05/16/2015 - 3:31am

Shortening femoral osteotomy with stemmed resurfacing total knee arthroplasty for severe flexion contracture in Juvenile Rheumatoid Arthritis.

J Orthop. 2015 Jun;12(2):118-21

Authors: Kitchen B, Sanchez HB, Wagner RA

Abstract
Juvenile Rheumatoid Arthritis (JRA) is a progressive disease characterized by pain, swelling, and loss of motion in the joints of adolescents. Total knee arthroplasty (TKA) can be indicated, during the adolescent years, in patients with advanced JRA to alleviate pain and improve function. Because of the relative infrequency of TKA in patients with JRA, evaluation of the type of TKA performed and the results merit review. This case report present two distinct operations performed to obtain full extension. 1. Distal femoral resection with conversion to hinged arthroplasty. 2. Femoral shortening osteotomy with resurfacing TKA.

PMID: 25972704 [PubMed]

Electrophoretic characterization of the Mammalian nuclear matrix proteome, nuclear envelope, nucleoli and covalently bound ADP-ribose polymers: potential applications to cancer.

Sat, 05/16/2015 - 3:31am
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Electrophoretic characterization of the Mammalian nuclear matrix proteome, nuclear envelope, nucleoli and covalently bound ADP-ribose polymers: potential applications to cancer.

Cancer Genomics Proteomics. 2014 Sep-Oct;11(5):217-23

Authors: Aranda XG, Racho RG, Pacheco-Rodríguez G, Alvarez-González R

Abstract
BACKGROUND/AIM: Nucleic acid metabolism is biochemically compartmentalized to the nucleus. Thus, it is necessary to define the proteome of the various macromolecular structures within this organelle.
MATERIALS AND METHODS: We isolated the nuclear matrix (NM) fraction from rat liver by sequential centrifugation steps at 13,000 rpm, staggered between endogenous nuclease treatment for 2 h at 37°C, followed by high-salt (H.S.; 2.0 M NaCl) and non-ionic detergent extractions (0.1%- or 1.0% Triton X-100) to eliminate the bulk of chromosomal DNA/RNA, histone proteins and the nuclear envelope (NE).
RESULTS: Integrity of the NM and NE structures was confirmed by electron microscopy. Next, we analyzed the NM proteome on a 20% polyacrylamide gel using the PhastSystem. We observed the absence of histone proteins and the characteristic presence of the lamins by Coomassie blue staining. By contrast, upon silver staining, following electrophoretic separation with a Tris-Borate-EDTA buffer, we observed the NM-associated nucleic RNA and protein-free ADP-ribose polymers. While polymers are found in much lower concentration than RNA in NM, they were purified by affinity chromatography on boronate resin prior to electrophoresis. We observed the electrophoretic resolution of free ADP-ribose chains (5-25 units) by silver staining.
CONCLUSION: The significance of our observations to cancer studies and carcinogenesis is discussed.

PMID: 25331794 [PubMed - indexed for MEDLINE]

Comparison of Hallux Interphalangeal Joint Arthrodesis Fixation Techniques: A Retrospective Multicenter Study.

Fri, 05/15/2015 - 3:29am

Comparison of Hallux Interphalangeal Joint Arthrodesis Fixation Techniques: A Retrospective Multicenter Study.

J Foot Ankle Surg. 2015 May 8;

Authors: Thorud JC, Jolley T, Shibuya N, Lew E, Britt M, Butterfield T, Boike A, Hardy M, Brancheau S, Motley T, Jupiter DC

Abstract
Few studies have investigated the complications that occur after hallux interphalangeal joint arthrodesis. The present study evaluated complications in 152 patients aged 18 to 80 years from 2005 to 2012 from 4 different academic institutions after hallux interphalangeal joint arthrodesis. Overall, 65.8% of the patients had ≥1 complication. Infections occurred in 16.5%, dehiscence in 12.5%, and reoperations in 27.0%. The clinical nonunion rate was ≥17.8%, and the radiographic nonunion rate was ≥13.8%. After logistic regression analysis, only the study site and peripheral neuropathy were associated with having ≥1 complication (p < .01 and p < .05, respectively). Single screw fixation compared with other fixation did not have a statistically significant influence on the postoperative complications. However, when fixation was expanded to 4 categories, single screw fixation had lower infection and reoperation rates than either crossed Kirschner wires or other fixation category but not compared with crossed screws on multivariate logistic regression analysis. Although additional studies are warranted, the findings from the present study might aid in both the prognosis of complications and the support of the use of a single screw over crossed Kirchner wire fixation in hallux interphalangeal joint arthrodesis.

PMID: 25960055 [PubMed - as supplied by publisher]

Caloric restriction and the aging process: a critique.

Fri, 05/15/2015 - 3:29am
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Caloric restriction and the aging process: a critique.

Free Radic Biol Med. 2014 Aug;73:366-82

Authors: Sohal RS, Forster MJ

Abstract
The main objective of this review is to provide an appraisal of the current status of the relationship between energy intake and the life span of animals. The concept that a reduction in food intake, or caloric restriction (CR), retards the aging process, delays the age-associated decline in physiological fitness, and extends the life span of organisms of diverse phylogenetic groups is one of the leading paradigms in gerontology. However, emerging evidence disputes some of the primary tenets of this conception. One disparity is that the CR-related increase in longevity is not universal and may not even be shared among different strains of the same species. A further misgiving is that the control animals, fed ad libitum (AL), become overweight and prone to early onset of diseases and death, and thus may not be the ideal control animals for studies concerned with comparisons of longevity. Reexamination of body weight and longevity data from a study involving over 60,000 mice and rats, conducted by a National Institute on Aging-sponsored project, suggests that CR-related increase in life span of specific genotypes is directly related to the gain in body weight under the AL feeding regimen. Additionally, CR in mammals and "dietary restriction" in organisms such as Drosophila are dissimilar phenomena, albeit they are often presented to be the very same. The latter involves a reduction in yeast rather than caloric intake, which is inconsistent with the notion of a common, conserved mechanism of CR action in different species. Although specific mechanisms by which CR affects longevity are not well understood, existing evidence supports the view that CR increases the life span of those particular genotypes that develop energy imbalance owing to AL feeding. In such groups, CR lowers body temperature, rate of metabolism, and oxidant production and retards the age-related pro-oxidizing shift in the redox state.

PMID: 24941891 [PubMed - indexed for MEDLINE]

Reduced Vascular Responses to Soluble Guanylyl Cyclase but Increased Sensitivity to Sildenafil in Female Rats with Type 2 Diabetes.

Tue, 05/12/2015 - 3:29am

Reduced Vascular Responses to Soluble Guanylyl Cyclase but Increased Sensitivity to Sildenafil in Female Rats with Type 2 Diabetes.

Am J Physiol Heart Circ Physiol. 2015 May 8;:ajpheart.00079.2015

Authors: Goulopoulou S, Hannan JL, Matsumoto T, Ogbi S, Ergul A, Webb RC

Abstract
Impaired nitric oxide (NO), soluble guanylyl cyclase (sGC) and cyclic guanosine monophosphate (cGMP) signaling (NO-sGC-cGMP) has been implicated in the pathogenesis of diabetic vascular dysfunction. Efforts to directly target this signaling have led to the development of sGC agonists that activate the heme group of sGC (stimulators) or preferentially activate sGC when the heme is oxidized (activators). In this study, we hypothesized that resistance arteries from female rats with spontaneous type 2 diabetes (Goto-Kakizaki rats) would have reduced vasodilatory responses to heme-dependent sGC activation and increased responses to heme-independent sGC activation as compared to control rats (Wistar). Endothelium-dependent and -independent relaxation was assessed in isolated segments from mesenteric resistance arteries (MA) mounted in a wire myograph. GK MA had reduced responses to acetylcholine (ACh; pEC50: 7.96 ± 0.06 vs. 7.66 ± 0.05, p<0.05) and sodium nitroprusside (SNP; pEC50: 8.34 ± 0.05 vs. 7.77 ± 0.04, p<0.05). There were no group differences in 8-Br-cGMP-induced relaxation and protein kinase G-1 (PKG-1) expression (p>0.05). GK MA had attenuated responses to BAY 41-2272 (heme-dependent sGC stimulator; pEC50: 7.56 ± 0.05 vs. 6.93 ± 0.06, p<0.05) and BAY 58-2667 (heme-independent sGC activator; pEC50: 10.82 ± 0.07 vs. 10.27 ± 0.08, p<0.05) and increased sensitivity to sildenafil [phosphodiestarase 5 (PDE5) inhibitor; pEC50: 7.89 ± 0.14 vs. 8.25 ± 0.13, p<0.05]. Isolated resistance arteries from female rats of reproductive age that spontaneously develop type 2 diabetes have increased sensitivity to PDE5 inhibition and reduced responsiveness to sGC activators and stimulators.

PMID: 25957216 [PubMed - as supplied by publisher]

Thymic Involution Perturbs Negative Selection Leading to Autoreactive T Cells That Induce Chronic Inflammation.

Tue, 05/12/2015 - 3:29am

Thymic Involution Perturbs Negative Selection Leading to Autoreactive T Cells That Induce Chronic Inflammation.

J Immunol. 2015 May 8;

Authors: Coder BD, Wang H, Ruan L, Su DM

Abstract
Thymic involution and the subsequent amplified release of autoreactive T cells increase the susceptibility toward developing autoimmunity, but whether they induce chronic inflammation with advanced age remains unclear. The presence of chronic low-level proinflammatory factors in elderly individuals (termed inflammaging) is a significant risk factor for morbidity and mortality in virtually every chronic age-related disease. To determine how thymic involution leads to the persistent release and activation of autoreactive T cells capable of inducing inflammaging, we used a Foxn1 conditional knockout mouse model that induces accelerated thymic involution while maintaining a young periphery. We found that thymic involution leads to T cell activation shortly after thymic egress, which is accompanied by a chronic inflammatory phenotype consisting of cellular infiltration into non-lymphoid tissues, increased TNF-α production, and elevated serum IL-6. Autoreactive T cell clones were detected in the periphery of Foxn1 conditional knockout mice. A failure of negative selection, facilitated by decreased expression of Aire rather than impaired regulatory T cell generation, led to autoreactive T cell generation. Furthermore, the young environment can reverse age-related regulatory T cell accumulation in naturally aged mice, but not inflammatory infiltration. Taken together, these findings identify thymic involution and the persistent activation of autoreactive T cells as a contributing source of chronic inflammation (inflammaging).

PMID: 25957168 [PubMed - as supplied by publisher]

Tip110 regulates the cross-talk between p53 and HIF-1α under hypoxia and promotes survival of cancer cells.

Sun, 05/10/2015 - 3:29am

Tip110 regulates the cross-talk between p53 and HIF-1α under hypoxia and promotes survival of cancer cells.

Mol Cell Biol. 2015 May 4;

Authors: Timani KA, Liu Y, Fan Y, Mohammad KS, He JJ

Abstract
Hypoxia often occurs under various physiological and pathophysiological conditions including solid tumors; it is linked to malignant transformation, metastatic progression and treatment failure or resistance. Tip110 protein plays important roles in several known physiological and pathophysiological processes including cancers. Thus, in the current study we investigated the regulation of Tip110 expression under hypoxia. Hypoxia led to Tip110 protein degradation through ubiquitin-proteasome system. Under hypoxia, Tip110 stabilized p53, which in return destabilized Tip110. In addition, Tip110 regulated HIF-1α, likely through enhancement of its protein stability. Furthermore, Tip110 up-regulated p300, a known co-activator for both p53 and HIF-1α. Expression of p53(22/23) mutant deficient in p300 binding accelerated Tip110 degradation under hypoxia. Tip110 knockdown resulted in the inhibition of cell proliferation and cell death in the presence of p53. Lastly, significantly less Tip110, p53, and HIF-1α were detected in the hypoxic region of bone metastases tumors in a mouse model of human melanoma cells. Taken together, these results suggest Tip110 as an important mediator in the cross-talk between p53 and HIF-1α in response to hypoxic stress.

PMID: 25939381 [PubMed - as supplied by publisher]

Total testosterone and neuropsychiatric symptoms in elderly men with Alzheimer's disease.

Sun, 05/10/2015 - 3:29am
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Total testosterone and neuropsychiatric symptoms in elderly men with Alzheimer's disease.

Alzheimers Res Ther. 2015;7(1):24

Authors: Hall JR, Wiechmann AR, Cunningham RL, Johnson LA, Edwards M, Barber RC, Singh M, Winter S, O'Bryant SE, Texas Alzheimer’s Research and Care Consortium

Abstract
INTRODUCTION: There has been a significant increase in the use of testosterone in aging men, but little investigation into its impact on men with Alzheimer's disease (AD). The findings of the few studies that have been done are inconsistent. In the present study, we investigated the relationship between total testosterone (TT) and neuropsychiatric symptoms (NPS) in a well-characterized sample of elderly men with mild to moderate AD.
METHODS: The sample, which was drawn from the Texas Alzheimer's Research Care Consortium Longitudinal Research Cohort, included 87 men who met the criteria for mild to moderate AD. The occurrence of NPS was gathered from caregivers and/or family members with the Neuropsychiatric Inventory. TT was analyzed, and the sample was divided into a low-testosterone group (TT ≤2.5 ng/ml; n = 44) and a borderline/normal group (TT ≥2.6 ng/ml; n = 43).
RESULTS: TT was correlated with symptoms of hallucinations, delusions, agitation, irritability and motor activity. The borderline/normal group was significantly more likely to have hallucinations (odds ratio (OR) = 5.56), delusions (OR = 3.87), motor activity (OR = 3.13) and irritability (OR = 2.77) than the low-testosterone group. Health status and apolipoprotein E ε4 status were not significant factors.
CONCLUSIONS: The findings of the present study have implications for the use of testosterone replacement therapy in men with AD or the prodromal stage of the disease.

PMID: 25937840 [PubMed]

AMPA receptor desensitization is the determinant of AMPA receptor mediated excitotoxicity in purified retinal ganglion cells.

Sun, 05/10/2015 - 3:29am
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AMPA receptor desensitization is the determinant of AMPA receptor mediated excitotoxicity in purified retinal ganglion cells.

Exp Eye Res. 2015 Mar;132:136-50

Authors: Park YH, Mueller BH, McGrady NR, Ma HY, Yorio T

Abstract
The ionotropic glutamate receptors (iGLuR) have been hypothesized to play a role in neuronal pathogenesis by mediating excitotoxic death. Previous studies on iGluR in the retina have focused on two broad classes of receptors: NMDA and non-NMDA receptors including the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) and kainate receptor. In this study, we examined the role of receptor desensitization on the specific excitotoxic effects of AMPAR activation on primary retinal ganglion cells (RGCs). Purified rat RGCs were isolated from postnatal day 4-7 Sprague-Dawley rats. Calcium imaging was used to identify the functionality of the AMPARs and selectivity of the s-AMPA agonist. Phosphorylated CREB and ERK1/2 expression were performed following s-AMPA treatment. s-AMPA excitotoxicity was determined by JC-1 mitochondrial membrane depolarization assay, caspase 3/7 luciferase activity assay, immunoblot analysis for α-fodrin, and Live (calcein AM)/Dead (ethidium homodimer-1) assay. RGC cultures of 98% purity, lacking Iba1 and GFAP expression were used for the present studies. Isolated prenatal RGCs expressed calcium permeable AMPAR and s-AMPA (100 μM) treatment of cultured RGCs significantly increased phosphorylation of CREB but not that of ERK1/2. A prolonged (6 h) AMPAR activation in purified RGCs using s-AMPA (100 μM) did not depolarize the RGC mitochondrial membrane potential. In addition, treatment of cultured RGCs with s-AMPA, both in the presence and absence of trophic factors (BDNF and CNTF), did not increase caspase 3/7 activities or the cleavage of α-fodrin (neuronal apoptosis marker), as compared to untreated controls. Lastly, a significant increase in cell survival of RGCs was observed after s-AMPA treatment as compared to control untreated RGCs. However, preventing the desensitization of AMPAR with the treatment with either kainic acid (100 μM) or the combination of s-AMPA and cyclothiazide (50 μM) significantly reduced cell survivability. Activation of the AMPAR in RGCs does not appear to activate a signaling cascade to apoptosis, suggesting that RGCs in vitro are not susceptible to AMPA excitotoxicity as previously hypothesized. Conversely, preventing AMPAR desensitization through differential agonist activation caused AMPAR mediated excitotoxicity. Activation of the AMPAR in increasing CREB phosphorylation was dependent on the presence of calcium, which may help explain this action in increasing RGC survival.

PMID: 25643624 [PubMed - indexed for MEDLINE]

Angiotensin II type 1a receptors in subfornical organ contribute towards chronic intermittent hypoxia-associated sustained increase in mean arterial pressure.

Wed, 05/06/2015 - 3:29am
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Angiotensin II type 1a receptors in subfornical organ contribute towards chronic intermittent hypoxia-associated sustained increase in mean arterial pressure.

Am J Physiol Heart Circ Physiol. 2015 Mar 1;308(5):H435-46

Authors: Saxena A, Little JT, Nedungadi TP, Cunningham JT

Abstract
Sleep apnea is associated with hypertension. The mechanisms contributing to a sustained increase in mean arterial pressure (MAP) even during normoxic awake-state remain unknown. Rats exposed to chronic intermittent hypoxia for 7 days, a model of the hypoxemia associated with sleep apnea, exhibit sustained increases in MAP even during the normoxic dark phase. Activation of the renin-angiotensin system (RAS) has been implicated in chronic intermittent hypoxia (CIH) hypertension. Since the subfornical organ (SFO) serves as a primary target for the central actions of circulating ANG II, we tested the effects of ANG II type 1a receptor (AT1aR) knockdown in the SFO on the sustained increase in MAP in this CIH model. Adeno-associated virus carrying green fluorescent protein (GFP) and small-hairpin RNA against either AT1aR or a scrambled control sequence (SCM) was stereotaxically injected in the SFO of rats. After recovery, MAP, heart rate, respiratory rate, and activity were continuously recorded using radiotelemetry. In the normoxic groups, the recorded variables did not deviate from the baseline values. Both CIH groups exhibited significant increases in MAP during CIH exposures (P < 0.05). During the normoxic dark phase in the CIH groups, only the SCM-injected group exhibited a sustained increase in MAP (P < 0.05). The AT1aR-CIH group showed significant decreases in FosB/ΔFosB staining in the median preoptic nucleus and the paraventricular nuclei of the hypothalamus compared with the SCM-CIH group. Our data indicate that AT1aRs in the SFO are critical for the sustained elevation in MAP and increased FosB/ΔFosB expression in forebrain autonomic nuclei associated with CIH.

PMID: 25539713 [PubMed - indexed for MEDLINE]

microRNA- 124 targets Tip110 expression and regulates hematopoiesis.

Sat, 05/02/2015 - 3:32am

microRNA- 124 targets Tip110 expression and regulates hematopoiesis.

Stem Cells Dev. 2015 Apr 30;

Authors: Liu Y, Huang X, Timani K, Broxmeyer HE, He JJ

Abstract
MicroRNA (miR) regulates hematopoiesis through targeting different genes posttranscriptionally. We have recently shown that Tip110 expression is down-regulated during hematopoietic stem cell (HSC) differentiation. However, the underlying mechanisms are not known. In this study, we identified a conserved miR-124 binding site on the Tip110 3' untranslated region (3'UTR) and showed that Tip110 was down-regulated by miR-124 through its 3'UTR. We then examined the relationship among miR-124 and Tip110 expression and differentiation of human cord blood CD34+ cells. We found that miR-124 was expressed in a low level in human cord blood CD34+ cells, but it was considerably up-regulated during culturing and differentiation of these cells. Moreover, we demonstrated that miR-124 expression decreased Tip110 expression and promoted differentiation of human cord blood CD34+ cells, while miR-124 knockdown increased Tip110 expression, slowed down differentiation of human cord blood CD34+ cells, and caused an expansion of hematopoietic progenitor cells in vitro. Finally, we used mouse embryonic fibroblasts derived from Tip110 transgenic mice, performed the exon array analysis and found that Tip110 altered a number of genes in the hematopoiesis pathways. Dnmt3a as de novo methyltransferase was also significantly up regulated. That miR-124 was markedly up-regulated during human cord blood CD34+ cell differentiation could be the result of direct loss of its promoter methylation from Dnmt3a. together, our study demonstrates that miR-124 regulates Tip110 expression and differentiation of human cord blood CD34+ cells and suggests important roles of miR- 124/Tip110 in hematopoiesis.

PMID: 25928721 [PubMed - as supplied by publisher]

Treatment for preventing tuberculosis in children and adolescents: a randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and isoniazid.

Sat, 05/02/2015 - 3:32am
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Treatment for preventing tuberculosis in children and adolescents: a randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and isoniazid.

JAMA Pediatr. 2015 Mar;169(3):247-55

Authors: Villarino ME, Scott NA, Weis SE, Weiner M, Conde MB, Jones B, Nachman S, Oliveira R, Moro RN, Shang N, Goldberg SV, Sterling TR, International Maternal Pediatric and Adolescents AIDS Clinical Trials Group, Tuberculosis Trials Consortium

Abstract
IMPORTANCE: Three months of a once-weekly combination of rifapentine and isoniazid for treatment of latent tuberculosis infection is safe and effective for persons 12 years or older. Published data for children are limited.
OBJECTIVES: To compare treatment safety and assess noninferiority treatment effectiveness of combination therapy with rifapentine and isoniazid vs 9 months of isoniazid treatment for latent tuberculosis infection in children.
DESIGN, SETTING, AND PARTICIPANTS: A pediatric cohort nested within a randomized, open-label clinical trial conducted from June 11, 2001, through December 17, 2010, with follow-up through September 5, 2013, in 29 study sites in the United States, Canada, Brazil, Hong Kong (China), and Spain. Participants were children (aged 2-17 years) who were eligible for treatment of latent tuberculosis infection.
INTERVENTIONS: Twelve once-weekly doses of the combination drugs, given with supervision by a health care professional, for 3 months vs 270 daily doses of isoniazid, without supervision by a health care professional, for 9 months.
MAIN OUTCOMES AND MEASURES: We compared rates of treatment discontinuation because of adverse events (AEs), toxicity grades 1 to 4, and deaths from any cause. The equivalence margin for the comparison of AE-related discontinuation rates was 5%. Tuberculosis disease diagnosed within 33 months of enrollment was the main end point for testing effectiveness. The noninferiority margin was 0.75%.
RESULTS: Of 1058 children enrolled, 905 were eligible for evaluation of effectiveness. Of 471 in the combination-therapy group, 415 (88.1%) completed treatment vs 351 of 434 (80.9%) in the isoniazid-only group (P = .003). The 95% CI for the difference in rates of discontinuation attributed to an AE was -2.6 to 0.1, which was within the equivalence range. In the safety population, 3 of 539 participants (0.6%) who took the combination drugs had a grade 3 AE vs 1 of 493 (0.2%) who received isoniazid only. Neither arm had any hepatotoxicity, grade 4 AEs, or treatment-attributed death. None of the 471 in the combination-therapy group developed tuberculosis vs 3 of 434 (cumulative rate, 0.74%) in the isoniazid-only group, for a difference of -0.74% and an upper bound of the 95% CI of the difference of +0.32%, which met the noninferiority criterion.
CONCLUSIONS AND RELEVANCE: Treatment with the combination of rifapentine and isoniazid was as effective as isoniazid-only treatment for the prevention of tuberculosis in children aged 2 to 17 years. The combination-therapy group had a higher treatment completion rate than did the isoniazid-only group and was safe.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00023452.

PMID: 25580725 [PubMed - indexed for MEDLINE]

Exosomes Are Unlikely Involved in Intercellular Nef Transfer.

Fri, 05/01/2015 - 3:30am

Exosomes Are Unlikely Involved in Intercellular Nef Transfer.

PLoS One. 2015;10(4):e0124436

Authors: Luo X, Fan Y, Park IW, He JJ

Abstract
HIV-1 Nef is an important pathogenic factor for HIV/AIDS pathogenesis. Several recent studies including ours have demonstrated that Nef can be transferred to neighboring cells and alters the function of these cells. However, how the intercellular Nef transfer occurs is in dispute. In the current study, we attempted to address this important issue using several complementary strategies, a panel of exosomal markers, and human CD4+ T lymphocyte cell line Jurkat and a commonly used cell line 293T. First, we showed that Nef was transferred from Nef-expressing or HIV-infected Jurkat to naïve Jurkat and other non-Jurkat cells and that the transfer required the membrane targeting function of Nef and was cell density-dependent. Then, we showed that Nef transfer was cell-cell contact-dependent, as exposure to culture supernatants or exosomes from HIV-infected Jurkat or Nef-expressing Jurkat and 293T led to little Nef detection in the target cells Jurkat. Thirdly, we demonstrated that Nef was only detected to be associated with HIV virions but not with acetylcholinesterase (AChE+) exosomes from HIV-infected Jurkat and not in the exosomes from Nef-expressing Jurkat. In comparison, when it was over-expressed in 293T, Nef was detected in detergent-insoluble AChE+/CD81low/TSG101low exosomes, but not in detergent-soluble AChE-/CD81high/TSG101high exosomes. Lastly, microscopic imaging showed no significant Nef detection in exosomal vesicle-like structures in and out 293T. Taken together, these results show that exosomes are unlikely involved in intercellular Nef transfer. In addition, this study reveals existence of two types of exosomes: AChE+/CD81low/TSG101low exosomes and AChE-/CD81high/TSG101high exosomes.

PMID: 25919665 [PubMed - as supplied by publisher]

Activation of mTOR: a culprit of Alzheimer's disease?

Fri, 05/01/2015 - 3:30am
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Activation of mTOR: a culprit of Alzheimer's disease?

Neuropsychiatr Dis Treat. 2015;11:1015-30

Authors: Cai Z, Chen G, He W, Xiao M, Yan LJ

Abstract
Alzheimer's disease (AD) is characterized by cognitive impairment in clinical presentation, and by β-amyloid (Aβ) production and the hyper-phosphorylation of tau in basic research. More highlights demonstrate that the activation of the mammalian target of rapamycin (mTOR) enhances Aβ generation and deposition by modulating amyloid precursor protein (APP) metabolism and upregulating β- and γ-secretases. mTOR, an inhibitor of autophagy, decreases Aβ clearance by scissoring autophagy function. mTOR regulates Aβ generation or Aβ clearance by regulating several key signaling pathways, including phosphoinositide 3-kinase (PI3-K)/protein kinase B (Akt), glycogen synthase kinase 3 [GSK-3], AMP-activated protein kinase (AMPK), and insulin/insulin-like growth factor 1 (IGF-1). The activation of mTOR is also a contributor to aberrant hyperphosphorylated tau. Rapamycin, the inhibitor of mTOR, may mitigate cognitive impairment and inhibit the pathologies associated with amyloid plaques and neurofibrillary tangles by promoting autophagy. Furthermore, the upstream and downstream components of mTOR signaling are involved in the pathogenesis and progression of AD. Hence, inhibiting the activation of mTOR may be an important therapeutic target for AD.

PMID: 25914534 [PubMed]

Circulating mitochondrial DNA and Toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats.

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

Circulating mitochondrial DNA and Toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats.

Cardiovasc Res. 2015 Apr 24;

Authors: McCarthy CG, Wenceslau CF, Goulopoulou S, Ogbi S, Baban B, Sullivan JC, Matsumoto T, Webb RC

Abstract
AIMS: Immune system activation is a common feature of hypertension pathogenesis. However, the mechanisms that initiate this activation are not well understood. Innate immune system recognition and response to danger is becoming apparent in many cardiovascular diseases. Danger signals can arise from not only pathogens, but also damage-associated molecular patterns (DAMPs). Our first hypothesis was that the DAMP, mitochondrial DNA (mtDNA), which is recognized by Toll-like receptor 9 (TLR9), is elevated in the circulation of spontaneously hypertensive rats (SHR), and that the deoxyribonuclease enzymes responsible for its degradation, have decreased activity in SHR. Based on these novel SHR phenotypes, we further hypothesized that (1) treatment of SHR with an inhibitory oligodinucleotide for TLR9 (ODN2088) would lower blood pressure and that (2) treatment of normotensive rats with a TLR9-specific CpG oligonucleotide (ODN2395) would cause endothelial dysfunction and increase blood pressure.
METHODS AND RESULTS: We observed that SHR have elevated circulating mtDNA and diminished deoxyribonuclease I and II activity. Additionally, treatment of SHR with ODN2088 lowered systolic blood pressure. On the other hand, treatment of normotensive rats with ODN2395 increased systolic blood pressure and rendered their arteries less sensitive to acetylcholine-induced relaxation and more sensitive to norepinephrine-induced contraction. This dysfunctional vasoreactivity was due to increased cyclooxygenase and p38 mitogen-activated protein kinase activation, increased reactive oxygen species generation, and reduced nitric oxide bioavailability.
CONCLUSION: Circulating mtDNA and impaired deoxyribonuclease activity may lead to the activation of the innate immune system, via TLR9, and contribute to elevated arterial pressure and vascular dysfunction in SHR.

PMID: 25910936 [PubMed - as supplied by publisher]

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

Sun, 04/26/2015 - 3:30am

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.

Sun, 04/26/2015 - 3:30am

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.

Sun, 04/26/2015 - 3:30am
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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.

Sun, 04/26/2015 - 3:30am
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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]

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