Recent Research Articles from UNTHSC

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Cell-cell contact viral transfer contributes to HIV infection and persistence in astrocytes.

Sat, 12/20/2014 - 11:31pm

Cell-cell contact viral transfer contributes to HIV infection and persistence in astrocytes.

J Neurovirol. 2014 Dec 19;

Authors: Luo X, He JJ

Abstract
Astrocytes are the most abundant cells in the central nervous system and play important roles in human immunodeficiency virus (HIV)/neuro-acquired immunodeficiency syndrome. Detection of HIV proviral DNA, RNA, and early gene products but not late structural gene products in astrocytes in vivo and in vitro indicates that astrocytes are susceptible to HIV infection albeit in a restricted manner. We as well as others have shown that cell-free HIV is capable of entering CD4- astrocytes through human mannose receptor-mediated endocytosis. In this study, we took advantage of several newly developed fluorescence protein-based HIV reporter viruses and further characterized HIV interaction with astrocytes. First, we found that HIV was successfully transferred to astrocytes from HIV-infected CD4+ T cells in a cell-cell contact- and gp120-dependent manner. In addition, we demonstrated that, compared to endocytosis-mediated cell-free HIV entry and subsequent degradation of endocytosed virions, the cell-cell contact between astrocytes and HIV-infected CD4+ T cells led to robust HIV infection of astrocytes but retained the restricted nature of viral gene expression. Furthermore, we showed that HIV latency was established in astrocytes. Lastly, we demonstrated that infectious progeny HIV was readily recovered from HIV latent astrocytes in a cell-cell contact-mediated manner. Taken together, our studies point to the importance of the cell-cell contact-mediated HIV interaction with astrocytes and provide direct evidence to support the notion that astrocytes are HIV latent reservoirs in the central nervous system.

PMID: 25522787 [PubMed - as supplied by publisher]

The link between sleep disturbance and depression among Mexican Americans: a Project FRONTIER study.

Sat, 12/20/2014 - 11:31pm
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The link between sleep disturbance and depression among Mexican Americans: a Project FRONTIER study.

J Clin Sleep Med. 2014 Apr 15;10(4):427-31

Authors: Roane BM, Johnson L, Edwards M, Hall J, Al-Farra S, O'Bryant SE

Abstract
OBJECTIVE: To examine the link between disturbed sleep and depression scores in Mexican Americans and non-Hispanic Whites.
METHODS: Data were analyzed for 566 participants (45% Mexican Americans) who were part of a rural healthcare study, Project FRONTIER. Mean age was 55.5 years for Mexican Americans (70% female) and 65.6 years for non-Hispanic Whites (69% female). Self-reported sleep disturbance was entered as the predictor, GDS-30 total and factor scores as the outcome variables, and age, sex, education, BMI, and medical diagnoses (hyperlipidemia, diabetes mellitus, and hypertension) entered as covariates.
RESULTS: Mexican Americans reported higher rates of sleep disturbances (25%) than non-Hispanic whites (17%). Sleep disturbances were significantly associated with GDS-30 total scores and the factors Dysphoria and Cognitive Impairment in both Mexican Americans and non-Hispanic whites.
CONCLUSIONS: In this study, Mexican Americans reported higher rates of sleep disturbances than non-Hispanic whites. Disturbed sleep was positively associated with depression and the factor scores for Dysphoria and Cognitive Impairment in both groups. Given the paucity of research on sleep disorders in Mexican Americans, identifying what sleep disorders are present and the impact treating these sleep disorders have on depression warrant further investigation.

PMID: 24733989 [PubMed - indexed for MEDLINE]

Acute intermittent optogenetic stimulation of nucleus tractus solitarius neurons induces sympathetic long-term facilitation.

Sat, 12/20/2014 - 3:30am

Acute intermittent optogenetic stimulation of nucleus tractus solitarius neurons induces sympathetic long-term facilitation.

Am J Physiol Regul Integr Comp Physiol. 2014 Dec 17;:ajpregu.00381.2014

Authors: Yamamoto K, Lalley PM, Mifflin SW

Abstract
Acute intermittent hypoxia (AIH) induces sympathetic and phrenic long-term facilitation (LTF), defined as a sustained increase in nerve discharge. We investigated the effects of AIH and acute intermittent optogenetic stimulation (AIO) of neurons labeled with AAV-CaMKIIa - hChR2(H134R) - mCherry in the nucleus of the solitary tract (NTS) of anesthetized, vagotomized, mechanically ventilated rats. We measured renal sympathetic nerve activity (RSNA), phrenic nerve activity (PNA), power spectral density and coherence, and we made cross-correlation measurements to determine how AIO and AIH affected synchronization between PNA and RSNA. Sixty min after AIH produced by ventilation with 10% oxygen in balanced nitrogen, RSNA and PNA amplitude increased by 80% and by 130%, respectively (P<0.01). Sixty min after AIO stimulation, RSNA and PNA amplitude increased by 60% and 100%, respectively, (P<0.01). These results suggest that acute intermittent stimulation of NTS neurons can induce renal sympathetic and phrenic LTF in the absence of hypoxia or chemoreceptor afferent activation. We also found that while acute intermittent optogenetic and hypoxic stimulations increased respiratory-related RSNA modulation (P<0.01), they did not increase synchronization between central respiratory drive and RSNA. We conclude that mechanisms that induce LTF originate within the caudal NTS and extend to other interconnecting neuronal elements of the central nervous cardiorespiratory network.

PMID: 25519734 [PubMed - as supplied by publisher]

Oxidative stress, testosterone, and cognition among Caucasian and Mexican-American men with and without Alzheimer's disease.

Fri, 12/19/2014 - 3:29am
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Oxidative stress, testosterone, and cognition among Caucasian and Mexican-American men with and without Alzheimer's disease.

J Alzheimers Dis. 2014;40(3):563-73

Authors: Cunningham RL, Singh M, O'Bryant SE, Hall JR, Barber RC

Abstract
BACKGROUND: The use of testosterone among aging men has been increasing, but results from studies addressing the effectiveness of testosterone replacement therapy have been equivocal.
OBJECTIVE: Given our prior pre-clinical studies that reported a major influence of oxidative stress on testosterone's neuroprotective effects, we investigated whether the negative effects of testosterone on brain function were predicted by oxidative load.
METHODS: In order to test our hypothesis, we determined whether circulating total testosterone and luteinizing hormone correlated with cognition in a subset of the Texas Alzheimer's Research & Care Consortium (TARCC) cohort, consisting of Caucasian (n = 116) and Mexican-American (n = 117) men. We also assessed whether oxidative stress (as indexed by homocysteine levels) modified this relationship between sex hormones and cognition, and whether the levels of two antioxidants, superoxide dismutase-1 and glutathione S-transferase (GST), varied as a function of circulating testosterone.
RESULTS: In a low oxidative stress environment, testosterone was positively associated with the level of the antioxidant, GST, while no deleterious effects on cognitive function were noted. In contrast, under conditions of high oxidative stress (homocysteine levels >12 μmol/L), testosterone and luteinizing hormone were associated with cognitive impairment, but only among Caucasians. The ethnic difference was attributed to significantly higher GST levels among Mexican-Americans.
CONCLUSION: While testosterone may be beneficial under conditions of low oxidative stress, testosterone appears to have negative consequences under conditions of elevated oxidative stress, but only in Caucasians. Mexican-Americans, however, were protected from any deleterious effects of testosterone, potentially due to higher levels of endogenous antioxidant defenses such as GST.

PMID: 24496073 [PubMed - indexed for MEDLINE]

Two-week normobaric intermittent-hypoxic exposures stabilize cerebral perfusion during hypocapnia and hypercapnia.

Thu, 12/18/2014 - 3:29am

Two-week normobaric intermittent-hypoxic exposures stabilize cerebral perfusion during hypocapnia and hypercapnia.

Exp Biol Med (Maywood). 2014 Dec 11;

Authors: Zhang P, Shi X, Downey HF

Abstract
The effect of moderately extended, intermittent-hypoxia (IH) on cerebral perfusion during changes in CO2 was unknown. Thus, we assessed the changes in cerebral vascular conductance (CVC) and cerebral tissue oxygenation (ScO2) during experimental hypocapnia and hypercapnia following 14-day normobaric exposures to IH (10% O2). CVC was estimated from the ratio of mean middle cerebral arterial blood flow velocity (transcranial Doppler sonography) to mean arterial pressure (tonometry), and ScO2 in the prefrontal cortex was monitored by near-infrared spectroscopy. Changes in CVC and ScO2 during changes in partial pressure of end-tidal CO2 (PETCO2, mass spectrometry) induced by 30-s paced-hyperventilation (hypocapnia) and during 6-min CO2 rebreathing (hypercapnia) were compared before and after 14-day IH exposures in eight young nonsmokers. Repetitive IH exposures reduced the ratio of %ΔCVC/ΔPETCO2 during hypocapnia (1.00 ± 0.13 vs 1.94 ± 0.35 vs %/mmHg, P = 0.026) and the slope of ΔCVC/ΔPETCO2 during hypercapnia (1.79 ± 0.37 vs 2.97 ± 0.64 %/mmHg, P = 0.021), but had no significant effect on ΔScO2/ΔPETCO2. The ventilatory response to hypercapnia during CO2 rebreathing was significantly diminished following 14-day IH exposures (0.83 ± 0.07 vs 1.14 ± 0.09 L/min/mmHg, P = 0.009). We conclude that repetitive normobaric IH exposures significantly diminish variations of cerebral perfusion in response to hypercapnia and hypocapnia without compromising cerebral tissue oxygenation. This IH-induced blunting of cerebral vasoreactivity during CO2 variations helps buffer excessive oscillations of cerebral underperfusion and overperfusion while sustaining cerebral O2 homeostasis.

PMID: 25504012 [PubMed - as supplied by publisher]

A News Media Analysis of the Economic and Reputational Penalties of the Hospital Readmissions Reduction Program.

Thu, 12/18/2014 - 3:29am

A News Media Analysis of the Economic and Reputational Penalties of the Hospital Readmissions Reduction Program.

Inquiry. 2014;51

Authors: Winborn MS, Alencherril J, Pagán JA

Abstract
Section 3025 of the Affordable Care Act (ACA) of 2010 established the Hospital Readmissions Reduction Program (HRRP), an initiative designed to penalize hospitals with excess 30-day readmissions. This study investigates whether readmission penalties under HRRP impose significant reputational effects on hospitals. Data extracted from 2012 to 2013 news stories suggest that the higher the actual penalty, the higher the perceived cost of the penalty, the more likely it is that hospitals will state they have no control over the low-income patients they serve or that they will describe themselves as safety net providers. The downside of being singled out as a low-quality hospital deserving a relatively high penalty seems to be larger than the upside of being singled out as a high-quality hospital facing a relatively low penalty. Although the financial burden of the penalties seems to be low, hospitals may be reacting to the fact that information about excess readmissions and readmission penalties is being released widely and is scrutinized by the news media and the general public.

PMID: 25500753 [PubMed - as supplied by publisher]

Arsenic exposure, hyperuricemia, and gout in US adults.

Thu, 12/18/2014 - 3:29am

Arsenic exposure, hyperuricemia, and gout in US adults.

Environ Int. 2014 Dec 11;76C:32-40

Authors: Kuo CC, Weaver V, Fadrowski JJ, Lin YS, Guallar E, Navas-Acien A

Abstract
BACKGROUND: There is very limited information on the association between arsenic and serum uric acid levels or gout. The aim of this study was to investigate the association of arsenic with hyperuricemia and gout in US adults.
METHODS: A cross-sectional study was conducted in 5632 adults aged 20years or older from the National Health and Nutrition Examination Survey (NHANES) 2003-2010 with determinations of serum uric acid and urine total arsenic and dimethylarsinate (DMA). Hyperuricemia was defined as serum uric acid higher than 7.0mg/dL for men and 6.0mg/dL for women. Gout was defined based on self-reported physician diagnosis and medication use.
RESULTS: After adjustment for sociodemographic factors, comorbidities and arsenobetaine levels, the increase in the geometric means of serum uric acid associated with one interquartile range increase in total arsenic and DMA levels was 3% (95% CI 2-5) and 3% (2-5), respectively, in men and 1% (0-3) and 2% (0-4), respectively, in women. In men, the adjusted odds ratio for hyperuricemia comparing the highest to lowest quartiles of total arsenic was 1.84 (95% CI, 1.26-2.68) and for DMA it was 1.41 (95% CI, 1.01-1.96). The corresponding odds ratios in women were 1.26 (0.77, 2.07) and 1.49 (0.96, 2.31), respectively. The odds ratio for gout comparing the highest to lowest tertiles was 5.46 (95% CI, 1.70-17.6) for total arsenic and 1.98 (0.64-6.15) for DMA among women older than 40years old. Urine arsenic was not associated with gout in men.
CONCLUSION: Low level arsenic exposures may be associated with the risk of hyperuricemia in men and with the prevalence of gout in women. Prospective research focusing on establishing the direction of the relationship among arsenic, hyperuricemia, and gout is needed.

PMID: 25499256 [PubMed - as supplied by publisher]

Different Angiotensin-Converting Enzyme Inhibitors and the Associations With Overall and Cause-Specific Mortalities in Patients With Hypertension.

Thu, 12/18/2014 - 3:29am

Different Angiotensin-Converting Enzyme Inhibitors and the Associations With Overall and Cause-Specific Mortalities in Patients With Hypertension.

Am J Hypertens. 2014 Dec 10;

Authors: Chang CH, Lin JW, Caffrey JL, Wu LC, Lai MS

Abstract
BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors have been widely used in the treatment of hypertension, but the comparative effectiveness in reducing mortality among different drugs is seldom reported.
METHODS: We identified hypertensive patients who started captopril, enalapril, lisinopril, fosinopril, perindopril, ramipril, or imidapril therapy from Taiwan's National Health Insurance database between 1 January 2004 and 31 December 2009. Overall and cause-specific mortalities were ascertained through a linkage to Taiwan's National Death Registry. Patients were followed from the initiation of ACE inhibitors to death, disenrollment, or study termination (31 December 2010). A Cox proportional hazard regression model was used to calculate the hazard ratio (HR) and 95% confidence interval (CI), using ramipril as the reference group.
RESULTS: A total of 989,489 hypertensive patients were included, with a mean follow-up ranging from 3.5 years for imidapril to 4.5 years for enalapril. Captopril initiators had the highest overall mortality rate (117.8 per 1,000,000 person-days) as compared to other ACE inhibitors (54.3-79.4 per 1,000,000 person-days). Patients who started captopril therapy had a significantly increased risk of overall mortality (HR: 1.28, 95% CI: 1.24-1.31) when compared with ramipril. Enalapril (HR: 1.08, 95% CI: 1.05-1.11) and fosinopril (HR: 1.08, 95% CI: 1.05-1.12) were also associated with a modestly increased risk. No difference in mortality was found for lisinopril, perindopril, and imidapril, as compared with ramipril.
CONCLUSIONS: There are differences in the mortality risk associated with different ACE inhibitors. However, potential residual confounding effects might still exist.

PMID: 25498540 [PubMed - as supplied by publisher]

Kinetic comparison of older men and women during walk-to-stair descent transition.

Thu, 12/18/2014 - 3:29am
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Kinetic comparison of older men and women during walk-to-stair descent transition.

Gait Posture. 2014 Sep;40(4):600-4

Authors: Singhal K, Kim J, Casebolt J, Lee S, Han KH, Kwon YH

Abstract
Stair walking is one of the most challenging tasks for older adults, with women reporting higher incidence of falls. The purpose of this study was to investigate the gender differences in kinetics during stair descent transition. Twenty-eight participants (12 male and 16 female; 68.5 and 69.0 years of mean age, respectively) performed stair descent from level walking in a step-over-step manner at a self-selected speed over a custom-made three-step staircase with embedded force plates. Kinematic and force data were combined using inverse dynamics to generate kinetic data for gender comparison. The top and the first step on the staircase were chosen for analysis. Women showed a higher trail leg peak hip abductor moment (-1.0 Nm/kg), lower trail leg peak knee extensor moment and eccentric power (0.74 Nm/kg and 3.15 W/kg), and lower peak concentric power at trail leg ankle joint (1.29 W/kg) as compared to men (p<0.05; -0.82 Nm/kg, 0.89 Nm/kg, 3.83 W/kg, and 1.78 W/kg, respectively). The lead leg knee eccentric power was also lower in women (p<0.05). This decreased ability to exert knee control during stair descent transition may predispose women to a higher risk of fall.

PMID: 25082325 [PubMed - indexed for MEDLINE]

Cancer-associated isocitrate dehydrogenase 1 (IDH1) R132H mutation and d-2-hydroxyglutarate stimulate glutamine metabolism under hypoxia.

Thu, 12/18/2014 - 3:29am
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Cancer-associated isocitrate dehydrogenase 1 (IDH1) R132H mutation and d-2-hydroxyglutarate stimulate glutamine metabolism under hypoxia.

J Biol Chem. 2014 Aug 22;289(34):23318-28

Authors: Reitman ZJ, Duncan CG, Poteet E, Winters A, Yan LJ, Gooden DM, Spasojevic I, Boros LG, Yang SH, Yan H

Abstract
Mutations in the cytosolic NADP(+)-dependent isocitrate dehydrogenase (IDH1) occur in several types of cancer, and altered cellular metabolism associated with IDH1 mutations presents unique therapeutic opportunities. By altering IDH1, these mutations target a critical step in reductive glutamine metabolism, the metabolic pathway that converts glutamine ultimately to acetyl-CoA for biosynthetic processes. While IDH1-mutated cells are sensitive to therapies that target glutamine metabolism, the effect of IDH1 mutations on reductive glutamine metabolism remains poorly understood. To explore this issue, we investigated the effect of a knock-in, single-codon IDH1-R132H mutation on the metabolism of the HCT116 colorectal adenocarcinoma cell line. Here we report the R132H-isobolome by using targeted (13)C isotopomer tracer fate analysis to trace the metabolic fate of glucose and glutamine in this system. We show that introduction of the R132H mutation into IDH1 up-regulates the contribution of glutamine to lipogenesis in hypoxia, but not in normoxia. Treatment of cells with a d-2-hydroxyglutarate (d-2HG) ester recapitulated these changes, indicating that the alterations observed in the knocked-in cells were mediated by d-2HG produced by the IDH1 mutant. These studies provide a dynamic mechanistic basis for metabolic alterations observed in IDH1-mutated tumors and uncover potential therapeutic targets in IDH1-mutated cancers.

PMID: 24986863 [PubMed - indexed for MEDLINE]

Between-centre variability in transfer function analysis, a widely used method for linear quantification of the dynamic pressure-flow relation: the CARNet study.

Thu, 12/18/2014 - 3:29am
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Between-centre variability in transfer function analysis, a widely used method for linear quantification of the dynamic pressure-flow relation: the CARNet study.

Med Eng Phys. 2014 May;36(5):620-7

Authors: Meel-van den Abeelen AS, Simpson DM, Wang LJ, Slump CH, Zhang R, Tarumi T, Rickards CA, Payne S, Mitsis GD, Kostoglou K, Marmarelis V, Shin D, Tzeng YC, Ainslie PN, Gommer E, Müller M, Dorado AC, Smielewski P, Yelicich B, Puppo C, Liu X, Czosnyka M, Wang CY, Novak V, Panerai RB, Claassen JA

Abstract
Transfer function analysis (TFA) is a frequently used method to assess dynamic cerebral autoregulation (CA) using spontaneous oscillations in blood pressure (BP) and cerebral blood flow velocity (CBFV). However, controversies and variations exist in how research groups utilise TFA, causing high variability in interpretation. The objective of this study was to evaluate between-centre variability in TFA outcome metrics. 15 centres analysed the same 70 BP and CBFV datasets from healthy subjects (n=50 rest; n=20 during hypercapnia); 10 additional datasets were computer-generated. Each centre used their in-house TFA methods; however, certain parameters were specified to reduce a priori between-centre variability. Hypercapnia was used to assess discriminatory performance and synthetic data to evaluate effects of parameter settings. Results were analysed using the Mann-Whitney test and logistic regression. A large non-homogeneous variation was found in TFA outcome metrics between the centres. Logistic regression demonstrated that 11 centres were able to distinguish between normal and impaired CA with an AUC>0.85. Further analysis identified TFA settings that are associated with large variation in outcome measures. These results indicate the need for standardisation of TFA settings in order to reduce between-centre variability and to allow accurate comparison between studies. Suggestions on optimal signal processing methods are proposed.

PMID: 24725709 [PubMed - indexed for MEDLINE]

Age estimation via quantification of signal-joint T cell receptor excision circles in Koreans.

Thu, 12/18/2014 - 3:29am
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Age estimation via quantification of signal-joint T cell receptor excision circles in Koreans.

Leg Med (Tokyo). 2014 May;16(3):135-8

Authors: Cho S, Ge J, Seo SB, Kim K, Lee HY, Lee SD

Abstract
The estimation of age from biological samples (i.e., remains) at crime scenes could provide useful information about both victims and other persons related to criminal activities. Signal-joint T cell receptor excision circle (sjTREC) levels in peripheral blood decline with age, and negative correlations between sjTREC levels and age have been demonstrated in several ethnic groups. To validate the utility of sjTREC for age estimation in Koreans, Taqman qPCR was used to quantify the sjTREC level in samples obtained from 172 individuals ranging from 16 to 65 years old. We modified the previously reported method by using a shorter amplicon and confirmed the efficiency and utility of this method in this report. Our results showed that the linear negative regression curve between sjTREC levels and age was characterized by r=-0.807 and a standard error of 8.49 years. These results indicate that sjTREC level is an effective age estimation method in Koreans. The value of the standard error of quantification was not different from previous reports for other population groups.

PMID: 24524944 [PubMed - indexed for MEDLINE]

Label-free LC-MS/MS identification of phosphatidylglycerol-regulated proteins in Synechocystis sp. PCC6803.

Wed, 12/17/2014 - 3:29am
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Label-free LC-MS/MS identification of phosphatidylglycerol-regulated proteins in Synechocystis sp. PCC6803.

Proteomics. 2014 May;14(9):1053-7

Authors: Talamantes T, Ughy B, Domonkos I, Kis M, Gombos Z, Prokai L

Abstract
We present a proteomics dataset combining SDS-PAGE prefractionation and data-dependent LC-MS/MS that enables the identification of phosphatidylglycerol-regulated proteins in the pgsA(-) mutant of Synechocystis sp. PCC6803, a cyanobacterium strain that grows with this indispensable phospholipid added exogenously. We searched the acquired raw data against a composite protein sequence database of Synechocystis using MASCOT, and employed Progenesis LC-MS software for label-free quantification based on extracted peptide intensities to detect changes in protein abundances upon phospholipid withdrawal. Protein identifications were validated using rigorous criteria, and our analysis of the dataset revealed 80 phosphatidylglycerol-regulated proteins involved in various cellular processes including photosynthesis, respiration, metabolism, transport, transcription, and translation. The data have been deposited to the ProteomeXchange with identifier PXD000363 (http://proteomecentral.proteomexchange.org/dataset/PXD000363).

PMID: 24574175 [PubMed - indexed for MEDLINE]

The role of TGF-β2 and bone morphogenetic proteins in the trabecular meshwork and glaucoma.

Wed, 12/17/2014 - 3:29am
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The role of TGF-β2 and bone morphogenetic proteins in the trabecular meshwork and glaucoma.

J Ocul Pharmacol Ther. 2014 Mar-Apr;30(2-3):154-62

Authors: Wordinger RJ, Sharma T, Clark AF

Abstract
Primary open-angle glaucoma (POAG) is the second leading cause of blindness worldwide. Elevated intraocular pressure (IOP) is a primary risk factor associated with POAG. Increased aqueous humor (AH) outflow resistance through the trabecular meshwork (TM) results in elevated IOP in POAG patients. Resistance to AH outflow is associated with increased accumulation of extracellular matrix (ECM) proteins in the TM. In addition, levels of transforming growth factor-beta2 (TGF-β2) are elevated in the AH and TM tissue of POAG patients. Elevated levels of TGF-β2 in other tissues have been associated with fibrosis and increased tissue stiffness. However, locally produced effectors that maintain homeostatic relationships must also be present. Bone morphogenetic proteins (BMPs) serve this purpose in the TM as they inhibit TGF-β2-induced ECM changes in TM cells. This review article first describes the TGF-β superfamily of growth factors including BMPs and their canonical and noncanonical signaling pathways. The article then addresses the role of TGF-β2 in the pathophysiology of POAG as related to the ECM and ECM crosslinking enzymes. This is followed by a discussion of potential homeostatic control mechanisms of TGF-β2 signaling in the TM including the inhibitory role of BMP-4 and BMP-7. We then describe the relationship of TGF-β2 and BMPs in TM fibrosis including the role of antagonists. Lastly, in future directions, we identify potential future studies that explore new and unique cellular interactions within the TM for potential therapeutic interventions.

PMID: 24517218 [PubMed - indexed for MEDLINE]

Role of the alternatively spliced glucocorticoid receptor isoform GRβ in steroid responsiveness and glaucoma.

Wed, 12/17/2014 - 3:29am
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Role of the alternatively spliced glucocorticoid receptor isoform GRβ in steroid responsiveness and glaucoma.

J Ocul Pharmacol Ther. 2014 Mar-Apr;30(2-3):121-7

Authors: Jain A, Wordinger RJ, Yorio T, Clark AF

Abstract
Glucocorticoid (GC)-induced ocular hypertension (OHT) is a serious side effect of GC therapy in susceptible individuals. This OHT is due to increased aqueous humor (AH) outflow resistance in the trabecular meshwork (TM) caused by GC-mediated changes in TM structure and function. GCs may also play a role in the development of primary open-angle glaucoma (POAG). Elevated cortisol levels in the AH or enhanced GC sensitivity may be one of the reasons for elevated intraocular pressure in POAG patients. The GC OHT responder population is at greater risk of developing POAG compared with non-responders. We recently have gained insight into the molecular mechanisms responsible for this differential GC responsiveness, which is attributed to differences in GC receptor isoform expression in the TM. This article summarizes current knowledge on alternative GC receptor splicing to generate GC receptor alpha (GRα) and GRβ and their roles in the regulation of GC responsiveness in normal and glaucoma TM.

PMID: 24506296 [PubMed - indexed for MEDLINE]

Lineage -CD34+CD31+ cells that appear in association with severe burn injury are inhibitory on the production of antimicrobial peptides by epidermal keratinocytes.

Wed, 12/17/2014 - 3:29am
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Lineage -CD34+CD31+ cells that appear in association with severe burn injury are inhibitory on the production of antimicrobial peptides by epidermal keratinocytes.

PLoS One. 2014;9(2):e82926

Authors: Yoshida S, Lee JO, Nakamura K, Suzuki S, Hendon DN, Kobayashi M, Suzuki F

Abstract
Antimicrobial peptides are major host defense effectors against Pseudomonas aeruginosa skin infections. Due to the lack of such peptide production, severely burned hosts are greatly susceptible to P. aeruginosa burn wound infection. β-Defensin (HBD) production by normal human epidermal keratinocytes (NHEK) was inhibited by lineage(-)CD34(+) cells isolated from peripheral blood of severely burned patients. Lineage(-)CD34(+) cells obtained from severely burned patients were characterized as CD31(+), while healthy donor lineage(-)CD34(+) cells were shown to be CD31(-) cells. Lineage(-)CD34(+)CD31(-) cells did not show any inhibitory activities on HBD-1 production by NHEK. CCL2 and IL-10 released from lineage(-)CD34(+)CD31(+) cells were shown to be inhibitory on the peptide production by NHEK, while these soluble factors were not produced by lineage(-)CD34(+)CD31(-) cells. After treatment with a mixture of mAbs for CCL2 and IL-10, the culture fluids of lineage(-)CD34(+)CD31(+) cells did not show any inhibitory activities on HBD-1 production by NHEK. Lineage(-)CD34(+)CD31(+) cells that appear in association with burn injuries play a role on the inhibition of antimicrobial peptide production by skin keratinocytes through the production of CCL2 and IL-10.

PMID: 24498256 [PubMed - indexed for MEDLINE]

Real-time imaging of exocytotic mucin release and swelling in Calu-3 cells using acridine orange.

Wed, 12/17/2014 - 3:29am
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Real-time imaging of exocytotic mucin release and swelling in Calu-3 cells using acridine orange.

Methods. 2014 Mar 15;66(2):312-24

Authors: Shumilov D, Popov A, Fudala R, Akopova I, Gryczynski I, Borejdo J, Gryczynski Z, Grygorczyk R

Abstract
Mucus secretion is the first-line of defence against the barrage of irritants inhaled into human lungs, but abnormally thick and viscous mucus results in many respiratory diseases. Understanding the processes underlying mucus pathology is hampered, in part, by lack of appropriate experimental tools for labeling and studying mucin granule secretion from live cells with high sensitivity and temporal resolution. In this report we present original spectroscopic properties of acridine orange (AO) which could be utilized to study granule release and mucin swelling with various advanced fluorescence imaging approaches. Low concentration (<200 μM) AO solutions presented absorption maximum at 494 nm, emission maximum at 525 nm and only ∼1.76 ns fluorescence lifetime. By contrast at high concentrations (4-30 mM) favoring formation of AO aggregates, a very different absorption with maximum at ∼440 nm, dramatically red-shifted emission with maximum at 630 nm, and over 10-fold increased fluorescence lifetime (∼20 ns) was observed. To verify potential utility of AO for real-time imaging we have performed confocal, total internal reflection fluorescence (TIRF) and fluorescence lifetime imaging (FLIM) of AO-stained Calu-3 cells. We found similar red-shifted fluorescence spectra and long fluorescence lifetime in intracellular granules as compared to that in the cytoplasm consistent with granular AO accumulation. Mechanical stimulation of Calu-3 cells resulted in multiple exocytotic secretory events of AO-stained granules followed by post-exocytotic swelling of their fluorescently-labeled content that was seen in single-line TIRF images as rapidly-expanding bright-fluorescence patches. The rate of their size expansion followed first-order kinetics with diffusivity of 3.98±0.07×10(-7)c m(2)/s, as expected for mucus gel swelling. This was followed by fluorescence decrease due to diffusional loss of AO that was ∼10-fold slower in the secreted mucus compared to bulk aqueous solution. In summary, we showed that AO-staining could be utilized for real-time TIRF imaging of mucin granule exocytosis and mucin swelling with high sensitivity and temporal resolution. Considering unique AO fluorescence properties that permit selective excitation of AO monomers versus aggregates, our study lays the groundwork for future development of two-color excitation scheme and two-color fluorescence FLIM live-cell imaging assay with potentially many biological applications.

PMID: 24055436 [PubMed - indexed for MEDLINE]

Multiple-pulse pumping for enhanced fluorescence detection and molecular imaging in tissue.

Wed, 12/17/2014 - 3:29am
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Multiple-pulse pumping for enhanced fluorescence detection and molecular imaging in tissue.

Methods. 2014 Mar 15;66(2):292-8

Authors: Rich RM, Gryczynski I, Fudala R, Borejdo J, Stankowska DL, Krishnamoorthy RR, Raut S, Maliwal BP, Shumilov D, Doan H, Gryczynski Z

Abstract
Applications of fluorescence based imaging techniques for detection in cellular and tissue environments are severely limited by autofluorescence of endogenous components of cells, tissue, and the fixatives used in sample processing. To achieve sufficient signal-to-background ratio, a high concentration of the probe needs to be used which is not always feasible. Since typically autofluorescence is in the nanosecond range, long-lived fluorescence probes in combination with time-gated detection can be used for suppression of unwanted autofluorescence. Unfortunately, this requires the sacrifice of the large portion the probe signal in order to sufficiently filter the background. We report a simple and practical approach to achieve a many-fold increase in the intensity of a long-lived probe without increasing the background fluorescence. Using controllable, well separated bursts of closely spaced laser excitation pulses, we are able to highly increase the fluorescence signal of a long-lived marker over the endogenous fluorescent background and scattering, thereby greatly increasing detection sensitivity. Using a commercially available confocal microscopy system equipped with a laser diode and time correlated single photon counting (TCSPC) detection, we are able to enhance the signal of a long-lived Ruthenium (Ru)-based probe by nearly an order of magnitude. We used 80 MHz bursts of pulses (12.5 ns pulse separation) repeated with a 320 kHz repetition rate as needed to adequately image a dye with a 380 ns lifetime. Just using 10 pulses in the burst increases the Ru signal almost 10-fold without any increase in the background signal.

PMID: 23994243 [PubMed - indexed for MEDLINE]

Mitochondrial DNA deletions in Alzheimer's brains: a review.

Wed, 12/17/2014 - 3:29am
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Mitochondrial DNA deletions in Alzheimer's brains: a review.

Alzheimers Dement. 2014 May;10(3):393-400

Authors: Phillips NR, Simpkins JW, Roby RK

Abstract
Mitochondrial dysfunction and increased oxidative stress have been associated with normal aging and are possibly implicated in the etiology of late-onset Alzheimer's disease (AD). DNA deletions, as well as other alterations, can result from oxidative damage to nucleic acids. Many studies during the past two decades have investigated the incidence of mitochondrial DNA deletions in postmortem brain tissues of late-onset AD patients compared with age-matched normal control subjects. Published studies are not entirely concordant, but their differences might shed light on the heterogeneity of AD itself. Our understanding of the role that mitochondrial DNA deletions play in disease progression may provide valuable information that could someday lead to a treatment.

PMID: 23850329 [PubMed - indexed for MEDLINE]

Risk of future offense among probationers with co-occurring substance use and mental health disorders.

Wed, 12/17/2014 - 3:29am
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Risk of future offense among probationers with co-occurring substance use and mental health disorders.

Community Ment Health J. 2014 Apr;50(3):288-95

Authors: Balyakina E, Mann C, Ellison M, Sivernell R, Fulda KG, Sarai SK, Cardarelli R

Abstract
The criminal justice system is the primary service delivery system for many adults with drug and alcohol dependence, mental health, and other health service needs. The purpose of this study was to examine the relationship between risk of future offense, mental health status and co-occurring disorders in a large substance abuse diversion probationer population. A purposive sample of 2,077 probationers completed an assessment to screen for mental health disorders, substance use disorders, risk of future crime and violence, and several demographic characteristics. Probationers who screened positive for co-occurring substance use and mental health disorders were significantly more likely to be at higher risk of future crime and violence compared to probationers who screened positive for only substance use, only a mental health disorder, or no substance use or mental health disorder. Implications for substance use and mental health service delivery are discussed, and recommendations are made for further research.

PMID: 23765181 [PubMed - indexed for MEDLINE]