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Effects of the Ion PGM™ Hi-Q™ sequencing chemistry on sequence data quality.

Recent Research Articles from UNTHSC - Thu, 09/07/2017 - 07:37
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Effects of the Ion PGM™ Hi-Q™ sequencing chemistry on sequence data quality.

Int J Legal Med. 2016 Sep;130(5):1169-80

Authors: Churchill JD, King JL, Chakraborty R, Budowle B

Abstract
Massively parallel sequencing (MPS) offers substantial improvements over current forensic DNA typing methodologies such as increased resolution, scalability, and throughput. The Ion PGM™ is a promising MPS platform for analysis of forensic biological evidence. The system employs a sequencing-by-synthesis chemistry on a semiconductor chip that measures a pH change due to the release of hydrogen ions as nucleotides are incorporated into the growing DNA strands. However, implementation of MPS into forensic laboratories requires a robust chemistry. Ion Torrent's Hi-Q™ Sequencing Chemistry was evaluated to determine if it could improve on the quality of the generated sequence data in association with selected genetic marker targets. The whole mitochondrial genome and the HID-Ion STR 10-plex panel were sequenced on the Ion PGM™ system with the Ion PGM™ Sequencing 400 Kit and the Ion PGM™ Hi-Q™ Sequencing Kit. Concordance, coverage, strand balance, noise, and deletion ratios were assessed in evaluating the performance of the Ion PGM™ Hi-Q™ Sequencing Kit. The results indicate that reliable, accurate data are generated and that sequencing through homopolymeric regions can be improved with the use of Ion Torrent's Hi-Q™ Sequencing Chemistry. Overall, the quality of the generated sequencing data supports the potential for use of the Ion PGM™ in forensic genetic laboratories.

PMID: 27025714 [PubMed - indexed for MEDLINE]

Pancreatic mitochondrial complex I exhibits aberrant hyperactivity in diabetes.

Recent Research Articles from UNTHSC - Tue, 09/05/2017 - 07:34
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Pancreatic mitochondrial complex I exhibits aberrant hyperactivity in diabetes.

Biochem Biophys Rep. 2017 Sep;11:119-129

Authors: Wu J, Luo X, Thangthaeng N, Sumien N, Chen Z, Rutledge MA, Jing S, Forster MJ, Yan LJ

Abstract
It is well established that NADH/NAD(+) redox balance is heavily perturbed in diabetes, and the NADH/NAD(+) redox imbalance is a major source of oxidative stress in diabetic tissues. In mitochondria, complex I is the only site for NADH oxidation and NAD(+) regeneration and is also a major site for production of mitochondrial reactive oxygen species (ROS). Yet how complex I responds to the NADH/NAD(+) redox imbalance and any potential consequences of such response in diabetic pancreas have not been investigated. We report here that pancreatic mitochondrial complex I showed aberrant hyperactivity in either type 1 or type 2 diabetes. Further studies focusing on streptozotocin (STZ)-induced diabetes indicate that complex I hyperactivity could be attenuated by metformin. Moreover, complex I hyperactivity was accompanied by increased activities of complexes II to IV, but not complex V, suggesting that overflow of NADH via complex I in diabetes could be diverted to ROS production. Indeed in diabetic pancreas, ROS production and oxidative stress increased and mitochondrial ATP production decreased, which can be attributed to impaired pancreatic mitochondrial membrane potential that is responsible for increased cell death. Additionally, cellular defense systems such as glucose 6-phosphate dehydrogenase, sirtuin 3, and NQO1 were found to be compromised in diabetic pancreas. Our findings point to the direction that complex I aberrant hyperactivity in pancreas could be a major source of oxidative stress and β cell failure in diabetes. Therefore, inhibiting pancreatic complex I hyperactivity and attenuating its ROS production by various means in diabetes might serve as a promising approach for anti-diabetic therapies.

PMID: 28868496 [PubMed]

Discriminative stimulus and locomotor effects of para-substituted and benzofuran analogs of amphetamine.

Recent Research Articles from UNTHSC - Sun, 09/03/2017 - 07:36

Discriminative stimulus and locomotor effects of para-substituted and benzofuran analogs of amphetamine.

Drug Alcohol Depend. 2017 Aug 24;180:39-45

Authors: Dolan SB, Forster MJ, Gatch MB

Abstract
Novel psychoactive substances have maintained a prominent role in the global drug culture, despite increased regulation by governing bodies. Novel compounds continue to become available on the market, often in "Ecstasy" or "Molly" formulations in lieu of MDMA, at a much faster rate than they can be properly characterized. The current study aimed to investigate the discriminative stimulus and locomotor effects of three putatively entactogenic compounds that have become increasingly prevalent on the drug market: 5-(2-aminopropyl)-benzofuran (5-APB), 6-(2-aminopropryl)-2,3-dihydrobenzofuran (6-APDB), and 4-fluoroamphetamine (4-FA). Locomotor stimulant effects were assessed in an open-field assay for locomotor activity using Swiss-Webster mice. Discriminative stimulus effects were assessed in Sprague-Dawley rats trained to discriminate either cocaine, methamphetamine, DOM, or MDMA from vehicle. The benzofuran compounds produced locomotor stimulation whereas 4-FA depressed locomotor activity. The benzofurans substituted for the discriminative stimulus effects of MDMA, but only partially or not at all for methamphetamine, cocaine, and DOM, whereas 4-FA fully substituted for MDMA, methamphetamine and cocaine, but not DOM. These results indicate an MDMA-like pattern of abuse might be expected for the benzofurans, whereas 4-FA may be substituted for psychostimulants and MDMA.

PMID: 28865391 [PubMed - as supplied by publisher]

Edoxaban: How Does the Newest Agent Fit into the DOAC Landscape?

Recent Research Articles from UNTHSC - Sat, 09/02/2017 - 07:34
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Edoxaban: How Does the Newest Agent Fit into the DOAC Landscape?

Am J Med. 2017 Aug;130(8):900-906

Authors: Gibson CM, Finks SW

Abstract
Edoxaban is the most recently approved factor Xa inhibitor within the class of direct oral anticoagulants (DOACs). Like other DOACs, edoxaban was approved by the US Food and Drug Administration for treatment of venous thromboembolism and prevention of stroke in patients with nonvalvular atrial fibrillation. Similar to other DOACs, edoxaban has fewer drug-drug interactions than warfarin and does not require routine laboratory monitoring. Unlike other DOACs, edoxaban has yet to be approved for secondary or postoperative venous thromboembolism thromboprophylaxis. Currently no antidote for edoxaban is available. To optimally prescribe agents in the DOAC class, it is critical that providers 1) understand how the agents compare; and 2) identify specific settings in which one agent may be preferred over another.

PMID: 28390791 [PubMed - indexed for MEDLINE]

The Third International Genomic Medicine Conference (3rd IGMC, 2015): overall activities and outcome highlights.

Recent Research Articles from UNTHSC - Sat, 09/02/2017 - 07:34
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The Third International Genomic Medicine Conference (3rd IGMC, 2015): overall activities and outcome highlights.

BMC Genomics. 2016 Oct 17;17(Suppl 9):747

Authors: Abu-Elmagd M, Assidi M, Dallol A, Buhmeida A, Pushparaj PN, Kalamegam G, Al-Hamzi E, Shay JW, Scherer SW, Agarwal A, Budowle B, Gari M, Chaudhary A, Abuzenadah A, Al-Qahtani M

Abstract
The Third International Genomic Medicine Conference (3(rd) IGMC) was organised by the Centre of Excellence in Genomic Medicine Research (CEGMR) at the King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia (KSA). This conference is a continuation of a series of meetings, which began with the first International Genomic Medicine Conference (1(st) IGMC, 2011) followed by the second International Genomic Medicine Conference (2(nd) IGMC, 2013). The 3(rd) IGMC meeting presented as a timely opportunity to bring scientists from across the world to gather, discuss, and exchange recent advances in the field of genomics and genetics in general as well as practical information on using these new technologies in different basic and clinical applications. The meeting undoubtedly inspired young male and female Saudi researchers, who attended the conference in large numbers, as evidenced by the oversubscribed oral and poster presentations. The conference also witnessed the launch of the first content for npj Genomic Medicine, a high quality new journal was established in partnership by CEGMR with Springer Nature and published as part of the Nature Partner Journal series. Here, we present a brief summary report of the 2-day meeting including highlights from the oral presentations, poster presentations, workshops, poster prize-winners and comments from the distinguished scientists.

PMID: 27766952 [PubMed - indexed for MEDLINE]

Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with Response-Adapted therapy.

Recent Research Articles from UNTHSC - Sat, 09/02/2017 - 07:34
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Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with Response-Adapted therapy.

Leukemia. 2017 Feb;31(2):333-339

Authors: Pui CH, Pei D, Raimondi SC, Coustan-Smith E, Jeha S, Cheng C, Bowman WP, Sandlund JT, Ribeiro RC, Rubnitz JE, Inaba H, Gruber TA, Leung WH, Yang JJ, Downing JR, Evans WE, Relling MV, Campana D

Abstract
To determine the clinical significance of minimal residual disease (MRD) in patients with prognostically relevant subtypes of childhood acute lymphoblastic leukemia (ALL), we analyzed data from 488 patients treated in St Jude Total Therapy Study XV with treatment intensity based mainly on MRD levels measured during remission induction. MRD levels on day 19 predicted treatment outcome for patients with hyperdiploid >50 ALL, National Cancer Institute (NCI) standard-risk B-ALL or T-cell ALL, while MRD levels on day 46 were prognostic for patients with NCI standard-risk or high-risk B-ALL. Patients with t(12;21)/(ETV6-RUNX1) or hyperdiploidy >50 ALL had the best prognosis; those with a negative MRD on day 19 had a particularly low risk of relapse: 1.9% and 3.8%, respectively. Patients with NCI high-risk B-ALL or T-cell ALL had an inferior outcome; even with undetectable MRD on day 46, cumulative risk of relapse was 12.7% and 15.5%, respectively. Among patients with NCI standard-risk B-ALL, the outcome was intermediate overall but was poor if MRD was ⩾1% on day 19 or MRD was detectable at any level on day 46. Our results indicate that the clinical impact of MRD on treatment outcome in childhood ALL varies considerably according to leukemia subtype and time of measurement.

PMID: 27560110 [PubMed - indexed for MEDLINE]

Challenges in the Development of Dopamine D2- and D3-selective Radiotracers for PET Imaging Studies.

Recent Research Articles from UNTHSC - Fri, 09/01/2017 - 07:38

Challenges in the Development of Dopamine D2- and D3-selective Radiotracers for PET Imaging Studies.

J Labelled Comp Radiopharm. 2017 Aug 31;:

Authors: Mach RH, Luedtke RR

Abstract
The dopamine D2-like receptors (i.e., D2/3 receptors) have been the most extensively studied CNS receptor with PET. The three different radiotracers which have been used in these studies are [(11) C]raclopride, [(18) F]fallypride, and [(11) C]PHNO. Since these radiotracers have a high affinity for both dopamine D2 and D3 receptors, the density of dopamine receptors in the CNS is reported as the D2/3 binding potential, which reflects a measure of the density of both receptor subtypes. Although the development of D2- and D3-selective PET radiotracers has been an active area of research for many years, this by and large presents an unmet need in the area of translational PET imaging studies. This article discusses some of the challenges that have inhibited progress in this area of research, and the current status of the development of subtype selective radiotracers for imaging D3 and D2 dopamine receptors with PET.

PMID: 28857231 [PubMed - as supplied by publisher]

Presence of Androgen Receptor Variant in Neuronal Lipid Rafts.

Recent Research Articles from UNTHSC - Fri, 09/01/2017 - 07:38

Presence of Androgen Receptor Variant in Neuronal Lipid Rafts.

eNeuro. 2017 Jul-Aug;4(4):

Authors: Garza-Contreras J, Duong P, Snyder BD, Schreihofer DA, Cunningham RL

Abstract
Fast, nongenomic androgen actions have been described in various cell types, including neurons. However, the receptor mediating this cell membrane-initiated rapid signaling remains unknown. This study found a putative androgen receptor splice variant in a dopaminergic N27 cell line and in several brain regions (substantia nigra pars compacta, entorhinal cortex, and hippocampus) from gonadally intact and gonadectomized (young and middle-aged) male rats. This putative splice variant protein has a molecular weight of 45 kDa and lacks an N-terminal domain, indicating it is homologous to the human AR45 splice variant. Interestingly, AR45 was highly expressed in all brain regions examined. In dopaminergic neurons, AR45 is localized to plasma membrane lipid rafts, a microdomain involved in cellular signaling. Further, AR45 protein interacts with membrane-associated G proteins Gαq and Gαo. Neither age nor hormone levels altered AR45 expression in dopaminergic neurons. These results provide the first evidence of AR45 protein expression in the brain, specifically plasma membrane lipid rafts. AR45 presence in lipid rafts indicates that it may function as a membrane androgen receptor to mediate fast, nongenomic androgen actions.

PMID: 28856243 [PubMed - in process]

Methylene blue inhibits GABAA receptors by interaction with GABA binding site.

Recent Research Articles from UNTHSC - Fri, 09/01/2017 - 07:38
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Methylene blue inhibits GABAA receptors by interaction with GABA binding site.

Neuropharmacology. 2017 Jun;119:100-110

Authors: Chen Z, Liu R, Yang SH, Dillon GH, Huang R

Abstract
Methylene blue (MB) is commonly used in diagnostic procedures and is also used to treat various medical conditions. Neurological effects of MB have been reported in clinical observations and experimental studies. Thus the modulation of GABAA receptor function by MB was investigated. Whole-cell GABA-activated currents were recorded from HEK293 cells expressing various GABAA receptor subunit configurations. MB inhibition of GABA currents was apparent at 3 μM, and it had an IC50 of 31 μM in human α1β2γ2 receptors. The MB action was rapid and reversible. MB inhibition was not mediated via the picrotoxin site, as a mutation (T6'F of the β2 subunit) known to confer resistance to picrotoxin had no effect on MB-induced inhibition. Blockade of GABAA receptors by MB was demonstrated across a range of receptors expressing varying subunits, including those expressed at extrasynaptic sites. The sensitivity of α1β2 receptors to MB was similar to that observed in α1β2γ2 receptors, indicating that MB's action via the benzodiazepine or Zn(2+) site is unlikely. MB-induced inhibition of GABA response was competitive with respect to GABA. Furthermore, mutation of α1 F64 to A and β2 Y205 to F in the extracellular N-terminus, both residues which are known to comprise GABA binding pocket, remarkably diminished MB inhibition of GABA currents. These data suggest that MB inhibits GABAA receptor function by direct or allosteric interaction with the GABA binding site. Finally, in mouse hippocampal CA1 pyramidal neurons, MB inhibited GABA-activated currents as well as GABAergic IPSCs. We demonstrate that MB directly inhibits GABAA receptor function, which may underlie some of the effects of MB on the CNS.

PMID: 28390894 [PubMed - indexed for MEDLINE]

Precision Medicine for Ischemic Stroke, Let Us Move Beyond Time Is Brain.

Recent Research Articles from UNTHSC - Wed, 08/30/2017 - 07:32
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Precision Medicine for Ischemic Stroke, Let Us Move Beyond Time Is Brain.

Transl Stroke Res. 2017 Aug 29;:

Authors: Yang SH, Lou M, Luo B, Jiang WJ, Liu R

PMID: 28849548 [PubMed - as supplied by publisher]

Markov Mixed Effects Modeling Using Electronic Adherence Monitoring Records Identifies Influential Covariates to HIV Preexposure Prophylaxis.

Recent Research Articles from UNTHSC - Wed, 08/30/2017 - 07:32
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Markov Mixed Effects Modeling Using Electronic Adherence Monitoring Records Identifies Influential Covariates to HIV Preexposure Prophylaxis.

J Clin Pharmacol. 2017 May;57(5):606-615

Authors: Madrasi K, Chaturvedula A, Haberer JE, Sale M, Fossler MJ, Bangsberg D, Baeten JM, Celum C, Hendrix CW

Abstract
Adherence is a major factor in the effectiveness of preexposure prophylaxis (PrEP) for HIV prevention. Modeling patterns of adherence helps to identify influential covariates of different types of adherence as well as to enable clinical trial simulation so that appropriate interventions can be developed. We developed a Markov mixed-effects model to understand the covariates influencing adherence patterns to daily oral PrEP. Electronic adherence records (date and time of medication bottle cap opening) from the Partners PrEP ancillary adherence study with a total of 1147 subjects were used. This study included once-daily dosing regimens of placebo, oral tenofovir disoproxil fumarate (TDF), and TDF in combination with emtricitabine (FTC), administered to HIV-uninfected members of serodiscordant couples. One-coin and first- to third-order Markov models were fit to the data using NONMEM(®) 7.2. Model selection criteria included objective function value (OFV), Akaike information criterion (AIC), visual predictive checks, and posterior predictive checks. Covariates were included based on forward addition (α = 0.05) and backward elimination (α = 0.001). Markov models better described the data than 1-coin models. A third-order Markov model gave the lowest OFV and AIC, but the simpler first-order model was used for covariate model building because no additional benefit on prediction of target measures was observed for higher-order models. Female sex and older age had a positive impact on adherence, whereas Sundays, sexual abstinence, and sex with a partner other than the study partner had a negative impact on adherence. Our findings suggest adherence interventions should consider the role of these factors.

PMID: 27922719 [PubMed - indexed for MEDLINE]

No increased risk of hospitalization for heart failure for patients treated with dipeptidyl peptidase-4 inhibitors in Taiwan.

Recent Research Articles from UNTHSC - Wed, 08/30/2017 - 07:32
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No increased risk of hospitalization for heart failure for patients treated with dipeptidyl peptidase-4 inhibitors in Taiwan.

Int J Cardiol. 2016 Oct 01;220:14-20

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

Abstract
BACKGROUND: Saxagliptin has been reported to be associated with an increased risk of hospitalization for heart failure (HF). The objective of this study was to test whether the increased risk is drug specific or a class effect for dipeptidyl peptidase-4 (DPP-4) inhibitors.
METHODS: Diabetic patients prescribed sitagliptin, saxagliptin, and vildagliptin between 2011 and 2013 were identified from Taiwan's National Health Insurance (NHI) claims database. The outcome of interest was the first hospitalization for HF. The patients were followed for one year from drug initiation to outcome occurrence, death, or study termination (December 31, 2013). A Cox proportional hazards regression model was used to calculate the hazard ratios (HR) and their 95% confidence intervals, using sitagliptin as the reference group.
RESULTS: A total of 239,669 patients, including 159,330 sitagliptin, 38,561 saxagliptin, and 41,778 vildagliptin initiators, were included in the analysis. With a follow-up period ranging from 269days (vildagliptin) to 313days (sitagliptin), the crude incidence rate of HF was 2.77, 2.63, and 1.91 per 100 person-years for sitagliptin, saxagliptin, and vildagliptin, respectively. Saxagliptin had a similar risk (HR: 0.98, 95% CI: 0.91-1.06) to sitagliptin, while vildagliptin was associated with a lower risk of HF (HR: 0.85, 95% CI: 0.78-0.93). Auxiliary analyses using acarbose (n=130,800) as a reference group consistently showed no increased risk of HF associated with DDP-4 inhibitors.
CONCLUSION: Three DPP-4 inhibitors studied seem to be safe regarding the risk of HF, while the reduced risk of vildagliptin might be a spurious association or a chance finding.

PMID: 27389437 [PubMed - indexed for MEDLINE]

Opioids' Effect on Healing of Venous Leg Ulcers.

Recent Research Articles from UNTHSC - Sun, 08/27/2017 - 07:34
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Opioids' Effect on Healing of Venous Leg Ulcers.

J Invest Dermatol. 2017 Aug 22;:

Authors: Herskovitz I, MacQuhae FE, Dickerson JE, Cargill DI, Slade HB, Margolis DJ, Kirsner RS

PMID: 28842329 [PubMed - as supplied by publisher]

Ten-Year Follow-Up of Metatarsal Head Resurfacing Implants for Treatment of Hallux Rigidus.

Recent Research Articles from UNTHSC - Sun, 08/27/2017 - 07:34
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Ten-Year Follow-Up of Metatarsal Head Resurfacing Implants for Treatment of Hallux Rigidus.

J Foot Ankle Surg. 2017 Sep - Oct;56(5):1052-1057

Authors: Hilario H, Garrett A, Motley T, Suzuki S, Carpenter B

Abstract
Controversy remains regarding the use of arthroplasty versus arthrodesis in the surgical treatment of late-stage hallux rigidus. The purpose of our retrospective study was to report the long-term follow-up results of the metatarsal head resurfacing implant used for hemiarthroplasty. The patient assessments were conducted using the American Orthopaedic Foot and Ankle Society (AOFAS) metatarsophalangeal clinical rating system and a satisfaction questionnaire. A total of 59 consecutive implantations were performed from January 2005 to December 2009 at our institution. Of the 59 patients, 2 had died and 12 were lost to follow-up, for a 76.3% follow-up rate (45 of 59 procedures) at a mean of 117.67 (range 96 to 143) months. The mean overall AOFAS scale score was 90.6 ± 7.6. The AOFAS pain scale score was 37.78 ± 4.71. One implant was removed, and all remaining patients were happy with their outcome and would repeat the procedure on their other foot, if needed. A subset of patients from a previous mid-term study at our institution showed no significant change in the AOFAS scale scores. Of these 32 patients, 30 (93.75%) were available for follow-up examination at a mean of 122.62 (range 96 to 143) months. We were able to obtain long-term results for 32 implants (30 patients), resulting in a 10-year follow-up rate of 93.7%. With the minimal resection required for this implant, salvage arthrodesis remains a viable option if revision is needed. The surgical treatment of late-stage hallux rigidus with metatarsal head resurfacing allows for low-risk and excellent outcomes at long-term follow-up point.

PMID: 28842091 [PubMed - in process]

Recent Progress in Vascular Aging: Mechanisms and Its Role in Age-related Diseases.

Recent Research Articles from UNTHSC - Sat, 08/26/2017 - 07:34
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Recent Progress in Vascular Aging: Mechanisms and Its Role in Age-related Diseases.

Aging Dis. 2017 Jul;8(4):486-505

Authors: Xu X, Wang B, Ren C, Hu J, Greenberg DA, Chen T, Xie L, Jin K

Abstract
As with many age-related diseases including vascular dysfunction, age is considered an independent and crucial risk factor. Complicated alterations of structure and function in the vasculature are linked with aging hence, understanding the underlying mechanisms of age-induced vascular pathophysiological changes holds possibilities for developing clinical diagnostic methods and new therapeutic strategies. Here, we discuss the underlying molecular mediators that could be involved in vascular aging, e.g., the renin-angiotensin system and pro-inflammatory factors, metalloproteinases, calpain-1, monocyte chemoattractant protein-1 (MCP-1) and TGFβ-1 as well as the potential roles of testosterone and estrogen. We then relate all of these to clinical manifestations such as vascular dementia and stroke in addition to reviewing the existing clinical measurements and potential interventions for age-related vascular dysfunction.

PMID: 28840062 [PubMed]

Dopamine Burden Induced the Inactivation of Sonic Hedgehog Signaling to Cognitive Decline in Minimal Hepatic Encephalopathy.

Recent Research Articles from UNTHSC - Sat, 08/26/2017 - 07:34
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Dopamine Burden Induced the Inactivation of Sonic Hedgehog Signaling to Cognitive Decline in Minimal Hepatic Encephalopathy.

Aging Dis. 2017 Jul;8(4):442-457

Authors: Ding S, Yang J, Huang X, Liu L, Hu J, Xu Z, Zhuge Q

Abstract
Minimal hepatic encephalopathy (MHE) is induced by elevated intracranial dopamine (DA). The relationship of the Shh pathway with memory loss in MHE, however, is elusive. In the current study, rats with MHE induced with DA displayed downregulation of the Shh pathway. Additionally, injection of Shh into MHE/DA-treated rats reversed downregulation of BDNF/NT3, whereas administration of cyclopamine (Cyc) enhanced the inhibition of expression of BDNF/NT3. Furthermore, naringin (Nrg) substantially prevented cognitive impairment in MHE/DA-treated rats and upregulated the Shh pathway, paralleling the elevated expression of BDNF/NT3. Overall, our results indicate that the Shh pathway can induce the expression of BDNF/NT3, and DA causes memory loss by inactivation of Shh pathway signaling to BDNF/NT3 in MHE rats, which is reversed by Nrg. Our study may provide new theory basis of pathogenesis and therapeutic target of MHE.

PMID: 28840059 [PubMed]

Limb Remote Ischemic Conditioning Promotes Myelination by Upregulating PTEN/Akt/mTOR Signaling Activities after Chronic Cerebral Hypoperfusion.

Recent Research Articles from UNTHSC - Sat, 08/26/2017 - 07:34
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Limb Remote Ischemic Conditioning Promotes Myelination by Upregulating PTEN/Akt/mTOR Signaling Activities after Chronic Cerebral Hypoperfusion.

Aging Dis. 2017 Jul;8(4):392-401

Authors: Li X, Ren C, Li S, Han R, Gao J, Huang Q, Jin K, Luo Y, Ji X

Abstract
Limb Remote ischemic conditioning (LRIC) has been proved to be a promising neuroprotective method in white matter lesions after ischemia; however, its mechanism underlying protection after chronic cerebral hypoperfusion remains largely unknown. Here, we investigated whether LRIC promoted myelin growth by activating PI3K/Akt/mTOR signal pathway in a rat chronic hypoperfusion model. Thirty adult male Sprague Dawley underwent permanent double carotid artery (2VO), and limb remote ischemic conditioning was applied for 3 days after the 2VO surgery. Cognitive function, oligodendrocyte counts, myelin density, apoptosis and proliferation activity, as well as PTEN/Akt/mTOR signaling activity were determined 4 weeks after treatment. We found that LRIC significantly inhibited oligodendrocytes apoptosis (p<0.05), promoted myelination (p<0.01) in the corpus callosum and improved spatial learning impairment (p<0.05) at 4 weeks after chronic cerebral hypoperfusion. Oligodendrocytes proliferation, along with demyelination, in corpus callosum were not obviously affected by LRIC (p>0.05). Western blot analysis indicated that LRIC upregulated PTEN/Akt/mTOR signaling activities in corpus callosum (p<0.05). Our results suggest that LRIC exerts neuroprotective effect on white matter injuries through activating PTEN/Akt/mTOR signaling pathway after chronic cerebral hypoperfusion.

PMID: 28840054 [PubMed]

Cyclical Blood Flow Restriction Resistance Exercise: A Potential Parallel to Remote Ischemic Preconditioning?

Recent Research Articles from UNTHSC - Fri, 08/25/2017 - 07:36
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Cyclical Blood Flow Restriction Resistance Exercise: A Potential Parallel to Remote Ischemic Preconditioning?

Am J Physiol Regul Integr Comp Physiol. 2017 Aug 23;:ajpregu.00112.2017

Authors: Sprick JD, Rickards CA

Abstract
Remote ischemic preconditioning (RIPC) is characterized by the cyclical application of limb blood flow restriction and reperfusion, and has been shown to protect vital organs during a subsequent ischemic insult. Blood flow restriction exercise (BFRE) similarly combines bouts of blood flow restriction with low-intensity exercise and thus could potentially emulate the protection demonstrated by RIPC. One concern with BFRE, however, is the potential for an augmented rise in sympathetic outflow, due to greater activation of the exercise pressor reflex. Due to the use of lower workloads, however, we hypothesized that BFRE would elicit an attenuated increase in sympathetic outflow (assessed via plasma norepinephrine (NE) and mean arterial pressure (MAP)), and middle cerebral artery velocity (MCAv) when compared with conventional exercise (CE). Fifteen subjects underwent two leg-press exercise interventions: 1.BFRE-220 mmHg bilateral thigh occlusion at 20% 1 rep-max (1RM), and; 2.CE-65% 1RM without occlusion. Each condition consisted of 4 x 5-min cycles of exercise, with 3 x 10-reps in each cycle. 5-min of rest and reperfusion (for BFRE) followed each cycle. MAP increased with exercise (P<0.001), and was 4-5 mmHg higher with CE vs. BFRE (P≤0.09). Mean MCAv also increased with exercise (P<0.001) and was higher with CE compared to BFRE during the first bout of exercise only (P=0.07). Plasma [NE] increased with CE only (P<0.001), and was higher than BFRE throughout exercise (P≤0.02). The attenuated sympathetic response combined with similar cerebrovascular responses suggest that cyclical BFRE could be explored as an alternative to CE in the clinical setting.

PMID: 28835448 [PubMed - as supplied by publisher]

Combining Remote Ischemic Preconditioning and Aerobic Exercise: A Novel Adaptation of Blood Flow Restriction Exercise.

Recent Research Articles from UNTHSC - Fri, 08/25/2017 - 07:36
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Combining Remote Ischemic Preconditioning and Aerobic Exercise: A Novel Adaptation of Blood Flow Restriction Exercise.

Am J Physiol Regul Integr Comp Physiol. 2017 Aug 23;:ajpregu.00111.2017

Authors: Sprick JD, Rickards CA

Abstract
Remote ischemic preconditioning (RIPC) can attenuate tissue damage sustained by ischemia-reperfusion injury. Blood flow restriction exercise (BFRE) restricts blood flow to exercising muscles. We implemented a novel approach to BFRE with cyclical bouts of blood flow restriction-reperfusion, reflecting the RIPC model. A concern about BFRE, however, is potential amplification of the exercise pressor reflex, which could be unsafe in at-risk populations. We hypothesized that cyclical BFRE would elicit greater increases in sympathetic outflow and arterial pressure than conventional exercise (CE), performed at the same relative intensity. We also assessed the cerebrovascular responses, due to potential implementation of BFRE in stroke rehabilitation. Fourteen subjects performed treadmill exercise at 65-70% HRmax with and without intermittent BFR (4x5-min intervals of bilateral thigh-cuff pressure followed by 5-min reperfusion periods). Mean arterial pressure (MAP), plasma norepinephrine (NE), and middle and posterior cerebral artery velocities (MCAv and PCAv) were compared between trials. As expected, BFRE elicited higher [NE] compared to CE (1249±170 vs 962±114 pg/ml; P=0.06). Unexpectedly, however, there were no differences in MAP between conditions (overall P=0.33), and MAP was 4-5 mmHg lower with BFRE vs. CE during the reperfusion periods (P≤0.05 for reperfusion periods 3 and 4). There were no differences in MCAv or PCAv between trials (P≥0.22), suggesting equivalent cerebro-metabolic demand. The exaggerated sympatho-excitatory response with BFRE was not accompanied by higher MAP, likely due to the cyclical reperfusions. This cyclical BFRE paradigm could be adapted to cardiac- or stroke-rehabilitation, where exercising patients could benefit from the cardio- and cerebro-protection associated with RIPC.

PMID: 28835447 [PubMed - as supplied by publisher]

Anterior chamber perfusion versus posterior chamber perfusion does not influence measurement of aqueous outflow facility in living mice by constant flow infusion.

Recent Research Articles from UNTHSC - Tue, 08/22/2017 - 07:40

Anterior chamber perfusion versus posterior chamber perfusion does not influence measurement of aqueous outflow facility in living mice by constant flow infusion.

Exp Eye Res. 2017 Aug 16;:

Authors: Lopez NN, Patel GC, Raychaudhuri U, Aryal S, Phan TN, Clark AF, Millar JC

Abstract
Mice are now routinely utilized in studies of aqueous humor outflow dynamics. In particular, conventional aqueous outflow facility (C) is routinely measured via perfusion of the aqueous chamber by a number of laboratories. However, in mouse eyes perfused ex-vivo, values for C are variable depending upon whether the perfusate is introduced into the posterior chamber (PC) versus the anterior chamber (AC). Perfusion via the AC leads to posterior bowing of the iris, and traction on the iris root/scleral spur, which may increase C. Perfusion via the PC does not yield this effect. But the equivalent situation in living mice has not been investigated. We sought to determine whether AC versus PC perfusion of the living mouse eye may lead to different values for C. All experiments were conducted in C57BL/6J mice (all ♀) between the ages of 20 and 30 weeks. Mice were divided into groups of 3-4 animals each. In all groups, both eyes were perfused. C was measured in groups 1 and 2 by constant flow infusion (from a 50 μL microsyringe) via needle placement in the AC, and in the PC, respectively. To investigate the effect of ciliary muscle (CM) tone on C, groups 3 and 4 were perfused live via the AC or PC with tropicamide (muscarinic receptor antagonist) added to the perfusate at a concentration of 100 μM. To investigate immediate effect of euthanasia, groups 5 and 6 were perfused 15-30 min after death via the AC or PC. To investigate the effect of CM tone on C immediately following euthanasia, groups 7 and 8 were perfused 15-30 min after death via the AC or PC with tropicamide added to the perfusate at a concentration of 100 μM. C in Groups 1 (AC perfusion) and 2 (PC perfusion) was computed to be 19.5 ± 0.8 versus 21.0 ± 2.1 nL/min/mmHg, respectively (mean ± SEM, p > 0.4, not significantly different). In live animals in which tropicamide was present in the perfusate, C in Group 3 (AC perfusion) was significantly greater than C in Group 4 (PC perfusion) (22.0 ± 4.0 versus 14.0 ± 2.0 nL/min/mmHg, respectively, p = 0.0021). In animals immediately following death, C in groups 5 (AC perfusion) and 6 (PC perfusion) was computed to be 21.2 ± 2.0 versus 22.8 ± 1.4 nL/min/mmHg, respectively (mean ± SEM, p = 0.1196, not significantly different). In dead animals in which tropicamide was present in the perfusate, C in group 7 (AC perfusion) was greater than C in group 8 (PC perfusion) (20.6 ± 1.4 versus 14.2 ± 2.6 nL/min/mmHg, respectively, p < 0.0001). C in eyes in situ in living mice or euthanized animals within 15-30 min post mortem is not significantly different when measured via AC perfusion or PC perfusion. In eyes of live or freshly euthanized mice, C is greater when measured via AC versus PC perfusion when tropicamide (a mydriatic and cycloplegic agent) is present in the perfusate.

PMID: 28822760 [PubMed - as supplied by publisher]

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