Recent Research Articles from UNTHSC

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Primary Cutaneous Diffuse Large B-Cell Lymphoma With a MYC-IGH Rearrangement and Gain of BCL2: Expanding the Spectrum of MYC/BCL2 Double-Hit Lymphomas.

Sat, 07/09/2016 - 06:30

Primary Cutaneous Diffuse Large B-Cell Lymphoma With a MYC-IGH Rearrangement and Gain of BCL2: Expanding the Spectrum of MYC/BCL2 Double-Hit Lymphomas.

Am J Dermatopathol. 2016 Jul 7;

Authors: Testo N, Olson LC, Subramaniyam S, Hanson T, Magro CM

Abstract
Aggressive extracutaneous B-cell lymphomas span the various stages of B-cell ontogeny and include B-cell lymphoblastic lymphoma, Burkitt lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma. Diffuse large B-cell lymphomas represent the most common histologic subtype of non-Hodgkin lymphomas, comprising 30% of adult non-Hodgkin lymphomas in the United States. A distinctive form of diffuse large B-cell lymphoma is the double-hit lymphoma, with most cases exhibiting a combined MYC and BCL2 rearrangement, leading some hematopathologists to propose the term MYC/BCL2 lymphoma. More recently, MYC rearrangement with multiple copies/gain of BCL2 or multiple copies/gain of MYC with a BCL2 rearrangement have been described and exhibit a very similar clinical course to conventional double-hit lymphomas. We report the seventh case of diffuse large B-cell lymphoma exhibiting this distinct cytogenetic abnormality and the first reported case in the skin. The patient's clinical course was aggressive, succumbing to disease 18 months after his initial presentation.

PMID: 27391453 [PubMed - as supplied by publisher]

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

Sat, 07/09/2016 - 06:30

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

Int J Cardiol. 2016 Jun 24;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 - as supplied by publisher]

Glucocorticoid Therapy and ocular hypertension.

Sat, 07/09/2016 - 06:30

Glucocorticoid Therapy and ocular hypertension.

Eur J Pharmacol. 2016 Jul 4;

Authors: Dibas A, Yorio T

Abstract
The projected number of people who will develop age-related macular degeneration in estimated at 2020 is 196 million and is expected to reach 288 million in 2040. Also, the number of people with Diabetic retinopathy will grow from 126.6 million in 2010 to 191.0 million by 2030. In addition, it is estimated that there are 2.3 million people suffering from uveitis worldwide. Because of the anti-inflammatory properties of glucocorticoids (GCs), they are often used topically and/or intravitreally to treat ocular inflammation conditions or edema associated with macular degeneration and diabetic retinopathy. Unfortunately, ocular GC therapy can lead to severe side effects. Serious and sometimes irreversible eye damage can occur as a result of the development of GC-induced ocular hypertension causing secondary open-angle glaucoma. According to the world health organization, glaucoma is the second leading cause of blindness in the world and it is estimated that 80 million will suffer from glaucoma by 2020. In the current review, mechanisms of GC-induced damage in ocular tissue, GC-resistance, and enhancing GC therapy will be discussed.

PMID: 27388141 [PubMed - as supplied by publisher]

Cross-sectional and longitudinal risk of physical impairment in a cohort of postmenopausal women who experience physical and verbal abuse.

Sat, 07/09/2016 - 06:30
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Cross-sectional and longitudinal risk of physical impairment in a cohort of postmenopausal women who experience physical and verbal abuse.

BMC Womens Health. 2015;15:98

Authors: Cannell MB, Weitlauf JC, Garcia L, Andresen EM, Margolis KL, Manini TM

Abstract
BACKGROUND: Exposure to interpersonal violence, namely verbal and physical abuse, is a highly prevalent threat to women's health and well-being. Among older, post-menopausal women, several researchers have characterized a possible bi-directional relationship of abuse exposure and diminished physical functioning. However, studies that prospectively examine the relationship between interpersonal abuse exposure and physical functioning across multiple years of observation are lacking. To address this literature gap, we prospectively evaluate the association between abuse exposure and physical functioning in a large, national cohort of post-menopausal women across 12 years of follow-up observation.
METHODS: Multivariable logistic regression was used to measure the adjusted association between experiencing abuse and physical function score at baseline in 154,902 Women's Health Initiative (WHI) participants. Multilevel modeling, where the trajectories of decline in physical function were modeled as a function of time-varying abuse exposure, was used to evaluate the contribution of abuse to trajectories of physical function scores over time.
RESULT: Abuse was prevalent among WHI participants, with 11 % of our study population reporting baseline exposure. Verbal abuse was the most commonly reported abuse type (10 %), followed by combined physical and verbal abuse (1 %), followed by physical abuse in the absence of verbal abuse (0.2 %). Abuse exposure (all types) was associated with diminished physical functioning, with women exposed to combined physical and verbal abuse presenting baseline physical functioning scores consistent with non-abused women 20 years senior. Results did not reveal a differential rate of decline over time in physical functioning based on abuse exposure.
CONCLUSIONS: Taken together, our findings suggest a need for increased awareness of the prevalence of abuse exposure among postmenopausal women; they also underscore the importance of clinician's vigilance in their efforts toward the prevention, early detection and effective intervention with abuse exposure, including verbal abuse exposure, in post-menopausal women. Given our findings related to abuse exposure and women's diminished physical functioning at WHI baseline, our work illuminates a need for further study, particularly the investigation of this association in younger, pre-menopausal women so that the temporal ordering if this relationship may be better understood.

PMID: 26554450 [PubMed - indexed for MEDLINE]

Aquaporins: Their role in gastrointestinal malignancies.

Thu, 07/07/2016 - 06:33
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Aquaporins: Their role in gastrointestinal malignancies.

Cancer Lett. 2016 Apr 1;373(1):12-8

Authors: Nagaraju GP, Basha R, Rajitha B, Alese OB, Alam A, Pattnaik S, El-Rayes B

Abstract
Aquaporins (AQPs) are small (~30 kDa monomers) integral membrane water transport proteins that allow water to flow through cell membranes in reaction to osmotic gradients in cells. In mammals, the family of AQPs has thirteen (AQP0-12) unique members that mediate critical biological functions. Since AQPs can impact cell proliferation, migration and angiogenesis, their role in various human cancers is well established. Recently, AQPs have been explored as potential diagnostic and therapeutic targets in gastrointestinal (GI) cancers. GI cancers encompass multiple sites including the colon, esophagus, stomach and pancreas. Research in the last three decades has revealed biological aspects and signaling pathways critical for the development of GI cancers. Since the majority of these cancers are very aggressive and rapidly metastasizes, identifying effective targets is crucial for treatment. Preclinical studies have utilized inhibitors of specific AQPs and knock down of AQP expression using siRNA. Although several studies have explored the role of AQPs in colorectal, esophageal, gastric, hepatocellular and pancreatic cancers, there is no comprehensive review compiling the available information on GI cancers as has been published for other malignancies such as ovarian cancer. Due to the similarities and association of various sites of GI cancers, it is helpful to consider these results collectively in order to better understand the role of specific AQPs in critical GI cancers. This review summarizes the current knowledge of the role of AQPs in GI malignancies with particular focus on diagnosis and therapeutic applications.

PMID: 26780474 [PubMed - indexed for MEDLINE]

Cerebral small vessel disease and Alzheimer's disease.

Thu, 07/07/2016 - 06:33
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Cerebral small vessel disease and Alzheimer's disease.

Clin Interv Aging. 2015;10:1695-704

Authors: Cai Z, Wang C, He W, Tu H, Tang Z, Xiao M, Yan LJ

Abstract
Cerebral small vessel disease (CSVD) is a group of pathological processes with multifarious etiology and pathogenesis that are involved into the small arteries, arterioles, venules, and capillaries of the brain. CSVD mainly contains lacunar infarct or lacunar stroke, leukoaraiosis, Binswanger's disease, and cerebral microbleeds. CSVD is an important cerebral microvascular pathogenesis as it is the cause of 20% of strokes worldwide and the most common cause of cognitive impairment and dementia, including vascular dementia and Alzheimer's disease (AD). It has been well identified that CSVD contributes to the occurrence of AD. It seems that the treatment and prevention for cerebrovascular diseases with statins have such a role in the same function for AD. So far, there is no strong evidence-based medicine to support the idea, although increasing basic studies supported the fact that the treatment and prevention for cerebrovascular diseases will benefit AD. Furthermore, there is still lack of evidence in clinical application involved in specific drugs to benefit both AD and CSVD.

PMID: 26604717 [PubMed - indexed for MEDLINE]

Absolute humidity and the human nose: A reanalysis of climate zones and their influence on nasal form and function.

Tue, 07/05/2016 - 18:34

Absolute humidity and the human nose: A reanalysis of climate zones and their influence on nasal form and function.

Am J Phys Anthropol. 2016 Jul 4;

Authors: Maddux SD, Yokley TR, Svoma BM, Franciscus RG

Abstract
OBJECTIVES: Investigations into the selective role of climate on human nasal variation commonly divide climates into four broad adaptive zones (hot-dry, hot-wet, cold-dry, and cold-wet) based on temperature and relative humidity. Yet, absolute humidity-not relative humidity-is physiologically more important during respiration. Here, we investigate the global distribution of absolute humidity to better clarify ecogeographic demands on nasal physiology.
METHODS: We use monthly observations from the Climatic Research Unit Timeseries 3 (CRU TS3) database to construct global maps of average annual temperature, relative humidity and absolute humidity. Further, using data collected by Thomson and Buxton (1923) for over 15,000 globally-distributed individuals, we calculate the actual amount of heat and water that must be transferred to inspired air in different climatic regimes to maintain homeostasis, and investigate the influence of these factors on the nasal index.
RESULTS: Our results show that absolute humidity, like temperature, generally decreases with latitude. Furthermore, our results demonstrate that environments typically characterized as "cold-wet" actually exhibit low absolute humidities, with values virtually identical to cold-dry environments and significantly lower than hot-wet and even hot-dry environments. Our results also indicate that strong associations between the nasal index and absolute humidity are, potentially erroneously, predicated on individuals from hot-dry environments possessing intermediate (mesorrhine) nasal indices.
DISCUSSION: We suggest that differentially allocating populations to cold-dry or cold-wet climates is unlikely to reflect different selective pressures on respiratory physiology and nasal morphology-it is cold-dry, and to a lesser degree hot-dry environments, that stress respiratory function. Our study also supports assertions that demands for inspiratory modification are reduced in hot-wet environments, and that expiratory heat elimination for thermoregulation is a greater selective pressure in such environments.

PMID: 27374937 [PubMed - as supplied by publisher]

[Novel therapeutic targets for reduction of intraocular pressure in primary open angle glaucoma].

Tue, 07/05/2016 - 18:34

[Novel therapeutic targets for reduction of intraocular pressure in primary open angle glaucoma].

Zhonghua Yan Ke Za Zhi. 2016 Jun 11;52(6):471-475

Authors: Mao WM, Liu Y, Wordinger YH, Clark AF, Pang IH

Abstract
Glaucoma is a major cause of blindness in China and the world. Currently, all therapeutic means in treating open-angle glaucoma are limited to control the progression of optic neuropathy by lowering intraocular pressure (IOP). Clinically available medicines lower IOP by either enhancing the uveoscleral pathway or inhibiting aqueous humor production. Since the primary cause of IOP elevation in POAG is elevated outflow resistance in the trabecular outflow pathway, current medicines are not able to correct the underlying pathogenesis and pathophysiology of the disease. In this review article, we discuss a series of new therapeutic targets and therapeutic approaches that are designed to directly modify the pathological changes related to the reduction in trabecular outflow in glaucoma patients. Some of these targets and approaches may produce a significant breakthrough in the treatment of this devastating disease. (Chin J Ophthalmol, 2016, 52: 471-475).

PMID: 27373575 [PubMed - as supplied by publisher]

5-(N, N-Hexamethylene) amiloride is a GABA-A ρ1 receptor positive allosteric modulator.

Sat, 07/02/2016 - 06:32

5-(N, N-Hexamethylene) amiloride is a GABA-A ρ1 receptor positive allosteric modulator.

Channels (Austin). 2016 Jul 1;:0

Authors: Snell HD, Gonzales EB

Abstract
Guanidine compounds act as ion channel modulators. In the case of Cys-loop receptors, the guanidine compound amiloride antagonized the heteromeric GABA-A, glycine, and nicotinic acetylcholine receptors. However, amiloride exhibits characteristics consistent with a positive allosteric modulator for the human GABA-A (hGABA-A) ρ1 receptor. Site-directed mutagenesis revealed that the positive allosteric modulation was influenced by the GABA-A ρ1 second transmembrane domain 15' position, a site implicated in ligand allosteric modulation of Cys-loop receptors. There are a variety of amiloride derivatives that provide opportunities to assess the significance of amiloride functional groups (e.g., the guanidine group, the pyrazine ring, etc.) in the modulation of the GABA-A ρ1 receptor activity. We utilized three amiloride derivatives (benzamil, phenamil, and 5-(N, N-Hexamethylene) amiloride) to assess the contribution of these groups towards the potentiation of the GABA-A ρ1 receptor. Benzamil and phenamil failed to potentiate on the wild type GABA-A ρ1 GABA-mediated current while HMA demonstrated efficacy only at the highest concentration studied. The hGABA-A ρ1 (I15'N) mutant receptor activity was potentiated by lower HMA concentrations compared to the wild type receptor. Our findings suggest that an exposed guanidine group on amiloride and amiloride derivatives is critical for modulating the GABA-A ρ1 receptor. The present study provides a conceptual framework for predicting which amiloride derivatives will demonstrate positive allosteric modulation of the GABA-A ρ1 receptor.

PMID: 27367557 [PubMed - as supplied by publisher]

Cholinergic Neurons in the Basal Forebrain Promote Wakefulness by Actions on Neighboring Non-Cholinergic Neurons: An Opto-Dialysis Study.

Sat, 07/02/2016 - 06:32
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Cholinergic Neurons in the Basal Forebrain Promote Wakefulness by Actions on Neighboring Non-Cholinergic Neurons: An Opto-Dialysis Study.

J Neurosci. 2016 Feb 10;36(6):2057-67

Authors: Zant JC, Kim T, Prokai L, Szarka S, McNally J, McKenna JT, Shukla C, Yang C, Kalinchuk AV, McCarley RW, Brown RE, Basheer R

Abstract
UNLABELLED: Understanding the control of sleep-wake states by the basal forebrain (BF) poses a challenge due to the intermingled presence of cholinergic, GABAergic, and glutamatergic neurons. All three BF neuronal subtypes project to the cortex and are implicated in cortical arousal and sleep-wake control. Thus, nonspecific stimulation or inhibition studies do not reveal the roles of these different neuronal types. Recent studies using optogenetics have shown that "selective" stimulation of BF cholinergic neurons increases transitions between NREM sleep and wakefulness, implicating cholinergic projections to cortex in wake promotion. However, the interpretation of these optogenetic experiments is complicated by interactions that may occur within the BF. For instance, a recent in vitro study from our group found that cholinergic neurons strongly excite neighboring GABAergic neurons, including the subset of cortically projecting neurons, which contain the calcium-binding protein, parvalbumin (PV) (Yang et al., 2014). Thus, the wake-promoting effect of "selective" optogenetic stimulation of BF cholinergic neurons could be mediated by local excitation of GABA/PV or other non-cholinergic BF neurons. In this study, using a newly designed opto-dialysis probe to couple selective optical stimulation with simultaneous in vivo microdialysis, we demonstrated that optical stimulation of cholinergic neurons locally increased acetylcholine levels and increased wakefulness in mice. Surprisingly, the enhanced wakefulness caused by cholinergic stimulation was abolished by simultaneous reverse microdialysis of cholinergic receptor antagonists into BF. Thus, our data suggest that the wake-promoting effect of cholinergic stimulation requires local release of acetylcholine in the basal forebrain and activation of cortically projecting, non-cholinergic neurons, including the GABAergic/PV neurons.
SIGNIFICANCE STATEMENT: Optogenetics is a revolutionary tool to assess the roles of particular groups of neurons in behavioral functions, such as control of sleep and wakefulness. However, the interpretation of optogenetic experiments requires knowledge of the effects of stimulation on local neurotransmitter levels and effects on neighboring neurons. Here, using a novel "opto-dialysis" probe to couple optogenetics and in vivo microdialysis, we report that optical stimulation of basal forebrain (BF) cholinergic neurons in mice increases local acetylcholine levels and wakefulness. Reverse microdialysis of cholinergic antagonists within BF prevents the wake-promoting effect. This important result challenges the prevailing dictum that BF cholinergic projections to cortex directly control wakefulness and illustrates the utility of "opto-dialysis" for dissecting the complex brain circuitry underlying behavior.

PMID: 26865627 [PubMed - indexed for MEDLINE]

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

Sat, 07/02/2016 - 06:32
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Limb remote ischemic per-conditioning in combination with post-conditioning reduces brain damage and promotes neuroglobin expression in the rat brain after ischemic stroke.

Restor Neurol Neurosci. 2015;33(3):369-79

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

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

PMID: 25868435 [PubMed - indexed for MEDLINE]

Surface Projection of Interosseous Foramen of the Leg - Cadaver Study: 696 Board #12 June 1, 3: 30 PM - 5: 00 PM.

Fri, 07/01/2016 - 06:31

Surface Projection of Interosseous Foramen of the Leg - Cadaver Study: 696 Board #12 June 1, 3: 30 PM - 5: 00 PM.

Med Sci Sports Exerc. 2016 May;48(5S Suppl 1):185-186

Authors: Arguello E, Richardson M, Stoddard C, Hartis A, Liu H

PMID: 27359839 [PubMed - as supplied by publisher]

Population pharmacokinetics of tenofovir in HIV-1 uninfected members of sero-discordant couples and effect of dose reporting methods.

Thu, 06/30/2016 - 10:30

Population pharmacokinetics of tenofovir in HIV-1 uninfected members of sero-discordant couples and effect of dose reporting methods.

Antimicrob Agents Chemother. 2016 Jun 27;

Authors: Lu Y, Goti V, Chaturvedula A, Haberer JE, Fossler MJ, Sale ME, Bangsberg D, Baeten JM, Celum CL, Hendrix CW

Abstract
Antiretroviral pre-exposure prophylaxis (PrEP) was shown to be effective for preventing HIV-1 infection in individuals who had HIV-1 seropositive partners (the Partners PrEP Study) with once daily dosing of tenofovir and tenofovir/emtricitabine. We developed a population pharmacokinetic model for tenofovir and investigated the impact of different dose reporting methods. Dosing information was collected by patient-reported dosing information (PRDI) from 404 subjects (corresponding to 1280 drug concentration records) from the main trial and electronic monitoring based adherence collected from 211 subjects (corresponding to 327 drug concentration records) in an ancillary adherence study. Model development was conducted with NONMEM (7.2) using PRDI with a steady-state assumption or using PRDI substituted with electronic monitoring records where available. A two-compartment model with first-order absorption was the best model from both modeling approaches with a need of absorption lag time when including electronic monitoring based dosing records in the analysis. Age, body weight and creatinine clearance were significant covariates on clearance, but only creatinine clearance was retained in the final models per stepwise selection. Sex was not a significant covariate on clearance. Tenofovir population pharmacokinetic parameter estimates and precision of the parameters from the two final models were comparable with the point estimates of the parameters differing from 0% to 35% and bootstrap confidence intervals widely overlapping. These findings indicate that the PRDI was sufficient for population pharmacokinetic model development in this study, with high level of adherence per multiple measures.

PMID: 27353269 [PubMed - as supplied by publisher]

The role of cerebral oxygenation and regional cerebral blood flow on tolerance to central hypovolemia.

Thu, 06/30/2016 - 10:30
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The role of cerebral oxygenation and regional cerebral blood flow on tolerance to central hypovolemia.

Am J Physiol Regul Integr Comp Physiol. 2016 Feb 15;310(4):R375-83

Authors: Kay VL, Rickards CA

Abstract
Tolerance to central hypovolemia is highly variable, and accumulating evidence suggests that protection of anterior cerebral blood flow (CBF) is not an underlying mechanism. We hypothesized that individuals with high tolerance to central hypovolemia would exhibit protection of cerebral oxygenation (ScO2), and prolonged preservation of CBF in the posterior vs. anterior cerebral circulation. Eighteen subjects (7 male/11 female) completed a presyncope-limited lower body negative pressure (LBNP) protocol (3 mmHg/min onset rate). ScO2 (via near-infrared spectroscopy), middle cerebral artery velocity (MCAv), posterior cerebral artery velocity (PCAv) (both via transcranial Doppler ultrasound), and arterial pressure (via finger photoplethysmography) were measured continuously. Subjects who completed ≥70 mmHg LBNP were classified as high tolerant (HT; n = 7) and low tolerant (LT; n = 11) if they completed ≤60 mmHg LBNP. The minimum difference in LBNP tolerance between groups was 193 s (LT = 1,243 ± 185 s vs. HT = 1,996 ± 212 s; P < 0.001; Cohen's d = 3.8). Despite similar reductions in mean MCAv in both groups, ScO2 decreased in LT subjects from -15 mmHg LBNP (P = 0.002; Cohen's d=1.8), but was maintained at baseline values until -75 mmHg LBNP in HT subjects (P < 0.001; Cohen's d = 2.2); ScO2 was lower at -30 and -45 mmHg LBNP in LT subjects (P ≤ 0.02; Cohen's d ≥ 1.1). Similarly, mean PCAv decreased below baseline from -30 mmHg LBNP in LT subjects (P = 0.004; Cohen's d = 1.0), but remained unchanged from baseline in HT subjects until -75 mmHg (P = 0.006; Cohen's d = 2.0); PCAv was lower at -30 and -45 mmHg LBNP in LT subjects (P ≤ 0.01; Cohen's d ≥ 0.94). Individuals with higher tolerance to central hypovolemia exhibit prolonged preservation of CBF in the posterior cerebral circulation and sustained cerebral tissue oxygenation, both associated with a delay in the onset of presyncope.

PMID: 26676249 [PubMed - indexed for MEDLINE]

Comments on 'A note on the variance of the estimate of the fixation index F'.

Wed, 06/29/2016 - 18:31
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Comments on 'A note on the variance of the estimate of the fixation index F'.

J Genet. 2016 Jun;95(2):229-30

Authors: Chakraborty R

PMID: 27350663 [PubMed - in process]

Comorbid Depression and Diabetes as a Risk for Mild Cognitive Impairment and Alzheimer's Disease in Elderly Mexican Americans.

Wed, 06/29/2016 - 18:31
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Comorbid Depression and Diabetes as a Risk for Mild Cognitive Impairment and Alzheimer's Disease in Elderly Mexican Americans.

J Alzheimers Dis. 2015;47(1):129-36

Authors: Johnson LA, Gamboa A, Vintimilla R, Cheatwood AJ, Grant A, Trivedi A, Edwards M, Hall JR, O'Bryant SE

Abstract
BACKGROUND: The links between diabetes, depression, and Alzheimer's disease (AD) has been established, but they are still poorly understood. However, little research has examined the effect that comorbidity of depression and diabetes has on cognitive impairment in an ethnically diverse sample.
OBJECTIVE: The purpose of this study was to investigate the relationship between comorbid diabetes and depression on cognitive dysfunction; and examine the relationship in an ethnically diverse population.
METHODS AND RESULTS: Analyses of data from 2,436 participants (914 men and 1,522 women) of three separate cohorts: HABLE, FRONTIER, and TARCC. In the HABLE cohort, comorbidity (odds ratio [OR] = 3.008; 95% CI = 1.358-6.667), age (OR = 1.138; 95% CI = 1.093-1.185), and education (OR = 0.915; 95% CI = 0.852-0.982) increased the risk of mild cognitive impairment (MCI) diagnosis among elderly Mexican American. In the TARCC cohort, results showed an increase risk of MCI in both non-Hispanic whites (OR = 18.795; 95% CI = 2.229-158.485) and Mexican Americans (OR = 8.417; 95% CI = 2.967-23.878). Finally, results in the FRONTIER cohort showed that in elderly Mexican Americans, comorbidity (OR = 2.754; 95% CI = 1.084-6.995) and age (OR = 1.069; 95% CI = 1.023-1.118) significantly increased risk of MCI. In non-Hispanic whites, comorbidity did not significantly increase risk of MCI.
CONCLUSIONS: Among elderly Mexican Americans, comorbid depression and diabetes significantly increased risk for MCI and AD across cohorts. Effects of comorbid diabetes and depression on MCI were inconclusive. Our results support the link between comorbid diabetes and depression and risk for cognitive decline among Mexican Americans. This finding is of critical importance as the Hispanic population is at higher risk of developing AD.

PMID: 26402761 [PubMed - indexed for MEDLINE]

Mitochondrial genome interrogation for forensic casework and research studies.

Tue, 06/28/2016 - 10:31
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Mitochondrial genome interrogation for forensic casework and research studies.

Curr Protoc Hum Genet. 2014;81:14.9.1-23

Authors: Roby RK, Sprouse M, Phillips N, Alicea-Centeno A, Shewale S, Shore S, Paul N

Abstract
This unit describes methods used in the analysis of mitochondrial DNA (mtDNA) for forensic and research applications. UNIT describes procedures specifically for forensic casework where the DNA from evidentiary material is often degraded or inhibited. In this unit, protocols are described for quantification of mtDNA before amplification; amplification of the entire control region from high-quality samples as well as procedures for interrogating the whole mitochondrial genome (mtGenome); quantification of mtDNA post-amplification; and, post-PCR cleanup and sequencing. The protocols for amplification were developed for high-throughput databasing applications for forensic DNA testing such as reference samples and population studies. However, these same protocols can be applied to biomedical research such as age-related disease and health disparities research.

PMID: 24763992 [PubMed - indexed for MEDLINE]

Inhibition of hypoxia inducible factor-1α downregulates the expression of epithelial to mesenchymal transition early marker proteins without undermining cell survival in hypoxic lens epithelial cells.

Sat, 06/25/2016 - 06:29
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Inhibition of hypoxia inducible factor-1α downregulates the expression of epithelial to mesenchymal transition early marker proteins without undermining cell survival in hypoxic lens epithelial cells.

Mol Vis. 2015;21:1024-35

Authors: Cammarata PR, Neelam S, Brooks MM

Abstract
PURPOSE: The purpose of this study was to identify potential therapeutic strategies to slow down or prevent the expression of early-onset epithelial to mesenchymal transition (EMT) marker proteins (fibronectin and alpha smooth muscle actin, α-SMA) without sacrificing the synthesis and accumulation of the prosurvival protein vascular endothelial growth factor (VEGF) in cultured virally transformed human lens epithelial (HLE) cells.
METHODS: HLE-B3 cells, maintained in a continuous hypoxic environment (1% oxygen), were treated with SB216763, a specific inhibitor of glycogen synthase kinase-3β (GSK-3β) catalytic activity. Western blot analysis was employed to detect the cytoplasmic and nuclear levels of β-catenin, as well as the total lysate content of fibronectin and α-SMA. Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of VEGF in cell culture medium. A hypoxia-inducible factor-1α (HIF-1α) translation inhibitor and an HIF-2α translation inhibitor were independently employed to evaluate the effect of hypoxia inducible factor inhibition on EMT marker protein and VEGF expression. XAV932 was used to assess the suppression of nuclear β-catenin and its downstream effect on EMT marker proteins and VEGF expression.
RESULTS: SB216763-treated HLE-B3 cells caused marked inhibition of GSK-3β activity prompting a significant increase in the translocation of cytoplasmic β-catenin to the nucleus. The enhancement of nuclear β-catenin looked as if it positively correlated with a significant increase in the basal expression of VEGF as well as increased expression of fibronectin and α-SMA. In conjunction with SB216763, coadministration of an HIF-1α translation inhibitor, but not an HIF-2α translation inhibitor, markedly suppressed the expression of fibronectin and α-SMA without affecting VEGF levels. Treatment with XAV932 significantly reduced the level of nuclear β-catenin, but the levels of neither the EMT marker proteins nor VEGF were changed.
CONCLUSIONS: Recently, we reported that nuclear β-catenin, but not HIF-2α, regulates the expression of fibronectin and α-SMA in atmospheric oxygen. In marked contrast, data from the hypoxic condition clearly establish that nuclear β-catenin plays little apparent role in the expression of EMT marker proteins. Instead, the loss of HIF-1α (but not HIF-2α) decreases the expression of the EMT marker proteins without sacrificing the levels of the prosurvival protein VEGF. These findings support the development of a potentially relevant therapeutic strategy to undermine the progression of normal cells to the mesenchymal phenotype in the naturally hypoxic lens without subverting cell viability.

PMID: 26392741 [PubMed - indexed for MEDLINE]

Acute inhalation of vaporized nicotine increases arterial pressure in young non-smokers: a pilot study.

Sat, 06/25/2016 - 06:29
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Acute inhalation of vaporized nicotine increases arterial pressure in young non-smokers: a pilot study.

Clin Auton Res. 2015 Aug;25(4):267-70

Authors: Cooke WH, Pokhrel A, Dowling C, Fogt DL, Rickards CA

Abstract
PURPOSE: Electronic cigarettes are growing in popularity, but the physiological consequences of vaporized nicotine are unknown.
METHODS: Twenty healthy non-smokers inhaled vaporized nicotine and placebo (randomized).
RESULTS: Nicotine inhalation was associated with higher arterial pressures in the seated position, and increased arterial pressures in the head-up positions with no other effects on autonomic control.
CONCLUSIONS: Our results show that vaporized nicotine inhalation is not innocuous. Longitudinal studies in otherwise healthy non-smokers should be conducted.

PMID: 26264837 [PubMed - indexed for MEDLINE]

Can Genetic Analysis of Putative Blood Alzheimer's Disease Biomarkers Lead to Identification of Susceptibility Loci?

Fri, 06/24/2016 - 06:29
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Can Genetic Analysis of Putative Blood Alzheimer's Disease Biomarkers Lead to Identification of Susceptibility Loci?

PLoS One. 2015;10(12):e0142360

Authors: Barber RC, Phillips NR, Tilson JL, Huebinger RM, Shewale SJ, Koenig JL, Mitchel JS, O'Bryant SE, Waring SC, Diaz-Arrastia R, Chasse S, Wilhelmsen KC, Alzheimer’s Disease Neuroimaging Initiative, Texas Alzheimer’s Research and Care Consortium

Abstract
Although 24 Alzheimer's disease (AD) risk loci have been reliably identified, a large portion of the predicted heritability for AD remains unexplained. It is expected that additional loci of small effect will be identified with an increased sample size. However, the cost of a significant increase in Case-Control sample size is prohibitive. The current study tests whether exploring the genetic basis of endophenotypes, in this case based on putative blood biomarkers for AD, can accelerate the identification of susceptibility loci using modest sample sizes. Each endophenotype was used as the outcome variable in an independent GWAS. Endophenotypes were based on circulating concentrations of proteins that contributed significantly to a published blood-based predictive algorithm for AD. Endophenotypes included Monocyte Chemoattractant Protein 1 (MCP1), Vascular Cell Adhesion Molecule 1 (VCAM1), Pancreatic Polypeptide (PP), Beta2 Microglobulin (B2M), Factor VII (F7), Adiponectin (ADN) and Tenascin C (TN-C). Across the seven endophenotypes, 47 SNPs were associated with outcome with a p-value ≤1x10(-7). Each signal was further characterized with respect to known genetic loci associated with AD. Signals for several endophenotypes were observed in the vicinity of CR1, MS4A6A/MS4A4E, PICALM, CLU, and PTK2B. The strongest signal was observed in association with Factor VII levels and was located within the F7 gene. Additional signals were observed in MAP3K13, ZNF320, ATP9B and TREM1. Conditional regression analyses suggested that the SNPs contributed to variation in protein concentration independent of AD status. The identification of two putatively novel AD loci (in the Factor VII and ATP9B genes), which have not been located in previous studies despite massive sample sizes, highlights the benefits of an endophenotypic approach for resolving the genetic basis for complex diseases. The coincidence of several of the endophenotypic signals with known AD loci may point to novel genetic interactions and should be further investigated.

PMID: 26625115 [PubMed - indexed for MEDLINE]

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