Recent Research Articles from UNTHSC

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Efficacy and safety of crofelemer for noninfectious diarrhea in HIV-seropositive individuals (ADVENT trial): a randomized, double-blind, placebo-controlled, two-stage study.

Tue, 02/04/2014 - 5:21am
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Efficacy and safety of crofelemer for noninfectious diarrhea in HIV-seropositive individuals (ADVENT trial): a randomized, double-blind, placebo-controlled, two-stage study.

HIV Clin Trials. 2013 Nov-Dec;14(6):261-73

Authors: Macarthur RD, Hawkins TN, Brown SJ, Lamarca A, Clay PG, Barrett AC, Bortey E, Paterson C, Golden PL, Forbes WP

Abstract
BACKGROUND: HIV-associated diarrhea remains a significant concern with limited treatment options.
OBJECTIVE: To determine the optimal dose, efficacy, and safety of crofelemer for noninfectious diarrhea.
METHODS: This randomized, double-blind, phase 3 trial used a 2-stage design. Both stages included 2-week screening, 4-week placebo-controlled treatment, and 20-week placebo-free (open-label) extension phases. In stage I, 196 HIV-seropositive patients with chronic diarrhea were randomized to crofelemer 125 mg, 250 mg, or 500 mg or placebo twice daily. Using a prospective analysis, the 125-mg twice-daily dose was selected for stage II. In stage II, 180 new patients were randomized to crofelemer 125 mg twice daily or placebo for 4 weeks. Primary efficacy analysis was the percentage of patients (stages I/II combined) who achieved clinical response (defined as ≤2 watery stools/week during ≥2 of 4 weeks). During the placebo-free extension phase, response (≤2 watery stools) was assessed weekly.
RESULTS: Significantly more patients receiving crofelemer 125 mg achieved clinical response versus placebo (17.6% vs 8.0%; one-sided, P = .01). Crofelemer 125 mg resulted in a greater change from baseline in number of daily watery bowel movements (P = .04) and daily stool consistency score (P = .02) versus placebo. During the placebo-free extension phase, percentages of weekly responders ranged from 40% to 56% at weeks 11 to 24. Crofelemer was minimally absorbed, well tolerated, did not negatively impact clinical immune parameters, and had a safety profile comparable to placebo.
CONCLUSIONS: In HIV-seropositive patients taking stable antiretroviral therapy, crofelemer provided significant improvement in diarrhea with a favorable safety profile.

PMID: 24334179 [PubMed - indexed for MEDLINE]

Long lived BSA Au clusters as a time gated intensity imaging probe.

Fri, 01/31/2014 - 11:32am

Long lived BSA Au clusters as a time gated intensity imaging probe.

Nanoscale. 2014 Jan 27;

Authors: Raut SL, Fudala R, Rich R, Kokate RA, Chib R, Gryczynski Z, Gryczynski I

Abstract
The work presented here reports the use of long lifetime (>1 μs) BSA Au clusters as a cellular/tissue, time gated, intensity imaging probe. By collecting the emission signal 50 ns post excitation, one can off-gate the intense auto-fluorescence background, thereby greatly enhancing the clarity/specificity in fluorescence imaging.

PMID: 24469148 [PubMed - as supplied by publisher]

Osteopathic manual treatment in patients with diabetes mellitus and comorbid chronic low back pain: subgroup results from the OSTEOPATHIC Trial.

Fri, 01/31/2014 - 11:32am
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Osteopathic manual treatment in patients with diabetes mellitus and comorbid chronic low back pain: subgroup results from the OSTEOPATHIC Trial.

J Am Osteopath Assoc. 2013 Jun;113(6):468-78

Authors: Licciardone JC, Kearns CM, Hodge LM, Minotti DE

Abstract
CONTEXT: Chronic pain is often present in patients with diabetes mellitus.
OBJECTIVE: To assess the effects of osteopathic manual treatment (OMT) in patients with diabetes mellitus and comorbid chronic low back pain (LBP).
DESIGN: Randomized, double-blind, sham-controlled, 2×2 factorial trial, including OMT and ultrasound therapy (UST) interventions.
SETTING: University-based study in Dallas-Fort Worth, Texas.
PATIENTS: A subgroup of 34 patients (7%) with diabetes mellitus within 455 adult patients with nonspecific chronic LBP enrolled in the OSTEOPAThic Health outcomes In Chronic low back pain (OSTEOPATHIC) Trial.
MAIN STUDY MEASURES: The Outpatient Osteopathic SOAP Note Form was used to measure somatic dysfunction at baseline. A 100-mm visual analog scale was used to measure LBP severity over 12 weeks from randomization to study exit. Paired serum concentrations of tumor-necrosis factor (TNF)-α obtained at baseline and study exit were available for 6 subgroup patients.
RESULTS: Key osteopathic lesions were observed in 27 patients (79%) with diabetes mellitus vs 243 patients (58%) without diabetes mellitus (P=.01). The reduction in LBP severity over 12 weeks was significantly greater in 19 patients with diabetes mellitus who received OMT than in 15 patients with diabetes mellitus who received sham OMT (mean between-group difference in changes in the visual analog scale pain score, -17 mm; 95% confidence interval [CI], -32 mm to -1 mm; P=.04). This difference was clinically relevant (Cohen d=0.7). A corresponding significantly greater reduction in TNF-α serum concentration was noted in patients with diabetes mellitus who received OMT, compared with those who received sham OMT (mean between-group difference, -6.6 pg/mL; 95% CI, -12.4 to -0.8 pg/mL; P=.03). This reduction was also clinically relevant (Cohen d=2.7). No significant changes in LBP severity or TNF-α serum concentration were associated with UST during the 12-week period.
CONCLUSION: Severe somatic dysfunction was present significantly more often in patients with diabetes mellitus than in patients without diabetes mellitus. Patients with diabetes mellitus who received OMT had significant reductions in LBP severity during the 12-week period. Decreased circulating levels of TNF-α may represent a possible mechanism for OMT effects in patients with diabetes mellitus. A larger clinical trial of patients with diabetes mellitus and comorbid chronic LBP is warranted to more definitively assess the efficacy and mechanisms of action of OMT in this population.

PMID: 23739758 [PubMed - indexed for MEDLINE]

Blood pressure regulation XI: overview and future research directions.

Wed, 01/29/2014 - 4:41am

Blood pressure regulation XI: overview and future research directions.

Eur J Appl Physiol. 2014 Jan 28;

Authors: Raven PB, Chapleau MW

Abstract
While the importance of regulating arterial blood pressure within a 'normal' range is widely appreciated, the definition of 'normal' and the means by which humans and other species regulate blood pressure under various conditions remain hotly debated. The effects of diverse physiological, pathological and environmental challenges on blood pressure and the mechanisms that attempt to maintain it at an optimal level are reviewed and critically analyzed in a series of articles published in this themed issue of the European Journal of Applied Physiology. We summarize here the major points made in these reviews, with emphasis on unifying concepts of regulatory mechanisms and future directions for research.

PMID: 24463603 [PubMed - as supplied by publisher]

Simultaneous quantification of mitochondrial DNA copy number and deletion ratio: A multiplex real-time PCR assay.

Wed, 01/29/2014 - 4:41am

Simultaneous quantification of mitochondrial DNA copy number and deletion ratio: A multiplex real-time PCR assay.

Sci Rep. 2014;4:3887

Authors: Phillips NR, Sprouse ML, Roby RK

Abstract
Mitochondrial dysfunction is implicated in a vast array of diseases and conditions, such as Alzheimer's disease, cancer, and aging. Alterations in mitochondrial DNA (mtDNA) may provide insight into the processes that either initiate or propagate this dysfunction. Here, we describe a unique multiplex assay which simultaneously provides assessments of mtDNA copy number and the proportion of genomes with common large deletions by targeting two mitochondrial sites and one nuclear locus. This probe-based, single-tube multiplex provides high specificity while eliminating well-to-well variability that results from assaying nuclear and mitochondrial targets individually.

PMID: 24463429 [PubMed - in process]

Pre-Clinical Evaluation of rHDL Encapsulated Retinoids for the Treatment of Neuroblastoma.

Tue, 01/28/2014 - 5:20am

Pre-Clinical Evaluation of rHDL Encapsulated Retinoids for the Treatment of Neuroblastoma.

Front Pediatr. 2013 Mar 21;1:6

Authors: Sabnis N, Pratap S, Akopova I, Bowman PW, Lacko AG

Abstract
Despite major advances in pediatric cancer research, there has been only modest progress in the survival of children with high risk neuroblastoma (NB) (HRNB). The long term survival rates of HRNB in the United States are still only 30-50%. Due to resistance that often develops during therapy, development of new effective strategies is essential to improve the survival and overcome the tendency of HRNB patients to relapse subsequent to initial treatment. Current chemotherapy regimens also have a serious limitation due to off target toxicity. In the present work, we evaluated the potential application of reconstituted high density lipoprotein (rHDL) containing fenretinide (FR) nanoparticles as a novel approach to current NB therapeutics. The characterization and stability studies of rHDL-FR nanoparticles showed small size (<40 nm) and high encapsulation efficiency. The cytotoxicity studies of free FR vs. rHDL/FR toward the NB cell lines SK-N-SH and SMS-KCNR showed 2.8- and 2-fold lower IC50 values for the rHDL encapsulated FR vs. free FR. More importantly, the IC50 value for retinal pigment epithelial cells (ARPE-19), a recipient of off target toxicity during FR therapy, was over 40 times higher for the rHDL/FR as compared to that of free FR. The overall improvement in in vitro selective therapeutic efficiency was thus about 100-fold upon encapsulation of the drug into the rHDL nanoparticles. These studies support the potential value of this novel drug delivery platform for treating pediatric cancers in general, and NB in particular.

PMID: 24459664 [PubMed]

Telehealth Personalized Cancer Risk Communication to Motivate Colonoscopy in Relatives of Patients With Colorectal Cancer: The Family CARE Randomized Controlled Trial.

Sat, 01/25/2014 - 5:31am

Telehealth Personalized Cancer Risk Communication to Motivate Colonoscopy in Relatives of Patients With Colorectal Cancer: The Family CARE Randomized Controlled Trial.

J Clin Oncol. 2014 Jan 21;

Authors: Kinney AY, Boonyasiriwat W, Walters ST, Pappas LM, Stroup AM, Schwartz MD, Edwards SL, Rogers A, Kohlmann WK, Boucher KM, Vernon SW, Simmons RG, Lowery JT, Flores K, Wiggins CL, Hill DA, Burt RW, Williams MS, Higginbotham JC

Abstract
PURPOSE: The rate of adherence to regular colonoscopy screening in individuals at increased familial risk of colorectal cancer (CRC) is suboptimal, especially among rural and other geographically underserved populations. Remote interventions may overcome geographic and system-level barriers. We compared the efficacy of a telehealth-based personalized risk assessment and communication intervention with a mailed educational brochure for improving colonoscopy screening among at-risk relatives of patients with CRC.
METHODS: Eligible individuals age 30 to 74 years who were not up-to-date with risk-appropriate screening and were not candidates for genetic testing were recruited after contacting patients with CRC or their next of kin in five states. Enrollees were randomly assigned as family units to either an active, personalized intervention that incorporated evidence-based risk communication and behavior change techniques, or a mailed educational brochure. The primary outcome was medically verified colonoscopy within 9 months of the intervention.
RESULTS: Of the 481 eligible and randomly assigned at-risk relatives, 79.8% completed the outcome assessments within 9 months; 35.4% of those in the personalized intervention group and 15.7% of those in the comparison group obtained a colonoscopy. In an intent-to-treat analysis, the telehealth group was almost three times as likely to get screened as the low-intensity comparison group (odds ratio, 2.83; 95% CI, 1.87 to 4.28; P < .001). Persons residing in rural areas and those with lower incomes benefitted at the same level as did urban residents.
CONCLUSION: Remote personalized interventions that consider family history and incorporate evidence-based risk communication and behavior change strategies may promote risk-appropriate screening in close relatives of patients with CRC.

PMID: 24449229 [PubMed - as supplied by publisher]

Metabolic Dysfunction of Astrocyte: An Initiating Factor in Beta-amyloid Pathology?

Thu, 01/23/2014 - 7:18am

Metabolic Dysfunction of Astrocyte: An Initiating Factor in Beta-amyloid Pathology?

Aging Neurodegener. 2013 Aug;1(1):7-14

Authors: Yan LJ, Xiao M, Chen R, Cai Z

Abstract
Astrocytes, the most important energy regulator in the brain, support brain energy needs. In the meantime, numerous studies have demonstrated that impaired brain glucose metabolism is closely linked to abnormal astrocytic metabolism in AD. Indeed, the interaction between amyloid plaques and perturbed astrocytic homeostasis contributes to AD pathogenesis and astrocytic metabolic dysfunction is thought to be a trigger for Aβ pathology through oxidative stress and neuroinflammation Moreover, astrocytic metabolic dysfunction may regulate Aβ generation via modulating proteolytic processing of amyloid precursor protein (APP) by β-secretase, γ-secretase, and α-secretase, and may also modulate APP post-translational modifications such as glycosylation, phosphorylation, and tyrosine sulfation. While it is known that metabolic dysfunction of astrocytes contributes to the failure of Aβ clearance, it has also been reported that such dysfunction has neuroprotective property and exhibits no detrimental outcomes. Therefore, the exact role of astrocytic metabolic dysfunction in Aβ pathology remains to be further investigated.

PMID: 24443714 [PubMed - as supplied by publisher]

Involvement of p38 Mapk in reactive astrogliosis induced by ischemic stroke.

Thu, 01/23/2014 - 7:18am

Involvement of p38 Mapk in reactive astrogliosis induced by ischemic stroke.

Brain Res. 2014 Jan 16;

Authors: Choudhury GR, Ryou MG, Poteet E, Wen Y, He R, Sun F, Yuan F, Jin K, Yang SH

Abstract
Reactive astrogliosis is an essential feature of astrocytic response to all forms of central nervous system (CNS) injury and disease, which may benefit or harm surrounding neural and non-neural cells. Despite extensive study, its molecular triggers remain largely unknown in term of ischemic stroke. In the current study we investigated the role p38 mitogen-activated protein kinase (MAPK) in astrogliosis both in vitro and in vivo. In a mouse model of middle cerebral artery occlusion (MCAO), p38 MAPK activation was observed in the glia scar area, along with increased glial fibrillary acidic protein (GFAP) expression. In primary astrocyte cultures, hypoxia and scratch injury-induced astrogliosis was attenuated by both p38 inhibition and knockout of p38 MAPK. In addition, both knockout and inhibition of p38 MAPK also reduced astrocyte migration, but did not affect astrocyte proliferation. In a mouse model of permanent MCAO, no significant difference in motor function recovery and lesion volume was observed between conditional GFAP/p38 MAPK knockout mice and littermates. While a significant reduction of astrogliosis was observed in the GFAP/p38 knockout mice compared with the littermates. Our findings suggest that p38 MAPK signaling pathway plays an important role in the ischemic stroke-induced astrogliosis and thus may serve as a novel target to control glial scar formation.

PMID: 24440774 [PubMed - as supplied by publisher]

An unlikely marriage: life as a wrist surgeon and career officer in the u.s. Navy.

Tue, 01/21/2014 - 5:20am

An unlikely marriage: life as a wrist surgeon and career officer in the u.s. Navy.

J Wrist Surg. 2013 Nov;2(4):288-93

Authors: Lichtman DM

PMID: 24436831 [PubMed]

Association between Helicobacter pylori and Barrett's Esophagus: A Case-Control Study.

Sat, 01/18/2014 - 5:30am
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Association between Helicobacter pylori and Barrett's Esophagus: A Case-Control Study.

Am J Gastroenterol. 2014 Jan 14;ajg

Authors: Fischbach LA, Graham DY, Kramer JR, Rugge M, Verstovsek G, Parente P, Alsarraj A, Fitzgerald S, Shaib Y, Abraham NS, Kolpachi A, Gupta S, Vela MF, Velez M, Cole R, Anand B, El Serag HB

Abstract
OBJECTIVES:The estimated association between Helicobacter pylori and Barrett's esophagus (BE) has been heterogenous across previous studies. In this study, we aimed to examine the association between H. pylori and BE and to identify factors that may explain or modify this association.METHODS:We conducted a case-control study in which we used screening colonoscopy controls recruited from primary care clinics as our primary control group in order to minimize selection bias. All participants underwent an esophagogastroduodenoscopy with gastric mapping biopsies. We used logistic regression to obtain odds ratios (ORs) and 95% confidence intervals (CIs) to estimate the association between H. pylori and BE while controlling for confounders.RESULTS:We identified 218 cases and 439 controls. The overall OR for the association between H. pylori and BE after controlling for age and white race was 0.55 (95% CI: 0.35-0.84). We observed an even stronger inverse association (OR: 0.28; 95% CI: 0.15, 0.50) among participants with corpus atrophy or antisecretory drug use ≥1 time per week (factors thought to lower gastric acidity), and no inverse association in patients without these factors (OR: 1.32; 95% CI: 0.66, 2.63).CONCLUSIONS:The association between H. pylori and a decreased risk for BE appears to occur in patients with factors that would likely lower gastric acidity (corpus atrophy or taking antisecretory drugs at least once a week).Am J Gastroenterol advance online publication, 14 January 2014; doi:10.1038/ajg.2013.443.

PMID: 24419485 [PubMed - as supplied by publisher]

An Optimal Test for Variance Components of Multivariate Mixed-Effects Linear Models.

Sat, 01/18/2014 - 5:30am
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An Optimal Test for Variance Components of Multivariate Mixed-Effects Linear Models.

J Multivar Anal. 2014 Feb;124

Authors: Aryal S, Bhaumik DK, Mathew T, Gibbons RD

Abstract
In this article we derive an optimal test for testing the significance of covariance matrices of random-effects of two multivariate mixed-effects linear models. We compute the power of this newly derived test via simulation for various alternative hypotheses in a bivariate set up for unbalanced designs and observe that power responds sharply when sample size and alternative hypotheses are changed. For some balanced designs we compare power of the optimal test to that of the likelihood ratio test via simulation, and find that the proposed test has greater power than the likelihood ratio test. The results are illustrated using real data on human growth. Other relevant applications of the model are highlighted.

PMID: 24415807 [PubMed - as supplied by publisher]

Pyruvate-enriched resuscitation: metabolic support of post-ischemic hindlimb muscle in hypovolemic goats.

Sat, 01/18/2014 - 5:30am
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Pyruvate-enriched resuscitation: metabolic support of post-ischemic hindlimb muscle in hypovolemic goats.

Exp Biol Med (Maywood). 2014 Jan 10;

Authors: Gurji HA, White DW, Hoxha B, Sun J, Harbor JP, Schulz DR, Williams AG, Olivencia-Yurvati AH, Mallet RT

Abstract
Tourniquet-imposed ischemia-reperfusion of extremities generates reactive oxygen and nitrogen species (RONS), which can disrupt intermediary metabolism and ATP production. This study tested the hypothesis that fluid resuscitation with pyruvate, a natural antioxidant and metabolic fuel, ameliorates the deleterious effects of ischemia-reperfusion on intermediary metabolism in skeletal muscle. Anesthetized male goats (∼25 kg) were bled to a mean arterial pressure of 48 ± 1 mmHg and then subjected to 90 min hindlimb ischemia with a tourniquet and femoral crossclamp, followed by 4-h reperfusion. Lactated Ringers (LR) or pyruvate Ringers (PR) was infused intravenous for 90 min, from 30 min ischemia to 30 min reperfusion, to deliver 0.05 mmol kg(-1) min(-1) lactate or pyruvate. Time controls (TC) underwent neither hemorrhage nor hindlimb ischemia. Lipid peroxidation product 8-isoprostane, RONS-sensitive aconitase and creatine kinase activities, antioxidant superoxide dismutase activity, and phosphocreatine phosphorylation potential ([PCr]/[{Cr}{Pi}]), an index of tissue energy state, were measured in reperfused gastrocnemius at 90 min resuscitation (n = 6 all groups) and 3.5 h post-resuscitation (n = 8 TC, 9 LR, 10 PR). PR more effectively than LR suppressed 8-isoprostane formation, prevented inactivation of aconitase and creatine kinase, doubled superoxide dismutase activity, and augmented [PCr]/([Cr][Pi]). Pyruvate-enriched Ringer's is metabolically superior to Ringer's lactate for fluid resuscitation of tourniqueted muscle.

PMID: 24414481 [PubMed - as supplied by publisher]

U.S. Population Estimates and Correlates of Sexual Abuse of Community-Dwelling Older Adults.

Sat, 01/18/2014 - 5:30am
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U.S. Population Estimates and Correlates of Sexual Abuse of Community-Dwelling Older Adults.

J Elder Abuse Negl. 2014 Jan 10;

Authors: Cannell MB, Manini T, Spence-Almaguer E, Maldonado-Molina M, Andresen EM

Abstract
Abstract We describe the annual prevalence of sexual abuse among community dwelling older adults in the United States. We also describe factors associated with experiencing sexual abuse. We used data from 24,343 older adults from the 2005 Behavioral Risk Factor Surveillance System pooled across 18 states. We estimated prevalence of sexual abuse, bivariate distributions, and odds ratio associations across demographic, health, and contextual factors. Our results show that 0.9% of older adults reported experiencing sexual abuse in the previous year. This represents approximately 90,289 community dwelling older adults. We also report on factors associated with experiencing recent sexual abuse. There was a significant gender-by-binge drinking interaction, with a stronger association among women. There is a need for health promotion efforts targeted specifically towards older adults, encouraging them to seek services, if possible, after exposure to sexual abuse.

PMID: 24410194 [PubMed - as supplied by publisher]

Estrogen receptors and ischemic neuroprotection: who, what, where, and when?

Wed, 01/15/2014 - 9:41am
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Estrogen receptors and ischemic neuroprotection: who, what, where, and when?

Brain Res. 2013 Jun 13;1514:107-22

Authors: Schreihofer DA, Ma Y

Abstract
Estrogens, particularly 17β-estradiol (E2), are powerful neuroprotective agents in animal models of cerebral ischemia. Loss of endogenous E2 in women at menopause or after surgical oopherectomy leads to an increase risk of stroke, neurodegenerative disease, and cognitive decline. However, several clinical trials found detrimental effects of E2 therapy after menopause, including increased stroke risk and dementia. Recent animal and human studies now support the "critical period" hypothesis for E2 neuroprotection whereby E2 therapy must begin soon after the loss of endogenous E2 production to have a beneficial effect. Although a wide array of mechanisms has been proposed for estradiol (E2)-dependent neuroprotection in cerebral ischemia and neurodegenerative disease, most of these mechanisms involve interactions of E2 with one of its cognate receptors, estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), or the G protein-coupled estrogen receptor (GPER). However, these receptors are not uniformly distributed throughout the brain, across different cell types, and within cellular compartments. Such differences likely play a role in the ability of E2 and ER selective ligands to protect the brain from ischemia. This review examines the changes in ER expression and location that may underlie the loss of E2 neuroprotection seen with aging and long-term estrogen deprivation (LTED). Recent results suggest that the loss of ERα that accompanies aging and LTED plays an important role in the loss of E2-dependent neuroprotection. This article is part of a Special Issue entitled Hormone Therapy.

PMID: 23500634 [PubMed - indexed for MEDLINE]

Does phytoestrogen supplementation affect cognition differentially in males and females?

Wed, 01/15/2014 - 9:41am
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Does phytoestrogen supplementation affect cognition differentially in males and females?

Brain Res. 2013 Jun 13;1514:123-7

Authors: Sumien N, Chaudhari K, Sidhu A, Forster MJ

Abstract
Phytoestrogens are plant-derived compounds found mainly in soy with known estrogenic properties and a potential for benefits to human health. Increased intake in phytoestrogens stemmed from the search for safe alternatives to hormone replacement therapies. Based on epidemiologic evidence comparing Western and Asian populations and clinical studies, phytoestrogens show promise to improve health and brain function. This review is focused on the effects of phytoestrogens on cognition by examining clinical and animal studies, with special attention placed on (1) a window of therapeutic opportunity which may explain the discrepancy among studies, and (2) whether a sex/gender difference exists in response to phytoestrogen intake and what the possible underlying mechanisms may be.

PMID: 23415935 [PubMed - indexed for MEDLINE]

Progesterone-induced neuroprotection: factors that may predict therapeutic efficacy.

Wed, 01/15/2014 - 9:41am
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Progesterone-induced neuroprotection: factors that may predict therapeutic efficacy.

Brain Res. 2013 Jun 13;1514:98-106

Authors: Singh M, Su C

Abstract
Both progesterone and estradiol have well-described neuroprotective effects against numerous insults in a variety of cell culture models, animal models and in humans. However, the efficacy of these hormones may depend on a variety of factors, including the type of hormone used (ex. progesterone versus medroxyprogesterone acetate), the duration of the postmenopausal period prior to initiating the hormone intervention, and potentially, the age of the subject. The latter two factors relate to the proposed existence of a "window of therapeutic opportunity" for steroid hormones in the brain. While such a window of opportunity has been described for estrogen, there is a paucity of information to address whether such a window of opportunity exists for progesterone and its related progestins. Here, we review known cellular mechanisms likely to underlie the protective effects of progesterone and furthermore, describe key differences in the neurobiology of progesterone and the synthetic progestin, medroxyprogesterone acetate (MPA). Based on the latter, we offer a model that defines some of the key cellular and molecular players that predict the neuroprotective efficacy of progesterone. Accordingly, we suggest how changes in the expression or function of these cellular and molecular targets of progesterone with age or prolonged duration of hormone withdrawal (such as following surgical or natural menopause) may impact the efficacy of progesterone. This article is part of a Special Issue entitled Hormone Therapy.

PMID: 23340161 [PubMed - indexed for MEDLINE]

Window of opportunity: estrogen as a treatment for ischemic stroke.

Wed, 01/15/2014 - 9:41am
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Window of opportunity: estrogen as a treatment for ischemic stroke.

Brain Res. 2013 Jun 13;1514:83-90

Authors: Liu R, Yang SH

Abstract
The neuroprotection research in the last 2 decades has witnessed a growing interest in the functions of estrogens as neuroprotectants against neurodegenerative diseases including stroke. The neuroprotective action of estrogens has been well demonstrated in both in vitro and in vivo models of ischemic stroke. However, the major conducted clinical trials so far have raised concern for the protective effect of estrogen replacement therapy in postmenopausal women. The discrepancy could be partly due to the mistranslation between the experimental stroke research and clinical trials. While predominant experimental studies tested the protective action of estrogens on ischemic stroke using acute treatment paradigm, the clinical trials have mainly focused on the effect of estrogen replacement therapy on the primary and secondary stroke prevention which has not been adequately addressed in the experimental stroke study. Although the major conducted clinical trials have indicated that estrogen replacement therapy has an adverse effect and raise concern for long term estrogen replacement therapy for stroke prevention, these are not appropriate for assessing the potential effects of acute estrogen treatment on stroke protection. The well established action of estrogen in the neurovascular unit and its potential interaction with recombinant tissue Plasminogen Activator (rtPA) makes it a candidate for the combined therapy with rtPA for the acute treatment of ischemic stroke. On the other hand, the "critical period" and newly emerged "biomarkers window" hypotheses have indicated that many clinical relevant factors have been underestimated in the experimental ischemic stroke research. The development and application of ischemic stroke models that replicate the clinical condition is essential for further evaluation of acute estrogen treatment on ischemic stroke which might provide critical information for future clinical trials. This article is part of a Special Issue entitled Hormone Therapy.

PMID: 23340160 [PubMed - indexed for MEDLINE]

Window of opportunity for estrogen and progestin intervention in brain aging and Alzheimer's disease.

Wed, 01/15/2014 - 9:41am
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Window of opportunity for estrogen and progestin intervention in brain aging and Alzheimer's disease.

Brain Res. 2013 Jun 13;1514:1-2

Authors: Singh M, Simpkins JW, Simpkins JW, Bimonte-Nelson HA, Bimonte-Nelson HA, Brinton RD, Brinton RD

PMID: 23726132 [PubMed - indexed for MEDLINE]

Therapeutic strategies in Friedreich's ataxia.

Wed, 01/15/2014 - 9:41am
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Therapeutic strategies in Friedreich's ataxia.

Brain Res. 2013 Jun 13;1514:91-7

Authors: Richardson TE, Kelly HN, Yu AE, Simpkins JW

Abstract
First established as a diagnosis by Nikolaus Friedreich in 1863, Friedreich's ataxia (FA) is an autosomal recessive progressive neurodegenerative disorder cause by a trinucleotide repeat expansion. FA begins with the functional absence of the FXN gene product frataxin, a protein whose exact function still remains unknown. This absence results in impaired intracellular antioxidant defenses, dysregulation of iron-sulfur cluster proteins, depression of aerobic electron transport chain respiration, massive mitochondrial dysfunction, and ultimately cell death in the brain, spinal cord and heart. Herein, we review the molecular and cellular pathogenesis leading to widespread organ system dysfunction, as well as current therapeutic research aimed at preventing the debilitating effects of frataxin loss and preventing the signs and symptoms associated of FA. We also discuss the ongoing treatment strategies employed by our laboratory to prevent mitochondrial damage using synergistic effects of 17β-estradiol and methylene blue, previously shown by our group and others to have protective effects in human FA fibroblasts. This article is part of a Special Issue entitled Hormone Therapy.

PMID: 23587934 [PubMed - indexed for MEDLINE]