Recent Research Articles from UNTHSC

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Pharmacological Modulation of Abnormal Involuntary DOI-Induced Head Twitch Response in Male DBA/2J Mice: I. Effects of D2/D3 and D2 Dopamine Receptor Selective Compounds.

Fri, 04/04/2014 - 3:37am

Pharmacological Modulation of Abnormal Involuntary DOI-Induced Head Twitch Response in Male DBA/2J Mice: I. Effects of D2/D3 and D2 Dopamine Receptor Selective Compounds.

Neuropharmacology. 2014 Mar 25;

Authors: Rangel-Barajas C, Malik M, Vangveravong S, Mach RH, Luedtke RR

Abstract
Because of the complexity and heterogeneity of human neuropsychiatric disorders, it has been difficult to identify animal models that mimic the symptoms of these neuropathologies and can be used to screen for antipsychotic agents. For this study we selected the murine 5HT2A/2C receptor agonist-induced head twitch response (HTR) induced by the administration of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), which has been proposed as an animal model of symptoms associated with a variety of behavioral and psychiatric conditions. We investigated the DOI-induced HTR in male DBA/2J mice using a panel of D2-like (D2, D3 and D4) and D2 dopamine receptor selective compounds. When DBA/2J mice were administered a daily dose of DOI (5 mg/kg), tolerance to the DOI occurs. However, administrations of the same dose of DOI every other day (48 hrs.) or on a weekly basis did not lead to tolerance and the ability to induce tolerance after daily administration of DOI remains intact after repeated weekly administration of DOI. Subsequently, a panel of D2-like dopamine receptor antagonists was found to effectively inhibit the DOI-induced HTR in DBA/2J mice. However, the benzamide eticlopride, which is a high affinity D2-like antagonist, was a notable exception. SV 293, SV-III-130s and N-methylbenperidol, which exhibit a high affinity for D2 versus the D3 dopamine receptor subtypes (60- to 100-fold binding selectivity), were also found to inhibit the HTR in DBA/2J mice. This observation suggests a functional interaction between dopaminergic and serotonergic systems through D2 dopamine receptors and the 5-HT2A serotonin receptors in vivo.

PMID: 24680675 [PubMed - as supplied by publisher]

The novel histone deacetylase inhibitor thailandepsin A inhibits anaplastic thyroid cancer growth.

Fri, 04/04/2014 - 3:37am

The novel histone deacetylase inhibitor thailandepsin A inhibits anaplastic thyroid cancer growth.

J Surg Res. 2014 Feb 28;

Authors: Weinlander E, Somnay Y, Harrison AD, Wang C, Cheng YQ, Jaskula-Sztul R, Yu XM, Chen H

Abstract
BACKGROUND: Anaplastic thyroid cancer (ATC) remains refractory to available surgical and medical interventions. Histone deacetylase (HDAC) inhibitors are an emerging targeted therapy with antiproliferative activity in a variety of thyroid cancer cell lines. Thailandepsin A (TDP-A) is a novel class I HDAC inhibitor whose efficacy remains largely unknown in ATC. Therefore, we aimed to characterize the effect of TDP-A on ATC.
METHODS: Human-derived ATC cells were treated with TDP-A. IC50 was determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) rapid colorimetric assay, and cell proliferation was measured by viable cell count. Molecular mechanisms of cell growth inhibition were investigated by Western blot analysis of canonical apoptosis markers, intrinsic and extrinsic apoptosis regulators, and cell cycle regulatory proteins. Cell cycle staging was determined with propidium iodide flow cytometry.
RESULTS: TDP-A dose- and time-dependently reduced cell proliferation. Increased cleavage of the apoptosis markers Caspase-9, Caspase-3, and poly adenosine diphosphate ribose polymerase were observed with TDP-A treatment. Levels of the intrinsic apoptosis pathway proteins BAD, Bcl-XL, and BAX remained unchanged. Importantly, the extrinsic apoptosis activator cleaved Caspase-8 increased dose-dependently, and the antiapoptotic proteins Survivin and Bcl-2 decreased. Among the cell cycle regulatory proteins, levels of CDK inhibitors p21/WAF1 and p27/KIP increased. Flow cytometry showed that ATC cells were arrested in G2/M phase with diminished S phase after TDP-A treatment.
CONCLUSIONS: TDP-A induces a notable dose- and time-dependent antiproliferative effect on ATC, which is mainly attributed to extrinsic apoptosis with concomitant cell cycle arrest. TDP-A therefore warrants further preclinical and clinical investigations.

PMID: 24679699 [PubMed - as supplied by publisher]

Effective removal of co-purified inhibitors from extracted DNA samples using synchronous coefficient of drag alteration (SCODA) technology.

Tue, 04/01/2014 - 4:40am
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Effective removal of co-purified inhibitors from extracted DNA samples using synchronous coefficient of drag alteration (SCODA) technology.

Int J Legal Med. 2013 Jul;127(4):749-55

Authors: Schmedes S, Marshall P, King JL, Budowle B

Abstract
Various types of biological samples present challenges for extraction of DNA suitable for subsequent molecular analyses. Commonly used extraction methods, such as silica membrane columns and phenol-chloroform, while highly successful may still fail to provide a sufficiently pure DNA extract with some samples. Synchronous coefficient of drag alteration (SCODA), implemented in Boreal Genomics' Aurora Nucleic Acid Extraction System (Boreal Genomics, Vancouver, BC), is a new technology that offers the potential to remove inhibitors effectively while simultaneously concentrating DNA. In this initial study, SCODA was tested for its ability to remove various concentrations of forensically and medically relevant polymerase chain reaction (PCR) inhibitors naturally found in tissue, hair, blood, plant, and soil samples. SCODA was used to purify and concentrate DNA from intentionally contaminated DNA samples containing known concentrations of hematin, humic acid, melanin, and tannic acid. The internal positive control (IPC) provided in the Quantifiler™ Human DNA Quantification Kit (Life Technologies, Foster City, CA) and short tandem repeat (STR) profiling (AmpFℓSTR® Identifiler® Plus PCR Amplification Kit; Life Technologies, Foster City, CA) were used to measure inhibition effects and hence purification. SCODA methodology yielded overall higher efficiency of purification of highly contaminated samples compared with the QIAquick® PCR Purification Kit (Qiagen, Valencia, CA). SCODA-purified DNA yielded no cycle shift of the IPC for each sample and yielded greater allele percentage recovery and relative fluorescence unit values compared with the QIAquick® purification method. The Aurora provided an automated, minimal-step approach to successfully remove inhibitors and concentrate DNA from challenged samples.

PMID: 23254459 [PubMed - indexed for MEDLINE]

Associations between bar patron alcohol intoxication and tobacco smoking.

Tue, 04/01/2014 - 4:40am
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Associations between bar patron alcohol intoxication and tobacco smoking.

Am J Health Behav. 2013 Nov;37(6):794-9

Authors: Rossheim ME, Thombs DL, O'Mara RJ, Bastian N, Suzuki S

Abstract
OBJECTIVE: To examine the event-specific relationship between alcohol intoxication and nighttime tobacco smoking among college bar patrons.
METHODS: In this secondary analysis of existing data, we examined event-specific associations between self-report measures of tobacco smoking and breath alcohol concentration (BrAC) readings obtained from 424 patrons exiting on-premise drinking establishments.
RESULTS: In a multivariable logistic regression analysis, acute alcohol intoxication was positively associated with same-night incidents of smoking tobacco, adjusting for the effects of established smoking practices and other potential confounders.
CONCLUSIONS: This investigation is the first known study using data collected in an on-premise drinking setting to link alcohol intoxication to specific incidents of tobacco smoking.

PMID: 24001628 [PubMed - indexed for MEDLINE]

Modulation of the Rate of Retinal Degeneration in T17M RHO Mice by Reprogramming the Unfolded Protein Response.

Sat, 03/29/2014 - 4:36am

Modulation of the Rate of Retinal Degeneration in T17M RHO Mice by Reprogramming the Unfolded Protein Response.

Adv Exp Med Biol. 2014;801:455-62

Authors: Choudhury S, Nashine S, Bhootada Y, Kunte MM, Gorbatyuk O, Lewin AS, Gorbatyuk M

Abstract
The goal of this study is to validate whether reprogramming of the UPR via modulation of pro-apoptotic caspase-7 and CHOP proteins could be an effective approach to slow down the rate of retinal degeneration in ADRP mice. In order to pursue our goal we created the T17M RHO CASP7 and T17M RHO CHOP mice to study the impact of the CASP7 or CHOP ablations in T17M RHO retina by ERG, SD-OCT, histology and western blot analysis. The scotopic ERG demonstrated that the ablation of the CASP7 in T17M RHO retina leads to significant preservation of the function of photoreceptors compared to control. Surprisingly, the ablation of pro-apoptotic CHOP protein in T17M RHO mice led to a more severe form of retinal degeneration. Results of the SD-OCT and histology were in agreement with the ERG data. The further analysis demonstrated that the preservation of the structure and function or the acceleration of the onset of the T17M RHO photoreceptor degeneration occurred via reprogramming of the UPR. In addition, the CASP7 ablation leads to the inhibition of cJUN mediated apoptosis, while the ablation of CHOP induces an increase in the HDAC. Thus, manipulation with the UPR requires careful examination in order to achieve a therapeutic effect.

PMID: 24664731 [PubMed - in process]

Chemokine CXCL8 Promotes HIV-1 Replication in Human Monocyte-Derived Macrophages and Primary Microglia via Nuclear Factor-κB Pathway.

Sat, 03/29/2014 - 4:36am

Chemokine CXCL8 Promotes HIV-1 Replication in Human Monocyte-Derived Macrophages and Primary Microglia via Nuclear Factor-κB Pathway.

PLoS One. 2014;9(3):e92145

Authors: Mamik MK, Ghorpade A

Abstract
BACKGROUND: Chemokine CXCL8 is an important neutrophil chemoattractant implicated in various neurodegenerative disorders. Cytokine/chemokine imbalance, with an increase in proinflammatory cytokines like interleukin-1β and tumor necrosis factor-α within the central nervous system, is a hallmark of human immunodeficiency virus (HIV)-1 infection. We previously reported that HIV-1 infection is linked to upregulation of CXCL8 in brain tissues and human astrocytes. Chemokines play crucial roles in trafficking of leukocytes and trafficking of HIV-1-infected across the blood-brain barrier play an important role in HIV-1 central nervous system disease. In the post-antiretroviral therapy era, low level of productive replication of HIV-1 in brain is a critical component of neuropathogenesis regulation. The present study investigated the effect of CXCL8 on productive infection of HIV-1 in human monocytes-derived macrophages (MDM) and primary human microglia.
RESULTS: Human MDM and microglia were infected with the blood or brain derived HIV-1 isolates, HIV-1ADA or HIV-1JRFL. Treatment with CXCL8 significantly upregulated HIV-1p24 levels in supernatants of both HIV-1-infected MDM as well as microglia. In addition, the formation of 2-long terminal repeat (LTR) circles, a measure of viral genome integration, was significantly higher in CXCL8-treated, HIV-1-infected MDM and microglia. Transient transfection of U937 cells with HIV-1 LTR luciferase reporter construct resulted in increased promoter activity when treated with CXCL8. Moreover, increased nuclear translocation of nuclear factor-κB was seen in HIV-1-infected MDM following CXCL8 treatment. Blocking CXCL8 receptors CXCR1 and CXCR2 abrogated the CXCL8-mediated enhanced HIV-1 replication.
CONCLUSION: Our results show that CXCL8 mediates productive infection of HIV-1 in MDM and microglia via receptors CXCR1 and CXCR2. These results demonstrate that CXCL8 exerts its downstream effects by increasing translocation of nuclear factor-κB into the nucleus, thereby promoting HIV-1 LTR activity.

PMID: 24662979 [PubMed - in process]

Selective chemoprecipitation to enrich nitropeptides from complex proteomes for mass-spectrometric analysis.

Wed, 03/26/2014 - 3:28am

Selective chemoprecipitation to enrich nitropeptides from complex proteomes for mass-spectrometric analysis.

Nat Protoc. 2014 Apr;9(4):882-95

Authors: Prokai L, Guo J, Prokai-Tatrai K

Abstract
Post-translational protein nitration has attracted interest owing to its involvement in cellular signaling, effects on protein function and potential as biomarker of nitroxidative stress. We describe a procedure for enriching nitropeptides for mass spectrometry (MS)-based proteomics that is a simple and reliable alternative to immunoaffinity-based methods. The starting material for this procedure is a proteolytic digest. The peptides are reacted with formaldehyde and sodium cyanoborohydride to dimethylate all the N-terminal and side chain amino groups. Sodium dithionite is added subsequently to reduce the nitro groups to amines; in theory, the only amino groups present will have originally been nitro groups. The peptide sample is then applied to a solid-phase active ester reagent (SPAER), and those peptides with amino groups will be selectively and covalently captured. Release of the peptides on hydrolysis with trifluoroacetic acid (TFA) results in peptides that have a 4-formyl-benzamido group where the nitro group used to be. In qualitative setups, the procedure can be used to identify proteins modified by reactive nitrogen species and to determine the specific sites of their nitration. Quantitative measurements can be performed by stable-isotope labeling of the peptides in the reductive dimethylation step. Preparation of the SPAER takes about 1 d. Enrichment of nitropeptides requires about 2 d, and sample preparations need 1-30 h, depending on the experimental design. LC-MS/MS assays take from 4 h to several days and data processing can be done in 1-7 d.

PMID: 24651500 [PubMed - in process]

Angiotensin II has acute effects on TRPC6 channels in podocytes of freshly isolated glomeruli.

Wed, 03/26/2014 - 3:28am
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Angiotensin II has acute effects on TRPC6 channels in podocytes of freshly isolated glomeruli.

Kidney Int. 2014 Mar 19;

Authors: Ilatovskaya DV, Palygin O, Chubinskiy-Nadezhdin V, Negulyaev YA, Ma R, Birnbaumer L, Staruschenko A

Abstract
A key role for podocytes in the pathogenesis of proteinuric renal diseases has been established. Angiotensin II causes depolarization and increased intracellular calcium concentration in podocytes; members of the cation TRPC channels family, particularly TRPC6, are proposed as proteins responsible for calcium flux. Angiotensin II evokes calcium transient through TRPC channels and mutations in the gene encoding the TRPC6 channel result in the development of focal segmental glomerulosclerosis. Here we examined the effects of angiotensin II on intracellular calcium ion levels and endogenous channels in intact podocytes of freshly isolated decapsulated mouse glomeruli. An ion channel with distinct TRPC6 properties was identified in wild-type, but was absent in TRPC6 knockout mice. Single-channel electrophysiological analysis found that angiotensin II acutely activated native TRPC-like channels in both podocytes of freshly isolated glomeruli and TRPC6 channels transiently overexpressed in CHO cells; the effect was mediated by changes in the channel open probability. Angiotensin II evoked intracellular calcium transients in the wild-type podocytes, which was blunted in TRPC6 knockout glomeruli. Pan-TRPC inhibitors gadolinium and SKF 96365 reduced the response in wild-type glomerular epithelial cells, whereas the transient in TRPC6 knockout animals was not affected. Thus, angiotensin II-dependent activation of TRPC6 channels in podocytes may have a significant role in the development of kidney diseases.Kidney International advance online publication, 19 March 2014; doi:10.1038/ki.2014.71.

PMID: 24646854 [PubMed - as supplied by publisher]

Multiple fruit-flavored alcoholic drinks in a can (MFAC): an overlooked class of potentially harmful alcohol products.

Wed, 03/26/2014 - 3:28am
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Multiple fruit-flavored alcoholic drinks in a can (MFAC): an overlooked class of potentially harmful alcohol products.

Am J Drug Alcohol Abuse. 2013 Sep;39(5):280-3

Authors: Rossheim ME, Thombs DL

Abstract
This article examines an overlooked class of alcohol products, described herein as multiple fruit-flavored alcoholic drinks in a can (MFAC). The article describes how characteristics of these products likely contribute to hazardous alcohol consumption among youth. Government regulation of these products may be needed to protect adolescent and young adult populations. National substance abuse surveillance systems should consider immediate adoption of MFAC use indicators to determine use and harm associated with these products, and to assess the effectiveness of future regulatory actions.

PMID: 23968170 [PubMed - indexed for MEDLINE]

Development of reusable logic for determination of statin exposure-time from electronic health records.

Sat, 03/22/2014 - 4:23am

Development of reusable logic for determination of statin exposure-time from electronic health records.

J Biomed Inform. 2014 Mar 14;

Authors: Miller AW, McCarty CA, Broeckel U, Hytopoulos V, Cross DS

Abstract
OBJECTIVE: We aim to quantify HMG-CoA reductase inhibitor (statin) prescriber-intended exposure-time using a generalizable algorithm that interrogates data stored in the electronic health record (EHR).
MATERIALS AND METHODS: This study was conducted using the Marshfield Clinic (MC) Personalized Medicine Research Project (PMRP) a central Wisconsin-based population and biobank with, on average, 30 years of electronic health data available in the independently-developed MC Cattails MD EHR. Individuals with evidence of statin exposure were identified from the electronic records, and manual chart abstraction of all mentions of prescribed statins was completed. We then performed electronic chart abstraction of prescriber-intended exposure time for statins, using previously identified logic to capture pill-splitting events, normalizing dosages to atorvastatin-equivalent dose. Four models using iterative training sets were tested to capture statin end-dates. Calculated cumulative provider-intended exposures were compared to manually abstracted gold-standard measures of ordered statin prescriptions, and aggregate model results (totals) for training and validation populations were compared. The most successful model was the one with the smallest discordance between modeled and manually abstracted Atorvastatin 10mg/year Equivalents (AEs).
RESULTS: Of the approximately 20,000 patients enrolled in the PMRP, 6,243 were identified with statin exposure during the study period (1997-2011), 59.8% of whom had been prescribed multiple statins over an average of approximately 11 years. When the best-fit algorithm was implemented and validated by manual chart review for the statin-ordered population, it was found to capture 95.9% of the correlation between calculated and expected statin provider-intended exposure time for a random validation set, and the best-fit model was able to predict intended statin exposure to within a standard deviation of 2.6 AEs, with a standard error of +0.23 AEs.
CONCLUSION: We demonstrate that normalized provider-intended statin exposure time can be estimated using a combination of structured clinical data sources, including a medications ordering system and a clinical appointment coordination system, supplemented with text data from clinical notes.

PMID: 24637142 [PubMed - as supplied by publisher]

Pathogenic Strains of Acanthamoeba Are Recognized by TLR4 and Initiated Inflammatory Responses in the Cornea.

Sat, 03/22/2014 - 4:23am
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Pathogenic Strains of Acanthamoeba Are Recognized by TLR4 and Initiated Inflammatory Responses in the Cornea.

PLoS One. 2014;9(3):e92375

Authors: Alizadeh H, Tripathi T, Abdi M, Smith AD

Abstract
Free-living amoebae of the Acanthamoeba species are the causative agent of Acanthamoeba keratitis (AK), a sight-threatening corneal infection that causes severe pain and a characteristic ring-shaped corneal infiltrate. Innate immune responses play an important role in resistance against AK. The aim of this study is to determine if Toll-like receptors (TLRs) on corneal epithelial cells are activated by Acanthamoeba, leading to initiation of inflammatory responses in the cornea. Human corneal epithelial (HCE) cells constitutively expressed TLR1, TLR2, TLR3, TLR4, and TLR9 mRNA, and A. castellanii upregulated TLR4 transcription. Expression of TLR1, TLR2, TLR3, and TLR9 was unchanged when HCE cells were exposed to A. castellanii. IL-8 mRNA expression was upregulated in HCE cells exposed to A. castellanii. A. castellanii and lipopolysaccharide (LPS) induced significant IL-8 production by HCE cells as measured by ELISA. The percentage of total cells positive for TLR4 was higher in A. castellanii stimulated HCE cells compared to unstimulated HCE cells. A. castellanii induced upregulation of IL-8 in TLR4 expressing human embryonic kidney (HEK)-293 cells, but not TLR3 expressing HEK-293 cells. TLR4 neutralizing antibody inhibited A. castellanii-induced IL-8 by HCE and HEK-293 cells. Clinical strains but not soil strains of Acanthamoeba activated TLR4 expression in Chinese hamster corneas in vivo and in vitro. Clinical isolates but not soil isolates of Acanthamoeba induced significant (P< 0.05) CXCL2 production in Chinese hamster corneas 3 and 7 days after infection, which coincided with increased inflammatory cells in the corneas. Results suggest that pathogenic species of Acanthamoeba activate TLR4 and induce production of CXCL2 in the Chinese hamster model of AK. TLR4 may be a potential target in the development of novel treatment strategies in Acanthamoeba and other microbial infections that activate TLR4 in corneal cells.

PMID: 24633052 [PubMed - in process]

Thoracic splenosis more than 40 years after thoracoabdominal trauma.

Sat, 03/22/2014 - 4:23am
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Thoracic splenosis more than 40 years after thoracoabdominal trauma.

J Am Osteopath Assoc. 2013 Nov;113(11):853-6

Authors: O-Yurvati AH, Thompson JB, Woods TN

Abstract
Splenosis is a rare occurrence that is defined as autotransplantation of splenic tissue usually after splenic rupture due to trauma and subsequent splenectomy. Although splenosis most commonly occurs in the abdomen, the authors report a rare case of thoracic splenosis after remote thoracoabdominal trauma. A 62-year-old woman was found to have lower-lobe, pleural-based nodular lesions in juxtaposition to the posteromedial segment of the lung during workup for an abdominal hernia. Surgical excision of the mass confirmed the diagnosis of ectopic splenic tissue, and splenosis was diagnosed. This woman was among the rare 18% of people who are found to have splenosis in the intrathoracic space. In the workup of pulmonary nodules in patients with a history of trauma, splenosis should be a consideration.

PMID: 24174507 [PubMed - indexed for MEDLINE]

Current perspectives on the link between neuroinflammation and neurogenesis.

Wed, 03/19/2014 - 4:30am

Current perspectives on the link between neuroinflammation and neurogenesis.

Metab Brain Dis. 2014 Mar 13;

Authors: Wang B, Jin K

Abstract
The link between neuroinflammation and neurogenesis is an area of intensive research in contemporary neuroscience. The burgeoning amount of evidence accumulated over the past decade has been incredible, and now there remains the figuring out of minutia to give us a more complete picture of what individual, synergistic, and antagonistic events are occurring between neurogenesis and neuroinflammation. An intricate study of the inflammatory microenvironment influenced by the presence of the various inflammatory components like cytokines, chemokines, and immune cells is essential for: 1) understanding how neurogenesis can be affected in such a specialized niche and 2) applying the knowledge gained for the treatment of cognitive and/or motor deficits arising from inflammation-associated diseases like stroke, traumatic brain injury, Alzheimer's disease, and Parkinson's disease. This review is written to provide the reader with up-to-date information explaining how these inflammatory components are effecting changes on neurogenesis.

PMID: 24623361 [PubMed - as supplied by publisher]

Nanobiosensors: role in cancer detection and diagnosis.

Fri, 03/14/2014 - 4:30am
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Nanobiosensors: role in cancer detection and diagnosis.

Adv Exp Med Biol. 2014;807:33-58

Authors: Gdowski A, Ranjan AP, Mukerjee A, Vishwanatha JK

Abstract
The ability to detect many cancers at an early stage in its clinical course has the potential to improve patient outcomes in terms of morbidity and mortality. Nanosized components incorporated into existing clinical diagnostic and detection systems as well as novel nanobiosensors have demonstrated improved sensitivity and specificity compared with traditional cancer testing approaches. Nanoparticles, nanowires, nanotubes, and nanocantilevers are examples of four nanobiosensor systems that have been used experimentally in the context of detection and diagnosis of prostate, breast, pancreatic, lung, and brain cancers over the past few years. Nanobiosensors will begin to transition into clinically validated tests as experimental and engineering techniques advance. This paper presents examples of some such nanobiosensors for cancer diagnosis and detection.

PMID: 24619617 [PubMed - in process]

Manual therapy, exercise, and education for low back pain and pelvic pain during pregnancy.

Fri, 03/14/2014 - 4:30am
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Manual therapy, exercise, and education for low back pain and pelvic pain during pregnancy.

Am J Obstet Gynecol. 2014 Mar 4;

Authors: Licciardone JC, Aryal S

PMID: 24607754 [PubMed - as supplied by publisher]

Erythropoietin: Powerful protection of ischemic and post-ischemic brain.

Thu, 03/13/2014 - 3:24pm
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Erythropoietin: Powerful protection of ischemic and post-ischemic brain.

Exp Biol Med (Maywood). 2014 Mar 4;

Authors: Nguyen AQ, Cherry BH, Scott GF, Ryou MG, Mallet RT

Abstract
Ischemic brain injury inflicted by stroke and cardiac arrest ranks among the leading causes of death and long-term disability in the United States. The brain consumes large amounts of metabolic substrates and oxygen to sustain its energy requirements. Consequently, the brain is exquisitely sensitive to interruptions in its blood supply, and suffers irreversible damage after 10-15 min of severe ischemia. Effective treatments to protect the brain from stroke and cardiac arrest have proven elusive, due to the complexities of the injury cascades ignited by ischemia and reperfusion. Although recombinant tissue plasminogen activator and therapeutic hypothermia have proven efficacious for stroke and cardiac arrest, respectively, these treatments are constrained by narrow therapeutic windows, potentially detrimental side-effects and the limited availability of hypothermia equipment. Mounting evidence demonstrates the cytokine hormone erythropoietin (EPO) to be a powerful neuroprotective agent and a potential adjuvant to established therapies. Classically, EPO originating primarily in the kidneys promotes erythrocyte production by suppressing apoptosis of proerythroid progenitors in bone marrow. However, the brain is capable of producing EPO, and EPO's membrane receptors and signaling components also are expressed in neurons and astrocytes. EPO activates signaling cascades that increase the brain's resistance to ischemia-reperfusion stress by stabilizing mitochondrial membranes, limiting formation of reactive oxygen and nitrogen intermediates, and suppressing pro-inflammatory cytokine production and neutrophil infiltration. Collectively, these mechanisms preserve functional brain tissue and, thus, improve neurocognitive recovery from brain ischemia. This article reviews the mechanisms mediating EPO-induced brain protection, critiques the clinical utility of exogenous EPO to preserve brain threatened by ischemic stroke and cardiac arrest, and discusses the prospects for induction of EPO production within the brain by the intermediary metabolite, pyruvate.

PMID: 24595981 [PubMed - as supplied by publisher]

Challenges in the development of glaucoma neuroprotection therapy.

Thu, 03/13/2014 - 3:24pm
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Challenges in the development of glaucoma neuroprotection therapy.

Cell Tissue Res. 2013 Aug;353(2):253-60

Authors: Liu Y, Pang IH

Abstract
Glaucoma, a disease of the optic nerve and retina, causes blindness in millions of people worldwide. Currently available therapies for this disease only attempt to reduce intraocular pressure, the major risk factor, without addressing the associated optic neuropathy and retinopathy. Development of glaucoma neuroprotective treatment is therefore a pressing unmet medical need. Unfortunately, many challenges hinder this effort, including an incomplete understanding of the mechanism of pathogenesis, leading to uncertain therapeutic targets and confounded by not yet validated preclinical models. Most importantly, with slow disease progression and a less than ideal endpoint measurement method, clinical trials are necessarily large, lengthy, expensive and, to many, prohibitive. No easy solution is available to overcome these challenges. Increased commitment to basic mechanistic research is an essential foundation for dealing with this problem. Innovations in clinical trials with novel surrogate endpoints, nontraditional study designs and the use of surrogate diseases might shorten the study time, reduce the patient sample size and consequently lower the budgetary hurdle for the development of new therapies.

PMID: 23474740 [PubMed - indexed for MEDLINE]

17β-estradiol eye drops protect the retinal ganglion cell layer and preserve visual function in an in vivo model of glaucoma.

Thu, 03/13/2014 - 3:24pm
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17β-estradiol eye drops protect the retinal ganglion cell layer and preserve visual function in an in vivo model of glaucoma.

Mol Pharm. 2013 Aug 5;10(8):3253-61

Authors: Prokai-Tatrai K, Xin H, Nguyen V, Szarka S, Blazics B, Prokai L, Koulen P

Abstract
Neuroprotection in glaucoma as a curative strategy complementary to current therapies to lower intraocular pressure (IOP) is highly desirable. This study was designed to investigate neuroprotection by 17β-estradiol (E2) to prevent retinal ganglion cell (RGC) death in a glaucoma model of surgically elevated IOP in rats. We found that daily treatment with E2-containing eye drops resulted in significant E2 concentration in the retina with concomitant profound neuroprotective therapeutic benefits, even in the presence of continually elevated IOP. The number of apoptotic cells in the RGC layer was significantly decreased in the E2-treated group, when compared to the vehicle-treated controls. Deterioration in visual acuity in these animals was also markedly prevented. Using mass spectrometry-based proteomics, beneficial changes in the expression of several proteins implicated in the maintenance of retinal health were also found in the retina of E2-treated animals. On the other hand, systemic side effects could not be avoided with the eye drops, as confirmed by the measured high circulating estrogen levels and through the assessment of the uterus representing a typical hormone-sensitive peripheral organ. Collectively, the demonstrated significant neuroprotective effect of topical E2 in the selected animal model of glaucoma provides a clear rationale for further studies aiming at targeting E2 into the eye while avoiding systemic E2 exposure to diminish undesirable off-target side effects.

PMID: 23841874 [PubMed - indexed for MEDLINE]

Assessment and management of back pain.

Fri, 03/07/2014 - 2:32pm

Assessment and management of back pain.

JAMA Intern Med. 2014 Mar 1;174(3):478-9

Authors: Licciardone JC, Gatchel R, Dagenais S

PMID: 24590092 [PubMed - in process]

Impact of a Community Based Implementation of REACH II Program for Caregivers of Alzheimer's Patients.

Wed, 03/05/2014 - 4:47am

Impact of a Community Based Implementation of REACH II Program for Caregivers of Alzheimer's Patients.

PLoS One. 2014;9(2):e89290

Authors: Lykens K, Moayad N, Biswas S, Reyes-Ortiz C, Singh KP

Abstract
BACKGROUND: In 2009 an estimated 5.3 million people in the United States were afflicted with Alzheimer's disease, a degenerative form of dementia. The impact of this disease is not limited to the patient but also has significant impact on the lives and health of their family caregivers. The Resources for Enhancing Alzheimer's Caregiver Health (REACH II) program was developed and tested in clinical studies. The REACH II program is now being delivered by community agencies in several locations. This study examines the impact of the REACH II program on caregiver lives and health in a city in north Texas.
STUDY DESIGN: Family caregivers of Alzheimer's patients were assessed using an instrument covering the multi-item domains of Caregiver Burden, Depression, Self-Care, and Social Support upon enrollment in the program and at the completion of the 6 month intervention. The domain scores were analyzed using a multivariate paired t-test and Bonferroni confidence interval for the differences in pre- and post-service domain scores.
RESULTS: A total of 494 families were enrolled in the program during the period January 1, 2011 through June 30, 2012. Of these families 177 completed the 6 month program and have pre - and post service domain scores. The median age for the caregivers was 62 years. The domain scores for Depression and Caregiver Burden demonstrated statistically significant improvements upon program completion.
CONCLUSION: The REACH II intervention was successfully implemented by a community agency with comparable impacts to those of the clinical trial warranting wider scale implementation.

PMID: 24586664 [PubMed - in process]