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Recent Research Articles from UNTHSC

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Herbal Formula Danggui-Shaoyao-San Promotes Neurogenesis and Angiogenesis in Rat Following Middle Cerebral Artery Occlusion.

Wed, 08/05/2015 - 3:29am
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Herbal Formula Danggui-Shaoyao-San Promotes Neurogenesis and Angiogenesis in Rat Following Middle Cerebral Artery Occlusion.

Aging Dis. 2015 Aug;6(4):245-53

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

Abstract
Current studies demonstrated that traditional Chinese herbal formula Danggui-Shaoyao-San (DSS) is not only used for the treatment of menstrual disorder, but has also found its use in neurological diseases. However, the neuroprotective role of DSS on ischemia-induced brain injury is still unclear. The aim of the present study is to explore the effect of DSS in ischemic brain injury. Total 30 adult female Sprague-Dawley rats underwent 90 min transient middle cerebral artery occlusion (MCAO). DSS (600 mg/kg) was administered through the intragastric route at the time of reperfusion and then performed every day thereafter until sacrifice. Results showed that DSS treatment significantly improved neurobehavioral outcomes (N=10 per group, P<0.05). Immunohistochemical staining showed that microvessel density in the perifocal region of DSS-treated rats was significantly increased compared to the saline-treated group (N=4 per group, P<0.01). Similarly, the numbers of BrdU(+)/DCX(+) cells in the subventricular zone were increased in DSS-treated rats compared to the saline-treated group (P<0.05). Furthermore, we demonstrated that DSS treatment activated vascular endothelial growth factor (N=4 per group, P<0.05) and promoted eNOS phosphorylation (N=4 per group, P<0.05). Thus, we concluded that DSS promoted focal angiogenesis and neurogenesis, and attenuated ischemia-induced brain injury in rats after MCAO, suggesting that DSS is a potential drug for ischemic stroke therapy.

PMID: 26236546 [PubMed]

Increasing Proliferation of Intrinsic Tubular Cells after Renal Ischemia-reperfusion Injury in Adult Rat.

Wed, 08/05/2015 - 3:29am
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Increasing Proliferation of Intrinsic Tubular Cells after Renal Ischemia-reperfusion Injury in Adult Rat.

Aging Dis. 2015 Aug;6(4):228-35

Authors: Feng J, Hu W, Feng C, Mao X, Jin K, Ye Y

Abstract
The kidney is capable of regeneration following injury. However, whether renal stem/progenitor cells contribute to the repair process after injury, as well as the origin of the cells that repair and replace damaged renal tubule cells remains debated. Therefore, better understanding of the repair process will be critical to developing new strategies for the treatment of acute renal failure. Using an ischemia-reperfusion injury mode and an immunocytochemistry method, we counted the number of BrdU-positive cells in damged regions at different durations of reperfusion. We found that BrdU, a cell proliferative marker, was mainly incorporated in the tubular cells of both medulla and cortex 1 day after reperfusion. The number of BrdU-positive cells reached a peak at 3 days and lasted for two months after injury. BrdU-positive cells were barely found in the renal glomerulus and the parietal layer of Bowman's capsule after injury, and only a few were found in the intersititium. PAX2, an embryonic renal marker, was also increased in renal tubule cells. Confocal images show that BrdU-positive cells co-expressed PAX2, but not the activated form of caspase-3, a cell death marker. Our data suggest that renal stem-like cells or dedifferentiation of surviving renal tubular cells in both the medulla and cortex may predominantly contribute to the repair process after renal ischemia-reperfusion injury in rat.

PMID: 26236544 [PubMed]

Iowa Gambling Task scores predict future drug use in bipolar disorder outpatients with stimulant dependence.

Wed, 08/05/2015 - 3:29am
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Iowa Gambling Task scores predict future drug use in bipolar disorder outpatients with stimulant dependence.

Psychiatry Res. 2013 Dec 30;210(3):871-9

Authors: Nejtek VA, Kaiser KA, Zhang B, Djokovic M

Abstract
Poor decision-making is associated with poor recovery in persons with bipolar disorder and drug relapse in persons with stimulant dependence. Cognitive predictors of stimulant use in those with comorbid bipolar and stimulant dependence are surprisingly absent. Our goal was to determine if a single baseline assessment of decision-making (Iowa Gambling Task, IGT) would predict future drug use in bipolar disorder outpatients with comorbid stimulant dependence. Ninety-four men and women of multiple race/ethnic origins consented to participate in a 20-week study. Data analyses were performed on 63 comorbid bipolar outpatients completing at least four study weeks and 28 cocaine dependent volunteers without a mood disorder who participated as cocaine controls. There were no significant differences in IGT scores between comorbid patients and cocaine controls. In the comorbid group, IGT scores significantly predicted future drug use during the study. Age, sex, race, years of mental illness, or mood state did not significantly influence IGT scores. This is the first longitudinal study to show that IGT scores obtained at a single baseline assessment predicts future objective drug use in comorbid bipolar disorder outpatients with cocaine or methamphetamine dependence. Evaluating decision-making with the IGT may provide clinicians with valuable insight about the trajectory of their patients' risk for future drug use. These data suggest a need to augment existing treatment with cognitive restructuring to prevent slips and relapses in comorbid bipolar patients. The lack of a bipolar control group and a modest sample size may limit data interpretations.

PMID: 24012163 [PubMed - indexed for MEDLINE]

Erratum.

Tue, 08/04/2015 - 3:30am
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Erratum.

J Forensic Sci. 2015 Jul;60(4):1114-1116

Authors: Moretti TR, Budowle B, Buckleton JS

PMID: 26225719 [PubMed - as supplied by publisher]

Cognitive set shifting deficits and their relationship to repetitive behaviors in autism spectrum disorder.

Sat, 08/01/2015 - 3:32am
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Cognitive set shifting deficits and their relationship to repetitive behaviors in autism spectrum disorder.

J Autism Dev Disord. 2015 Mar;45(3):805-15

Authors: Miller HL, Ragozzino ME, Cook EH, Sweeney JA, Mosconi MW

Abstract
The neurocognitive impairments associated with restricted and repetitive behaviors (RRBs) in autism spectrum disorder (ASD) are not yet clear. Prior studies indicate that individuals with ASD show reduced cognitive flexibility, which could reflect difficulty shifting from a previously learned response pattern or a failure to maintain a new response set. We examined different error types on a test of set-shifting completed by 60 individuals with ASD and 55 age- and nonverbal IQ-matched controls. Individuals with ASD were able to initially shift sets, but they exhibited difficulty maintaining new response sets. Difficulty with set maintenance was related to increased severity of RRBs. General difficulty maintaining new response sets and a heightened tendency to revert to old preferences may contribute to RRBs.

PMID: 25234483 [PubMed - indexed for MEDLINE]

Disulfide cross-linked micelles of novel HDAC inhibitor thailandepsin A for the treatment of breast cancer.

Thu, 07/30/2015 - 3:29am

Disulfide cross-linked micelles of novel HDAC inhibitor thailandepsin A for the treatment of breast cancer.

Biomaterials. 2015 Jul 17;67:183-193

Authors: Xiao K, Li YP, Wang C, Ahmad S, Vu M, Kuma K, Cheng YQ, Lam KS

Abstract
Histone deacetylase (HDAC) inhibitors are an emerging class of targeted therapy against cancers. Thailandepsin A (TDP-A) is a recently discovered class I HDAC inhibitor with broad anti-proliferative activities. In the present study, we aimed to investigate the potential of TDP-A in the treatment of breast cancer. We demonstrated that TDP-A inhibited cell proliferation and induced apoptosis in breast cancer cells at low nanomolar concentrations. TDP-A activated the intrinsic apoptotic pathway through increase of pro-apoptotic protein Bax, decrease of anti-apoptotic Bcl-2, and cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP). TDP-A also induced cell cycle arrest at the G2/M phase, and promoted the production of reactive oxygen species (ROS). We have successfully encapsulated TDP-A into our recently developed disulfide cross-linked micelles (DCMs), improving its water solubility and targeted delivery. TDP-A loaded DCMs (TDP-A/DCMs) possess the characteristics of high loading capacity (>20%, w/w), optimal and monodisperse particle size (16 ± 4 nm), outstanding stability with redox stimuli-responsive disintegration, sustained drug release, and preferential uptake in breast tumors. In the MDA-MB-231 breast cancer xenograft model, TDP-A/DCMs were more efficacious than the FDA-approved FK228 at well-tolerated doses. Furthermore, TDP-A/DCMs exhibited synergistic anticancer effects when combined with the proteasome inhibitor bortezomib (BTZ) loaded DCMs (BTZ/DCMs). Our results indicate that TDP-A nanoformulation alone or in combination with BTZ nanoformulation are efficacious against breast cancer.

PMID: 26218744 [PubMed - as supplied by publisher]

Fetal Growth, Obesity, and Atopic Disorders in Adolescence: a Retrospective Birth Cohort Study.

Thu, 07/30/2015 - 3:29am

Fetal Growth, Obesity, and Atopic Disorders in Adolescence: a Retrospective Birth Cohort Study.

Paediatr Perinat Epidemiol. 2015 Jul 28;

Authors: Lin MH, Hsieh CJ, Caffrey JL, Lin YS, Wang IJ, Ho WC, Chen PC, Wu TN, Lin RS

Abstract
BACKGROUND: Developmental status at birth and subsequent obesity have been implicated in the development of childhood atopic dermatitis (AD) and allergic rhinitis (AR).
METHODS: The current study analysed the cohort data of 74 688 junior high school students from a national retrospective birth cohort study in Taiwan. A random 10% sample was selected from singleton livebirths with complete data on the analytical variables of interest. Atopic disorders, including AD and AR, were assessed by questionnaires (International Study of Asthma and Allergies in Childhood). Logistic regression analyses were applied with adjustments for related risk factors.
RESULTS: Among subjects mainly 13-15 years of age, the estimated prevalence was 7.6% for AD and 22.4% for AR. While the role of fetal growth in allergic disorders was less evident, the risk of developing AD and AR were both influenced by a combination of fetal growth status and adolescent body mass index (BMI). Compared with those with normal fetal growth and school-aged BMI, the risk of developing AD increased 64% among adolescents with both restricted fetal growth and high BMI (odds ratio 1.64, 95% confidence interval 1.37, 1.97). The risk for this combination was higher than that for either restricted fetal growth or high BMI alone. Nevertheless, the overall interaction between BMI and fetal growth status on atopic disorders did not reach statistical significance.
CONCLUSIONS: Excessive weight gain could be an important risk factor related to developing atopic dermatitis and allergic rhinitis during adolescence, especially among infants born small for gestational age.

PMID: 26218618 [PubMed - as supplied by publisher]

The relationship between electronic goal reminders and subsequent drug use and treatment initiation in a criminal justice setting.

Thu, 07/30/2015 - 3:29am

The relationship between electronic goal reminders and subsequent drug use and treatment initiation in a criminal justice setting.

Addict Behav. 2015 Jul 16;51:51-56

Authors: Spohr SA, Taxman FS, Walters ST

Abstract
INTRODUCTION: Opportunities to influence behavior through the use of electronic reminders has not been examined in a criminal justice population. The purpose of this study was to assess probationer preferences for short-term goals from a web-based program and evaluate the role of voluntary electronic reminders (e.g., text messaging, email) in achieving early treatment and probation tasks.
METHODS: We used data from drug-involved offenders (n=76) participating in a clinical trial of a 2-session motivational computer program. As part of the program, participants could choose to receive text or email reminders about their probation and treatment goals for the next month. Poisson regression models were utilized to evaluate goal and reminder selection in relation to the days of substance use and treatment attendance at two-month follow-up.
RESULTS: The most common goals were related to probation and treatment tasks, relationships, and cognitive reappraisals. Forty-five percent of probationers elected to receive electronic goal reminders at Session 1 with a slight increase at Session two (49%). Probationers who opted to receive electronic goal reminders at Session one selected significantly more goals on average (M=4.4, SD=2.1) than probationers who did not want reminders (M=3.4, SD=1.8), (t=2.41, p=.019). Reminder selection and total number of goals selected predicted days of substance use and treatment attendance at a two-month follow-up. Probationers who opted not to receive electronic reminders and those who only chose to receive reminders at one visit had more days of substance use compared to those who chose to receive reminders at both visits, 1.66 and 2.31 times respectively. Probationers who chose not to receive electronic reminders attended 56% fewer days of treatment compared to those who chose to receive reminders at both visits.
CONCLUSIONS: People's choice of short-term goals and reminders can provide advance notification of the likelihood of substance use and treatment initiation. Probation systems might use such information to triage at-risk probationers to a higher level of service, before problems have emerged.

PMID: 26217929 [PubMed - as supplied by publisher]

Contra-Directional Expression of Serum Homocysteine and Uric Acid as Important Biomarkers of Multiple System Atrophy Severity: A Cross-Sectional Study.

Thu, 07/30/2015 - 3:29am
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Contra-Directional Expression of Serum Homocysteine and Uric Acid as Important Biomarkers of Multiple System Atrophy Severity: A Cross-Sectional Study.

Front Cell Neurosci. 2015;9:247

Authors: Chen D, Wei X, Zou J, Wang R, Liu X, Xu X, Lu J, Wang Z, Tang B, Wang B, Jin K, Wang Q

Abstract
HIGHLIGHTS: Serum Hcy was higher in MSA patients when compared to healthy subjects, particularly in male patients.Serum UA was lower in MSA patients when compared healthy subjects, particularly in male patients.Serum Hcy levels were significantly positively correlated with the severity of MSA.The ROC curve for the combination of Hcy and UA showed potential diagnostic value in discriminating MSA from healthy subjects.
AIM: There is evidence suggesting that inflammatory responses play a critical role in the pathogenesis of multiple system atrophy (MSA). Whether inflammatory mediators can be used as reliable biomarkers to detect the severity and progression of MSA remains largely unknown.
METHODS: We performed a cross-sectional study that included 47 patients with MSA and 50 healthy age-matched controls. Serum levels of homocysteine (Hcy), uric acid (UA), and C-reactive protein (CRP) were measured. These levels positively correlated with the severity of MSA, based on both motor and non-motor symptoms. Several scales were used to rate the severity of MSA, including the Unified multiple system atrophy rating scale, Parkinson's disease sleep scale, Non-motor Symptoms Scale, the Schwab & England activities of daily living scale, Webster Scale, modified Hoehn and Yahr staging scale, and the Mini-Mental State Examination. Receiver operating characteristic (ROC) curves was applied to map the diagnostic accuracy of MSA against healthy subjects.
RESULTS: Compared with healthy subjects, we found that serum Hcy was higher, UA was lower, and CRP levels were unchanged in MSA patients. These findings were especially prominent in male patients. No significant differences of serum Hcy and UA were observed between patients of MSA and PD. Interestingly, there was a significant correlation between Hcy levels and MSA severity such as movement dysfunction, declined cognition, and cardiovascular symptoms. Additionally, the ROC curve for the combination of Hcy and UA (AUC 0.736) showed potential diagnostic value in discriminating MSA from healthy subjects.
CONCLUSION: Our findings suggest that the inflammatory mediators Hcy and UA may play important roles in the pathogenesis of MSA. The measurement of serum Hcy and UA levels could then be a useful tool to accurately distinguish MSA from healthy subjects.

PMID: 26217177 [PubMed]

Chronic pain and health care spending: an analysis of longitudinal data from the Medical Expenditure Panel Survey.

Wed, 07/29/2015 - 3:30am
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Chronic pain and health care spending: an analysis of longitudinal data from the Medical Expenditure Panel Survey.

Health Serv Res. 2015 Jun;50(3):847-70

Authors: Stockbridge EL, Suzuki S, Pagán JA

Abstract
OBJECTIVE: To estimate average incremental health care expenditures associated with chronic pain by health care service category, expanding on prior research that focused on specific pain conditions instead of general pain, excluded low levels of pain, or did not incorporate pain duration.
DATA SOURCE: Medical Expenditure Panel Survey (MEPS) data (2008-2011; N = 26,671).
STUDY DESIGN: Differences in annual expenditures for adults at different levels of pain that interferes with normal work, as measured by the SF-12, were estimated using recycled predictions from two-part logit-generalized linear regression models.
PRINCIPAL FINDINGS: "A little bit" of chronic pain-related interference was associated with a $2,498 increase in total adjusted expenditures over no pain interference (p < .0001) and a $1,008 increase over nonchronic pain interference (p = .0001). Moderate and severe chronic pain-related interference was associated with a $3,707 and $5,804 increase in expenditures over no pain interference and a $2,218 and $4,315 increase over nonchronic interference, respectively (p < .0001). Expenditure increases were most pronounced for inpatient and hospital outpatient expenditures compared to other types of health care expenditures.
CONCLUSIONS: Chronic pain limitations are associated with higher health care expenditures. Results underscore the substantial cost of pain to the health care system.

PMID: 25424348 [PubMed - indexed for MEDLINE]

Fully Threaded Versus Partially Threaded Screws: Determining Shear in Cancellous Bone Fixation.

Tue, 07/28/2015 - 3:30am

Fully Threaded Versus Partially Threaded Screws: Determining Shear in Cancellous Bone Fixation.

J Foot Ankle Surg. 2015 Jul 23;

Authors: Downey MW, Kosmopoulos V, Carpenter BB

Abstract
Many researchers have studied and compared various forms of intraosseous fixation. No studies have examined the effects of shear through stiffness and failure strength of a fully threaded versus a partially threaded screw. Our hypothesis was that the fully threaded lag screw technique would provide greater shear strength and resistance. Thirty-six synthetic sawbone blocks were used to test screw fixation. In group 1 (n = 9), 2 blocks were fixed together using a fully threaded 4.0-mm stainless steel cancellous bone screw and the lag technique. In group 2 (n = 8), 2 blocks were fixed together using the standard manufacturer-recommended method for inserting 4.0-mm partially threaded stainless steel cancellous bone screws. The constructs were then mechanically tested. Shear was applied by compressing each construct at an axial displacement rate of 0.5 mm/s until failure. The fully threaded screw had a significantly greater (p = .026) initial stiffness (106.4 ± 15.8 N/mm) than the partially threaded screw (80.1 ± 27.5 N/mm). The yield load and displacement for the fully threaded group (429.4 ± 11.7 N and 7.2 ± 0.35 mm) were 64% and 67% greater than those for the partially threaded screw group (261.4 ± 26.1 N and 4.3 ± 1.03 mm), respectively. The results of the present study have demonstrated the importance of a full-thread construct to prevent shear and to decrease strain at the fracture. The confirmation of our hypothesis questions the future need and use of partially threaded screws for cancellous bone fixation.

PMID: 26210079 [PubMed - as supplied by publisher]

Targeting Caspase-12 to Preserve Vision in Mice With Inherited Retinal Degeneration.

Mon, 07/27/2015 - 3:29am

Targeting Caspase-12 to Preserve Vision in Mice With Inherited Retinal Degeneration.

Invest Ophthalmol Vis Sci. 2015 Jul 1;56(8):4725-4733

Authors: Bhootada Y, Choudhury S, Gully C, Gorbatyuk M

Abstract
Purpose: The unfolded protein response is known to contribute to the inherited retinal pathology observed in T17M rhodopsin (T17M) mice. Recently it has been demonstrated that the endoplasmic reticulum stress-associated caspase-12 is activated during progression of retinal degeneration in different animal models. Therefore, we wanted to explore the role of caspase-12 in the mechanism of retinopathy in T17M mice and determine if inhibiting apoptosis in this way is a viable approach for halting retinal degeneration.
Methods: One, two-, and three-month-old C57BL6/J, caspase-12-/-, T17M, and T17M caspase-12-/- mice were analyzed by scotopic ERG, spectral-domain optical coherence tomography (SD-OCT), histology, quantitative (q)RT-PCR, and Western blot of retinal RNA and protein extracts. Calpain and caspase-3/7 activity assays were measured in postnatal (P) day 30 retinal extracts.
Results: Caspase-12 ablation significantly prevented a decline in the a- and b-wave ERG amplitudes in T17M mice during three months, increasing the amplitudes from 232% to 212% and from 160% to 138%, respectively, as compared to T17M retinas. The SD-OCT results and photoreceptor row counts demonstrated preservation of retinal structural integrity and postponed photoreceptor cell death. The delay in photoreceptor cell death was due to significant decreases in the activity of caspase-3/7 and calpain, which correlated with an increase in calpastatin expression.
Conclusions: We validated caspase-12 as a therapeutic target, ablation of which significantly protects T17M photoreceptors from deterioration. Although the inhibition of apoptotic activity alone was not sufficient to rescue T17M photoreceptors, in combination with other nonapoptotic targets, caspase-12 could be used to treat inherited retinopathy.

PMID: 26207309 [PubMed - as supplied by publisher]

Midcarpal Instability: A Comprehensive Review and Update.

Mon, 07/27/2015 - 3:29am
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Midcarpal Instability: A Comprehensive Review and Update.

Hand Clin. 2015 Aug;31(3):487-93

Authors: Niacaris T, Ming BW, Lichtman DM

Abstract
Midcarpal instability has been well described as a clinical entity but the pathokinematics and pathologic anatomy continue to be poorly understood. This article presents a comprehensive review of the existing knowledge and literature-based evidence for the diagnosis and management of the various entities comprising midcarpal instability. It discusses the limitations of the current understanding of midcarpal instability and proposes new directions for furthering knowledge of the causes and treatment of midcarpal instability and wrist pathomechanics in general.

PMID: 26205710 [PubMed - in process]

Bitropic D3 Dopamine Receptor Selective Compounds s Potential Antipsychotics.

Mon, 07/27/2015 - 3:29am
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Bitropic D3 Dopamine Receptor Selective Compounds s Potential Antipsychotics.

Curr Pharm Des. 2015 Jul 23;

Authors: Luedtke RR, Rangel-Barajas C, Malik M, Reichert DE, Mach RH

Abstract
Neuropsychiatric disorders represents a substantial social and health care issue. The National Institutes of Health estimates that greater than 2 million adults suffer from neuropsychiatric disorders in the USA. These individuals experience symptoms that can include auditory hallucinations, delusions, unrealistic beliefs and cognitive dysfunction. Although antipsychotic medications are available, suboptimal therapeutic responses are observed for approximately one-third of patients. Therefore, there is still a need to explore new pharmacotherapeutic strategies for the treatment of neuropsychiatric disorders. Many of the medications that are used clinically to treat neuropsychiatric disorders have a pharmacological profile that includes being an antagonist at D2-like (D2, D2 and D4) dopamine receptor subtypes. However, dopamine receptor subtypes are involved in a variety of neuronal circuits that include movement coordination, cognition, emotion, affect, memory and the regulation of prolactin. Consequently, antagonism at D2-like receptors can also contribute to some of the adverse side effects associated with the long-term use of antipsychotics including the a) adverse extrapyramidal symptoms associated with the use of typical antipsychotics and b) metabolic side effects (weight gain, hyperglycemia, increased risk of diabetes mellitus, dyslipidemia and gynecomastia) associated with atypical antipsychotic use. Preclinical studies suggest that D3 versus D2 dopamine receptor selective compounds might represent an alternative strategy for the treatment of the symptoms of schizophrenia. In this review we discuss a) how bitropic N-phenylpiperazine D3 dopamine receptor selective compounds have been developed by modification of the primary (orthosteric) and secondary (allosteric or modulatory) pharmacophores to optimize D3 receptor affinity and D2/D3 binding selectivity ratios and b) the functional selectivity of these compounds. Examples of how these compounds might be modified to develop bivalent ligands capable of interacting with receptor dimers or oligomers are also provided. Preclinical studies using bitropic D3 dopamine receptor selective ligands are also discussed as strategy to pharmacologically dissect the role of the D2 and D3 dopamine receptor subtypes in animal models of neuropsychiatric, neurological and substance abuse disorders. This research has the potential to a) advance the understanding of the role of the D2 and D3 dopamine receptor subtypes in neuropsychiatric disorders and b) lead to new treatment strategies for neuropsychiatric disorders.

PMID: 26205291 [PubMed - as supplied by publisher]

Tip110 binding to U6 small nuclear RNA and its participation in pre-mRNA splicing.

Sat, 07/25/2015 - 3:31am
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Tip110 binding to U6 small nuclear RNA and its participation in pre-mRNA splicing.

Cell Biosci. 2015;5:40

Authors: Liu Y, Liu J, Wang Z, He JJ

Abstract
BACKGROUND: RNA-protein interactions play important roles in gene expression control. These interactions are mediated by several recurring RNA-binding motifs including a well-known and characterized ribonucleoprotein motif or so-called RNA recognition motif (RRM).
RESULTS: In the current study, we set out to identify the RNA ligand(s) of a RRM-containing protein Tip110, also known as p110(nrb), SART3, or p110, using a RNA-based yeast three-hybrid cloning strategy. Six putative RNA targets were isolated and found to contain a consensus sequence that was identical to nucleotides 34-46 of U6 small nuclear RNA. Tip110 binding to U6 was confirmed to be specific and RRM-dependent in an electrophoretic mobility shift assay. Both in vitro pre-mRNA splicing assay and in vivo splicing-dependent reporter gene assay showed that the pre-mRNA splicing was correlated with Tip110 expression. Moreover, Tip110 was found in the spliceosomes containing pre-spliced pre-mRNA and spliced mRNA products. Nonetheless, the RRM-deleted mutant (ΔRRM) that did not bind to U6 showed promotion in vitro pre-mRNA splicing, whereas the nuclear localization signal (NLS)-deleted mutant ΔNLS that bound to U6 promoted the pre-mRNA splicing both in vitro and in vivo. Lastly, RNA-Seq analysis confirmed that Tip110 regulated a number of gene pre-mRNA splicing including several splicing factors.
CONCLUSIONS: Taken together, these results demonstrate that Tip110 is directly involved in constitutive eukaryotic pre-mRNA splicing, likely through its binding to U6 and regulation of other splicing factors, and provide further evidence to support the global roles of Tip110 in regulation of host gene expression.

PMID: 26203351 [PubMed]

The prodrug DHED selectively delivers 17β-estradiol to the brain for treating estrogen-responsive disorders.

Sat, 07/25/2015 - 3:31am
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The prodrug DHED selectively delivers 17β-estradiol to the brain for treating estrogen-responsive disorders.

Sci Transl Med. 2015 Jul 22;7(297):297ra113

Authors: Prokai L, Nguyen V, Szarka S, Garg P, Sabnis G, Bimonte-Nelson HA, McLaughlin KJ, Talboom JS, Conrad CD, Shughrue PJ, Gould TD, Brodie A, Merchenthaler I, Koulen P, Prokai-Tatrai K

Abstract
Many neurological and psychiatric maladies originate from the deprivation of the human brain from estrogens. However, current hormone therapies cannot be used safely to treat these conditions commonly associated with menopause because of detrimental side effects in the periphery. The latter also prevents the use of the hormone for neuroprotection. We show that a small-molecule bioprecursor prodrug, 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), converts to 17β-estradiol in the brain after systemic administration but remains inert in the rest of the body. The localized and rapid formation of estrogen from the prodrug was revealed by a series of in vivo bioanalytical assays and through in vivo imaging in rodents. DHED treatment efficiently alleviated symptoms that originated from brain estrogen deficiency in animal models of surgical menopause and provided neuroprotection in a rat stroke model. Concomitantly, we determined that 17β-estradiol formed in the brain from DHED elicited changes in gene expression and neuronal morphology identical to those obtained after direct 17β-estradiol treatment. Together, complementary functional and mechanistic data show that our approach is highly relevant therapeutically, because administration of the prodrug selectively produces estrogen in the brain independently from the route of administration and treatment regimen. Therefore, peripheral responses associated with the use of systemic estrogens, such as stimulation of the uterus and estrogen-responsive tumor growth, were absent. Collectively, our brain-selective prodrug approach may safely provide estrogen neuroprotection and medicate neurological and psychiatric symptoms developing from estrogen deficiency, particularly those encountered after surgical menopause, without the adverse side effects of current hormone therapies.

PMID: 26203081 [PubMed - in process]

Validation of a serum screen for Alzheimer's disease across assay platforms, species, and tissues.

Sat, 07/25/2015 - 3:31am
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Validation of a serum screen for Alzheimer's disease across assay platforms, species, and tissues.

J Alzheimers Dis. 2014;42(4):1325-35

Authors: O'Bryant SE, Xiao G, Zhang F, Edwards M, German DC, Yin X, Como T, Reisch J, Huebinger RM, Graff-Radford N, Dickson D, Barber R, Hall J, O'Suilleabhain P, Grammas P

Abstract
BACKGROUND: There is a significant need for rapid and cost-effective biomarkers of Alzheimer's disease (AD) for advancement of clinical practice and therapeutic trials.
OBJECTIVE: The aim of the current study was to cross-validate our previously published serum-based algorithm on an independent assay platform as well as validate across tissues and species. Preliminary analyses were conducted to examine the utility in distinguishing AD from non-AD neurological disease (Parkinson's disease, PD).
METHODS: Serum proteins from our previously published algorithm were quantified from 150 AD cases and 150 controls on the Meso Scale Discovery (MSD) platform. Serum samples were analyzed from 49 PD cases and compared to a random sample of 51 AD cases and 62 controls. Support vector machines (SVM) were used to discriminate PD versus AD versus controls. Human and AD mouse model microvessel images were quantified with HAMAMATSU imaging software. Mouse serum biomarkers were assayed via MSD.
RESULTS: Analysis of 21 serum proteins from 150 AD cases and 150 controls yielded an algorithm with sensitivity and specificity of 0.90 for correctly classifying AD. This multi-marker approach was then validated across species and tissue. Assay of the top proteins in human and AD mouse model brain microvessels correctly classified 90-100% of the samples. SVM analyses were highly accurate at distinguishing PD versus AD versus controls.
CONCLUSIONS: This serum-based biomarker panel should be tested in a community-based setting to determine its utility as a first-line screen for AD and non-AD neurological diseases for primary care providers.

PMID: 25024345 [PubMed - indexed for MEDLINE]

STRait Razor v2.0: the improved STR Allele Identification Tool--Razor.

Fri, 07/24/2015 - 3:29am
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STRait Razor v2.0: the improved STR Allele Identification Tool--Razor.

Forensic Sci Int Genet. 2015 Jan;14:182-6

Authors: Warshauer DH, King JL, Budowle B

Abstract
STRait Razor (the STR Allele Identification Tool - Razor) was developed as a bioinformatic software tool to detect short tandem repeat (STR) alleles in massively parallel sequencing (MPS) raw data. The method of detection used by STRait Razor allows it to make reliable allele calls for all STR types in a manner that is similar to that of capillary electrophoresis. STRait Razor v2.0 incorporates several new features and improvements upon the original software, such as a larger default locus configuration file that increases the number of detectable loci (now including X-chromosome STRs and Amelogenin), an enhanced custom locus list generator, a novel output sorting method that highlights unique sequences for intra-repeat variation detection, and a genotyping tool that emulates traditional electropherogram data. Users also now have the option to choose whether the program detects autosomal, X-chromosome, Y-chromosome, or all STRs. Concordance testing was performed, and allele calls produced by STRait Razor v2.0 were completely consistent with those made by the original software.

PMID: 25450790 [PubMed - indexed for MEDLINE]

Combining select neuropsychological assessment with blood-based biomarkers to detect mild Alzheimer's disease: a molecular neuropsychology approach.

Fri, 07/24/2015 - 3:29am
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Combining select neuropsychological assessment with blood-based biomarkers to detect mild Alzheimer's disease: a molecular neuropsychology approach.

J Alzheimers Dis. 2014;42(2):635-40

Authors: Edwards M, Balldin VH, Hall J, O'Bryant S

Abstract
BACKGROUND: Current work has sought to establish a rapid and cost effective means of screening for Alzheimer's disease (AD) with the most recent findings showing utility of integrating blood-based biomarkers with cognitive measures.
OBJECTIVE: The current project sought to create a combined biomarker-cognitive profile to detect mild AD.
METHODS: Data was analyzed from 266 participants (129 AD cases [Early AD n = 93; Very Early AD n = 36]; 137 controls) enrolled in the Texas Alzheimer's Research and Care Consortium (TARCC). Non-fasting serum samples were collected from each participant and assayed via a multi-plex biomarker assay platform using electrochemiluminescence. Logistic Regression was utilized to detect early AD using two serum biomarkers (TNFα and IL7), demographic information (age), and one neuropsychological measure (Clock 4-point) as predictor variable. Disease severity was determined via Clinical Dementia Rating (CDR) scale global scores.
RESULTS: In the total sample (all levels of CDR scores), the combination of biomarkers, cognitive test score, and demographics yielded the obtained sensitivity (SN) of 0.94, specificity (SP) of 0.90, and an overall accuracy of 0.92. When examining early AD cases (i.e.m CDR = 0.5-1), the biomarker-cognitive profile yielded SN of 0.94, SP of 0.85, and an overall accuracy of 0.91. When restricted to very early AD cases (i.e., CDR = 0.5), the biomarker-cognitive profile yielded SN of 0.97 and SP of 0.72, with an overall accuracy of 0.91.
CONCLUSIONS: The combination of demographics, two biomarkers, and one cognitive test created a biomarker-cognitive profile that was highly accurate in detecting the presence of AD, even in the very early stages.

PMID: 24916542 [PubMed - indexed for MEDLINE]

Are positive allosteric modulators of α7 nAChRs clinically safe?

Tue, 07/21/2015 - 3:30am
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Are positive allosteric modulators of α7 nAChRs clinically safe?

J Neurochem. 2015 Jul 14;

Authors: Uteshev V

Abstract
In a recent research article published in the May 2015 issue of this journal (Journal of Neurochemistry 2015, 133: 309-319), Guerra-Alvarez et al. reported a cytotoxic potential of PNU120596, a Type-II positive allosteric modulator (PAMII) of α7 nicotinic acetylcholine receptors (α7 nAChRs). The authors used human SH-SY5Y neuroblastoma cells, rat organotypic hippocampal slice culture, electrophysiology and fluorescent Ca(2+) imaging to evaluate cellular responsiveness and survival after various treatments with nicotinic agonists and PNU120596. This article is protected by copyright. All rights reserved.

PMID: 26182952 [PubMed - as supplied by publisher]

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