bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional deprivation promotes amyloid plaque pathogenesis in Tg2576 mouse olfactory bulb and piriform cortex
Authors: Zhang Xue‐Mei , Xiong Kun , Cai Yan , Cai Huaibin , Luo Xue‐Gang , Feng Jia‐Chun , Clough Richard W. , Patrylo Peter R. , Struble Robert G. , Yan Xiao‐Xin 
Published: February 2010

AbstractCerebral hypometabolism and amyloid accumulation are principal neuropathological manifestations of Alzheimer’s disease (AD). Whether and how brain/neuronal activity might modulate certain pathological processes of AD are interesting topics of recent clinical and basic research in the field, and may be of potential medical relevance in regard to both the disease etiology and intervention. Using the Tg2576 transgenic mouse model of AD, this study characterized a promotive effect of neuronal hypoactivity associated with functional deprivation on amyloid plaque pathogenesis in the olfactory pathway. Unilateral naris‐occlusion caused β‐secretase‐1 (BACE1) elevation in neuronal terminals in the deprived relative to the non‐deprived bulb and piriform cortex in young adult mice. In parallel with the overall age‐related plaque development in the forebrain, locally increased BACE1 immunoreactivity co‐occurred with amyloid deposition first in the piriform cortex then within the bulb, more prominent on the deprived relative to the non‐deprived side. Biochemical analyses confirmed elevated BACE1 protein levels, enzymatic activity and products in the deprived relative to non‐deprived bulbs. Plaque‐associated BACE1 immunoreactivity in the bulb and piriform cortex was localized preferentially to swollen/sprouting glutamatergic axonal terminals, with Aβ immunoreactivity occurring inside as well as around these terminals. Together, these findings suggest that functional deprivation or neuronal hypoactivity facilitates amyloid plaque formation in the forebrain in a transgenic model of AD, which operates synergistically with age effect. The data also implicate an intrinsic association of amyloid accumulation and plaque formation with progressive axonal pathology.
Mouse strain differences in locomotor, sensitisation and rewarding effect of heroin; association with alterations in MOP‐r activation and dopamine transporter binding
Authors: Bailey Alexis , Metaxas Athanasios , Al‐Hasani Ream , Keyworth Helen L. , Forster Duncan M. , Kitchen Ian 
Published: February 2010

AbstractThere is growing agreement that genetic factors play an important role in the risk to develop heroin addiction, and comparisons of heroin addiction vulnerability in inbred strains of mice could provide useful information on the question of individual vulnerability to heroin addiction. This study examined the rewarding and locomotor‐stimulating effects of heroin in male C57BL/6J and DBA/2J mice. Heroin induced locomotion and sensitisation in C57BL/6J but not in DBA/2J mice. C57BL/6J mice developed conditioned place preference (CPP) to the highest doses of heroin, while DBA/2J showed CPP to only the lowest heroin doses, indicating a higher sensitivity of DBA/2J mice to the rewarding properties of heroin vs C57BL/6J mice. In order to investigate the neurobiological substrate underlying some of these differences, the effect of chronic ‘intermittent’ escalating dose heroin administration on the opioid, dopaminergic and stress systems was explored. Twofold higher μ‐opioid receptor (MOP‐r)‐stimulated [35S]GTPγS binding was observed in the nucleus accumbens and caudate of saline‐treated C57BL/6J mice compared with DBA/2J. Heroin decreased MOP‐r density in brain regions of C57BL/6J mice, but not in DBA/2J. A higher density of dopamine transporters (DAT) was observed in nucleus accumbens shell and caudate of heroin‐treated DBA/2J mice compared with heroin‐treated C57BL/6J. There were no effects on D1and D2binding. Chronic heroin administration decreased corticosterone levels in both strains with no effect of strain. These results suggest that genetic differences in MOP‐r activation and DAT expression may be responsible for individual differences in vulnerability to heroin addiction.
A role for ephrin‐As in maintaining topographic organization in register across interconnected central visual pathways
Authors: Wilks Tenelle A. , Rodger Jennifer , Harvey Alan R. 
Published: February 2010

AbstractThe retina sends spatially ordered visual information to the superior colliculus (SC) directly and indirectly via the thalamus and primary visual cortex (V1). Gradients of Ephs and ephrins are present in all of these regions, and have been shown to be involved in establishing topography of at least some of these interconnected visual pathways. Studies in ephrin‐A knockout mice show that abnormal retinotectal termination zones (TZs) are present in a majority of mice lacking (−/−) ephrin‐A2 (57%), and ephrin‐A2 and ‐A5 (89%). A similar but seemingly less disordered pattern is detected in the retina‐to‐dorsal lateral geniculate nucleus (dLGN) and dLGN‐to‐V1 projections. Here we analyse the dLGN‐to‐V1 and V1‐to‐SC projections in ephrin‐A−/− mice to determine the extent to which topographic errors are transmitted across synaptic relays. Fluorescent tracers were injected into V1 of wild‐type (WT), ephrin‐A2−/− or ephrin‐A2A5−/− mice. We examined the number, location and size of anterograde TZs in SC, and mapped the distribution of retrogradely labelled neurons in dLGN. Compared with WT and ephrin‐A2−/− mice, the volume of individual TZs in the SC was smaller in ephrin‐A2A5−/− mice (P = 0.002). Single V1 injections labelled two foci of dLGN neurons in 70%, and two SC TZs in 80% of ephrin‐A2A5−/− mice. Abnormalities in one or other of the projections were detected in 10% of ephrin‐A2−/− mice. Importantly, there was no consistent correspondence between the organization of geniculocortical and corticotectal projections in either genotype, suggesting a role for ephrin‐As in maintaining topographic organization in register across multiple interconnected central visual pathways.
Differential regulation of mature and precursor microRNA expression by NMDA and metabotropic glutamate receptor activation during LTP in the adult dentate gyrus in vivo
Authors: Wibrand Karin , Panja Debabrata , Tiron Adrian , Ofte May L. , Skaftnesmo Kai‐O. , Lee Cherin S , Pena John T.G. , Tuschl Thomas , Bramham Clive R. 
Published: February 2010

AbstractRegulation of microRNA (miRNA) expression and function in the context of activity‐dependent synaptic plasticity in the adult brain is little understood. Here, we examined miRNA expression during long‐term potentiation (LTP) in the dentate gyrus of adult anesthetized rats. Microarray expression profiling identified a subpopulation of regulated mature miRNAs 2 h after the induction of LTP by high‐frequency stimulation (HFS) of the medial perforant pathway. Real‐time polymerase chain reaction analysis confirmed modest upregulation of miR‐132 and miR‐212, and downregulation of miR‐219, while no changes occurred at 10 min post‐HFS. Surprisingly, pharmacological blockade of N‐methyl‐d‐aspartate receptor (NMDAR)‐dependent LTP enhanced expression of these mature miRNAs. This HFS‐evoked expression was abolished by local infusion of the group 1 metabotropic glutamate receptor (mGluR) antagonist, (RS)‐1‐aminoindan‐1,5‐dicarboxylic acid (AIDA). AIDA had no effect on LTP induction or maintenance, but blocked activity‐dependent depotentiation of LTP. Turning to the analysis of miRNA precursors, we show that HFS elicits 50‐fold elevations of primary (pri) and precursor (pre) miR‐132/212 that is transcription dependent and mGluR dependent, but insensitive to NMDAR blockade. Primary miR‐219 expression was unchanged during LTP. In situ hybridization showed upregulation of the pri‐miR‐132/212 cluster restricted to dentate granule cell somata. Thus, HFS induces transcription miR‐132/212 that is mGluR dependent and functionally correlated with depotentiation rather than LTP. In contrast, NMDAR activation selectively downregulates mature miR‐132, ‐212 and ‐219 levels, indicating accelerated decay of these mature miRNAs. This study demonstrates differential regulation of primary and mature miRNA expression by mGluR and NMDAR signaling following LTP induction, the function of which remains to be defined.
Fesoterodine in patients with overactive bladder syndrome: can the severity of baseline urgency urinary incontinence predict dosing requirement?
Authors: Cardozo Linda , Khullar Vik , Wang Joseph T. , Guan Zhonghong , Sand Peter K. 
Published: February 2010

Study Type – Therapy (RCT) Level of Evidence 1bOBJECTIVESTo determine whether baseline urgency urinary incontinence (UUI) episodes predict the need for increased doses of fesoterodine in patients with overactive bladder (OAB), as clinicians would benefit from data that help to predict which patients require higher doses of antimuscarinics to manage UUI episodes.PATIENTS AND METHODSIn this pooled analysis of data from two double‐blind, placebo‐controlled trials, patients were randomized to placebo or fesoterodine 4 or 8 mg for 12 weeks and stratified into tertiles (>0–<2, 2–<4, or ≥4) according to the number of UUI episodes/24 h as recorded in 3‐day bladder diaries at baseline. The change in mean UUI episodes/24 h from baseline to end of study was assessed using analysis of covariance.RESULTSIn a post hoc analysis of data from two clinical trials, there were significant reductions from baseline in UUI episodes for fesoterodine 4 and 8 mg vs placebo in patients (n) with >0–<2 (422), 2–<4 (424) and ≥4 (481) UUI episodes at baseline (all P < 0.01). In patients with 2–<4 and ≥4 UUI episodes at baseline, fesoterodine 8 mg gave significantly greater mean reductions (−1.92 and −4.17, respectively) vs fesoterodine 4 mg (−1.43 and −3.31) (P < 0.05). The most common adverse events were dry mouth (placebo, 8%; fesoterodine 4 mg, 19%; and 8 mg, 35%) and constipation (placebo, 2%; fesoterodine 4 mg, 5%; and 8 mg, 6%).CONCLUSIONFesoterodine 4 and 8 mg significantly reduced UUI episodes vs placebo; this effect appeared to be greater with fesoterodine 8 mg in patients with ≥2 UUI episodes/24 h at baseline. Fesoterodine was well tolerated, although higher doses increased the incidence of adverse events. These findings might aid the clinical identification of patients with OAB who would most benefit from increasing the dose of fesoterodine from 4 to 8 mg.
A placebo‐controlled exploratory study investigating the efficacy and safety of the phosphodiesterase type 5 inhibitor UK‐369,003 for the treatment of men with storage lower urinary tract symptoms associated with a clinical diagnosis of overactive bladder
Authors: Giuliano Francois A. , Lamb Janice , Crossland Anna , Haughie Scott , Ellis Peter , Tamimi Nihad A.M. 
Published: February 2010

Study Type – Therapy (RCT) Level of Evidence 1bOBJECTIVESTo evaluate the efficacy and safety of the phosphodiesterase type 5 inhibitor, UK‐369,003 modified release (MR), for the treatment of storage lower urinary tract symptoms (LUTS) in men with and without erectile dysfunction (ED).PATIENTS AND METHODSThis was a multicentre, double‐blind, placebo‐controlled, parallel‐group study conducted across 50 centres in North and South America, Europe and Australia. In all, 310 men aged ≥18 years with a clinical diagnosis of overactive bladder (OAB; voiding frequency ≥8 times/24 h, urgency episode frequency once or more per 24 h and a mean voided volume of <300 mL) and maximum urinary flow rate of >5 mL/s in a voided volume of >150 mL were stratified into two groups (with or without ED) and randomized to one of five treatment groups (10, 25, 50 or 100 mg UK‐369,003; or placebo once a day) for 12 weeks. The primary study endpoints were those derived from the bladder diary that recorded the number of voluntary urinary voids, volume of urine per void, leaks and urgency episodes over a 72‐h period, before baseline and again at 2, 4 and 12 weeks. Secondary efficacy measures included the International Prostate Symptom Score (total and storage and voiding subscores), International Index of Erectile Function–Erectile Function domain (IIEF‐EF), questions 5 and 6 of the Quality of Erection Questionnaire (QEQ), the Overactive Bladder Questionnaire Short Form, the Patient Perception of Bladder Condition, the International Consultation on Incontinence Questionnaire–Male LUTS, and the patient‐reported treatment impact questionnaire.RESULTSOverall, there were no clinically relevant treatment differences in voiding frequency, mean voided volume, urgency episode frequency, or nocturia frequency for any dose of UK‐369,003 MR compared with placebo. In the subset of patients with ED there were improvements in the IIEF‐EF and QEQ scores in all UK‐369,003 treatment groups compared with placebo.CONCLUSIONSThese data provide no evidence of efficacy for UK‐369,003 in the treatment of storage LUTS in men (based on classic OAB eligibility criteria). However, although the endpoints on these classic OAB efficacy variables were negative, there is evidence to suggest a greater preference, satisfaction and willingness to use UK‐369,003 again for all treatment groups compared with placebo.
Development of a scale to assess patient misperceptions about treatment choices for localized prostate cancer
Authors: Beydoun Hind A. , Mohan Ravinder , Beydoun May A. , Davis John , Lance Raymond , Schellhammer Paul 
Published: February 2010

Study Type – Prevalence (case series) Level of Evidence 4OBJECTIVESTo develop a questionnaire to assess a patient’s knowledge of his cancer, understanding of treatment choices, and judgement of his survival (KUJ) with and without treatment, as treatment for localized prostate cancer (LPC) can lead to urinary, sexual and bowel side‐effects and might not improve survival in 75% of patients.PATIENTS AND METHODSAlthough >90% of patients in the USA are diagnosed with LPC, ≈94% of them choose treatment, such that newly diagnosed patients need individualized counselling to address misperceptions about the management of LPC. The internal consistency of an 18‐item KUJ scale was evaluated among 184 patients recently diagnosed with LPC at a major urology practice. Principal‐component analyses were applied for computing a KUJ index. Logistic regression modelling was used to identify predictors of the KUJ index.RESULTSCronbach’s α for the KUJ scale was 0.76. Nearly half of the patients provided incorrect answers to most KUJ items. Of the patients, 68% had an income of >US$50 000 and 90% had at least high (or secondary) school literacy level. Quality‐of‐life measures suggested that most patients were physically, mentally and socially healthy. Higher education, income and functional capacity were associated with worse KUJ.CONCLUSIONThe KUJ scale is internally consistent and clinicians can use it to identify the educational needs of patients with LPC before treatment selection. Overall, patients who were socioeconomically disadvantaged and those with physical ailments were better informed about the diagnosis, treatment options and prognosis of prostate cancer.
External validation of the SEARCH model for predicting aggressive recurrence after radical prostatectomy: results from the Duke Prostate Center Database
Authors: Teeter Anna E. , Sun Leon , Moul Judd W. , Freedland Stephen J. 
Published: February 2010

Study Type – Prognosis (retrospective cohort) Level of Evidence 2bOBJECTIVETo validate a model previously developed using the Shared Equal Access Regional Cancer Hospital (SEARCH) database to predict the risk of aggressive recurrence after surgery, defined as a prostate‐specific antigen (PSA) doubling time (DT) of <9 months, incorporating pathological stage, preoperative PSA level and pathological Gleason sum, that had an area under the curve (AUC) of 0.79 using a cohort of men from the Duke Prostate Center (DPC).PATIENTS AND METHODSData were included from 1989 men from the DPC database who underwent RP for node‐negative prostate cancer between 1987 and 2003. Of these men, 100 had disease recurrence, with a PSADT of <9 months, while 1889 either did not have a recurrence but had ≥36 months of follow‐up or had a recurrence with a PSADT of ≥9 months. We examined the ability of the SEARCH model to predict aggressive recurrence within the DPC cohort, and examined the correlation between the predicted risk of aggressive recurrence and the actual outcome within DPC.RESULTSThe SEARCH model predicted aggressive recurrence within DPC with an AUC of 0.82. There was a strong and significant correlation between the predicted risk of aggressive recurrence based on the SEARCH tables and the actual outcomes within DPC (r= 0.68, P < 0.001), although the model predictions tended to be slightly higher than the actual risk.CONCLUSIONSThe SEARCH model to predict aggressive recurrence after RP predicted aggressive recurrence in an external dataset with a high degree of accuracy. These tables, now validated, can be used to help select men for adjuvant therapy and clinical trials.
Mechanisms of inhibition of human benign prostatic hyperplasia in vitro by the luteinizing hormone‐releasing hormone antagonist cetrorelix
Authors: Siejka Agnieszka , Schally Andrew V. , Block Norman L. , Barabutis Nektarios 
Published: February 2010

OBJECTIVETo assess the mechanism by which the luteinizing hormone‐releasing hormone (LHRH) antagonist cetrorelix exerts its effects in men with benign prostatic hyperplasia (BPH), as it produces a long‐lasting improvement in lower urinary tract symptoms that is only partly accounted for by the transient reduction in testosterone levels, and the beneficial results could be due to direct inhibitory effects of cetrorelix on the prostate exerted through prostatic LHRH receptors.MATERIALS AND METHODSUsing the BPH‐1 cell line we evaluated the effects of cetrorelix in vitro on the proliferation and the expression of receptors for LHRH, epidermal growth factor (EGF), α1A‐adrenergic receptor, STAT‐3 transcription factor and the response to growth factors insulin‐like growth factor (IGF)‐1 and ‐II and fibroblast growth factor (FGF)‐2.RESULTSThere was expression of LHRH receptors in the human BPH‐1 cell line. Cetrorelix had inhibitory effects on the proliferation rate of BPH‐1 cells, also reflected by the decrease in the expression of the proliferating cell nuclear antigen (PCNA). Cetrorelix inhibited the stimulatory effect of the growth factors IGF‐I and ‐II and FGF‐2 on the proliferation of this line. Cetrorelix also downregulated the expression of the receptors for LHRH and EGF, as well as of α1A‐adrenergic receptors, and inhibited the activation of the STAT3 transcription factor.CONCLUSIONSThe results show that in vitro cetrorelix can directly inhibit the proliferation rate of the human BPH‐1 cell line by counteracting growth factors like IGF‐I and ‐II and FGF‐2, and downregulating the LHRH receptor and α‐adrenergic receptors, as well as transcription factors.
Association of statin and nonsteroidal anti‐inflammatory drug use with prostate cancer outcomes: results from CaPSURE
Authors: Katz Matthew S. , Carroll Peter R. , Cowan Janet E. , Chan June M. , D’Amico Anthony V. 
Published: February 2010

Study Type – Prevalence (prospective cohort) Level of Evidence 1bOBJECTIVETo determine whether 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins) and nonsteroidal anti‐inflammatory drugs (NSAIDs) are associated with the risk of prostate cancer and improved survival in men with prostate cancer.PATIENTS AND METHODSWe retrospectively examined the association between NSAID and statin use among 7042 men who underwent radical prostatectomy (RP, 4611) or radiotherapy (RT, 2431) for prostate cancer between 1990 and 2003 identified in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), a primarily community‐based national prostate cancer registry. We compared clinical and sociodemographic variables by statin and NSAID use, using chi‐square tests and multinomial logistic regression. We examined associations between medications and comorbid illness with mortality using unadjusted and adjusted Cox proportional hazard models.RESULTSThe median (range) follow‐up from treatment was 4 (0–16) years. In multivariate survival analysis, statin ‘ever‐use’ was associated with a reduced risk of all‐cause mortality (ACM) after RP (hazard ratio, HR, 0.35, 95% confidence interval, CI, 0.21–0.58) and RT (0.59, 0.37–0.94). NSAID ever‐use was also associated with a reduced risk of ACM after RP (HR 0.47, 95% CI 0.30–0.75) and RT (0.39, 0.25–0.59).CONCLUSIONSIn a population of men with prostate cancer, statin and NSAID ever‐use were associated with a reduced risk of ACM. Our study highlights the importance of multidisciplinary survivorship care for men with prostate cancer.
Changes in symptoms of renal cell carcinoma over four decades
Authors: Sunela Kaisa L. , Kataja Matti J. , Kellokumpu‐Lehtinen Pirkko‐Liisa I. 
Published: February 2010

Study Type – Symptom prevalence (case series) Level of Evidence 4OBJECTIVETo determine whether there has been a change in typical symptoms of renal cell carcinoma (RCC), by evaluating the symptoms of patients diagnosed during four decades, as although the increasing incidence of a diagnosis of incidental RCC has been widely reported, the change in other symptoms has not.PATIENTS AND METHODSThe study included RCC cases diagnosed in the Pirkanmaa Hospital District between 1964 and 1997. The original medical records of 970 patients with 982 RCC tumours were analysed. Primary symptoms were recorded and changes were analysed in three groups, i.e. diagnoses made before 1980, in the 1980s and in the 1990s. Symptoms were also analysed according to stage, tumour class, gender and age.RESULTSThe incidence of haematuria (P < 0.01) and an increased erythrocyte sedimentation rate (P < 0.001) decreased, but there was no change in other symptoms. Incidental diagnoses increased from 12% to 19% (P < 0.01). Less chronic or systemic symptoms were noted more recently. Stage and tumour class were highly correlated with symptoms: systemic symptoms increased (24% in stage I to 72% in stage IV, a highly statistically significant increase) and asymptomatic tumours became rarer (27% in stage I to 8% in stage IV, again a highly significant increase) with increasing stage. Haematuria was more common in male patients, anaemia and flank pain in women. Elderly patients were more often asymptomatic than younger patients, with 70–79‐year‐olds being the least symptomatic.CONCLUSIONSIncidental cases of RCC have recently become more common. Haematuria, hypersedimentation, chronic and systemic symptoms have decreased. Stage, tumour class, gender and age are correlated with symptoms.
Institutional Investors and Institutional Environment: A Comparative Analysis and Review
Authors: Johnson Richard A. , Schnatterly Karen , Johnson Scott G. , Chiu Shih‐Chi 
Published: February 2010

abstractWe provide a review of the literature surrounding institutional investor classifications, and we extend this research by examining the aforementioned classification systems and relate this to the three predominant financial systems (market‐based, family‐centred, and bank‐centred systems). After integrating this literature we propose that future research can contribute to the corporate governance field in three main ways: through improved measurement of the central constructs, through more complex research designs (through moderated and/or longitudinal relationships), and through asking new types of questions. We suggest several questions and approaches for future research on institutional investors and their interrelationship with country financial systems.