bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased Apolipoprotein Deposits in Early Atherosclerotic Lesions Distinguish Symptomatic From Asymptomatic Patients
Authors: Wyler von Ballmoos Moritz , Dubler Denise , Mirlacher Martina , Cathomas Gieri , Muser Jürgen , Biedermann Barbara C.
Published: December 2005

Objective—

Apolipoprotein E (apoE) and apolipoprotein B100 (apoB) are both involved in receptor-mediated uptake of atherogenic lipoproteins by the liver. Inefficient hepatic clearance of these lipoproteins leads to symptomatic atherosclerosis. Using arterial tissue microarrays, we tested the hypothesis that apoE and apoB accumulation in the arterial wall discriminates between patients with symptomatic atherosclerosis and patients who never experienced cardiovascular events.

Methods and Results—

In a postmortem study involving 49 patients (22 patients with symptomatic atherosclerosis), we quantified apolipoprotein deposits in arterial rings obtained from the left main coronary, the common carotid, the common iliac, and the renal artery applying tissue microarray technology and semiquantitative immunohistochemistry. In early atherosclerotic lesions, even before atheroma appeared, symptomatic patients had significantly more arterial apoE and apoB deposits than patients without cardiovascular events (
P
<0.001). Among the symptomatic patients, those without diabetes had more intense apolipoprotein deposits than diabetics. Large amounts of apoE and apoB were found in advanced atherosclerotic lesions, regardless of the activity of the disease.

Conclusions—

Increased apolipoprotein deposits are an early sign of symptomatic atherosclerosis. They may reflect either enhanced retention of atherogenic lipoproteins or impaired local apolipoprotein degradation. The arterial lipoprotein turnover may be different in diabetic patients.
Elevated Markers of Endothelial Dysfunction Predict Type 2 Diabetes Mellitus in Middle-Aged Men and Women From the General Population
Authors: Thorand Barbara , Baumert Jens , Chambless Lloyd , Meisinger Christa , Kolb Hubert , Döring Angela , Löwel Hannelore , Koenig Wolfgang
Published: December 2005

Objective—Using the Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA)/Cooperative Research in the Region of Augsburg (KORA) database, we investigated prospectively whether increased levels of soluble E-selectin (sE-selectin), soluble intercellular adhesion molecule 1 (sICAM-1), and von Willebrand factor (vWF), all considered to be sensitive markers of endothelial dysfunction, are associated with an increased risk of incident type 2 diabetes mellitus.

Methods and Results—In a case–cohort study, concentrations of adhesion molecules were measured in stored samples of 532 case subjects and 1712 noncase subjects. VWF was measured in a subsample with available plasma samples (n=191 case and 580 noncase subjects). Men and women with elevated levels of sE-selectin had a significantly increased risk of type 2 diabetes after multivariable adjustment. Hazard ratios (95% CIs) comparing tertile extremes of sE-selectin were 2.63 (1.79 to 3.88) and 1.71 (1.07 to 2.75) for men and women, respectively. Elevated levels of sICAM-1 were also associated with an increased risk of type 2 diabetes; however, the association was not independent of other diabetes risk factors including E-selectin [hazard ratio (95% CI) for tertile 3 versus tertile 1: men, 1.32 (0.89 to 1.96); women, 1.03 (0.64 to 1.67)]. In this study, vWF was not associated with risk of type 2 diabetes.

Conclusions—These data support a role of endothelial dysfunction in the etiology of type 2 diabetes.
Radiation Induces Endothelial Dysfunction in Murine Intestinal Arterioles via Enhanced Production of Reactive Oxygen Species
Authors: Hatoum Ossama A. , Otterson Mary F. , Kopelman Doron , Miura Hiroto , Sukhotnik Igor , Larsen Brandon T. , Selle Rebecca M. , Moulder John E. , Gutterman David D.
Published: December 2005

Objective—Endothelial dysfunction and vascular dysregulation contribute to the pathological effects of radiation on tissues. The objectives of this study were to assess the acute effect of irradiation on acetylcholine (Ach)-induced dilation of gut submucosal microvessels.

Methods and Results—Rats were exposed in vivo to 1 to 9 cGy in 3 fractions per week on alternate days for 3 successive weeks for a total dose of up to 2250 cGy. Submucosal microvessels were isolated after varying levels of irradiation. Diameters of isolated vessels were measured using videomicroscopy, and the dose-response relationship to Ach was determined. Dihydroethidine and 2′, 7′-dichlorodihydrofluorescein diacetate fluorescent probes were used to assess reactive oxygen species (ROS) production. After constriction (30% to 50%) with endothelin, dilation to graded doses of Ach (10−9−10−4M) was observed in control vessels (maximal dilation [MD] 87±3%; n=7). However, Ach-induced dilation was reduced in vessels from irradiated rats (MD=3±9%; n=7;P=<0.05 versus controls). Significant increases in superoxide and peroxides were observed in irradiated microvessels. Irradiated microvessels pretreated with superoxide dismutase–mimetic demonstrated significant improvement in Ach-induced vasodilation compared with irradiation alone, suggesting that superoxide contributes to impaired dilation to Ach after irradiation.

Conclusions—Radiation induces acute microvascular dysfunction in the resistance arterioles of the intestine. Enhanced ROS contribute to this dysfunction and therefore may represent a novel therapeutic target to minimize radiation toxicity in the gut.
Cdc42 Regulates Adherens Junction Stability and Endothelial Permeability by Inducing α-Catenin Interaction With the Vascular Endothelial Cadherin Complex
Authors: Broman Michael T. , Kouklis Panos , Gao Xiaopei , Ramchandran Ramaswamy , Neamu Radu F. , Minshall Richard D. , Malik Asrar B.
Published: December 2005

The endothelial adherens junctions (AJs) consist of
trans
-oligomers of membrane spanning vascular endothelial (VE)-cadherin proteins, which bind β-catenin through their cytoplasmic domain. β-Catenin in turn binds α-catenin and connects the AJ complex with the actin cytoskeleton. We addressed the in vivo effects of loss of VE-cadherin interactions on lung vascular endothelial permeability and the role of specific Rho GTPase effectors in regulating the increase in permeability induced by AJ destabilization. We used cationic liposomes encapsulating the mutant of VE-cadherin lacking the extracellular domain (ΔEXD) to interfere with AJ assembly in mouse lung endothelial cells. We observed that lung vascular permeability (quantified as microvessel filtration coefficient [
K

f,c

]) was increased 5-fold in lungs expressing ΔEXD. This did not occur to the same degree on expression of the VE-cadherin mutant, ΔEXDΔβ, lacking the β-catenin–binding site. The increased vascular permeability was the result of destabilization of VE-cadherin homotypic interaction induced by a shift in the binding of β-catenin from wild-type VE-cadherin to the expressed ΔEXD mutant. Because ΔEXD expression in endothelial cells activated the Rho GTPase Cdc42, we addressed its role in the mechanism of increased endothelial permeability induced by AJ destabilization. Coexpression of dominant-negative Cdc42 (N17Cdc42) prevented the increase in
K

f,c

induced by ΔEXD. This was attributed to inhibition of the association of α-catenin with the ΔEXD–β-catenin complex. The results demonstrate that Cdc42 regulates AJ permeability by controlling the binding of α-catenin with β-catenin and the consequent interaction of the VE-cadherin/catenin complex with the actin cytoskeleton.
Urgent Clinical Challenges in Children With Ischemic Stroke
Authors: Kuhle Stefan , Mitchell Lesley , Andrew Maureen , Chan Anthony K. , Massicotte Patricia , Adams Margaret , deVeber Gabrielle
Published: December 2005

Background and Purpose—

Clinical trials are lacking in pediatric stroke. As a result, physicians caring for children with stroke face significant challenges. The patient characteristics and specific nature of clinical challenges facing practicing clinicians can inform the design of and priorities for developing relevant clinical trials.

Methods—

Physicians consulted the 1-800-NOCLOTS toll-free pediatric stroke telephone consultation service on children (birth to 18 years) with ischemic stroke. Pediatric neurologist or hematologists provided telephone consultation and documented caller and patient characteristics, antithrombotic treatments and callers’ questions for entry into a computerized database. Children referred from January 1, 1995 to January 1, 2004, comprised the study cohort.

Results—

Stroke consults were completed on 1065 children located predominantly in the United States (76%). Children had arterial ischemic stroke (AIS; 679; 64%) or cerebral sinovenous thrombosis (CSVT; 386; 36%) and were 54% male and 16% neonates. Risk factors and antithrombotic agents (none, aspirin, warfarin, and heparins) differed by stroke type. In 60% of patients, callers had not initiated antithrombotic therapy. Callers’ questions for both stroke types usually concerned treatment selection (83%), but for AIS, questions more frequently (
P
<0.0001) concerned the selection and interpretation of etiological investigations.

Conclusions—

Research is urgently needed in pediatric stroke to provide direction for management in “real-life” settings. Research efforts should address the unique challenges within different stroke types and include observational studies addressing investigation of the child with AIS. For AIS and CSVT, randomized controlled trials investigating the efficacy of antithrombotic treatment are urgently needed.
Novel Representation of Astasia Associated With Posterior Cingulate Infarction
Authors: Kataoka Hiroshi , Sugie Kazuma , Kohara Nobuo , Ueno Satoshi
Published: December 2005

Background and Purpose—

The representation elicited in the cingulate motor area has been demonstrated in animals, but remains unclear in humans. In particular, the representation and pathogenic mechanisms of the posterior cingulate cortex are poorly understood, especially in humans. We describe a case of posterior cingulate infarction associated with contralateral astasia.

Case Description—

A 67-year-old right-handed man with a 10-year history of hypertension suddenly presented with right-sided pulsion on attempting to stand or sit. On the following day, he could not maintain a sitting position. The patient immediately fell to the floor because of instability, characterized by marked right-sided pulsion despite no muscle weakness, sensorial deficits, or cerebellar ataxia. Magnetic resolution imaging of the brain showed abnormal intensity in the posterior parts of the cingulate, with no other clinically significant lesions.

Conclusions—

Because the cingulate motor area is connected to the vestibulocerebellar system through the thalamic nuclei, disruption of this connection by posterior cingulate infarction may result in astasia.
Susceptibility to Deterioration of Mobility Long-Term After Stroke
Authors: van de Port Ingrid G.L. , Kwakkel Gert , van Wijk Iris , Lindeman Eline
Published: December 2005

Background and Purpose—

The aim of the present study was to identify clinical determinants able to predict which individuals are susceptible to deterioration of mobility from 1 to 3 years after stroke.

Methods—

Prospective cohort study of stroke patients consecutively admitted for inpatient rehabilitation. A total of 205 relatively young, first-ever stroke patients were assessed at 1 and 3 years after stroke. Mobility status was determined by the Rivermead Mobility Index (RMI), and decline was defined as a deterioration of ≥2 points on the RMI. Univariate and multivariate logistic regression analyses were performed to identify prognostic factors for mobility decline. The discriminating ability of the model was determined using a receiver operating characteristic curve.

Results—

A decline in mobility status was found in 21% of the patients. Inactivity and the presence of cognitive problems, fatigue, and depression at 1 year after stroke were significant predictors of mobility decline. The multivariate model showed a good fit (Hosmer–Lemeshow test
P
>0.05), and discriminating ability was good (area under the curve 0.79).

Conclusions—

Mobility decline is an essential concern in chronic stroke patients, especially because it might lead to activities of daily living dependence and affects social reintegration. Early recognition of prognostic factors in patients at risk may guide clinicians to apply interventions aimed to prevent deterioration of mobility status in chronic stroke.
An Examination of the Effects of Delayed Versus Immediate Prompts on Safety Belt Use
Authors: Austin John , Sigurdsson Sigurdur Oli , Rubin Yonata Shpak
Published: December 2005

A three-group designwas used to evaluate the effects of immediate and delayed verbal prompts on seat belt use versus a no-prompt control condition. Participants in this study were drivers who used valet parking services at a hotel. In the immediate-prompt condition, participants were prompted to buckle up immediately before entering a vehicle; in the delayed-prompt condition, the prompt was delivered when participants delivered the ticket to have their vehicles retrieved. The average delay between a prompt and when participants'vehicles were in motionwas nearly 30 s in the immediate-prompt condition, whereas the delay in the delayed-prompt condition was nearly 5 min 30 s. It was hypothesized that (a) delayed prompts would result in increased seat belt usage rates as compared to the control condition and (b) immediate prompts would lead to higher seat belt usage than delayed prompts. Results supported the second hypothesis but not the first.
The ‘Gujarat’ earthquake and the political economy of nostalgia
Authors: Simpson Edward
Published: December 2005

This article is an ethnographic exploration of the rise and fall of nostalgia as a form of collective narrative among survivors of the 2001 ‘Gujarat’ earthquake. In the social sciences, nostalgia is commonly regarded as an inevitable consequence of alienation from natural and social worlds in both space and time. My data is presented here as a way of scrutinising the complex series of social relationships that create the misleading appearance of cause (alienation) and effect (nostalgia).
Skin-derived interleukin-7 contributes to the proliferation of lymphocytes in cutaneous T-cell lymphoma
Authors: Yamanaka Kei-ichi , Clark Rachael , Rich Benjamin , Dowgiert Rebecca , Hirahara Kazuki , Hurwitz Daniel , Shibata Michio , Mirchandani Nina , Jones David A. , Goddard Deborah S. , Eapen Sara , Mizutani Hitoshi , Kupper Thomas S.
Published: December 2005

Cutaneous T-cell lymphomas (CTCLs) are malignancies of T cells that have a special affinity for the skin. We have previously reported that much of the T-cell receptor repertoire is altered in CTCL, and both malignant and nonmalignant clones are numerically expanded, presumably in response to T-cell trophic cytokines. We therefore examined levels of the T-cell trophic cytokines IL-2, IL-4, IL-7, IL-12, IL-13, and IL-15 in plasma in 93 CTCL patients and healthy controls. Only IL-7 levels were elevated in CTCL. We next looked at lesional skin from patients with CTCL and found elevated levels of IL-7 mRNA. Explant cultures of normal and lesional CTCL skin biopsies revealed significantly more IL-7 protein production in CTCL skin. Additionally, cultures of CTCL skin released greater numbers of T cells than normal skin; this was blocked by the addition of an IL-7 neutralizing antibody. Finally, these cultures induced proliferation of normal peripheral skin-homing T cells that were added to the cultures. These observations led us to postulate that IL-7 produced by skin cells contributes to the survival and proliferation of T cells within skin lesions and is likely the source of elevated circulating IL-7 in CTCL. (Blood. 2006;107:2440-2445)
Distinct gene expression patterns in chronic lymphocytic leukemia defined by usage of specific VH genes
Authors: Kienle Dirk , Benner Axel , Kröber Alexander , Winkler Dirk , Mertens Daniel , Bühler Andreas , Seiler Till , Jäger Ulrich , Lichter Peter , Döhner Hartmut , Stilgenbauer Stephan
Published: December 2005

The mutation status and usage of specific VH genes such as V3-21 and V1-69 are potentially independent pathogenic and prognostic factors in chronic lymphocytic leukemia (CLL). To investigate the role of antigenic stimulation, we analyzed the expression of genes involved in B-cell receptor (BCR) signaling/activation, cell cycle, and apoptosis control in CLL using these specific VH genes compared to VH mutated (VH-MUT) and VH unmutated (VH-UM) CLL not using these VH genes. V3-21 cases showed characteristic expression differences compared to VH-MUT (up: ZAP70 [or ZAP-70]; down: CCND2, P27) and VH-UM (down: PI3K, CCND2, P27, CDK4, BAX) involving several BCR-related genes. Similarly, there was a marked difference between VH unmutated cases using the V1-69 gene and VH-UM (up: FOS; down: BLNK, SYK, CDK4, TP53). Therefore, usage of specific VH genes appears to have a strong influence on the gene expression pattern pointing to antigen recognition and ongoing BCR stimulation as a pathogenic factor in these CLL subgroups.
Fluctuations of functionally distinct CD8+ T-cell clonotypes demonstrate flexibility of the HIV-specific TCR repertoire
Authors: Meyer-Olson Dirk , Brady Kristen W. , Bartman Melissa T. , O'Sullivan Kristin M. , Simons Brenna C. , Conrad Joseph A. , Duncan Coley B. , Lorey Shelly , Siddique Atif , Draenert Rika , Addo Marylyn , Altfeld Marcus , Rosenberg Eric , Allen Todd M. , Walker Bruce D. , Kalams Spyros A.
Published: December 2005

T-cell receptor (TCR) diversity of virus-specific CD8+ T cells likely helps prevent escape mutations in chronic viral infections. To understand the dynamics of the virus-specific T cells in more detail, we followed the evolution of the TCR repertoire specific for a dominant HLA-B*08–restricted epitope in Nef (FLKEKGGL) in a cohort of subjects infected with HIV. Epitope-specific CD8+ T cells used structurally diverse TCR repertoires, with different TCRβ variable regions and with high amino acid diversity within antigen recognition sites. In a longitudinal study, distinct Vβ populations within the HIV-specific TCR repertoire expanded simultaneously with changes in plasma viremia, whereas other Vβ populations remained stable or even decreased. Despite antigenic variation in some subjects, all subjects had the consensus sequence present during the study period. Functional analysis of distinct Vβ populations revealed differences in HIV-specific IFN-γ secretion ex vivo as well as differences in tetramer binding, indicating functional heterogeneity among these populations. This contrasts with findings in a subject on antiretroviral therapy with suppression of viremia to less than 50 copies/mL, where we observed long-term persistence of a single clonotype. Our findings illustrate the flexibility of a heterogeneous HIV-1–specific CD8+ TCR repertoire in subjects with partial control of viremia.
Variable phosphorylation states of pigment-epithelium–derived factor differentially regulate its function
Authors: Maik-Rachline Galia , Seger Rony
Published: December 2005

The pigment epithelium–derived factor (PEDF) belongs to the family of noninhibitory serpins. Although originally identified in the eye, PEDF is widely expressed in other body regions including the plasma. This factor can act either as a neurotrophic or as an antiangiogenic factor, and we previously showed that the 2 effects of PEDF are regulated through phosphorylation by PKA and CK2. Here, we studied the interplay between the PKA and CK2 phosphorylation of PEDF, and found that a PEDF mutant mimicking the CK2-phosphorylated PEDF cannot be phosphorylated by PKA, while the mutant mimicking the PKA-phosphorylated PEDF is a good CK2 substrate. Using triple mutants that mimic the PKA- and CK2-phosphorylated and nonphosphorylated PEDF, we found that PEDF can induce several distinct cellular activities dependent on its phosphorylation. The mutant mimicking the accumulative PKA plus CK2 phosphorylation exhibited the strongest antiangiogenic and neurotrophic activities, while the mutants mimicking the individual phosphorylation site mutants had either a reduced activity or only one of these activities. Thus, differential phosphorylation induces variable effects of PEDF, and therefore contributes to the complexity of PEDF action. It is likely that the triple phosphomimetic mutant can be used to generate effective antiangiogenic or neurotrophic drugs.
Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver
Authors: Nathwani Amit C. , Gray John T. , Ng Catherine Y. C. , Zhou Junfang , Spence Yunyu , Waddington Simon N. , Tuddenham Edward G. D. , Kemball-Cook Geoffrey , McIntosh Jenny , Boon-Spijker Mariette , Mertens Koen , Davidoff Andrew M.
Published: December 2005

Transduction with recombinant adeno-associated virus (AAV) vectors is limited by the need to convert its single-stranded (ss) genome to transcriptionally active double-stranded (ds) forms. For AAV-mediated hemophilia B (HB) gene therapy, we have overcome this obstacle by constructing a liver-restricted mini–human factor IX (hFIX) expression cassette that can be packaged as complementary dimers within individual AAV particles. Molecular analysis of murine liver transduced with these self-complementary (sc) vectors demonstrated rapid formation of active ds-linear genomes that persisted stably as concatamers or monomeric circles. This unique property resulted in a 20-fold improvement in hFIX expression in mice over comparable ssAAV vectors. Administration of only 1 × 1010 scAAV particles led to expression of hFIX at supraphysiologic levels (8I U/mL) and correction of the bleeding diathesis in FIX knock-out mice. Of importance, therapeutic levels of hFIX (3%-30% of normal) were achieved in nonhuman primates using a significantly lower dose of scAAV than required with ssAAV. Furthermore, AAV5-pseudotyped scAAV vectors mediated successful transduction in macaques with pre-existing immunity to AAV8. Hence, this novel vector represents an important advance for hemophilia B gene therapy.
Total therapy 2 without thalidomide in comparison with total therapy 1: role of intensified induction and posttransplantation consolidation therapies
Authors: Barlogie Bart , Tricot Guido , Rasmussen Erik , Anaissie Elias , van Rhee Frits , Zangari Maurizio , Fassas Athanasios , Hollmig Klaus , Pineda-Roman Mauricio , Shaughnessy John , Epstein Joshua , Crowley John
Published: December 2005

Patients with myeloma, treated on the thalidomide arm of total therapy 2 (TT2), had a higher complete response (CR) rate and improved event-free survival (EFS) but not overall survival (OS). To evaluate the benefit of TT2's posttandem autotransplant consolidation chemotherapy and dexamethasone maintenance, outcomes were compared on TT2 without thalidomide (n = 345; median follow-up, 3.5 years) and on predecessor trial TT1 (n = 231; median follow-up, 11.5 years). CR rates were similar (43% vs 41%); however, 5-year estimates of continuous CR (45% vs 32%, P < .001) and 5-year EFS (43% vs 28%, P < .001) were superior with TT2, with a trend for improved OS (62% vs 57%; P = .11). OS was also superior among patients achieving CR and receiving the second transplantation early after the first transplantation. Superior EFS and OS with TT2 versus TT1 was noted in the two thirds presenting without cytogenetic abnormalities (CAs); 4-year posttandem transplantation OS for patients with CAs was 47% with TT1 and 76% with TT2 when combination chemotherapy rather than DEX was applied for consolidation (P = .040). Thus, TT2 (without thalidomide) improved OS of patients without CAs; those with CAs benefited from posttransplantation consolidation chemotherapy. The favorable effects of CR and rapidly sequenced second transplantation attest to the validity of a melphalan dose-response effect in myeloma.
ArrayQuest: a web resource for the analysis of DNA microarray data
Authors: Argraves Gary L , Jani Saurin , Barth Jeremy L , Argraves W Scott
Published: December 2005

Background

Numerous microarray analysis programs have been created through the efforts of Open Source software development projects. Providing browser-based interfaces that allow these programs to be executed over the Internet enhances the applicability and utility of these analytic software tools.

Results

Here we present ArrayQuest, a web-based DNA microarray analysis process controller. Key features of ArrayQuest are that (1) it is capable of executing numerous analysis programs such as those written in R, BioPerl and C++; (2) new analysis programs can be added to ArrayQuest Methods Library at the request of users or developers; (3) input DNA microarray data can be selected from public databases (i.e., the Medical University of South Carolina (MUSC) DNA Microarray Database or Gene Expression Omnibus (GEO)) or it can be uploaded to the ArrayQuest center-point web server into a password-protected area; and (4) analysis jobs are distributed across computers configured in a backend cluster. To demonstrate the utility of ArrayQuest we have populated the methods library with methods for analysis of Affymetrix DNA microarray data.

Conclusion

ArrayQuest enables browser-based implementation of DNA microarray data analysis programs that can be executed on a Linux-based platform. Importantly, ArrayQuest is a platform that will facilitate the distribution and implementation of new analysis algorithms and is therefore of use to both developers of analysis applications as well as users. ArrayQuest is freely available for use at http://proteogenomics.musc.edu/arrayquest.html.
Polymorphisms of the Flavin containing monooxygenase 3 (FMO3) gene do not predispose to essential hypertension in Caucasians
Authors: Dolan Ciara , Shields Denis C , Stanton Alice , O'Brien Eoin , Lambert Deborah M , O'Brien John K , Treacy Eileen P
Published: December 2005

Background

The recessive disorder trimethylaminuria is caused by defects in theFMO3gene, and may be associated with hypertension. We investigated whether common polymorphisms of theFMO3gene confer an increased risk for elevated blood pressure and/or essential hypertension.

Methods

FMO3genotypes (E158K, V257M, E308G) were determined in 387 healthy subjects with ambulatory systolic and diastolic blood pressure measurements, and in a cardiovascular disease population of 1649 individuals, 691(41.9%) of whom had a history of hypertension requiring drug treatment. Haplotypes were determined and their distribution noted.

Results

There was no statistically significant association found between any of the 4 common haplotypes and daytime systolic blood pressure in the healthy population (p = 0.65). Neither was a statistically significant association found between the 4 common haplotypes and hypertension status among the cardiovascular disease patients (p = 0.80).

Conclusion

These results suggest that the variants in theFMO3gene do not predispose to essential hypertension in this population.
The effect of body mass index on global brain volume in middle-aged adults: a cross sectional study
Authors: Ward Michael A , Carlsson Cynthia M , Trivedi Mehul A , Sager Mark A , Johnson Sterling C
Published: December 2005

Background

Obesity causes or exacerbates a host of medical conditions, including cardiovascular, pulmonary, and endocrine diseases. Recently obesity in elderly women was associated with greater risk of dementia, white matter ischemic changes, and greater brain atrophy. The purpose of this study was to determine whether body type affects global brain volume, a marker of atrophy, in middle-aged men and women.

Methods

T1-weighted 3D volumetric magnetic resonance imaging was used to assess global brain volume for 114 individuals 40 to 66 years of age (average = 54.2 years; standard deviation = 6.6 years; 43 men and 71 women). Total cerebrospinal fluid and brain volumes were obtained with an automated tissue segmentation algorithm. A regression model was used to determine the effect of age, body mass index (BMI), and other cardiovascular risk factors on brain volume and cognition.

Results

Age and BMI were each associated with decreased brain volume. BMI did not predict cognition in this sample; however elevated diastolic blood pressure was associated with poorer episodic learning performance.

Conclusion

These findings suggest that middle-aged obese adults may already be experiencing differentially greater brain atrophy, and may potentially be at greater risk for future cognitive decline.
Prevalence of antiplatelet therapy in patients with diabetes
Authors: Miller Shaun R , Littenberg Benjamin , MacLean Charles D
Published: December 2005

Objective

To determine the prevalence of, and patient characteristics associated with, antiplatelet therapy in a cohort of primary care patients with Type 1 or Type2 diabetes.

Methods

Subjects participating in a randomized trial of a decision support system were interviewed at home and medication usage verified by a research assistant. Eligibility for antiplatelet therapy was determined by American Diabetes Association criteria and clinical contraindications. The association between antiplatelet use and patient characteristics was examined using bivariate and multivariate logistic regression.

Results

The mean age of subjects was 64 years (range 31–93). The prevalence of antiplatelet use was 54% overall; 45% for subjects without known CVD vs. 78% for those with CVD; 46% for women vs. 63% for men; and 45% for younger subjects (age< 65) vs. 62% for senior citizens. After controlling for race/ethnicity, income, education, marital status, insurance status and prescription coverage, the following were associated with the use of antiplatelet therapy: presence of known CVD (OR 3.4 [2.2, 5.1]), male sex (OR 2.0 [1.4, 2.8]), and age > = 65 (OR 1.9 [1.3, 2.7]). The prevalence of antiplatelet therapy for younger women without CVD was 32.8% compared to a prevalence of 90.3% for older men with CVD.

Conclusion

Despite clinical practice guidelines recommending antiplatelet therapy for patients with diabetes, there are still many eligible patients not receiving this beneficial therapy, particularly patients under 65, women, and patients without known CVD. Effective methods to increase antiplatelet use should be considered at the national, community, practice and provider level.
Analysis of adequacy levels for human resources improvement within primary health care framework in Africa
Authors: Parent Florence , Fromageot Audrey , Coppieters Yves , Lejeune Colette , Lemenu Dominique , Garant Michèle , Piette Danielle , Levêque Alain , De Ketele Jean-Marie
Published: December 2005

Human resources in health care system in sub-Saharan Africa are generally picturing a lack of adequacy between expected skills from the professionals and health care needs expressed by the populations. It is, however, possible to analyse these various lacks of adequacy related to human resource management and their determinants to enhance the effectiveness of the health care system. From two projects focused on nurse professionals within the health care system in Central Africa, we present an analytic grid for adequacy levels looking into the following aspects:

- adequacy between skills-based profiles for health system professionals, quality of care and service delivery (health care system /medical standards), needs and expectations from the populations,

- adequacy between allocation of health system professionals, quality of care and services delivered (health care system /medical standards), needs and expectations from the populations,

- adequacy between human resource management within health care system and medical standards,

- adequacy between human resource management within education/teaching/training and needs from health care system and education sectors,

- adequacy between basic and on-going education and realities of tasks expected and implemented by different categories of professionals within the health care system body,

- adequacy between intentions for initial and on-going trainings and teaching programs in health sciences for trainers (teachers/supervisors/health care system professionals/ directors (teaching managers) of schools...).

This tool is necessary for decision-makers as well as for health care system professionals who share common objectives for changes at each level of intervention within the health system. Setting this adequacy implies interdisciplinary and participative approaches for concerned actors in order to provide an overall vision of a more broaden system than health district, small island with self-rationality, and in which they operate.
Control of hyperuricemia in subjects with refractory gout, and induction of antibody against poly(ethylene glycol) (PEG), in a phase I trial of subcutaneous PEGylated urate oxidase
Authors: Ganson Nancy J , Kelly Susan J , Scarlett Edna , Sundy John S , Hershfield Michael S
Published: December 2005

PEG-modified recombinant mammalian urate oxidase (PEG-uricase) is being developed as a treatment for patients with chronic gout who are intolerant of, or refractory to, available therapy for controlling hyperuricemia. In an open-label phase I trial, single subcutaneous injections of PEG-uricase (4 to 24 mg) were administered to 13 such subjects (11 had tophaceous gout), whose plasma uric acid concentration (pUAc) was 11.3 ± 2.1 mg/dl (mean ± SD). By day seven after injection of PEG-uricase, pUAc had declined by an average of 7.9 mg/dl and had normalized in 11 subjects, whose mean pUAc decreased to 2.8 ± 2.2 mg/dl. At doses of 8, 12, and 24 mg, the mean pUAc at 21 days after injection remained no more than 6 mg/dl. In eight subjects, plasma uricase activity was still measurable at 21 days after injection (half-life 10.5 to 19.9 days). In the other five subjects, plasma uricase activity could not be detected beyond ten days after injection; this was associated with the appearance of relatively low-titer IgM and IgG antibodies against PEG-uricase. Unexpectedly, these antibodies were directed against PEG itself rather than the uricase protein. Three PEG antibody-positive subjects had injection-site reactions at 8 to 9 days after injection. Gout flares in six subjects were the only other significant adverse reactions, and PEG-uricase was otherwise well tolerated. A prolonged circulating life and the ability to normalize plasma uric acid in markedly hyperuricemic subjects suggest that PEG-uricase could be effective in depleting expanded tissue stores of uric acid in subjects with chronic or tophaceous gout. The development of anti-PEG antibodies, which may limit efficacy in some patients, is contrary to the general assumption that PEG is non-immunogenic. PEG immunogenicity deserves further investigation, because it has potential implications for other PEGylated therapeutic agents in clinical use.
Heterogeneity of psychophysiological stress responses in fibromyalgia syndrome patients
Authors: Thieme Kati , Turk Dennis C
Published: December 2005

Dysregulated psychophysiological responses have been observed in patients with fibromyalgia syndrome (FMS), although the results are inconsistent. Surface electromyographic (EMG), systolic and diastolic blood pressure, heart rate (HR), and skin conductance levels (SCLs) were continuously recorded at baseline, and during a series of stress and relaxation tasks in 90 FMS patients and 30 age and sex matched healthy controls (HCs). The patient sample demonstrated lower baseline EMG levels compared to the HCs on all tasks. In contrast, the patients displayed elevated HR and SCL (sympathetic vasomotor and sudomotor indices, respectively) during both stress tasks. A cluster analysis identified four psychophysiological response patterns: 63.3% of HCs showed increased muscle tension and stable cardiovascular responses; 34.8% of FMS patients showed a pattern of increased sympathetic vasomotor reactivity with stable sudomotor and reduced muscular response; 12.2% of FMS patients showed a pattern of increased sympathetic sudomotor reactivity connected with increased sympathetic vasomotor response and reduced muscular response; and, in contrast, 46.7% of FMS patients showed a pattern of parasympathetic vasomotor reactivity and reduced sudomotor as well as muscular response. The identification of low baseline muscle tension in FMS is discrepant with other chronic pain syndromes and suggests that unique psychophysiological features may be associated with FMS. The different psychophysiological response patterns within the patient sample support the heterogeneity of FMS.
The design of transcription-factor binding sites is affected by combinatorial regulation
Authors: Bilu Yonatan , Barkai Naama
Published: December 2005

Background

Transcription factors regulate gene expression by binding to specific cis-regulatory elements in gene promoters. Although DNA sequences that serve as transcription-factor binding sites have been characterized and associated with the regulation of numerous genes, the principles that govern the design and evolution of such sites are poorly understood.

Results

Using the comprehensive mapping of binding-site locations available in Saccharomyces cerevisiae, we examined possible factors that may have an impact on binding-site design. We found that binding sites tend to be shorter and fuzzier when they appear in promoter regions that bind multiple transcription factors. We further found that essential genes bind relatively fewer transcription factors, as do divergent promoters. We provide evidence that novel binding sites tend to appear in specific promoters that are already associated with multiple sites.

Conclusion

Two principal models may account for the observed correlations. First, it may be that the interaction between multiple factors compensates for the decreased specificity of each specific binding sequence. In such a scenario, binding-site fuzziness is a consequence of the presence of multiple binding sites. Second, binding sites may tend to appear in promoter regions that are subject to low selective pressure, which also allows for fuzzier motifs. The latter possibility may account for the relatively low number of binding sites found in promoters of essential genes and in divergent promoters.
The discovery, positioning and verification of a set of transcription-associated motifs in vertebrates
Authors: Ettwiller Laurence , Paten Benedict , Souren Marcel , Loosli Felix , Wittbrodt Jochen , Birney Ewan
Published: December 2005

We have developed several new methods to investigate transcriptional motifs in vertebrates. We developed a specific alignment tool appropriate for regions involved in transcription control, and exhaustively enumerated all possible 12-mers for involvement in transcription by virtue of their mammalian conservation. We then used deeper comparative analysis across vertebrates to identify the active instances of these motifs. We have shown experimentally in Medaka fish that a subset of these predictions is involved in transcription.
A low-cost open-source SNP genotyping platform for association mapping applications
Authors: Macdonald Stuart J , Pastinen Tomi , Genissel Anne , Cornforth Theodore W , Long Anthony D
Published: December 2005

Association mapping aimed at identifying DNA polymorphisms that contribute to variation in complex traits entails genotyping a large number of single-nucleotide polymorphisms (SNPs) in a very large panel of individuals. Few technologies, however, provide inexpensive high-throughput genotyping. Here, we present an efficient approach developed specifically for genotyping large fixed panels of diploid individuals. The cost-effective, open-source nature of our methodology may make it particularly attractive to those working in nonmodel systems.
Ulysses - an application for the projection of molecular interactions across species
Authors: Kemmer Danielle , Huang Yong , Shah Sohrab P , Lim Jonathan , Brumm Jochen , Yuen Macaire MS , Ling John , Xu Tao , Wasserman Wyeth W , Ouellette BF Francis
Published: December 2005

We developed Ulysses as a user-oriented system that uses a process called Interolog Analysis for the parallel analysis and display of protein interactions detected in various species. Ulysses was designed to perform such Interolog Analysis by the projection of model organism interaction data onto homologous human proteins, and thus serves as an accelerator for the analysis of uncharacterized human proteins. The relevance of projections was assessed and validated against published reference collections. All source code is freely available, and the Ulysses system can be accessed via a web interface http://www.cisreg.ca/ulysses.
Angiotensin II Stimulates Transcription of Insulin-Like Growth Factor I Receptor in Vascular Smooth Muscle Cells: Role of Nuclear Factor-κB
Authors: Ma Yewei , Zhang Liping , Peng Tao , Cheng Jizhong , Taneja Shilpa , Zhang Jiqiang , Delafontaine Patrice , Du Jie
Published: December 2005

Increased expression of the IGF-I receptor (IGF-IR) is associated with proliferation and survival of vascular smooth muscle cells (VSMCs). In cultured VSMCs, we reported that angiotensin II (Ang II) increases transcription and expression of IGF-IR. Now, we show that mesenteric arteries of rats infused with Ang II develop thickening and increased IGF-IR expression. To determine how Ang II transcriptionally regulates IGF-IR expression in VSMCs, we generated 5′-end deletions of the IGF-IR promoter and measured Ang II-induced promoter-luciferase activity in VSMCs. Activities from these promoter sequences suggested that the Ang II-responsive region is located between −270 and −135 of the IGF-IR promoter. Using a DNase I foot printing analysis, we identified two putative nuclear factor-κB (NF-κB)-like sequences located in the same region of the IGF-IR promoter. When we mutated either of these NF-κB-like sites, Ang II-induced IGF-IR promoter activity decreased sharply. Electrophoretic mobility gel shift, anti-p50 of NF-κB supershift and chromatin immunoprecipitation assays demonstrated that both the p65 and p50 subunits of NF-κB will bind to this Ang II response element in the IGF-IR promoter. When we blocked the Ras/MAPK kinase 1 pathway or the inhibitory-κB kinase pathway, both Ang II-induced IGF-IR promoter activity and expression of IGF-IR protein significantly declined. Our results indicate that the mechanism by which Ang II stimulates IGF-IR expression in VSMCs involves NF-κB binding to NF-κB sites in the IGF-IR promoter, leading to expression of IGF-IR through both Ras/MAPK kinase 1-and inhibitory-κB kinase-dependent pathways. Because IGF-IR is a major factor associated with thickening of mesenteric vessels, our results provide potential therapeutic targets.
A test of mouth-opening and hyoid-depression mechanisms during prey capture in a catfish using high-speed cineradiography
Authors: Van Wassenbergh Sam , Herrel Anthony , Adriaens Dominique , Aerts Peter
Published: December 2005

Detailed morphological analyses have identified a number of different mechanical pathways by which the morphologically complex cranial system of fishes can achieve mouth opening and hyoid depression. However, many of these proposed mechanisms remain untested. Furthermore, very little is known about the precise timing of activity of each of these mechanisms, and about the magnitude of each mechanism's total contribution to its proposed function. In the present study, all mouth opening and hyoid depression mechanisms described for Clarias gariepinus, an air-breathing catfish, are analysed. High-speed X-ray videos were recorded during prey capture of three catfish implanted with small, radio-opaque markers in the cranial elements potentially involved. A kinematic analysis was performed from which data were used as input in planar four-bar models. This analysis shows that the opercular mouth-opening mechanism initiates mouth opening, but is not able to cause the complete mouth openings as observed on the X-ray videos. The latter is accomplished through the protractor hyoidei muscles, which couple hyoid depression to lower jaw depression in a four-bar system and also reinforce lower jaw depression by shortening during the final stage of mouth opening. Although the angulo-ceratohyal ligament was previously hypothesised to play a part in mouth opening, our results show that it probably does not, but rather functions as a hyoid-elevator during mouth closure. Finally, hyoid depression is exclusively achieved by the four-bar mechanism involving neurocranial elevation and pectoral girdle retraction, generally without any reinforcement by shortening of the sternohyoideus muscle. In contrast to the results from a recent analysis on sunfish, the catfish's sternohyoideus gradually elongates during hyoid depression.
Honeybee (Apis mellifera) vision can discriminate between and recognise images of human faces
Authors: Dyer Adrian G. , Neumeyer Christa , Chittka Lars
Published: December 2005

Recognising individuals using facial cues is an important ability. There is evidence that the mammalian brain may have specialised neural circuitry for face recognition tasks, although some recent work questions these findings. Thus, to understand if recognising human faces does require species-specific neural processing, it is important to know if non-human animals might be able to solve this difficult spatial task. Honeybees (Apis mellifera) were tested to evaluate whether an animal with no evolutionary history for discriminating between humanoid faces may be able to learn this task. Using differential conditioning, individual bees were trained to visit target face stimuli and to avoid similar distractor stimuli from a standard face recognition test used in human psychology. Performance was evaluated in non-rewarded trials and bees discriminated the target face from a similar distractor with greater than 80% accuracy. When novel distractors were used,bees also demonstrated a high level of choices for the target face, indicating an ability for face recognition. When the stimuli were rotated by 180°there was a large drop in performance, indicating a possible disruption to configural type visual processing.
Long-lasting potassium channel inactivation in myoepithelial fibres is related to characteristics of swimming in diphyid siphonophores
Authors: Inoue Isao , Tsutsui Izuo , Bone Quentin
Published: December 2005

Diphyid siphonophores swim using bursts of propulsive jets, which are produced by contractions of a monolayer of subumbrellar myoepithelial fibres lining the nectophore. This swimming behaviour is characterised by successive increases in the force generating the jets during the initial jets of the burst. Action potentials that generate the contractions propagate throughout the myoepithelial layer: both their amplitude and duration successively increase during the first part of the burst. To investigate the ionic mechanism of this action potential augmentation, single myoepithelial cells were enzymatically dissociated and whole-cell voltage clamped. Na+,Ca2+ and K+ currents were recorded under different internal and external salt compositions. The Na+ current was blocked by a relatively high concentration (4 μmol l–1 or higher) of tetrodotoxin (TTX), indicating that the Na+ channel belongs to a group of TTX-resistant Na+ channels. The Ca2+ current was blocked by nifedipine (10 μmol l–1) and Co2+ (5 mmol l–1),indicating that the Ca2+ channel is L-type. The K+current possessed a unique property of long-lasting inactivation. The K+ current fully inactivated during a depolarisation to +30 mV with a time-constant of ∼9 ms, and the time constant of recovery from inactivation at –70 mV was 13.2 s. This long-lasting inactivation of the K+ channel was the major factor in the augmentation of both action potentials and contractions of the myoepithelial sheet during the initial part of the burst.