bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurovascular Protection Reduces Early Brain Injury After Subarachnoid Hemorrhage
Authors: Park S. , Yamaguchi M. , Zhou C. , Calvert J.W. , Tang J. , Zhang John H.
Published: August 2004

Background and Purpose—

Cell death, especially apoptosis, occurred in brain tissues after subarachnoid hemorrhage (SAH). We examined the relationships between apoptosis and the disruption of blood–brain barrier (BBB), brain edema, and mortality in an established endovascular perforation model in male Sprague-Dawley rats.

Methods—

A pan–caspase inhibitor (z-VAD-FMK) was administered intraperitoneally at 1 hour before and 6 hours after SAH. Expression of caspase-3 and positive TUNEL was examined as markers for apoptosis.

Results—

Apoptosis occurred mostly in cerebral endothelial cells, partially in neurons in the hippocampus, and to a lesser degree in the cerebral cortex. Accordingly, increased BBB permeability and brain water content were observed, accompanied by neurological deficit and a high mortality at 24 hours after SAH. z-VAD-FMK suppressed TUNEL and caspase-3 staining in endothelial cells, decreased caspase-3 activation, reduced BBB permeability, relieved vasospasm, abolished brain edema, and improved neurological outcome.

Conclusions—

The major effect of z-VAD-FMK on early brain injury after SAH was probably neurovascular protection of cerebral endothelial cells, which results in less damage on BBB.
Infusion of Human Umbilical Cord Blood Cells in a Rat Model of Stroke Dose-Dependently Rescues Behavioral Deficits and Reduces Infarct Volume
Authors: Vendrame Martina , Cassady Jordan , Newcomb Jennifer , Butler Tanya , Pennypacker Keith R. , Zigova Tanja , Davis Sanberg Cyndy , Sanberg Paul R. , Willing Alison E.
Published: August 2004

Background and Purpose—

Intravenously delivered human umbilical cord blood cells (HUCBC) have been previously shown to improve functional recovery of stroked rats. To extend these findings, we examined the behavioral recovery and stroke infarct volume in the presence of increasing doses of HUCBC after permanent middle cerebral artery occlusion (MCAO).

Methods—

Rats were subjected to MCAO and allowed to recover for 24 hours before intravenous infusion of 10
4
up to 3 to 5×10
7
HUCBC. Behavioral tests (spontaneous activity, step test, elevated body swing test) were performed 1 week before MCAO and at 2 and 4 weeks after HUCBC infusion. On completion of behavioral testing, animals were euthanized and brain infarct volumes quantified. HUCBC were identified by immunofluorescence for human nuclei and by polymerase chain reaction (PCR) using primers specific for human glycerol 3-phosphate dehydrogenase.

Results—

At 4 weeks after infusion, there was a significant recovery in behavioral performance when 10
6
or more HUCBC were delivered (p=0.001 to p=0.05). Infarct volume measurements revealed an inverse relationship between HUCBC dose and damage volume, which reached significance at the higher HUCBC doses (10
7
cells, p<0.01; 3 to 5×10
7
cells, p<0.05). Moreover, HUCBC were localized by immunohistochemistry and PCR analysis only in the injured brain hemisphere and spleen.

Conclusions—

These results extend previous observations of HUCBC infusion in the MCAO rat stroke model by demonstrating a dose relationship between HUCBC, behavioral improvement, and neuronal sparing.
Higher Risk of Further Vascular Events Among Transient Ischemic Attack Patients With Diffusion-Weighted Imaging Acute Ischemic Lesions
Authors: Purroy Francisco , Montaner Joan , Rovira Álex , Delgado Pilar , Quintana Manuel , Álvarez-Sabín José
Published: August 2004

Background and Purpose—

Recently, a new definition of transient ischemic attack (TIA) has been proposed based on the duration of symptoms and diffusion-weighted imaging (DWI) findings. We investigate the value of temporal and neuroimaging data on the prognoses of TIA patients.

Methods—

Clinical data, symptom duration, DWI, and ultrasonographic findings were collected in 83 consecutive classical TIA patients attended in the emergency department. Stroke recurrence, myocardial infarction, or any vascular event was recorded at follow-up (mean of 389 days).

Results—

A total of 27 (32.5%) patients revealed focal abnormalities on DWI, whereas 37(44.6%) had symptoms lasting >1 hour. Large-artery disease was detected in 37 (44.6%) patients. Twenty (24.1%) patients experienced an endpoint: 2 (2.4%) myocardial infarctions, 16 (19.3%) cerebral ischemic events, and 2 cases (2.4%) of peripheral arterial disease. Cox proportional hazards multivariate analyses identified the association of symptoms >1 hour with DWI abnormalities as independent predictors of further cerebral ischemic events or any vascular event (hazard ratio [HR], 5.02; CI, 1.37 to 18.30;
P
=0.015; and HR, 3.77; CI, 1.09 to 13.00;
P
=0.029). Large-artery occlusive disease also remained an independent predictor of both endpoints (HR, 4.22; CI, 1.17 to 15.22;
P
=0.028; and HR, 3.60; CI, 1.14 to 11.39;
P
=0.0293).

Conclusions—

TIA patients with DWI abnormalities associated with duration of symptoms >1 hour and those with large-artery occlusive disease have a higher risk of further vascular events. Routine use of DWI and Doppler ultrasonographic examinations will be useful for identifying TIA patients at high risk to plan aggressive prevention therapies.
Chimera Contemporary: The Enduring Art of the Composite Beast
Authors: Powell Dave
Published: August 2004

The author examines the history of artists' depictions of fanciful organisms that are formed by combining parts of various species. Broadly tracing the progression of this pursuit from prehistory through the Ancient, Renaissance and Romantic Periods and up to the 20th century and contemporary genetic art, the article analyzes the seemingly consistent effort to render these forms simultaneously nonthreatening or vulnerable in attitude and visually realistic. The author asks whether this practice, which seems to stem from aesthetic concerns, is sufficiently critical in regards to current trends in genetic engineering.
Day-Dreaming States in Interfaced Environments: Telematic Rituals in Ouroboros
Authors: Domingues Diana
Published: August 2004

The anthropological effects of cyberspace grant to the interfaced body a new capacity for attempting higher and more complex levels of interaction. The author's on-line project Ouroboros provides first and second interactivity. The web site explores the seamless condition of being a reptile in interaction with various environments as it evokes the symbolism of the great world serpent Ouroboros. The author proposes that interactive technologies return us to forms of communication similar to the rituals of primitive societies. Feedback and emergent behaviors effected through tele-immersion, remote action and self-organizations related to the lives of snakes are intended to provide the sensation of being in a day-dreaming state.
Mapping the Database: Trajectories and Perspectives
Authors: Daniel Sharon , O'Rourke Karen
Published: August 2004

The authors attempt to re-imagine classification systems as emergent systems—where names, categories and associated data structures arise from the bottom up through collective usage. Each has employed cartographic methodology as an interaction metaphor in the design of dynamic, evolving systems that allow participants to create and archive their own itineraries and maps on-line. These systems explore the aesthetic dimensions of the database. The authors have presented and tested prototypes of two developing systems, Subtract the Sky and A Map Larger Than the Territory, in a workshop/exhibition. This article provides a brief description of the premise and implementation of both projects. It concludes with some preliminary findings from the workshop/exhibition and the authors' shared research.
Shame in Two Cultures: Implications for Evolutionary Approaches
Authors: Fessler Daniel
Published: August 2004

Cross-cultural comparisons can a) illuminate the manner in which cultures differentially highlight, ignore, and group various facets of emotional experience, and b) shed light on our evolved species-typical emotional architecture. In many societies, concern with shame is one of the principal factors regulating social behavior. Three studies conducted in Bengkulu (Indonesia) and California explored the nature and experience of shame in two disparate cultures. Study 1, perceived term use frequency, indicated that shame is more prominent in Bengkulu, a collectivistic culture, than in California, an individualistic culture. Study 2, comparing naturally occurring shame events (Bengkulu) with reports thereof (California), revealed that shame is associated with guilt-like accounts in California but not in Bengkulu, and subordinance events in Bengkulu but not in California; published reports suggest that the latter pattern is prominent worldwide. Study 3 mapped the semantic domain of shame using a synonym task; again, guilt was prominent in California, subordinance in Bengkulu. Because shame is overshadowed by guilt in individualistic cultures, and because these cultures downplay aversive emotions associated with subordinance, a fuller understanding of shame is best arrived at through the study of collectivistic cultures such as Bengkulu. After reviewing evolutionary theories on the origins and functions of shame, I evaluate these perspectives in light of facets of this emotion evident in Bengkulu and elsewhere. The available data are consistent with the proposition that shame evolved from a rank-related emotion and, while motivating prestige competition, cooperation, and conformity, nevertheless continues to play this role in contemporary humans.
'Sheep in the Jaws of So Many Ravenous Wolves': the Slave Trade and Anglican Missionary Activity at Cape Coast Castle, 1752-1816
Authors: Reese Ty
Published: August 2004

This article examines the Anglican missions established at Cape Coast Castle in 1752 and 1766. The first, established by SPG missionary Thomas Thompson, lasted from 1752 to 1755 and his lack of success, coupled with ill health, formed the basis for the second mission, that of Philip Quaque. Quaque, a Fetu youth sent to England for twelve years, returned to Cape Coast in 1766, remaining there until his death in 1816. Of all the insurmountable obstacles created by the slave trade, the most important obstacle Thompson and Quaque faced was the combination of the coastal desire for education and the European, African and Eurafrican opposition to proselytization. For Quaque, his new identity as a Black Protestant, coupled with little direct or indirect support from the SPG, hindered his endeavors. While the missions of Thompson and Quaque have often been viewed as failures they, along with the growing abolitionist attack upon the slave trade, marked a turning point in the relationship between England and the Gold Coast.
Evaluating Community Policing in the Netherlands
Authors: van der Vijver Kees , Zoomer Olga
Published: August 2004

In this article we shall present an overview of research in the field of community policing in the Netherlands. Before we go into the problems of establishing the impact of community policing, we shall describe the organisation of the Dutch police system. Without at least some knowledge of the system, it is hard to follow the developments that have taken place over the last decades. After that we shall discuss the developments in community policing in the Netherlands and its current state as to, for instance, how it is organised. Next we shall look into the research that has been carried out to try and measure the results of different versions of community policing in terms of internal and external effects. The significance of the results and indicators of efficacy, as well as the current developments of community policing will be discussed in the last section.
Evaluating the Police: A Political, Professional and Scientific Issue: 25 Years of Experience Evaluating the Police in Belgium
Authors: Tange Carrol
Published: August 2004

For the past quarter of a century, in Belgium like all over Europe, the police have often been put into question. This has transformed the issue of police reform into a political debate which has brought about the wish to develop useable knowledge regarding the police force, thanks namely to ad hoc evaluation procedures used to help strengthen police legitimacy. The present article examines the evolution of the equilibrium between different means of evaluating the police in Belgium, before and since the reform of the police, launched by an act of law in 1998.
'I Order You to Adapt': Evaluating the Community Policing, French-Style
Authors: Ferret Jérôme
Published: August 2004

This article presents a meta-evaluation of the evaluative researches on the 'police de proximité' led in France over the past twenty years. Five certainties have been highlighted concerning the evaluation of these ambiguous forms of police: the many meanings behind the concept of 'community policing', the danger of a management by the 'numbers' to evaluate a performance, the two meanings of the word 'impact', the problematic idea of 'good practices' in matters of community policing and the misleading idea of the 'resistance to change' in police organisations. Furthermore, the evaluative research on the performance of police organisation will always be dependant two major constitutive doubts: the 'black box' of complex police organisations and the role of politics in the policies of the police. To conclude, we can say that on the one hand a technical form of evaluation exists but, also a politic form of police evaluation is more important in the western states, taking into consideration the 'politisation' of matters of security.
The Implementation and Evaluation of Community Policing in Spain: Results and Future Prospects
Authors: Rabot Audrey
Published: August 2004

This article offers an overview of the implementation and evaluation of community policing programs in Spain today through the analysis of two particularly illustrative practical experiences. The controversial results of the Policía 2000 project – Spain's most consummate nationwide community policing program – pleads for a local imple- mentation of the community policing model. Indeed, as shown by another pioneering reform in Sant Boi de Llobregat (a big town near Barcelona) – which today offers many lessons in matters of evaluation and management of community policing – it is mainly at this level that experiences have been most conclusive.
Telomere dynamics in Fancg-deficient mouse and human cells
Authors: Franco Sonia , van de Vrugt Henri J. , Fernández Piedad , Aracil Miguel , Arwert Fre , Blasco María A.
Published: August 2004

A number of DNA repair proteins also play roles in telomere metabolism. To investigate whether the accelerated telomere shortening reported in Fanconi anemia (FA) hematopoietic cells relates to a direct role of the FA pathway in telomere maintenance, we have analyzed telomere dynamics in Fancg-deficient mouse and human cells. We show here that both hematopoietic (stem and differentiated bone marrow cells, B and T lymphocytes) and nonhematopoietic (germ cells, mouse embryonic fibroblasts [MEFs]) Fancg-/- mouse cells display normal telomere length, normal telomerase activity, and normal chromosome end-capping, even in the presence of extensive clastogen-induced cytogenetic instability (mitomycin C [MMC], gamma-radiation). In addition, telomerase-deficient MEFs with humanlike telomere length and decreased Fancg expression (G5 Terc-/-/Fancg shRNA3 MEFs) display normal telomere maintenance. Finally, early-passage primary fibroblasts from patients with FA of complementation group G as well as primary human cells with reduced FANCG expression (FANCG shRNA IMR90 cells) show no signs of telomere dysfunction. Our observations indicate that accelerated telomere shortening in patients with FA is not due to a role of FANCG at telomeres but instead may be secondary to the disease. These findings suggest that telomerase-based therapies could be useful prophylactic agents in FA aplastic anemia by preserving their telomere reserve in the context of the disease. (Blood. 2004;104:3927-3935)
Lysophosphatidic acid accelerates the development of human mast cells
Authors: Bagga Savita , Price Kursteen S. , Lin Debby A. , Friend Daniel S. , Austen K. Frank , Boyce Joshua A.
Published: August 2004

Mast cells (MCs) initiate immune responses from mucosal surfaces and perivascular spaces. Stem cell factor (SCF) regulates MC development and viability, but the role of innate serum factors in MC development is unexplored. Cultured cord blood-derived human MCs (hMCs) express mRNA transcripts for all 4 known receptors for lysophosphatidic acid (LPA), an abundant serum-associated lipid growth factor. In an SCF-dependent serum-free culture system, LPA (2.5-10 μM) increased the total number of hMCs by approximately 10-fold compared with cultures maintained in the absence of LPA under otherwise identical conditions. LPA was comitogenic with SCF but did not prolong MC survival. LPA-mediated proliferation was blocked by VPC-32179, a competitive antagonist of LPA1 and LPA3 receptors, and by pertussis toxin, and it was also attenuated by GW9662, a selective antagonist of peroxisome proliferator-activated receptor (PPAR)-γ. LPA accelerated the acquisition of hMC granules and increased Kit expression. hMCs derived in the presence of LPA were functional, as evidenced by their immunoglobulin E (IgE)-dependent histamine release and by their characteristic proliferative responses to interleukin-3 (IL-3), IL-4, and IL-9 in combination with SCF. Thus, LPA acts through LPA receptor and PPAR-γ-dependent pathways to accelerate hMC proliferation and differentiation, and it modulates their phenotype without providing cytoprotection. LPA could facilitate MC hyperplasia in inflammation associated with either innate or adaptive immunity. (Blood. 2004; 104:4080-4087)
Patients with severe sepsis vary markedly in their ability to generate activated protein C
Authors: Liaw Patricia C. Y. , Esmon Charles T. , Kahnamoui Kamyar , Schmidt Shelley , Kahnamoui Sarah , Ferrell Gary , Beaudin Suzanne , Julian Jim A. , Weitz Jeffrey I. , Crowther Mark , Loeb Mark , Cook Deborah
Published: August 2004

Activated protein C (APC) supplementation significantly reduces mortality in patients with severe sepsis, presumably by down-regulating coagulation, inflammation, and apoptosis. In vivo, endogenous APC is generated from protein C (PC) “on demand” in response to elevated thrombin levels. Thrombomodulin and endothelial cell protein C receptor are endothelial receptors required to generate APC endogenously. Since these receptors may be down-regulated in sepsis, we measured plasma markers of APC generation in 32 patients with severe sepsis to determine whether APC generation is impaired and whether markers of APC generation correlate with 28-day mortality. Relative to normals, all patients had elevated F1 + 2 and thrombin-antithrombin complex (TAT) levels (markers of thrombin generation and inhibition, respectively), and 28 of 32 patients had reduced PC levels. In 20 patients, APC levels paralleled elevated F1 + 2 levels, whereas 12 patients had low APC levels despite elevated F1 + 2 levels, suggesting that APC generation is impaired in the latter. No significant differences exist between survivors and nonsurvivors with respect to baseline PC levels, F1 + 2 levels, and APACHE II (acute physiology and chronic health evaluation) scores. Baseline APC levels were higher in survivors (P = .024), and baseline F1 + 2/APC ratios were lower in survivors (P = .047). Larger studies are warranted to establish whether APC generation profiles aid in managing sepsis. (Blood. 2004;104:3958-3964)
Regulation of transferrin receptor 2 protein levels by transferrin
Authors: Robb Aeisha , Wessling-Resnick Marianne
Published: August 2004

Transferrin receptor 2 (TfR2) plays a critical role in iron homeostasis because patients carrying disabling mutations in the TFR2 gene suffer from hemochromatosis. In this study, iron-responsive regulation of TfR2 at the protein level was examined in vitro and in vivo. HepG2 cell TfR2 protein levels were up-regulated after exposure to holotransferrin (holoTf) in a time- and dose-responsive manner. ApoTf or high-iron treatment with non–Tf-bound iron failed to elicit similar effects, suggesting that TfR2 regulation reflects interactions of the iron-bound ligand. Hepatic TfR2 protein levels also reflected an adaptive response to changing iron status in vivo. Liver TfR2 protein levels were down- and up-regulated in rats fed an iron-deficient and a high-iron diet, respectively. TfR2 was also up-regulated in Hfe-/- mice, an animal model that displays liver iron loading. In contrast, TfR2 levels were reduced in hypotransferrinemic mice despite liver iron overload, supporting the idea that regulation of the receptor is dependent on Tf. This idea is confirmed by up-regulation of TfR2 in β-thalassemic mice, which, like hypotransferrinemic mice, are anemic and incur iron loading, but have functional Tf. Based on these combined results, we hypothesize that TfR2 acts as a sensor of iron status such that receptor levels reflect Tf saturation.
The α1 helix-β13 strand spanning Leu214 to Val229 of platelet glycoprotein Ibα facilitates the interaction with von Willebrand factor: evidence from characterization of the epitope of monoclonal antibody AP1
Authors: Peng Yuandong , Berndt Michael C. , Cruz Miguel A. , López José A.
Published: August 2004

The glycoprotein Ib-IX-V (GP Ib-IX-V) complex mediates platelet binding to von Willebrand factor (VWF) through its largest polypeptide, GP Ibα. Of the many GP Ibα monoclonal antibodies described, AP1 is of particular interest because it blocks static VWF binding induced by 2 modulators, ristocetin and botrocetin, and platelet adhesion to VWF surfaces under flow. We mapped the AP1 binding site to a region encompassing Arg218 to Tyr228, comprising the α1 helix and β13 strand defined by the GP Ibα crystal structure. AP1 binding absolutely required Arg218, Asp222, and Glu225. We evaluated the ability of cells expressing mutants of this region to bind VWF under static conditions in the presence of modulators, and to attach to and roll on a VWF matrix under flow. These data indicate that 2 regions within the sequence Arg218 to Tyr228 have important roles in VWF binding: the α1 helix has a regulatory role and the β turn and β13 strand bind VWF directly. Despite this, the only effect of a synthetic peptide corresponding to Leu214 to Val229 was to slightly increase the rolling velocity of GP Ibα-expressing Chinese hamster ovary (CHO) cells on VWF. This region thus appears to be more important for maintaining the regional conformation of GP Ibα, thereby facilitating the interaction with VWF. (Blood. 2004;104:3971-3978)
Individualizing therapy – in search of approaches to maximize the benefit of drug treatment (II)
Authors: Pater Cornel
Published: August 2004

Adjusting drug therapy to the individual, a common approach in clinical practice, has evolved from 1) dose adjustments based on clinical effects to 2) dose adjustments made in response to drug levels and, more recently, to 3) dose adjustments based on deoxyribonucleic acid (DNA) sequencing of drug-metabolizing enzyme genes, suggesting a slow drug metabolism phenotype. This development dates back to the middle of the 20th century, when several different drugs were administered on the basis of individual plasma concentration measurements. Genetic control of drug metabolism was well established by the 1960s, and pharmakokinetic-based individualized therapy was in use by 1973.
Equivalence and noninferiority trials – are they viable alternatives for registration of new drugs? (III)
Authors: Pater Cornel
Published: August 2004

The scientific community's reliance on active-controlled trials is steadily increasing, as widespread agreement emerges concerning the role of these trials as viable alternatives to placebo trials. These trials present substantial challenges with regard to design and interpretation as their complexity increases, and the potential need for larger sample sizes impacts the cost and time variables of the drug development process. The potential efficacy and safety benefits derived from these trials may never be demonstrated by other methods. Active-controlled trials can develop valuable data to inform both prescribers and patients about the dose- and time-dependent actions of any new drug and can contribute to the management and communication of risks associated with the relevant therapeutic products.
IdentiCS – Identification of coding sequence and in silico reconstruction of the metabolic network directly from unannotated low-coverage bacterial genome sequence
Authors: Sun Jibin , Zeng An-Ping
Published: August 2004

Background

A necessary step for a genome level analysis of the cellular metabolism is the in silico reconstruction of the metabolic network from genome sequences. The available methods are mainly based on the annotation of genome sequences including two successive steps, the prediction of coding sequences (CDS) and their function assignment. The annotation process takes time. The available methods often encounter difficulties when dealing with unfinished error-containing genomic sequence.

Results

In this work a fast method is proposed to use unannotated genome sequence for predicting CDSs and for an in silico reconstruction of metabolic networks. Instead of using predicted genes or CDSs to query public databases, entries from public DNA or protein databases are used as queries to search a local database of the unannotated genome sequence to predict CDSs. Functions are assigned to the predicted CDSs simultaneously. The well-annotated genome of Salmonella typhimurium LT2 is used as an example to demonstrate the applicability of the method. 97.7% of the CDSs in the original annotation are correctly identified. The use of SWISS-PROT-TrEMBL databases resulted in an identification of 98.9% of CDSs that have EC-numbers in the published annotation. Furthermore, two versions of sequences of the bacterium Klebsiella pneumoniae with different genome coverage (3.9 and 7.9 fold, respectively) are examined. The results suggest that a 3.9-fold coverage of the bacterial genome could be sufficiently used for the in silico reconstruction of the metabolic network. Compared to other gene finding methods such as CRITICA our method is more suitable for exploiting sequences of low genome coverage. Based on the new method, a program called IdentiCS (Identi fication of C oding S equences from Unfinished Genome Sequences) is delivered that combines the identification of CDSs with the reconstruction, comparison and visualization of metabolic networks (free to download at http://genome.gbf.de/bioinformatics/index.html).

Conclusions

The reversed querying process and the program IdentiCS allow a fast and adequate prediction protein coding sequences and reconstruction of the potential metabolic network from low coverage genome sequences of bacteria. The new method can accelerate the use of genomic data for studying cellular metabolism.
Disparities in lipid management for African Americans and Caucasians with coronary artery disease: A national cross-sectional study
Authors: Massing Mark W , Foley Kathleen A , Carter-Edwards Lori , Sueta Carla A , Alexander Charles M , Simpson Ross J
Published: August 2004

Background

Individuals with coronary artery disease are at high risk for adverse health outcomes. This risk can be diminished by aggressive lipid management, but adherence to lipid management guidelines is far from ideal and substantial racial disparities in care have been reported. Lipid treatment and goal attainment information is not readily available for large patient populations seen in the fee-for-service setting. As a result, national programs to improve lipid management in this setting may focus on lipid testing as an indicator of lipid management. We describe the detection, treatment, and control of dyslipdemia for African Americans and Caucasians with coronary artery disease to evaluate whether public health programs focusing on lipid testing can eliminate racial disparities in lipid management.

Methods

Physicians and medical practices with high numbers of prescriptions for coronary artery disease medications were invited to participate in the Quality Assurance Program. Medical records were reviewed from a random sample of patients with coronary artery disease seen from 1995 through 1998. Data related to the detection, treatment, and control of dyslipidemia were abstracted from the medical record and evaluated in cross-sectional stratified and logistic regression analyses using generalized estimation equations.

Results

Data from the medical records of 1,046 African Americans and 22,077 Caucasians seen in outpatient medical practices in 23 states were analyzed. African-American patients were younger, more likely to be women and to have diabetes, heart failure, and hypertension. The low density lipoprotein cholesterol (LDL-C) testing rate for Caucasian men was over 1.4 times higher than that for African-American women and about 1.3 times higher than that for African-American men. Almost 60% of tested Caucasian men and less than half of tested African Americans were prescribed lipid-lowering drugs. Tested and treated Caucasian men had the highest LDL-C goal attainment (35%) and African-American men the lowest (21%).

Conclusions

Although increased lipid testing is clearly needed for African Americans, improvements in treatment and control are also necessary to eliminate racial disparities in lipid management. Disparities in treatment and goal attainment must be better understood and reflected in policy to improve the health of underserved populations.
Prospective open-label study of add-on and monotherapy topiramate in civilians with chronic nonhallucinatory posttraumatic stress disorder
Authors: Berlant Jeffrey L
Published: August 2004

Background

In order to confirm therapeutic effects of topiramate on posttraumatic stress disorder (PTSD) observed in a prior study, a new prospective, open-label study was conducted to examine acute responses in chronic, nonhallucinatory PTSD.

Methods

Thirty-three consecutive newly recruited civilian adult outpatients (mean age 46 years, 85% female) with DSM-IV-diagnosed chronic PTSD, excluding those with concurrent auditory or visual hallucinations, received topiramate either as monotherapy (n = 5) or augmentation (n = 28). The primary measure was a change in the PTSD Checklist-Civilian Version (PCL-C) score from baseline to 4 weeks, with response defined as a ≥ 30% reduction of PTSD symptoms.

Results

For those taking the PCL-C at both baseline and week 4 (n = 30), total symptoms declined by 49% at week 4 (paired t-test, P < 0.001) with similar subscale reductions for reexperiencing, avoidance/numbing, and hyperarousal symptoms. The response rate at week 4 was 77%. Age, sex, bipolar comorbidity, age at onset of PTSD, duration of symptoms, severity of baseline PCL-C score, and monotherapy versus add-on medication administration did not predict reduction in PTSD symptoms. Median time to full response was 9 days and median dosage was 50 mg/day.

Conclusions

Promising open-label findings in a new sample converge with findings of a previous study. The use of topiramate for treatment of chronic PTSD, at least in civilians, warrants controlled clinical trials.
The clinical significance of serum and bronchoalveolar lavage inflammatory cytokines in patients at risk for Acute Respiratory Distress Syndrome
Authors: Bouros Demosthenes , Alexandrakis Michael G , Antoniou Katerina M , Agouridakis Panagiotis , Pneumatikos Ioannis , Anevlavis Stavros , Pataka Athanasia , Patlakas George , Karkavitsas Nikolaos , Kyriakou Despina
Published: August 2004

Background

The predictive role of many cytokines has not been well defined in Acute Respiratory Distress Syndrome (ARDS).

Methods

We measured prospectively IL-4, IL-6, IL-6 receptor, IL-8, and IL-10, in the serum and bronchoalveolar lavage fluid (BALF) in 59 patients who were admitted to ICU in order to identify predictive factors for the course and outcome of ARDS. The patients were divided into three groups: those fulfilling the criteria for ARDS (n = 20, group A), those at risk for ARDS and developed ARDS within 48 hours (n = 12, group B), and those at risk for ARDS but never developed ARDS (n = 27, group C).

Results

An excellent negative predictive value for ARDS development was found for IL-6 in BALF and serum (100% and 95%, respectively). IL-8 in BALF and IL-8 and IL-10 serum levels were higher in non-survivors in all studied groups, and were associated with a high negative predictive value. A significant correlation was found between IL-8 and APACHE score (r = 0.60, p < 0.0001). Similarly, IL-6 and IL-6r were highly correlated with PaO2/FiO2 (r = -0.27, p < 0.05 and r = -0.55, p < 0.0001, respectively).

Conclusions

BALF and serum levels of the studied cytokines on admission may provide valuable information for ARDS development in patients at risk, and outcome in patients either in ARDS or in at risk for ARDS.
A faster way to make GFP-based biosensors: Two new transposons for creating multicolored libraries of fluorescent fusion proteins
Authors: Sheridan Douglas L , Hughes Thomas E
Published: August 2004

Background

There are now several ways to generate fluorescent fusion proteins by randomly inserting DNA encoding the Green Fluorescent Protein (GFP) into another protein's coding sequence. These approaches can be used to map regions in a protein that are permissive for GFP insertion or to create novel biosensors. While remarkably useful, the current insertional strategies have two major limitations: (1) they only produce one kind, or color, of fluorescent fusion protein and (2) one half of all GFP insertions within the target coding sequence are in the wrong orientation.

Results

We have overcome these limitations by incorporating two different fluorescent proteins coding sequences in a single transposon, either in tandem or antiparallel. Our initial tests targeted two mammalian integral membrane proteins: the voltage sensitive motor, Prestin, and an ER ligand gated Ca2+ channel (IP3R).

Conclusions

These new designs increase the efficiency of random fusion protein generation in one of two ways: (1) by creating two different fusion proteins from each insertion or (2) by being independent of orientation.
The planetary biology of cytochrome P450 aromatases
Authors: Gaucher Eric A , Graddy Logan G , Li Tang , Simmen Rosalia CM , Simmen Frank A , Schreiber David R , Liberles David A , Janis Christine M , Benner Steven A
Published: August 2004

Background

Joining a model for the molecular evolution of a protein family to the paleontological and geological records (geobiology), and then to the chemical structures of substrates, products, and protein folds, is emerging as a broad strategy for generating hypotheses concerning function in a post-genomic world. This strategy expands systems biology to a planetary context, necessary for a notion of fitness to underlie (as it must) any discussion of function within a biomolecular system.

Results

Here, we report an example of such an expansion, where tools from planetary biology were used to analyze three genes from the pig Sus scrofa that encode cytochrome P450 aromatases–enzymes that convert androgens into estrogens. The evolutionary history of the vertebrate aromatase gene family was reconstructed. Transition redundant exchange silent substitution metrics were used to interpolate dates for the divergence of family members, the paleontological record was consulted to identify changes in physiology that correlated in time with the change in molecular behavior, and new aromatase sequences from peccary were obtained. Metrics that detect changing function in proteins were then applied, including KA/KS values and those that exploit structural biology. These identified specific amino acid replacements that were associated with changing substrate and product specificity during the time of presumed adaptive change. The combined analysis suggests that aromatase paralogs arose in pigs as a result of selection for Suoidea with larger litters than their ancestors, and permitted the Suoidea to survive the global climatic trauma that began in the Eocene.

Conclusions

This combination of bioinformatics analysis, molecular evolution, paleontology, cladistics, global climatology, structural biology, and organic chemistry serves as a paradigm in planetary biology. As the geological, paleontological, and genomic records improve, this approach should become widely useful to make systems biology statements about high-level function for biomolecular systems.
Investigation of hydrophobic moment and hydrophobicity properties for transmembrane α-helices
Authors: Wallace James , Daman Onkabetse A , Harris Frederick , Phoenix David A
Published: August 2004

Integral membrane proteins are the primary targets of novel drugs but are largely without solved structures. As a consequence, hydrophobic moment plot methodology is often used to identify putative transmembrane α-helices of integral membrane proteins, based on their local maximum mean hydrophobic moment (<μH>) and the corresponding mean hydrophobicity (). To calculate these properties, the methodology identifies an optimal eleven residue window (L = 11), assuming an amino acid angular frequency, θ, fixed at 100°.

Using a data set of 403 transmembrane α-helix forming sequences, the relationship between <μH> and , and the effect of varying of L and / or θ on this relationship, was investigated. Confidence intervals for correlations between <μH> and  are established. It is shown, using bootstrapping procedures that the strongest statistically significant correlations exist for small windows where 7 ≤ L ≤ 16. Monte Carlo analysis suggests that this correlation is dependent upon amino acid residue primary structure, implying biological function and indicating that smaller values of L give better characterisation of transmembrane sequences using <μH>. However, varying window size can also lead to different regions within a given sequence being identified as the optimal window for structure / function predictions. Furthermore, it is shown that optimal periodicity varies with window size; the optimum, based on <μH> over the range of window sizes, (7 ≤ L ≤ 16), was at θ = 102° for the transmembrane α-helix data set.
The retroviral RNA dimer linkage: different structures may reflect different roles
Authors: Greatorex Jane
Published: August 2004

Retroviruses are unique among virus families in having dimeric genomes. The RNA sequences and structures that link the two RNA molecules vary, and these differences provide clues as to the role of this feature in the viral lifecycles. This review draws upon examples from different retroviral families. Differences and similarities in both secondary and tertiary structure are discussed. The implication of varying roles for the dimer linkage in related viruses is considered.
Computational identification of developmental enhancers: conservation and function of transcription factor binding-site clusters in Drosophila melanogaster and Drosophila pseudoobscura
Authors: Berman Benjamin P , Pfeiffer Barret D , Laverty Todd R , Salzberg Steven L , Rubin Gerald M , Eisen Michael B , Celniker Susan E
Published: August 2004

Background

The identification of sequences that control transcription in metazoans is a major goal of genome analysis. In a previous study, we demonstrated that searching for clusters of predicted transcription factor binding sites could discover active regulatory sequences, and identified 37 regions of the Drosophila melanogaster genome with high densities of predicted binding sites for five transcription factors involved in anterior-posterior embryonic patterning. Nine of these clusters overlapped known enhancers. Here, we report the results of in vivo functional analysis of 27 remaining clusters.

Results

We generated transgenic flies carrying each cluster attached to a basal promoter and reporter gene, and assayed embryos for reporter gene expression. Six clusters are enhancers of adjacent genes: giant, fushi tarazu, odd-skipped, nubbin, squeeze and pdm2; three drive expression in patterns unrelated to those of neighboring genes; the remaining 18 do not appear to have enhancer activity. We used the Drosophila pseudoobscura genome to compare patterns of evolution in and around the 15 positive and 18 false-positive predictions. Although conservation of primary sequence cannot distinguish true from false positives, conservation of binding-site clustering accurately discriminates functional binding-site clusters from those with no function. We incorporated conservation of binding-site clustering into a new genome-wide enhancer screen, and predict several hundred new regulatory sequences, including 85 adjacent to genes with embryonic patterns.

Conclusions

Measuring conservation of sequence features closely linked to function - such as binding-site clustering - makes better use of comparative sequence data than commonly used methods that examine only sequence identity.
Global nucleosome occupancy in yeast
Authors: Bernstein Bradley E , Liu Chih Long , Humphrey Emily L , Perlstein Ethan O , Schreiber Stuart L
Published: August 2004

Background

Although eukaryotic genomes are generally thought to be entirely chromatin-associated, the activated PHO5 promoter in yeast is largely devoid of nucleosomes. We systematically evaluated nucleosome occupancy in yeast promoters by immunoprecipitating nucleosomal DNA and quantifying enrichment by microarrays.

Results

Nucleosome depletion is observed in promoters that regulate active genes and/or contain multiple evolutionarily conserved motifs that recruit transcription factors. The Rap1 consensus was the only binding motif identified in a completely unbiased search of nucleosome-depleted promoters. Nucleosome depletion in the vicinity of Rap1 consensus sites in ribosomal protein gene promoters was also observed by real-time PCR and micrococcal nuclease digestion. Nucleosome occupancy in these regions was increased by the small molecule rapamycin or, in the case of the RPS11B promoter, by removing the Rap1 consensus sites.

Conclusions

The presence of transcription factor-binding motifs is an important determinant of nucleosome depletion. Most motifs are associated with marked depletion only when they appear in combination, consistent with a model in which transcription factors act collaboratively to exclude nucleosomes and gain access to target sites in the DNA. In contrast, Rap1-binding sites cause marked depletion under steady-state conditions. We speculate that nucleosome depletion enables Rap1 to define chromatin domains and alter them in response to environmental cues.
Equity of access to adult hospice inpatient care within north-west England
Authors: Wood D J , Clark D , Gatrell A C
Published: August 2004

There is a growing debate about the question of equity of access to hospice and palliative care services. Even countries with relatively well developed palliative care systems are considered to have problems of access and inequity of provision. Despite these concerns, we still lack a relevant evidence base to serve as a guide to action. We present an analysis of access to adult hospice inpatient provision in the north-west region of England that employs Geographical Information Systems (GIS). Measures of the possible demand for, and supply of, hospice inpatient services are used to determine the potential accessibility of cancer patients, assessed at the level of small areas (electoral wards). Further, the use of deprivation scores permits an analysis of the equity of access to adult inpatient hospice care, leading to the identification of areas where additional service provision may be warranted. Our research is subject to a number of caveats–it is limited to inpatient hospice provision and does not include other kinds of inpatient and community-based palliative care services. Likewise, we recognise that not everyone with cancer will require palliative care and also that palliative care needs exist among those with nonmalignant conditions. Nevertheless, our methodology is one that can also be applied more generally.
A retrospective review of the use of alfentanil in a hospital palliative care setting
Authors: Urch C E , Carr S , Minton O
Published: August 2004

Alfentanil is becoming an alternative to diamorphine when parental opioids are required, especially in the presence of renal insufficiency. Its pharmacokinetic properties suggest that tolerance may be rapidly induced, whilst concomitant administration of drugs that interfere with the cytochrome P450 system may alter its metabolism. This retrospective audit looked at the use of subcutaneous alfentanil in a palliative care setting over a 21-month period. Forty-eight out of the 81 notes identified were available for analysis. Alfentanil was used for a median of 9 days (range 1–81) with median increase in dose of 80% (range 0–1125%). No significant correlation was found between duration of infusion and dose escalation. In addition no significant correlation was found between dose escalation and concomitant drugs that either inhibited or induced the P450 system. This is the first study to investigate the use of relatively long-term use of parenteral alfentanil. The results suggest that neither tolerance nor concomitant drug administration is of clinical significance in the dose escalation.
Emotional burden of nurses in palliative sedation therapy
Authors: Morita Tatsuya , Miyashita Mitsunori , Kimura Rieko , Adachi Isamu , Shima Yasuo
Published: August 2004

Background: Palliative sedation therapy is often required in terminally ill cancer patients, and may cause emotional burden for nurses. The primary aims of this study were 1) to clarify the levels of nurses' emotional burden related to sedation, and 2) to identify the factors contributing to the burden levels. Methods: A questionnaire survey of 3187 nurses, with a response rate of 82%. Results: Eighty-two percent of the nurses (n=2607) had clinical experience in continuous-deep sedation. Thirty per cent reported that they wanted to leave their current work situation due to sedation-related burden (answering occasionally, often, or always). Also, 12% of the nurses stated that being involved in sedation was a burden, 12% that they felt helpless when patients received sedation, 11% that they would avoid a situation in which they had to perform sedation if possible, and 4% that they felt what they had done was of no value when they performed sedation. The higher nurse perceived burden was significantly associated with shorter clinical experience, nurse perceived insufficient time in caring for patients, lack of common understanding of sedation between physicians and nurses, team conference unavailability, frequent experience of conflicting wishes for sedation between patient and family, nurse-perceived inadequate interpersonal skills, belief that it was difficult to diagnose refractory symptoms, belief that sedation would hasten death, belief that sedation was ethically indistinguishable from euthanasia, nurse-perceived inadequate coping with their own grief, and nurses' personal values contradictory to sedation therapy. Conclusions: A significant number of nurses felt serious emotional burden related to sedation. To relieve nurses' emotional burden, we encourage 1) management efforts to reduce work overload, 2) a team approach to resolving conflicting opinions, especially between physicians and nurses, 3) co-ordination of early patient-family meetings to clarify their preferred end-of-life care, 4) education and training about sedation specifically focused on interpersonal skills, systematic approaches to diagnosing refractory symptoms, minimum life-threatening potency in sedation, and ethical principals differentiating sedation from euthanasia, and 5) exploring nurses' personal values through the patient-centered principle.