bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk of monoclonal gammopathy of undetermined significance (MGUS) and subsequent multiple myeloma among African American and white veterans in the United States
Authors: Landgren Ola , Gridley Gloria , Turesson Ingemar , Caporaso Neil E. , Goldin Lynn R. , Baris Dalsu , Fears Thomas R. , Hoover Robert N. , Linet Martha S.
Published: October 2005

The age-adjusted incidence of multiple myeloma (MM) is 2-fold higher in African Americans than in whites. A few small studies have reported a higher prevalence of monoclonal gammopathy of undetermined significance (MGUS) in African Americans versus whites. Etiologic factors for MGUS and determinants for transformation of MGUS to MM are unknown. We quantified the prevalence of MGUS and subsequent risk of MM among 4 million African American and white male veterans admitted to Veterans Affairs (VA) hospitals. The age-adjusted prevalence ratio of MGUS in African Americans compared with whites was 3.0 (2.7-3.3 95% confidence interval). Among 2046 MGUS cases, the estimated cumulative risk of MM during the first 10 years of follow-up was similar (P = .37) for African Americans (17%) and whites (15%). In the largest study to date, we suggest that the excess risk of MM in African Americans results from an increase in risk of MGUS rather than an increased risk of progression from MGUS to MM.
Severe malarial anemia of low parasite burden in rodent models results from accelerated clearance of uninfected erythrocytes
Authors: Evans Krystal J. , Hansen Diana S. , van Rooijen Nico , Buckingham Lynn A. , Schofield Louis
Published: October 2005

Severe malarial anemia (SMA) is the most frequent life-threatening complication of malaria and may contribute to the majority of malarial deaths worldwide. To explore the mechanisms of pathogenesis, we developed a novel murine model of SMA in which parasitemias peaked around 1.0% of circulating red blood cells (RBCs) and yet hemoglobin levels fell to 47% to 56% of baseline. The severity of anemia was independent of the level of peak or cumulative parasitemia, but was linked kinetically to the duration of patent infection. In vivo biotinylation analysis of the circulating blood compartment revealed that anemia arose from accelerated RBC turnover. Labeled RBCs were reduced to 1% of circulating cells by 8 days after labeling, indicating that the entire blood compartment had been turned over in approximately one week. The survival rate of freshly transfused RBCs was also markedly reduced in SMA animals, but was not altered when RBCs from SMA donors were transferred into naive recipients, suggesting few functional modifications to target RBCs. Anemia was significantly alleviated by depletion of either phagocytic cells or CD4+ T lymphocytes. This study demonstrates that immunologic mechanisms may contribute to SMA by promoting the accelerated turnover of uninfected RBCs.
Comparison of the gene expression profile of undifferentiated human embryonic stem cell lines and differentiating embryoid bodies
Authors: Bhattacharya Bhaskar , Cai Jingli , Luo Youngquan , Miura Takumi , Mejido Josef , Brimble Sandii N , Zeng Xianmin , Schulz Thomas C , Rao Mahendra S , Puri Raj K
Published: October 2005

Background

The identification of molecular pathways of differentiation of embryonic stem cells (hESC) is critical for the development of stem cell based medical therapies. In order to identify biomarkers and potential regulators of the process of differentiation, a high quality microarray containing 16,659 seventy base pair oligonucleotides was used to compare gene expression profiles of undifferentiated hESC lines and differentiating embryoid bodies.

Results

Previously identified "stemness" genes in undifferentiated hESC lines showed down modulation in differentiated cells while expression of several genes was induced as cells differentiated. In addition, a subset of 194 genes showed overexpression of greater than ≥ 3 folds in human embryoid bodies (hEB). These included 37 novel and 157 known genes. Gene expression was validated by a variety of techniques including another large scale array, reverse transcription polymerase chain reaction, focused cDNA microarrays, massively parallel signature sequencing (MPSS) analysis and immunocytochemisty. Several novel hEB specific expressed sequence tags (ESTs) were mapped to the human genome database and their expression profile characterized. A hierarchical clustering analysis clearly depicted a distinct difference in gene expression profile among undifferentiated and differentiated hESC and confirmed that microarray analysis could readily distinguish them.

Conclusion

These results present a detailed characterization of a unique set of genes, which can be used to assess the hESC differentiation.
Evidence of recombination among early-vaccination era measles virus strains
Authors: Schierup Mikkel H , Mordhorst Carl H , Muller Claude P , Christensen Laurids S
Published: October 2005

Background

The advent of live-attenuated vaccines against measles virus during the 1960'ies changed the circulation dynamics of the virus. Earlier the virus was indigenous to countries worldwide, but now it is mediated by a limited number of evolutionary lineages causing sporadic outbreaks/epidemics of measles or circulating in geographically restricted endemic areas of Africa, Asia and Europe. We expect that the evolutionary dynamics of measles virus has changed from a situation where a variety of genomic variants co-circulates in an epidemic with relatively high probabilities of co-infection of the individual to a situation where a co-infection with strains from evolutionary different lineages is unlikely.

Results

We performed an analysis of the partial sequences of the hemagglutinin gene of 18 measles virus strains collected in Denmark between 1965 and 1983 where vaccination was first initiated in 1987. The results were compared with those obtained with strains collected from other parts of the world after the initiation of vaccination in the given place. Intergenomic recombination among pre-/early-vaccination strains is suggested by 1) estimations of linkage disequilibrium between informative sites, 2) the decay of linkage disequilibrium with distance between informative sites and 3) a comparison of the expected number of homoplasies to the number of apparent homoplasies in the most parsimonious tree. No significant evidence of recombination could be demonstrated among strains circulating at present.

Conclusion

We provide evidence that recombination can occur in measles virus and that it has had a detectable impact on sequence evolution of pre-vaccination samples. We were not able to detect recombination from present-day sequence surveys. We believe that the decreased rate of visible recombination may be explained by changed dynamics, since divergent strains do not meet very often in current epidemics that are often spawned by a single sequence type. Signs of pre-vaccination recombination events in the present-day sequences are not strong enough to be detectable.
Non-classical protein secretion in bacteria
Authors: Bendtsen Jannick D , Kiemer Lars , Fausbøll Anders , Brunak Søren
Published: October 2005

Background

We present an overview of bacterial non-classical secretion and a prediction method for identification of proteins following signal peptide independent secretion pathways. We have compiled a list of proteins found extracellularly despite the absence of a signal peptide. Some of these proteins also have known roles in the cytoplasm, which means they could be so-called "moon-lightning" proteins having more than one function.

Results

A thorough literature search was conducted to compile a list of currently known bacterial non-classically secreted proteins. Pattern finding methods were applied to the sequences in order to identify putative signal sequences or motifs responsible for their secretion. We have found no signal or motif characteristic to any majority of the proteins in the compiled list of non-classically secreted proteins, and conclude that these proteins, indeed, seem to be secreted in a novel fashion. However, we also show that the apparently non-classically secreted proteins are still distinguished from cellular proteins by properties such as amino acid composition, secondary structure and disordered regions. Specifically, prediction of disorder reveals that bacterial secretory proteins are more structurally disordered than their cytoplasmic counterparts. Finally, artificial neural networks were used to construct protein feature based methods for identification of non-classically secreted proteins in both Gram-positive and Gram-negative bacteria.

Conclusion

We present a publicly available prediction method capable of discriminating between this group of proteins and other proteins, thus allowing for the identification of novel non-classically secreted proteins. We suggest candidates for non-classically secreted proteins in Escherichia coli and Bacillus subtilis. The prediction method is available online.
Mindboggle: Automated brain labeling with multiple atlases
Authors: Klein Arno , Mensh Brett , Ghosh Satrajit , Tourville Jason , Hirsch Joy
Published: October 2005

Background

To make inferences about brain structures or activity across multiple individuals, one first needs to determine the structural correspondences across their image data. We have recently developed Mindboggle as a fully automated, feature-matching approach to assign anatomical labels to cortical structures and activity in human brain MRI data. Label assignment is based on structural correspondences between labeled atlases and unlabeled image data, where an atlas consists of a set of labels manually assigned to a single brain image. In the present work, we study the influence of using variable numbers of individual atlases to nonlinearly label human brain image data.

Methods

Each brain image voxel of each of 20 human subjects is assigned a label by each of the remaining 19 atlases using Mindboggle. The most common label is selected and is given a confidence rating based on the number of atlases that assigned that label. The automatically assigned labels for each subject brain are compared with the manual labels for that subject (its atlas). Unlike recent approaches that transform subject data to a labeled, probabilistic atlas space (constructed from a database of atlases), Mindboggle labels a subject by each atlas in a database independently.

Results

When Mindboggle labels a human subject's brain image with at least four atlases, the resulting label agreement with coregistered manual labels is significantly higher than when only a single atlas is used. Different numbers of atlases provide significantly higher label agreements for individual brain regions.

Conclusion

Increasing the number of reference brains used to automatically label a human subject brain improves labeling accuracy with respect to manually assigned labels. Mindboggle software can provide confidence measures for labels based on probabilistic assignment of labels and could be applied to large databases of brain images.
Case management for the treatment of patients with major depression in general practices – rationale, design and conduct of a cluster randomized controlled trial – PRoMPT (Primary care Monitoring for depressive Patient's Trial) [ISRCTN66386086] – Study protocol
Authors: Gensichen Jochen , Torge Marion , Peitz Monika , Wendt-Hermainski Heike , Beyer Martin , Rosemann Thomas , Krauth Christian , Raspe Heiner , Aldenhoff Josef B , Gerlach Ferdinand M
Published: October 2005

Background

Depression is a disorder with high prevalence in primary health care and a significant burden of illness. The delivery of health care for depression, as well as other chronic illnesses, has been criticized for several reasons and new strategies to address the needs of these illnesses have been advocated. Case management is a patient-centered approach which has shown efficacy in the treatment of depression in highly organized Health Maintenance Organization (HMO) settings and which might also be effective in other, less structured settings.

Methods/Design

PRoMPT (PRimary care Monitoring for depressive Patients Trial) is a cluster randomised controlled trial with General Practice (GP) as the unit of randomisation. The aim of the study is to evaluate a GP applied case-management for patients with major depressive disorder. 70 GPs were randomised either to intervention group or to control group with the control group delivering usual care. Each GP will include 10 patients suffering from major depressive disorder according to the DSM-IV criteria. The intervention group will receive treatment based on standardized guidelines and monthly telephone monitoring from a trained practice nurse. The nurse investigates the patient's status concerning the MDD criteria, his adherence to GPs prescriptions, possible side effects of medication, and treatment goal attainment. The control group receives usual care – including recommended guidelines. Main outcome measure is the cumulative score of the section depressive disorders (PHQ-9) from the German version of the Prime MD Patient Health Questionnaire (PHQ-D). Secondary outcome measures are the Beck-Depression-Inventory, self-reported adherence (adapted from Moriskey) and the SF-36. In addition, data are collected about patients' satisfaction (EUROPEP-tool), medication, health care utilization, comorbidity, suicide attempts and days out of work.

The study comprises three assessment times: baseline (T0) , follow-up after 6 months (T1) and follow-up after 12 months (T2).

Discussion

Depression is now recognized as a disorder with a high prevalence in primary care but with insufficient treatment response. Case management seems to be a promising intervention which has the potential to bridge the gap of the usually time-limited and fragmented provision of care. Case management has been proven to be effective in several studies but its application in the private general medical practice setting remains unclear.
Avidin related protein 2 shows unique structural and functional features among the avidin protein family
Authors: Hytönen Vesa P , Määttä Juha AE , Kidron Heidi , Halling Katrin K , Hörhä Jarno , Kulomaa Tuomas , Nyholm Thomas KM , Johnson Mark S , Salminen Tiina A , Kulomaa Markku S , Airenne Tomi T
Published: October 2005

Background

The chicken avidin gene family consists of avidin and several avidin related genes (AVRs). Of these gene products, avidin is the best characterized and is known for its extremely high affinity for D-biotin, a property that is utilized in numerous modern life science applications. Recently, the AVR genes have been expressed as recombinant proteins, which have shown different biotin-binding properties as compared to avidin.

Results

In the present study, we have employed multiple biochemical methods to better understand the structure-function relationship of AVR proteins focusing on AVR2. Firstly, we have solved the high-resolution crystal structure of AVR2 in complex with a bound ligand, D-biotin. The AVR2 structure reveals an overall fold similar to the previously determined structures of avidin and AVR4. Major differences are seen, especially at the 1–3 subunit interface, which is stabilized mainly by polar interactions in the case of AVR2 but by hydrophobic interactions in the case of AVR4 and avidin, and in the vicinity of the biotin binding pocket. Secondly, mutagenesis, competitive dissociation analysis and differential scanning calorimetry were used to compare and study the biotin-binding properties as well as the thermal stability of AVRs and avidin. These analyses pinpointed the importance of residue 109 for biotin binding and stability of AVRs. The I109K mutation increased the biotin-binding affinity of AVR2, whereas the K109I mutation decreased the biotin-binding affinity of AVR4. Furthermore, the thermal stability of AVR2(I109K) increased in comparison to the wild-type protein and the K109I mutation led to a decrease in the thermal stability of AVR4.

Conclusion

Altogether, this study broadens our understanding of the structural features determining the ligand-binding affinities and stability as well as the molecular evolution within the protein family. This novel information can be applied to further develop and improve the tools already widely used in avidin-biotin technology.
In Memorium: Swamy Laxminarayan [1939–2005]
Authors: Foster Kenneth R , Kun Luis G
Published: October 2005

Swamy Narasimha Laxminarayan, known to his many friends and colleagues as Swamy, passed away on September 29, 2005. He was one of the most prominent biomedical engineers on the international scene, and contributed immensely to the globalization of this new field.
The Population Health Approach: health GIS as a bridge from theory to practice
Authors: Barnard Deborah Kelly , Hu Weimin
Published: October 2005

Background

The Population Health Approach, proposed by Health Canada, is the articulation of a long advocated model of human health. This approach strives to ensure that the health system is appropriately oriented to improve health status by applying evidence based practices across the continuum from health determinants to service interventions. Although conceptually appealing, it has been difficult to implement widely in the existing program-based health care system. The Population Health Surveillance Unit (PHSU) of the Vancouver Island Health Authority (VIHA) has developed a health geographical information system (HGIS), where GIS is used as both platform for information integration and as an analytical tool supporting comprehensive data analysis. With the assistance of the HGIS, the theory of the population health approach can be transformed into a practical, stepwise process supporting health services and program planning.

Results

Three important components of a health service planning and evaluation framework grounded in population health theory are described in this article. In particular, a stepwise methodological process to enable the incorporation of the principles of a population health into practical applications is presented; the technical functionality to integrate multiple sources of information, with different levels and scales is discussed; and sources of information about the health of the population at the appropriate level to populate this frame are proposed. An application of the methodology in the planning of health services for a high needs neighbourhood is presented as an illustrative example.

Conclusion

The population health approach incorporates the consideration of health determinants and the context within which the health conditions arise in communities. The complexity of these relationships requires the application of innovative methodologies such as Health GIS to frame the issues practically. A population health based foundation for the planning and evaluation of health services can now move from theory to practice.
Needle and syringe sharing practices of injecting drug users participating in an outreach HIV prevention program in Tehran, Iran: A cross-sectional study
Authors: Vazirian Mohsen , Nassirimanesh Bijan , Zamani Saman , Ono-Kihara Masako , Kihara Masahiro , Mortazavi Ravari Shahrzad , Gouya Mohammad Mehdi
Published: October 2005

HIV infection rates have reached epidemic proportions amongst injecting drug users (IDUs) in Iran. Although a number of community-based interventions have being implemented in the country, there is little information on the risk behaviors of IDU participants in these programs. This cross-sectional report aimed to compare the risk behaviors of injecting drug users with differential exposure rates to an HIV outreach program in Tehran, Iran. Results indicated that shared use of needle/syringe in the past month was significantly lower among IDUs who received estimated ≥ 7 syringes per week than those who did not [adjusted odds ratio (OR) = 14.36, 95% confidence interval (CI) 2.30–89.56]. While the effectiveness of this outreach program needs further evaluation through a longitudinal investigation, our preliminary findings suggest that the outreach program in Tehran may have been beneficial in reducing direct sharing among those who received more than several needles/syringes from the program.
HIV-1 reverse transcriptase mutations that confer decreased in vitro susceptibility to anti-RT DNA aptamer RT1t49 confer cross resistance to other anti-RT aptamers but not to standard RT inhibitors
Authors: Fisher Timothy S , Joshi Pheroze , Prasad Vinayaka R
Published: October 2005

RNA and DNA aptamers specific for HIV-1 reverse transcriptase (RT) can inhibit reverse transcription in vitro. RNA aptamers have been shown to potently block HIV-1 replication in culture. We previously reported mutants of HIV-1 RT with substitutions N255D or N265D that display resistance to the DNA aptamer RT1t49. Variant viruses bearing these mutations singly or in combination were compromised for replication. In order to address the wider applicability of such aptamers, HIV-1 RT variants containing the N255D, N265D or both (Dbl) were tested for the extent of their cross-resistance to other DNA/RNA aptamers as well as to other RT inhibitors. Both N265D and Dbl RTs were resistant to most aptamers tested. N255D mutant displayed mild resistance to two of the DNA aptamers, little change in sensitivity to three and hypersensitivity to one. Although all mutants displayed wild type-like ribonuclease H activity, their activity was compromised under conditions that prevent re-binding. This suggests that the processivity defect caused by these mutations can also affect RNase H function thus contributing further to the replication defect in mutant viruses. These results indicate that mutants conferring resistance to anti-RT aptamers significantly affect many HIV-1 RT enzymatic activities, which could contribute to preventing the development of resistance in vivo. If such mutations were to arise in vivo, our results suggest that variant viruses should remain susceptible to many existing anti-RT inhibitors. This result was tempered by the observation that NRTI-resistance mutations such as K65R can confer resistance to some anti-RT aptamers.
A preliminary study of clinical assessment of left unilateral spatial neglect using a head mounted display system (HMD) in rehabilitation engineering technology
Authors: Tanaka Toshiaki , Sugihara Shunichi , Nara Hiroyuki , Ino Shuichi , Ifukube Tohru
Published: October 2005

Purpose

Unilateral spatial neglect (USN) is a common syndrome in which a patient fails to report or respond to stimulation from the side of space opposite a brain lesion, where these symptoms are not due to primary sensory or motor deficits. The purpose of this study was to analyze an evaluation process system of USN in various visual fields using HMD in order to understand more accurately any faults of USN operating in the object-centred co-ordinates.

Method

Eight stroke patients participated in this study and they had Left USN in clinical test, and right hemisphere damage was checked by CT scan. Assessments of USN were performed the BIT common clinical test (the line and the stars cancellation tests) and special tests the zoom-in condition (ZI) condition and the zoom-out condition (ZO) condition. The subjects were first evaluated by the common clinical test without HMD and then two spatial tests with HMD. Moreover, we used a video-recording for all tests to analyze each subject's movements.

Results

For the line cancellation test under the common condition, the mean percentage of the correct answers at the left side in the test paper was 94.4%. In the ZI condition, the left side was 61.8.% and the right side was 92.4.%. In the ZO condition, the left side was 79.9% and the right side was 91.7.%. There were significant differences among the three conditions. The results of the stars cancellation test also showed the same tendency as the line bisection test.

Conclusion

The results showed that the assessment of USN using a technique of HMD system may indicate the disability of USN more than the common clinical tests. Moreover, it might be hypothesized that the three dimensional for USN test may be more related to various damage and occurrence of USN than only the two dimensional test.
Principles for characterizing the potential human health effects from exposure to nanomaterials: elements of a screening strategy
Authors: Oberdörster Günter , Maynard Andrew , Donaldson Ken , Castranova Vincent , Fitzpatrick Julie , Ausman Kevin , Carter Janet , Karn Barbara , Kreyling Wolfgang , Lai David , Olin Stephen , Monteiro-Riviere Nancy , Warheit David , Yang Hong ,   A report from the ILSI Research Foundation/Risk Science Institute Nanomaterial Toxicity Screening Working Group
Published: October 2005

The rapid proliferation of many different engineered nanomaterials (defined as materials designed and produced to have structural features with at least one dimension of 100 nanometers or less) presents a dilemma to regulators regarding hazard identification. The International Life Sciences Institute Research Foundation/Risk Science Institute convened an expert working group to develop a screening strategy for the hazard identification of engineered nanomaterials. The working group report presents theelementsof a screening strategy rather than a detailed testing protocol. Based on an evaluation of the limited data currently available, the report presents a broad data gathering strategy applicable to this early stage in the development of a risk assessment process for nanomaterials. Oral, dermal, inhalation, and injection routes of exposure are included recognizing that, depending on use patterns, exposure to nanomaterials may occur by any of these routes. The three key elements of the toxicity screening strategy are: Physicochemical Characteristics,In VitroAssays (cellular and non-cellular), andIn VivoAssays.

There is a strong likelihood that biological activity of nanoparticles will depend on physicochemical parameters not routinely considered in toxicity screening studies. Physicochemical properties that may be important in understanding the toxic effects of test materials include particle size and size distribution, agglomeration state, shape, crystal structure, chemical composition, surface area, surface chemistry, surface charge, and porosity.

In vitrotechniques allow specific biological and mechanistic pathways to be isolated and tested under controlled conditions, in ways that are not feasible inin vivotests. Tests are suggested for portal-of-entry toxicity for lungs, skin, and the mucosal membranes, and target organ toxicity for endothelium, blood, spleen, liver, nervous system, heart, and kidney. Non-cellular assessment of nanoparticle durability, protein interactions, complement activation, and pro-oxidant activity is also considered.

Tier 1in vivoassays are proposed for pulmonary, oral, skin and injection exposures, and Tier 2 evaluations for pulmonary exposures are also proposed. Tier 1 evaluations include markers of inflammation, oxidant stress, and cell proliferation in portal-of-entry and selected remote organs and tissues. Tier 2 evaluations for pulmonary exposures could include deposition, translocation, and toxicokinetics and biopersistence studies; effects of multiple exposures; potential effects on the reproductive system, placenta, and fetus; alternative animal models; and mechanistic studies.
ROS-mediated genotoxicity of asbestos-cement in mammalian lung cells in vitro
Authors: Dopp Elke , Yadav Santosh , Ansari Furquan Ahmad , Bhattacharya Kunal , von Recklinghausen Ursula , Rauen Ursula , Rödelsperger Klaus , Shokouhi Behnaz , Geh Stefan , Rahman Qamar
Published: October 2005

Asbestos is a known carcinogen and co-carcinogen. It is a persisting risk in our daily life due to its use in building material as asbestos-cement powder. The present study done on V79-cells (Chinese hamster lung cells) demonstrates the cytotoxic and genotoxic potential of asbestos-cement powder (ACP) in comparison with chrysotile asbestos. A co-exposure of chrysotile and ACP was tested using the cell viability test and the micronucleus assay. The kinetochore analysis had been used to analyse the pathway causing such genotoxic effects. Thiobarbituric acid-reactive substances were determined as evidence for the production of reactive oxygen species. Both, asbestos cement as well as chrysotile formed micronuclei and induced loss of cell viability in a concentration- and time- dependent way. Results of TBARS analysis and iron chelator experiments showed induction of free radicals in ACP- and chrysotile exposed cultures. CaSO4 appeared to be a negligible entity in enhancing the toxic potential of ACP. The co-exposure of both, ACP and chrysotile, showed an additive effect in enhancing the toxicity. The overall study suggests that asbestos-cement is cytotoxic as well as genotoxic in vitro. In comparison to chrysotile the magnitude of the toxicity was less, but co-exposure increased the toxicity of both.
Most nuclear systemic autoantigens are extremely disordered proteins: implications for the etiology of systemic autoimmunity
Authors: Carl Philip L , Temple Brenda RS , Cohen Philip L
Published: October 2005

Patients with systemic autoimmune diseases usually produce high levels of antibodies to self-antigens (autoantigens). The repertoire of common autoantigens is remarkably limited, yet no readily understandable shared thread links these apparently diverse proteins. Using computer prediction algorithms, we have found that most nuclear systemic autoantigens are predicted to contain long regions of extreme structural disorder. Such disordered regions would generally make poor B cell epitopes and are predicted to be under-represented as potential T cell epitopes. Consideration of the potential role of protein disorder may give novel insights into the possible role of molecular mimicry in the pathogenesis of autoimmunity. The recognition of extreme autoantigen protein disorder has led us to an explicit model of epitope spreading that explains many of the paradoxical aspects of autoimmunity – in particular, the difficulty in identifying autoantigen-specific helper T cells that might collaborate with the B cells activated in systemic autoimmunity. The model also explains the experimentally observed breakdown of major histocompatibility complex (MHC) class specificity in peptides associated with the MHC II proteins of activated autoimmune B cells, and sheds light on the selection of particular T cell epitopes in autoimmunity. Finally, the model helps to rationalize the relative rarity of clinically significant autoimmunity despite the prevalence of low specificity/low avidity autoantibodies in normal individuals.
Mortality prediction using SAPS II: an update for French intensive care units
Authors: Le Gall Jean Roger , Neumann Anke , Hemery François , Bleriot Jean Pierre , Fulgencio Jean Pierre , Garrigues Bernard , Gouzes Christian , Lepage Eric , Moine Pierre , Villers Daniel
Published: October 2005

Introduction

The standardized mortality ratio (SMR) is commonly used for benchmarking intensive care units (ICUs). Available mortality prediction models are outdated and must be adapted to current populations of interest. The objective of this study was to improve the Simplified Acute Physiology Score (SAPS) II for mortality prediction in ICUs, thereby improving SMR estimates.

Method

A retrospective data base study was conducted in patients hospitalized in 106 French ICUs between 1 January 1998 and 31 December 1999. A total of 77,490 evaluable admissions were split into a training set and a validation set. Calibration and discrimination were determined for the original SAPS II, a customized SAPS II and an expanded SAPS II developed in the training set by adding six admission variables: age, sex, length of pre-ICU hospital stay, patient location before ICU, clinical category and whether drug overdose was present. The training set was used for internal validation and the validation set for external validation.

Results

With the original SAPS II calibration was poor, with marked underestimation of observed mortality, whereas discrimination was good (area under the receiver operating characteristic curve 0.858). Customization improved calibration but had poor uniformity of fit; discrimination was unchanged. The expanded SAPS II exhibited good calibration, good uniformity of fit and better discrimination (area under the receiver operating characteristic curve 0.879). The SMR in the validation set was 1.007 (confidence interval 0.985–1.028). Some ICUs had better and others worse performance with the expanded SAPS II than with the customized SAPS II.

Conclusion

The original SAPS II model did not perform sufficiently well to be useful for benchmarking in France. Customization improved the statistical qualities of the model but gave poor uniformity of fit. Adding simple variables to create an expanded SAPS II model led to better calibration, discrimination and uniformity of fit, producing a tool suitable for benchmarking.
Testosterone Inhibits Adipogenic Differentiation in 3T3-L1 Cells: Nuclear Translocation of Androgen Receptor Complex with β-Catenin and T-Cell Factor 4 May Bypass Canonical Wnt Signaling to Down-Regulate Adipogenic Transcription Factors
Authors: Singh Rajan , Artaza Jorge N. , Taylor Wayne E. , Braga Melissa , Yuan Xin , Gonzalez-Cadavid Nestor F. , Bhasin Shalender
Published: October 2005

Testosterone supplementation in men decreases fat mass; however, the mechanisms by which it inhibits fat mass are unknown. We hypothesized that testosterone inhibits adipogenic differentiation of preadipocytes by activation of androgen receptor (AR)/β-catenin interaction and subsequent translocation of this complex to the nucleus thereby bypassing canonical Wnt signaling. We tested this hypothesis in 3T3-L1 cells that differentiate to form fat cells in adipogenic medium. We found that these cells express AR and that testosterone and dihydrotestosterone dose-dependently inhibited adipogenic differentiation as analyzed by Oil Red O staining and down-regulation of CCAAT/enhancer binding protein-α and -δ and peroxisome proliferator-activated receptor-γ2 protein and mRNA. These inhibitory effects of androgens were partially blocked by flutamide or bicalutamide. Androgen treatment was associated with nuclear translocation of β-catenin and AR. Immunoprecipitation studies demonstrated association of β-catenin with AR and T-cell factor 4 (TCF4) in the presence of androgens. Transfection of TCF4 cDNA inhibited adipogenic differentiation, whereas a dominant negative TCF4 cDNA construct induced adipogenesis and blocked testosterone’s inhibitory effects. Our gene array analysis indicates that testosterone treatment led to activation of some Wnt target genes. Expression of constitutively activated AR fused with VP-16 did not inhibit the expression of CCAAT/enhancer binding protein-α in the absence of androgens. Testosterone and dihydrotestosterone inhibit adipocyte differentiation in vitro through an AR-mediated nuclear translocation of β-catenin and activation of downstream Wnt signaling. These data provide evidence for a regulatory role for androgens in inhibiting adipogenic differentiation and a mechanistic explanation consistent with the observed reduction in fat mass in men treated with androgens.
Changes in Hypothalamic Corticotropin-Releasing Hormone, Neuropeptide Y, and Proopiomelanocortin Gene Expression during Chronic Rapid Eye Movement Sleep Deprivation of Rats
Authors: Koban Michael , Le Wei Wei , Hoffman Gloria E.
Published: October 2005

Chronic rapid eye movement (paradoxical) sleep deprivation (REM-SD) of rats leads to two conspicuous pathologies: hyperphagia coincident with body weight loss, prompted by elevated metabolism. Our goals were to test the hypotheses that 1) as a stressor, REM-SD would increase CRH gene expression in the hypothalamus and that 2) to account for hyperphagia, hypothalamic gene expression of the orexigen neuropeptide Y (NPY) would increase, but expression of the anorexigen proopiomelanocortin (POMC) would decrease. Enforcement of REM-SD of adult male rats for 20 d with the platform (flowerpot) method led to progressive hyperphagia, increasing to approximately 300% of baseline; body weight steadily declined by approximately 25%. Consistent with changes in food intake patterns, NPY expression rapidly increased in the hypothalamic arcuate nucleus by d 5 of REM-SD, peaking at d 20; by contrast, POMC expression decreased progressively during REM-SD. CRH expression was increased by d 5, both in mRNA and ability to detect neuronal perikaryal staining in paraventricular nucleus with immunocytochemistry, and it remained elevated thereafter with modest declines. Taken together, these data indicate that changes in hypothalamic neuropeptides regulating food intake are altered in a manner consistent with the hyperphagia seen with REM-SD. Changes in CRH, although indicative of REM-SD as a stressor, suggest that the anorexigenic actions of CRH are ineffective (or disabled). Furthermore, changes in NPY and POMC agree with current models of food intake behavior, but they are opposite to their acute effects on peripheral energy metabolism and thermogenesis.
Both Testosterone and Follicle-Stimulating Hormone Independently Inhibit Spermatogonial Differentiation in Irradiated Rats
Authors: Shetty Gunapala , Weng Connie C. Y. , Meachem Sarah J. , Bolden-Tiller Olga U. , Zhang Zhen , Pakarinen Pirjo , Huhtaniemi Ilpo , Meistrich Marvin L.
Published: October 2005

Simultaneous suppression of both testosterone and FSH with GnRH antagonists (GnRH-ant) reverses the radiation-induced block in spermatogonial differentiation in F1 hybrids of Lewis and Brown-Norway rats. Although addition of exogenous testosterone restores the block, it also raises FSH, and hence it had not been possible to conclusively determine which hormone was inhibiting spermatogonial differentiation. In the present study, we establish the relative roles of testosterone and FSH in this inhibition using three different approaches. The first approach involved the treatment of irradiated rats, in which differentiation was stimulated by GnRH-ant plus flutamide, with FSH for 2 wk; the FSH reduced the percentage of tubules that were differentiated (TDI) by about 2-fold, indicating that FSH does have an inhibitory role. The second approach involved treatment of irradiated, hypophysectomized rats with exogenous testosterone for 10 wk; testosterone also reduced the TDI, demonstrating that testosterone had a definite inhibitory effect, independent of pituitary hormones. Furthermore, in this protocol we showed that TDI in the hypophysectomized testosterone-treated group, which had higher intratesticular testosterone levels but lacked FSH, was slightly higher than the TDI in a GnRH-antagonist-testosterone-treated group of irradiated rats, which had normal physiological levels of FSH; this result supports a role for endogenous FSH in suppressing spermatogonial differentiation in the latter group. The third approach involved injection of an active anti-FSH antibody for 10 d in untreated, GnRH-ant plus flutamide-treated, or GnRH-ant plus testosterone-treated irradiated rats. This was not sufficient to increase the TDI. However, flutamide given in a similar treatment schedule did increase the TDI in GnRH-ant plus testosterone-treated rats. We conclude that both testosterone and FSH individually inhibit spermatogonial differentiation after irradiation, but testosterone is a more highly potent inhibitor than is FSH.
Direct, Androgen Receptor-Mediated Regulation of the FKBP5 Gene via a Distal Enhancer Element
Authors: Magee Jeffrey A. , Chang Li-wei , Stormo Gary D. , Milbrandt Jeffrey
Published: October 2005

Androgen signaling via the androgen receptor (AR) transcription factor is crucial to normal prostate homeostasis and prostate tumorigenesis. Current models of AR function are predominantly based on studies of prostate-specific antigen regulation in androgen-responsive cell lines. To expand on these in vitro paradigms, we used the mouse prostate to elucidate the mechanisms through which AR regulates another direct target, FKBP5, in vivo. FKBP5 encodes an immunophilin that has been previously implicated in glucocorticoid and progestin signaling pathways and that likely influences prostate physiology in the presence of androgens. In this work, we show that androgens directly regulate FKBP5 via an interaction between the AR and a distal enhancer located 65 kb downstream of the transcription start site in the fifth intron of the FKBP5 gene. We have found that AR selectively recruits cAMP response element-binding protein to this enhancer. These interactions, in turn, result in chromatin remodeling that affects the enhancer proper but not the FKBP5 locus as a whole. Furthermore, in contrast to prostate-specific antigen-regulatory mechanisms, we show that transactivation of the FKBP5 gene does not rely on a single looping complex to mediate communication between the distal enhancer and proximal promoter. Rather, the distal enhancer complex and basal transcription apparatus communicate indirectly with one another, implicating a regulatory mechanism that has not been previously appreciated for AR target genes.
Hydrodynamic simulation (computational fluid dynamics) of asymmetrically positioned tablets in the paddle dissolution apparatus: impact on dissolution rate and variability
Authors: D'Arcy D M , Corrigan O I , Healy A M
Published: October 2005

The aim of this work was to investigate the dissolution rate from both the curved and planar surfaces of cylindrical compacts of benzoic acid, which were placed centrally and non-centrally at the base of the vessel of the paddle dissolution apparatus. The effect of fixing the compacts to a particular position on the variability of dissolution results was also examined. In addition, computational fluid dynamics (CFD) was used to simulate fluid flow around compacts in the different positions in the vessel, and the relationship between the local hydrodynamics in the region of the compacts and the dissolution rate determined. The dissolution rate was found to increase from the centre position to the off-centre positions for each surface examined. There was a corresponding increase in maximum fluid velocities calculated from the CFD fluid flow simulations at a fixed distance from the compact. There was less variability in dissolution from compacts fixed to any of the positions compared with those that were not fixed. Fluid flow around compacts in different positions could be successfully modelled, and hydrodynamic variability examined, using CFD. The effect of asymmetric fluid flow was evident visually from the change in shape of the eroded compacts.
Nebulization of four commercially available amphotericin B formulations in persistently granulocytopenic rats with invasive pulmonary aspergillosis: evidence for long-term biological activity
Authors: Ruijgrok Elisabeth J , Fens Marcel H A , Bakker-Woudenberg Irma A J M , Van Etten Els W M , Ruijgrok Elisabeth J , Vulto Arnold G
Published: October 2005

The nebulization of amphotericin B desoxycholate (AMB-DOC), liposomal amphotericin B (L-AMB), amphotericin B lipid complex (ABLC) and amphotericin B colloidal dispersion (ABCD) has been investigated. Particle sizes of generated aerosol droplets were measured. Pulmonary amphotericin B deposition and amphotericin B concentration in blood directly after nebulization and at six weeks after nebulization was measured in healthy rats. The efficacy of nebulized amphotericin B formulations was evaluated in persistently granulocytopenic rats with invasive pulmonary aspergillosis. Treatment was given either after or before fungal inoculation. The endpoint was survival of animals. Aerosol particle sizes, expressed as the values for the mass median diameter were 1.38, 2.43, 0.90 and 2.29 μm for AMB-DOC, L-AMB, ABLC and ABCD, respectively. Amphotericin B concentrations in the lungs directly after nebulization exceeded the minimum inhibitory concentration of Aspergillus fumigatus and amphotericin B was still detected in lungs of rats at six weeks after nebulization. Treatment, started at 16 h after fungal inoculation, resulted in a significantly prolonged survival as compared with sham-treated rats for all four formulations. Prophylactic treatment at one week before fungal inoculation resulted in a significantly prolonged survival for all four formulations. Aerosol treatment given at two weeks before inoculation was effective only for AMB-DOC and L-AMB, whereas treatment given at six weeks resulted in a significantly prolonged survival for L-AMB only. All commercially available amphotericin B preparations could be nebulized efficiently and may be of value in the prophylactic treatment of invasive pulmonary aspergillosis.
Antinociceptive action of the extract and the flavonoid quercitrin isolated from Bauhinia microstachya leaves
Authors: Gadotti Vinícius M , Santos Adair R S , Meyre-Silva Christiane , Schmeling Leonardo O , Machado Claúdia , Liz Fernanda H , Filho Valdir Cechinel
Published: October 2005

This study examined the antinociceptive effect of Bauhinia microstachya (Leguminosae), a native plant widely distributed in the South of Brazil, in several chemical and mechanical models of pain. The methanolic extract (ME) from B. microstachya (3–30 mg kg−1, i.p.) and the isolated compound quercitrin (1–10 mg kg−1, i.p.), given 30 min earlier, produced a dose-dependent inhibition of acetic-acid-induced visceral pain in mice, with a mean ID50 value (dose necessary to reduce the nociceptive response by 50% relative to the control value) of 7.9 and 2.4 mg kg−1, respectively. The ME of B. microstachya (3–100 mg kg−1, i.p., 30 min earlier) also caused a dose-dependent inhibition of capsaicin-induced pain, with a mean ID50 value of 18.8 mg kg−1. Moreover, the ME (3–100 mg kg−1, i.p., 30 min earlier) produced marked inhibition of both phases of formalin-induced pain, with mean ID50 values for the neurogenic and the inflammatory phases of 30.3 and 17.2 mg kg−1, respectively. In addition, the ME of B. microstachya (3–300 mg kg −1, i.p., 30 min earlier) inhibited, in a graded manner, the hyperalgesia induced by bradykinin (3.2 μg/paw), substance P (13.5 μg/paw), carrageenan (300 μg/paw), capsaicin (100 μg/paw) and adrenaline (100ng/paw) in the rat paw, with mean ID50 values of 20.5, 17.9, 101.8, 54.2 and 99.7 mg kg−1, respectively. Taken together, these data demonstrate that ME of B. microstachya elicited a pronounced antinociceptive action against several chemical and mechanical models of pain in mice and rats. The precise mechanism responsible for the antinociceptive effect of the extract still remains unclear, but seems to be partly related to modulation of the release or action of pro-inflammatory mediators involved in the models of pain used. Finally, the flavonoid quercitrin isolated from this plant appears to contribute for the antinociceptive property of the methanolic extract.
Bioavailability of glycyrrhizin from Shaoyao-Gancao-Tang in laxative-treated rats
Authors: Goto Emi , He Ju-Xiu , Akao Teruaki , Tani Tadato
Published: October 2005

Shaoyao-Gancao-Tang (SGT), a traditional Chinese formulation composed of Shaoyao (Paeoniae Radix) and Gancao (Glycyrrhizae Radix), is frequently used in conjunction with laxatives such as sodium picosulfate in colonoscopy to relieve abdominal pains. We have investigated the alterations of the bioavailability of glycyrrhizin when SGT was co-administered with sodium picosulfate and we tried to identify a regimen that might minimize the alterations. Glycyrrhizin is one of the active glycosides in Gancao and SGT and is hydrolysed into the bioactive metabolite, 18β-glycyrrhetic acid (GA) by intestinal bacteria following oral administration. We found that the maximum plasma concentration (Cmax) and the area under the mean concentration vs time curve from zero to 24 h (AUC0–24 h) of GA from a single dose of SGT administered 5 h after a single pretreatment with sodium picosulfate were significantly reduced to 15% and 20% of the control level in rats, respectively. These reductions were still significant four days after sodium picosulfate pretreatment, but were restored by repetitive administration of SGT following sodium picosulfate pretreatment. Similar reductions and recovery were observed for the glycyrrhizin-metabolizing activity of intestinal bacteria in rat faeces. The results warrant clinical studies for co-administration of laxatives such as sodium picosulfate and SGT.