bluuebunny/crossref_metadata_2025 huggingface dataset:
Intraperitoneal Heparin Ameliorates the Systemic Inflammatory Response in PD Patients
Authors: Sjøland Jonas Angel , Smith Pedersen Robert , Jespersen Jørgen , Gram Jørgen
Published: April 2005

Background: Patients with end-stage renal disease (ESRD) suffer from high mortality rates of cardiovascular diseases, conditions closely linked to the magnitude of their chronic low-grade inflammation. As heparins have been suggested to possess anti-inflammatory properties, we set out to investigate the impact of long-term treatment with intraperitoneal heparin on local and systemic inflammation in peritoneal dialysis (PD) patients. Methods: In a double-blinded cross-over study, 21 PD patients with ESRD were randomised to inject either 4,500 anti-Xa IU tinzaparin or placebo (isotonic saline) into their morning dialysis bags every day for two periods of 3 months separated by a 1-month wash-out period. Blood and dialysate samples were analysed for inflammatory markers at the start and end of each treatment period. In dialysate, the appearance rates of the inflammatory markers were calculated to adjust for ultrafiltration variations. Results: Eleven patients completed the trial. Treatment with intraperitoneal tinzaparin was accompanied with a median 25.8% reduction of the plasma C-reactive protein concentration (p = 0.032), a 7.3% reduction of the plasma fibrinogen concentration (p = 0.042) and a 54.5% reduction of the dialysate interleukin 6 appearance rate (p = 0.007) compared with placebo. Conclusion: Long-term treatment with intraperitoneal tinzaparin of ESRD patients on PD reduces local and systemic concentrations of inflammatory markers.
Bezafibrates Cause Moderate, Reversible Impairment in Renal Function in Patients without Prior Renal Disease
Authors: Charach Gideon , Grosskopf Itamar , Rotmensch Heschi H. , Kitzis Ilan , Weintraub Moshe
Published: April 2005

Background/Aims: To determine whether bezafibrates have adverse effects on renal function. Methods: (1) A 3-year retrospective survey of 526 patients who were on bezafibrate for a while and 614 controls following fluctuations of serum creatinine levels. (2) A prospective study on 33 patients with previous evidence of bezafibrate-induced elevation in serum creatinine. The patients were examined after 3 months on bezafibrate 400 mg/day and then after 3 months without bezafibrate. Eight patients repeated the tests after 3 months on bezafibrate 200 mg/day. Results:Retrospective: 295 bezafibrate-treated patients (56%) and 67 controls (11%) demonstrated fluctuations ≧0.2 mg/dl in serum creatinine levels (p < 0.001); 113 patients (21%) and 16 controls (3%) showed fluctuations ≧0.3 mg/dl (p < 0.001). Prospective: bezafibrate 400 mg/dl increased serum creatinine from 1.16 ± 0.19 to 1.42 ± 0.2 mg/dl (p < 0.001) and urea from 37 ± 8 to 44 ± 8 mg/dl (p < 0.001); creatinine clearance (Ccr) decreased from 104 ± 23 to 82 ± 27 ml/min (p < 0.001). CPK increased from 82 ± 32 to 130 ±58 mg/dl (p < 0.0001) and urinary myoglobin increased from 95.4 ± 21 to 199 ± 99 mg/dl (p < 0.0001). The 8 patients given bezafibrate 200 mg/dl experienced similar dose-dependent changes. Conclusions: Bezafibrate causes quiet common, dose-dependent and reversible changes in serum creatinine in patients with normal renal function, associated with a significant increase in serum CPK and urine myoglobin, suggestive of drug-induced mild subclinical skeletal muscle injury compromising renal function.
Large-Scale Albuminuria Screen for Nephropathy Models in Chemically Induced Mouse Mutants
Authors: Rathkolb Birgit , Tran Tuyen V. , Klempt Martina , Hrabé de Angelis Martin , Wanke Rüdiger , Wolf Eckhard , Aigner Bernhard
Published: April 2005

Background/Aim: Phenotype-driven screening of a great pool of randomly mutant mice and subsequent selection of animals showing symptoms equivalent to human kidney diseases may result in the generation of novel suitable models for the study of the pathomechanisms and the identification of genes involved in kidney dysfunction. Methods: We carried out a large-scale analysis of ethylnitrosourea (ENU)-induced mouse mutants for albuminuria by using qualitative SDS-polyacrylamide gel electrophoresis. Results: The primary albuminuria screen preceded the comprehensive phenotypic mutation analysis in a part of the mice of the Munich ENU project to avoid loss of mutant animals as a consequence of prolonged suffering from severe nephropathy. The primary screen detected six confirmed phenotypic variants in 2,011 G1 animals screened for dominant mutations and no variant in 48 G3 pedigrees screened for recessive mutations. Further breeding experiments resulted in two lines showing a low phenotypic penetrance of albuminuria. The secondary albuminuria screen was carried out in mutant lines which were established in the Munich ENU project without preceding primary albuminuria analysis. Two lines showing increased plasma urea levels were chosen to clarify if severe kidney lesions are involved in the abnormal phenotype. This analysis revealed severe albuminuria in mice which are affected by a recessive mutation leading to increased plasma urea and cholesterol levels. Conclusion: Thus, the phenotypic selection of ENU-induced mutants according to the parameter proteinuria in principle demonstrates the feasibility to identify nephropathy phenotypes in ENU-mutagenized mice.
Cyclooxygenase-2 Inhibitor Decreases Extracellular Matrix Synthesis in Stretched Renal Fibroblasts
Authors: El Chaar Maher , Attia Erik , Chen Jie , Hannafin Jo , Poppas Dix P. , Felsen Diane
Published: April 2005

Background/Aims: Both TGF-β and cyclooxygenase-2 have been implicated in the pathogenesis of interstitial fibrosis in unilateral ureteral obstruction (UUO). Cyclic tensile stretch has been used in vitro to mimic the changes in intrarenal pressure in UUO. We sought to determine the effect of meloxicam (a selective cyclooxygenase-2 inhibitor) on extracellular matrix and TGF-β synthesis in stretched renal fibroblasts (NRK-49F). Methods: NRK-49F cells were subject to cyclic stretch (6 cycles/min, 15% elongation) using a Flexcell apparatus. Cells were stretched in the absence or presence of meloxicam for 48 h, and then cells and supernatants were isolated. Collagen was quantified by the Sircol assay; fibronectin and laminin were visualized using immunofluorescence. TGF-β was quantified by ELISA, and protease activity determined by a colorimetric assay. Results: Bothcollagen and TGF-β synthesis were increased following a 48-hour stretch of NRK-49F. Meloxicam significantly decreased the collagen and TGF-β response to stretch. Stretch-induced fibronectin and laminin synthesis was also decreased by meloxicam. NRK-49F protease activity was decreased by stretch; this was unaffected by meloxicam. Conclusions: Stretch of NRK-49F results in extracellular matrix synthesis, a process which may be activated in UUO and contribute to interstitial fibrosis. Inhibition of cyclooxygenase-2 may reduce fibrosis through a TGF-β-dependent process.
Treatment of Fistulas in ano with Fibrin Glue
Authors: Gisbertz Suzanne S. , Sosef Meindert N. , Festen Sebastiaan , Gerhards Michael F.
Published: April 2005

Background: Recent publications show promising results using fibrin glue in the treatment of anal fistulas. The technique is simple, repeatable, with minor surgical trauma so that sphincter function is preserved and further treatment options are not compromised. The aim of this pilot study was to analyse if we could reproduce the results reported in the literature, using this simple technique. Methods: Patients with a primary or recurrent anal fistula were included in this trial. Patients with a complex fistula were excluded. Under general or spinal anaesthesia, the fistulas were curetted and injected with fibrin glue. Follow-up visits were scheduled for 1 week, 6 weeks and 6 months. Results: Twenty-seven patients were included. The overall success rate was 33% after a mean follow-up of 27 weeks. Patients with a recurrent fistula had a poorer outcome (success rate 14%). None of the patients suffered from postoperative continence problems, and no other complications were recorded. Conclusion: This study confirms the safety of fibrin glue in the treatment of anal fistulas. However, a high success rate could not be reproduced.
Urgent Laparoscopic Cholecystectomy Is the Best Management for Biliary Colic
Authors: Salman Bülent , Yüksel Osman , Irkörücü Oktay , Akyürek Nusret , Tezcaner Tugan , Doğan İbrahim , Erdem Özlem , Tatlicioğlu Ertan
Published: April 2005

Background/Aim: Delay of laparoscopic cholecystectomy after the diagnosis of biliary colic may increase the probability of recurrent emergency admission while awaiting elective cholecystectomy. The aim of this study was to compare the possible advantages and safety of urgent laparoscopic cholecystectomy (ULC) with elective laparoscopic cholecystectomy (ELC) in patients with biliary colic. Patients and Methods: Between 2001 and 2003, 75 patients with biliary colic were included in this study. The patients were classified into following two groups: patients who had ULC in 24 h were in group I (n = 28) and patients who had ELC (mean interval 4.22 ± 1.42 months) were in group II (n = 35). Conversion to open cholecystectomy, operative time, postoperative hospital stay, costs, and complications were evaluated. Results: In group II, 9 patients made a total of 13 return visits to the emergency department with recurrent attacks of biliary colic or complications of gallstone disease. Mean operative time increased from 35.1 ± 6.74 min for urgent laparascopic cholecystectomy to 49.9 ± 6.12 min for ELC (p > 0.05) and hospital stay time increased from 1.06 ± 0.4 to 2.31 ± 2.36 days (p < 0.05). Conversion to open cholecystectomy increased from 0% in group I to 17.2% in group II (p < 0.05). Discussion: ULC for biliary colic may be the most medically efficacious and cost-effective treatment.
Feasibility of Hepatocyte Transplantation-Based Therapies for Primary Hyperoxalurias
Authors: Guha Chandan , Yamanouchi Kosho , Jiang Jinlan , Wang Xia , Roy Chowdhury Namita , Santana Alfredo , Shapiro Lawrence J. , Salido Eduardo , Roy-Chowdhury Jayanta
Published: April 2005

Primary hyperoxalurias (PHs) are diseases caused by overproduction of oxalate by hepatocytes. Most patients with PHs develop nephrocalcinosis and renal failure. Combined liver-kidney transplantation is often used as a definitive treatment of PHs, but because of a large body oxalate load at the time of transplantation, the procedure is not always successful. Because all hepatocytes overproduce oxalate, partial liver replacement procedures, such as auxiliary transplantation of a liver lobe or hepatocyte transplantation are not expected to be useful in this disorder. In this paper we describe novel techniques, based on preparative hepatic irradiation and stimulation of hepatocyte mitosis, through loss of liver mass or administration of hepatic growth factor, which permit transplanted wild-type hepatocytes to massively repopulate the liver, replacing up to 90% of the hepatocytes in recipient mouse livers. Application of this procedure in a recently developed Agxt-gene-deleted mouse model of PH1 resulted in marked amelioration of hyperoxaluria. We propose that further refinement of the different components of this procedure may permit early cell-based therapies of PHs, thereby preventing renal failure and its complications.
Mitochondrial Hydroxyproline Metabolism: Implications for Primary Hyperoxaluria
Authors: Knight John , Holmes Ross P.
Published: April 2005

Background/Aims:Primary hyperoxaluria results from an alteration in enzymes that metabolize glyoxylate. The metabolism that leads to glyoxylate synthesis is not well defined. The aim of this study was to investigate the production of glyoxylate in liver mitochondria when they metabolize hydroxyproline. Methods:Mitochondria were isolated from mouse liver using Percoll gradient centrifugation. The metabolism of hydroxyproline was examined by a combination of HPLC and ion chromatography/mass spectrometry techniques. Results:Glyoxylate production was substantially greater when mitochondria were incubated with hydroxyproline in comparison with proline. Inclusion of malate and glutamate with hydroxyproline resulted in a drop in glyoxylate and an increase in glycolate in the incubation mixture. This suggests an increased NAD(P)+ reduction which occurred with the inclusion of glutamate/malate and that the NAD(P)H production was required to stimulate the glyoxylate reductase-catalyzed conversion of glyoxylate to glycolate. The presence of glyoxylate reductase in these mitochondria was confirmed by measuring enzymatic activity and by Western blotting. Conclusion:These results indicate that studies on isolated mitochondria have the potential to help unravel the metabolism associated with glyoxylate and oxalate production and understand the metabolic function of glyoxylate reductase.
Implications of Genotype and Enzyme Phenotype in Pyridoxine Response of Patients with Type I Primary Hyperoxaluria
Authors: Monico Carla G. , Olson Julie B. , Milliner Dawn S.
Published: April 2005

Background: Marked hyperoxaluria due to liver-specific deficiency of alanine:glyoxylate aminotransferase activity (AGT) characterizes type I primary hyperoxaluria (PHI). Approximately half of PHI patients experience improvement in the degree of hyperoxaluria following pyridoxine (VB6) treatment. Recently, we showed an association between VB6 response and the commonest PHI mutation G170R, with patients possessing one or two copies showing 50% reduction or complete to near complete normalization of oxaluria, respectively. Two patients showed responses varying from this pattern. To further clarify the molecular basis of VB6 response in PHI, we performed additional genotyping. Methods: 23 PHI patients diagnosed via hepatic enzyme analysis, hyperoxaluria and hyperglycolic aciduria or homozygosity for a known mutation, availability of pre- and post-VB6 24-hour urine oxalate and GFR >40 ml/min/1.73 m2 were included. Data was retrieved retrospectively, oxalate measured by oxalate oxidase, and genotyping performed by PCR-based methods. Results: VB6 response was associated with the G170R and F152I mutations. Eight new sequence changes were detected. Conclusions: In PHI, two mutations resulting in AGT mistargeting are associated with VB6 response. Whether this favorable effect is specific to the peroxisomal-to-mitochondrial mistargeting caused by these changes or due to another mechanism remains to be determined.
Calcification of Advanced Atherosclerotic Lesions in the Innominate Arteries of ApoE-Deficient Mice
Authors: Rattazzi Marcello , Bennett Brian J. , Bea Florian , Kirk Elizabeth A. , Ricks Jerry L. , Speer Mei , Schwartz Stephen M. , Giachelli Cecilia M. , Rosenfeld Michael E.
Published: April 2005

Objective—

Advanced atherosclerotic lesions in the innominate arteries of chow-fed apolipoprotein E–deficient mice become highly calcified with 100% frequency by 75 weeks of age. The time course, cell types, and mechanism(s) associated with calcification were investigated.

Methods and Results—

The deposition of hydroxyapatite is preceded by the formation of fibro-fatty nodules that are populated by cells that morphologically resemble chondrocytes. These cells are spatially associated with small deposits of hydroxyapatite in animals between 45 and 60 weeks of age. Immunocytochemical analyses with antibodies recognizing known chondrocyte proteins show that these cells express the same proteins as chondrocytes within developing bone. Histological and electron microscopic analyses of lesions from animals between 45 and 60 weeks of age show that the chondrocyte-like cells are surrounded by dense connective tissue that stains positive for type II collagen. Nanocrystals of hydroxyapatite can be seen within matrix vesicles derived from the chondrocyte-like cells. In mice between 75 and 104 weeks of age, the lesions have significantly reduced cellularity and contain large calcium deposits. The few remaining chondrocyte-like cells are located adjacent to or within the large areas of calcification.

Conclusions—

Calcification of advanced lesions in chow-fed apolipoprotein E–deficient mice occurs reproducibly in mice between 45 and 75 weeks of age. The deposition of hydroxyapatite is mediated by chondrocytes, which suggests that the mechanism of calcification may in part recapitulate the process of endochondral bone formation.
Difference in Matrix-Degrading Protease Expression and Activity Between Thrombus-Free and Thrombus-Covered Wall of Abdominal Aortic Aneurysm
Authors: Kazi Monsur , Zhu Chaoyong , Roy Joy , Paulsson-Berne Gabrielle , Hamsten Anders , Swedenborg Jesper , Hedin Ulf , Eriksson Per
Published: April 2005

Objective—

It has been suggested that the intraluminal thrombus of abdominal aortic aneurysms (AAAs) predisposes for AAA rupture. Here, we examined the possibility that the intraluminal thrombus influences expression and activity of matrix-degrading proteases in the AAA wall.

Methods and Results—

Twenty patients undergoing elective repair of AAAs were included. From each patient, specimens from both thrombus-covered and thrombus-free wall were taken for analysis. Gene arrays and quantitative real-time polymerase chain reaction showed that matrix metalloproteinase (MMP)-1, -7, -9, and -12 expressions were upregulated in the thrombus-free wall compared with the thrombus-covered wall. Immunohistochemistry confirmed the differential expression of MMP-9 but also localized MMP-9 to the interface between the thrombus and the underlying vessel wall. MMP-9 expression was colocalized with the presence of macrophages. Similar expression patterns were observed for urokinase plasminogen activator (uPA), uPA receptor, and plasminogen activator inhibitor-1. Gelatinase activity was detected in the same regions as MMP-9 protein expression, ie, within the thrombus-free wall and in the interface between the thrombus and the underlying wall.

Conclusion—

The present work demonstrates that protease expression and activity differs within the aneurysm wall. The source and activity of the proteases responsible for the degradation of the thrombus-covered wall need to be further determined.
A Locus on Chromosome 2 Influences Levels of Tissue Factor Pathway Inhibitor
Authors: Almasy L. , Soria J.M. , Souto J.C. , Warren D.M. , Buil A. , Borrell M. , Muñoz X. , Sala N. , Lathrop M. , Fontcuberta J. , Blangero J.
Published: April 2005

Objective—

Levels of tissue factor pathway inhibitor (TFPI) have been associated with arteriosclerosis and thrombotic disease. Although a genetic component to variation in TFPI levels is well-documented, no systematic genome-wide screens have been conducted to localize genes influencing levels of TFPI.

Methods and Results—

We studied TFPI levels in 397 individuals in 21 Spanish families participating in the Genetic Analysis of Idiopathic Thrombosis (GAIT) study. Twelve families were selected through a proband with idiopathic thrombosis and 9 were ascertained without regard to phenotype. A genome scan was performed using microsatellite markers spaced at approximately 10 cM intervals. Standard multipoint variance component linkage methods were used. The heritability of TFPI levels was 0.52 (
P
<0.0001), with no evidence for shared household effects. In the genome screen, only 1 LOD score >2 was observed. On chromosome 2q, the maximum multipoint LOD score was 3.52 near marker D2S1384. This is near the structural gene for TFPI, which is located at 2q32. In follow-up association analyses, marginal evidence of association (
P
=0.04) was observed with the TFPI promoter variant C-399T.

Conclusion—

These results suggest that polymorphisms in and around the TFPI structural gene may be the major genetic determinants of variation in TFPI levels.
D-4F and Statins Synergize to Render HDL Antiinflammatory in Mice and Monkeys and Cause Lesion Regression in Old Apolipoprotein E–Null Mice
Authors: Navab Mohamad , Anantharamaiah G.M. , Hama Susan , Hough Greg , Reddy Srinivasa T. , Frank Joy S. , Garber David W. , Handattu Shaila , Fogelman Alan M.
Published: April 2005

Objectives—

We tested for synergy between pravastatin and D-4F by administering oral doses of each in combination that were predetermined to be ineffective when given as single agents.

Methods and Results—

The combination significantly increased high-density lipoprotein (HDL)–cholesterol levels, apolipoprotein (apo)A-I levels, paraoxonase activity, rendered HDL antiinflammatory, prevented lesion formation in young (79% reduction in en face lesion area;
P
<0.0001) and caused regression of established lesions in old apoE null mice (ie, mice receiving the combination for 6 months had lesion areas that were smaller than those before the start of treatment (
P
=0.019 for en face lesion area;
P
=0.004 for aortic root sinus lesion area). After 6 months of treatment with the combination, en face lesion area was 38% of that in mice maintained on chow alone;
P
<0.00004) with a 22% reduction in macrophage content in the remaining lesions (
P
=0.001), indicating an overall reduction in macrophages of 79%. The combination increased intestinal apoA-I synthesis by 60% (
P
=0.011). In monkeys, the combination also rendered HDL antiinflammatory.

Conclusions—

These results suggest that the combination of a statin and an HDL-based therapy may be a particularly potent treatment strategy.
Porphyromonas gingivalis
Bacteremia Induces Coronary and Aortic Atherosclerosis in Normocholesterolemic and Hypercholesterolemic Pigs
Authors: Brodala Nadine , Merricks Elizabeth P. , Bellinger Dwight A. , Damrongsri Damrong , Offenbacher Steven , Beck James , Madianos Phoebus , Sotres Daniela , Chang Yu-Ling , Koch Gary , Nichols Timothy C.
Published: April 2005

Objectives—

The aim of this study was to determine whether recurrent intravenous injections with
Porphyromonas gingivalis
(
P gingivalis
), mimicking periodontitis-associated bacteremia, promotes coronary artery and aortic atherosclerosis in pigs.

Methods and Results—

Pigs (n=36) fed low- or high-fat chow were divided into
P gingivalis
–sensitized and
P gingivalis
–challenged groups or
P gingivalis
–sensitized controls and saline-treated controls. Pigs were sensitized with 10
9
killed
P gingivalis
subcutaneously. Four weeks later all sensitized pigs in the group to be challenged started intravenous injections thrice weekly for 5 months with 10
6
to 10
7
colony forming units of
P gingivalis
while controls received saline. Anti–
P gingivalis
antibody, serum cholesterol, and complete blood counts were assayed monthly. Pigs were euthanized 2 weeks after the last injection, and coronary arteries and aortas were analyzed by histomorphometry and immunohistochemistry. Anti–
P gingivalis
antibody was increased by
P gingivalis
exposure.
P gingivalis
–challenged pigs developed a significantly greater amount of coronary and aortic atherosclerosis than controls in the normocholesterolemic group and nearly significant in the hypercholesterolemic group.
P gingivalis
was detected by polymerase chain reaction in arteries from most (94%, 16 of 17)
P gingivalis
–challenged pigs but not controls.

Conclusions—

Recurrent
P gingivalis
bacteremia induces aortic and coronary lesions consistent with atherosclerosis in normocholesterolemic pigs and increases aortic and coronary atherosclerosis in hypercholesterolemic pigs.
Category Preservation and Proximity versus Phonetic Approximation in Loanword Adaptation
Authors: LaCharité Darlene , Paradis Carole
Published: April 2005

In this article, we argue that loanword adaptation is overwhelmingly phonological and that phonetic approximation plays a limited role in the sound changes that loanwords undergo. Explicit criteria are used to compare the predictions of the phonetic approximation and phonological stances against 12 large corpora of recent English and French loanwords in several different languages. We show that category proximity is overwhelmingly preferred over perceptual proximity and that typical L2 perception/interpretation errors are not reflected in the adaptations of the loanwords of this database. Borrowers accurately identify L2 sound categories, operating on the mental representation of an L2 sound, not directly on its surface phonetic form.
Merge and Move: Wh-Dependencies Revisited
Authors: Adger David , Ramchand Gillian
Published: April 2005

In this article, we argue that, under current conceptions of the architecture of the grammar, apparentwh-dependencies can, in principle, arise from either a movement or a base-generation strategy, where Agree establishes the syntactic connection in the latter case. The crucial diagnostics are not locality effects, but identity effects. We implement the base-generation analysis using a small set of semantically interpretable features, together with a simple universal syntax-semantics correspondence. We show that parametric variation arises because of the different ways the features are bundled on functional heads. We further argue that it is the bundling of two features on a single lexical item, together with the correspondence that requires them to be interpreted apart, that is responsible for the displacement property of human languages.
T/B lineage choice occurs prior to intrathymic Notch signaling
Authors: Harman Benjamin C. , Jenkinson William E. , Parnell Sonia M. , Rossi Simona W. , Jenkinson Eric J. , Anderson Graham
Published: April 2005

Commitment of hemopoietic progenitors to the T-cell lineage is a crucial requirement for T-cell development, yet the timing and developmental cues regulating this process remain controversial. Here we have devised a technique to analyze the T-cell/B-cell lineage potential of precursors that have been recruited to the fetal mouse thymus but which have yet to contact the thymic epithelial microenvironment. We show that lymphoid progenitors arriving at the thymus are not bipotent T/B precursors, and provide evidence that intrathymic Notch signaling is not the mechanism determining T/B lineage choice in migrant precursors. Rather, we provide evidence that Notch signaling influences T/B lineage choice in lymphoid precursors through interactions with defined stromal components within the fetal liver. Collectively, our data redefine our understanding of the role and timing of Notch signaling in relation to lineage choices in lymphoid precursors.
Immunomodulatory effects of HSV-2 infection on immature macaque dendritic cells modify innate and adaptive responses
Authors: Peretti Silvia , Shaw Andrew , Blanchard James , Bohm Rudolf , Morrow Gavin , Lifson Jeffrey D. , Gettie Agegnehu , Pope Melissa
Published: April 2005

Herpes simplex viruses (HSV) infect human and murine dendritic cells (DCs) and interfere with their immunostimulatory functions in culture. HSV-2 infection increases human immunodeficiency virus (HIV) spread in patients, and DCs also promote HIV infection. We have studied these topics in rhesus macaque monocyte-derived DCs (moDCs) to set the stage for future studies of these issues in animals. We provide the first evidence that macaque DCs become infected by HSV-2. Structural viral proteins (ICP5 [infected cell protein 5], glycoprotein D [gD], envelope) were detected in the cell periphery, and a functional protein (infected cell protein 8 [ICP8]) was predominantly found in the nucleus after infection. Infectious HSV-2 induced apoptotic death, decreased expression of HLA-DR, CD40, CD80, CD83, and CD86, and increased release of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), macrophage inflammatory protein-1α (MIP-1α) (CCL3), and RANTES (regulated on activation normal T cells expressed and secreted) (CCL5) but not IL-12 or interferon-α (IFN-α) by macaque DCs. This coincided with HSV-2–infected DCs stimulating weak T-cell responses, including impaired SIV-specific responses. Comparable HSV-2 protein expression, DC apoptosis, as well as membrane immunophenotype and functional modifications were observed in HSV-2–exposed human moDCs. Such HSV-2–induced modifications of macaque and human DCs could augment DC-driven immunodeficiency virus infection. This work affords the basis for future macaque studies to explore how HSV-2 impacts the efficacy of strategies being developed to prevent HIV transmission.
BK DNA viral load in plasma: evidence for an association with hemorrhagic cystitis in allogeneic hematopoietic cell transplant recipients
Authors: Erard Veronique , Kim Hyung Woo , Corey Lawrence , Limaye Ajit , Huang Meei-Li , Myerson David , Davis Chris , Boeckh Michael
Published: April 2005

We performed a case-control study to determine the association of BK plasma viremia with hemorrhagic cystitis (HC) in hematopoietic cell transplant (HCT) recipients. Thirty cases of HC (14 of which occurred after platelet engraftment with documented BK viruria [BK-HC]) were compared with matched controls. Weekly plasma samples were tested for BK virus DNA by polymerase chain reaction (PCR). BK viremia detected before or during the disease was independently associated with HC (adjusted odds ratio = 30, P < .001); BK viremia was even important before clinical symptoms of HC occurred (odds ratio = 11, P < .001). Cases of HC and BK-HC had a significantly higher peak of BK plasma viral load than controls. BK virus was detected by in situ hybridization in bladder biopsies of 2 cases with severe HC and long-lasting BK viremia. BK virus seems to play a role in the development of HC and quantitative detection of BK DNA in plasma appears to be a marker of BK virus disease in HCT recipients.
Human physiologically based pharmacokinetic model for propofol
Authors: Levitt David G , Schnider Thomas W
Published: April 2005

Background

Propofol is widely used for both short-term anesthesia and long-term sedation. It has unusual pharmacokinetics because of its high lipid solubility. The standard approach to describing the pharmacokinetics is by a multi-compartmental model. This paper presents the first detailed human physiologically based pharmacokinetic (PBPK) model for propofol.

Methods

PKQuest, a freely distributed software routine http://www.pkquest.com, was used for all the calculations. The "standard human" PBPK parameters developed in previous applications is used. It is assumed that the blood and tissue binding is determined by simple partition into the tissue lipid, which is characterized by two previously determined set of parameters: 1) the value of the propofol oil/water partition coefficient; 2) the lipid fraction in the blood and tissues. The model was fit to the individual experimental data of Schnider et. al., Anesthesiology, 1998; 88:1170 in which an initial bolus dose was followed 60 minutes later by a one hour constant infusion.

Results

The PBPK model provides a good description of the experimental data over a large range of input dosage, subject age and fat fraction. Only one adjustable parameter (the liver clearance) is required to describe the constant infusion phase for each individual subject. In order to fit the bolus injection phase, for 10 or the 24 subjects it was necessary to assume that a fraction of the bolus dose was sequestered and then slowly released from the lungs (characterized by two additional parameters). The average weighted residual error (WRE) of the PBPK model fit to the both the bolus and infusion phases was 15%; similar to the WRE for just the constant infusion phase obtained by Schnider et. al. using a 6-parameter NONMEM compartmental model.

Conclusion

A PBPK model using standard human parameters and a simple description of tissue binding provides a good description of human propofol kinetics. The major advantage of a PBPK model is that it can be used to predict the changes in kinetics produced by variations in physiological parameters. As one example, the model simulation of the changes in pharmacokinetics for morbidly obese subjects is discussed.
Frequency of alcohol use and obesity in community medicine patients
Authors: Rohrer James E , Rohland Barbara M , Denison Anne , Way Anthony
Published: April 2005

Background

Obesity is an important public health problem. However, the effects of alcohol use on the risk for obesity have not been thoroughly explored. This study focuses on how frequency of alcohol use is related to the risk of obesity in a community medicine clinic population.

Methods

This study used a cross-sectional survey to test the hypothesis that obesity (BMI > 30) is associated with alcohol use. The convenience sample was drawn from three clinics that primarily serve low-income populations. Independent variables included frequency of alcohol use, frequency of binge drinking, demographic characteristics, health behaviors and health status.

Results

In comparison to non-drinkers, people who consumed alcohol 3 or more days per month had lower odds of being obese (Adjusted Odds Ratio = .49, p < .04). As expected, there was a significant association between watching eight or more hours of television per day and obesity (AOR = 2.34, p < .01).

Conclusion

More frequent drinking and less television time are independently associated with reduced odds of obesity in this sample of community medicine patients. Additional research is needed to isolate casual mechanisms.
Rationale, design and conduct of a comprehensive evaluation of a school-based peer-led anti-smoking intervention in the UK: the ASSIST cluster randomised trial [ISRCTN55572965]
Authors: Starkey Fenella , Moore Laurence , Campbell Rona , Sidaway Mark , Bloor Michael ,   ASSIST (A Stop Smoking In Schools Trial)
Published: April 2005

Background

To date, no school-based intervention has been proven to be effective in preventing adolescent smoking, despite continuing concern about smoking levels amongst young people in the United Kingdom. Although formal teacher-led smoking prevention interventions are considered unlikely to be effective, peer-led approaches to reducing smoking have been proposed as potentially valuable.

Methods/design

ASSIST (A Stop Smoking in Schools Trial) is a comprehensive, large-scale evaluation to rigorously test whether peer supporters in Year 8 (age 11–12) can be recruited and trained to effect a reduction in smoking uptake among their fellow students. The evaluation is employing a cluster randomised controlled trial (RCT) design with secondary school as the unit of randomisation, and is being undertaken in 59 schools in South East Wales and the West of England. Embedded within the trial are an economic evaluation of the intervention costs, a process evaluation to provide detailed information on how the intervention was delivered and received, and an analysis of social networks to consider whether such a peer group intervention could work amongst schoolchildren in this age group.

Schools were randomised to either continue with normal smoking education (n = 29 schools, 5562 students), or to do so and additionally receive the ASSIST intervention (n = 30 schools, 5481 students). No schools withdrew once the trial had started, and the intervention was successfully implemented in all 30 schools, with excellent participation rates from the peer supporters. The primary outcome is regular (weekly) smoking, validated by salivary cotinine, and this outcome has been obtained for 94.4%, 91.0% and 95.6% of eligible students at baseline, immediate post-intervention, and one-year follow-up respectively.

Discussion

Comprehensive evaluations of complex public health interventions of this scale and nature are rare in the United Kingdom. This paper demonstrates the feasibility of conducting cluster RCTs of complex public health interventions in schools, and how the rigour of such designs can be maximised both by thorough implementation of the protocol and by broadening the scope of questions addressed in the trial by including additional evaluative components.
The effectiveness of extra corporeal shock wave therapy for plantar heel pain: a systematic review and meta-analysis
Authors: Thomson Colin E , Crawford Fay , Murray Gordon D
Published: April 2005

Background

There is considerable controversy regarding the effectiveness of extracorporeal shock wave therapy in the management of plantar heel pain. Our aim was to conduct a systematic review of randomised controlled trials to investigate the effectiveness of extracorporeal shock wave therapy and to produce a precise estimate of the likely benefits of this therapy.

Methods

We conducted a systematic review of all randomised controlled trials (RCTs) identified from the Cochrane Controlled trials register, MEDLINE, EMBASE and CINAHL from 1966 until September 2004. We included randomised trials which evaluated extracorporeal shock wave therapy used to treat plantar heel pain. Trials comparing extra corporeal shock wave therapy with placebo or different doses of extra corporeal shock wave therapy were considered for inclusion in the review. We independently applied the inclusion and exclusion criteria to each identified randomised controlled trial, extracted data and assessed the methodological quality of each trial.

Results

Six RCTs (n = 897) permitted a pooled estimate of effectiveness based on pain scores collected using 10 cm visual analogue scales for morning pain. The estimated weighted mean difference was 0.42 (95% confidence interval 0.02 to 0.83) representing less than 0.5 cm on a visual analogue scale. There was no evidence of heterogeneity and a fixed effects model was used.

Conclusion

A meta-analysis of data from six randomised-controlled trials that included a total of 897 patients was statistically significant in favour of extracorporeal shock wave therapy for the treatment of plantar heel pain but the effect size was very small. A sensitivity analysis including only high quality trials did not detect a statistically significant effect.
Reactions to treatment debriefing among the participants of a placebo controlled trial
Authors: Di Blasi Zelda , Crawford Fay , Bradley Colin , Kleijnen Jos
Published: April 2005

Background

A significant proportion of trial participants respond to placebos for a variety of conditions. Despite the common conduct of these trials and the strong emphasis placed on informed consent, very little is known about informing participants about their individual treatment allocation at trial closure. This study aims to address this gap in the literature by exploring treatment beliefs and reactions to feedback about treatment allocation in the participants of a placebo-controlled randomized clinical trial (RCT).

Methods

Survey of trial participants using a semi-structured questionnaire including close and open-ended questions administered as telephone interviews and postal questionnaires. Trial participants were enrolled in a double-blind placebo-controlled RCT evaluating the effectiveness of corticosteroid for heel pain (ISRCTN36539116). The trial had closed and participants remained blind to treatment allocation. We assessed treatment expectations, the percentage of participants who wanted to be informed about their treatment allocation, their ability to guess and reactions to debriefing.

Results

Forty-six (73%) contactable participants responded to our survey. Forty-two were eligible (four participants with bilateral disease were excluded as they had received both treatments). Most (79%) participants did not have any expectations prior to receiving treatment, but many 'hoped' that something would help. Reasons for not having high expectations included the experimental nature of their care and possibility that they may get a placebo. Participants were hopeful because their pain was so severe and because they trusted the staff and services. Most (83%) wanted to be informed about their treatment allocation and study results. Over half (55%) said they could not guess which treatment they had been randomized to, and many of those who attempted a guess were incorrect. Reactions to treatment debriefing were generally positive, including in placebo responders.

Conclusion

Our study suggests that most trial participants want to be informed about their treatment allocation and trial results. Further research is required to develop measure of hope and expectancy and to rigorously evaluate the effects of debriefing prospectively.
The Arabidopsis AtRaptor genes are essential for post-embryonic plant growth
Authors: Anderson Garrett H , Veit Bruce , Hanson Maureen R
Published: April 2005

Background

Flowering plant development is wholly reliant on growth from meristems, which contain totipotent cells that give rise to all post-embryonic organs in the plant. Plants are uniquely able to alter their development throughout their lifespan through the generation of new organs in response to external signals. To identify genes that regulate meristem-based growth, we considered homologues of Raptor proteins, which regulate cell growth in response to nutrients in yeast and metazoans as part of a signaling complex with the target of rapamycin (TOR) kinase.

Results

We identified AtRaptor1A and AtRaptor1B, two loci predicted to encode Raptor proteins in Arabidopsis. Disruption of AtRaptor1B yields plants with a wide range of developmental defects: roots are thick and grow slowly, leaf initiation and bolting are delayed and the shoot inflorescence shows reduced apical dominance. AtRaptor1A AtRaptor1B double mutants show normal embryonic development but are unable to maintain post-embryonic meristem-driven growth. AtRaptor transcripts accumulate in dividing and expanding cells and tissues.

Conclusion

The data implicate the TOR signaling pathway, a major regulator of cell growth in yeast and metazoans, in the maintenance of growth from the shoot apical meristem in plants. These results provide insights into the ways in which TOR/Raptor signaling has been adapted to regulate plant growth and development, and indicate that in plants, as in other eukaryotes, there is some Raptor-independent TOR activity.
Comparison of amplification enzymes for Hepatitis C Virus quasispecies analysis
Authors: Polyak Stephen J , Sullivan Daniel G , Austin Michael A , Dai James Y , Shuhart Margaret C , Lindsay Karen L , Bonkovsky Herbert L , Di Bisceglie Adrian M , Lee William M , Morishima Chihiro , Gretch David R ,   the HALT-C Trial Group
Published: April 2005

Background

Hepatitis C virus (HCV) circulates as quasispecies (QS), whose evolution is associated with pathogenesis. Previous studies have suggested that the use of thermostable polymerases without proofreading function may contribute to inaccurate assessment of HCV QS. In this report, we compared non-proofreading (Taq) with proofreading (Advantage High Fidelity-2; HF-2) polymerases in the sensitivity, robustness, and HCV QS diversity and complexity in the second envelope glycoprotein gene hypervariable region 1 (E2-HVR1) on baseline specimens from 20 patients in the HALT-C trial and in a small cohort of 12 HCV/HIV co-infected patients. QS diversity and complexity were quantified using heteroduplex mobility assays (HMA).

Results

The sensitivities of both enzymes were comparable at 50 IU/ml, although HF-2 was more robust and slightly more sensitive than Taq. Both enzymes generated QS diversity and complexity scores that were correlated (r = 0.68; p < 0.0001, and r = 0.47; p < 0.01; Spearman's rank correlation). QS diversity was similar for both Taq and HF-2 enzymes, although there was a trend for higher diversity in samples amplified by Taq (p = 0.126). Taq amplified samples yielded complexity scores that were significantly higher than HF-2 samples (p = 0.033). HALT-C patients who were HCV positive or negative following 20 weeks of pegylated IFN plus ribavirin therapy had similar QS diversity scores for Taq and HF-2 samples, and there was a trend for higher complexity scores from Taq as compared with HF-2 samples. Among patients with HCV and HIV co-infection, HAART increased HCV QS diversity and complexity as compared with patients not receiving therapy, suggesting that immune reconstitution drives HCV QS evolution. However, diversity and complexity scores were similar for both HF-2 and Taq amplified specimens.

Conclusion

The data suggest that while Taq may overestimate HCV QS complexity, its use does not significantly affect results in cohort-based studies of HCV QS analyzed by HMA. However, the use of proofreading enzymes such as HF-2 is recommended for more accurate characterization of HCV QS in vivo.
Global health priorities – priorities of the wealthy?
Authors: Ollila Eeva
Published: April 2005

Health has gained importance on the global agenda. It has become recognized in forums where it was once not addressed. In this article three issues are considered: global health policy actors, global health priorities and the means of addressing the identified health priorities. I argue that the arenas for global health policy-making have shifted from the public spheres towards arenas that include the transnational for-profit sector. Global health policy has become increasingly fragmented and verticalized. Infectious diseases have gained ground as global health priorities, while non-communicable diseases and the broader issues of health systems development have been neglected. Approaches to tackling the health problems are increasingly influenced by trade and industrial interests with the emphasis on technological solutions.
Prenatal exposure to alcohol does not affect radial maze learning and hippocampal mossy fiber sizes in three inbred strains of mouse
Authors: Sluyter Frans , Jamot Laure , Bertholet Jean-Yves , Crusio Wim E
Published: April 2005

Background

The aim of this study was to investigate the effects of prenatal alcohol exposure on radial-maze learning and hippocampal neuroanatomy, particularly the sizes of the intra- and infrapyramidal mossy fiber (IIPMF) terminal fields, in three inbred strains of mice (C57BL/6J, BALB/cJ, and DBA/2J).

Results

Although we anticipated a modification of both learning and IIPMF sizes, no such effects were detected. Prenatal alcohol exposure did, however, interfere with reproduction in C57BL/6J animals and decrease body and brain weight (in interaction with the genotype) at adult age.

Conclusion

Prenatal alcohol exposure influenced neither radial maze performance nor the sizes of the IIPMF terminal fields. We believe that future research should be pointed either at different targets when using mouse models for Fetal Alcohol Syndrome (e.g. more complicated behavioral paradigms, different hippocampal substructures, or other brain structures) or involve different animal models.
TNF-α promotes a stop signal that inhibits neutrophil polarization and migration via a p38 MAPK pathway
Authors: Lokuta Mary A , Huttenlocher Anna
Published: April 2005

Neutrophils are a major component of the inflammatory response in patients with asthma and other inflammatory conditions. Proinflammatory cytokines, such as tumor necrosis factor α (TNF-α), are increased in the airway of patients with severe asthma and have been implicated in the recruitment of neutrophils into areas of inflammation. Here, we show that TNF-α induces a stop signal that promotes firm neutrophil adhesion and inhibits neutrophil polarization and chemotaxis to chemoattractants including interleukin-8 and C5a. TNF-α treatment of neutrophils plated on a fibrinogen-coated surface promotes firm neutrophil adhesion and the formation of vinculin-containing focal complexes. TNF-α induces a more than tenfold increase in p38 mitogen-activated protein kinase (MAPK) but not extracellular signal-regulated kinase phosphorylation. Inhibition of p38 MAPK in neutrophils treated with TNF-α causes neutrophil polarization and motility. These findings suggest that TNF-α initiates a stop signal through a p38 MAPK pathway, which may promote the retention of neutrophils in inflammatory sites. Together, our data suggest that inhibition of p38 MAPK may be an attractive target to limit inflammatory responses that are mediated by TNF-α.