bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of initial graft tension on the biomechanical properties of a healing ACL replacement graft: A study in goats
Authors: Abramowitch Steven D. , Papageorgiou Christos D. , Withrow John D. , Gilbert Thomas W. , Woo Savio L‐Y.
Published: March 2003

While a number of in vitro studies have shown that the tension on an anterior cruciate ligament (ACL) replacement graft at the time of fixation has an affect on joint stability, most in vivo studies have reported little or no long‐term difference in outcome. The objectives of this study were to (1) establish a large animal model in which differences in knee stability are present at time‐zero after ACL reconstruction with grafts fixed at a low (5 N) and high (35 N) initial tension and to (2) quantitatively determine if these initial effects remain after six weeks of healing and if the tensile properties of an ACL replacement graft are influenced by initial graft tension. Seventeen skeletally mature female Saanan breed goats were used. Using the robotic/UFS testing system, the knee kinematics and in situ forces in the replacement graft in response to an externally applied 67 N anterior‐posterior (A‐P) tibial load were evaluated at time‐zero and after six weeks of healing. Afterward, the femur‐ACL graft‐tibia complexes (FGTCs) from the six‐week group were tested under uniaxial tension so that the stress relaxation and structural properties of the FGTC were obtained.

At time‐zero, knees fixed with a high initial graft tension could better reproduce the A‐P translation of the intact knee in response to the 67 N A‐P tibial load. Further, in situ forces in these grafts were also closer to those in the intact ACL under the same external loading condition. After six weeks of healing, the A‐P translation of the knee and in situ forces in the replacement grafts became similar for the low and high tension groups, while both were significantly different from controls. Further, the percentage of stress relaxation as well as the stiffness, ultimate load at failure, ultimate elongation at failure, and energy absorbed of the FGTCs for both reconstruction groups were not significantly different from each other, but were significantly different from controls. These results demonstrate that while the high initial graft tension could better replicate the normal knee kinematics at time‐zero, these effects may diminish during the early graft healing process. © 2003 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.
A resorbable porous ceramic composite bone graft substitute in a rabbit metaphyseal defect model
Authors: Walsh W. R. , Chapman‐Sheath P. J. , Cain S. , Debes J. , Bruce W. J. M. , Svehla M. J. , Gillies R. M.
Published: March 2003

The success of converted corals as a bone graft substitute relies on a complex sequence of events of vascular ingrowth, differentiation of osteoprogenitor cells, bone remodeling and graft resorption occurring together with host bone ingrowth into and onto the porous coralline microstructure or voids left behind during resorption. This study examined the resorption rates and bone infiltration into a family of resorbable porous ceramic placed bilaterally in critical sized defects in the tibial metaphyseal–diaphyseal of rabbits. The ceramics are made resorbable by partially converting the calcium carbonate of corals to form a hydroxyapatite (HA) layer on all surfaces. Attempts have been made to control the resorption rate of the implant by varying the HA thickness. New bone was observed at the periosteal and endosteal cortices, which flowed into the centre of the defect supporting the osteoconductive nature of partially converted corals. The combination of an HA layer and calcium carbonate core provides a composite bone graft substitute for new tissue integration. The HA‐calcium carbonate composite demonstrated an initial resorption of the inner calcium carbonate phase but the overall implant resorption and bone ingrowth behaviour did not differ with HA thickness. © 2003 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.
Cell‐adhesion and morphological changes are not sufficient to support anchorage‐dependent cell growth via non‐integrin‐mediated attachment
Authors: Chang Hsin‐Hou , Kau Jyh‐Hwa , Lo Szecheng J , Sun Der‐Shan
Published: March 2003

Cell‐adhesion and spread are important for cell survival. Although extensive studies have suggested several potential mechanisms of action, it is not yet clear how important cell‐morphological change per se contributes to the cell‐surviving signal. We employed a non‐integrin‐mediated cell‐adhesion system to explore this question. BHK—Japanese encephalitis virus (JEV) cells (BHK21 cells that are persistently infected with JEV) express a large amount of JEV‐envelope protein (JEV E) on their surfaces, and can attach and form pseudopodia on the anti‐JEV E antibody‐coated substrates. However, cells that adhered on the antibody substrate underwent a caspase‐3‐mediated apoptosis together with a down‐regulation of mitogen‐activated protein kinase activity within 20 h after adhesion, which indicates that viral‐protein‐mediated cell‐adhesion and cell‐spread are not sufficient for supporting cell survival. This provides a different perspective for the study of the relationships between the cell‐morphological change and the cell‐survival signal.
Effect of melanins from black yeast fungi on proliferation and differentiation of cultivated human keratinocytes and fibroblasts
Authors: Blinova M.I , Yudintseva N.M , Kalmykova N.V , Kuzminykh E.V , Yurlova N.A , Ovchinnikova O.A , Potokin I.L
Published: March 2003

The effects of melanin preparations from black yeast fungi (BYF) on the proliferation and differentiation of normal cultivated human skin keratinocytes and embryonic pulmonary fibroblasts have been investigated. Melanin preparations in the range of 5–0.1 μg/ml were optimally active, with a more pronounced effect on keratinocyte than on fibroblast proliferation. Of 17 dihydroxynaphthalene (DHN) natural melanin preparations and two commercial dihydroxyphenylalanine (DOPA) melanin preparations, only one preparation—DOPA melanin (of animal origin) significantly stimulated proliferation of keratinocytes at 5 μg/ml; four preparations (DHN melanin from BYF) significantly inhibited proliferation of these cells at 5 or 1 μg/ml. The remaining preparations had no significant effect. Similarly, of the 17 preparations of DHN melanin from BYF, one preparation significantly stimulated fibroblast proliferation, and four significantly inhibited proliferation at 5 μg/ml, one at all the concentrations, and three from 1 down to 0.1 μg/ml. These melanin preparations were also shown to affect the in vitro differentiation of keratinocytes.
Factors influencing the length of hospital stay of patients with heart failure
Authors: Wright S.P. , Verouhis D. , Gamble G. , Swedberg K. , Sharpe N. , Doughty R.N.
Published: March 2003

Introduction:

Heart failure (HF) is characterised by frequent hospital admissions and prolonged length of hospital stay. Admissions for HF have increased over the last decade while length of stay has decreased; the reasons for this change in length of stay are uncertain. This study investigates the effect of patient‐related variables, in‐hospital progress and complications on length of stay.

Methods:

Patients admitted to Auckland Hospital general medical service and randomised into the Auckland Heart Failure Management Programme were included in this study.

Results:

One hundred and ninety‐seven patients were included in this study. Mean age 73 years, mean left ventricular ejection fraction 32%; 52% had one or more previous HF admissions and 75% were New York Heart Association class IV at admission. Median length of hospital stay was 6 days (IQR 4, 9) which is comparable to the national average from New Zealand admission databases. Longer than average length of stay, defined as >6 days, was associated with the presence of peripheral congestion, duration of treatment with intravenous diuretic, the development of renal impairment, other acute medical problems at admission, iatrogenic complications during hospital stay, and social problems requiring intervention. Factors independently associated with length of stay in the top quartile (>10 days) on logistic regression included the presence of oedema at admission (OR 10.5), change in weight during stay (OR 1.3), duration of treatment with iv diuretic (OR 7.5), the development of renal impairment (OR 9.8), concurrent respiratory problems requiring specific treatment (OR 3.8), and social problems requiring intervention (OR 6.8).

Conclusions:

Peripheral congestion, concomitant acute medical problems requiring specific treatment, the development of renal impairment and the presence of social problems were related to a longer than average length of hospital stay. Multivariate models only partly explained variance in hospital stay, suggesting the importance of pre‐admission and post‐discharge factors, including the healthcare environment, the availability of primary and secondary care resources, and the threshold for hospital admission.
The relevance of heart failure severity for treatment with evidence‐based pharmacotherapy in general practice
Authors: Pont Lisa G. , van Gilst Wiek H. , Lok Dirk J.A. , Kragten Hans J.A. , Haaijer‐Ruskamp Flora M. ,   on behalf of the Dutch Working Group on Heart Failure
Published: March 2003

Aims:

Internationally, research indicates that pharmacotherapy for chronic heart failure (CHF) is sub‐optimal. Traditionally, assessment of drug use in heart failure has focused on the use of individual agents irrespective of CHF severity. This study investigates drug use for CHF patients in general practice with respect to the available evidence, incorporating both disease severity and the use of combination drug regimes.

Methods and results:

A cross‐sectional survey of 769 Dutch CHF patients was performed as part of IMPROVEMENT of HF study. For each New York Heart Association severity classification the minimum treatment appropriate for the heart failure severity according to the scientific evidence available at the time of the study (1999) was defined. The proportion of patients treated with each drug increased with increasing severity, with the exception of the β‐blockers. Patients with less severe heart failure were approximately four to eight times more likely to receive evidence‐based treatment than those with more severe heart failure.

Discussion:

To assess pharmacological treatment of heart failure, in relation to the available evidence, it is important to take severity into account. While the number of drugs prescribed increased with increasing severity, the use of evidence‐based regimes was lower in patients with more severe heart failure.
Distinct left bundle branch block pattern in ischemic and non‐ischemic dilated cardiomyopathy
Authors: Bayes‐Genis Antoni , Lopez Laura , Viñolas Xavier , Elosua Roberto , Brossa Vicenç , Campreciós Marta , Mateo Miriam , Cinca Juan , de Luna Antonio Bayes
Published: March 2003

Background:

A high percentage of patients with dilated cardiomyopathy have the electrocardiographic (ECG) pattern of advanced left bundle branch block (LBBB). In the present study we sought to investigate whether patients with dilated cardiomyopathy of ischemic or non‐ischemic etiology can be differentiated on the basis of LBBB pattern.

Methods and Results:

The study population included 41 patients with dilated cardiomyopathy of non‐ischemic (NIC) (n=26) or ischemic origin (IC) (n=15) and LBBB on surface ECG. ECG duration and voltage were digitally measured. The presence of notching of S wave in right precordial leads (V1–V3) was not statistically different between the groups. The voltages of precordial leads V2, V3 and the Σ(V1+V2+V3 voltages) were significantly more prominent in patients with NIC (P=0.002, P<0.001 and P=0.002, respectively). The discriminative power of receiver operating characteristic analysis was best at voltages of V3 of 2100 μV (area under the curve, 0.805; standard error, 0.001). The sensitivity and specificity of V3 voltage >2100 μV on surface ECG in the presence of LBBB to identify a cardiomyopathy of non‐ischemic origin were 85 and 73%, respectively.

Conclusions:

A single ECG criteria, voltage of lead V3, appears to be a useful parameter to identify patients with dilated cardiomyopathy of ischemic or non‐ischemic origin in the presence of advanced LBBB.
Bedside B‐type natriuretic peptide and functional capacity in chronic heart failure
Authors: Jourdain P. , Funck F. , Bellorini M. , Guillard N. , Loiret J. , Thebault B. , Desnos M. , Duboc D.
Published: March 2003

Objectives:

To determine if B‐type natriuretic peptide (BNP) measurement could be useful in determination of functional capacity in patients suffering from chronic heart failure.

Background:

Evaluating functional capacity is a crucial factor in the follow‐up of patients with chronic heart failure. There are numerous methods for measuring functional capacity and their relative merits remain under discussion. Clinical classifications are very subjective and other methods are difficult to use in clinical practice.

Methods:

We evaluated functional capacity in 151 consecutive patients using the 6‐min walk test. All patients were clinically classified using the New York Heart Association (NYHA) classification. We measured BNP plasma levels using a bedside BNP test.

Results:

Six minute walk test performance decreased through NYHA classes 1 to 4 (469±87, 411±82, 325±83 and 196±63 m, respectively, P<0.01) and BNP levels increased through NYHA classes 1 to 4 (26.3±7.2, 73±13, 401±74 and 924±84 pg/ml, respectively, P<0.001). There was a significant correlation between 6‐min walk test performance and BNP plasma levels (R=0.69 P<0.001) and a weaker correlation between BNP and left ventricular ejection fraction (R=0.45 P<0.04). In some patients there was a mismatch between NYHA classification and 6‐min walk test performance. In all cases BNP could correct the clinical estimation of functional capacity. When we divided the patients into three sub‐groups within each NYHA class, we showed that using BNP could better define functional capacity in patients suffering from chronic heart failure in NYHA classes I to III.

Conclusion:

The measurement of BNP levels thus usefully supplements the clinical examination. The existence of bedside BNP testing methods facilitates its use in routine clinical practice. It also permits easier follow‐up of patients with chronic heart failure.
Patterns of pharmacotherapy in patients hospitalised for congestive heart failure
Authors: Bouvy Marcel L. , Heerdink Eibert R. , Leufkens Hubert G.M. , Hoes Arno W.
Published: March 2003

Background:

In the 1990s, a number of cardiovascular drugs were evaluated in randomised clinical trials. Treatment guidelines for heart failure were modified to include these evidence‐based treatments.

Aim:

To evaluate the impact of new medical treatments for heart failure between 1990 and 1998.

Methods and results:

A retrospective cohort study of 2764 patients with a first hospital admission for heart failure between 1990 and 1998. The percentage of patients treated with different cardiovascular drugs after hospitalisation was calculated and compared over time. Use of loop diuretics remained steady approximately 80%, digoxin decreased from 57.6 to 42.7%, angiotensin converting enzyme (ACE) inhibitors showed a slight increase from 49.8 to 54.8%, beta‐blockers almost tripled from 11.3 to 28.7%, low dose prophylactic acetylsalicylic acid quadrupled from 9.9 to 39.9%. Kaplan–Meier survival estimates showed highest continuation rates of drug treatment for antithrombotics and diuretics, intermediate for digoxin and ACE inhibitors and low for beta‐blockers. More than a quarter of the users discontinued beta‐blockers in the first year after hospitalisation.

Conclusions:

We observed an increase in the prescribing of several important drug classes, reflecting changes in treatment guidelines during the study period. However, our findings show that not all patients were receiving optimal treatment. More research into the reasons for this is warranted.
Effect of biventricular pacing on heart rate variability in patients with chronic heart failure
Authors: Livanis Efthimios G. , Flevari Panagiota , Theodorakis George N. , Kolokathis Fotis , Leftheriotis Dionyssios , Kremastinos Dimitrios Th.
Published: March 2003

Background:

Biventricular pacing is emerging as a long‐term therapy for symptomatic heart failure. Analysis of heart rate variability (HRV) has become an important predictive tool in this syndrome.

Aim of the study:

To assess whether chronic resynchronization therapy can affect HRV in patients with heart failure.

Methods and results:

Thirteen patients with heart failure were studied (mean age±1 S.E. 65±2.2 years, QRS 195±5.3 ms, NYHA class 3.2±0.1, LVEF 21±1.7%). The protocol included a preliminary no pacing period for 1 month following device implantation. Twenty‐four hour Holter ECG recordings were performed at the end of this period (baseline) and after 3 months of biventricular stimulation (VDD mode). Prior to and following pacing patients underwent NYHA class evaluation, 6‐min walk test, Quality of Life Assessment and a cardiopulmonary exercise test. Biventricular pacing improved functional class (P<0.0001) and Quality of life (P<0.0001), increased 6‐min walk distance, (P=0.008) and exercise duration (P<0.0001) but had no significant effect on peak exercise VO2. Resynchronization therapy increased mean 24‐h RR (922±58 vs. 809±41 ms at baseline, P=0.006), SDNN (111±11 vs. 83±8 ms, P=0.003), SDNN‐I (56±10 vs. 40±5 ms, P=0.02), rMSSD (66±14 vs. 41±8 ms, P=0.003), Total Power (5724±1875 vs. 2074±553 ms2, P=0.03), Ultra Low Frequency Power (1969±789 vs. 653±405 ms2, P=0.03) and Very Low Frequency Power (2407±561 vs. 902±155 ms2, P=0.004).

Conclusion:

Biventricular pacing in heart failure improves autonomic function by increasing HRV. This may have important prognostic implications.
Pulmonary hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver transplantation
Authors: Krowka Michael J. , Plevak David J. , Findlay James Y. , Rosen Charles B. , Wiesner Russell H. , Krom Ruud A.F.
Published: March 2003

In the setting of moderate to severe pulmonary artery hypertension, orthotopic liver transplantation (OLT) may be complicated by pulmonary hemodynamic instability and cardiopulmonary mortality. We retrospectively studied the relationship between cardiopulmonary-related mortality and initial (untreated) pre-OLT pulmonary hemodynamics in 43 patients with portopulmonary hypertension who underwent attempted OLT. Thirty-six patients were reported in 18 peer-reviewed studies, and 7 patients underwent OLT at our institution since 1996. Transplantation procedure outcome, mean pulmonary artery pressure (MPAP), pulmonary vascular resistance (PVR), cardiac output, pulmonary capillary wedge pressure, and transpulmonary gradient (TPG) are summarized. Overall mortality was reported in 15 of 43 patients (35%). Fourteen of the 15 deaths (93%) were primarily related to cardiopulmonary dysfunction. Two deaths were intraoperative, 8 deaths occurred during the transplantation hospitalization, and 4 patients died of cardiopulmonary deterioration posthospitalization. In 4 patients, the transplantation procedure could not be successfully completed. Cardiopulmonary mortality was associated with greater pre-OLT MPAP (49 ± 14 v 36 ± 7 mm Hg; P < .005), PVR (441 ± 173 v 261 ± 156 dynes·s·cm−5; P < .005), and TPG (37 ± 13 v 22 ± 10 mm Hg; P < .005). MPAP of 50 mm Hg or greater was associated with 100% cardiopulmonary mortality. In patients with an MPAP of 35 to less than 50 mm Hg and PVR of 250 dynes·s·cm−5 or greater, the mortality rate was 50%. No mortality was reported in patients with a pre-OLT MPAP less than 35 mm Hg or TPG less than 15 mm Hg. Cardiopulmonary-related mortality in OLT patients with portopulmonary hypertension was frequent and associated with significantly increased pre-OLT MPAP, PVR, and TPG compared with survivors. Treated or untreated, we recommend intraoperative cancellation or advise against proceeding to OLT for an MPAP of 50 mm Hg or greater. Patients with an MPAP of 35 to less than 50 mm Hg and PVR of 250 dynes·s·cm−5 or greater appear to be at high risk for cardiopulmonary-related mortality after OLT. A prospective study is needed to define optimal pretransplantation treatments and pulmonary hemodynamic criteria that minimize OLT mortality associated with portopulmonary hypertension.
Pulmonary edema in patients after liver transplantation
Authors: Snowden Christopher P. , Hughes Tracey , Rose John , Roberts David R.D.
Published: March 2003

The aim of this study is to determine the incidence of radiological pulmonary edema in elective liver transplant recipients and its relationship to perioperative factors and postoperative course. We reviewed 102 chest radiographs from 34 patients who had undergone orthotopic liver transplantation (OLT). Films were assessed by 2 trained radiologists for evidence of pulmonary edema using a standardized system. Clinical and outcome data from the 34 patients were also recorded. There was a high incidence (47%) of postoperative radiological pulmonary edema that was associated with deterioration in gaseous exchange, elevated pulmonary artery pressure, and increased duration of ventilator dependence and intensive care stay. Eighteen percent of the patients developed edema immediately after surgery, which was associated with greater pulmonary artery pressure and transfusion requirements during surgery. An additional 29% developed edema during the next 16 to 20 hours, but there was no association with fluid replacement. We conclude that pulmonary edema is common after OLT and will influence postoperative recovery in a substantial proportion of transplant recipients. Excess perioperative fluid replacement is unlikely to be the sole mechanism of edema in these patients.
A Dual Role of the GTPase Rac in Cardiac Differentiation of Stem Cells
Authors: Pucéat Michel , Travo Pierre , Quinn, Mark T. , Fort Philipe
Published: March 2003

The function of the GTPase Rac1, a molecular switch transducing intracellular signals from growth factors, in differentiation of a specific cell type during early embryogenesis has not been investigated. To address the question, we used embryonic stem (ES) cells differentiated into cardiomyocytes, a model that faithfully recapitulates early stages of cardiogenesis. Overexpression in ES cells of a constitutively active Rac (RacV12) but not of an active mutant (RacL61D38), which does not activate the NADPH oxydase generating ROS, prevented MEF2C expression and severely compromised cardiac cell differentiation. This resulted in poor expression of ventricular myosin light chain 2 (MLC2v) and its lack of insertion into sarcomeres. Thus ES-derived cardiomyocytes featured impaired myofibrillogenesis and contractility. Overexpression of MEF2C or addition of catalase in the culture medium rescued the phenotype of racV12 cells. In contrast, RacV12 specifically expressed in ES-derived ventricular cells improved the propensity of cardioblasts to differentiate into beating cardiomyocytes. This was attributed to both a facilitation of myofibrillogenesis and a prolongation in their proliferation. The dominant negative mutant RacN17 early or lately expressed in ES-derived cells prevented myofibrillogenesis and in turn beating of cardiomyocytes. We thus suggest a stage-dependent function of the GTPase during early embryogenesis.
Stress Tolerance of Misfolded Carboxypeptidase Y Requires Maintenance of Protein Trafficking and Degradative Pathways
Authors: Spear Eric D. , Ng Davis T.W.
Published: March 2003

The accumulation of aberrantly folded proteins can lead to cell dysfunction and death. Currently, the mechanisms of toxicity and cellular defenses against their effects remain incompletely understood. In the endoplasmic reticulum (ER), stress caused by misfolded proteins activates the unfolded protein response (UPR). The UPR is an ER-to-nucleus signal transduction pathway that regulates a wide variety of target genes to maintain cellular homeostasis. We studied the effects of ER stress in budding yeast through expression of the well-characterized misfolded protein, CPY*. By challenging cells within their physiological limits to resist stress, we show that the UPR is required to maintain essential functions including protein translocation, glycosylation, degradation, and transport. Under stress, the ER-associated degradation (ERAD) pathway for misfolded proteins is saturable. To maintain homeostasis, an “overflow” pathway dependent on the UPR transports excess substrate to the vacuole for turnover. The importance of this pathway was revealed through mutant strains compromised in the vesicular trafficking of excess CPY*. Expression of CPY* at levels tolerated by wild-type cells was toxic to these strains despite retaining the ability to activate the UPR.
MID-INFRARED LASING INDUCED BY NOISE
Authors: SHERSTNEV V. V. , KRIER A. , BALANOV A. G. , JANSON N. B. , SILCHENKO A. N. , McCLINTOCK P. V. E.
Published: March 2003

We demonstrate that external noise can play a constructive role in a laser diode, inducing coherent mid-infrared radiation. Depending on noise intensity, the induced lasing can be either unimode or mulitimode. The coherence of the radiation in each mode reaches its maximum at an optimal noise intensity that differs depending on the mode. The phenomenon can therefore be classified as a multiple coherence resonance.
The RNA Polymerase II Core Promoter
Authors: Smale Stephen T. , Kadonaga James T.
Published: March 2003

▪ Abstract  The events leading to transcription of eukaryotic protein-coding genes culminate in the positioning of RNA polymerase II at the correct initiation site. The core promoter, which can extend ∼35 bp upstream and/or downstream of this site, plays a central role in regulating initiation. Specific DNA elements within the core promoter bind the factors that nucleate the assembly of a functional preinitiation complex and integrate stimulatory and repressive signals from factors bound at distal sites. Although core promoter structure was originally thought to be invariant, a remarkable degree of diversity has become apparent. This article reviews the structural and functional diversity of the RNA polymerase II core promoter.
NaturallyArisingCD4+RegulatoryT Cells forImmunologicSelf-Tolerance andNegativeControl ofImmuneResponses
Authors: Sakaguchi Shimon
Published: March 2003

▪ Abstract  Naturally occurring CD4+regulatory T cells, the majority of which express CD25, are engaged in dominant control of self-reactive T cells, contributing to the maintenance of immunologic self-tolerance. Their depletion or functional alteration leads to the development of autoimmune disease in otherwise normal animals. The majority, if not all, of such CD25+CD4+regulatory T cells are produced by the normal thymus as a functionally distinct and mature subpopulation of T cells. Their repertoire of antigen specificities is as broad as that of naive T cells, and they are capable of recognizing both self and nonself antigens, thus enabling them to control various immune responses. In addition to antigen recognition, signals through various accessory molecules and via cytokines control their activation, expansion, and survival, and tune their suppressive activity. Furthermore, the generation of CD25+CD4+regulatory T cells in the immune system is at least in part developmentally and genetically controlled. Genetic defects that primarily affect their development or function can indeed be a primary cause of autoimmune and other inflammatory disorders in humans. Based on recent advances in our understanding of the cellular and molecular basis of this T cell–mediated immune regulation, this review discusses how naturally arising CD25+CD4+regulatory T cells contribute to the maintenance of immunologic self-tolerance and negative control of various immune responses, and how they can be exploited to prevent and treat autoimmune disease, allergy, cancer, and chronic infection, or establish donor-specific transplantation tolerance.
VITAMINDAND ITSANALOGS ASREGULATORS OFIMMUNEACTIVATION ANDANTIGENPRESENTATION
Authors: Griffin Matthew D. , Xing Nianzeng , Kumar Rajiv
Published: March 2003

▪ Abstract  It has been a little more than 20 years since the first appreciation that the biologically active hormonal form of the secosteroid vitamin D—classically categorized as a regulator of calcium/phosphorous metabolism and bone mineralization—can exert effects on cells of the immune system. Since then a substantial literature has accumulated to suggest that these effects are exerted on multiple immune cell types, are predominantly suppressive at pharmacologic levels, and are potent enough to have true therapeutic potential in the management or prevention of immune-mediated diseases. Less clear at present, however, are the physiological roles played by the vitamin D endocrine system in the regulation of normal and abnormal immune responses. In this review, an appraisal of the current understanding of vitamin D–mediated immune regulation is presented that emphasizes progress towards its clinical application as well as the manner in which emerging models of normal immune function may facilitate a more complete understanding of its physiologic significance.
Myeloid and monocytic dyspoiesis as determined by flow cytometric scoring in myelodysplastic syndrome correlates with the IPSS and with outcome after hematopoietic stem cell transplantation
Authors: Wells Denise A. , Benesch Martin , Loken Michael R. , Vallejo Carlos , Myerson David , Leisenring Wendy M. , Deeg H. Joachim
Published: March 2003

Marrow cells of myeloid lineage from 115 patients with myelodysplastic syndrome (MDS) were characterized by multidimensional flow cytometry and compared with findings in 104 patients with various disorders and 25 healthy donors. Based on phenotypic and scatter characteristics, a flow cytometric scoring system (FCSS) was developed that allowed for a simple numerical display of results. The flow cytometric scores were categorized as normal/mild (0-1), moderate (2-3), or severe (≥ 4). Most flow cytometric abnormalities were significantly (P < .05) more frequent in patients with MDS than in the control cohort. Flow cytometric scores in MDS patients were then retrospectively compared with marrow blast counts assessed by morphology, cytogenetics, hematologic parameters, and International Prognostic Scoring System (IPSS) risk categorization. The flow cytometric scores correlated inversely with leukocyte and absolute neutrophil counts (P < .01) and correlated directly with IPSS scores (P < .01) and with IPSS cytogenetic risk categories (P < .01). In 111 MDS patients who underwent allogeneic hematopoietic stem cell transplantation, flow scores correlated with posttransplantation outcome. The probabilities of posttransplantation relapse were 3%, 15%, and 33% for patients with mild, moderate, and severe FCSS scores, respectively (P < .01), and overall survival was 74%, 40%, and 36%, respectively, for the 3 groups (P < .01). In multivariate analyses, there was a significant contribution of the flow score independent of the IPSS in predicting survival and relapse (P < .01, P = .02, and P = .03, respectively). These data suggest that FCSS is useful in assessing marrows for diagnosis of MDS and in determining the prognostic outcome in patients with this disorder. (Blood. 2003;102:394-403)
Graft-versus-host disease following allogeneic transplantation from HLA-identical sibling with antithymocyte globulin–based reduced-intensity preparative regimen
Authors: Mohty Mohamad , Bay Jacques-Olivier , Faucher Catherine , Choufi Bachra , Bilger Karin , Tournilhac Olivier , Vey Norbert , Stoppa Anne-Marie , Coso Diane , Chabannon Christian , Viens Patrice , Maraninchi Dominique , Blaise Didier
Published: March 2003

Reduced-intensity conditioning (RIC) regimens are increasingly used for allogeneic stem cell transplantation (allo-SCT). RIC has been shown to allow engraftment with minimal early transplantation-related mortality (TRM). However, in the context of RIC, predictive factors for acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively) and their effect on outcome remain unknown. In this report, we analyzed the outcome of 101 high-risk patients (70 hematologic and 31 nonhematologic malignancies) who received an HLA-identical sibling allo-SCT after RIC, including fludarabine, busulfan, and antithymocyte globulin (ATG). The cumulative incidence of grade II-IV aGVHD was 36% (95% confidence interval [CI], 27%-45%), whereas the cumulative incidence of cGVHD at 2 years was 43% (95% CI, 33%-53%). In multivariate analysis, the incidence of aGVHD was significantly associated with the ATG dose infused during conditioning (P = .0005), whereas peripheral blood as stem cell source was the only predictive factor for the development of cGVHD (P = .0007). The 1-year cumulative incidences of disease progression or relapse in patients with (n = 69) and without (n = 31) GVHD (whatever its form or grade) were 30% (95% CI, 19%-41%) and 55% (95% CI, 37%-72%), respectively (P = .02), suggesting that a potent graft-versus-tumor (GVT) effect can be achieved in high-risk patients following RIC. Moreover, the GVT effect was closely associated with GVHD without an increased risk of TRM (cumulative incidence of TRM, 18% [95% CI, 10%-25%]). Collectively, these results provide a framework for the refinement of RIC approaches designed to enhance the GVT effect with an acceptable risk of GVHD.
ATP gradients inhibit the migratory capacity of specific human dendritic cell types: implications for P2Y11 receptor signaling
Authors: Schnurr Max , Toy Tracey , Stoitzner Patrizia , Cameron Paul , Shin Amanda , Beecroft Tina , Davis Ian D. , Cebon Jonathan , Maraskovsky Eugene
Published: March 2003

Dendritic cells (DCs) are specialized antigen-presenting cells residing in tissues, from which they take up antigen. Activated DCs migrate through chemokine gradients from sites of inflammation to lymph nodes to stimulate T cells. At sites of inflammation, nucleotides, such as adenosine triphosphate (ATP), are released by activated or dying cells and can function as signaling molecules through P2 receptors (P2Rs). We investigated P2R expression in different DC populations and the effect of nucleotides on chemokine-directed migration. Exposure of monocyte-derived DCs (MoDCs) and CD1a+ dermal DCs to gradients of ATP inhibited their migratory capacity in a dose-dependent manner. Studies using P2R agonists and antagonists implicated signaling through the P2Y11R. On maturation, MoDCs down-regulated P2Y11R expression and were less sensitive to ATP-mediated inhibition of migration. In contrast, ATP did not inhibit the migration of CD1c+ peripheral blood (PB) DCs or interleukin-3 receptor-positive (IL-3R+) plasmacytoid DCs. Although all 4 DC populations expressed mRNA for P2Y11R, calcium-flux studies showed that blood DC types were unresponsive to P2Y11R agonists. In conclusion, DCs use distinct subtypes of P2R. The formation of ATP gradients at sites of inflammation may transiently inhibit the migration of local DCs, thus prolonging the time of antigen encounter. P2R inhibition may represent a new strategy to improve the migration of antigen-loaded DCs from the vaccination site to lymph nodes.
Comparative response of plasma VWF in dogs to up-regulation of VWF mRNA by interleukin-11 versus Weibel-Palade body release by desmopressin (DDAVP)
Authors: Olsen Eva H. N. , McCain Arlene S. , Merricks Elizabeth P. , Fischer Thomas H. , Dillon Ivy M. , Raymer Robin A. , Bellinger Dwight A. , Fahs Scot A. , Montgomery Robert R. , Keith James C. , Schaub Robert G. , Nichols Timothy C.
Published: March 2003

Recombinant human interleukin-11 (rhIL-11), a glycoprotein 130 (gp130)–signaling cytokine approved for treatment of thrombocytopenia, also raises von Willebrand factor (VWF) and factor VIII (FVIII) by an unknown mechanism. Desmopressin (1-deamino-8-d-arginine vasopressin [DDAVP]) releases stored VWF and FVIII and is used for treatment of VWF and FVIII deficiencies. To compare the effect of these 2 agents, heterozygous von Willebrand disease (VWD) and normal dogs were treated with either rhIL-11 (50 μg/kg/d subcutaneously × 7 days) or DDAVP (5 μg/kg/d intravenously × 7 days). The rhIL-11 produced a gradual and sustained elevation of VWF and FVIII levels in both heterozygous VWD and normal dogs while DDAVP produced a rapid and unsustained increase. Importantly, rhIL-11 treatment produced a 2.5- to 11-fold increase in VWF mRNA in normal canine heart, aorta, and spleen but not in homozygous VWD dogs, thus identifying a mechanism for elevation of plasma VWF in vivo. Moreover, dogs pretreated with rhIL-11 retain a DDAVP-releasable pool of VWF and FVIII, suggesting that rhIL-11 does not significantly alter trafficking of these proteins to or from storage pools. The half-life of infused VWF is unchanged by rhIL-11 in homozygous VWD dogs. These results show that rhIL-11 and DDAVP raise plasma VWF by different mechanisms. Treatment with rhIL-11 with or without DDAVP may provide an alternative to plasma-derived products for some VWD and hemophilia A patients if it is shown safe in clinical trials.
Developmental Expression of Genes Involved in Neurosteroidogenesis: 3β-Hydroxysteroid Dehydrogenase/Δ5-Δ4 Isomerase in the Rat Brain
Authors: Ibanez Chrystelle , Guennoun Rachida , Liere Philippe , Eychenne Bernard , Pianos Antoine , El-Etr Martine , Baulieu Etienne-Emile , Schumacher Michael
Published: March 2003

In the central nervous system, neurosteroids, in particular progesterone, have neurotrophic and neuroprotective effects. We thus decided to study the developmental expression of 3β-hydroxysteroid-dehydrogenase/Δ5-Δ4 isomerase (3βHSD), an enzyme that converts pregnenolone to progesterone, in the male rat brain at 0, 7, 14, and 70 d after birth.

3βHSD mRNA was widely distributed throughout the brain, as shown by in situ hybridization. At all ages, the same cerebral structures were labeled, but the intensity of the hybridization signal constantly decreased during postnatal development. As the hippocampus is of particular interest because of its neuronal plasticity, we chose to quantify the changes in 3βHSD mRNA levels as well as progesterone and pregnenolone concentrations in this structure. Quantitative in situ hybridization confirmed a decrease in the expression of 3βHSD mRNA with progressing age, as revealed by a significant reduction in the density of silver grains per cell in the CA1 layer. This decrease was confirmed by semiquantitative RT-PCR on hippocampal samples. Concentrations of hippocampal pregnenolone and progesterone measured by gas chromatography/mass spectrometry were highest on the day of birth and lower at the other ages. Plasma concentrations of these steroids were lower than those in the hippocampus, suggesting that they may have been mostly synthesized in situ since the day of birth. These results demonstrate variations in the expression of a gene coding for an enzyme critically involved in progesterone synthesis in the hippocampus throughout postnatal development.
Phosphodiesterase Regulation Is Critical for the Differentiation and Pattern of Gene Expression in Granulosa Cells of the Ovarian Follicle
Authors: Park Jy-Young , Richard Francois , Chun Sang-Young , Park Jeong-Hoh , Law Evelyn , Horner Kathleen , Jin S-L Catherine , Conti Marco
Published: March 2003

Feedback regulations are integral components of the cAMP signaling required for most cellular processes, including gene expression and cell differentiation. Here, we provide evidence that one of these feedback regulations involving the cyclic nucleotide phosphodiesterase PDE4D plays a critical role in cAMP signaling during the differentiation of granulosa cells of the ovarian follicle. Gonadotropins induce PDE4D mRNA and increase the cAMP hydrolyzing activity in granulosa cells, demonstrating that a feedback regulation of cAMP is operating in granulosa cells in vivo. Inactivation of the PDE4D by homologous recombination is associated with an altered pattern of cAMP accumulation induced by the gonadotropin LH/human chorionic gonadotropin (hCG), impaired female fertility, and a markedly decreased ovulation rate. In spite of a disruption of the cAMP response, LH/hCG induced P450 side chain cleavage expression and steroidogenesis in a manner similar to wild-type controls. Morphological examination of the ovary of PDE4D−/− mice indicated luteinization of antral follicles with entrapped oocytes. Consistent with the morphological finding of unruptured follicles, LH/hCG induction of genes involved in ovulation, including cyclooxygenase-2, progesterone receptor, and the downstream genes, is markedly decreased in the PDE4D−/− ovaries. These data demonstrate that PDE4D regulation plays a critical role in gonadotropin mechanism of action and suggest that the intensity and duration of the cAMP signal defines the pattern of gene expression during the differentiation of granulosa cells.
Screening Men for Prostate and Colorectal Cancer in the United States
Authors: Sirovich Brenda E. , Schwartz Lisa M. , Woloshin Steven
Published: March 2003

Context

The debate about the efficacy of prostate-specific antigen (PSA) screening for prostate cancer has received substantial attention in the medical literature and the media, but the extent to which men are actually screened is unknown. If practice were evidence-based, PSA screening would be less common among men than colorectal cancer screening, a preventive service of broad acceptance and proven efficacy.

Objective

To compare the prevalences of PSA and colorectal cancer screening among US men.

Design, Setting, and Population

The 2001 Behavioral Risk Factor Surveillance System, an annual population-based telephone survey of US adults conducted by the Centers for Disease Control and Prevention, was used to gather data on a representative sample of men aged 40 years or older from all 50 states and the District of Columbia (n = 49 315).

Main Outcome Measures

Proportions of men ever screened and up to date on screening for prostate cancer (with PSA testing) and colorectal cancer (with fecal occult blood testing, flexible sigmoidoscopy, or colonoscopy).

Results

Overall, men are more likely to report having ever been screened for prostate cancer than for colorectal cancer; 75% of those aged 50 years or older have had a PSA test vs 63% for any colorectal cancer test (risk ratio [RR], 1.20; 95% confidence interval [CI], 1.18-1.21). Up-to-date PSA screening is also more common than colorectal cancer screening for men of all ages. Among men aged 50 to 69 years (those for whom there is the greatest consensus in favor of screening), 54% reported an up-to-date PSA screen, while 45% reported up-to-date testing for colorectal cancer (RR, 1.19; 95% CI, 1.16-1.21). In state-level analyses of this age group, men were significantly more likely to be up to date on prostate cancer screening compared with colorectal cancer screening in 27 states, while up-to-date colorectal cancer screening was more common in only 1 state.

Conclusion

Among men in the United States, prostate cancer screening is more common than colorectal cancer screening. Physicians should ensure that men who choose to be screened for cancer are aware of the known mortality benefit of colorectal cancer screening and the uncertain benefits of screening for prostate cancer.
Probabilistic advisory systems for data‐intensive applications
Authors: Quinn A. , Ettler P. , Jirsa L. , Nagy I. , Nedoma P.
Published: March 2003

Real‐world, multidimensional, dynamic, non‐linear processes typically exhibit many distinct modes of operation. Mixtures of dynamic models improve greatly on traditional one‐component linear models in this context. Improved prediction then points the way to effective adaptive control design. This paper presents the experience gained under the EU Project, ProDaCTool, in designing and implementing advisory systems, based on dynamic mixtures, in diverse domains: urban traffic regulation, therapy recommendations in nuclear medicine, and operator support for metal‐strip rolling mills. Efficient, recursive estimation of the dynamic mixtures from archive data is accomplished using the quasi‐Bayes (QB) algorithm, implemented with dedicated software developed within ProDaCTool. The advisory systems are designed using the probabilistic control design technique presented in the previous paper. Highly encouraging prediction and performance enhancements are reported for the applications considered. Copyright © 2003 John Wiley & Sons, Ltd.
Acquired von Willebrand's syndrome: A single institution experience
Authors: Kumar Shaji , Pruthi Rajiv K. , Nichols William L.
Published: March 2003

Acquired von Willebrand's disease or syndrome (AVWS) is a rare bleeding disorder distinguished from congenital von Willebrand's disease by age at presentation and absence of personal and family history of bleeding disorders. We report on 22 patients with AVWS seen over 25 years. Mean age at diagnosis was 61.3 years (range 38–86 years); most patients had a spontaneous or a post‐operative hemorrhage at presentation. Gastrointestinal bleeding and epistaxis were the most common spontaneous symptoms. Bleeding time was prolonged in most patients, associated with marked reductions in plasma von Willebrand factor antigen and ristocetin cofactor activity. Plasma VWF multimer distribution was normal (type 1 pattern) in 5 patients, indeterminate (no multimers detectable) in 6 patients (type 3 pattern), and abnormal (decreased higher‐molecular‐weight multimers, type 2 pattern) in 11 patients. None of 17 patients tested had an inhibitor of ristocetin cofactor activity. An underlying malignant or benign hematologic disease was found in 18 patients, and 1 patient had Crohn's disease. Desmopressin was effective in only half the patients so treated, but all patients responded to treatment with VWF‐containing concentrates. Resolution of AVWS occurred with therapy of lymphoma (1 patient) and chronic lymphocytic leukemia (1 patient). Sixteen patients were alive at last follow‐up; no deaths were related to bleeding. AVWS may be more prevalent than has been appreciated; we estimate up to 0.04%. Awareness of the existence of AVWS is essential for diagnosis and appropriate management. Therapy of associated diseases may improve the bleeding disorder. Am. J. Hematol. 72:243–247, 2003. © 2003 Wiley‐Liss, Inc.
Relationship between the Structure and Antimycobacterial Activity of Substituted Salicylanilides
Authors: Waisser Karel , Bureš Otakar , Holý Pavel , Kuneš Jiří , Oswald Radek , Jirásková Lucie , Pour Milan , Klimešová Věra , Kubicová Lenka , Kaustová Jarmila
Published: March 2003

A series of 143 salicylanilides substituted in positions 4 and 5 and in positions 3′ and 4′ was synthesized. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii, and Mycobacterium avium. To describe the structure‐antimycobacterial activity relationships (QSARs), an approach based on the combination of the Free‐Wilson and Hansch methods was employed (the substituent constants were used in the case of the substituents on the phenyl ring; indicator parameters were used for the substituents on the acyl moiety). The relationships between the antimycobacterial activity and physico‐chemical parameters of all substituents were also explored. The quadratic representation of lipophilicity parameters did not lead to significant correlations.