bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized study of valacyclovir as prophylaxis against cytomegalovirus reactivation in recipients of allogeneic bone marrow transplants
Authors: Ljungman Per , de la Camara Rafael , Milpied Noel , Volin Liisa , Russell Charlotte A. , Crisp Adam , Webster Alison ,   the Valacyclovir International Bone Marrow Transplant Study Group
Published: October 2002

Abstract
Oral valacyclovir for cytomegalovirus (CMV) prophylaxis in bone marrow transplantation (BMT) was investigated in a randomized, double-blind, acyclovir-controlled, multicenter clinical trial in recipients of allogeneic BMT who were CMV seropositive (or donor positive) before transplantation and were aged 13 years or older. Patients were randomized before BMT. All initially received intravenous acyclovir (500 mg/m2) 3 times daily until day 28 after transplantation or after discharge, then oral valacyclovir (2 g) or acyclovir (800 mg) 4 times daily until week 18 after transplantation. Evidence of CMV infection, CMV disease, and death were documented for 22 weeks. Primary end points were time to CMV infection (detection of CMV in blood, broncho-alveolar lavage) or CMV disease and survival. Preemptive CMV therapy was permitted. Seven hundred twenty-seven patients were evaluable for efficacy. After the administration of intravenous acyclovir, valacyclovir was significantly more effective than oral acyclovir in reducing the incidence of CMV infection. CMV infection or disease developed in 102 (28%) valacyclovir patients, compared with 143 (40%) acyclovir patients (HR, 0.59; 95% CI, 0.46-0.76; P &lt; .0001). Survival did not differ between treatments (76% and 75% in the valacyclovir and acyclovir groups, respectively). The safety of oral valacyclovir was similar to that of high-dose oral acyclovir. Valacyclovir was more effective than acyclovir in preventing CMV reactivation in BMT recipients and showed a similar safety profile. CMV disease incidence was low, and no differences were observed between oral valacyclovir and acyclovir. Survival was similar in each group. Valacyclovir prophylaxis provides a clinically valuable intervention but must be part of an overall strategy for CMV prevention in BMT.
High-dose therapy and autologous blood stem cell transplantation in POEMS syndrome
Authors: Jaccard Arnaud , Royer Bruno , Bordessoule Dominique , Brouet Jean-Claude , Fermand Jean-Paul 
Published: October 2002

Abstract
We treated 5 patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome and multifocal bone lesions or diffuse bone marrow plasmacytic infiltration with high-dose therapy (HDT) and autologous blood stem cell transplantation. In all cases, the treatment produced remission of plasma cell proliferation associated with marked improvement in the patients' performance status, neurologic symptoms, and other manifestations of the syndrome. HDT with stem cell support should be investigated further as a therapeutic option in patients with POEMS syndrome and disseminated plasma cell dyscrasia.
Functional amelioration of murine galactosialidosis by genetically modified bone marrow hematopoietic progenitor cells
Authors: Leimig Thasia , Mann Linda , Martin Maria del Pilar , Bonten Erik , Persons Derek , Knowles James , Allay James A. , Cunningham John , Nienhuis Arthur W. , Smeyne Richard , d'Azzo Alessandra 
Published: October 2002

AbstractProtective protein/cathepsin A (PPCA), a lysosomal carboxypeptidase, is deficient in the neurodegenerative lysosomal disorder galactosialidosis (GS). PPCA−/− mice display a disease course similar to that of severe human GS, resulting in nephropathy, ataxia, and premature death. Bone marrow transplantation (BMT) in mutant animals using transgenic BM overexpressing the corrective enzyme in either erythroid cells or monocytes/macrophages has proven effective for the improvement of the phenotype, and encouraged the use of genetically modified BM cells for ex vivo gene therapy of GS. Here, we established stable donor hematopoiesis in PPCA−/− mice that received hematopoietic progenitors transduced with a murine stem cell virus (MSCV)–based, bicistronic retroviral vector overexpressing PPCA and the green fluorescent protein (GFP) marker. We observed complete correction of the disease phenotype in the systemic organs up to 10 months after transplantation. PPCA+ BM-derived cells were detected in all tissues, with the highest expression in liver, spleen, BM, thymus, and lung. In addition, a lysosomal immunostaining was seen in nonhematopoietic cells, indicating efficient uptake of the corrective protein by these cells and cross-correction. Expression in the brain occurred throughout the parenchyma but was mainly localized on perivascular areas. However, PPCA expression in the central nervous system was apparently sufficient to delay the onset of Purkinje cell degeneration and to correct the ataxia. The long-term expression and internalization of the PPCA by cells of systemic organs and the clear improvement of the neurologic phenotype support the use of this approach for the treatment of GS in humans.
Constitutive and functional association of the platelet collagen receptor glycoprotein VI–Fc receptor γ-chain complex with membrane rafts
Authors: Ezumi Yasuharu , Kodama Kumi , Uchiyama Takashi , Takayama Hiroshi 
Published: October 2002

AbstractThe platelet collagen receptor glycoprotein (GP) VI–Fc receptor γ-chain (FcRγ) complex transduces signals in an immunoreceptorlike manner. We examined a role for the Triton X-100–insoluble membrane rafts in GPVI–FcRγ complex signaling. Methyl-β-cyclodextrin (MβCD)-induced disruption of the membrane rafts inhibited not only platelet aggregation and secretion but also tyrosine phosphorylation of signaling molecules on stimulation through the GPVI–FcRγ complex. The GPVI–FcRγ complex was constitutively associated with membrane rafts wherein the Src family kinases and LAT were also present. Their association was not affected by the complex engagement but was highly sensitive to MβCD treatment. Thus, we provide the first evidence that the GPVI–FcRγ complex is constitutively and functionally associated with membrane rafts.
Tumor lysate–specific cytotoxic T lymphocytes in multiple myeloma: promising effector cells for immunotherapy
Authors: Wen Yue-Jin , Min Rui , Tricot Guido , Barlogie Bart , Yi Qing 
Published: October 2002

AbstractThe idiotype protein, secreted by myeloma plasma cells, is a tumor-specific but weak antigen. Idiotype-based immunotherapy has been explored in myeloma patients with disappointing results. It is conceivable that myeloma cells contain a multitude of tumor antigens that can more effectively stimulate antitumor T cells. To explore the possibility of using whole myeloma cells as a source of tumor antigens for immunotherapy, the current study was undertaken to generate and examine the function of myeloma-specific cytotoxic T lymphocytes (CTLs) by using dendritic cells (DCs) pulsed with myeloma cell lysates as stimulating cells. After repeated stimulation, specific CTL lines, containing CD4+ and CD8+ T cells, were generated from myeloma patients. Our results show that these T cells not only recognized and lysed autologous myeloma protein–pulsed DCs, they also killed autologous primary myeloma cells. Occasionally, CTLs responded to autologous idiotype–pulsed DCs and to allogeneic primary myeloma cells. No cytolytic activity, however, was detected against autologous lymphocytes including B cells, suggesting that the T cells acted specifically against myeloma cells. Cytotoxicity against target cells was major histocompatibility complex class 1 and, to a lesser extent, class 2 restricted and was dependent mainly on the perforin-mediated pathway. CTLs secreted predominantly interferon-γ and tumor necrosis factor-α on antigenic stimulation, indicating a type 1 T-cell subset. These findings represent the first demonstration that tumor cell lysate–primed CTLs kill only myeloma cells, not autologous lymphocytes. This provides a rationale for myeloma cell–based immunotherapy in multiple myeloma.
Heavy chain ferritin activates regulatory T cells by induction of changes in dendritic cells
Authors: Gray Christian P. , Arosio Paolo , Hersey Peter 
Published: October 2002

AbstractHeavy chain ferritin (H-ferritin) is a component of the iron-binding protein, ferritin. We have previously shown that H-ferritin inhibits anti-CD3–stimulated lymphocyte proliferation and that this was due to increased production of interleukin-10 (IL-10). In the present study we have shown that induction of IL-10 production was due to effects of H-ferritin on adherent antigen-presenting cells (APCs) in blood and monocyte-derived dendritic cells (MoDCs). IL-10 was produced by a subpopulation of CD4 T cells, which expressed the CD25 component of the IL-2 receptor and the CTLA-4 receptor characteristic of regulatory T cells. The changes induced in MoDCs were compared with those induced by CD40L and their significance tested by inhibition with monoclonal antibodies. These studies indicated that H-ferritin induced relatively greater expression of CD86 and B7-H1 on MoDCs and that monoclonal antibodies against their receptors, CTLA-4 and programmed death receptor-1 (PD-1), inhibited IL-10 production from the regulatory T cells. H-ferritin did not appear to induce direct production of the cytokines IL-2, IL-4, IL-6, IL-10, IL-12, or interferon-γ from the DCs. These results are consistent with the thesis that H-ferritin induces B7-H1 and CD86 (B7-2) on APCs, which in turn induce IL-10 production from regulatory T cells. This is possibly one mechanism by which melanoma cells may induce changes in APCs in the vicinity of the tumor and result in suppression of immune responses by induction of regulatory T cells.
Stimulation of toll-like receptor 4 expression in human mononuclear phagocytes by interferon-γ: a molecular basis for priming and synergism with bacterial lipopolysaccharide
Authors: Bosisio Daniela , Polentarutti Nadia , Sironi Marina , Bernasconi Sergio , Miyake Kensuke , Webb Ginette R. , Martin Michael U. , Mantovani Alberto , Muzio Marta 
Published: October 2002

AbstractIn human monocytes and macrophages, interferon-γ (IFNγ) augmented mRNA and surface expression of toll-like receptor 4 (TLR4), a crucial component of the signaling receptor complex for bacterial lipopolysaccharide (LPS). Expression of the accessory component MD-2 and of the adapter protein MyD88 was also increased. LPS increased TLR4 mRNA levels, but concomitantly decreased its surface expression. IFNγ counteracted the LPS-induced downregulation of TLR4. IFNγ-primed monocytes showed increased responsiveness to LPS in terms of phosphorylation of the interleukin-1 receptor–associated kinase (IRAK; immediately downstream of the MyD88 adapter protein), NF-kB DNA binding activity, and, accordingly, of cytokine (tumor necrosis factor α [TNFα] and interleukin-12 [IL-12]) production. These results suggest that enhanced TLR4 expression underlies the long-known priming by IFNγ of mononuclear phagocytes for pathogen recognition and killing as well as its synergism with LPS in macrophage activation.
Erythrocyte survival is promoted by plasma and suppressed by a Bak-derived BH3 peptide that interacts with membrane-associated Bcl-XL
Authors: Walsh Melanie , Lutz Robert J. , Cotter Thomas G. , O'Connor Rosemary 
Published: October 2002

AbstractErythrocytes have a defined lifespan in vivo, and the signals that maintain their survival in circulation or trigger their death are unknown. Here, we investigated the control of erythrocyte survival and death in an in vitro culture system where erythrocytes survived for 10 days in serum-free medium in the presence or absence of bovine serum. Death of the cells in culture was correlated with increased exposure of phosphatidylserine and increased levels of intracellular calcium. Cell death could be suppressed by supplementing the medium with human plasma or serum, resulting in a doubling of the lifespan to 20 days. Freshly isolated erythrocytes and cultured erythrocytes were both found to express Bcl-XL and, to a lesser extent, Bak in membrane protein extracts. Treatment of the cells with a Bak-derived BH3 peptide fused to the internalization sequence of the antennapedia protein, which has previously been shown to enter cells by diffusion and antagonize Bcl-XL, resulted in substantial cell death in erythrocyte cultures. BH3-induced death was accompanied by an immediate increase in accumulation of intracellular calcium and could be suppressed by plasma, but not by the caspase inhibitor zVAD. A BH3 peptide mutated at amino acid 78 of full-length Bak required for heterodimerization with Bcl-XL had no effect on cell viability or calcium levels. We conclude that the BH3 peptide accelerates erythrocyte death through antagonization of Bcl-XL. The data suggest that erythrocyte survival is promoted by survival factors in plasma and by membrane-associated Bcl-XL.
The voluntary drive to breathe is not decreased in hypercapnic patients with severe COPD
Authors: Topeli A. , Laghi F. , Tobin M.J. 
Published: October 2002

How do the respiratory centres of patients with chronic obstructive pulmonary disease (COPD) and hypercapnia respond to acute increases in inspiratory load? A depressed respiratory motor output has long been postulated, but studies on this issue have yielded inconsistent results, partly due to limitations of investigative techniques. Many of these limitations can be overcome by the twitch interpolation technique, which is capable of accurately quantifying the degree of diaphragmatic activation, termed the voluntary drive to breathe. The hypothesis that patients with COPD and hypercapnia compensate for an acute increase in mechanical load on the inspiratory muscles with a lower voluntary drive to breathe than is the case with normocapnic patients was tested.Measurements were obtained in 15 patients with COPD, six of whom displayed hypercapnia and nine normocapnia. The maximum degree of diaphragmatic activation, expressed as a voluntary activation index (mean±sem), was higher in hypercapnic than in normocapnic patients (98.7±0.7versus94.5±0.9% (p=0.006)), as was the mean value (94.5±0.7versus88.5±1.9% (p=0.01)). Within-patient values of the index were also less variable in the hypercapnic patients (coefficients of variation, 3.4±0.3versus6.1±0.9%, p=0.01). Multiple regression analysis revealed the ratio of dynamic elastance to maximum transdiaphragmatic pressure, an index of inspiratory muscle loading, and pH as the only variables that correlated with maximum voluntary activation index (r2=0.69, p=0.02 for each variable).Contrary to the hypothesis, it was concluded that voluntary activation of the diaphragm was greater and less variable in hypercapnic patients than normocapnic patients with severe chronic obstructive pulmonary disease during an acute increase in inspiratory mechanical load. Whether greater diaphragmatic recruitment during episodes of a severe exacerbation of chronic obstructive pulmonary disease provides a survival advantage for hypercapnic patients with chronic obstructive pulmonary disease remains to be determined.
Partial liquid ventilation improves lung function in ventilation-induced lung injury
Authors: Vazquez de Anda G.F. , Lachmann R.A. , Verbrugge S.J.C. , Gommers D. , Haitsma J.J. , Lachmann B. 
Published: October 2002

Disturbances in lung function and lung mechanics are present after ventilation with high peak inspiratory pressures (PIP) and low levels of positive end-expiratory pressure (PEEP). Therefore, the authors investigated whether partial liquid ventilation can re-establish lung function after ventilation-induced lung injury.Adult rats were exposed to high PIP without PEEP for 20 min. Thereafter, the animals were randomly divided into five groups. The first group was killed immediately after randomization and used as an untreated control. The second group received only sham treatment and ventilation, and three groups received treatment with perfluorocarbon (10 mL·kg−1, 20 mL·kg−1, and 20 ml·kg−1plus an additional 5 mL·kg−1after 1 h). The four groups were maintained on mechanical ventilation for a further 2-h observation period. Blood gases, lung mechanics, total protein concentration, minimal surface tension, and small/large surfactant aggregates ratio were determined.The results show that in ventilation-induced lung injury, partial liquid ventilation with different amounts of perflubron improves gas exchange and pulmonary function, when compared to a group of animals treated with standard respiratory care. These effects have been observed despite the presence of a high intra-alveolar protein concentration, especially in those groups treated with 10 and 20 mL of perflubron.The data suggest that replacement of perfluorocarbon, lost over time, is crucial to maintain the constant effects of partial liquid ventilation.
Noninvasive measurement of mean alveolar carbon dioxide tension and Bohr's dead space during tidal breathing
Authors: Koulouris N.G. , Latsi P. , Dimitroulis J. , Jordanoglou B. , Gaga M. , Jordanoglou J. 
Published: October 2002

The lack of methodology for measuring the alveolar carbon dioxide tension (PA,CO2) has forced investigators to make several assumptions, such as thatPA,CO2is equal to end-tidal (PET,CO2) and arterial CO2tension (Pa,CO2).The present study measured the meanPA,CO2and Bohr's dead space ratio (Bohr's dead space/tidal volume (VD,Bohr/VT)) during tidal breathing. The method used is a new, simple and noninvasive technique, based on the analysis of the expired CO2volume per breath (VCO2)versusthe exhaledVT. This curve was analysed in 21 normal, healthy subjects and 35 chronic obstructive pulmonary disease (COPD) patients breathing tidally through a mouthpiece apparatus in the sitting position.It is shown that: 1)PA,CO2is similar toPa,CO2in normal subjects, whilst it is significantly lower thanPa,CO2in COPD patients; 2)PA,CO2is significantly higher thanPET,CO2in all subjects, especially in COPD patients; 3)VD,Bohr/VTis increased in COPD patients as compared to normal subjects; and 4)VD,Bohr/VTis lower than the “physiological” dead space ratio (VD,phys/VT) in COPD patients.It is concluded that the expired carbon dioxideversustidal volume curve is a useful tool for research and clinical work, because it permits the noninvasive and accurate measurement of Bohr's dead space and mean alveolar carbon dioxide tension accurately during spontaneous breathing.
Glucocorticoid treatment reduces exhaled nitric oxide in cystic fibrosis patients
Authors: Linnane S.J. , Thin A.G. , Keatings V.M. , Moynihan J.B. , McLoughlin P. , FitzGerald M.X. 
Published: October 2002

In cystic fibrosis (CF), low concentrations of exhaled nitric oxide (NO) and reduced expression of inducible nitric oxide synthase (iNOS) in airway epithelium have been reported. However, abundant iNOS expression has been found in the subepithelial tissues and elevated concentrations of NO metabolites in breath condensate and sputum. These conflicting results may be explained by increased scavenging of NO by superoxide radicals, resulting in rapid conversion to peroxynitrite, so that only a small proportion of the NO produced in the lung tissue reaches the airway lumen. If iNOS were active in the CF lung, exhaled NO would be further reduced by glucocorticoid treatment.CF patients (n=13) were recruited to a double-blind, placebo-controlled study with crossover. Treatment comprised prednisolone or placebo for 5 days with a 9 day washout. After each treatment, exhaled NO was measured, spirometry performed and blood collected for measurement of serum nitrogen dioxide/nitrous oxide (NO2/NO3).Ten patients (8 male) completed the study. Following prednisolone treatment (mean±sd) exhaled NO concentration (3.1±1.6 parts per billion (ppb)) was significantly reducedversusplacebo treatment (4.9±4.2 ppb; p<0.05, Wilcoxon signed-rank test). Spirometric indices and serum NO2/NO3concentration were unchanged.These findings support the hypothesis that glucocorticoids suppress nitric oxide production in cystic fibrosis airways by reducing inducible nitric oxide synthase expression or by inhibiting recruitment of neutrophils, cells which express inducible nitric oxide synthase.
Human lung fibroblasts secrete nerve growth factor: effect of inflammatory cytokines and glucocorticoids
Authors: Olgart C. , Frossard N. 
Published: October 2002

Nerve growth factor (NGF) has recently been suggested to contribute to inflammation and bronchial hyperresponsiveness in asthma. However, the cell types capable of NGF production in the human lung and airways, as well as the regulatory role of pro-inflammatory cytokines and of glucocorticoids on NGF secretion in pulmonary cells, have not been described.Human pulmonary fibroblasts were cultured in the presence or absence of either interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α) and/or glucocorticoids. NGF secretion was measured by enzyme-linked immunosorbent assay.The human pulmonary fibroblasts constitutively secreted NGFin vitro. The rate of NGF secretion was shown to be cell density-dependent, since higher NGF secretion was detected in preconfluent cells,i.e.ones with less established cell-to-cell contact (41.0±5.0 pg·10−6cells at 80% confluence), than cells in higher densities (8.2±3.4 pg·10−6cells at 100% confluence). Stimulation with the pro-inflammatory cytokines IL-1β (0.3–30 U·mL−1) or TNF-α (0.1–30 ng·mL−1) dose- and time-dependently (8–72 h) elevated the NGF secretion (effective concentration causing 50% of the maximum response (EC50)=2.9 U·mL−1and 1.0 ng·mL−1, respectively). Treatment with the glucocorticoid budesonide (10−7 M) markedly reduced the constitutive secretion of NGF by 42%, and attenuated the cytokine-stimulated NGF secretion to the same level.In conclusion, human lung fibroblasts may serve as a source of nerve growth factor in the lung, positively regulated by the asthma-associated and pro-inflammatory cytokines interleukin-1β and tumour necrosis factor-α, and negatively regulated by the anti-inflammatory glucocorticoids.
Aerosolized PGE1, PGI2and nitroprusside protect against vascular leakage in lung ischaemia-reperfusion
Authors: Schütte H. , Löckinger A. , Seeger W. , Grimminger F. 
Published: October 2002

High permeability oedema is an important feature in lung injury secondary to ischaemia-reperfusion. This study investigated the influence of aerosolized prostaglandin E1(PGE1), prostaglandin I2(PGI2) and the nitric oxide (NO)-donor, sodium nitroprusside (SNP) on microvascular barrier function in pulmonary ischaemia-reperfusion.Buffer-perfused rabbit lungs were exposed to 180 or 210 min of warm ischaemia while maintaining anoxic ventilation and a positive intravascular pressure.Reperfusion provoked a transient, mostly precapillary elevation of vascular resistance, followed by a severe increase of the capillary filtration coefficient (Kfc)versusnonischaemic controls (3.17±0.34versus0.85±0.05 cm3 s−1·cmH2O−1·g−1·10−4after 30 min of reperfusion), and progressive oedema formation. Short-term aerosolization of SNP, PGE1or PGI2at the beginning of ischaemia largely suppressed the Kfc increase (1.36±0.22, 1.32±0.23 and 1.32±0.22 cm3·s−1·cmH2O−1·g−1·10−4, respectively) and oedema formation. In contrast, application prior to reperfusion was much less effective, with some reduction of Kfc increase by PGI2and SNP and no effect of PGE1(1.79±0.31, 2.2±0.53 and 3.2±0.05 cm3·s−1·cmH2O−1·g−1·10−4, respectively). Haemodynamics, including microvascular pressure, were only marginally affected by the chosen doses of aerosolized vasodilators.It is concluded that short-term aerosolization of prostaglandin E1, prostaglandin I2and sodium nitroprusside at the onset of ischaemia is highly effective in maintaining endothelial barrier properties in pulmonary ischaemia-reperfusion. This effect is apparently attributable to nonvasodilatory mechanisms exerted by these agents. Alveolar deposition of prostaglandins and/or nitric oxide donors by the aerosol technique may offer pulmonary protection in ischaemia-reperfusion injury.