bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunologic mechanisms of extracorporeal photochemotherapy in chronic graft-versus-host disease
Authors: Gorgun Gullu , Miller Kenneth B. , Foss Francine M. 
Published: October 2002

AbstractExtracorporeal photochemotherapy (ECP) has been shown to be an effective therapy for patients with acute and chronic graft-versus-host disease (GVHD) following allogeneic bone marrow transplantation, but its biologic mechanism is not understood. We reported that clinical response to ECP was associated not only with normalization of skewed CD4/CD8 ratios but also with an increase in CD3−/CD56+ natural killer cells and a decrease in the number of CD80+ and CD123+ circulating dendritic cells (DCs). To further elucidate the effects of ECP on activated lymphocyte subpopulations and the interaction between effector lymphocytes and antigen-presenting DCs, we isolated and characterized DC populations from patients with chronic GVHD undergoing ECP therapy. Antigen-presenting activity of DCs was measured as proliferation of antigen-stimulated autologous and allogeneic T cells by mixed-lymphocyte reaction (MLR). In MLR assays the proliferation of T cells was decreased in all 10 patients by a mean of 84% (range, 75%-95%; P ≤ .002) after a 2-day cycle of ECP and longitudinally over the 12-month course of therapy. Immunophenotypic analysis of DC populations revealed a preponderance of DC1 monocytic dendritic cells in all patients before the initiation of ECP. Nine of 10 patients demonstrated a shift from DC1 to DC2 and as a concordant shift from a predominantly Th1 (interleukin-2 [IL-2], interferon-γ) to Th2 (IL-4, IL-10) cytokine profile after ECP, and 8 of 10 had a clinical response to ECP. Our results suggest that ECP alters alloreactivity by affecting allo-targeted effector T cells and antigen-presenting DCs.
NAD(P)H oxidase–dependent platelet superoxide anion release increases platelet recruitment
Authors: Krötz Florian , Sohn Hae Young , Gloe Torsten , Zahler Stefan , Riexinger Tobias , Schiele Thomas M. , Becker Bernhard F. , Theisen Karl , Klauss Volker , Pohl Ulrich 
Published: October 2002

Abstract
Platelets, although not phagocytotic, have been suggested to release O2−. Since O2−-producing reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidases can be specifically activated by certain agonists and are found in several nonphagocytotic tissues, we investigated whether such an enzyme is the source of platelet-derived O2−. We further studied which agonists cause platelet O2−release and whether platelet-derived O2− influences thrombus formation in vitro. Collagen, but not adenosine 5′-diphosphate (ADP) or thrombin, increased O2− formation in washed human platelets. This was a reduced nicotinamide adenine dinucleotide (NADH)–dependent process, as shown in platelet lysates. Consistent with a role of a platelet, NAD(P)H oxidase expression of its subunits p47phox and p67phoxand inhibition of platelet O2− formation by diphenylene-iodoniumchloride (DPI) and by the specific peptide-antagonist gp91ds-tat were observed. Whereas platelet-derived O2− did not influence initial aggregation, platelet recruitment to a preformed thrombus following collagen stimulation was significantly attenuated by superoxide dismutase (SOD) or DPI. It was also inhibited when ADP released during aggregation was cleaved by the ectonucleotidase apyrase. ADP in supernatants of collagen-activated platelets was decreased in the presence of SOD, resulting in lower ADP concentrations available for recruitment of further platelets. Exogenous O2−increased ADP- concentrations in supernatants of collagen-stimulated platelets and induced irreversible aggregation when platelets were stimulated with otherwise subthreshold concentrations of ADP. These results strongly suggest that collagen activation induces NAD(P)H oxidase–dependent O2− release in platelets, which in turn enhances availability of released ADP, resulting in increased platelet recruitment.
Creation of a genetic system for analysis of the phagocyte respiratory burst: high-level reconstitution of the NADPH oxidase in a nonhematopoietic system
Authors: Price Marianne O. , McPhail Linda C. , Lambeth J. David , Han Chang-Hoon , Knaus Ulla G. , Dinauer Mary C. 
Published: October 2002

AbstractThe phagocyte nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) oxidase was functionally reconstituted in monkey kidney COS-7 cells by transfection of essential subunits, gp91phox, p22phox, p47phox, and p67phox. COS-7 cells express the essential small guanosine 5′-triphosphatase, Rac1. Transgenic COS-phox cells were capable of arachidonic acid–induced NADPH oxidase activity up to 80% of that of human neutrophils, and of phorbol myristate acetate (PMA)–induced activity up to 20% of that of neutrophils. Expression of all 4 phox components was required for enzyme activity, and enzyme activation was associated with membrane translocation of p47phox, p67phox, and Rac1. Expression of p47phox Ser303Ala/Ser304Ala or Ser379Ala phosphorylation-deficient mutants resulted in significantly impaired NAPDH oxidase activity, compared with expression of wild-type p47phox or the p47phox Ser303Glu/Ser304Glu phosphorylation mimic, suggesting that p47phoxphosphorylation contributes to enzyme activity in the COS system, as is the case in neutrophils. Hence, COS-phox cells should be useful as a new whole-cell model that is both capable of high-level superoxide production and readily amenable to genetic manipulation for investigation of NADPH oxidase function. PMA-elicited superoxide production in COS-phox cells was regulated by activation of protein kinase C (PKC) and Rac. Although COS-7 cells differ from human neutrophils in PKC isoform expression, transient expression of major neutrophil isoforms in COS-phox cells did not increase PMA-induced superoxide production, suggesting that endogenous isoforms were not rate limiting. Val204 in p67phox, previously shown to be required for NADPH oxidase activity under cell-free conditions, was found to be essential for superoxide production by intact COS-phox cells, on the basis of transfection studies using a p67phox(Val204Ala) mutant.
Coronary no-reflow is caused by shedding of active tissue factor from dissected atherosclerotic plaque
Authors: Bonderman Diana , Teml Alexander , Jakowitsch Johannes , Adlbrecht Christopher , Gyöngyösi Mariann , Sperker Wolfgang , Lass Harald , Mosgoeller Wilhelm , Glogar Dietmar H. , Probst Peter , Maurer Gerald , Nemerson Yale , Lang Irene M. 
Published: October 2002

Abstract
Defined angiographically, no-reflow (NR) manifests as an acute reduction in coronary flow in the absence of epicardial vessel obstruction. One candidate protein to cause coronary NR is tissue factor (TF), which is abundant in atherosclerotic plaque and a cofactor for activated plasma coagulation factor VII. Scrapings from atherosclerotic carotid arteries contained TF activity (corresponding to 33.03 ± 13.00 pg/cm2 luminal plaque surface). Active TF was sedimented, indicating that TF was associated with membranes. Coronary blood was drawn from 6 patients undergoing coronary interventions with the distal protection device PercuSurge GuardWire (Traatek, Miami, FL). Fine particulate material that was recovered from coronary blood showed TF activity (corresponding to 91.1 ± 62.16 pg/mL authentic TF). To examine the role of TF in acute coronary NR, blood was drawn via a catheter from coronary vessels in 13 patients during NR and after restoration of flow. Mean TF antigen levels were elevated during NR (194.3 ± 142.8 pg/mL) as compared with levels after flow restoration (73.27 ± 31.90 pg/mL; P = .02). To dissect the effects of particulate material and purified TF on flow, selective intracoronary injection of atherosclerotic material or purified relipidated TF was performed in a porcine model. TF induced NR in the model, thus strengthening the concept that TF is causal, not just a bystander to atherosclerotic plaque material. The data suggest that active TF is released from dissected coronary atherosclerotic plaque and is one of the factors causing the NR phenomenon. Thus, blood-borne TF in the coronary circulation is a major determinant of flow.
Moyamoya syndrome in childhood sickle cell disease: a predictive factor for recurrent cerebrovascular events
Authors: Dobson Scott R. , Holden Kenton R. , Nietert Paul J. , Cure Joel K. , Laver Joseph H. , Disco Deborah , Abboud Miguel R. 
Published: October 2002

AbstractWe conducted a retrospective study to determine whether the presence of moyamoya collaterals influenced the risk of recurrence of cerebrovascular events (CVEs: stroke or transient ischemic attack) in patients with sickle cell disease placed on chronic transfusions after a stroke. Forty-three patients with homozygous sickle cell anemia (HbSS) and 1 with HbSOArab (16 females, 28 males) who had suffered strokes while under the age of 18 were studied. All patients had been on transfusions aimed at maintaining the sickle hemoglobin (HbS) level below 30%. They were followed for a mean of 6.6 years (2.2 to 20.4 years). The presence of collaterals was diagnosed based on either magnetic resonance angiography or conventional angiography. Eighteen (41%) of the 44 patients suffered recurrent CVEs. Nineteen (43%) (6 females, 13 males) patients had moyamoya collaterals. Eleven (58%) of these 19 experienced 21 total recurrent CVEs, including 4 strokes in 4 patients (21%). In comparison, 7 (28%) of 25 patients without moyamoya collaterals experienced 9 recurrent CVEs (P &lt; .05) with only 1 recurrent stroke (4%). Moyamoya patients were also more likely to have 2 recurrent CVEs (42% vs 8%,P &lt; .05) as well as poorer neuropsychological testing results. A proportional hazards regression analysis indicated that patients with moyamoya were more than twice as likely to incur a subsequent CVE (hazard ratio, 2.40; 95% confidence interval, 0.85, 6.75). We conclude that up to 41% of patients with sickle cell disease experience recurrent CVEs after an initial stroke despite chronic transfusions and that the risk of recurrence is significantly higher for those who have moyamoya collaterals.
Glycoprotein VI–mediated platelet fibrinogen receptor activation occurs through calcium-sensitive and PKC-sensitive pathways without a requirement for secreted ADP
Authors: Quinton Todd M. , Ozdener Fatih , Dangelmaier Carol , Daniel James L. , Kunapuli Satya P. 
Published: October 2002

AbstractCollagen activates platelets by transducing signals through glycoprotein VI (GPVI). It is not clear whether collagen can directly activate fibrinogen receptors on the adherent platelets without a role for positive feedback agonists. We investigated the contribution of secondary G protein signaling to the mechanism of GPVI-stimulated platelet aggregation using the GPVI-selective agonists, convulxin and collagen-related peptide (CRP) as well as collagen. Adenosine diphosphate (ADP) scavengers or ADP receptor antagonists shifted the concentration-response curve slightly to the right at low concentrations of convulxin, whereas platelet aggregation at higher concentrations of convulxin was unaffected by these agents. ADP receptor antagonists shifted the concentration-response curve of collagen- or CRP-induced platelet aggregation to the right at all the concentrations. Protein kinase C inhibitor, Ro 31-8220, or a calcium chelator 5,5′-dimethyl-BAPTA shifted the concentration-response curve of convulxin-induced platelet aggregation to the right. In addition, pretreatment with both Ro 31-8220 and dimethyl-BAPTA resulted in total inhibition of convulxin-mediated aggregation. Blockade of either the calcium- or protein kinase C–regulated pathway leads to inhibition of fibrinogen receptor activation on platelets adherent to collagen, but inhibition of both pathways leads to abolished fibrinogen receptor activation. We conclude that collagen-induced activation of fibrinogen receptor on adherent platelets through GPVI signaling occurs without any significant role for secreted ADP or thromboxane A2. Furthermore, protein kinase C– and calcium-regulated pathways independently contribute to GPVI-mediated platelet aggregation.
Alanine-170 and proline-172 are critical determinants for extracellular CD20 epitopes; heterogeneity in the fine specificity of CD20 monoclonal antibodies is defined by additional requirements imposed by both amino acid sequence and quaternary structure
Authors: Polyak Maria J. , Deans Julie P. 
Published: October 2002

AbstractIn vivo ablation of malignant B cells can be achieved using antibodies directed against the CD20 antigen. Fine specificity differences among CD20 monoclonal antibodies (mAbs) are assumed not to be a factor in determining their efficacy because evidence from antibody-blocking studies indicates limited epitope diversity with only 2 overlapping extracellular CD20 epitopes. However, in this report a high degree of heterogeneity among antihuman CD20 mAbs is demonstrated. Mutation of alanine and proline at positions 170 and 172 (AxP) (single-letter amino acid codes; x indicates the identical amino acid at the same position in the murine and human CD20 sequences) in human CD20 abrogated the binding of all CD20 mAbs tested. Introduction of AxP into the equivalent positions in the murine sequence, which is not otherwise recognized by antihuman CD20 mAbs, fully reconstituted the epitope recognized by B1, the prototypic anti-CD20 mAb. 2H7, a mAb previously thought to recognize the same epitope as B1, did not recognize the murine AxP mutant. Reconstitution of the 2H7 epitope was achieved with additional mutations replacing VDxxD in the murine sequence for INxxN (positions 162-166 in the human sequence). The integrity of the 2H7 epitope, unlike that of B1, further depends on the maintenance of CD20 in an oligomeric complex. The majority of 16 antihuman CD20 mAbs tested, including rituximab, bound to murine CD20 containing the AxP mutations. Heterogeneity in the fine specificity of these antibodies was indicated by marked differences in their ability to induce homotypic cellular aggregation and translocation of CD20 to a detergent-insoluble membrane compartment previously identified as lipid rafts.
Humoral immune responses against Wilms tumor gene WT1product in patients with hematopoietic malignancies
Authors: Elisseeva Olga A. , Oka Yoshihiro , Tsuboi Akihiro , Ogata Kiyoyuki , Wu Fei , Kim Eui Ho , Soma Toshihiro , Tamaki Hiroya , Kawakami Manabu , Oji Yusuke , Hosen Naoki , Kubota Takeshi , Nakagawa Masashi , Yamagami Tamotsu , Hiraoka Akira , Tsukaguchi Machiko , Udaka Keiko , Ogawa Hiroyasu , Kishimoto Tadamitsu , Nomura Taisei , Sugiyama Haruo 
Published: October 2002

AbstractWilms tumor gene WT1 is expressed at high levels in hematopoietic malignancies, such as leukemias and myelodysplastic syndromes (MDS), and in various kinds of solid tumors, including lung cancer, and it exerts an oncogenic function in these malignancies. IgM and IgG WT1 antibodies were measured by means of dot blot assay in 73 patients with hematopoietic malignancies (16 acute myeloid leukemia [AML], 11 acute lymphoid leukemia [ALL], 13 chronic myeloid leukemia [CML], and 33 MDS) and 43 healthy volunteers. Immunoglobulin IgM, IgG, and IgM+IgG WT1 antibodies were detected in 40 (54.8%), 40 (54.8%), and 24 (32.8%), respectively, of the 73 patients with hematopoietic malignancies, whereas 7 (16.2%), 2 (4.7%), and none of the 43 healthy volunteers had IgM, IgG, or IgM+IgG WT1 antibodies, respectively. Furthermore, immunoglobulin isotype class switching of WT1 antibodies from IgM to IgG occurred in conjunction with disease progression from refractory anemia (RA) to RA with excess of blasts (RAEB), and further to RAEB in transformation (RAEB-t) in MDS patients. These results showed that humoral immune responses against the WT1 protein could be elicited in patients with WT1-expressing hematopoietic malignancies, and they suggested that the helper T-cell responses needed to induce humoral immune responses and immunoglobulin isotype class switching from IgM to IgG were also generated in these patients. Our findings may provide new insight into the rationale for elicitation of cytotoxic T-cell responses against the WT1 protein in cancer immunotherapy using the WT1 vaccine.
Changes in fatal and near-fatal asthma in an urban area of South Africa from 1980–1997
Authors: Zar H.J. , Stickells D. , Toerien A. , Wilson D. , Klein M. , Bateman E.D. 
Published: October 2002

Over the past two decades, changes in the health services designed to improve access to and quality of asthma care have occurred in South Africa. The aim of this study was to investigate the incidence of fatal and near-fatal asthma (NFA) from 1980–1997 in an urban part of South Africa.A retrospective analysis of fatal asthma and NFA in the Cape Town City Council area was performed. Mortality data were obtained from death notification records. Data on NFA were obtained from the records of patients admitted for asthma to intensive care units (ICUs) at major academic hospitals serving the area.There were 1,506 deaths (mean age 56 yrs) from asthma reported; 39 and 3% occurred in people under 55 and 15 yrs, respectively. Average annual asthma mortality rate (8.1±1.9 per 100,000 population) was highest amongst people of mixed race (10.1±2.0), followed by Blacks (6.8±3.1) and Whites (5.0±1.9, p<0.001). Asthma mortality declined by 0.28 deaths per 100,000 population per year; rates decreased in all ethnic groups. Most deaths (72.3%) were outside a health facility and a higher number of deaths occurred on weekends (223 deaths·day−1) than weekdays (207 deaths·day−1, p=0.014). Paediatric asthma ICU admissions declined by 1.81 children·yr−1. The annual number of adults admitted to ICU for asthma, and the proportion requiring intermittent positive pressure ventilation did not change.These results indicate that the incidence of fatal and near-fatal asthma in this area has declined over the period and this may reflect improved asthma management. However, the relatively high asthma mortality rate in people of mixed race and the predominance of deaths outside health facilities and on weekends suggest problems with access to care.
Pneumococcal vaccination: current and future issues
Authors: Örtqvist Å. 
Published: October 2002

Infection withStreptococcus pneumoniaeremains a major global health burden meaning the development of effective vaccines is urgently needed. The current 23-valent polysaccharide vaccine has been shown to prevent pneumococcal pneumonia in immunocompetent young adults, but not in elderly persons.However, in prevention of invasive pneumococcal disease, the vaccine is efficacious in the elderly and may also be effective in some groups of immunocompromised patients. The polysaccharide vaccine is, therefore, recommended in all older (≥55–65 yrs of age) adults and in young children (>2 yrs of age) who have a high risk for pneumococcal disease. Revaccination can be safely performed and is recommended 5 yrs after the first dose.In children <2 yrs of age, the new polysaccharide-protein conjugate vaccines, including 7–11 serotypes, seem to be effective in the prevention of invasive disease, severe pneumonia and serotype-specific (and vaccine-related types) otitis media. The low serotype coverage, need for repeated doses, and high price, may decrease the usefulness of the new conjugates. However, the included serotypes correspond to those most often associated with penicillin resistance and vaccination is, therefore, a possible tool in limiting the spread of antibiotic-resistant pneumococci.
Initial risk class and length of hospital stay in community-acquired pneumonia
Authors: Menéndez R. , Ferrando D. , Vallés J.M. , Martínez E. , Perpiñá M. 
Published: October 2002

The total medical costs of community-acquired pneumonia are directly related to the costs of hospital admission and length of stay. The aim of the present study was to evaluate the reasons for prolonged duration of stay in patients stratified in five risk classes for death, and to identify factors associated with prolonged stay.The study population consisted of 295 patients. According to lower (classes I, II, III) or to higher (classes IV, V) risk, the target duration of hospitalization was set at 5 and 7 days, respectively. The causes of prolonged hospitalization were classified as pneumonia-related, complications, unstable comorbid diseases and nonclinical factors.The overall percentage of patients with appropriate duration of hospitalization was 32%. Causes of prolonged hospitalization were related mainly to pneumonia (32%) from all risk classes. Morbid complications and instability of the underlying illness were greater in class V patients. Nonclinical factors were present in 29.5% of cases. Hypoxaemia, anaemia, hypoalbuminaemia, and complications appearing before 72 h were associated with prolonged hospitalization.The cause of prolonged hospitalization of patients with community-acquired pneumonia is multifactorial, depending mainly on pneumonia and comorbid conditions but there is a large number of unnecessary hospitalization days that could be reduced by improving the efficiency of hospital care.
Is overall asthma control being achieved? A hypothesis-generating study
Authors: Bateman E.D. , Bousquet J. , Braunstein G.L. 
Published: October 2002

The efficacy of asthma therapy is traditionally measured using single  end-points. In contrast, the aim of therapy is to achieve overall control, defined by management guidelines as achieving a number of treatment goals. These goals reflect expert opinion, rather than being evidence based. The objective of this study was to determine whether guideline-defined asthma control is achievable.Eight studies of salmeterol/fluticasone propionate combination therapy were analysed using three asthma control measures of varying stringency, derived from the guideline goals. For each measure, only patients meeting all goals were classified as controlled.The analysis demonstrated that asthma control, as defined by management guidelines, can be achieved. For a given therapy, similar proportions of patients achieved control irrespective of disease severity, suggesting that outcome expectations should not be reduced for patients with more severe disease. Substantially more patients achieved the target values for individual goals than achieved overall control, indicating that reliance on individual end-points is likely to result in significant overestimation of true control.The findings of this hypothesis-generating study should be prospectively tested. Future research will include a randomized controlled study designed to assess the proportion of patients able to achieve overall control of asthma when treatment is titrated appropriately.