bluuebunny/crossref_metadata_2025 huggingface dataset:
Granzyme B and perforin: constitutive expression in human polymorphonuclear neutrophils
Authors: Wagner Christof , Iking-Konert Christof , Denefleh Birgit , Stegmaier Sabine , Hug Friederike , Hänsch G. Maria
Published: September 2003

Polymorphonuclear neutrophils (PMNs) produce an abundance of bactericidal and cytotoxic molecules consistent with their role as first-line defense against bacterial infection. PMNs, however, also cause efficient cellular cytotoxicity when targeted through Fc receptors to appropriate antibody-coated target cells. Although this so-called antibody-dependent cellular cytotoxicity (ADCC) was described many years ago, the mechanism of killing is still elusive. We now have found that PMNs contain perforin and granzyme B, the 2 molecules known as the cytotoxic entity of natural killer cells and of cytotoxic T lymphocytes as well. Lysates of PMNs were lytic for chicken erythrocytes in a time-, temperature-, and Ca2+-dependent manner. Moreover, apoptosis of Jurkat cells was induced, consistent with the observation that the PMN lysates contain enzymatically active granzyme B. Taken together, our data provide evidence for the presence of perforin and granzyme B within the cytotoxic arsenal of PMNs. (Blood. 2004;103:1099-1104)
Helper-dependent adenoviral vectors mediate therapeutic factor VIII expression for several months with minimal accompanying toxicity in a canine model of severe hemophilia A
Authors: Brown Brian D. , Shi Chang Xin , Powell Sandra , Hurlbut David , Graham Frank L. , Lillicrap David
Published: September 2003

Two helper-dependent (HD) adenoviral vectors encoding a canine factor VIII B-domain–deleted transgene (cFVIII) were constructed and evaluated in 4 hemophilia A dogs. One vector was regulated by the cytomegalovirus (CMV) promoter (HD-CMV-cFVIII), while the other vector contained a tissue-restricted promoter comprised of the human FVIII proximal promoter with an upstream concatemer of 5 hepatocyte nuclear factor 1 binding sites (HD-HNF-cFVIII). We detected no toxicity at low dose (5 × 1011 vp/kg), but at higher vector doses (> 1 × 1012 vp/kg) transient hepatotoxicity and thrombocytopenia were observed. Low-level increases in FVIII activity were detected in all 3 HD-HNF-cFVIII–treated dogs, which corresponded with decreased whole blood clotting times. None of the animals receiving the HD-HNF-cFVIII vector developed FVIII inhibitors, and in 1 of the 3 animals, FVIII activity was sustained for over 6 months after treatment. One animal, which received the HD-CMV-cFVIII vector, achieved peak levels of FVIII above 19 000 mU/mL, but FVIII activity disappeared within 1 week, coincident with the development of a potent anti–canine FVIII antibody response. This study supports previous demonstrations of improved safety using HD gene transfer and suggests that these vectors can provide transient FVIII expression with minimal, acute toxicity in the absence of inhibitor formation.
Recent insights into the mechanisms of myeloid leukemogenesis in Down syndrome
Authors: Gurbuxani Sandeep , Vyas Paresh , Crispino John D.
Published: September 2003

GATA-1 is the founding member of a transcription factor family that regulates growth and maturation of a diverse set of tissues. GATA-1 is expressed primarily in hematopoietic cells and is essential for proper development of erythroid cells, megakaryocytes, eosinophils, and mast cells. Although loss of GATA-1 leads to differentiation arrest and apoptosis of erythroid progenitors, absence of GATA-1 promotes accumulation of immature megakaryocytes. Recently, we and others have reported that mutagenesis of GATA1 is an early event in Down syndrome (DS) leukemogenesis. Acquired mutations in GATA1 were detected in the vast majority of patients with acute megakaryoblastic leukemia (DS-AMKL) and in nearly every patient with transient myeloproliferative disorder (TMD), a “preleukemia” that may be present in as many as 10% of infants with DS. Although the precise pathway by which mutagenesis of GATA1 contributes to leukemia is unknown, these findings confirm that GATA1 plays an important role in both normal and malignant hematopoiesis. Future studies to define the mechanism that results in the high frequency of GATA1 mutations in DS and the role of altered GATA1 in TMD and DS-AMKL will shed light on the multistep pathway in human leukemia and may lead to an increased understanding of why children with DS are markedly predisposed to leukemia.
Overexpression of murine TSLP impairs lymphopoiesis and myelopoiesis
Authors: Osborn Mark J. , Ryan Patricia L. , Kirchhof Nicole , Panoskaltsis-Mortari Angela , Mortari Frank , Tudor Kim-Sue R. S.
Published: September 2003

The role of thymic stromal cell–derived lymphopoietin (TSLP) in regulating hematopoiesis is poorly characterized, so we investigated its regulatory effects in vivo using TSLP transgenic mice. Overexpression of TSLP disrupted hematopoietic homeostasis by causing imbalances in lymphopoiesis and myelopoiesis. Mice harboring a TSLP transgene had 5- to 700-fold fewer B and T precursors and no detectable pre-B lymphocyte colonyforming activity in the marrow or spleen. Conversely, TSLP transgenic mice possessed 15 to 20 times more splenic myeloid precursors than their littermates, and progenitor activity of the granulocyteerythrocyte-macrophage-megakaryocyte colony-forming units was significantly elevated. The arrest in lymphopoiesis and the expansion of myeloid progenitor cells in TSLP transgenic mice suggest that TSLP has negative and positive regulatory effects on lymphoid and myeloid development, respectively.
A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group
Authors: Rowe Jacob M. , Neuberg Donna , Friedenberg William , Bennett John M. , Paietta Elisabeth , Makary Adel Z. , Liesveld Jane L. , Abboud Camille N. , Dewald Gordon , Hayes F. Ann , Tallman Martin S. , Wiernik Peter H.
Published: September 2003

The optimal induction for older adults with acute myeloid leukemia (AML) is unknown. Several anthracyclines have been proposed, but the data remain equivocal. Additionally, few prospective trials of priming with hematopoietic growth factors to cycle leukemia cells prior to induction chemotherapy have been conducted. Three hundred and sixty-two older adults with previously untreated AML were randomized to either daunorubicin, idarubicin or mitoxantrone with a standard dose of cytarabine as induction therapy. In addition, 245 patients were also randomized to receive granulocyte-macrophage colony-stimulating factor (GM-CSF) or placebo beginning 2 days prior to induction chemotherapy and continuing until marrow aplasia. No difference was observed in the disease-free overall survival or in toxicity among patients receiving any of the 3 induction regimens or among those receiving growth factor or placebo for priming. However, the complete remission rate for the first 113 analyzable patients, who did not participate in the priming study and started induction therapy 3 to 5 days earlier than those who did, was significantly higher (50% versus 38%; P = .03). None of the anthracyclines is associated with improved outcome in older adults. Priming with hematopoietic growth factor did not improve response when compared with placebo. Furthermore, delaying induction therapy in older adults may lead to a lower complete remission rate.
Identification of the earliest prethymic T-cell progenitors in murine fetal blood
Authors: Ikawa Tomokatsu , Masuda Kyoko , Lu Min , Minato Nagahiro , Katsura Yoshimoto , Kawamoto Hiroshi
Published: September 2003

During murine fetal development, hemato-poietic progenitors start to colonize the thymic anlage at day 11 of gestation via blood stream. The present study aims at identifying the earliest prethymic progenitors in circulation. Here, we show that the interleukin-7 receptor–positive (IL-7R+) cells in Lin– c-kit+ population are circulating exclusively between days 11 and 14 of fetal age. Clonal analysis revealed that these IL-7R+ cells mostly contain T-cell lineage–restricted progenitors (p-Ts). The proportion of circulating p-Ts reaches 30% of the total p-Ts during these fetal ages, whereas virtually all B-cell lineage–restricted progenitors stay in the fetal liver, suggesting that the p-Ts are selectively released to the circulation. The circulating p-Ts retain the potential to generate natural killer cells and dendritic cells and exhibit extensive proliferation before the occurrence of T-cell receptor β (TCRβ) chain gene rearrangement. We propose that the wave of p-Ts in fetal blood disclosed by this study represents the ontogenically earliest thymic immigrants.
Tracking angiogenesis induced by skin wounding and contact hypersensitivity using a Vegfr2-luciferase transgenic mouse
Authors: Zhang Ning , Fang Zuxu , Contag Pamela R. , Purchio Anthony F. , West David B.
Published: September 2003

The vascular endothelial growth factor-2 (VEGFR2) gene is transcriptionally regulated during angiogenesis. The ability to monitor and quantify VEGFR2 expression in vivo may facilitate a better understanding of the role of VEGFR2 in different states. Here we describe a transgenic mouse, Vegfr2-luc, in which a luciferase reporter is under control of the murine VEGFR2 promoter. In adult mice, luciferase activity was highest in lung and uterus, intermediate in heart, skin, and kidney, and lower in other tissues. Luciferase expression in these tissues correlated with endogenous VEGFR2 mRNA expression. In a cutaneous wound-healing model, Vegfr2-luc expression was induced in the wound tissue. Histologic and immunohistochemical studies showed significant macrophage infiltration into the wound and induction of Vegfr2-luc expression in endothelial and stromal cells. Dexamethasone significantly suppressed Vegfr2-luc expression and macrophage infiltration into the wound, resulting in delayed healing and impaired angiogenesis. In a skin hypersensitivity reaction produced by treatment with oxazolone, Vegfr2-luc expression was induced in the ear. Treatment by dexamethasone markedly suppressed Vegfr2-luc expression and leukocyte infiltration in the ear and was correlated with reduced dermal edema and epidermal hyperplasia. The Vegfr2-luc model will be valuable in monitoring the ability of drugs to affect angiogenesis in vivo.
Alphastatin, a 24–amino acid fragment of human fibrinogen, is a potent new inhibitor of activated endothelial cells in vitro and in vivo
Authors: Staton Carolyn A. , Brown Nicola J. , Rodgers Gary R. , Corke Kevin P. , Tazzyman Simon , Underwood James C. E. , Lewis Claire E.
Published: September 2003

Angiogenesis, the development of new blood vessels from existing vasculature, is crucial for the development and metastasis of solid tumors. Here, we show for the first time that a 24–amino acid peptide derived from the amino terminus of the alpha chain of human fibrinogen (termed “alphastatin”) has potent antiangiogenic properties, inhibiting both the migration and tubule formation of human dermal microvascular endothelial cells in response to vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) in vitro. Moreover, alphastatin markedly inhibits the growth of tumors in a syngeneic murine model. Tumors from mice receiving daily injections of alphastatin for 12 days exhibited large areas of intravascular disruption and thrombosis with substantial cellular necrosis. Importantly, alphastatin administration had no detectable effect on vessels in such normal tissues as liver, lungs, and kidney. Taken together, these data indicate that alphastatin is a potent new antiangiogenic agent in vitro and antivascular agent in vivo.
Antibodies against lepirudin are polyspecific and recognize epitopes on bivalirudin
Authors: Eichler Petra , Lubenow Norbert , Strobel Ulrike , Greinacher Andreas
Published: September 2003

Bivalirudin is a synthetic antithrombin sharing a sequence of 11 amino acids with the recombinant hirudin lepirudin. We investigated whether antilepirudin antibodies recognize epitopes on bivalirudin. Antilepirudin antibody–positive sera of 43 patients, treated with lepirudin for heparin-induced thrombocytopenia, were analyzed. Lepirudin- and bivalirudin-coated microtiter plates were used for antibody testing in an enzyme-linked immunosorbent assay (ELISA) system. Of the 43 sera-containing antibodies binding to lepirudin, 22 (51.2%) contained antibodies that also recognized bivalirudin. Binding of these antibodies to bivalirudin was inhibited by more than 70% by preincubation with high doses of bivalirudin. However, if lepirudin-coated microtiter plates were used, high concentrations of bivalirudin inhibited only 2 of the 43 positive sera by more than 30%. Therefore antihirudin antibodies must be polyspecific. The clinical consequences of this cross-reactivity are unknown but bivalirudin, targeted by antibodies of patients treated with lepirudin previously, could potentially boost antibody titers in such patients or even trigger an immune response by itself. Clinically significant antibody formation in response to bivalirudin monotherapy has not been observed, however. Yet, as lepirudin and antilepirudin antibodies have recently been implicated in severe anaphylactic reactions, caution is warranted when using bivalirudin in patients previously treated with lepirudin.
Unique CD18 mutations involving a deletion in the extracellular stalk region and a major truncation of the cytoplasmic domain in a patient with leukocyte adhesion deficiency type 1
Authors: Hixson Patricia , Smith C. Wayne , Shurin Susan B. , Tosi Michael F.
Published: September 2003

Two novel CD18 mutations were identified in a patient who was a compound heterozygote with type 1 leukocyte adhesion deficiency and whose phenotype was typical except that he exhibited hypertrophic scarring. A deletion of 36 nucleotides in exon 12 (1622del36) predicted the net loss of 12 amino acid (aa) residues in the third cysteine-rich repeat of the extracellular stalk region (mut-1). A nonsense mutation in exon 15 (2200G>T), predicted a 36-aa truncation of the cytoplasmic domain (mut-2). Lymphocyte function-associated antigen 1 (LFA-1) and macrophage antigen-1 (Mac-1) containing the mut-1 β2 subunit were expressed at very low levels compared with wild-type (wt) β2. Mac-1 and LFA-1 expression with the mut-2 β2 subunit were equivalent to results with wt β2. Binding function of Mac-1 with mut-2 β2 was equivalent to that with wt β2. However, binding function of LFA-1 with the mut-2 β2 subunit was reduced by 50% versus wt β2. It was concluded that (1) the portion of the CD18 stalk region deleted in mut-1 is critical for β2 integrin heterodimer expression but the portion of the cytoplasmic domain truncated in mut-2 is not; and (2) the mut-2 cytoplasmic domain truncation impairs binding function of LFA-1 but not of Mac-1. Studies with the patient's neutrophils (PMNs) were consistent with functional impairment of LFA-1 but not of Mac-1. (Blood. 2004;103:1105-1113)
Transregulation of memory CD8 T-cell proliferation by IL-15Rα+ bone marrow–derived cells
Authors: Schluns Kimberly S. , Klonowski Kimberly D. , Lefrançois Leo
Published: September 2003

Interleukin 15 (IL-15) and the IL-15 receptor α (IL-15Rα) chain are both required for the basal proliferation of memory CD8 T cells, but which cell types are required to express IL-15 or IL-15Rα to mediate this proliferation is not known. Using bone marrow (BM) chimeras, we showed that virus-specific CD8 memory T-cell proliferation was driven by IL-15 produced by either BM-derived or parenchymal cells. Experiments using mixed BM chimeras showed that IL-15Rα expression by memory CD8 T cells was not required for their division. In addition, wild-type memory CD8 T cells did not divide after transfer into IL-15Rα-/- mice. Further analyses demonstrated that IL-15Rα+ BM-derived cells were crucial in driving memory CD8 T-cell division in the spleen while both parenchymal and BM-derived cells promoted memory cell division in the lung. Proliferation in response to soluble IL-15 in vivo required expression of IL-15Rα by opposing cells and IL-15Rβ by CD8 memory cells, indicating that IL-15 interacted directly with the T cells. These results indicate that transpresentation of IL-15 by IL-15Rα on BM-derived cells mediates the basal proliferation of memory CD8 T cells. (Blood. 2004;103:988-994)
Pulmonary reimplantation response in single-lung transplantation
Authors: Sleiman C , Mal H , Fournier M , Duchatelle JP , Icard P , Groussard O , Jebrak G , Mollo JL , Raffy O , Roue C , et al.
Published: September 2003

We studied the characteristics of the pulmonary reimplantation response (PRR) in single-lung transplantation (SLT), and detailed the occurrence, evolution, prognosis and risk factors of this complication. Forty single-lung transplant recipients were studied. Twenty four patients developed hypoxaemia and allograft infiltrates consistent with the PRR. In 40% of the cases hypoxaemia was severe, precluding weaning and requiring prolonged mechanical ventilation with high fractional inspiratory oxygen (FIO2). The mean duration of ventilation was 7 days (range 1-19 days). Clearing of the chest radiographs was progressive, with complete resolution between 6 and 21 days. In all cases, the pulmonary arterial wedge pressure was normal (6 +/- 2 mmHg) suggesting low pressure oedema. Sampling of the pulmonary oedema fluid revealed that the ratio of protein concentration in oedema fluid to that in serum exceeded 0.5. In patients with severe PRR (40% of cases) clinical, radiographic and haemodynamic abnormalities were identical to adult respiratory distress syndrome (ARDS), but the prognosis was more favourable with no death directly related to PRR in our patients. The mean duration of graft ischaemia of the oedematous grafts (241 +/- 103 min) was significantly longer than that of nonoedematous grafts (155 +/- 71 min). These date suggest that prolongation of graft ischaemia increased the incidence of PRR.
Cystic fibrosis sputum induces a secretory response from airway gland serous cells that can be prevented by neutrophil protease inhibitors
Authors: Schuster A , Fahy JV , Ueki I , Nadel JA
Published: September 2003

High activities of the neutrophil proteases, elastase and cathepsin G, are found in the sputum of patients with cystic fibrosis (CF). Because both proteases have been shown to be potent secretagogues for airway submucosal glands, and because hypersecretion is a characteristic feature of CF, the objective of the present study was to examine whether there is secretagogue activity in CF sputum, and to determine the contribution of neutrophil proteases to the secretagogue activity. Confluent monolayers of cultured bovine tracheal serous cells were pulse-labelled with Na2(35)SO4, incubated with diluted CF sputum supernatants in the presence or absence of different protease inhibitors, and the subsequent release of the radio-labelled macromolecules was measured. CF sputum potently induced secretion concentration-dependently. Addition of the selective neutrophil elastase inhibitor ICI 200,355 inhibited the secretory response to CF sputum supernatant by 89%. Addition of a cathepsin G-inhibitor resulted in further inhibition of the secretory response. Addition of phosphoramidon, a drug known to inhibit Pseudomonas aeruginosa elastase, had no effect. We conclude that CF sputum potently stimulates airway submucosal gland cell secretion. These studies with protease inhibitors suggest that neutrophil proteases account substantially for the secretagogue activity present in CF sputum.
One month treatment with the once daily oral beta 2-agonist bambuterol in asthmatic patients
Authors: Persson G , Baas A , Knight A , Larsen B , Olsson H
Published: September 2003

Bambuterol is a new long-acting oral bronchodilator for once daily use in patients with asthma. It is a prodrug of terbutaline, designed to be slowly metabolized to terbutaline. Results from comparative studies have shown that it has similar clinical efficacy to other oral bronchodilators, but less side-effects. The present study was aimed at verifying the 24 h effect duration of bambuterol, 10 and 20 mg in comparison with placebo during a one month treatment period. The study was conducted as a double-blind, randomized, parallel group placebo-controlled, multicentre trial. It started with a one week run-in period with placebo, when oral bronchodilators were withdrawn. At the end of this reference period, the patients were randomized to one of three treatments: placebo, bambuterol 10 mg, or bambuterol 20 mg, once daily in the evening. The treatment period lasted for 4 weeks. Four hundred and eighty seven patients with a mean age of 45 yrs were included. Mean baseline forced expiratory volume in one second (FEV1) and FEV1% of predicted were 2.05 l and 62%, respectively. Administration of 10 mg bambuterol resulted in a significant 24 h effect duration, expressed as an increase in mean daily morning and evening peak expiratory flow (PEF) (+11 l.min-1, adjusted means) throughout the study, as compared with placebo. Bambuterol, 20 mg, gave a significant 24 h effect duration in both FEV1 and morning and evening PEF as compared with placebo. Furthermore, the adverse events observed during the study were relatively few and mild.(ABSTRACT TRUNCATED AT 250 WORDS)
Chronic respiratory symptoms and airway responsiveness to methacholine are associated with eosinophilia in older men: the Normative Aging Study
Authors: Annema JT , Sparrow D , O'Connor GT , Rijcken B , Koeter GH , Postma DS , Weiss ST
Published: September 2003

Identification of subsets of patients with chronic obstructive lung disease (COLD) in order to determine disease outcomes and, possibly, the effects of treatment is an area of clinical interest. At present, it remains unclear which patients with COLD are most likely to benefit from anti-inflammatory therapy. We investigated this question in a community-dwelling sample of men. In this study, the relationship of chronic respiratory symptoms, airway responsiveness to methacholine, and skin test reactivity to peripheral-blood eosinophil and neutrophil counts was examined among 894 male participants in the Normative Aging Study (mean age 60 yrs; range 41-90 yrs). The symptoms considered were asthma, persistent wheeze, dyspnoea, chronic cough and phlegm. Responsiveness to methacholine was defined as a provocative dose producing a 20% fall in forced expiratory volume in one second (PD20FEV1) of < or = 8.6 mumol, a positive skin test as a wheal diameter of > or = 5 mm after subtraction of the diameter of any wheal reaction to a glycerin control, and eosinophilia as an eosinophil count of > or = 275 cells.mm-3 in peripheral blood. Chronic symptoms (odds ratio (OR) 2.0; 95% confidence interval (CI) 1.4-2.7), airway responsiveness (OR 1.7; CI 1.1-2.7), and the combination of symptoms and airway responsiveness (OR 3.4; CI 2.0-5.6) were positively and significantly related to peripheral-blood eosinophil counts. These relationships remained significant after adjustment for the effects of age and smoking, and after exclusion of asthmatic subjects. Symptoms and airway responsiveness combined were not significantly related to neutrophil counts.(ABSTRACT TRUNCATED AT 250 WORDS)
Predictors for nocturnal hypoxaemia (mean SaO2 < 90%) in normoxic and mildly hypoxic patients with COPD
Authors: Vos PJ , Folgering HT , van Herwaarden CL
Published: September 2003

Detection of nocturnal hypoxaemia, defined as a mean arterial oxygen saturation below 90%, in normoxic or mildly hypoxic chronic obstructive pulmonary disease (COPD) patients seems clinically relevant, since this feature may precede pulmonary hypertension. Nocturnal studies are expensive and time-consuming procedures. The current study investigates to what extent it is possible to predict nocturnal hypoxaemia from daytime parameters. Forty two COPD patients with a daytime arterial oxygen tension (PaO2) above 8 kPa participated. Nocturnal oxygenation, daytime blood gas values, and ventilatory responses to hypercapnia were measured. In 10 patients, enough desaturations occurred to qualify as nocturnal hypoxaemia. They had a significantly lower daytime PaO2 value, and a lower steady-state hypercapnic ventilatory response. They also smoked more often, and complained about daytime sleepiness. Multiple linear regression analysis demonstrated that daytime PaO2 (32%) was the best independent predictor. Sleepiness (12%), and number of cigarettes smoked (5%) also contributed independently, but in a minor way. Patients with a high daytime PaO2 (> 11 kPa) did not develop nocturnal hypoxaemia. The hypercapnic ventilatory response was used to distinguish nocturnal hypoxaemic from normoxaemic patients. Only patients with a low response (< 3.5 l.min-1.kPa-1) appeared to run a risk of developing nocturnal hypoxaemia. The sensitivity of this test was 80%, and the specificity 70%. It is concluded that daytime PaO2, hypercapnic ventilatory response and sleepiness are helpful in predicting nocturnal hypoxaemia.
Does phase 2 of the expiratory PCO2 versus volume curve have diagnostic value in emphysema patients?
Authors: Kars AH , Goorden G , Stijnen T , Bogaard JM , Verbraak AF , Hilvering C
Published: September 2003

It has been postulated that serial inhomogeneity of ventilation in the peripheral airways in emphysema is represented by the shape of expiratory carbon dioxide tension versus volume curve. We examined the diagnostic value of this test in patients with various degrees of emphysema. The volumes between 25-50% (V25-50) and 25-75% (V25-75) of the expiratory carbon dioxide tension versus volume curve were determined in 29 emphysematous patients (20 severely obstructed and 9 moderately obstructed), 12 asthma patients in exacerbation of symptoms, and 28 healthy controls. Discriminant analysis was used to examine whether these diagnostic groups could be separated. With regard to phase 2 of the expiratory CO2 versus volume curve (mixture of anatomic deadspace and alveolar air), a plot of intercept versus slope of the relationships of (V25-50) and (V25-75) versus inspiratory volume (VI) from functional residual capacity (FRC), obtained during natural breathing frequency, proved to be most discriminating in the separation between healthy controls and severely obstructed emphysema patients. Separating healthy controls and severely obstructed emphysema patients on the basis of the discriminant line for V25-50, 9 of the 12 asthma patients in exacerbation were classified as normal, and only 5 of the 9 moderately obstructed emphysema patients as emphysematous. For V25-75 involvement of phase 3 of the curve (alveolar plateau) in asthma patients in exacerbation caused a marked overlap with the severely obstructed emphysema patients. In the healthy controls, a fixed breathing frequency of 20 breaths.min-1 led to an increase of both volumes.(ABSTRACT TRUNCATED AT 250 WORDS)
Maximal expiratory flows generated by rapid chest compression following end-inspiratory occlusion or expiratory clamping in young children
Authors: Kerem E , Reisman J , Gaston S , Levison H , Bryan AC
Published: September 2003

Partial forced expiratory flow-volume curves obtained by the rapid chest compression technique are being widely used to assess pulmonary function in infants and young children. The aim of this study is to assess whether in this age group flow limitation is achieved with the partial forced expiratory flow-volume curve with rapid chest compression. In eight infants and young children sedated with chloral hydrate, flow-volume curves were obtained by regular rapid chest compression technique, end-inspiratory airway occlusion prior to rapid chest compression, and expiratory clamping prior to rapid chest compression. In each technique, beginning with a cuff pressure of 20 cmH2O, the cuff pressure was increased by 10 cmH2O increments until the compression pressure reached 90 cmH2O. Maximal flow-volume curves were generated by each technique. End-inspiratory occlusion prior to rapid chest compression caused higher flows over the entire phase of expiration than the regular rapid chest compression. This increase could be observed over the entire phase of expiration. Forced expiratory flow at 50% and at 75% of vital capacity (V50 and V75) with regular rapid chest compression were 207 +/- 44 ml.s-1 (mean +/- SD) and 138 +/- 59 ml.sec-1, respectively. When end-inspiratory occlusion preceded rapid chest compression, V50 and V75 increased to 283 +/- 114 and 206 +/- 61 ml.sec-1 respectively, with a mean increase in V50 of 34% and in V75 of 31%. When expiratory clamping preceded the compression, even higher expiratory flows resulted.(ABSTRACT TRUNCATED AT 250 WORDS)
Mechanical and morphometrical changes in progressive bilateral pneumothorax and pleural effusion in normal rats
Authors: Sousa AS , Moll RJ , Pontes CF , Saldiva PH , Zin WA
Published: September 2003

Respiratory changes resulting from stepwise intrathoracic injections of 4 ml of either room air or warm (37 degrees C) Haemaccel, simulating pneumothorax and pleural effusion, respectively, were evaluated in anaesthetized, paralysed, and mechanically-ventilated rats. Respiratory system, lung, and chest wall resistances and elastances (static and dynamic) were determined in 14 animals. For this purpose, the end-inflation occlusion during constant inspiratory flow method was used. Chest wall configuration at both functional residual capacity (FRC) and end-inspiration tidal volume (i.e. FRC+(VT)) was also evaluated in: 1) 15 rats by measurements of lateral and anteroposterior diameters, and circumferences at the 3rd intercostal space and xiphoid levels; and 2) in 16 rats by measurements of thoracic cephalocaudal diameter. In addition, changes in functional residual capacity were measured. Both in pneumothorax and pleural effusion, resistances were not altered, but static and dynamic respiratory system and lung elastances increased progressively. Morphometric changes were similar at both functional residual capacity and end-inspiration; however, whereas pleural effusion increased all diameters, pneumothorax did not modify lateral diameter. Functional residual capacity was decreased in both conditions. In conclusion, pneumothorax and pleural effusion induced similar mechanical changes, but thoracic configuration was differently affected, since lateral diameters were increased in pleural effusion only.
Time constant/volume relationship of passive expiration in mechanically ventilated ARDS patients
Authors: Guttmann J , Eberhard L , Fabry B , Bertschmann W , Zeravik J , Adolph M , Eckart J , Wolff G
Published: September 2003

Since the adult respiratory distress syndrome (ARDS) lung is known to be inhomogeneous, one could expect an uneven distribution of expiratory time constant during uninterrupted mechanical ventilation. We investigated the time constant/volume relationship of passive expiration, and their modification by external resistive elements. In 12 paralysed intubated ARDS patients, we determined the expiratory time constant (tau E) as a function of the expired volume (VE) during uninterrupted mechanical ventilation. Mean expiratory time was 2.9 +/- 0.3 s (+/- SD). VE was divided into five equal volume slices (portions) and a mean tau E calculated from the expiratory tidal volume/flow curve for each slice. The mean values of tau E for each volume slice did not differ significantly throughout expiration, averaging 690 +/- 218 ms (mean +/- SD of five slices and 12 patients). We show that the flow-dependent resistance of the endotracheal tube (RETT) is mainly responsible for the observed time constant homogeneity. We conclude that in ARDS patients during uninterrupted mechanical ventilation the time constants of passive expiration are markedly modified by the flow-dependent resistance of the endotracheal tube (RETT), and also by the external resistance of tubing and ventilator (REX). RETT and REX render tau E about three times larger than the time constant of the patient's respiratory system alone.
Modelling the mechanical effects of tracheal tubes in normal subjects
Authors: Rocco PR , Zin WA
Published: September 2003

The addition of tracheal tubes to the respiratory system contributes an extra mechanical burden in terms of pressure necessary to overcome its own resistance. On the basis of experimental data from the literature and on a previously reported mathematical model of the inspirogram, we wished to study predictions of pressures, volume, flow and work of breathing during the use of tracheal tubes. The present investigation indicates that: 1) the loss in volume is greater at the beginning of inspiration and with narrower tubes; 2) in order to preserve tidal volume the inspiratory drive must be increased at any time during inspiration with the use of diminishing internal diameter of the tubes; 3) alternatively, tidal volume can be maintained by increasing inspiratory duration; and 4) the addition of tubes with internal diameter of 9 mm (no.9) and 8 mm (no. 8) increases the total resistive work by 115 and 154%, respectively, whilst total elastic work decreases 9 and 16% in relation to the nonintubated patient. These findings are consequent to the turbulent flow pattern that normally occurs within the tracheal tubes and connectors themselves. We believe they are relevant to the physician confronted with a patient needing tracheal intubation.
Respiratory muscle function in infants
Authors: Gaultier C
Published: September 2003

In newborns and infants a variety of respiratory disorders lead to ventilatory failure. In early life the ventilatory response to loaded breathing is limited. The risk factors of ventilatory failure are related to the developing respiratory pump because of the immaturity of the chest wall, respiratory muscles and coupling between thoracic and abdominal movements. Assessment of respiratory muscle function in infants is limited, due to the objections to using invasive techniques. However, measurement of airway pressures during crying may provide an index of respiratory muscle strength in infants. Real-time ultrasonography allows investigation of diaphragmatic movements. Pattern of thoracoabdominal motion can be assessed using uncalibrated respiratory inductive plethysmography. Finally, electromyographic recording of respiratory muscles by surface electrodes is of clinical usefulness during sleep studies.
The role of the combination of IL-2 and TGF-β or IL-10 in the generation and function of CD4+ CD25+ and CD8+regulatory T cell subsets
Authors: Horwitz David A , Zheng Song Guo , Gray J Dixon
Published: September 2003

Recently, considerable attention has been focused on thymus-derived CD4+ regulatory T cells that constitutively express CD25 and have a contact-dependent, cytokine-independent mechanism in vitro. However, peripheral CD4+ and CD8+ T cells can also be induced to become regulatory T cells. Here we review our studies using the combination of IL-2 and transforming growth factor β (TGF-β) to generate regulatory T cell subsets ex vivo, and the work of others using IL-10 to induce suppressive activity. Under certain conditions, the autocrine effects of TGF-β and IL-10 induce peripheral T cells to produce immunosuppressive levels of each of these cytokines. This effect of TGF-β is IL-2 dependent. Under other conditions IL-2 and TGF-β can induce CD4+ cells to develop potent contact-dependent, cytokine-independent regulatory activity. At present, there is considerable confusion concerning the mechanism of action of CD4+ CD25+ cells because cytokine-producing regulatory T cells generated in the periphery can express CD25 and other markers displayed by naturally occurring, thymus-derived regulatory T cells. We, therefore, propose a nomenclature that identifies thymus-derived and peripheral regulatory cells, and that also differentiates T regulatory cells from T helper cells. Because T regulatory cells broadly control T helper cell reactivity, the mechanisms that control regulatory cell function are also reviewed. Finally, the potential use of regulatory T cells generated ex vivo as an adoptive immunotherapy for certain autoimmune diseases, to prevent organ graft rejection, or to prevent pathologic host responses to infectious agents is discussed.
Psychiatry in Britain one hundred years ago
Authors: Rollin Henry R.
Published: September 2003

In early 1985, in the course of conversation, Hugh Freeman (then Editor of the British Journal of Psychiatry) casually threw out the suggestion that I might write a column for the journal similar to one entitled ‘One Hundred Years Ago’, occasionally published in the BMJ. I was immediately intrigued and, despite a degree of apprehension, agreed on the spot. Once I began, the element of apprehension evaporated: a job that I feared I might have found a crashing bore became a labour of love. Suitable items, I discovered, were there in plenty so that the problem soon became one of exclusion rather than inclusion. The journals systematically trawled, dating from 1885 onwards, were the BMJ, the Lancet, the Journal of Mental Science (the forerunner of the British Journal of Psychiatry), the American Journal of Psychiatry and occasionally the daily press. The first selected item was published in April 1985, and with one exception an item has appeared in every subsequent issue, now more than 250 in total. What I have attempted to do in this article is to collate a selected number of these items and to categorise them so that they present a composite of snapshots of the passing scene as it impinged on aspects of psychiatry and psychiatrists (alienists) at the turn of the previous century.
Psychosocial treatment for severe personality disorder
Authors: Chiesa Marco , Fonagy Peter
Published: September 2003

Background

In a previous report a step-down psychosocial programme for severe personality disorders was found to be more effective at expected termination of treatment than a longer in-patient treatment with no planned after-care.

Aims

To evaluate the clinical effectiveness of these two psychosocial specialist programmes over a 3-year follow-up period.

Method

Two samples allocated to the in-patienttreatment and to the step-down programme were compared prospectively on symptom severity, social adjustment, global assessment of mental health and other clinical indicators at 6, 12, 24 and 36 months after intake.

Results

Improvements were significantly greater in the step-down programme for social adjustment and global assessment of mental health. Patientsin the programme were found to self-mutilate, attempt suicide and be readmitted significantly less at 24- and 36-month follow-up than patients in the in-patient group.

Conclusions

Improvements associated with specialist residential treatment continued 2 years after discharge. A step-down model has significant advantages over a purely in-patient model.
Slovenia: difficulties and strengths of psychiatric research in a small country
Authors: Dernovsek Mojca Z. , Tavcar Rok
Published: September 2003

With a population of nearly 2 000 000 and an area of about 20 000 km2, Slovenia is a heterogeneous European country that extends from the Mediterranean Sea to the Alps. Slovenian political history dates back to the 6th century, when the first free principality of the ancient Slovenians was established – Caranthania – famous for its democratic institutions, legal system, popular elections of dukes and progressive legal rights for women. From the 13th century until 1918, Slovenians were ruled by the Habsburgs. After 1918, Slovenia became a part of Yugoslavia and again enjoyed a considerable degree of autonomy. But as the political and economic crisis of Yugoslavia worsened, at the plebiscite in December 1990 87% of the voting population voted in favour of sovereignty. Thus, Slovenia declared its independence on 25 June 1991, and became a member of the United Nations in May 1992. Until the Second World War the psychiatric tradition in Slovenia was German. Afterwards, the Anglo-Saxon tradition has gradually entered Slovene psychiatry.
‘Reforming the Mental Health Act’: implications of the Government's white paper for the management of patients with eating disorders
Authors: Webster Peter , Schmidt Ulrike , Treasure Janet
Published: September 2003

Patients with severe anorexia nervosa have a high mortality and relapse rate, yet specialist services and practitioners are few. A significant minority need detention with involuntary treatment. Furthermore, the mean age at presentation is 16 years, where detention under the Mental Health Act 1983 or parental consent is unclear and variable. This article addresses the implications of the proposed new Mental Health Act for people with eating disorders. The main issues are those of incapacity, assessment procedures, community detention, detention in 16–18-year-olds, implications for carers and resource implications. We hope to show that eating disorders, just like other illness categories, have special needs that cannot be blanketed under one process and that the Act has positive features, but also presents significant concerns.
Psychiatric comorbidity and medication use in autism: a community survey
Authors: Morgan Caryl N. , Roy Meera , Chance Patrick
Published: September 2003

Aims and Method

Individuals with autism often have complex needs. In this paper, we attempt to establish the prevalence rates of other major psychiatric illnesses in learning disabled adults diagnosed with autism and analyse the use of medication in these individuals. A total of 571 clients with learning disability were screened for autistic spectrum disorder, identifying 164 individuals for study. Psychiatric and medical diagnoses were also reviewed.

Results

Of the individuals with autism, 35% had another comorbid psychiatric disorder. An overall prevalence rate of 10% for hypothyroidism was also identified and 35% of people with autism and no other psychiatric diagnosis were on neuroleptics.

Clinical Implications

Planning of services for autism will have to take into account the high comorbidity of autism and other psychiatric conditions. Individuals with autism will also benefit from close monitoring of mental state and the development of hypothyroidism.
Formarrhoea
Authors: Hardwick Peter
Published: September 2003

The epidemic of formarrhoea blighting adult mental health services is spreading to child and adolescent mental health. Threatening to arrive all about the same time are forms to do with risk assessment, care programme approach, outcome and activity recording, Commission for Health Improvement, child protection, assessment of trainees … and more. They will likely cause an avalanche when added to the mountain of existing forms and Government circulars already piled up on my desk. Forms are increasingly governing all aspects of clinical practice. They threaten to get in the way of doing the job.
Quantification of Free Circulating DNA As a Diagnostic Marker in Lung Cancer
Authors: Sozzi Gabriella , Conte Davide , Leon MariaElena , Cirincione Rosalia , Roz Luca , Ratcliffe Cathy , Roz Elena , Cirenei Nicola , Bellomi Massimo , Pelosi Giuseppe , Pierotti Marco A. , Pastorino Ugo
Published: September 2003

Purpose: Analysis of circulating DNA in plasma can provide a useful marker for earlier lung cancer detection. This study was designed to assess the sensitivity and specificity of a quantitative molecular assay of circulating DNA to identify patients with lung cancer and monitor their disease.

Materials and Methods: The amount of plasma DNA was determined through the use of real-time quantitative polymerase chain reaction (PCR) amplification of the human telomerase reverse transcriptase gene (hTERT) in 100 non–small-cell lung cancer patients and 100 age-, sex-, and smoking-matched controls. Screening performance of the assay was calculated through the receiver operating characteristic (ROC) curve. Odds ratios were calculated using conditional logistic regression analysis.

Results: Median concentration of circulating plasma DNA in patients was almost eight times the value detected incontrols (24.3 v 3.1 ng/mL). The area under the ROC curve was 0.94 (95% CI, 0.907 to 0.973). Plasma DNA was a strong risk factor for lung cancer; concentrations in the upper tertile were associated with an 85-fold higher risk than were those in the lowest tertile.

Conclusion: This study shows that higher levels of free circulating DNA can be detected in patients with lung cancer compared with disease-free heavy smokers by a PCR assay, and suggests a new, noninvasive approach for early detection of lung cancer. Levels of plasma DNA could also identify higher-risk individuals for lung cancer screening and chemoprevention trials.
Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Biomarker for the Pharmacological Response of PTK787/ZK 222584, an Inhibitor of the Vascular Endothelial Growth Factor Receptor Tyrosine Kinases, in Patients With Advanced Colorectal Cancer and Liver Metastases: Results From Two Phase I Studies
Authors: Morgan Bruno , Thomas Anne L. , Drevs Joachim , Hennig Juergen , Buchert Martin , Jivan Asvina , Horsfield Mark A. , Mross Klauss , Ball Howard A. , Lee Lucy , Mietlowski William , Fuxius Stefan , Unger Clemens , O’Byrne Ken , Henry Andrew , Cherryman Graham R. , Laurent Dirk , Dugan Margaret , Marmé Dieter , Steward William P.
Published: September 2003

Purpose: PTK787/ZK 222584 (PTK/ZK), an orally active inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, inhibits VEGF-mediated angiogenesis. The pharmacodynamic effects of PTK/ZK were evaluated by assessing changes in contrast-enhancement parameters of metastatic liver lesions using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced colorectal cancer treated in two ongoing, dose-escalating phase I studies.

Patients and Methods: Twenty-six patients had DCE-MRI performed at baseline, day 2, and at the end of each 28-day cycle. Doses of oral PTK/ZK ranged from 50 to 2000 mg once daily. Tumor permeability and vascularity were assessed by calculating the bidirectional transfer constant (Ki). The percentage of baseline Ki (% of baseline Ki) at each time point was compared with pharmacokinetic and clinical end points.

Results: A significant negative correlation exists between the % of baseline Ki and increase in PTK/ZK oral dose and plasma levels (P = .01 for oral dose; P = .0001 for area under the plasma concentration curve at day 2). Patients with a best response of stable disease had a significantly greater reduction in Ki at both day 2 and at the end of cycle 1 compared with progressors (mean difference in % of baseline Ki, 47%, P = .004%; and 51%, P = .006; respectively). The difference in % of baseline Ki remained statistically significant after adjusting for baseline WHO performance status.

Conclusion: These findings should help to define a biologically active dose of PTK/ZK. These results suggest that DCE-MRI may be a useful biomarker for defining the pharmacological response and dose of angiogenesis inhibitiors, such as PTK/ZK, for further clinical development.