bluuebunny/crossref_metadata_2025 huggingface dataset:
Substance P-Fibronectin-Cytokine Interactions in Myeloproliferative Disorders with Bone Marrow Fibrosis
Authors: Rameshwar P. , Oh H.S. , Yook C. , Gascon P. , Chang V.T.
Published: April 2003

Bone marrow (BM) fibrosis could occur secondarily to several clinical disorders: hematological and nonhematological. Clinical presentation of fibrosis could occur in myeloproliferative diseases, lymphoma, myelodysplastic syndrome and myeloma. The pathophysiology underlying BM fibrosis remains unclear despite intensive study, with a corresponding lack of specific therapy. This review discusses new insights in the role of substance P, cytokines and fibronectin in the development of BM fibrosis. Substance P is a neuropeptide that possesses pleiotropic properties, e.g. neurotransmission and immune/hematopoietic modulation and is linked to BM fibrosis. Cytokines and growth factors, in particular those associated with fibrogenic properties, e.g. TGF-β, IL-1 and platelet-derived growth factor, are linked to BM fibrosis. Extracellular matrix proteins are increased in patients with BM fibrosis. Fibronectin in the sera of patients with BM fibrosis is complexed to substance P. Fibronectin appears to protect substance P from degradation by endogenous peptidases. This review describes the preliminary findings on the colocalization of substance P and fibronectin in the BM of patients with fibrosis. These data are reviewed in the context of published reports with particular focus on the relevant cytokines. A more detailed understanding of intra- and intercellular mechanisms in BM fibrosis may lead to effective therapy.
Apoptosis in Relation to CD34 Antigen Expression in Normal and Myelodysplastic Bone Marrow
Authors: Pecci Alessandro , Travaglino Erica , Klersy Catherine , Invernizzi Rosangela
Published: April 2003

An increased bone marrow (BM) apoptosis is one of the mechanisms responsible for the ineffective hematopoiesis of myelodysplastic syndromes (MDS). It is controversial whether the excessive apoptosis in myelodysplasia predominantly involves the subset of progenitor cells or of maturing cells. We investigated the degree of apoptosis in MDS BM and its differences from normal marrow in relation to CD34 antigen expression. A double-labelling technique that combined the Tdt-mediated dUTP nick end labelling (TUNEL) method with immunocytochemistry for CD34 antigen was used on BM slides of 18 MDS patients and 11 controls. The apoptotic rate (AR) appeared significantly higher in CD34-negative than in CD34-positive cell subsets both in myelodysplastic and in normal BM. When MDS and normal CD34-negative cell populations were compared, a greater AR in MDS CD34-negative cells was found, while no statistical difference in AR resulted from the comparison between MDS and normal CD34-positive cell populations. Our results suggest that in myelodysplastic as well as in normal BM the apoptotic phenomenon predominantly involves the maturing cells. The increase in apoptotic levels which can be observed in myelodysplastic compared to normal BM seems to be mainly due to an increase in apoptosis in the differentiated cell population.
Residual cftr Expression Varies with Age in cftrtm1Hgu Cystic Fibrosis Mice: Impact on Morphology and Physiology
Authors: Larbig M. , Jansen S. , Dorsch M. , Bernhard W. , Bellmann B. , Dorin J.R. , Porteous D.J. , von der Hardt H. , Steinmetz I. , Hedrich H.-J. , Tuemmler B. , Tschernig T.
Published: April 2003

Mouse models for cystic fibrosis (CF) mimic intestinal manifestations of the human disease, but the lung disease phenotypes are lacking in most strains. In this work, the issue was addressed whether aging of the respiratory tract leads to lung pathophysiology in the exon 10 insertional mutant cftrtm1Hgu mouse. Weight gain, body weight and life-span of cftrtm1Hgu mice were significantly reduced compared with control mice. cftrtm1Hgu mice expressed 20, 21 or 37% (median) of wild-type cystic fibrosis conductance transmembrane regulator (cftr) mRNA transcript in lungs, intestine and kidney. Wild-type cftr mRNA in renal and respiratory epithelia varied with age from levels similar to Ztm:MF1 controls at the age of 2 and 4 months to levels seen in patients with CFTR splice mutations beyond the age of 6 months. The morphology of the bronchi and more distal airways was apparently normal in cftrtm1Hgu mice during their first year of life. The alveolar surfactant phospholipid pool was increased in cftrtm1Hgu mice by 1.5- to 2-fold compared with Ztm:MF1 controls. Alveolar clearance of γ-labelled scandium oxide – the first report of lung clearance measurement in living mice – was reduced in cftrtm1Hgu mice compared with littermate controls. Although no progressive lung pathology was seen in the cftr expression of cftrtm1Hgu mice, surfactant phospholipid homeostasis, and alveolar and mucociliary clearance were abnormal. Therefore, the described model is useful for studying the initial CF lung pathophysiology.
Mouse Soluble CD14 Truncated at Amino Acid 71 in Transgenic Mice: Preventive Effect on Endotoxin-Mediated Toxic Shock
Authors: Higuchi Yasunori , Hijiya Naoki , Matsuura Keiko , Yasui Atsushi , Uchida Tomohisa , Yamamoto Shunsuke
Published: April 2003

Mouse soluble CD14 truncated at amino acid 71 (N71) contains the lipopolysaccharide (LPS)-binding sequence. Transgenic mice carrying α1-antitrypsin (AT) promoter-N71 fusion genes, designated AT363-1 and AT363-2, were produced. These mice constitutively produced elevated levels of N71. The concentration of LPS in sera after intraperitoneal LPS injection was lower in AT363-1 mice than in nontransgenic mice. The expression of N71 mRNA was enhanced by subcutaneous turpentine oil injection. The levels of serum LPS and tumor necrosis factor-alpha (TNF-α) after intraperitoneal LPS injections were lower in AT363-1 mice than in nontransgenic mice. Cell surface TNF-α and CD14 expression in exudate peritoneal macrophages prepared by intraperitoneal injection of proteose peptone and then LPS were higher in AT363-1 mice than in nontransgenic mice. Neutrophil infiltration in the liver after induction of the generalized Shwartzman reaction was lower in AT363-1 mice than in nontransgenic mice. Lethality of the Shwartzman reaction was significantly lower in AT363-1 than in nontransgenic mice. These findings suggest that the endotoxin-binding protein (N71) from CD14 prevents endotoxin-mediated toxic shock.
Factors Associated with Increased Risk of Exacerbation and Hospital Admission in a Cohort of Ambulatory COPD Patients: A Multiple Logistic Regression Analysis
Authors: Miravitlles Marc , Guerrero Tina , Mayordomo Cristina , Sánchez-Agudo Leopoldo , Nicolau Felip , Segú José Luis
Published: April 2003

Background and Objective: The aim of this study was to develop and validate two models to estimate the probabilities of frequent exacerbations (more than 1 per year) and admissions for chronic obstructive pulmonary disease (COPD) that can be used in a primary care setting. Methods: Information was obtained in a cross-sectional observational study on ambulatory COPD patients performed in 201 general practices located throughout Spain. The model for admissions included 713 cases, 499 for the developmental sample and 214 in the validation sample; the model for frequent exacerbations included 896 patients, 627 in the developmental sample and 269 in the validation model. Candidate variables to be included in both models were: age, sex, body mass index (BMI), FEV1 as percent predicted [FEV1 (% pred.)] , active smoking, chronic mucus hypersecretion (CMH) and significant comorbidity. Results: The admission model contained 2 readily obtainable variables: comorbidity (OR = 1.97; CI 95% = 1.24–3.14) and FEV1(% pred.) (OR = 0.72; 0.58–0.88, for every 10 units), and well calibrated in developmental and validation samples (goodness-of-fit tests: p = 0.989 and p = 0.720, respectively). The model for frequent exacerbations included 3 variables: age (OR = 1.21; 1.01–1.44; for every 10 years of increasing age), FEV1 (% pred.) (OR = 0.82; 0.70–0.96, for every 10 units) and CMH (OR = 1.54; 1.11–2.14) and also well calibrated (p = 0.411 and p = 0.340 in the developmental and validation samples, respectively). Conclusions: Our results suggest that FEV1 impairment explains part of the risk of frequent exacerbations and hospital admissions. Furthermore, CMH and increasing age are significantly associated with the risk of frequent exacerbations, but severity of exacerbations provoking hospital admissions is associated with the presence of significant comorbidity. These important and easily measurable variables contain valuable information for optimal management of ambulatory patients with COPD.
Detection of Sleep Apnea with the Forced Oscillation Technique Compared to Three Standard Polysomnographic Signals
Authors: Reisch S. , Daniuk J. , Steltner H. , Rühle K.-H. , Timmer J. , Guttmann J.
Published: April 2003

Background: The forced oscillation technique (FOT) allows analysis of the upper airway impedance and, hence, detection of obstructive sleep apnea. Objective: To evaluate FOT with respect to sensitivity and to specificity in online detection of sleep-disordered breathing patterns and to compare algorithmic onset detection time with manual onset time markers of staff physicians. Methods: We compared the absolute value ∣Z∣ of the impedance with three routinely obtained polysomnographic signals – nasal airflow v̇nasal, thoracic excursion Thox and esophageal pressure Pes – by retrospective analysis of the diagnostic polysomnograms of 51 patients. For each signal we evaluated algorithms for online detection of respiratory events. For each out of five apnea classes, 50 respiratory events marked by staff physicians were drawn randomly from the 51 polysomnograms to optimize the online detection algorithms (learning set). The algorithm analyzes relative changes of signal baseline and amplitude. Again 50 respiratory events were drawn randomly for each apnea class to examine to what extent it is possible to detect event onsets with the algorithms (test set). Results: The sensitivity of the signals varied between 56 and 94% and was on average 74%. The specificity was 96 ± 1.5% on average. The onset was detected 4–6 s after the initially evaluated onset of the staff physicians. Conclusion: We conclude that nasal airflow and FOT are equivalent sensitive measurands for detection of respiratory events.
Measurement of Ceruloplasmin in the Lungs of Patients with Acute Respiratory Distress Syndrome: Is Plasma or Local Production the Major Source?
Authors: Baker Cathy S. , Evans Timothy W. , Haslam Patricia L.
Published: April 2003

Background:  Oxidant-induced tissue damage is thought to contribute to the lung injury seen in patients with acute respiratory distress syndrome (ARDS). Ceruloplasmin (CP) is a major circulating antioxidant, increased levels of which have been measured in bronchoalveolar lavage fluid (BALF) taken from such patients. Traditionally, CP detected in these circumstances was thought to be plasma-derived, moving into the alveolar spaces as a consequence of the increased alveolar-capillary permeability that characterises ARDS. However, recent studies in murine models suggest that CP may be synthesised in the airways and even alveoli under physiological conditions. Objectives: The aims of this investigation were therefore to identify the source of any increased levels of CP detectable in BALF taken from patients with established ARDS. Methods: Matched BALF and plasma samples taken from patients with ARDS (n = 46) and from controls without lung disease (n = 11) were analysed for CP (132 kD) and plasma specific albumin (ALB, 68 kD) and (α2-macroglobulin (α2-M, 820 kD). Results: All three proteins were increased in BALF taken from patients with ARDS compared to controls (p < 0.01, ALB and CP; p < 0.001, α2-M). When protein levels were expressed as the ratios of BALF: plasma (designated Q), QCP and Qα2-M increased in parallel to QALB (p < 0.001), indicating that all increases were primarily plasma-derived. Their relative coefficients of excretion (RCE: QCP/QALB and Qα2-M/QALB) demonstrated that the larger molecular weight protein, α2-M, gave the best discrimination between patients with ARDS and normal controls (0.85 vs. 0.04; p < 0.01), indicating that this was the most sensitive marker of alveolar-capillary permeability. Conclusions: Increased levels of CP in BALF from patients with ARDS are mainly attributable to plasma exudation.
Innovations in Gastro-Intestinal Endoscopy: Endoscopic Antireflux Therapies for Gastro-Oesophageal Reflux Disease
Authors: Mahmood Zahid , McMahon Barry , O’Morain Colm , Weir Donald G.
Published: April 2003

Background: Gastro-oesophageal reflux disease (GORD) is a common disorder which significantly impairs the quality of life. Recently a number of endoscopic antireflux procedures have been described, with a view to the management of GORD, thus obviating the need for long-term proton pump inhibitors and the cost and potential risk of laparoscopic Nissen fundoplication. Aim: To evaluate the status of new techniques using gastro-intestinal endoscopy for the management of GORD. Methods: Review of the literature (publications and abstracts) regarding safety, efficacy, and durability of these new antireflux procedures. Results: These antireflux techniques have produced significant improvement in GORD symptomatology and quality of life and have reduced the use of antireflux medication, without causing serious morbidity or mortality. However, the majority of these techniques have failed to adequately control oesophageal acid reflux. Conclusions: Endoscopic antireflux therapies have the potential to treat patients with GORD. However, further studies are necessary to determine what modifications to these techniques are required in order to produce the maximum clinical efficacy and durability.
The Wireless Capsule: New Light in the Darkness
Authors: Fritscher-Ravens Annette , Swain C. Paul
Published: April 2003

The development of wireless capsule endoscopy offers the potential to examine the whole small intestine, with its 5-meter length, and has the advantage of being painless. Using a miniature CMOS camera and a short focal length lens, images are obtained, as the optical window of the capsule sweeps past the gut wall, without requiring air inflation of the gut lumen. The capsule endoscope is propelled by peristalsis through the gastrointestinal tract. The video images are transmitted using radiotelemetry to an array of aerials attached to the body which allows image capture. The images are stored on a small portable recorder carried on a belt and subsequently downloaded for analysis. The system allows more than 7 h of continuous recording of images of the gastrointestinal tract. The patients are free to continue their daily routine during the examination. The capsule endoscope has performed well in trials in patients with difficult gastrointestinal bleeding and in comparative studies with push enteroscopy. It has received both a CE mark and FDA approval for use in patients. It has been used to date in about 4,000 patients. The current clinical data are reviewed.
Effects of Sildenafil Citrate (Viagra) on Choroidal Congestion
Authors: McCulley Timothy J. , Luu James K. , Marmor Michael F. , Feuer William J.
Published: April 2003

This study evaluates the effect of sildenafil on choroidal vascular congestion and its correlation with visual effects. Thirteen healthy subjects were randomized to a sildenafil group (n = 7, 3 M, 4 F), who received 200 mg of sildenafil, and a control (n = 6, 5 F, 1 M) group, who received no drug. Measurements of choroidal thickness with ultrasonography, color vision with Desaturated Panel D-15 Test, and contrast sensitivity with CSV-1000e charts (Vector Vision) were performed at baseline and at 90 and 180 min. Mean choroidal thickness and contrast sensitivity did not change significantly relative to baseline in either group. However, the variance in differences between repeat and baseline measurements of choroidal thickness was significantly higher at 90 min (p = 0.003) in the sildenafil subjects. Color discrimination error scores increased after sildenafil but did not correlate with changes in choroidal thickness. An oral dose of 200 mg of sildenafil caused small inconsistent changes in choroidal thickness, which did not correlate with visual effects.
Pediatric Skull Base Surgery
Authors: Brockmeyer Douglas , Gruber David P. , Haller Jeffrey , Shelton Clough , Walker Marion L.
Published: April 2003

In the second of these two articles, we will discuss our clinical experience with skull base surgery in the pediatric population. We present a retrospective analysis of 55 patients less than 16 years of age who underwent skull base surgical approaches at the Primary Children’s Medical Center or the University of Utah Medical Center between January 1992 and April 1999. There were 30 boys and 25 girls (mean age 9.8 years). Patient follow-up averaged 58 months. Most patients had pathology that required either an anterior or anterolateral approach; 6 patients underwent a far-lateral or a transpetrosal exposure. Thirty-five procedures were performed by a neurosurgeon, a pediatric otolaryngologist performed 11 procedures, and 10 procedures were performed by both services together. Ninety-six percent of patients (n = 53) had a Glasgow Outcome Score of 4 or 5. Complications included 4 sustained cranial nerve palsies and 2 hemipareses. There were no CSF leaks, infections or deaths. Patients with sellar region pathology had a disproportionately higher incidence of postoperative morbidity. We conclude that in selected pediatric cases, skull base surgical techniques can be performed effectively and safely with the use of multidisciplinary teams. To implement these techniques, knowledge of their limitations and of the anatomical differences between the adult and pediatric cranial base is essential.
Reconstruction of the Stapes Superstructure with a Combined Glass-Ceramic (Bioverit®) Implant in Guinea Pigs
Authors: Dost Philipp , Ellermann Stefanie , Missfeldt Nina N. , Leyden Peter J. , Jahnke Klaus
Published: April 2003

Background: Reconstruction of the stapes superstructure continues to be a problem for otologists. Optimal fixation of implants on the stapes footplate has not yet been achieved. Methods: We postulated that bony fixation, between implant and stapes, could be confined exclusively to the footplate region by modifying the bioactivity of the implant material. Therefore, after removal of the superstructure in guinea pigs a combined biovitro ceramic implant (Bioverit® I and Bioverit® II) was placed on the stapes footplate in 10 guinea pigs. As a control, we employed a group of 6 animels in which the stapes superstructure was removed without placing any implant. Results: After 25 weeks the implants were found to be dislocated laterally. We observed fixation with the wall of the middle ear. In the control group we also found new bone formation and even a bow shaped regeneration of the stapes superstructure. Conclusion: Combined Bioverit® stapedial implants were found to routinely fix to the middle ear wall of the guinea pig. The guinea pigs’ enormous potential for bone regeneration in the middle ear ossicular chain make this species unsuitable for exploring hypotheses on human middle ear reconstruction.
Blood Group in Otitis media with Effusion
Authors: Apostolopoulos Kostas , Labropoulou Ekaterini , Konstantinos Bogris , Rhageed Samaan , Ferekidis Eleftherios
Published: April 2003

The aim of the present study was to assess whether blood group ABO is a risk factor for otitis media with effusion (OME). In a screening program 889 children were studied with pneumatic otoscopy, tuning fork tests, audiometry, impedance measures and blood group tests. Among these children, there were 51 children with OME at the time of examination (5.7%), and 838 healthy children. Multivariate logistic regression risk for OME was compared between children with different blood groups, taking sociodemographic and history-related risk factors into account. Blood group and OME were found to be statistically related. Considering children of blood group A as a reference, children with blood group O had a statistically significant lower risk of OME. Children with blood group B did not have lower risk. Children with blood group AB had lower relative risk for OME, but not significantly so. Examining Rhesus factor as a predictor for OME, no relationship was found. It is concluded that blood group O (and possibly AB) plays a preventive role, while blood group A or B are burdensome for OME.
Persistently High Corticosterone Levels but Not Normal Circadian Fluctuations of the Hormone Affect Cell Proliferation in the Adult Rat Dentate Gyrus
Authors: Ambrogini Patrizia , Orsini Laura , Mancini Cecilia , Ferri Paola , Barbanti Icaro , Cuppini Riccardo
Published: April 2003

The dentate gyrus is one of the few brain structures where new neurons are added throughout adulthood in several mammalian species, including humans. Production of new neurons can be regulated by factors which influence cell proliferation or newborn cell survival. Supplementation or deprivation of glucocorticoids, adrenal hormones involved in the response to stress, affect cell proliferation, leading to a decrease or an increase, respectively, in the number of newborn cells. Glucocorticoid secretion under physiological conditions follows a circadian pattern. We thus investigated a possible relationship between cell proliferation and circadian oscillations of corticosterone secretion in the adult rat dentate gyrus. Corticosterone is the species-specific glucocorticoid hormone of the rat. 5-Bromo-2′-deoxyuridine was used to evaluate cell proliferation at 4 different time points in the light-dark cycle. No correlation was found between corticosterone circadian oscillations and cell proliferation in the adult dentate gyrus. In contrast, constantly high corticosterone levels, obtained by implanting corticosterone pellets, decreased cell proliferation in particular zones of the dentate gyrus, i.e. the hilus and the superior blade of the granule cell layer. These findings show that a short, physiologically occurring exposure to high corticosterone levels does not influence cell proliferation, whereas a lengthy exposure to this hormone does induce anatomically localized proliferative changes.
IgG-Mediated Signal Transduction in Canine Mastocytoma-Derived Cells
Authors: Sato Yoshitaka , Teshima Reiko , Nakamura Ryosuke , Sasaki Nobuo , Morita Yutaka , Sawada Jun-ichi , Kitani Seiichi
Published: April 2003

Background: We have reported canine cutaneous mastocytoma-derived cells named CM-MC sensitized with monomeric IgG released histamine upon anti-IgG stimulation. However, IgG or IgE-mediated signal transduction in the cells remains to be examined. Methods: Monomeric IgG-binding to cells was measured by flow cytometry using FITC-anti-IgG. IgG-mediated protein tyrosine phosphorylation was studied by Western blotting using anti-phosphotyrosine antibody. We monitored the intracellular Ca2+ concentration ([Ca2+]i) when IgG-primed cells were activated with anti-canine IgG. Release of Ca2+ from intracellular stores was analyzed with thapsigargin in the absence of extracellular Ca2+. The Ca2+ entry via store-operated Ca2+ channel from the external environment was characterized using Ba2+, Ni2+ and EGTA. Cells sensitized with canine serum abundant in IgG and IgE or heat-inactivated serum were activated by anti-canine IgG or anti-canine IgE. The effect of extracellular Ca2+ and reaction time on IgG-mediated histamine release was examined. Staurosporine and ER-27319 were used to clarify the IgG-mediated protein tyrosine phosphorylation. Results: Abundant IgG-binding sites on the cell were detected by FACS analysis. Anti-IgG induced rapid protein tyrosine phosphorylation and [Ca2+]i elevation. When extracellular Ca2+ was excluded by EGTA, a mild and transient increase in [Ca2+]i was observed, indicating the release of Ca2+ from anti-IgG-sensitive intracellular Ca2+ stores. The constant Ba2+ entry from external environment proved the Ca2+ influx occurred mainly via a store-operated Ca2+ channel which was inhibited by Ni2+ and EGTA. Canine serum-sensitized cells showed a rapid and sustained increase in [Ca2+]i upon both anti-IgG and anti-IgE stimulation. The [Ca2+]i elevation induced by anti-IgE was decreased in the cells sensitized with heat-inactivated serum. Histamine release from CM-MCs was absolutely dependent on extracellular Ca2+, and reached equilibrium within 5 min. Staurosporine inhibited the tyrosine phosphorylation of 38-, 65-, 70-, 80-kD proteins. ER-27319 inhibited the tyrosine phosphorylation of 38- and 70-kD proteins. Staurosporine also inhibited IgG-mediated [Ca2+]i elevation and histamine release in a dose-dependent manner. Conclusions: Canine cutaneous mastocytoma-derived (CM-MC) cells were activated by both IgG- and IgE-mediated mechanisms. IgG-mediated protein tyrosine phosphorylation and Ca2+ influx were similar to those mediated by IgE. CM-MC cells are useful for the study of allergic inflammation caused by IgG-dependent mechanisms.
Enhancement of Allergic Skin Wheal Responses by Microwave Radiation from Mobile Phones in Patients with Atopic Eczema/Dermatitis Syndrome
Authors: Kimata Hajime
Published: April 2003

Microwave radiation from mobile phones enhanced skin wheal responses induced by house dust mite and Japanese cedar pollen while it had no effect on wheal responses induced by histamine in patients with atopic eczema/dermatitis syndrome (AEDS). Microwave radiation also increased plasma levels of substance P (SP) and vasoactive intestinal peptide (VIP) in patients with AEDS. These results indicate that microwave radiation from mobile phones may enhance allergen-induced wheal responses in association with the release of SP and VIP. This finding may be useful in elucidating the pathophysiology and treatment of AEDS.
Airway Responsiveness and Airway Remodeling after Chronic Exposure to Procaterol and Fenoterol in Guinea Pigs in vivo
Authors: Nishimura Hideko , Tokuyama Kenichi , Arakawa Hirokazu , Ohki Yasushi , Sato Akira , Kato Masahiko , Mochizuki Hiroyuki , Morikawa Akihiro
Published: April 2003

Background: Chronic exposure to fenoterol (FEN), a β2-adrenergic receptor (β2-AR) agonist, was shown to induce both airway hyperresponsiveness and airway remodeling in experimental animals. Objective: We wanted to know the effects of chronic exposure to procaterol (PRO), a β2-AR agonist, on airway function and structure, because this agent is widely used as a bronchodilator in Japan. For comparison, the effects of FEN were also examined. Methods: Aerosolized PRO (0.1 or 1 mg/ml), FEN (1 mg/ml) or vehicle (0.9% NaCl) was given to guinea pigs 3 times a day for 6 weeks. Sublaryngeal deposition of these agents was calculated using radioisotopes. At 72 h after the last inhalation of PRO, FEN or vehicle, the dose-response relationship between lung resistance (RL) and intravenously administered acetylcholine (ACh) was measured. After measuring RL, histological changes in noncartilaginous airway dimensions were evaluated. Results: The amount of sublaryngeal deposition of 0.1 mg/ml PRO in the present study was speculated to be 100 times larger than that of therapeutic dose. ACh concentrations causing 2-fold, 10-fold and maximal increases in RL were not different in 4 groups tested. In the smaller membranous airways (<0.4 mm in diameter), but not the larger ones, thickening of adventitial areas was significantly greater in animals treated with β2-AR agonists than in control animals (23 and 25, and 96% higher in animals treated with 0.1 and 1 mg/ml PRO or 1 mg/ml FEN, respectively). The degree of the increase was significantly less in PRO-treated animals than in FEN-treated animals (p < 0.01). Conclusion: Our results did not provide any evidence that regular inhalation of PRO at the therapeutic dose might induce bronchial hyperresponsiveness. In addition, huge amounts of PRO only caused a mild thickening of the adventitial areas, suggesting that PRO may be a weak inducer of airway remodeling compared with FEN.
The Immune Response to Intrinsic and Extrinsic Allergens: Determinants of Allergic Disease
Authors: Woodfolk Judith A. , Platts-Mills Thomas A.E.
Published: April 2003

A central role for Th2 effector cells in IgE-mediated allergic disease is well established. However, the question of why some individuals develop allergic disease and others do not remains largely unanswered. Until recently, the prevailing view was that the allergic response reflected a shift in the Th1/Th2 ‘balance’ to favor production of Th2 cytokines and IgE antibody isotype switching. Evidence is now emerging to suggest that distinct allergic responses cannot be distinguished simply on the basis of type 1 and type 2 cytokine profiles. For example, delayed-type hypersensitivity responses to intrinsic allergens derived from the dermatophyte fungus Trichophyton are associated with a paradoxical increase in Th2 cytokines compared with immediate hypersensitivity responses. In contrast, analysis of ‘tolerant’ responses to extrinsic allergens which are induced by specific immunotherapy or high-dose natural exposure to inhaled allergen (the modified Th2 response) supports a role for both the Th1 cytokine IFN-γ and the regulatory cytokine IL-10. However, IL-10 may also be a critical mediator in the allergic response. In this article, we examine how analysis of epitope-specific T cell responses may lead to an understanding of how T lymphocyte cytokines relate to distinct allergic phenotypes. The relevance of Th1/Th2 and regulatory cytokines to development of new allergen-specific therapies is also discussed.
The Role of IL-10 and TGF-β in the Differentiation and Effector Function of T Regulatory Cells
Authors: Levings Megan K. , Bacchetta Rosa , Schulz Ute , Roncarolo Maria Grazia
Published: April 2003

Suppression by T regulatory (Tr) cells is essential for the induction of peripheral tolerance. Many types of CD4+ Tr cells have been described in a number of systems, and although the precise mechanisms which mediate their effects remain to be defined, it is well established that they can suppress immune responses via cell-cell interactions and/or the production of interleukin-10 (IL-10) and transforming growth factor-β (TGF-β). Type 1 T regulatory (Tr1) cells are defined by their ability to produce high levels of IL-10 and TGF-β, and these cytokines mediate their ability to suppress pathological immune responses in the settings of transplantation, allergy and autoimmune disease. Tr1 cell activity is not necessarily beneficial, and they can also suppress immune responses to antigens from tumours and pathogens. In vivo, the differentiation of Tr1 cells is likely controlled by certain dendritic cells which promote IL-10 production and may express tolerogenic costimulatory molecules. Another subset of CD4+ Tr cells is defined by constitutive expression of CD25, and although these CD4+CD25+ Tr cells appear to suppress via mechanisms which are largely independent of cytokines, they may actively promote the differentiation of Tr1 cells. Many questions about the basic biology of Tr1 cells remain to be answered, but the development of therapeutic strategies designed to harness their immunoregulatory effects can already be contemplated.
Laparoscopic Resection of the Left Pancreas: Technique and Indication
Authors: Bärlehner E. , Anders S. , Schwetling R.
Published: April 2003

Laparoscopic pancreatic resections are rare procedures. A particular position is held by the left resection. In animal trials and 37 operations performed to date, this laparoscopic procedure has been positively assessed. The diseases operated upon were nearly exclusively benign. From November 1998 to July 2001, we performed 5 laparoscopic distal pancreatic resections at our hospital. The indications were: 2 adenocarcinomas; 1 neuroendocrine carcinoma; 1 high malignant T-cell lymphoma, and 1 cystadenoma. Additional procedures in 3 patients were: gastrectomy and resection of the left liver in the case with T-cell lymphoma; resection of a distant metastasis in the liver in the case with advanced pancreatic carcinoma, and a partial adrenalectomy in the case with cystadenoma. We did not note any intra- or postoperative complications in our patients. First of all, benefit is to be found in the early postoperative course. All oncosurgical criteria could be fulfilled.
Prediction of Protein Essentiality Based on Genomic Data
Authors: Jeong Hawoong , Oltvai Zoltn N. , Barabási Albert-Lszl
Published: April 2003

A major goal of pharmaceutical bioinformatics is to develop computational tools for systematic in silico molecular target identification. Here we demonstrate that in the yeast Saccharomyces cerevisiae the phenotypic effect of single gene deletions simultaneously correlates with fluctuations in mRNA expression profiles, the functional categorization of the gene products, and their connectivity in the yeasts protein-protein interaction network. Building on these quantitative correlations, we developed a computational method for predicting the phenotypic effect of a given genes functional disabling or removal. Our subsequent analyses were in good agreement with the results of systematic gene deletion experiments, allowing us to predict the deletion phenotype of a number of untested yeast genes. The results underscore the utility of large genomic databases for in silico systematic drug target identification in the postgenomic era.
Efficient Score Statistics for Mapping Quantitative Trait Loci with Extended Pedigrees
Authors: Wang Kai
Published: April 2003

The method of variance components is the method of choice for mapping quantitative trait loci (QTLs) with general pedigrees. Being a likelihood-based method, this method can be computation intensive even for nuclear families, and has excessive false positive rates under some situations. Here two efficient score statistics to detect QTLs are derived, one assumes that the candidate locus has no dominance effect, and the other one does not make such an assumption. These two score statistics are asymptotically equivalent to the method of variance components but they are easier to compute and more robust than the likelihood ratio statistic. The derivation of these score statistics is facilitated by separating the segregation parameters, the parameters that describe the distribution of the phenotypic value in the population, from the linkage parameters, the parameters that measure the effect of the candidate locus on the phenotypic value. Such a separation of the model parameters greatly reduces the number of parameters to be dealt with in the analysis of linkage. The asymptotic distributions of both score statistics are derived. Simulation studies indicate that, compared to the method of variance components, both score statistics have comparable or higher power, and their false-positive rates are closer to their respective nominal significance levels.
The Philosophical Background: From Principles to Rules and Analysis
Authors: Sommerville Ann
Published: April 2003

Encounters between doctors and patients are subtle but complex forms of social interaction. Attempts to regulate aspects of the doctor–patient relationship have a long history. Initially, the production of guidance on principles and conduct was the domain of practitioners. In the 21st century, modern medical ethics still reflects some of this traditional thinking even though the responsibility for formulating ethical guidance increasingly falls to policy-makers, lawyers and theoreticians rather than doctors. Ethical concepts are also increasingly interwoven with contemporaneous concepts of patient autonomy, human rights and law. In a brief and necessarily sketchy overview of some of the key influences on European ethical development, this article traces the development of medical ethics through three broad stages: from principles to rules to providing tools for detailed moral analysis. It also discusses whether the original Hippocratic principles still find echo with modern doctors.
An Introductory Course for Training in Endoscopy
Authors: Ladas Spiros D. , Malfertheiner Peter , Axon Anthony
Published: April 2003

Endoscopy practice must respect the ethical aspects of medicine, and the principles of humanism must be reinforced when teaching endoscopy. A well-organized, structured training is essential if we are to ensure that procedures are performed in a safe and effective manner. The most difficult period of training is with the novice endoscopist, so we recommend the introduction of a structured pre-endoscopy training curriculum. This should ideally include introductory lectures and courses, the use of didactic videotapes and training in endoscopy on a computer-based simulator. We also advocate ‘train the trainers’ international courses to encourage a uniform approach to the teaching of endoscopy. Their aim will be to educate skilled endoscopists in the principles of teaching, which should be thoroughly grounded in the ethics of our profession.
Endoscopy-Based Research in Healthy Volunteers
Authors: Treiber Gerhard , Malfertheiner Peter
Published: April 2003

The role of healthy volunteers (HV) in research covers a wide spectrum. In gastrointestinal research HV are often considered a control population. Endoscopy-based investigations are rare in terms of all studies performed in this field. The term ‘healthy’ must be questioned in some cases, as Helicobacter pylori-positive individuals are included as well. Problems arise from several fields, e.g. safety, financial compensation, incomplete ethical votes, lack of documentation, lack of defining limitations, overuse of invasive procedures. This article will discuss these problems in detail and will finally give an overview of key issues for extended ‘good clinical practice’.
Infestation of the Human Kidney with Dioctophyma renale
Authors: Ignjatovic Ivan , Stojkovic Ivica , Kutlesic Cedo , Tasic Suzana
Published: April 2003

Human infestation with Dioctophyma renale is presented. Clinical signs and diagnostic findings are unspecific. They are discussed and a conservative therapeutic approach is suggested.
Differences in Umbilical Cord Blood Units Collected during Cesarean Section, before or after the Delivery of the Placenta
Authors: Pafumi C. , Farina M. , Bandiera S. , Cavallaro A. , Pernicone G. , Russo A. , Iemmola A. , Chiarenza M. , Leonardi I. , Calogero A.E. , Calcagno A. , Cianci A.
Published: April 2003

Umbilical cord blood is largely employed as an alternative source of stem cells in the treatment of hemato-oncological diseases. Current results show that the success rate of purified umbilical cord blood engraftment is comparable to that obtained using bone marrow, and it is directly related to the number of pluripotent stem cells transplanted. The technique of fetal blood collection varies among different umbilical cord blood banks. Many authors collect umbilical cord blood during vaginal delivery, after placental detachment, while others collect it while the placenta is still within the uterus. In a previous randomized trial, we showed a greater collection of umbilical cord blood before placental detachment during vaginal delivery. The present study was performed to determine whether umbilical cord blood collection before placental detachment (group A) during cesarean section is superior to that after placental delivery (group B) puncturing the umbilical vein once and using a closed bag system. To accomplish this, 47 pregnant women subjected to cesarean section were enrolled in the study. Twenty-one of them were allocated to group A, while the remaining 26 formed group B. The volume of umbilical cord blood collected from the patients of group A was greater than that collected from patients of group B. The cord blood volume collected was 90.7 ± 6.0 versus 60.9 ± 13.7 ml; the cord blood nucleated cell number was 10.1 ± 1.2 × 108 vs. 7.1 ± 0.8 × 108; and the mean cord blood CD34+ cell number was 20.0 ± 6.0 × 105 vs. 16.4 ± 2.4 × 105, respectively.
A Regulatory Monoamine Oxidase A Promoter Polymorphism and Personality Traits
Authors: Garpenstrand Håkan , Norton Nadine , Damberg Mattias , Rylander Gunnar , Forslund Kaj , Mattila-Evenden Marja , Gustavsson J. Petter , Ekblom Jonas , Oreland Lars , Bergman Hans , Owen Michael J. , Jönsson Erik G.
Published: April 2003

Monoamine oxidase type A (MAOA) has been implicated to be part of mechanisms underlying human temperament and psychiatric disorders. We hypothesised that a functional polymorphism in the 5′ untranslated region of the MAOA gene is associated with specific personality traits. In 371 healthy Caucasians, we estimated personality traits by the use of the Karolinska Scales of Personality (KSP), Scandinavian Universities Scales of Personality, Health-Relevant 5-Factor Personality inventory, Temperament and Character Inventory and the revised NEO Personality Inventory. In the same subjects, we analysed the genotype of a polymorphic region consisting of a variable number of a 30-bp repeat sequence located approximately 1.2 kb upstream of the MAOA gene. After correction for multiple testing, no statistically significant differences between MAOA genotype and personality were observed in men (n = 206) nor in women (n = 165). We conclude that the structure of this MAOA promoter region does not have a large impact on the expression of personality characteristics in the present Swedish population.
Less Common Methods to Treat Acne
Authors: Kaminsky Ana
Published: April 2003

Effective medications to treat acne sometimes become unavailable in certain countries, either for economic reasons or for shortage of them in the pharmaceutical market. The purpose of this report is to review a series of drugs of topical and systemic use; some old and some new. The topical group includes agents such as sulfur, salicylic acid and the alpha-hydroxy acids, while the systemic group includes diaminodiphenylsulfone, clofazimine, ibuprofen and others. Some presumably useful physical methodologies and the recent findings in phototherapy, particularly the properties of blue light and blue-red light, are also reviewed. Finally, we report on the results obtained from the combined use of isotretinoin and methylprednisone in severe inflammatory acne, to prevent a possible triggering of the ‘pseudo’ acne fulminans.
Inflammation and Atherosclerosis in End-Stage Renal Disease
Authors: Zoccali Carmine , Mallamaci Francesca , Tripepi Giovanni
Published: April 2003

Atherosclerosis is a multifaceted process which may be initiated by various insults to vascular endothelium. Independently of the nature of the offending factor, the endothelial dysfunction that results from the initial insult is characterized by increased adhesiveness of the endothelium to leukocytes and platelets and by the synthesis of vasoactive molecules, cytokines and procoagulant factors. This defensive response is characterized by classical inflammatory changes and may lead to plaque formation, luminal obstruction and plaque rupture. Factors involved in arterial damage in end-stage renal disease (ESRD) span from classical risk factors to disease-peculiar factors (anemia, secondary hyperparathyroidism and exposure to bioincompatible dialysis membranes and/or contaminated dialysis fluid) and to emerging and novel risk factors such as hyperhomocysteinemia, infections and accumulation of the endogenous inhibitor of NO synthase, asymmetric dimethylarginine (ADMA). There is strong and consistent evidence that acute phase reactants like C-reactive protein and cytokines like IL-β, TNF-α and IL-6 are independently associated with death and atherosclerosis in ESRD patients. The experimental and epidemiological data collected thus far coherently show that endothelial dysfunction resulting from inflammation may promote abnormal vascular behavior and thrombosis in ESRD. There are several possible therapeutic approaches for reducing the risk excess associated with inflammation in ESRD. These possibilities range from drugs interfering with the angiotensin system or with adrenergic activity to anti-inflammatory and antilipid agents to vitamins, antioxidants, to the amino acid precursor of nitric oxide, L-arginine, and perhaps to antibiotics. The intellectual framework is well delineated but very few controlled trials have been performed or are underway in patients with ESRD.
Primary Jejunal Leiomyosarcoma Mimicking a Gynecologic Tumor
Authors: Long Cheng Yu , Lee Yi Ming , Tsai Kun Bow , Su Jinu Huang , Hsu Shih Cheng
Published: April 2003

Alimentary leiomyosarcoma (LMS) is not uncommon; however, LMS which metastasizes to the ovary and uterine serosa is extremely rare. We present a case diagnosed as LMS due to the negative finding on the CD117 stain, which is the most specific criterion for the differential diagnosis of gastrointestinal stromal tumor and LMS. Despite the daunting reoperation which was performed within a short interval in this case, the patient made a rapid recovery from both procedures.
Studies on the Human Leukocyte Antigen Class I Antigens in Japanese Patients with Macroscopically Diagnosed Endometriosis
Authors: Ishii Keisuke , Takakuwa Koichi , Adachi Hiroshi , Higashino Masahiko , Hataya Isao , Tanaka Kenichi
Published: April 2003

An increasing number of reports suggest that endometriosis is associated with abnormal immune function, although the etiology of the disease remains undefined. The human leukocyte antigen system (HLA) is known to play a role in the etiology of a number of diseases. This study examines the possible association between the HLA system and endometriosis. Fifty-five patients diagnosed with endometriosis by laparoscopic examination were typed for HLA class I antigens – HLA-A, -B, and -C antigens – using the standard microlymphocytotoxity technique of Terasaki. The frequency of HLA-B 54 and that of HLA-Cw7 were significantly higher in the patient population than in the control population. No significant difference was found between the two groups in the frequencies of the other HLA-class I antigens. The results of this study may implicate the HLA system in the development of endometriosis.
New Frontiers in the Future of Aging: From Successful Aging of the Young Old to the Dilemmas of the Fourth Age
Authors: Baltes Paul B. , Smith Jacqui
Published: April 2003

We review research findings on the oldest old that demonstrate that the fourth age entails a level of biocultural incompleteness, vulnerability and unpredictability that is distinct from the positive views of the third age (young old). The oldest old are at the limits of their functional capacity and science and social policy are constrained in terms of intervention. New theoretical and practical endeavors are required to deal with the challenges of increased numbers of the oldest old and the associated prevalence of frailty and forms of psychological mortality (e.g., loss of identity, psychological autonomy and a sense of control). Investigation of the fourth age is a new and challenging interdisciplinary research territory. Future study and discussion should focus on the critical question of whether the continuing major investments into extending the life span into the fourth age actually reduce the opportunities of an increasing number of people to live and die in dignity.