bluuebunny/crossref_metadata_2025 huggingface dataset:
Respiratory resistive impedance in obstructive patients: linear regression analysis vs viscoelastic modelling
Authors: Lorino AM , Zerah F , Mariette C , Harf A , Lorino H
Published: March 2003

The aim of this study was to test the ability of a simple two segment model to describe the frequency dependence of resistive impedance in obstructive patients, and to investigate the significance of parameters derived from this model. The study was performed in 38 patients, in the basal state and after inhalation of 200 micrograms salbutamol. Impedance data measured over 4-32 Hz were fitted by a general four parameter viscoelastic model describing gas redistribution, and completed by an inertial component. This model yielded Newtonian resistance (Rmin) and maximal resistance (Rmax = Rmin plus delayed resistance due to gas redistribution). Resistive impedance data were also submitted to linear regression analysis over the 4-16 and 17-32 Hz frequency ranges, which respectively, yielded resistive impedance extrapolated at 0 Hz (R0) and resistive impedance estimated at 32 Hz (R32). R0 and R32 were compared to Rmax and Rmin, respectively. The airway response to salbutamol inhalation was assessed by the percentage changes in these parameters (R0%, R32%, Rmax%, and Rmin%, respectively). Significant linear correlations (p < 0.0001) were found between R0 and Rmax, R32 and Rmin, and R0% and Rmax%. Furthermore, the linear regression lines of R0 vs Rmax, and R0% vs Rmax%, were not significantly different from the identity line. These results demonstrate that resistive impedance extrapolated at zero frequency is equivalent to maximal resistive impedance, and can be proposed as an index, not only of the level of airway obstruction, but also of its reversibility.
The effect of dipyridamole and theophylline on hypercapnic ventilatory responses: the role of adenosine
Authors: Griffiths TL , Christie JM , Parsons ST , Holgate ST
Published: March 2003

The purine nucleoside, adenosine, has been implicated as a neuromodulator in central respiratory depression during prolonged exposure to hypoxia. It may also be a mediator of hypoxic hyperpnoea, acting on the carotid bodies. As there may be adenosine-sensitive mechanisms of hypoxic respiratory control, we sought to determine whether adenosine might be involved as a respiratory modulator in another central but non-oxygen-related control mechanism, the ventilatory response to hyperoxic hypercapnia. Twelve normal subjects were studied following 3 days of oral treatment with placebo, dipyridamole (which potentiates adenosine effects by inhibiting cellular uptake), and theophylline (a specific adenosine antagonist of cell surface receptors). The drugs were given in a random order, double-blind fashion. Resting end-tidal carbon dioxide tension (PET,CO2) and the maximum rate of isometric inspiratory pressure change at the mouth ((dP/dt) max), an index of respiratory drive, were determined in all subjects on each treatment. Hyperoxic, hypercapnic ventilatory responses were determined in seven of these subjects using a rebreathing technique. For each hypercapnic response, minute ventilation (V1E) and (dP/dt) max were plotted against PET,CO2 breath-by-breath. Resting PET,CO2 breathing room air was lower with theophylline (5.47 (SD 0.21) kPa) than with placebo (5.74 (0.26) kPa) or dipyridamole (5.86 (0.34) kPa), with no significant drug differences in resting (dP/dt)max. However, neither the slope nor the PET, CO2 intercept of the relationship between ventilation or respiratory drive and PET, CO2 were altered by the study drugs under hyperoxic conditions. We conclude that endogenous adenosine-related mechanisms are unlikely to be involved in determining either the sensitivity or the threshold of the ventilatory response to carbon dioxide under hyperoxic conditions. However, in normoxia, a centrally-acting, tonic, adenosine-mediated, respiratory modulation is not ruled out.
Influence of awareness of the recording of breathing on respiratory pattern in healthy humans
Authors: Han JN , Stegen K , Cauberghs M , Van de Woestijne KP
Published: March 2003

This study was designed to test whether awareness of the measurement of breathing influences the breathing pattern in healthy subjects under routine laboratory conditions. Seventy four subjects (40 females and 34 males), aged 21-63 yrs, were studied under three different conditions whilst their breathing was being recorded for 5 min by means of inductance plethysmography (Respitrace): 1) subjects were misled into believing that their breathing was not being recorded but that they had to wait for 5 min whilst equipment was calibrated; 2) subjects were instructed that their breathing pattern was being recorded for 5 min; 3) the subject's breathing was recorded for 5 min with mouthpiece and pneumotachograph. The first two conditions were randomized. The Respitrace was calibrated by means of multiple linear regression carried out during the 5 min period of quiet breathing through a mouthpiece. Awareness of the recording of breathing caused prolongation of inspiratory (tI) and expiratory time (tE). Breathing through the mouthpiece resulted in an increase of tI, tE and tidal volume (VT). The breathing irregularities (sighs and end-expiratory pauses) decreased when subjects were aware of the recording of breathing and nearly disappeared when subjects breathed through the mouthpiece. The end-tidal carbon dioxide concentration was not significantly different between the three conditions. Mouthpiece breathing often induced some respiratory discomfort and even anxiety, particularly in females. Awareness by the subject that his or her breathing was being recorded altered the spontaneous breathing pattern, mainly the breathing frequency. In addition, use of a mouthpiece markedly increased tidal volume, particularly in females in whom mouthpiece breathing induced more complaints than in males.
Patient-ventilator interaction and inspiratory effort during pressure support ventilation in patients with different pathologies
Authors: Nava S , Bruschi C , Fracchia C , Braschi A , Rubini F
Published: March 2003

The aim of this study was to evaluate whether pressure support ventilation (PSV) requires different diaphragmatic efforts and patient-ventilator matching, according to the underlying disease. Four groups of patients requiring PSV were studied: Group A, recovering from an episode of acute respiratory failure due to adult respiratory distress syndrome (ARDS); Group B, with postsurgical complications; and two subsets of chronic obstructive pulmonary disease (COPD) patients, with "normal" static compliance of the respiratory system (Cst,rs) (Group C) or elevated Cst,rs (Group D). Ventilatory pattern, transdiaphragmatic pressure (Pdi), the pressure-time product of the diaphragm (PTPdi), static (PEEPi,stat) and dynamic intrinsic positive end-expiratory pressure (PEEPi,dyn), Cst,rs and resistance of the total respiratory system (Rrs) were recorded. The matching between patient and ventilator was analysed, recording the number of "ineffective efforts" (inspiratory efforts not efficient enough to trigger a new ventilator cycle, despite a positive deflection in Pdi). A satisfactory blood gas equilibrium arterial oxygen saturation (Sa,O2 > 93%, with a pH > 7.32) was obtained in the various groups with different levels of PSV. Minute ventilation was found to be significantly higher in Groups A and B, due to the longer expiratory time (tE) in the COPD groups. Group A (2 out of 7), Group B (3 out of 7), Group C (3 out of 5) patients showed sporadic "ineffective efforts". All Group D patients manifested continuous mismatching with the ventilator, so that the pressure-time product of the diaphragm per minute (PTPdi/min), reflecting the metabolic work of the diaphragm, was not different in the four groups. Tidal volume and the spontaneous inspiratory efforts were similar in the four groups, but the number of breaths delivered by the ventilator was significantly higher in Groups A and B. The application of different levels of pressure support ventilation in patients with acute respiratory failure due to different pathologies, led them to breathe with comparable pressure time product of the diaphragm. The majority of the patients showed mismatching with the ventilator, although this effect was more pronounced in the groups with chronic obstructive pulmonary disease.
Comparison of two different modes for noninvasive mechanical ventilation in chronic respiratory failure: volume versus pressure controlled device
Authors: Schonhofer B , Sonneborn M , Haidl P , Bohrer H , Kohler D
Published: March 2003

The most commonly used mode of noninvasive mechanical ventilation (NMV) is volume-controlled intermittent positive pressure ventilation (IPPV). Pressure support ventilation has recently become increasingly popular, but its merits have not been clearly defined. In an open, nonrandomized follow-up study, we evaluated two modes of NMV, volume-controlled (IPPV) and pressure-controlled ventilation (PCV) over 6 months in 30 consecutive patients (24 males and 6 females, aged 49 +/- 19 yrs) with chronic respiratory failure (CRF). The baseline assessments comprised both physiological and subjective data. In all cases, nasal IPPV was initially administered for 1 month, followed by a second month of nasal PCV. Thereafter, responders or nonresponders to PCV were defined according to the patients' subjective symptom score and/or the recurrence of hypercapnia. During the IPPV phase, in all but two patients the subjective and objective parameters improved significantly. During the following 1 month PCV phase, stabilization was maintained in 18 patients ("responders"), while 10 patients were defined as "nonresponders". In nonresponders, hypercapnia increased (arterial carbon dioxide tension (Pa,CO2): 5.7 +/- 0.4 to 6.6 +/- 0.5 kPa; p < 0.05) and symptom scores decreased. Compared with responders, nonresponders had a lower mean nocturnal arterial oxygen saturation (Sa,O2) (p < 0.05) and a higher daytime Pa,CO2 (p < 0.05) at baseline. We con clude that the majority of patients suffering from chronic respiratory failure who are initially satisfactorily ventilated with intermittent positive pressure ventilation may also be adequately maintained with pressure-controlled ventilation. However, there is a subgroup with more severe chronic respiratory failure at baseline, in whom pressure-controlled ventilation is inadequate. After 4 weeks of treatment with pressure-controlled ventilation, the subjective scores and the arterial carbon dioxide tension values reliably distinguished between long-term responders and nonresponders to pressure-controlled ventilation.
Additive nature of distension and surfactant perturbation on alveolocapillary permeability
Authors: John J , Taskar V , Evander E , Wollmer P , Jonson B
Published: March 2003

The aim of this study was to determine whether the effects of alveolar distention and surfactant dysfunction on alveolocapillary barrier function are different and additive. Pulmonary clearance of aerosolized technetium-99m-labelled human serum albumin (99mTc-HSA) was used to characterize barrier function after perturbing the surfactant system with the detergent dioctyl sodium sulphosuccinate either singly or in combination with large tidal volume ventilation (LTVV). Clearance was measured for 3 h (Experimental ventilation) in four groups (n = 6 each) of rabbits: 1) Controls; 2) Detergent; 3) LTVV; and 4) Detergent + LTVV. Restoration of clearance (Recovery) was studied for 3 h under conventional ventilation. The half-life of clearance (t 1/2) decreased during LTVV (305 min) compared to 1,055 min in Controls. Detergent induced a biexponential clearance with slow (t 1/2S) and fast (t 1/2F) half-lives of 670 and 15.4 min, respectively. The fast fraction (fF) was 0.20. Clearance in the Detergent + LTVV group was also biexponential. The t 1/2F and fF were similar to the Detergent group. The t 1/2S was similar to the LTVV group. The fF in this group increased to 0.36 during Recovery (p < 0.01 versus Detergent group and p < 0.05 versus Experimental ventilation). The diverse kinetics of clearance during large tidal volume ventilation and surfactant dysfunction suggest the presence of different mechanisms affecting the barrier. The mechanisms have additive characteristics, which superimpose to produce lung injury.
The acoustic properties of capsaicin-induced cough in healthy subjects
Authors: Doherty MJ , Wang LJ , Donague S , Pearson MG , Downs P , Stoneman SA , Earis JE
Published: March 2003

Acoustic analysis of cough both in the time and frequency domain has been reported using voluntary and spontaneous cough. The main aim of this study was to discover whether such analysis of capsaicin-induced cough enables differences between normal subjects to be recognized. We present data from 13 healthy subjects (with normal lung function and no history of respiratory disease) using a new method of acoustic analysis, which presents the data in three graphical forms: 1) spectrogram; 2) overall spectral energy, 3) root mean square (RMS) pressure plots. Using the RMS sound pressure traces, different subjects had either two peaks, a single peak or multiple peaks. The occurrence of single and multiple peaks has previously been associated with disease states but we found them in normal subjects. The number of peaks and the visual pattern of the spectrogram was reproducible within and specific to each individual over time. During a peal of coughs in a single expiration, the peak amplitude of successive coughs decreased as lung volume reduced. Despite similarities in the overall spectral energy between individuals, there were marked differences in the small visual details of the spectrograms. However, in an individual, these small details were remarkably constant both within and between days, and can be regarded as a "cough signature". This type of spectrographic analysis provides a new approach to the analysis both of normal and abnormal cough sounds, and has identified similarities and differences in capsaicin-induced cough in normal individuals. It has potential as a tool with which to study the pathophysiology of cough.
Lung volume reduction surgery for emphysema
Authors: Russi EW , Stammberger U , Weder W
Published: March 2003

Lung volume reduction surgery (LVRS) is performed to alleviate dyspnoea of selected patients with severe pulmonary emphysema and to improve their pulmonary function, performance in daily activity and quality of life. By resection of destroyed lung areas the achievable improvements in function may consist of: 1) a reduction in hyperinflation resulting in amelioration of diaphragm and chest wall mechanics; 2) an increase of elastic recoil pressure, thereby augmenting expiratory flow rates; and 3) possibly an improvement in gas exchange. Meticulous selection of suitable patients, refinements in operative techniques, anaesthesiological and postoperative management has lowered perioperative mortality to less than 5% in groups who are experienced with this type of procedure. The best functional results are achieved by bilateral resection, which can either be performed by median sternotomy or by video-assisted thoracoscopy (VAT). The average increase in forced expiratory volume in one second (FEV1), obtained by bilateral resection in patients already receiving optimal medical therapy ranges 32-93%, and the reduction in hyperinflation, assessed by a decrease in total lung capacity ranges 15-20%. These favourable improvements have been reported to last in most of the patients for at least one year.
Physiology and pathophysiology of pleural fluid turnover
Authors: Miserocchi G
Published: March 2003

The pleural space contains a tiny amount (approximately 0.3 mL.kg-1) of hypooncotic fluid (approximately 1 g.dL-1 protein). Pleural fluid turnover is estimated to be approximately 0.15 mL.kg-1.h-1. Pleural fluid is produced at parietal pleural level, mainly in the less dependent regions of the cavity. Reabsorption is accomplished by parietal pleural lymphatics in the most dependent part of the cavity, on the diaphragmatic surface and in the mediastinal regions. The flow rate in pleural lymphatics can increase in response to an increase in pleural fluid filtration, acting as a negative feedback mechanism to control pleural liquid volume. Such control is very efficient, as a 10 fold increase in filtration rate would only result in a 15% increase in pleural liquid volume. When filtration exceeds maximum pleural lymphatic flow, pleural effusion occurs: as an estimate, in man, maximum pleural lymph flow could attain 30 mL.h-1, equivalent to approximately 700 mL.day-1 (approximately 40% of overall lymph flow). Under physiological conditions, the lung interstitium and the pleural space behave as functionally independent compartments, due to the low water and solute permeability of the visceral pleura. Pleural fluid circulates in the pleural cavity and intrapleural fluid dynamics may be represented by a porous flow model. Lubrication between lung and chest wall is assured by oligolamellar surfactant molecules stratified on mesothelial cells of the opposing pleurae. These molecules carry a charge of similar sign and, therefore, repulse each other, assuring a graphite-like lubrication.
Reactive airways dysfunction syndrome due to chlorine: sequential bronchial biopsies and functional assessment
Authors: Lemiere C , Malo JL , Boutet M
Published: March 2003

Very little information is available on the acute histopathological bronchial alterations caused by reactive airways dysfunction syndrome (RADS). We had the opportunity to carry out sequential bronchial biopsies in a subject with RADS due to chlorine (60 h, 15 days, 2 and 5 months after the acute exposure), and also to assess spirometry and bronchial responsiveness to methacholine. A 36 year old worker in a water-filtration plant (nonsmoker) abruptly inhaled high concentrations of chlorine on September 12, 1994. He experienced immediate nasal and throat burning, retrosternal burning and wheezing, and these symptoms persisted during and after the workshift. Two days later, he complained of retrosternal burning, dyspnoea and wheezing. Inspiratory wheezing was documented. His forced expiratory volume in one second (FEV1) was 66% of predicted and the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) was slightly abnormal (2.5 mg.mL-1). On the following day, the patient underwent bronchial biopsies, which showed almost complete replacement of the epithelium by a fibrinohaemorhagic exsudate. The subject was prescribed inhaled steroids. Fifteen days after the accident, the PC20 was improved to 6 mg.mL-1. Bronchial biopsies showed considerable epithelial desquamation with an inflammatory exudate and swelling of the subepithelial space. Five weeks after the accident, the PC20 was normal (57 mg.mL-1). Inhaled steroids were stopped. Two months after the accident, the PC20 deteriorated to 4 mg.mL-1. Biopsies then showed regeneration of the epithelium by basal cells and there was still a pronounced inflammatory infiltrate. Inhaled steroids were restarted. Three and five months later, the PC20 was normal (24 mg.mL-1). Bronchial biopsies showed a greatly improved epithelium and reduction of the inflammatory infiltrate. This case report shows that reactive airways dysfunction syndrome can cause acute, marked, though partially reversible, histological abnormalities. Inhaled steroids may modulate changes in bronchial responsiveness in this condition.
Necrotizing sarcoid granulomatosis with extrapulmonary involvement
Authors: Dykhuizen RS , Smith CC , Kennedy MM , McLay KA , Cockburn JS , Kerr KM
Published: March 2003

Pulmonary lesions, with sarcoid-like granulomas exhibiting noncaseous necrosis, with associated granulomatous arteritis fulfil the diagnostic criteria of necrotizing sarcoid granulomatosis (NSG). We report the case of a woman who presented with recurrent headaches, transient right hemipareses and left-sided ophthalmoplegia. An excised left retro-orbital lesion demonstrated sarcoid like changes, and the illness responded to steroid therapy. Twelve years later, the patient developed a tumour in the right lung. The resected specimen showed the histological hallmarks of NSG, and careful review of the retro-orbital lesion, removed 12 years previously, revealed similar histology. Extrapulmonary involvement in NSG is rare and has been histologically proven on only one previous occasion. The presentation of necrotizing sarcoid granulomatosis in two different systems 12 years apart is unusual and was considered worth reporting.
Chronic pneumonia caused by Rhodococcus equi in a patient without impaired immunity
Authors: Linares MJ , Lopez-Encuentra A , Perea S
Published: March 2003

A 48 year old, human immunodeficiency virus (HIV)-negative, immunocompetent male patient had a chronic progressive pulmonary infiltrate, without radiological cavitation, in the middle lobe of the right lung produced by Rhodococcus equi. He reported direct contact with a diseased dog. The patient was diagnosed by thoracotomy and treated by lobectomy. After 16 months of follow-up, the patient was asymptomatic and had neither recurrence nor immunological disturbances.
Issues in adapting a computer-assisted career guidance system for use in another country
Authors: Lokan Jan , Fleming Marianne
Published: March 2003

An extensive adaptation exercise was undertaken by the Australian Council for Educational Research (ACER) when it was decided to modify the 1988 version of the American ‘SIGI Plus’ (System for Interactive Guidance, plus more) (Educational Testing Service, 1981 and later dates) for Australian conditions. The information is of several kinds, requiring varying degrees of validation and checking for local appropriateness.Although the same language, English, was involved, there are substantial differences in education systems and educational pathways, and noticeable differences in occupational conditions and people’s value systems.

Adaptations were needed at the level of the language (terminology), factual details relating to the vocational world (starting salaries, workplace conditions, legislation), and the educational world (educational programs, extracurricular facilities, further education). The self-assessment modules had to be adapted and then validated against Australian occupational criteria. Teams comprising occupational psychologistsfrom government departments, career teachers, and counsellors both from educational and corporate settings adapted and verified all information and assessment components. Finally, all adaptations needed to be implemented in the computer program, requiring frequent and thorough system testing. The steps in the adaptation and validation procedures are outlined following a brief discussion of elements of career guidance and a description of SIGI Plus itself.
Adaptation of a picture-type creativity test for pre-school children
Authors: Chae Sunhee
Published: March 2003

The Test for Creative Thinking - Drawing Production (TCT-DP) is a creativity test, suitable for most age and ability groups. It was developed by Jellen and Urban (1986) and has been used mainly in Europe. This study explores the possibility of implementing TCT-DP amongst kindergarten children in Korea. Results from a TCT-DP field study on 1366 Korean pre-school children are comparable to those found in previously reported German studies of TCT-DP. The article presents steps taken to adapt TCT-DP to a different culture. These steps include: test translation, test implementation, scoring, selection and training of test agents and graders, norm construction, and score interpretation. The findings provide useful information for practitioners wishing to adapt foreign psychological tests such as TCTDP to different cultures, especially in relation to the assessment of pre-school children.
PISA reading: cultural equivalence in a cross-cultural study
Authors: McQueen Joy , Mendelovits Juliette
Published: March 2003

The first cycle of the OECD Programme for International Student Assessment (PISA) was conducted in 2000. Students in 32 countries were surveyed to assess their reading literacy, mathematical literacy and scientific literacy. It is essential in an international study of this type that the assessment materials be culturally appropriate for the many participating groups. They must also be linguistically equivalent, and make sense psychometrically for individual countries as well as for the group of participants as a whole. This article discusses the steps taken to attain cultural relevance and appropriateness in the reading literacy construct, and in the stimulus materials and items which operationalizeit. It explains the influence of multilingual considerations on the development of the reading literacy assessment instrument and notes some psychometric procedures used to maximize the validity of the instrument in an international context.
Translation procedures in OECD/PISA 2000 international assessment
Authors: Grisay Aletta
Published: March 2003

As a part of the OECD Programme for International Student Assessment (PISA), an international survey was conducted in 2000 to assess the Reading, Mathematics and Science literacy of 15-year-old students in 31 countries (see McQueen and Mendelovits, this issue; see Grisay, 2002). The article describes the procedures implemented by the PISA International Co-ordination Centre for the development of national versions of the assessment instruments in all instruction languages used in the participating countries. It also presents data (collected during the field trial of the instruments) that provide some empirical information on the effectiveness of these procedures. The International Centre developed two source versions (in English and French) of the instruments. It was recommended that the national adaptation teams produce two independent translations (one from the English and the other from the French source version) of the assessment material into the language of instruction in their country and that they reconcile them into a single national version. A group of international verifiers appointed and trained by the International Centre then checked the equivalence of all national versions against the source versions.
Henry Kunkel Festschrift
Authors: Schur P H , Liang M
Published: March 2003

This Festschift by his former trainees is dedicated to the memory of Dr Henry G Kunkel. Dr Kunkel spent most of his academic life at The Rockefeller University. He has been called the father of Clinical Immunology. His trainees became professors and leaders in this field. Dr Kunkel’s laboratory led to the elucidation of the immunology of the LE cell, the significance of anti-DNA and immune deposits in lupus nephritis, the recognition of antibodies to other nucleic acids and cellular constituents, the role of complement, genetics, hormones and cellular immunology—in the area of lupus and other rheumatic diseases.
Autoantibodies and glomerulonephritis in systemic lupus erythematosus
Authors: Fu S M , Castillo J D , Deshmukh U S , Lewis J E , Waters S T , Gaskin F
Published: March 2003

Autoantibody diversification to a variety of autoantigens is a hallmark for systemic autoimmunity.SLE representsa prototype.In this article the roots of the important questions probed by the Kunkel laboratory in SLE research are traced. Data from the recent animal work by the laboratory of Shu Man Fu are summarized to emphasize the importance of further exploration of autoantibody specificities in lupus with a special emphasis on nephritis and to suggest a broader perspective regarding lupus autoantibody reactivities in addition to those against nuclear components.
Why the lupus problem remains unsolved and I am a human geneticist
Authors: German J
Published: March 2003

A personal account is given: 1) of my early work with lupus erythematosus including the first observation of formation of the LE cell and the experimental production in animal renal glomeruli of hematoxyphil bodies, the pathognomonic lesion of lupus; and, 2) of how discontinuationof work on lupus - by decree - diverted my life in science away from immunology into another area of human genetics, namely cytogenetics, the discovery of genetically determined genomic instability and the choice of Bloom’s syndrome as an investigational model for human cancer.
Clinical research helps elucidate the role of tumor necrosis factor-αin the pathogenesis of T1-mediated immune disorders: use of targeted immunotherapeutics as pathogenic probes
Authors: Gottlieb A B
Published: March 2003

Psoriasis is a life-disabling disorder in which 8-10% of patients aged 18-54 actively contemplate suicide because of their disease. Owing to the toxicity and=or inconvenience of current, FDA-approved treatments far moderate-to-severe psoriasis, they are generally used intermittently so that patients experience cycles of remission-flare-remission-flare, etc. The challenge to drug development for moderate-to-severe psoriasis is to provide safe and effective long-term management. Immunobiologics offer the hope for safe, long-term control of psoriasis because they lack targeted organ toxicity. Thus the treatment paradigm may shift from one of intermittent treatment limited by toxicity with resultant flares of disease, to one similar to that seen in diabetesor hypertension in which disease is controlled continuously.Additionally, immunobiologics may alter the natural history of psoriasis. Etanercept, which targets TNF-, controls signs and symptoms and halts joint destruction in patients with psoriatic arthritis. The long-lived remissions observed after cessation of alefacept or infliximab (anti-TNF-monoclonal antibody) treatment lead this author to speculate that these immunobiologics may actually alter the natural history of the cutaneous manifestations of psoriasis.
Why not work on T and NK cells in the Kunkel laboratory?
Authors: Kabelitz D
Published: March 2003

Coming from Hans Wigzell’s laboratory in Uppsala, Sweden, I joined the Kunkel laboratory in 1981 to spend a post-doctoral fellowship period financed by the German Research Organization. While I initially worked with Nick Chiorazzi in an attempt to generate monoclonal antibody-secreting human B-cell hybridomas, I later studied the in vitro effects of tumor promoters on human natural killer cells and collaborated with Mary Crow on some aspects of the so-called autologous mixed lymphocyte reaction. Working in the stimulating atmosphere of the Kunkel laboratory was an exceptionalexperience.I was particularlyimpressed by the efficient organizationof clinical research at Rockefeller University. The following is a very personal resumee of my stay in the Kunkel laboratory.
Lupus and desoxyribonuclease
Authors: Lachmann P J
Published: March 2003

The dominant autoantigen in SLE is the nucleosome and immune complexes involving nucleosomes are the major cause of tissue damage. Nucleosomes can be broken down in vivo with Desoxyribonuclease1. DNase 1 from humans and mice is inhibited by actin and it is proposed that the release of platelet actin at inflammatory sites is one mechanism which causes nucleosomes to become antigenic. Rats whose DNase 1 is not inhibited by actin do not get lupus. Treatment of NZB=W mice with recombinantDNase slows the onset of their disease if given early and improves the renal disease if given later. This disease can also be entirely prevented by treatment with dexamethasone. Mice whose DNase 1 gene is knocked out are known to develop lupus and to be otherwise normal. DNase 1 especially in its mutant actin and salt resistant forms remains an attractive candidate for the treatment of SLE.
On being a Kunkel acolyte
Authors: Laurence J
Published: March 2003

Everything is interesting if you look at it deeply enough. There is no trivial question. This sentiment, attributed to Nobel laureate and physicist Richard Feynman, was Professor Henry Kunkel’s message to all who began work in his laboratory.Learn as much as you can from a single informative patient. Keep looking. Play. But play, of course, in the Kunkel sense of exploration. The life of a Kunkel acolyte might be characterized as rejection, endurance and very late dinners. But then, on a few occasions, there was the thrill of a discovery he’d always help guide.
Genetic studies of pulmonary arterial hypertension
Authors: Morse J H
Published: March 2003

These genetic studies of primary pulmonary hypertension (PPH) initially tried to define immunogenetic subsets. Because only small subsets could be classified when defined by HLA=autoantibodyassociationsand the familial form of PPH failed to segregate with the HLA class II locus, the focus shifted to a genome scan of families with PPH (FPPH). This approach identified a gene on chromosome 2q33,34 called PPH1. Mutations in this gene, now known to be bone morphogenetic protein receptor 2 (BMPR2), can cause PPH. Mutations in a second gene, ALK-1, present in families with hereditary hemorrhagic telangiectasia type 2, also causes PPH. Both genes, involved in TGF-B signaling, provide exciting clues for defining the pathogenesis of PPH.
Henry Kunkel, Stephanie Smith, clinical immunology, and split genes
Authors: Reeves W H , Narain S , Satoh M
Published: March 2003

The York Avenue (New York) ‘ecosystem’from the 1940s through the 1980s enabled Henry Kunkel to apply new scientific methodology to understandinghuman disease. Stephanie Smith, a young woman with lupus, was treated at the Rockefeller University Hospital in the 1960s. Studies of her antinuclear antibodies by Kunkel and Eng Tan led to the discovery of a precipitin line specific for lupus, and the responsible antigen was designated Sm (for ‘Smith’). This review outlines the history of Sm antigen from an interesting precipitin line to the identification of small nuclear RNA molecules and small nuclear ribonucleoproteins, and subsequently the discovery of RNA splicing. The story illustrates Henry Kunkel’s approach to science, emphasizing how ‘accidental’clinical observations, in the hands of skilled investigators, can have unexpectedand potentiallymomentous implications.
Circulating human plasmacytoid dendritic cells are highly sensitive to corticosteroid administration
Authors: Shodell M , Shah K , Siegal F P
Published: March 2003

Plasmacytoid dendritic cells (pDC), the major interferon-producingcell type found in human blood, have been implicated in the pathogenesisof systemic lupus erythematosus (SLE). Previous studies in SLE have shown substantial deviations from normal in this minor but immunologically important leukocyte population.Many of the lupus patients studied were receiving corticosteroids.To determine the effects of steroid administration on pDC in healthy adults, four volunteerswere given prednisone, 15-30 mg daily, for 4 days. Both counts of pDC, and their ability to produceIFN-were significantly reduced (P 0.02 and 0.004, respectively) during steroid administration, and rapidly recovered after discontinuation of the hormones. The overall reduction in pDC-derived IFN appeared to be attributable to falls of both number of circulating cells and of IFN produced per pDC. The effects observed with pDC were comparable in magnitude but opposite in direction to that observed for granulocytes. In contrast, other blood leukocytes were little affected during steroid therapy.
Recollections from the Kunkel Laboratory, 1956-1958
Authors: Vesell E S
Published: March 2003

The Kunkel laboratory provided a unique environment for dedicated young scientists to learn the art of clinical investigation.
Reflections on Henry G Kunkel as a mentor in clinical investigation
Authors: Winfield J B
Published: March 2003

Henry Kunkel spent nearly his entire professional life doing basic and clinical research at Rockefeller University. Many believe that he deserved to be a Nobel Laureate, not for one line of investigation, but for several in entirely distinct areas of medicine. Many of the leaders in immunology research during the last 50 years, especially research on systemic lupus erythematosus, received their research training in Henry Kunkel’s laboratory.In this article, I attempt to illustratehis genius as a mentor from recollections of his scientific style and approach when I was a fellow in his laboratory almost 30 years ago. Henry Kunkel’s legacy as a mentor continues today through the continuing contributions of his Fellows and their own trainees in immunological research.
Nucleolar association of pEg7 and XCAP-E, two members ofXenopus laeviscondensin complex in interphase cells
Authors: Uzbekov Rustem , Timirbulatova Elmira , Watrin Erwan , Cubizolles Fabien , Ogereau David , Gulak Pavel , Legagneux Vincent , Polyakov Vladimir Ju. , Le Guellec Katherine , Kireev Igor
Published: March 2003

Cell cycle dynamics and localization of condensins — multiprotein complexes involved in late stages of mitotic chromosome condensation —were studied in Xenopus laevis XL2 cell line. Western blot analysis of synchronized cells showed that the ratio of levels of both pEg7 and XCAP-E to β-tubulin levels remains almost constant from G1 to M phase. pEg7 and XCAP-E were localized to the mitotic chromosomes and were detected in interphase nuclei. Immunostaining for condensins and nucleolar proteins UBF,fibrillarin and B23 revealed that both XCAP-E and pEg7 are localized in the granular component of the nucleolus. Nucleolar labeling of both proteins is preserved in segregated nucleoli after 6 hours of incubation with actinomycin D (5 mg/ml), but the size of the labeled zone was significantly smaller. The data suggest a novel interphase function of condensin subunits in spatial organization of the nucleolus and/or ribosome biogenesis.
Sphingosine-1-phosphate decreases melanin synthesis via sustained ERK activation and subsequent MITF degradation
Authors: Kim Dong-Seok , Hwang Eui-Soo , Lee Jai-Eun , Kim Sook-Young , Kwon Sun-Bang , Park Kyoung-Chan
Published: March 2003

Sphingosine-1-phosphate (S1P) has emerged as a bioactive lipid modulator that mediates a variety of cell functions. However, the effects of S1P on melanogenesis are not well known. Therefore, we investigated the actions of S1P on melanin synthesis using a spontaneously immortalized mouse melanocyte cell line, Mel-Ab. This study shows that S1P significantly inhibits melanin synthesis in a concentration-dependent manner, and also that the activity of tyrosinase was reduced in S1P-treated cells. In contrast, a specific extracellular signal-regulated protein kinase (ERK) pathway inhibitor,PD98059, increased tyrosinase activity and melanin production, and PD98059 also restored the S1P-induced reduction of tyrosinase activity and pigmentation. In addition, we found that S1P induces the sustained activation of ERK and the subsequent degradation of microphthalmia-associated transcription factor (MITF), which plays a key role in melanogenesis. Thus, we further studied the relationship between the ERK pathway and melanin synthesis. PD98059 was found to prevent the S1P-induced MITF phosphorylation and degradation and to abrogate the S1P-induced downregulation of tyrosinase and of tyrosinase-related protein 1 (TRP1) production. These results indicate that the ERK pathway is potently involved in the melanogenic signaling cascade, and that S1P-induced ERK activation contributes to reduced melanin synthesis via MITF degradation. Therefore, we suggest that S1P reduces melanin synthesis by ERK activation, MITF phosphorylation and degradation, and by the subsequent downregulation of tyrosinase and TRP-1 production.
Molecular and cellular characterisation of highly purified stromal stem cells derived from human bone marrow
Authors: Gronthos Stan , Zannettino Andrew C. W. , Hay Shelley J. , Shi Songtao , Graves Stephen E. , Kortesidis Angela , Simmons Paul J.
Published: March 2003

Previous studies have provided evidence for the existence of adult human bone marrow stromal stem cells (BMSSCs) or mesenchymal stem cells. Using a combination of cell separation techniques, we have isolated an almost homogeneous population of BMSSCs from adult human bone marrow. Lacking phenotypic characteristics of leukocytes and mature stromal elements, BMSSCs are non-cycling and constitutively express telomerase activity in vivo. This mesenchymal stem cell population demonstrates extensive proliferation and retains the capacity for differentiation into bone, cartilage and adipose tissue in vitro. In addition, clonal analysis demonstrated that individual BMSSC colonies exhibit a differential capacity to form new bone in vivo. These data are consistent with the existence of a second population of bone marrow stem cells in addition to those for the hematopoietic system. Our novel selection protocol provides a means to generate purified populations of BMSSCs for use in a range of different tissue engineering and gene therapy strategies.
Accumulation of c-Myc and proteasomes at the nucleoli of cells containing elevated c-Myc protein levels
Authors: Arabi Azadeh , Rustum Cecilia , Hallberg Einar , Wright Anthony P. H.
Published: March 2003

c-Myc is a predominately nuclear transcription factor that is a substrate for rapid turnover by the proteasome system. Cancer-related mutations in c-Myc lead to defects in its degradation and thereby contribute to the increase in its cellular level that is associated with the disease. Little is known about the mechanisms that target c-Myc to the proteasomes. By using a GFP fusion protein and live analysis we show that c-Myc shuttles between the nucleus and cytoplasm and thus it could be degraded in either compartment. Strikingly, at elevated levels of expression c-Myc accumulates at nucleoli in some cells,consistent with saturation of a nucleolus-associated degradation system in these cells. This idea is further supported by the observation that proteasome inhibitor treatment causes accumulation of c-Myc at the nucleoli of essentially all cells. Under these conditions c-Myc is relatively stably associated with the nucleolus, as would be expected if the nucleolus functions as a sequestration/degradation site for excess c-Myc. Furthermore, during elevated c-Myc expression or proteasome inhibition, nucleoli that are associated with c-Myc also accumulate proteasomes. c-Myc and proteasomes co-localise in intranucleolar regions distinct from the dense fibrillar component of the nucleolus. Based on these results we propose a model for c-Myc downregulation where c-Myc is sequestered at the nucleoli. Sequestration of c-Myc is accompanied by recruitment of proteasomes and may lead to subsequent degradation.
TheDrosophilaEAST protein associates with a nuclear remnant during mitosis and constrains chromosome mobility
Authors: Wasser Martin , Chia William
Published: March 2003

Drosophila EAST protein associates with an interior nonchromosomal compartment of the interphase nucleus. Because overexpression of eastcan dramatically alter nuclear architecture we investigated a potential role for EAST in changing chromosome organization during the cell cycle. Following nuclear envelope breakdown, EAST remains enriched in the mitotic remnant of the interphase nucleus until the onset of anaphase. Loss of eastexpression affects the accuracy of division cycles. In female meiosis, east mutations lead to abnormal segregation of nonexchange chromosomes. During the syncytial nuclear cycles, increased frequency of mitotic errors leads to the depletion of surface nuclei. In the post-syncytial cell cycles, abnormal congression of chromosomes in prometaphase delays the onset of anaphase. Loss of east expression also results in abnormal chromosome morphology in male meiosis. We propose that EAST constitutes a component of a nucleoskeleton that helps to constrain the mobility of chromosomes in interphase, mitosis and meiosis.
Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12-Apg5 conjugate
Authors: Mizushima Noboru , Kuma Akiko , Kobayashi Yoshinori , Yamamoto Akitsugu , Matsubae Masami , Takao Toshifumi , Natsume Tohru , Ohsumi Yoshinori , Yoshimori Tamotsu
Published: March 2003

Macroautophagy is the major intracellular degradation system delivering cytoplasmic components to the lysosome/vacuole. We have shown that, in yeast and mammalian cells, the Apg12-Apg5 protein conjugate, which is formed by a ubiquitin-like system, is essential for autophagosome formation. In yeast, the Apg12-Apg5 conjugate interacts with a small coiled-coil protein, Apg16, to form a ∼350 kDa multimeric complex. We demonstrate that the mouse Apg12-Apg5 conjugate forms a ∼800 kDa protein complex containing a novel WD-repeat protein. Because the N-terminal region of this novel protein shows homology with yeast Apg16, we have designated it mouse Apg16-like protein(Apg16L). Apg16L, however, has a large C-terminal domain containing seven WD repeats that is absent from yeast Apg16. Apg16L interacts with both Apg5 and additional Apg16L monomers; neither interaction, however, depends on the WD-repeat domain. In conjunction with Apg12-Apg5, Apg16L associates with the autophagic isolation membrane for the duration of autophagosome formation. Because these features are similar to yeast Apg16, we concluded Apg16L is the functional counterpart of the yeast Apg16. We also found that membrane targeting of Apg16L requires Apg5 but not Apg12. Because WD-repeat proteins provide a platform for protein-protein interactions, the ∼800 kDa complex is expected to function in autophagosome formation, further interacting with other proteins in mammalian cells.
HIF-1α controls extracellular matrix synthesis by epiphyseal chondrocytes
Authors: Pfander David , Cramer Thorsten , Schipani Ernestina , Johnson Randall S.
Published: March 2003

The transcription factor HIF-1α plays a crucial role in modifying gene expression during low oxygen tension. In a previous study, we demonstrated that HIF-1α is essential for chondrocyte growth arrest and survival in vivo. To explore further the role of HIF-1α in cartilage biology, we undertook studies with primary epiphyseal chondrocytes with a targeted deletion of HIF-1α. In this study, we show that HIF-1α is necessary for regulating glycolysis under aerobic and anaerobic conditions. HIF-1α-null chondrocytes were unable to maintain ATP levels in hypoxic microenvironments, indicating a fundamental requirement for this factor for the regulation of chondrocyte metabolism. Synthesis of the angiogenic factor vascular endothelial growth factor was also significantly induced by hypoxia,and this increase is lost in HIF-1α-null mutant cells. Under hypoxic conditions, aggrecan mRNA and protein levels were significantly reduced in chondrocytes lacking the HIF-1α transcription factor. Interestingly,strongly increased type-II collagen protein levels were detected in wild-type cells after 44 hours of hypoxia. In addition, type-II collagen mRNA and protein levels were strongly decreased under low oxygen in chondrocytes lacking HIF-1α. In summary, our results clearly demonstrate the importance of HIF-1α in maintenance of anaerobic glycolysis, and thereby extracellular matrix synthesis, of epiphyseal chondrocytes.
Linear element formation and their role in meiotic sister chromatid cohesion and chromosome pairing
Authors: Molnar Monika , Doll Eveline , Yamamoto Ayumu , Hiraoka Yasushi , Kohli Jürg
Published: March 2003

Fission yeast does not form synaptonemal complexes in meiotic prophase. Instead, linear elements appear that resemble the axial cores of other eukaryotes. They have been proposed to be minimal structures necessary for proper meiotic chromosome functions. We examined linear element formation in meiotic recombination deficient mutants. The rec12, rec14 and meu13 mutants showed altered linear element formation. Examination of rec12 and other mutants deficient in the initiation of meiotic recombination revealed that occurrence of meiosis-specific DNA breaks is not a precondition for the formation of linear elements. The rec11 and rec8 mutants exhibited strongly impaired linear elements with morphologies specific for these meiotic cohesin mutants. The rec10and rec16/rep1 mutants lack linear elements completely. The region specificity of loss of recombination in the rec8, rec10 and rec11 mutants can be explained by their defects in linear element formation. Investigation of the rec10 mutant showed that linear elements are basically dispensable for sister chromatid cohesion, but contribute to full level pairing of homologous chromosomes.