bluuebunny/crossref_metadata_2025 huggingface dataset:
Does ketotifen have a steroid-sparing effect in childhood asthma?
Authors: Canny GJ , Reisman J , Levison H
Published: March 2003

In view of the possible systemic side-effects of inhaled corticosteroids (ICS), a study was performed to determine whether ketotifen (versus placebo) can replace or allow a reduction in the dose of ICS required for the maintenance treatment of childhood asthma. Sixty six children (aged 6-13 yrs) with asthma (confirmed by methacholine challenge), who were maintained on ICS, at a dose of < or = 1 mg.day-1, were selected, and 52 subjects completed the trial. Children on long-term oral steroids or cromoglycate were excluded. After a 4 week baseline period, the children were randomized to receive ketotifen, 2 mg.day-1, or placebo for 32 Weeks. Between weeks 13-20 of the study, the daily dose of steroid was tapered by 25% every second week to the minimum dose tolerated by the patients. For the remainder of the study (Weeks 21-32) the patients continued on this dose (if tolerated). Beta 2-agonists were allowed, as necessary, for symptom relief. During the baseline period, the mean daily ICS dosage was 432 micrograms in the ketotifen group versus 408 micrograms in the placebo group (NS). Among the-patients who completed the study, the average ICS dosage during the final phase of the study (Weeks 21-32) was only 18% of baseline in the ketotifen group versus 35% in the placebo group (NS). Lung function, diurnal variability in peak flow rates and methacholine sensitivity (provocative concentration producing a 20% fall in forced expiratory volume in one second (PC20)) remained unchanged in both groups throughout the study. During the last 12 weeks of the study, the ketotifen-treated patients were symptomatically better controlled. In the present study, ketotifen did not have a greater steroid-sparing effect than placebo.
Effect of influenza A virus infection on acid-induced cough response in children with asthma
Authors: Shimizu T , Mochizuki H , Morikawa A
Published: March 2003

Although it is well-known that some types of respiratory viral infections cause airway hyperresponsiveness in humans, the effect of viral infection on the cough threshold in asthmatics is not known. We, therefore, evaluated the effects of naturally-acquired influenza A virus infection on the cough threshold to inhaled acid in children with asthma. Twelve children with asthma (9 boys and 3 girls, mean +/- SEM age of 10.8 +/- 0.6 yrs), who had naturally-acquired influenza A virus infection in winter (January-February, 1992) during an epidemic of influenza A (H1N1), were enrolled in this prospective, uncontrolled study. All patients underwent acetic acid (AA) inhalation challenge 2, 4 and 6 weeks after the influenza infection. The cough threshold values (the lowest concentrations of AA eliciting coughs) after 2, 4 and 6 weeks of the illness were 3.7 +/- 0.9, 5.3 +/- 1.0 and 8.1 +/- 1.4% (mean +/- SEM), respectively. Cough threshold values 4 or 6 weeks after the illness improved significantly over that at 2 weeks (p < 0.05 and p < 0.01, respectively). In contrast, baseline forced expiratory volume in one second did not change throughout the study. These results indicate that influenza A virus infection attenuates the cough threshold independently of airway obstruction in children with asthma. The enhanced cough response following virus infection is probably mediated by damage to the airways epithelium.
Short-term variations in oscillatory and spirometric lung function indices among school children
Authors: Timonen KL , Randell JT , Salonen RO , Pekkanen J
Published: March 2003

The aim of this study was to compare immediate, daily and weekly variation in respiratory resistance measured by means of the forced oscillation technique (Rrs,FOT) to spirometric indices in 7-12 year old children with chronic respiratory symptoms. The lung function measurements were performed in 19 children on 4 days, i.e. two consecutive days during two consecutive weeks. On each day, the measurements were carried out at the same time of day and always repeated three times. In addition, Rrs,FOT and spirometric lung function indices were compared with an exercise challenge test in 12 children. Intrasubject coefficients of variation (CoVs) for Rrs,FOT were larger than those for spirometric indices. Only in the immediately repeated measurements was the CoV of maximal expiratory flow at 25% vital capacity larger than that of Rrs,FOT (16.6 vs 14.9%). At all time intervals, the smallest CoVs were observed in forced vital capacity (FVC) or in the ratio of forced expiratory volume in one second to FVC (2.0-2.6%). When excluding Rrs,FOT values which were not within 2 SD (0.11 kPa.L-1.s) of the differences between the immediately repeated measurements, the CoV of the immediately repeated measurements of Rrs,FOT was reduced to 9.1%, being smaller than that of maximal mid-expiratory flow (10.1%). However, even then the day-to-day variation in Rrs,FOT was clearly larger (16.0%) than those of the airflow indices at specified lung volumes (7.2-8.3%). This was also true for the weekly variation. In the exercise challenge test, there were larger changes in Rrs,FOT values than in the spirometric indices, but Rrs,FOT was the most sensitive index to detect changes in the respiratory system. In conclusion, the variation in Rrs,FOT values was larger than that of most spirometric indices. When a reliability index was applied, the immediate variation in Rrs,FOT values was comparable to those of the airflow indices at specified lung volumes. Rrs,FOT was also the most sensitive index in the exercise challenge test, and therefore it seems to be suitable for detection of short-term functional changes in the respiratory system. However, the relatively low repeatability of Rrs,FOT over days and weeks may limit its applicability to longer-term follow-ups.
Low diagnostic value of respiratory impedance measurements in children
Authors: Cuijpers CE , Wesseling GJ , Kessels AG , Swaen GM , Mertens PL , de Kok ME , Broer J , Sturmans F , Wouters EF
Published: March 2003

The aim of this study was to determine whether impedance values in children with various chronic respiratory complaints differed from those observed in symptom-free children. Respiratory impedance was measured using the forced oscillation technique in 1,776 Dutch children aged 6-12 yrs. In addition to the commonly used parameters of resistance and reactance, further impedance parameters were obtained by using linear and quadratic regression to describe individual resistance and reactance curves as a function of frequency. Furthermore, the diagnostic value of the individual impedance parameters was evaluated by means of receiver operator characteristic (ROC) curves. Statistically significant differences in impedance values were found in girls with symptoms suggesting asthma compared to symptom-free girls, but not in boys. In children with chronic cough, impedance was not significantly different from the values of symptom-free children. The results obtained by the additional impedance parameters were comparable to those of the commonly used measures. We conclude that the diagnostic values of the impedance parameters appeared to be low, as no cut-off points were found to discriminate clearly between symptomatic and symptom-free children. These findings may reflect absence of functional abnormalities in symptomatic children at this age.
Long-term follow-up after surgical treatment of obstructive sleep apnoea by maxillomandibular advancement
Authors: Conradt R , Hochban W , Brandenburg U , Heitmann J , Peter JH
Published: March 2003

Obstructive sleep apnoea (OSA) is a common disorder with potentially serious consequences. If maxillary and mandibular deficiency, often in combination with a narrow posterior airway space is present, therapy of OSA by maxillomandibular osteotomy is possible. However, long-term follow-up of patients undergoing these procedures is lacking. We present the results of 15 OSA patients (1 female and 14 males), who underwent maxillomandibular advancement surgery with a follow-up of at least 2 yrs. Polysomnography was performed before surgery, after 6-12 weeks, and 1 and 2 yrs postoperatively. Mean apnoea/hypopnoea index (AHI) decreased from 51.4 events.h-1 before therapy to 5.0 events.h-1 6 weeks postoperatively, and was 8.5 events.h-1 after 2 yrs. Oxygen saturation significantly increased following surgery. After 2 yrs, the AHI was < 10 events.h-1 in 12 out of 15 subjects. No significant changes were found comparing the 6-12 weeks versus the 2 year follow-up data. The significant increase in stage 3/4 non-rapid eye movement (NREM) sleep and decrease in stage 1 NREM sleep, indicative of the restoration of normal physiological sleep structure, persisted in 14 of the 15 subjects 2 yrs postoperatively. Three patients, however, did not show satisfactory improvement 2 yrs postoperatively; two showed obstructive and one central respiratory events. This study demonstrates that maxillomandibular advancement is successful in a high percentage of patients carefully selected by cephalometric and polysomnographic investigation. Postoperative success has proved to be stable over a period of 2 yrs. Further preoperative evaluation seems necessary in patients with predominantly mixed or central apnoeas.
Lung function and clinical outcome in postpolio patients: a prospective cohort study during 11 years
Authors: Midgren B
Published: March 2003

The object of this investigation was to prospectively study the annual decline in lung function in a cohort of postpolio patients, and to determine the usefulness of initial lung function tests in the prediction of a subsequent poor outcome. Cross-sectional data were analysed in 55 patients from the total cohort of 350 survivors of poliomyelitis in our admission area of 550,000 inhabitants. Longitudinal data (> 5 yrs, average 8.9 yrs) were available for 31 patients. Seventeen of the patients had a poor outcome (13 were started on domiciliary artificial ventilation and five died from respiratory failure; with one overlap). At the time of entry to the study (on average 4.3 years before the poor outcome), these patients had a lower vital capacity (VC) (43 vs 65% of predicted; p < 0.01) and arterial oxygen tension (Pa,O2) (9.9 vs 11 kPa; p < 0.05) and a higher arterial carbon dioxide tension (Pa,CO2) (6.0 vs 5.0 kPa; p < 0.01). They also had a more rapid increase in Pa,CO2 (0.3 vs 0.03 kPa.yr-1; p < 0.01), but the difference in decline in VC (40 vs 30 mL.yr-1) was not significant. Initial VC < 50% of predicted and/or Pa,CO2 > 6 kPa was associated with a poor prognosis. In conclusion, annual decline in vital capacity was not abnormally rapid but annual increase in arterial carbon dioxide tension was higher in patients with a poor outcome. Initial determination of vital capacity and initial and repeated blood gas analysis appear to be useful in identifying high-risk postpolio patients.
Unsteadiness of breathing in patients with hyperventilation syndrome and anxiety disorders
Authors: Han JN , Stegen K , Simkens K , Cauberghs M , Schepers R , Van den Bergh O , Clement J , Van de Woestijne KP
Published: March 2003

The breathing pattern of 399 patients with hyperventilation syndrome (HVS) and/or with anxiety disorders and that of 347 normal controls was investigated during a 5 min period of quiet breathing and after a 3 min period of voluntary hyperventilation. The diagnosis of HVS was based on the presence of several suggestive complaints occurring in the context of stress, and reproduced by voluntary hyperventilation. Organic diseases as a cause of the symptoms were excluded. The anxiety disorders were diagnosed by means of an abbreviated version of the Anxiety Disorders Interview Schedule (ADIS). There was a large overlap between the two diagnoses. Simply breathing via a mouthpiece and pneumotachograph made end-tidal CO2 fractional concentration (FET,CO2) decrease progressively both in hyperventilators and in patients with anxiety disorders, but not in normals. At the start of the measurement the FET,CO2 was not different between patients and healthy subjects. In patients < or = 28 yrs, the decrease of FET,CO2 resulted from a higher tidal volume, and in patients > or = 29 years from an increase in frequency. After voluntary hyperventilation, the recovery of FET,CO2, was delayed in patients, due to a slower normalization of respiratory frequency in females and in older males, and of tidal volume in younger males, and also due to less frequent end-expiratory pauses. When breathing was recorded first by means of inductive plethysmography (Respitrace), the progressive decline of FET,CO2 seen in patients was not observed: from the onset of the recording, FET,CO2 was reduced in patients. It did not change further when, immediately afterwards, the subject switched to mouthpiece breathing. The finding that breathing through a mouthpiece induces hyperventilation in patients and that recovery of FET,CO2 is delayed after voluntary hyperventilation, suggests that the respiratory control system is less resistant to challenges (mouthpiece or voluntary hyperventilation) in those patients. On the other hand, the lower values of FET,CO2 measured during recording by means of a Respitrace probably result from a challenge, prior to the recordings, induced by the fitting of the measuring device to the patient. This unsteadiness of breathing characterizes patients with hyperventilation syndrome and those with anxiety disorders, but is not sufficiently sensitive to be used for individual diagnosis.
The effect of nitrous oxide on the measurement of single-breath transfer factor
Authors: Phillips CL , Simmul R , Smith AI , Berend N
Published: March 2003

One hour after a bone marrow biopsy and inhalation of Entonox gas (50% nitrous oxide (N2O) and 50% oxygen), a patient had a markedly reduced transfer factor of the lung for carbon monoxide (TL,CO). Three hours after Entonox, the patient had a normal TL,CO. Since carbon monoxide (CO) and N2O have similar spectral wavelengths, it was proposed that residual N2O in the lungs was interfering with the infra-red analysers used to detect CO concentrations. Experiments were performed to verify the "interference" effect and its duration. Five healthy volunteers performed serial triplicate TL,CO measurements over 3 h on two randomized days (Control vs N2O). The first triplicate TL,CO on each day served as a baseline measurement. Following the baseline measurement on the N2O day, each subject inhaled Entonox for 10 min. To serve as a control for the infrared effect, the identical protocol was repeated using a gas chromatography method for TL,CO determination. The infra-red method showed a marked reduction (> 50%) in TL,CO 30 min after N2O inhalation. This reduction did not return to baseline levels for at least 2 h. In comparison, the gas chromatography method showed no significant reduction in TL,CO. In a group of healthy nonsmoking subjects, N2O markedly affected the measurement of the transfer factor of the lungs for carbon monoxide using infra-red analysers. The time course over which the measurement was reduced was at least 2 h for a 10 min inhalation period. The effect was entirely due to a measurement error associated with infra-red technology.
Heart-lung interactions: applications in the critically ill
Authors: Fessler HE
Published: March 2003

Since the circulatory and pulmonary systems are both driven by pressure and share space in the thorax, it is inevitable that they interact. These mechanical interactions, whilst relatively few in number, are protean in their manifestations. The circulatory system of the critically ill is often particularly susceptible to interference from respiration. Compensatory reserve is limited, ventilatory effort increased, and many critical care respiratory interventions place strain on the circulation, not seen in health. This review will examine the basic physiological mechanisms through which the pulmonary and circulatory systems interact. These mechanisms will then be applied to a variety of weaning, positive end-expiratory pressure (PEEP), and cardiopulmonary resuscitation techniques. It is hoped that this will provide the tools to understand clinical observations which would otherwise appear inexplicable.
Occupational asthma due to a widely used soft solder flux not containing colophony
Authors: Convery RP , Ward RJ , Hendrick DJ
Published: March 2003

A 19 year old woman presented with symptoms suggestive of occupational asthma. The causative agent was thought to be a soft solder flux, which did not contain colophony. The diagnosis was established by specific inhalation challenge tests, which demonstrated both late asthmatic reactions and short-lived increases in airway responsiveness.
Does item-level DIF manifest itself in scale-level analyses? Implications for translating language tests
Authors: Zumbo Bruno D.
Published: March 2003

Based on the observation that scale-level methods are sometimes exclusively used to investigate measurement invariance for test translation, this article describes the results of a simulation study investigating whether item-level differential item functioning (DIF) manifests itself in scale-level analyses such as single and multi-group factor analyses and per group coefficient alpha. The simulation factors were two levels of DIF (moderate and large) and four levels of percentage of items with DIF (ranging from approximately 3-41% of the items). The results indicate that item-level DIF did not manifest itself in the scale-level results. Clearly, then, translation efforts in language testing should ensure measurement equivalence by investigatingitem-level translation DIF, and it may be misleading to give consideration only to the scale-level methods results as evidence of translation equivalence.
Appraising item equivalence across multiple languages and cultures
Authors: Sireci Stephen G. , Allalouf Avi
Published: March 2003

Activity in the area of language testing is expanding beyond second language acquisition. In many contexts, tests that measure language skills are being translated into several different languages so that parallel versions exist for use in multilingual contexts. To ensure that translated items are equivalent to their original versions, both statistical and qualitative analyses are necessary. In this article, we describe a statistical method for evaluating the translation equivalence of test items that are scored dichotomously. We provide an illustration of the method to a portion of the verbal subtest of the Psychometric Entrance Test, which is a large-scale postsecondary admissions test used in Israel. By evaluating translated items statistically, language test-developers can ensure the comparability of tests across languages and they can identify the types of problems that should be avoided in future translation efforts.
Test translation and adaptation in public education in the USA
Authors: Stansfield Charles W.
Published: March 2003

The use of translated versions of formal educationalassessments is becoming more common in the United States of America (USA). This is due to two converging factors:

1) legislation passed during the Clinton and Bush administrations;

2) an influx of non-English-speaking immigrants, especially from Latin America. Against this background, this article discusses theoretical and practical issues pertaining to the translation or adaptation of educational assessments in the USA. These issues include the role of language proficiency and academic background in performance on standards-based achievement tests in different languages, factors affecting the decision whether to translate tests, translation methods and procedures, the degree to which translated tests are used in the USA, current laws influencing the use of translation, and the role that language testing specialists may play in this arena.
Studies of autologous T cell activation in the Kunkel laboratory
Authors: Crow M K
Published: March 2003

T helper cells and their antigen receptors were topics of keen interest in Henry Kunkel’s laboratory during the early 1980s. The activation of human T cells by foreign antigen, allogeneic cells and autologousnon-T cells had been established, but the most effective stimulator cells in those responses had not yet been identified. Dendritic cells, along with activated B cells, were demonstrated to be important stimulators of autologous T cells, and studies of peripheral blood from patients with SLE supported the conclusion that the non-T cells in those patients were deficient in their capacity to stimulate an autologous mixed lymphocyte reaction (AMLR). Subsequent studies have defined the role of apoptotic cells processed by dendritic cells in autologous T cell activation. In view of recent data demonstrating depletion of dendritic cell subsets in SLE peripheral blood and recruitment of those cells to sites of immune system activity, it is proposed that SLE T cells are indeed capable of self-reactivity and that the impaired in vitro proliferative response to autologous non-T cells as assessed in the AMLR may reflect the shift of dendritic cells, with their antigen presenting activity augmented by adjuvant-likefactors, from peripheral blood to peripheral lymphoid organs and sites of disease.
Street conversations with Henry Kunkel
Authors: Elkon K B
Published: March 2003

Nineteen eighty two was a fertile time for lupus research on York Avenue. The molecular and functional characteristics of the lupus autoantigens were being discovered by the newly introduced technologies, immunoprecipitation and western blotting. Were the antigens providing the essential clue to the cause of lupus? Was it their intracellular location? Was it their function? Was it their immunochemical structure? Were they cross-reactive with foreign antigens? Henry Kunkel discusses.
Evolution of the Kunkel phenotype
Authors: Thoburn R
Published: March 2003

The original Kunkel phenotype was that of an immunologist in pursuit of excellence with broad interests. The Kunkel Society members are perpetuating this legacy. Genetic factors and the environmentdetermine the phenotype.Education has a major impact on the directiontaken. Creativity and experience contribute to the process of developing new knowledge. Because of the decline in plasticity of the brain after age 30 years the process of education and research experience in your domain should begin sooner. One should define their talents at the earliest possible age and pursue them with passion to achieve the most success.Teaching is stimulant to the process of idea generation. Business professionals should be considered for administrative and management assistance. Networking in close physical proximity to improve communication may be the most efficient way of accelerating knowledge build-up.
Risk Factors for Locoregional Recurrence Among Breast Cancer Patients: Results From International Breast Cancer Study Group Trials I Through VII
Authors: Wallgren A. , Bonetti M. , Gelber R.D. , Goldhirsch A. , Castiglione-Gertsch M. , Holmberg S.B. , Lindtner J. , Thürlimann B. , Fey M. , Werner I.D. , Forbes J.F. , Price K. , Coates A.S. , Collins J.
Published: March 2003

Purpose: To explore prognostic factors for locoregional failures (LRF) among women treated for invasive breast cancer within clinical trials of adjuvant therapies.

Patients and Methods: The study population consisted of 5,352 women who were treated with a modified radical mastectomy and enrolled in one of seven International Breast Cancer Study Group randomized trials. A total of 1,275 women with node-negative disease received either no adjuvant therapy or a single cycle of perioperative chemotherapy, and 4,077 women with node-positive disease received adjuvant chemotherapy of at least 3 months’ duration and/or tamoxifen. Median follow-up is 12 to 15.5 years.

Results: In women with node-negative disease, factors associated with increased risk of LRF were vascular invasion (VI) and tumor size greater than 2 cm for premenopausal and VI for postmenopausal patients. Of the 1,275 patients, 345 (27%) met criteria for the highest risk groups, and the 10-year cumulative incidences of LRF with or without distant metastases were 16% for premenopausal and 19% for postmenopausal women. For the node-positive cohort, number of nodes and tumor grade were factors for both menopausal groups, with additional prediction provided by VI for premenopausal and tumor size for postmenopausal patients. Of the 4,077 patients, 815 (20%) met criteria for the highest risk groups, and 10-year cumulative incidences were 35% for premenopausal and 34% for postmenopausal women.

Conclusion: LRFs are a significant problem after mastectomy alone even for some patients with node-negative breast cancer, as well as after mastectomy and adjuvant treatment for some subgroups of patients with node-positive disease. In addition to number of positive lymph nodes, predictors of LRF include tumor-related factors, such as vascular invasion, higher grade, and larger size.
Pharmacokinetics and Pharmacodynamics of Oral Etoposide in Children With Relapsed or Refractory Acute Lymphoblastic Leukemia
Authors: Edick Mathew J. , Gajjar Amar , Mahmoud Hazem H. , van de Poll Matthijs E.C. , Harrison Patricia L. , Panetta John C. , Rivera Gaston K. , Ribeiro Raul C. , Sandlund John T. , Boyett James M. , Pui Ching-Hon , Relling Mary V.
Published: March 2003

Purpose: To study the pharmacokinetics and pharmacodynamics of once- versus twice-daily oral etoposide in children with relapsed or refractory acute lymphoblastic leukemia (ALL).

Patients and Methods: Fifty-eight patients were randomly assigned to etoposide at 50 mg/m2/d with once- versus twice-daily doses for 22 days. On day 8, vincristine, asparaginase, and dexamethasone were started. Etoposide pharmacokinetics and pharmacodynamics were studied for 47, 28, and 26 patients on day 1, 8, and 22, respectively, of remission reinduction therapy.

Results: Of 48 patients with pharmacokinetic data, 42 (87.5%) achieved complete remission, three (6.3%) failed to achieve remission, and three (6.3%) died during induction. Median etoposide day 8 area under concentration-time curve (AUC) and cumulative AUC tended to be greater (P = .06 and P = .07, respectively) in patients (n = 23) who achieved complete remission (24 and 522 μmol/L • h, respectively) than in patients (n = 3) who did not (14 and 303 μmol/L • h, respectively). Three of eight patients with plasma concentrations exceeding 1.7 μM (1 μg/mL) for more than 8 hours daily, compared with one of 20 patients with concentrations exceeding 1.7 μM for ≤ 8 hours daily, were unable to receive all 22 days of etoposide because of toxicity. There was no difference in the AUC at day 1 or day 8 with once- versus twice-daily doses (P = .55 and P = .86, respectively).

Conclusion: A pharmacodynamic relationship exists between systemic etoposide exposure and response to therapy when oral etoposide is used as part of remission induction regimens for relapsed or refractory childhood ALL.
Importance of Faith on Medical Decisions Regarding Cancer Care
Authors: Silvestri Gerard A. , Knittig Sommer , Zoller James S. , Nietert Paul J.
Published: March 2003

Purpose: Decisions regarding cancer treatment choices can be difficult. Several factors may influence the decision to undergo treatment. One poorly understood factor is the influence of a patient’s faith on how they make medical decisions. We compared the importance of faith on treatment decisions among doctors, patients, and patient caregivers.

Methods: One hundred patients with advanced lung cancer, their caregivers, and 257 medical oncologists were interviewed. Participants were asked to rank the importance of the following factors that might influence treatment decisions: cancer doctor’s recommendation, faith in God, ability of treatment to cure disease, side effects, family doctor’s recommendation, spouse’s recommendation, and children’s recommendation.

Results: All three groups ranked the oncologist’s recommendation as most important. Patients and caregivers ranked faith in God second, whereas physicians placed it last (P < .0001). Patients who placed a high priority on faith in God had less formal education (P < .0001).

Conclusion: Patients and caregivers agree on the factors that are important in deciding treatment for advanced lung cancer but differ substantially from doctors. All agree that the oncologist’s recommendation is most important. This is the first study to demonstrate that, for some, faith is an important factor in medical decision making, more so than even the efficacy of treatment. If faith plays an important role in how some patients decide treatment, and physicians do not account for it, the decision-making process may be unsatisfactory to all involved. Future studies should clarify how faith influences individual decisions regarding treatment.
Safety of Yttrium-90 Ibritumomab Tiuxetan Radioimmunotherapy for Relapsed Low-Grade, Follicular, or Transformed Non-Hodgkin’s Lymphoma
Authors: Witzig Thomas E. , White Christine A. , Gordon Leo I. , Wiseman Gregory A. , Emmanouilides Christos , Murray James L. , Lister John , Multani Pratik S.
Published: March 2003

Purpose: Radioimmunotherapy (RIT) with yttrium-90 (90Y)-labeled anti-CD20 antibody (90Y ibritumomab tiuxetan; Zevalin, IDEC Pharmaceuticals Corporation, San Diego, CA) has a high rate of tumor response in patients with relapsed or refractory, low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma (NHL). This study presents the safety data from 349 patients in five studies of outpatient treatment with 90Y ibritumomab tiuxetan.

Patients and Methods: Patients received rituximab 250 mg/m2 on days 1 and 8, and either 0.4 mCi/kg (15 MBq/kg) or 0.3 mCi/kg (11 MBq/kg) of 90Y ibritumomab tiuxetan on day 8 (maximum dose, 32 mCi). Patients were observed for up to 4 years after therapy or until progressive disease.

Results: Infusion-related toxicities were typically grade 1 or 2 and were associated with rituximab. No significant organ toxicity was noted. Toxicity was primarily hematologic, with nadir counts occurring at 7 to 9 weeks and lasting approximately 1 to 4 weeks depending on the method of calculation. After the 0.4-mCi/kg dose, grade 4 neutropenia, thrombocytopenia, and anemia occurred in 30%, 10%, and 3% of patients, respectively, and after the 0.3-mCi/kg dose, these grade 4 toxicities occurred in 35%, 14%, and 8% of patients, respectively. The risk of hematologic toxicity increased with degree of baseline bone marrow involvement with NHL. Seven percent of patients were hospitalized with infection (3% with neutropenia) and 2% had grade 3 or 4 bleeding events. Myelodysplasia or acute myelogenous leukemia was reported in five patients (1%) 8 to 34 months after treatment.

Conclusion: Single-dose 90Y ibritumomab tiuxetan RIT has an acceptable safety profile in relapsed NHL patients with less than 25% lymphoma marrow involvement, adequate marrow reserve, platelets greater than 100,000 cells/μL, and neutrophils greater than 1,500 cells/μL.
Egr-1 Induction in Rat Granulosa Cells by Follicle-Stimulating Hormone and Luteinizing Hormone: Combinatorial Regulation By Transcription Factors Cyclic Adenosine 3′,5′-Monophosphate Regulatory Element Binding Protein, Serum Response Factor, Sp1, and Early Growth Response Factor-1
Authors: Russell Darryl L. , Doyle Kari M. H. , Gonzales-Robayna Ignacio , Pipaon Carlos , Richards Joanne S.
Published: March 2003

Early growth response factor (Egr-1) is an inducible zinc finger transcription factor that binds specific GC-rich enhancer elements and impacts female reproduction. These studies document for the first time that FSH rapidly induces Egr-1 expression in granulosa cells of small growing follicles. This response is transient but is reinitiated in preovulatory follicles exposed to the LH analog, human chorionic gonadotropin. Immunohistochemical analysis also showed gonadotropin induced Egr-1 in theca cells. The Egr-1 gene regulatory region responsive to gonadotropin signaling was localized within −164 bp of the transcription initiation site. Binding of Sp1/Sp3 to a proximal GC-box at −64/−46 bp was enhanced by FSH in immature granulosa cells but reduced after human chorionic gonadotropin stimulation of preovulatory follicles despite constant protein expression. This dynamic regulation of Sp1 binding was dependent on gonadotropin-regulated mechanisms that modulate Sp1/3-DNA binding activity. Serum response factor was active in granulosa cells and bound a consensus CArG-box/serum response element site, whereas two putative cAMP response elements within the −164-bp region bound cAMP regulatory element (CRE) binding protein (CREB) and a second cAMP-inducible protein immunologically related to CREB. Transient transfection analyses using Egr-1 promoter-luciferase constructs and site-specific mutations show that the serum response element, GC-box, and CRE−131 are involved in gonadotropin regulation of Egr-1 expression in granulosa cells. Specific kinase inhibitors of Erk or protein kinase A antagonized this induction while exogenously expressed Egr-1 enhanced reporter expression. These observations indicate that the Egr-1 gene is a target of both FSH and LH action that may mediate molecular programs of proliferation and/or differentiation during follicle growth, ovulation, and luteinization.
Dynamic association of RNA-editing enzymes with the nucleolus
Authors: Desterro Joana M. P. , Keegan Liam P. , Lafarga Miguel , Berciano Maria Teresa , O'Connell Mary , Carmo-Fonseca Maria
Published: March 2003

ADAR1 and ADAR2 are editing enzymes that deaminate adenosine to inosine in long double stranded RNA duplexes and specific pre-mRNA transcripts. Here, we show that full-length and N-terminally truncated forms of ADAR1 are simultaneously expressed in HeLa and COS7 cells owing to the usage of alternative starting methionines. Because the N-terminus of ADAR1 contains a nuclear export signal, the full-length protein localizes predominantly in the cytoplasm, whereas the N-terminally truncated forms are exclusively nuclear and accumulate in the nucleolus. ADAR2, which lacks a region homologous to the N-terminal domain of ADAR1, localizes exclusively to the nucleus and similarly accumulates in the nucleolus. Within the nucleolus, ADAR1 and ADAR2 co-localize in a novel compartment. Photobleaching experiments demonstrate that, in live cells, ADAR1 and ADAR2 are in constant flux in and out of the nucleolus. When cells express the editing-competent glutamate receptor GluR-B RNA, endogenous ADAR1 and ADAR2 de-localize from the nucleolus and accumulate at sites where the substrate transcripts accumulate. This suggests that ADAR1 and ADAR2 are constantly moving through the nucleolus and might be recruited onto specific editing substrates present elsewhere in the cell.
Global amplification polymerase chain reaction reveals novel transitional stages during osteoprogenitor differentiation
Authors: Liu Fina , Malaval Luc , Aubin Jane E.
Published: March 2003

Mesenchymal stem cells give rise to osteoprogenitors that proliferate and differentiate into identifiable preosteoblasts, osteoblasts, bone lining cells and osteocytes. To identify and establish a molecular profile for the more primitive and uncharacterized cells in the lineage, relatively rare (<1%)osteoprogenitors present in primary cultures of fetal rat calvaria cell populations were identified by a replica plating technique. Since the cell number was limited in each colony sampled, we used global amplification PCR to analyze the repertoire of genes expressed in osteoprogenitors. We established a molecular fingerprint and a developmental sequence based on simultaneous expression patterns for both known osteoblast-associated markers (collagen type I, alkaline phosphatase, osteopontin, bone sialoprotein, PTH1R and osteocalcin) and potential regulatory molecules (i.e. FGFR1, PDGF-Rα and PTHrP). By analysis of 99 osteoprogenitor and osteoblast colonies captured by replica plating at different developmental stages, we found: (1) a recognizable cohort of cells considered more primitive than committed osteoprogenitors; (2) a cohort of early progenitors transiently expressing bone sialoprotein; and (3) that mRNAs for FGF-R1, PDGF-Rα and PTH1R were expressed earlier than other markers and tended to increase and decrease in relative concert with the osteoblast-specific markers. The observations suggest that within the osteoblast differentiation sequence both discrete stages and continua of changing marker expression levels occur with variation in expression for any given marker. This combined approach of replica plating and global amplification PCR allows molecular fingerprinting of definitive primitive osteoprogenitors and will aid in identifying novel developmental stages and novel differentiation stage-specific genes as these cells progress through their differentiation sequence.
The endo-β-1,3-glucanase eng1p is required for dissolution of the primary septum during cell separation inSchizosaccharomyces pombe
Authors: Martín-Cuadrado Ana Belén , Dueñas Encarnación , Sipiczki Matthias , de Aldana Carlos R. Vázquez , del Rey Francisco
Published: March 2003

Schizosaccharomyces pombe cells divide by medial fission throughout contraction of an actomyosin ring and deposition of a multilayered division septum that must be cleaved to release the two daughter cells. Although many studies have focused on the actomoysin ring and septum assembly,little information is available concerning the mechanism of cell separation. Here we describe the characterization of eng1+, a new gene that encodes a protein with detectable endo-β-1,3-glucanase activity and whose deletion is not lethal to the cells but does interfere in their separation. Electron microscopic observation of mutant cells indicated that this defect is mainly due to the failure of the cells to degrade the primary septum, a structure rich in β-1,3-glucans, that separates the two sisters cells. Expression of eng1+ varies during the cell cycle,maximum expression being observed before septation, and the protein localizes to a ring-like structure that surrounds the septum region during cell separation. This suggests that it could also be involved in the cleavage of the cylinder of the cell wall that covers the division septum. The expression of eng1+ during vegetative growth is regulated by a C2H2 zinc-finger protein (encoded by the SPAC6G10.12c ORF), which shows significant sequence similarity to the Saccharomyces cerevisiae ScAce2p,especially in the zinc-finger region. Mutants lacking this transcriptional regulator (which we have named ace2+) show a severe cell separation defect, hyphal growth being observed. Thus, ace2p may regulate the expression of the eng1+ gene together with that of other genes whose products are also involved in cell separation.
Permeabilization in a cerebral endothelial barrier model by pertussis toxin involves the PKC effector pathway and is abolished by elevated levels of cAMP
Authors: Brückener Kerstin E. , el Bayâ Ali , Galla Hans-Joachim , Schmidt M. Alexander
Published: March 2003

Respiratory tract infections caused by Bordetella pertussis are occasionally accompanied by severe neurologic disorders and encephalopathies. For these sequelae to occur the integrity of cerebral barriers needs to be compromised. The influence of pertussis toxin, a decisive virulence factor in the pathogenesis of pertussis disease, on barrier integrity was investigated in model systems for blood-liquor (epithelial) and blood-brain (endothelial)barriers. While pertussis toxin did not influence the barrier function in Plexus chorioideus model systems, the integrity of cerebral endothelial monolayers was severely compromised. Cellular intoxication by pertussis toxin proceeds via ADP-ribosylation of α-Giproteins, which not only interferes with the homeostatic inhibitory regulation of adenylate cyclase stimulation but also results in a modulation of the membrane receptor coupling. Increasing intra-endothelial cAMP levels by employing cholera toxin or forskolin even inhibited the pertussis toxin-induced permeabilization of endothelial barriers. Therefore,pertussis-toxin-induced permeabilization has to be mediated via a cAMP-independent pathway. To investigate potential signalling pathways we employed several well established cellular drugs activating or inhibiting central effectors of signal transduction pathways, such as phosphatidylinositol 3-kinase, adenylate cyclase, phospholipase C, myosin light chain kinase and protein kinase C. Only inhibitors and activators of protein kinase C and phosphatidylinositol 3-kinase affected the pertussis toxin-induced permeability. In summary, we conclude that permeabilization of cerebral endothelial monolayers by pertussis toxin does not depend on elevated cAMP levels and proceeds via the phosphokinase C pathway.
Modeling human peroxisome biogenesis disorders in the nematodeCaenorhabditis elegans
Authors: Thieringer Heather , Moellers Britta , Dodt Gabriele , Kunau Wolf-H. , Driscoll Monica
Published: March 2003

Peroxisomes are ubiquitous eukaryotic organelles. The proteins required for peroxisome biogenesis are called peroxins, and mutations in the peroxin genes cause the devastating human developmental syndromes called the peroxisome biogenesis disorders. Our interest is in elaborating the roles that peroxisomes play in Caenorhabditis elegans development, and in establishing an invertebrate model system for the human peroxisome biogenesis disorders. The genome of C. elegans encodes homologs of 11 of the 13 human peroxins. We disrupted five nematode peroxins using RNA interference(RNAi) and found that RNAi knockdown of each one causes an early larval arrest at the L1 stage. Using a green fluorescent protein reporter targeted to the peroxisome, we establish that peroxisomal import is impaired in prx-5(RNAi) nematodes. prx-5(RNAi) animals are blocked very early in the L1 stage and do not initiate normal postembryonic cell divisions,similar to starvation-arrested larvae. Cell and axonal migrations that normally occur during the L1 stage also appear blocked. We conclude that peroxisome function is required for C. elegans postembryonic development and that disruption of peroxisome assembly by prx-5(RNAi)prevents scheduled postembryonic cell divisions. Defects in the cellular localization of peroxisomal proteins and in development are shared features of human and nematode peroxisome biogenesis disorders. In setting up a C. elegans model of peroxisomal biogenesis disorders, we suggest that genetic screens for suppression of the Prx developmental block will facilitate identification of novel intervention strategies and may provide new insights into human disease pathogenesis.
The formin-homology-domain-containing protein FHOD1 enhances cell migration
Authors: Koka Sreenivas , Neudauer Cheryl L. , Li Xiaodong , Lewis Robert E. , McCarthy James B. , Westendorf Jennifer J.
Published: March 2003

Formin-homology-domain-containing proteins interact with Rho-family GTPases and regulate actin cytoskeleton organization and gene transcription. FHOD1 is a member of this family, interacts with Rac1 and induces transcription from the serum response element. In this study, we examined the effects of FHOD1 expression on cytoskeletal organization and function in mammalian cells. FHOD1 proteins were stably expressed in WM35 melanoma cells and NIH-3T3 fibroblasts. Cells expressing full-length FHOD1 demonstrated an elongated phenotype compared with vector-transfected cells and cells expressing a truncated FHOD1(1-421) that lacks the conserved FH1 and FH2 domains. Full-length FHOD1 co-localized with filamentous actin at cell peripheries. Cells transiently expressing a C-terminal FHOD1 truncation mutant (ΔC, residues 1-1010),which lacks an autoinhibitory protein-protein interaction domain, displayed prominent stress fibers. FHOD1 (1-421) did not induce stress fibers but localized to membrane ruffles in a manner similar to the full-length protein,indicating that the FH1 and FH2 domains are required for stress fiber appearance. FHOD1 ΔC (1-1010)-dependent stress fibers were sensitive to dominant-negative RacN17 and the RhoA and ROCK inhibitors, C3 transferase and Y-27632. Stable overexpression of full-length FHOD1 enhanced the migration of WM35 and NIH-3T3 cells to type-I collagen and fibronectin, respectively. Cells expressing FHOD1 (1-421) migrated similar to control cells. Integrin expression and activation were not affected by FHOD1 expression. Moreover,FHOD1 overexpression did not alter integrin usage during adhesion or migration. These data demonstrate that FHOD1 interacts with and regulates the structure of the cytoskeleton and stimulates cell migration in an integrin-independent manner.
The intracellular localisation of TAF7L, a paralogue of transcription factor TFIID subunit TAF7, is developmentally regulated during male germ-cell differentiation
Authors: Pointud Jean-Christophe , Mengus Gabrielle , Brancorsini Stefano , Monaco Lucia , Parvinen Martti , Sassone-Corsi Paolo , Davidson Irwin
Published: March 2003

Transcription regulation in male germ cells can involve specialised mechanisms and testis-specific paralogues of the general transcription machinery. Here we describe TAF7L, a germ-cell-specific paralogue of the TFIID subunit TAF7. TAF7L is expressed through most of the male germ-cell differentiation programme, but its intracellular localisation is dynamically regulated from cytoplasmic in spermatogonia and early spermatocytes to nuclear in late pachytene spermatocytes and haploid round spermatids. Import of TAF7L into the nucleus coincides with decreased TAF7 expression and a strong increase in nuclear TBP expression, which suggests that TAF7L replaces TAF7 as a TFIID subunit in late pachytene spermatocytes and in haploid cells. In agreement with this, biochemical experiments indicate that a subpopulation of TAF7L is tightly associated with TBP in both pachytene and haploid cells and TAF7L interacts with the TFIID subunit TAF1. We further show that TAF3, TAF4 and TAF10 are all strongly expressed in early spermatocytes, but that in contrast to TBP and TAF7L, they are downregulated in haploid cells. Hence,different subunits of the TFIID complex are regulated in distinct ways during male germ-cell differentiation. These results show for the first time how the composition of a general transcription factor such as TFIID and other TAF-containing complexes are modulated during a differentiation programme highlighting the unique nature of the transcription regulatory machinery in spermatogenesis.
Surveys on the use of cardiac markers in the UK
Authors: Tsang Wing Man , Owen Avril M. , Collinson Paul O. , Barth Julian H.
Published: March 2003

Background: Troponin measurements are now central to the diagnosis of acute coronary syndromes and for the stratification of the severity of cardiac disease. Some laboratories have quickly adopted the new testing strategies, which include troponin measurement for the diagnosis of acute myocardial infarction, while others are still developing appropriate protocols for cardiac testing that they can support financially. However, it is not known how widespread is the adoption of these new strategies across the UK.

Methods: The National Audit Committee of the Association of Clinical Biochemists commissioned two surveys in 1999 and 2001 to assess the status of cardiac markers currently being offered by laboratories in the UK and how this service might develop in the future.

Results: The results show that many laboratories are continuously adapting and improving their cardiac marker testing in line with current recommendations for acute myocardial infarction. Although most laboratories are confident in the use of troponin measurement in the diagnosis of myocardial infarction, they are less confident in the use of biochemical markers in assessing prognostic outcome in the other cardiac conditions.

Conclusions: Finance, staffing and equipment constraints may offer significant impediments to troponin testing with a 1-h turnaround time.