bluuebunny/crossref_metadata_2025 huggingface dataset:
Fatigue associated with multiple sclerosis: diagnosis, impact and management
Authors: Bakshi Rohit
Published: May 2003

In patients with multiple sclerosis (MS) fatigue is the most common symptom and one of the most disabling features. A s many as 40% have described it as the single most disabling symptom - a higher percentage than weakness, spasticity, motor problems, or bowel or bladder problems. The etiology and patho physiology of MS-related fatigue remain unknown. Studies have failed to demonstrate an association between MS-related fatigue and the level of disability, clinical disease subtype, or gender, although recent data show an association between MS-related fatigue and depression and quality of life. Imaging studies using positron emission tomography suggest that fatigue in MS is related to hypometabolism of specific brain areas, including the frontal and subcortical circuits. The impact of fatigue on patient functioning and quality of life clearly warrants intervention. In addition to nonpharmacologic measures, such as exercise and energy conservation strategies, several pharmacologic agents have been evaluated for their ability to reduce MS-related fatigue, including amantadine, central nervous system stimulants (pemoline), and the novel wake-promoting agent modafinil.
Myelopathy in seronegative Sjögren syndrome and/or primary progressive multiple sclerosis
Authors: Pericot I , Brieva L , Tintoré M , Río J , Sastre-Garriga J , Nos C , Montalban X
Published: May 2003

Objective: The relationship between multiple sclerosis (MS) and Sjögren syndrome (SS) is controversial. Nine patients, previously diagnosed with primary progressive MS (PPMS) and who fulfilled the diagnostic criteria for SS, are described. Methods: The European classification criteria for SS were used to study nine PPMS patients that complained of sicca complex symptoms. The following tests were performed: Schirmer test, rose bengal staining, salivary scintigraphy, minor salivary gland biopsy and serologic tests (antibodies Ro/SS-A, La/SS-B and antinuclear antibodies). Results: The nine patients met criteria to be diagnosed with SS (at least four criteria). A ll patients were women with a mean age of 46.6 years at symptom onset. Spastic paraparesis was the presenting symptom in all patients, and spinal cord magnetic resonance imaging (MRI) showed abnormalities in most; anti-Ro and anti-La antibodies were mostly negative. Conclusions: Some MS patients, predominantly women over 45 years of age, with progressive spastic paraparesis, antiextractable nuclear antigen antibodies (Ro/SS-A or La/SS-B) negative and with abnormalities in spinal cord MRI, may have SS as an additional or alternative diagnosis.
T cells from multiple sclerosis patients recognize immunoglobulin G from cerebrospinal fluid
Authors: Holmøy T , Vandvik B , Vartdal F
Published: May 2003

Idiotopic sequences are created after V, D and J recombinations and by somatic mutations during affinity maturation of immuglobulin (Ig) molecules, and may therefore be potential immunogenic epitopes. Idiotope-specific T cells are able to activate and sustain the B cells producing such idiotopes. It is therefore possible that idiotope-specific intrathecal T cells could help maintain the persisting intrathecal synthesis of oligoclonal IgG observed in patients with multiple sclerosis (MS). This study was undertaken to examine T-cell responses to cerebrospinal fluid (CSF) IgG. Peripheral blood mononuclear cells (PBMC) from 14 of 21 MS patients and four of 17 control patients with other neurological diseases proliferated upon stimulation with autologous C SF IgG, while five and three, respectively, responded to serum IgG. By comparison, responses to myelin basic protein were recorded in only four MS and three control patients. Data from a limited number of patients indicate that the C SF IgG responsive cells were CD4+ and human leucocyte antigen DR restricted, that PBMC also respond to C SF IgG from other MS patients and that the C SF may contain T cells responding to autologous C SF IgG. This suggests that C SF IgG, or substances bound to this IgG, may represent T-cell immunogens, which could contribute to the intrathecal immune response in MS.
Open-label study of pirfenidone in patients with progressive forms of multiple sclerosis
Authors: Bowen James D , Maravilla Kenneth , Margolin Solomon B
Published: May 2003

Background: Pirfenidone is an oral medicatio n with a number of actions affecting the immune system. It has been proposed as a possible treatment for multiple sclerosis (MS). Methods: An early-phase study of progressive forms of MS was conducted. Pirfenidone was slowly titrated to 2400 mg/day. Safety, clinical, quality-of-life, and magnetic resonance image (MRI) outcomes were measured. Results: Twenty people were enrolled (13 with secondary progressive and seven with primary progressive MS). The mean age was 47.7 years; the mean Expanded Disability Status Scale (EDSS) was 5.15; 75% were female. Eighteen patients achieved the full dose, although five additional patients eventually had to decrease the dose, primarily because of nausea. The Neurologic Rating Scale showed a slight worsening, from 69.89-8.4 at baseline to 71.89-8.9 at one year (P=0.03). O ther clinical outcomes remained stable, including the EDSS, ambulation index, and nine-ho le peg test. The Short-Form Health Survey (SF-36) quality-of-life measure remained unchanged. C omparisons of MRI scans at baseline and one year found that 715 plaques were unchanged, six were better, and 10 were worse. Three patients had plaques that improved and two patients had plaques that were worse. There were eight gadolinium-enhancing lesions on the baseline scans and 14 on the one-year scans. Conclusions: Pirfenidone was well tolerated in patients with MS. Patients with primary progressive or secondary progressive MS tolerated the medicatio n and remained clinically stable during the one year of follow up. Placebo-controlled blinded studies are needed to determine clinical effectiveness.
Somatosensory evoked potentials and sensory involvement in multiple sclerosis: comparison with clinical findings and quantitative sensory tests
Authors: Leocani Letizia , Martinelli Vittorio , Natali-Sora Maria Grazia , Rovaris Marco , Comi Giancarlo
Published: May 2003

Sensory disturbances are one of the most common findings in patients with multiple sclerosis (MS). However, they are usually assessed at the standard neurological examination only. Q uantitative Sensory Tests (Q STs) for temperature and vibratory sense allow a more objective evaluation. In a group of 19 clinically definite MS patients, we compared vibratory and temperatur e thresholds with sensory symptoms or signs at clinical neurological examination and somatosensory evoked potentials (SEPs) at the four limbs. The frequency of abnormalities of clinical symptoms/signs, vibration threshold and median SEPs were 69%, 33% and 55%, respectively. C orrelation between degree of abnormality of SEPs and clinically assessed vibration sense (V) was statistically significant (P B-0.007; Spearmann rank coefficient), as well as between SEPs and vibration perceptio n threshold (P B-0.02). C linical evaluation of thermal sense did not show false positive results compared to quantitative thermal threshold, but false negative findings (35%). This study suggests that the combined use of vibration threshold and SEPs allows a better objectivation of sensory function, allowing the detection of subclinical abnormalities and possibly reducing the number of false positive results introduced by clinical assessment. Moreover, Q STs are to be preferred to clinical evaluation in the assessment of thermal sense, due to their superior sensitivity.
Multiple sclerosis characteristics in A frican A merican patients in the New York State Multiple Sclerosis C onsortium
Authors: Weinstock-Guttman B , Jacobs L D , Brownscheidle C M , Baier M , Rea D F , Apatoff B R , Blitz K M , Coyle P K , Frontera A T , Goodman A D , Gottesman M H , Herbert J , Holub R , Lava N S , Lenihan M , Lusins J , Mihai C , Miller A E , Perel A B , Snyder D H , Bakshi R , Granger C V , Greenberg S J , Jubelt B , Krupp L , Munschauer F E , Rubin D , Schwid S , Smiroldo J ,   The New York State Multiple Sclerosis Consortium
Published: May 2003

The objective of this study was to determine the clinical characteristics of multiple sclerosis (MS) in A frican A merican (A A) patients in the New York State Multiple Sclerosis C onsortium (NYSMSC) patient registry. The NYSMSC is a group of 18 MS centers throughout New York State organized to prospectively assess clinical characteristics of MS patients. AA s comprise 6% (329) of the total NYSMSC registrants (5602). Demographics, disease course, therapy, and socioeconomic status were compared in A A registrants versus nonA frican A mericans (NA A). There was an increased female preponderance and a significantly younger age at diagnosis in the AA group. A A patients were more likely to have greater disability with increased disease duration. No differences were seen in types of MS and use of disease modifying therapies. O ur findings suggest a racial influence in MS. Further genetic studies that consider race differences are warranted to elucidate mechanisms of disease susceptibility.
Sample size estimates for determining treatment effects in high-risk patients with early relapsing-remitting multiple sclerosis
Authors: Scott Thomas F , Schramke Carol J , Cutter Gary
Published: May 2003

Background: Risk factors for short-term progression in early relapsing-remitting MS have been identified recently. Previously we determined potential risk factors for rapid progression of early relapsing-remitting MS and identified three groups of high-risk patients. These non-mutually exclusive groups of patients were drawn from a consecutively studied sample of 98 patients with newly diagnosed MS. High-risk patients had a history of either poor recovery from initial attacks, more than two attacks in the first two years of disease, or a combination of at least four other risk factors. Objective: To determine differences in sample sizes required to show a meaningful treatment effect when using a high-risk sample versus a random sample of patients. Methods: Power analyses were used to calculate the different sample sizes needed for hypothetical treatment trials. Results: We found that substantially smaller numbers of patients should be needed to show a significant treatment effect by employing these high-risk groups of patients as compared to a random population of MS patients (e.g., 58% reduction in sample size in one model). Conclusion: The use of patients at higher risk of progression to perform drug treatment trials can be considered as a means to reduce the number of patients needed to show a significant treatment effect for patients with very early MS.
Preliminary magnetic resonance study of the macromolecular proton fraction in white matter: a potential marker of myelin?
Authors: Davies G R , Ramani A , Dalton C M , Tozer D J , Wheeler-Kingshott C AM , Barker G J , Thompson A J , Miller D H , Tofts P S
Published: May 2003

We report on a new quantitative magnetization transfer (MT) technique that allows for the in vivo estimation of the macromolecular proton fraction (f) and the bound pool T2 relaxation time (T2b), whilst permitting whole brain coverage. In this pilot study, five subjects with multiple sclerosis (MS) and five healthy controls were studied. Both f and T2b were significantly different between MS lesions and normal control white matter (WM). Relationships between f and T1 relaxation time [Spearman’s rank correlation coefficient (rs) =-0.97, P <0.001] and f and the magnetization transfer ratio (MTR; rs =0.80, P <0.001) were observed. C ompared with MTR, f and T2b have the potential advantage of relative independence from MT acquisition protocol while offering more pathologically specific information. In particular, f may provide a more direct indication of myelin content in WM.
Unconventional therapy in multiple sclerosis
Authors: Sastre-Garriga Jaume , Munteis Elvira , Río Jordi , Pericot Imma , Tintoré Mar , Montalban Xavier
Published: May 2003

Background: The use of unconventional therapies is growing in western countries. Few studies on their frequency and rationale among multiple sclerosis (MS) patients have been carried out in Europe. Objective: To assess the frequency of use of unconventional therapies among MS patients and to explore associated clinical variables. Methods: Structured questionnaires were given to 380 consecutive patients seen at two hospital-based MS clinics in Barcelona. C linical and demographical data were recorded at the same time. The questionnaire inquired about demographical features, educatio n, income, use of unconventional therapies for MS and satisfaction with conventional medicine both in general and specifically in MS. Results: The response rate was 50.78%. Forty-one per cent of patients admitted using unconventional therapies during the previous year. Low levels of satisfaction with conventional medicine in general and for MS, and higher Expanded Disability Status Scale (EDSS) scores (EDSS mean: 4.43 in users versus 3.48 in nonusers) were significantly associated with use of unconventional therapies. Conclusion: Use of unconventional therapies is not rare among MS patients, and it is associated with high disability levels and dissatisfaction with conventional medicine.
Long-term follow up of patients with clinically isolated syndromes, relapsing-remitting and secondary progressive multiple sclerosis
Authors: Eriksson Maja , Andersen Oluf , Runmarker Björn
Published: May 2003

This paper extends on previous data on prognosis in multiple sclerosis (MS), to encompass the entire course of the disease. The first episode suggestive of MS [the clinically isolated syndrome (CIS)] was included as a starting point, and the speed of secondary progression as an end point. Primary progressive MS was not included. Unique preconditions, with one neurological service covering the G öteborg district, allowed for establishing a strictly population-based, essentially untreated 15-year incidence cohort of 308 MS patients who were followed for 25 years. Survival analysis was performed as Kaplan -Meyer graphs, and independent predictors were ascertained by C ox regression analysis. A matrix of several predictors and end points was created. From C IS, a higher risk of developing clinically definite MS (C DMS), secondary progressive course and Disability Status Scale 7 (DSS7) was predicted by efferent tract lesions. However, less than 25% had reached DSS7 25 years after C IS with pure afferent lesions or other favorable predicto rs. During the first five years, higher relapse frequency, as well as incomplete remission of early bouts, predicted higher risks of secondary progressive course and DSS7 during follow-up to 25 years. However, these early predictors were unable to predict the rate of progression, which seems to contain an element of the disease process unassociated with its early events. O nly late predictors, such as a shorter time from onset to secondary progression (1-10 years) and a higher number of functional systems involved at onset of progression predicted a faster progression rate. Predictors from this study could be used to refine historically controlled trials.
Multiple sclerosis and depression: influence of interferon b therapy
Authors: Zephir Hélène , De Seze Jérôme , Stojkovic Tanya , Delisse Brigitte , Ferriby Didier , Cabaret Marilyn , Vermersch Patrick
Published: May 2003

Background and objectives: Depression is frequently part of the clinical picture of multiple sclerosis (MS). Major depression affects one in two patients with MS during the course of their lifetime. O ur objectives were to determine first, whether interferon b-1a (IFNb-1a) treatment increases the risk or level of depression and, secondly, whether depression status and depression evolution are related to the clinical characteristics of the disease. Patients and methods: We investigated 106 consecutive patients with relapsing-remitting MS treated with IFNb-1a (Avonex®). Patients with evidence of severe depression were excluded. The depression status, scored on the Beck Depression Inventory (BDI-II) (stratified as minimum, mild, moderate or severe level), and disability, scored on the Expanded Disability Status Scale (EDSS), were evaluated before and after 12 months of IFNb-1a treatment. Results: At baseline, 85% of patients had a minimum or a mild depression status and after 12 months of treatment most of them (83%) retained their baseline status. Beck scores before and after treatment were not significantly different (P =0.63). There was no correlation between age, gender, duration of illness or EDSS score and Beck score at baseline (P =0.696). Patients with disability progression after one year of IFNb-1a treatment had a significantly higher Beck score at baseline than patients without disability progression (P =0.003). Conclusion: IFNb-1a (Avonex®) does not seem to significantly influence the depression status of MS patients even in those with disability progression.
Serum from patients with multiple sclerosis downregulates occludin and VE-cadherin expression in cultured endothelial cells
Authors: Minagar Alireza , Ostanin Dmitry , Long Ann C , Jennings Merilyn , Kelley Roger E , Sasaki Makoto , Alexander J Steven
Published: May 2003

Disruption of the blood -brain barrier (BBB) and transendothelial migration of inflammatory cells are crucial steps in the development of demyelinating lesions in multiple sclerosis (MS). O ccludin and vascular endothelial-cadher in (VE-cadherin) are two major components of the tight junctions (TJs) in the brain microvasculature that help to create the BBB. In the present study, we investigated the effect of serum from MS patients on the expression of these two junctional markers and on the endothelial integrity. Serum from six MS patients in exacerbation, six in remission, and six normal controls (10% by volume) was incubated with cultured endothelial cells, and the expression of occludin and VE-cadherin was measured by immunoblotting. Serum from MS patients in exacerbation significantly reduced the expression of occludin and VE-cadherin compared with patients in remission and normal controls. This disintegrating effect was more pronounced for occludin than for VE-cadherin. We assume that the elevation in cytokines or other serum-soluble factors in MS patients in exacerbation likely provokes downregulation of occludin and VE-cadherin. This downregulation of TJs proteins may, therefore, contribute to the disruption of the BBB in this condition.
Increased plasma homocysteine levels without signs of vitamin B12 deficiency in patients with multiple sclerosis assessed by blood and cerebrospinal fluid homocysteine and methylmalonic acid
Authors: Vrethem M , Mattsson E , Hebelka H , Leerbeck K , Österberg A , Landtblom A-M , Balla B , Nilsson H , Hultgren M , Brattström L , Kågedal B
Published: May 2003

Objective: The aim of this study was to evaluate if multiple sclerosis (MS) is associated with vitamin B12 (cobalamin) deficiency. Methods: We measured serum vitamin B12, plasma folate, serum methylmalonic acid (MMA), plasma homocysteine (tHcy) and also cerebrospinal fluid (C SF) MMA and tHcy in 72 patients with MS and 23 controls. Results: The mean plasma tHcy level was significantly increased in MS patients (11.6 mmol/L) compared with controls (7.4 mmol/L) (P =4-0.002). Seven patients showed low serum vitamin B12levels but only one of them had concomitant high plasma tHcy. None of them showed high serum MMA. Plasma or blood folate levels did not differ between MS patients and controls. We found no significant differences in mean values or frequency of pathological tests of serum B12, serum MMA, mean corpuscular volume (MC V), haemoglobin concentration, C SF tHcy or C SF MMA between patients and healthy subjects. There were no correlations between C SF and serum/plasma levels of MMA or tHcy. Serum vitamin B12, serum MMA, plasma tHcy, C SF Hcy or C SF MMA were not correlated to disability status, activity of disease, duration of disease or age. Conclusions:The relevance of the increased mean value of plasma tHcy thus seems uncertain and does not indicate functional vitamin B12 deficiency. We can not, however, exclude the possibility of a genetically induced dysfunction of the homocysteine metabolism relevant for the development of neuroinflammation/degeneration. O ur findings indicate that, regardless of a significant increase in plasma tHcy in MS patients, the MS disease is not generally associated with vitamin B12 deficiency since we did not find any other factors indicating vitamin B12 deficiency. A nalysis of C SF MMA and C SF tHcy, which probably reflects the brain vitamin B12 status better than serum, are not warranted in MS. We conclude that B12 deficiency, in general, is not associated with MS.
The risk of multiple sclerosis in nurses: a population-based epidemiological study
Authors: Stenager Egon , Brønnum-Hansen Henrik , Koch-Henriksen Nils
Published: May 2003

The incidence of multiple sclerosis (MS) in nurses during the period 1980-1996 was calculated in a nationwide study. The cohort consisted of 69 428 nurses, 2185 men and 67243 women. Sixty (two men and 58 women) with definite MS were observed, whereas 69.3 were expected. We found no significant difference between the observed and expected number of MS cases (standardized incidence ratio =0.87; 95% confidence interval, 0.66-1.12).
Longitudinal evaluation of depression and anxiety in patients with clinically isolated syndrome at high risk of developing early multiple sclerosis
Authors: Di Legge S , Piattella M C , Pozzilli C , Pantano P , Caramia F , Pestalozza I F , Paolillo A , Lenzi G L
Published: May 2003

We investigated the relationship between emotional changes, brain lesion burden and development of multiple sclerosis (MS). Thirty-seven consecutive patients with clinically isolated syndrome (C IS) were prospectively assessed with the Expanded Disability Status Scale (EDSS), the 21-item Beck Depression Inventory (BDI), the State-Trait A nxiety Inventory (STAI) and gadolinium enhanced (Gd+) MRI scans. BDI and STAI were also administered to 36 age-matched controls. C onversion to MS was defined as the occurrence of a clinical relapse.

C IS patients were more likely to endorse symptoms of anxiety and depression than controls. Baseline scores for depression and anxiety did not correlate with the total lesion load (i.e., volume of Gd+, T2 and T1 lesions) and the number of Gd+ lesions during the first six months of follow-up. A positive correlation was found between severity of depressive scores and the lesion load in the right temporal region (P =0.005). After 339-6 months of the study entry, patients who had a clinical relapse were more frequently depressed (P =0.001) than those relapse free.

Emotional disturbances are frequently observed in C IS patients and show a tendency towards a normalization in relapse-free patients. The increased rate of depressive symptoms observed in patients who developed MS seems to result from a combination of psychological and organic features. The lesion load in the right temporal region is confirmed as a key area for developing depressive symptoms, even in the early phase of the disease.
A review of the development of daylighting in schools
Authors: Wu Wei , Ng Edward
Published: May 2003

This paper reviews the progress of daylighting in school buildings. It examines the publications that discuss daylighting design for school buildings in early 1874. It also traces the developments of the open-air school movement from 1900 up to the 1930s and describes research at the present day in the context of an emphasis on environmental factors defining healthy and comfortable buildings for education. The regulations and standards of lighting in schools in the different periods in Britain are summarized. The review reveals that there is a need to examine the relationships between the responses of school occupants and the quantity of daylighting. The conclusion of the paper gives an overall summary of daylighting in schools and identifies gaps in current knowledge. In addition, it provides the authors’ opinions for future lighting research in schools.
Reflections on glare
Authors: Vos Johannes J
Published: May 2003

This paper describes the philosophy and research leading up to the recent publication of the CIE-report No 146 ‘CIE equations for Disability Glare’. It extends, however, to a consideration of discomfort glare and dazzling glare. It starts with a critical discussion of glare terminology, resulting in suggestions for more accurate wording, followed by a review of research on disability glare, including ocular causes of entoptic scatter, the Stiles-Holladay equation, and age dependence. This section ends with the present state of the art as described in the CIE report and concretized in three generalizations of the Stiles-Holladay equation. Finally, suggestions are made for a more structured research on discomfort and dazzling glare.
Daylight distribution in the living rooms of four types of public housing building in Singapore
Authors: Ullah MB , Lin Liaw Wee
Published: May 2003

The Housing Development Board of Singapore has been designing and constructing multi-storey high density housing estates since the 1970s. Newer developments have less open space between building blocks, though they offer more communal spaces within the configuration of the buildings. This study simulates the daylighting availability in the living rooms of the typical residential units in four generations of housing estates up to the late 1990s. It finds that illuminances are lower in the newer estates. Three sky conditions were modelled (clear, cloudy and partly cloudy) and the interior daylight was calculated at 10a.m. in living rooms at three story levels and four orientations.
Daylight measurement error
Authors: Hayman Simon
Published: May 2003

The International Daylight Measurement Programme has stimulated wide research in daylighting measurement analysis and modelling, however there are deficiencies in all these areas. Data collection, especially, is still limited geographically and some variables, such as cloud cover and distribution, have proved difficult to measure and have, consequently, largely been ignored. Furthermore, data that has been collected has limitations on its accuracy that does not appear to have been factored into much analysis and model building. This paper discusses errors associated with techniques of data gathering and measurement accuracy with examples. The extension of daylight measurement in tropical regions will not be immune from these potential sources of error even with superficially static daylight climates.
Studies on daylight design and regulation of high-density residential housing in Hong Kong
Authors: Ng Edward
Published: May 2003

Around 20 cities in the world have 10 million inhabitants or more. In these cities, buildings are fighting each other for natural light. Finding ways optimize the natural agent without compromising development density is a task for architects and engineers. This paper reports a series of research projects, commissioned by the government of Hong Kong, to understand the problem and to develop a new design and regulatory method for Hong Kong. The study first looked into the issue in terms of existing rules and policy, and identified their shortcomings. It then investigated daylight performance of the existing building stock with on-site measurements. Though a territory-wide user survey, the study proceeded to relate these quantitative data to user satisfaction and requirements. A minimum performance standard based on Vertical Daylight Factor (VDF) on the surface of the window was established. Using theoretical modeling, on-site measurements and computational studies of real and hypothetical cases, a design method based on Unobstructed Vision Area (UVA) was developed. The government of Hong Kong has adopted this performance-based approach; new building regulations are currently undergoing on-site trial.
Multi-Institutional Randomized Phase II Trial of Gefitinib for Previously Treated Patients With Advanced Non–Small-Cell Lung Cancer
Authors: Fukuoka Masahiro , Yano Seiji , Giaccone Giuseppe , Tamura Tomohide , Nakagawa Kazuhiko , Douillard Jean-Yves , Nishiwaki Yutaka , Vansteenkiste Johan , Kudoh Shinzoh , Rischin Danny , Eek Richard , Horai Takeshi , Noda Kazumasa , Takata Ichiro , Smit Egbert , Averbuch Steven , Macleod Angela , Feyereislova Andrea , Dong Rui-Ping , Baselga José
Published: May 2003

Purpose: To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non–small-cell lung cancer (NSCLC).

Patients and Methods: This was a randomized, double-blind, parallel-group, multicenter phase II trial. Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens (at least one containing platinum) were randomized to receive either 250-mg or 500-mg oral doses of gefitinib once daily.

Results: Efficacy was similar for the 250- and 500-mg/d groups. Objective tumor response rates were 18.4% (95% confidence interval [CI], 11.5 to 27.3) and 19.0% (95% CI, 12.1 to 27.9); among evaluable patients, symptom improvement rates were 40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1); median progression-free survival times were 2.7 and 2.8 months; and median overall survival times were 7.6 and 8.0 months, respectively. Symptom improvements were recorded for 69.2% (250 mg/d) and 85.7% (500 mg/d) of patients with a tumor response. Adverse events (AEs) at both dose levels were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent in the higher-dose group. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500 mg/d, respectively.

Conclusion: Gefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients. At 250 mg/d, gefitinib had a favorable AE profile. Gefitinib 250 mg/d is an important, novel treatment option for patients with pretreated advanced NSCLC.
Inhibition of Cyclooxygenase-2 Activity Enhances Steroidogenesis and Steroidogenic Acute Regulatory Gene Expression in MA-10 Mouse Leydig Cells
Authors: Wang XingJia , Dyson Matthew T. , Jo Youngah , Stocco Douglas M.
Published: May 2003

To study the mechanism for the regulatory effect of arachidonic acid (AA) on steroidogenesis, the role of cyclooxygenase (COX) in steroid production and steroidogenic acute regulatory (StAR) gene expression was investigated. Although stimulation with 0.05 mm dibutyryl cAMP (Bt2cAMP) did not increase StAR protein or progesterone in MA-10 mouse Leydig cells, the addition of 1 μm of the COX inhibitor indomethacin increased StAR protein expression and progesterone production by 5.7-fold and 34.3-fold, respectively. In the presence of indomethacin, the level of Bt2cAMP required for maximal steroidogenesis was reduced from 1.0 mm to 0.25 mm. Similar results were obtained in studies on StAR promoter activity and in Northern blot analyses of StAR mRNA expression, suggesting that inhibition of COX activity enhanced StAR gene transcription. COX2 (an inducible isoform of COX) was constitutively detected in MA-10 cells. Although SC560, a selective COX1 inhibitor, did not affect steroidogenesis, the COX2 inhibitor NS398 significantly enhanced Bt2cAMP-stimulated StAR protein expression and steroid production. Overexpression of the COX2 gene in COS-1 cells significantly inhibited StAR promoter activity. The results of the present study suggest that inhibition of COX2 activity increases the sensitivity of steroidogenesis to cAMP stimulation in MA-10 Leydig cells.
17β-Estradiol Stimulates Arachidonate Release from Human Amnion-Like WISH Cells through a Rapid Mechanism Involving a Membrane Receptor
Authors: Fiorini Sara , Ferretti Maria E. , Biondi Carla , Pavan Barbara , Lunghi Laura , Paganetto Guglielmo , Abelli Luigi
Published: May 2003

17β-Estradiol (17β-E2) greatly and dose-dependently stimulates [3H]arachidonic acid (AA) release from the human amnion-like Wistar Institute Susan Hayflick (WISH) cells. This action is abolished by the phospholipase A2 inhibitor AACOCF3, significantly reduced by the estrogen receptor (ER) antagonist ICI 182,780, and uninfluenced by cycloheximide. The estradiol-BSA conjugate E2coBSA, which binds putative membrane ERs and is unable to enter the cell, also highly stimulates [3H]AA release from WISH cells, although to a lesser extent compared with 17β-E2. The fluorescent conjugate E2coBSA-FITC specifically binds to the surface of a subset of intact WISH cells, and labeling intensity appears dose and time dependent. Cell permeabilization results in a dense intracellular staining, mainly in the peripheral cytoplasm. H-150, an antibody against the N terminus of human ERβ, also labels the plasma membrane of intact WISH cells and the cytoplasm of permeabilized cells. Almost no labeling is observed using ER-21, an antibody against the N terminus of human ERα. RT-PCR evidences the presence of mRNA for ERβ, not for ERα. Our data suggest that 17β-E2 stimulates [3H]AA release from WISH cells through an apparently nongenomic pathway and interaction with membrane binding sites. These last are, at least in part, similar if not identical to ERβ.
Phosphorylation of Insulin-Like Growth Factor (IGF) Binding Protein-3 by Breast Cancer Cell Membranes Enhances IGF-I Binding
Authors: Mishra Suresh , Murphy Liam J.
Published: May 2003

Cross-linking of nonglycosylated biotinylated IGF binding protein (IGFBP)-3 to T-47D cell membranes identifies complexes with Mr of 32, 50, 70, and 100 kDa. Nonbiotinylated glycosylated IGFBP-3 competed for binding to each of these sites. The 32-kDa band approximated the size of intact nonglycosylated IGFBP-3, but its abundance was enhanced by cross-linking, and it had a more acidic isoelectric point on isoelectric focusing, suggesting that it had undergone phosphorylation. Immobilized IGFBP-3 was phosphorylated in the presence of 32P-γATP by both T-47D cell membranes and by intact cells treated with phenylarsine oxide to inhibit internalization. MCF-7 and COS-1 cells were also able to bind and phosphorylated IGFBP-3. IGF-I inhibited both IGFBP-3 binding to membranes and phosphorylation. However, incubation of T-47D cells with IGFBP-3 enhanced binding of 125I-IGF-I to the cell monolayer indicating that membrane bound IGFBP-3 was able to bind IGF-I. Immobilized IGFBP-3 when phosphorylated by T-47D membranes bound significantly more 125I-IGF-I than nonphosphorylated IGFBP-3. Treatment with alkaline phosphatase significantly reduced 125I-IGF-I binding to phosphorylated immobilized IGFBP-3 and also reduced 125I-IGF-I to T-47D cell monolayers preincubated with IGFBP-3. Phosphorylation of IGFBP-3 by T-47D membranes was partially blocked by inhibitors of both protein kinase A and C. These data demonstrate that binding of IGFBP-3 to breast cancer membranes is accompanied by phosphorylation at the plasma membrane and that both processes are inhibited by IGF-I. However, once phosphorylated the ability of IGFBP-3 to bind IGF-I is enhanced, resulting in increased association of the IGF-I with the cell membrane.
Cardiac Lipid Accumulation Associated with Diastolic Dysfunction in Obese Mice
Authors: Christoffersen Christina , Bollano Entela , Lindegaard Marie L. S. , Bartels Emil D. , Goetze Jens P. , Andersen Claus B. , Nielsen Lars B.
Published: May 2003

Obesity may confer cardiac dysfunction due to lipid accumulation in cardiomyocytes. To test this idea, we examined whether obese ob/ob mice display heart lipid accumulation and cardiac dysfunction. Ob/ob mouse hearts had increased expression of genes mediating extracellular generation, transport across the myocyte cell membrane, intracellular transport, mitochondrial uptake, and β-oxidation of fatty acids compared with ob/+ mice. Accordingly, ob/ob mouse hearts contained more triglyceride (6.8 ± 0.4 vs. 2.3 ± 0.4 μg/mg; P < 0.0005) than ob/+ mouse hearts. Histological examinations showed marked accumulation of neutral lipid droplets within cardiac myocytes but not increased deposition of collagen between myocytes in ob/ob compared with ob/+ mouse hearts. On echocardiography, the ratio of E to A transmitral flow velocities (an indicator of diastolic function) was 1.8 ± 0.1 in ob/ob mice and 2.5 ± 0.1 in ob/+ mice (P = 0.0001). In contrast, the indexes of systolic function and heart brain natriuretic peptide mRNA expression were only marginally affected and unaffected, respectively, in ob/ob compared with ob/+ mice. The results suggest that ob/ob mouse hearts have increased expression of cardiac gene products that stimulate myocyte fatty acid uptake and triglyceride storage and accumulate neutral lipids within the cardiac myocytes. The results also suggest that the cardiac lipid accumulation is paralleled by cardiac diastolic dysfunction in ob/ob mice.
Biological Activity of Activating Thyroid-Stimulating Hormone Receptor Mutants Depends on the Cellular Context
Authors: Fuhrer D. , Lewis M. D. , Alkhafaji F. , Starkey K. , Paschke R. , Wynford-Thomas D. , Eggo M. , Ludgate M. , Führer-Sakel Dagmar
Published: May 2003

Activating TSH receptor (TSHR) mutations are a major cause of toxic thyroid adenoma and familial hyperthyroidism, and more than 37 such mutations have been described. Previously their functional activity had been assessed in terms of cAMP and inositol phosphate production and predominantly in transiently transfected COS-7 (monkey embryonic kidney cells), a model that does not reflect effects on thyrocyte proliferation and function. Here we have performed a systematic comparison of wild-type and seven gain-of-function TSHR mutants, introduced into rat FRTL-5 and human thyrocytes, using retroviral vectors. Our results show that 1) biological potency of TSHR mutants in thyroid cells does not correlate with their cAMP levels in transfected COS cells, highlighting the importance of cellular context and level of expression when assessing biological effects of oncogenic mutations; 2) dissociation between stimulation of function and growth occurs with thyrocyte differentiated functions more readily stimulated than growth; 3) TSHR mutants show a similar order of potency in FRTL-5 cells and human thyrocytes; 4) mutants inducing the highest stimulation of adenylyl cyclase may paradoxically fail to induce proliferation; and 5) biological effects of cAMP activating TSHR mutants are attenuated by complex counterregulatory mechanisms at least at the level of phosphodiesterases and cAMP regulatory element modulator isoforms.
Retinal pigmented epithelium determination requires the redundant activities of Pax2 and Pax6
Authors: Bäumer Nicole , Marquardt Till , Stoykova Anastassia , Spieler Derek , Treichel Dieter , Ashery-Padan Ruth , Gruss Peter
Published: May 2003

The transcription factors Pax2 and Pax6 are co-expressed in the entire optic vesicle (OV) prior and concomitant with the establishment of distinct neuroretinal, retinal, pigmented-epithelial and optic-stalk progenitor domains, suggesting redundant functions during retinal determination. Pax2; Pax6 compound mutants display a dose-dependent reduction in the expression of the melanocyte determinant Mitf, accompanied by transdifferentiation of retinal pigmented epithelium (RPE) into neuroretina(NR) in Pax2-/-; Pax6+/- embryos,which strongly resembles the phenotype of Mitf-null mutants. In Pax2-/-; Pax6-/- OVs Mitffails to be expressed and NR markers occupy the area that usually represents the Mitf+ RPE domain. Furthermore, both, Pax2 and Pax6 bind to and activate a MITF RPE-promoter element in vitro,whereas prolonged expression of Pax6 in the Pax2-positive optic stalk leads to ectopic Mitf expression and RPE differentiation in vivo. Together,these results demonstrate that the redundant activities of Pax2 and Pax6 direct the determination of RPE, potentially by directly controlling the expression of RPE determinants.
TheC. elegansHand gene controls embryogenesis and early gonadogenesis
Authors: Mathies Laura D. , Henderson Samuel T. , Kimble Judith
Published: May 2003

The C. elegans genome encodes a single Hand bHLH transcription factor. Either hnd-1(RNAi) or a hnd-1 deletion causes partially penetrant defects in viability and gonadogenesis. Dead embryos and young larvae are often misshapen at the posterior end. Our primary focus has been the role of hnd-1 in gonadogenesis. Wild-type C. elegans has two somatic gonadal precursors and two primordial germ cells in stereotyped positions within its four-celled gonadal primordium. The hnd-1 gene affects the presence and position of both the somatic gonadal precursors and primordial germ cells within the primordium, but does not appear to have any role in later gonadogenesis. hnd-1 probably acts within the somatic gonadal precursors or their mesodermal predecessors;defects in primordial germ cells and germ line appear to be secondary. In hnd-1 mutants, somatic gonadal precursors are generated normally, but are not maintained properly and sometimes die. A similar role in controlling the maintenance of precursor fates has been described for other genes governing early organogenesis, including the zebrafish Hand gene hands off. We also report the discovery of two genes, ehn-1 and ehn-3, that have overlapping functions with hnd-1 in embryogenesis and gonadogenesis.
Myogenic cells fates are antagonized by Notch only in asymmetric lineages of theDrosophilaheart, with or without cell division
Authors: Han Zhe , Bodmer Rolf
Published: May 2003

During the formation of the Drosophila heart, a combinatorial network that integrates signaling pathways and tissue-specific transcription factors specifies cardiac progenitors, which then undergo symmetric or asymmetric cell divisions to generate the final population of diversified cardiac cell types. Much has been learned concerning the combinatorial genetic network that initiates cardiogenesis, whereas little is known about how exactly these cardiac progenitors divide and generate the diverse population of cardiac cells. In this study, we examined the cell lineages and cell fate determination in the heart by using various cell cycle modifications. By arresting the cardiac progenitor cell divisions at different developing stages, we determined the exact cell lineages for most cardiac cell types. We found that once cardiac progenitors are specified, they can differentiate without further divisions. Interestingly, the progenitors of asymmetric cell lineages adopt a myocardial cell fate as opposed to a pericardial fate when they are unable to divide. These progenitors adopt a pericardial cell fate,however, when cell division is blocked in numb mutants or in embryos with constitutive Notch activity. These results suggest that a numb/Notch-dependent cell fate decision can take place even in undivided progenitors of asymmetric cell divisions. By contrast, in symmetric lineages, which give rise to a single type of myocardial-only or pericardial-only progeny, repression or constitutive activation of the Notch pathway has no apparent effect on progenitor or progeny fate. Thus, inhibition of Notch activity is crucial for specifying a myogenic cell fate only in asymmetric lineages. In addition, we provide evidence that whether or not Suppressor-of-Hairless can become a transcriptional activator is the key switch for the Numb/Notch activity in determining a myocardial versus pericardial cell fate.
pannierandpointedP2act sequentially to regulateDrosophilaheart development
Authors: Alvarez Alejandra D. , Shi Weiyang , Wilson Beth A. , Skeath James B.
Published: May 2003

The Drosophila heart consists of two major cell types:cardioblasts, which form the contractile tube of the heart; and pericardial cells, which flank the cardioblasts and are thought to filter and detoxify the blood or hemolymph of the fly. We present the completion of the entire cell lineage of all heart cells. Notably, we detect a previously unappreciated distinction between the lineages of heart cells located in the posterior seven segments relative to those located more anteriorly. Using a genetic screen, we have identified the ETS-transcription factor pointed as a key regulator of cardioblast and pericardial cell fates in the posterior seven segments of the heart. In this domain, pointed promotes pericardial cell development and opposes cardioblast development. We find that this function of pointed is carried out primarily if not exclusively by the pointedP2 isoform and, that in this context, pointedP2may act independently of Ras/MAPK pathway activity. We go on to show that the GATA transcription factor pannier acts early in dorsal mesoderm development to promote the development of the cardiac mesoderm and thus all heart cells. Finally, we demonstrate that pannier acts upstream of pointed in a developmental pathway in which pannier promotes cardiac mesoderm formation, and pointed acts subsequently in this domain to distinguish between cardioblast and pericardial cell fates.
Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth
Authors: Yu Kai , Xu Jingsong , Liu Zhonghao , Sosic Drazen , Shao Jiansu , Olson Eric N. , Towler Dwight A. , Ornitz David M.
Published: May 2003

Human craniosynostosis syndromes, resulting from activating or neomorphic mutations in fibroblast growth factor receptor 2 (FGFR2), underscore an essential role for FGFR2 signaling in skeletal development. Embryos harboring homozygous null mutations in FGFR2 die prior to skeletogenesis. To address the role of FGFR2 in normal bone development, a conditional gene deletion approach was adopted. Homologous introduction of cre recombinase into the Dermo1 (Twist2) gene locus resulted in robust expression of CRE in mesenchymal condensations giving rise to both osteoblast and chondrocyte lineages. Inactivation of a floxed Fgfr2 allele with Dermo1-cre resulted in mice with skeletal dwarfism and decreased bone density. Although differentiation of the osteoblast lineage was not disturbed,the proliferation of osteoprogenitors and the anabolic function of mature osteoblasts were severely affected.
Epidermal patterning genes are active during embryogenesis in Arabidopsis
Authors: Costa Silvia , Dolan Liam
Published: May 2003

Epidermal cells in the root of Arabidopsis seedling differentiate either as hair or non-hair cells, while in the hypocotyl they become either stomatal or elongated cells. WEREWOLF (WER) and GLABRA2 (GL2) are positive regulators of non-hair and elongated cell development. CAPRICE (CPC) is a positive regulator of hair cell development in the root. We show that WER, GL2and CPC are expressed and active during the stages of embryogenesis when the pattern of cells in the epidermis of the root-hypocotyl axis forms. GL2 is first expressed in the future epidermis in the heart stage embryo and its expression is progressively restricted to those cells that will acquire a non-hair identity in the transition between torpedo and mature stage. The expression of GL2 at the heart stage requires WERfunction. WER and CPC are transiently expressed throughout the root epidermal layer in the torpedo stage embryo when the cell-specific pattern of GL2 expression is being established in the epidermis. We also show that WER positively regulates CPC transcription and GL2 negatively regulates WER transcription in the mature embryo. We propose that the restriction of GL2 to the future non-hair cells in the root epidermis can be correlated with the activities of WER and CPC during torpedo stage. In the embryonic hypocotyl we show that WER controls GL2 expression. We also provide evidence indicating that CPC may also regulate GL2 expression in the hypocotyl.