bluuebunny/crossref_metadata_2025 huggingface dataset:
The American College of Rheumatology criteria for the classification of systemic lupus erythematosus: Strengths, weaknesses, and opportunities for improvement
Authors: Smith E L , Shmerling R H
Published: November 2003

The American College of Rheumatology classification criteria were developed to operationalize the definition of systemic lupus erythematosus (SLE) to allow comparison of clinical research from different centers, but also serve to facilitate education and to guide clinical practice. The classification criteria have been critical to research, but should be viewed as a temporary step until improved understanding of the pathogenesis of SLE emerges. Criteria have inherent limitations, including bias towards more severe and longer duration disease, equal weighting of features that vary in clinical significance, and exclusion of patients with SLE from research because they do not meet criteria. For some SLE research questions, it may be appropriate to include patients diagnosed with SLE who do not meet criteria, if these patients' manifestations and criteria are documented explicitly. SLE disease activity, cumulative organ damage, disease duration, criteria ever met, and criteria met at time of enrollment are important data that should be presented in clinical studies of SLE regardless of the number of criteria met. The criteria should be reevaluated periodically, utilizing patients and controls with a range of diseases and disease severity. A simplified weighting system may more accurately reflect clinical practice.
Sample size considerations for superiority trials in systemic lupus erythematosus (SLE)
Authors: Moore Andrew D , Joseph Lawrence
Published: November 2003

For reasons of efficiency and ethics, sample size calculations are an important part of the design of all clinical trials. This paper highlights the statistical issues inherent to the estimation of sample size requirements in superiority trials particular to SLE. Calculations based on statistical power for testing hypotheses have historically been the method of choice for sample size determination in clinical trials. The advantages of using confidence intervals (CI's) rather than P-values in reporting results of clinical trials is now well established. Since the design of a trial should match the analysis that will eventually be performed, sample size methods based on ensuring accurate estimation of important parameters via sufficiently narrow CI widths should be preferred to methods based on hypothesis testing. Methods and examples are given for sample size calculations for continuous and dichotomous outcomes from both a power and confidence interval width viewpoint. An understanding of sample size calculations in association with expert statistical consultation will result in better designed clinical trials that accurately estimate clinically relevant differences between treatment outcomes, thereby furthering the treatment of patients with SLE.
Ensuring reliability of clinical assessments for SLE trials
Authors: Ramsey-Goldman Rosalind , Hayes Karen W
Published: November 2003

Conducting clinical trials in lupus presents unique challenges for the investigator. Since reliable data are crucial for precisely evaluating results, strategies must be in place to ensure that outcome assessments are accurate and consistent throughout a study. This paper reviews reliability in clinical research and specifically with lupus outcome measures. Suggested recommendations for ensuring reliability in lupus trials are provided.
Discordance between patients and their physicians in the assessment of lupus disease activity: relevance for clinical trials
Authors: Yen Jim C , Neville Carolyn , Fortin Paul R
Published: November 2003

Discordance between patient and physician assessment of lupus activity occurs frequently and its determinants are not known. Examples of discordance between patients and physicians in other disease models can be found in the literature. A better understanding of the discordance between patients and physicians can help us achieve a shared decision-making model of health care, improve patient satisfaction, improve patient compliance, and improve physician understanding of how lupus impacts on their patients. Understanding discordance also impacts on the design and interpretation of clinical trials.
Recruitment strategies in superiority trials in SLE: lessons from the study of methotrexate in lupus erythematosus (SMILE)
Authors: Ferland Diane , Fortin Paul R
Published: November 2003

The task of recruiting patients for a research project can prove to be the most difficult aspect of the entire research process. A large portion of the work of research is devoted to the identification of strategies which ensure a successful recruitment of patients. Every researcher has learned from experience the many methods needed to enhance patient enrollment into trials. Superiority trials in SLE have not been frequent in previous years. This paper describes the challenges encountered with the multicentre SMILE trial in progress across Canada. We identify areas where patient recruitment is a problem, potential reasons for the problem, and the results of tactics used to increase enrollment.
Proving non-inferiority or equivalence of two treatments with dichotomous endpoints using exact methods
Authors: Chan I SF
Published: November 2003

Since the early work of RA Fisher, exact methods have been recognized as important tools in data analysis because they provide valid statistical inference even with small sample sizes, or with sparse or skewed data. With the recent advance of computational power and the availability of commercial software packages, exact methods have gained substantial popularity over the past two decades. However, most of these exact methods have been devoted to testing classical null hypotheses of no differences, and until recently little was known about exact methods dealing with non-inferiority or equivalence hypotheses. The presence of nuisance parameters in testing non-inferiority/equivalence hypotheses presents a special challenge for exact methods because of the intense computational requirement. In this paper, we review exact methods available for proving non-inferiority or equivalence of two treatments with a dichotomous endpoint. First, we present the general methodology for conducting exact tests for non-inferiority or equivalence; we then discuss several unconditional and conditional methods available for constructing hypothesis tests and confidence intervals based on three commonly used measures, namely, the difference, relative risk, and odds ratio of two independent proportions or rates. Finally, we illustrate with several examples the application of these exact methods in analysing and planning non-inferiority or equivalence trials.
Power and sample size for ordered categorical data
Authors: Rabbee N , Coull B A , Mehta C , Patel N , Senchaudhuri P
Published: November 2003

We propose a new method for computing power and sample size for linear rank tests of differences between two ordered multinomial populations. The method is flexible in that it is applicable to any general alternative hypothesis and for any choice of rank scores. We show that the method, though asymptotic, closely approximates existing exact methods. At the same time it overcomes the computational limitations of the exact methods. This advantage makes our asymptotic approach more practical for sample size computations at the planning stages of a large study. We illustrate the method with data arising from both proportional and non-proportional odds models in the two ordered multinomial setting.
Detecting activation in fMRI data
Authors: Worsley K J
Published: November 2003

We present a simple approach to the analysis of fMRI data collected from several runs, sessions and subjects. We take advantage of the spatial nature of the data to reduce the noise in certain key parameters, achieving an increase in degrees of freedom for a mixed effects analysis. Our main interest is the analysis of the resulting images of test statistics using the geometry of random fields. We show how the Euler characteristic of the excursion set plays a key role in setting the threshold of the image to detect regions of the brain activated by a stimulus.
Controlling the familywise error rate in functional neuroimaging: a comparative review
Authors: Nichols Thomas , Hayasaka Satoru
Published: November 2003

Functional neuroimaging data embodies a massive multiple testing problem, where 100 000 correlated test statistics must be assessed. The familywise error rate, the chance of any false positives is the standard measure of Type I errors in multiple testing. In this paper we review and evaluate three approaches to thresholding images of test statistics: Bonferroni, random field and the permutation test. Owing to recent developments, improved Bonferroni procedures, such as Hochberg’s methods, are now applicable to dependent data. Continuous random field methods use the smoothness of the image to adapt to the severity of the multiple testing problem. Also, increased computing power has made both permutation and bootstrap methods applicable to functional neuroimaging. We evaluate these approaches on t images using simulations and a collection of real datasets. We find that Bonferroni-related tests offer little improvement over Bonferroni, while the permutation method offers substantial improvement over the random field method for low smoothness and low degrees of freedom. We also show the limitations of trying to find an equivalent number of independent tests for an image of correlated test statistics.
What can modern statistics offer imaging neuroscience?
Authors: Lange Nicholas
Published: November 2003

This paper presents a mixed-effects model, region-of-interest analysis of a longitudinal functional magnetic resonance imaging (fMRI) study of drug effects on human memory function. A key region of interest is the human hippocampus, affected by brain disorders such as Alzheimer’s disease and schizophrenia. A brief section on human hippocampal cell microscopy complements the discussion of the macroscopic fMRI study. Statistical issues confronted in these two applications are then placed in a broader context for further discussion of the future roles of biostatisticians and our methods in the fertile intersection of applied mathematical abstraction and imaging neuroscience. Neuroscientific and fMRI background is provided for readers new to either area.
Are our data symmetric?
Authors: Mandrekar Sumithra J , Mandrekar Jayawant N
Published: November 2003

Skewness indicates a lack of symmetry in a distribution. Knowing the symmetry of the underlying data is essential for parametric analysis, fitting distributions or doing transformations to the data. The coefficient of skewness is the commonly used measure to identify a lack of symmetry in the underlying data, although graphical procedures can also be effective. We discuss three different methods to assess skewness: traditional coefficient of skewness index, skewness index based on the L-moments discussed by Hosking and the asymptotic test of symmetry developed by Randles et al. With this work, we provide easy-to-implement S-PLUS functions as well as discuss the advantages and shortcomings of each technique.
Comparison of methods to identify outliers observed in health services small area variation studies
Authors: To Teresa , Williams J Ivan , Wu Keyi , Theriault Marc-Erick , Goel Vivek
Published: November 2003

Small area variation analysis (SAV) is an established methodology in health services and epidemiological research. The goal is to demonstrate that rates differ across areas, and to explain these differences by differences in physician practice styles or patient characteristics. While the SAV statistics provide an overall variation estimate, they do not provide a statistical means to identify significant outliers. We compared the chi-square (ϰ2) test with three approaches in determining significant outliers in SAV. We used data from the Canadian Institute for Health Information (CIHI) for Ontario residents discharged between 1989 and 1991. Coronary artery bypass surgery, hysterectomy and hip replacement data were used to compare four statistics in determining outliers: the ϰ2 test, Swift’s approximate bootstrap confidence interval (ABC), Carriere’s T2(T2) with simultaneous confidence intervals (SCI), and Gentleman’s normalized scores (GNS). Both the ABC and SCI correct the skewness of the distribution of the adjusted rates. With large data, confidence intervals calculated by the normal or the ABC methods are indistinguishable. The T2 can be applied to also nonbinary events. For binary events, it is asymptotically the same as the ϰ2. The GNS ranks the rates, but the distribution of these ranks does not differ significantly from that of the adjusted rates. We concluded that when using large data with binary events, there is little advantage in using the ABC, SCI or GNS over the commonly known ϰ2. The ϰ2 remains a useful tool in small area variation analysis to ‘screen’ or ‘ag potential differences beyond chance alone.
Equipping Leviathan: Ordnance Factories of British India, 1859-1913
Authors: Roy Kaushik
Published: November 2003

The ordnance establishment of British India was rightly regarded as the fourth arm of defence by the British. Especially after the 1857 mutiny, they understood that fire-power generated by the artillery and advanced small arms actually led to victory against numerically superior ‘rebels’. Instead of depending on imports from Britain, which were not only time-consuming, but costly and also intermittent, the colonial state decided to lay the foundation of an industrial base for manufacturing military stores. This was in anticipation of future military threats.

Neverthless, several factors hampered the expansion and modernization of the arms and munitions factories. This article, based on some hitherto unused sources, is the first attempt to chart the evolution of the ordnance factories until the Great War.
A Study of the Ethical Sensitivity of Physicians in Turkey
Authors: Ersoy Nermin , Gündoğmuş Ümit N
Published: November 2003

In order to prepare bioethics and clinical ethics courses for clinicians in Turkey, we needed to know the attitudes of physicians when placed in ethically difficult care situations. We presented four cases to 207 physicians who are members of the Physicians’ Association in Kocaeli, Turkey. Depending on the decisions they made in each case, we determined whether they were aware of the ethical aspects of the cases and the principles they chose as a basis for their decisions. We aimed to gain information about their ethical tendencies and moral sensitivity.

A small number of physicians stated that they would ‘show respect for a patient’s living will’ in the first case, but more stated that they would ‘let the patient refuse the treatment’ in the second. In the third case, where medical confidentiality was the significant ethical issue, most of the physicians said that they would act in order to maintain confidentiality. For the last case, more than half the physicians chose to ‘tell the truth’ to the patient. The paternalism shown in the doctors’ decisions on the first two cases was no longer observed in those made for the last two cases. We concluded that the physicians who participated in our study have low sensitivity to living wills (or advance directives) and patients refusing treatment. However, when issues of medical confidentiality and truth-telling are concerned, they take care to protect the autonomy of the individual and are relatively more aware of the ethical aspects of these cases.
Ethical Issues in Adolescent Consent for Research
Authors: Lind Candace , Anderson Beverly , Oberle Kathleen
Published: November 2003

Different opinions are expressed in the literature regarding when children and adolescents can start to make decisions to participate in research and give informed consent. Nurses are frequently involved in research, either as investigators or caregivers, and must therefore have a thorough understanding of consent and related issues. In this article the issues are explored from a Canadian perspective. The argument is put forward that adolescents may be capable of a greater involvement in the research consent process than is the norm. Increasing adolescents’ involvement in research has the potential to enhance their growing autonomy and capabilities. Adolescents appreciate being treated with respect and dignity by adults. This can be achieved in an environment in which protection from harm does not also mean prevention from decision making. The use of empowering processes by nurses to enhance adolescent involvement will provide benefit to adolescents in their transition to adult levels of responsibility.
In the Company of Women: enacting autonomy within the perinatal nursing relationship
Authors: Goldberg Lisa
Published: November 2003

An understanding of autonomy has important significance in North American health care. Although a respect for autonomy is necessary to protect the self-determination and agency of birthing women in hospital settings, I suggest that enactments of autonomy that are independent of relationships offer only an incomplete interpretation of such a vital concept. In this article I explore an understanding of autonomy situated within the context of a relational birthing narrative. In so doing, autonomy becomes conceptualized as contextual and concrete, giving rise to an embodied view of the birthing woman.
Struggling to Become Ready for Consolation: experiences of suicidal patients
Authors: Talseth Anne-Grethe , Gilje Fredricka , Norberg Astrid
Published: November 2003

Although there has been a vast amount of research about suicide, very few studies focus on the inner world of the suicidal patient. A secondary analysis of two exemplar narrative interviews with Norwegian patients reveals a glimpse of the inner world of suicidal patients’ longing for consolation. The results of a phenomenological hermeneutic study inspired by Ricoeur’s philosophy reveal five themes and one main theme. The themes are: ‘longing for closeness’, ‘desiring connectedness’, ‘struggling to open up inner dialogue’, ‘breaking into outer dialogue’, and ‘liberating inner and outer dialogue’. The main theme is ‘struggling to become ready for consolation’. These results describe a process of becoming ready for consolation, which, when interpreted in the light of the model of consolation by Norberg et al., reveals that the end of the process of becoming ready for consolation is consolation itself as praxis.
Korean Nursing Students’ Ethical Problems and Ethical Decision Making
Authors: Park Hyeoun-Ae , Cameron Miriam E , Han Sung-Suk , Ahn Sung-Hee , Oh Hyo-Sook , Kim Kyeong-Uoon
Published: November 2003

This Korean study replicated a previously published American study. The conceptual framework and method combined ethical enquiry and phenomenology. The research questions were: (1) What is nursing students’ experience of ethical problems involving nursing practice? and, (2) What is nursing students’ experience of using an ethical decision-making model? The participants were 97 senior baccalaureate nursing students, each of whom described one ethical problem and chose to use one of five ethical decision-making models. From 97 ethical problems, five content categories emerged, the largest being health professionals (69%). The basic nature of the ethical problems was the students’ experience of conflict, resolution and rationale. Using an ethical decision-making model helped 94% of the students. A comparison of the Korean and American results yields important implications for nursing ethics education, practice and research.
The Ethics of Nurse Poaching from the Developing World
Authors: Singh Jerome A , Nkala Busi , Amuah Eric , Mehta Nalin , Ahmad Aasim
Published: November 2003

Recruiting nurses from other countries is a long-standing practice. In recent years many countries in the developed world have more frequently recruited nurses from the developing world, causing an imbalance in the health services in often already impoverished countries. Despite guidelines and promises by developed countries that the practice should cease, it has largely failed to do so. A consortium of authors from countries that have experienced significant nurse poaching consider the ethical aspects behind this continuing practice.
Palmar-plantar erythrodysesthesia
Authors: Gilbar Peter
Published: November 2003

Objective. To provide a comprehensive review of the chemotherapy induced dermatological toxi-city, palmar-plantar erythrodysesthesia (PPE), including clinical presentation, drugs implication in causing the reaction, and approaches for management.

Data sources. A search of MEDLINE (1966-2002), IDIS (1985- 2002) and CANCERLIT (1993-2002) databases was conducted using the terms (and variations of the terms) palmar-plantar erythrodysesthesia, hand-foot syndrome, and acral erythema. Bibliographies from selected articles were also reviewed for appropriate references.

Data extraction. The retrieved literature was reviewed to include all articles pertaining to the incidence, clinical presentation, mechanism, pathology, diagnosis, treatment and prevention of PPE.

Data synthesis. PPE is a distinctive, localized cutaneous reaction to certain antineoplastic agents. A number of drugs have been implicated, including most commonly cytarabine, fluorouracil, doxorubicin, and capecitabine. There appears to be an association with administration schedules that lead to elevated peak plasma concentrations, such as in high-dose therapy, or after prolonged periods of constant exposure, as with continuous infusions, regular oral dosing, or liposomal formulations. The extent and severity of the reaction, time of onset, and duration are variable. Symptoms can occur to both hands and feet, and include dysesthesia, paresthesia, erythema, swelling, pain, blistering, ulceration, and desquamination. Cessation of the offending agent appears to be the most important step in the management of PPE. Dose modification may be necessary for subsequent cycles. As the course of PPE is self-limiting, treatment is commonly supportive and based on the type and severity of symptoms encountered. This can include analgesia, emollient or soothing creams, wound care, and cold compresses. Administration of corticosteroids has produced mixed results. Pyridoxine shows promise as both a treatment and preventative strategy, although confirmation in prospective clinical trials is needed. Advice should be provided to patients to ensure prompt recognition of toxicity and plans for prevention and amelioration of symptoms provided.
Gefitinib (ZD1839, Iressa®): a selective epidermal growth factor receptor-tyrosine kinase inhibitor
Authors: Shah Sachin R , Walsh Tracey L , Williams Casey B , Soefje Scott A
Published: November 2003

Objective: To provide a comprehensive review of the clinical pharmacology and toxicology of gefitinib, with particular attention to its use in early clinical trials.

Data source: A PubMed search was conducted using the terms ZD1839, gefitinib, and epidermal growth factor receptor (EGFR). All data from this search were reviewed and other relevant papers identified. The abstracts from the annual meetings of the American Society of Clinical Oncology were also reviewed.

Data extraction: The aim of the review was to be comprehensive and descriptive. The authors reviewed studies and case reports containing information deemed to be of interest.

Conclusions: EGFR is expressed, overex-pressed, or disregulated in a variety of human solid tumors, resulting in an enhancement of tumor growth. Gefitinib is a selective reversible inhibitor of EGFR that has shown activity in several tumor types. As an oral agent, it is extensively metabolized in the liver through the cytochrome P450 enzyme system, particularly the isoenzyme CYP3A4. In the phase II, IDEAL 1 and 2 trials, gefitinib has shown a response rate of 8.8% -18.4% in refractory lung cancer. Clinical trials in various other nonlung cancer patients include studies of gefitinib as a monotherapy or in combination with various chemotherapy, radiation, and/or hormone therapy regimens. Skin and gastrointestinal toxi-cities are the most frequent adverse events of gefitinib. Recently, interstitial pneumonia has emerged as one of the serious adverse effects among gefitinib patients. In summary, the role of gefitinib in combination or as a monotherapy for a variety of cancers is still evolving.
C onversion to multiple sclerosis after a clinically isolated syndrome of the brainstem: cranial magnetic resonance imaging, cerebrospinal fl uid and neurophysiological findings
Authors: Sastre-Garriga J , Tintoré M , Rovira A , Grivé E , Pericot I , Comabella M , Thompson A J , Montalban X
Published: November 2003

B ackground and aim: C onversion to multiple sclerosis (MS) after optic neuritis and myelitis has been thoroughly studied; however, limited data are available regarding conversion to MS after a clinically isolated syndrome of the brainstem (CISB). The aim of this study was to investigate conversion to MS in patients with C ISB. Methods: Fifty-one patients with C ISB were prospectively studied. C ranial magnetic resonance imaging (MRI), determination of oligoclonal bands (OBs) in the cerebrospinal fluid (C SF) and evoked potentials (EPs) were performed. Based on conversion to MS at follow-up, the sensitivity, specificity, accuracy and positive and negative predictive values of these tests were calculated. Results: C linically definite MS developed in 18 (35%) patients after a mean follow-up of 37 months. Paty’s MRI criteria showed a sensitivity of 89%, a specificity of 52% and an accuracy of 65%; Fazekas’ criteria showed a sensitivity of 89%, a specificity of 48% and an accuracy of 63%; Barkhof’s criteria showed a sensitivity of 78%, a specificity of 61% and an accuracy of 67%. The presence of O Bs in the C SF showed a sensitivity of 100%, a specificity of 42% and an accuracy of 63%. No differences for neurophysiological parameters were found between patients who did and those who did not convert to MS. C onclusion: Fulfilling Paty’s, Fazekas’ or Barkhof’s MRI criteria and the presence of O Bs in the C SF are associated with a higher risk of conversion to MS in patients with C ISB. Determinatio n of O Bs in the C SF has the greatest sensitivity of all tests. Barkhof’s MRI criteria have greater specificity (although less than previously published for mixed cohorts of clinically isolated syndromes) in predicting conversion to MS for C ISB than either Paty’s or Fazekas’ criteria.
Screening for multiple sclerosis cognitive impairment using a self-administered 15-item questionnaire
Authors: Benedict R HB , Munschauer F , Linn R , Miller C , Murphy E , Foley F , Jacobs L
Published: November 2003

Since there is a need for cost-effective screening techniques to identify neuropsychological impairment in multiple sclerosis (MS) patients, and because existing methods require cognitive testing with subsequent interpretation by a neuropsychologist, a brief self-report procedure was developed to screen for neuropsychological impairment in MS. In the first phase of the study, a pool of 80 items was generated based on a literature review and consultation with healthcare professionals. The set was reduced to 15 via Rasch analysis. Using these items, a brief (five minute) MS Neuropsychological Screening Q uestionnaire (MSNQ), including patient- and informant-report forms, was composed. In phase II, 50 MS patients and their caregivers completed the MSNQ. A comprehensive neuropsychological test battery was also administered. A nalyses covered the reliability of the MSNQ and correlations between both patient- and informant-report scores and objective neuropsychological testing. C ronbach’s a coefficients were 0.93 and 0.94 for the patient- and informant-report forms, respectively, and both forms of the test were strongly correlated with a more general cognitive complaints questionnaire. The patient MSNQ form correlated significantly with measures of depression but not with objective tests of cognitive function. In contrast, the informant form was correlated with patient cognitive performance but not depression. A cut-off score of 27 on the informant form of the MSNQ optimally separated patients based on a neuropsychological summary score encompassing measures of processing speed and memory. There were two false-negatives and one false-positive, giving the test a sensitivity of 0.83 and a specificity of 0.97. It is concluded, therefore, that this self-administered neuropsychological screening test is reliable and predicts neuropsychological impairment in MS patients with a reasonable degree of accuracy.
Intention tremor during manual aiming: a study of eye and hand movements
Authors: Feys P , Helsen W F , Lavrysen A , Nuttin B , Ketelaer P
Published: November 2003

A ccurate goal-directed movements toward a visual target require a precise coordination of both the oculomotor and limb motor systems. Intentio n tremor and eye movement deficits are frequently observed in multiple sclerosis (MS). The goal of this study was to examine the characteristics of intentio n tremor and simultaneously produced eye movements during rapid goal-directed movements. Eye and hand movements were synchronously measured in 16 MS patients with intentio n tremor and 16 control subjects. Manual performances of the patient group were character ized by a delayed onset, slower executio n and aiming inaccuracies. In line with the clinically defined picture of intention tremor, differences between patients and control subjects were most pronounced toward the end of the movement. Dependent variables were obviously greater in MS patients compared with control subjects, and correlated well with clinical outcome measures. The application of an inertial load to the limb did not show any effect on intention tremor. In addition to impaired limb coordination, evidence has been found that eye movements, too, were abnormal in patients compared with control subjects. Moreover, eye and hand movement deficits seemed to be closely related, suggesting a common underlying command structure. Inaccurate eye movements were likely to hamper an accurate motor performance of the hand.
Horizontal monocular saccadic failure: an unusual clinically isolated syndrome progressing to multiple sclerosis
Authors: Frohman Elliot M , Frohman Teresa C
Published: November 2003

This paper describes an unusual clinically isolated syndrome of inflammatory demyelination that was characterized by a right VI nerve palsy and right internuclear ophthalmoparesis (INO), along with an unusual form of dissociated nystagmus. Magnetic resonance imaging (MRI) revealed an isolated lesion within the right dorsomediolateral pontine tegmentum. Four years later, the subject developed a partial sensory transverse myelitis, confirming clinically definite multiple sclerosis (MS). This paper extends the range of isolated syndromes associated with MS.
A ntibodies against a human endogenous retrovirus and the preponderance of env splice variants in multiple sclerosis patients
Authors: Christensen T , Sørensen P D , Hansen H J , Møller-Larsen A
Published: November 2003

The human endogenous retrovirus HERV-H is associated with multiple sclerosis (MS). Previously performed reverse transcriptase-polymerase chain reactio ns (RT-PC R) on virion-RNA demonstrated sequence variants of the HERV-H family located in the particulate fraction of MS patient plasma samples and not in controls. In this study a significantly elevated level of antibodies towards peptides derived from HERV-H/RGH-2 DNA sequences in serum and cerebrospinal fluid (C SF) from MS patients is demonstrated. Further, Wistar rats immunized with purified virions develop a specific serologic response, indicating that some virion proteins are encoded by HERV-H-related sequences. A lso shown is that in RNA from blood cells, a HERV-H protease-env splice variant can be found together with an env splice variant in about 40% of MS patients but only in 10% of controls. The results substantiate the association between activated HERV-H and MS, but a causal relationship is yet to be demonstrated. HERV-H could represent a causal factor either by eliciting an autoimmune response or through the pathogenic potential of the retrovirus itself.
C erebral atrophy and disability in relapsing-remitting and secondary progressive multiple sclerosis over four years
Authors: Turner Benjamin , Lin Xia , Calmon Guillaume , Roberts Neil , Blumhardt Lance D
Published: November 2003

Pathology and magnetic resonance imaging (MRI) studies have provided evidence of widespread axonal loss and reductio ns of cerebral and spinal cord volume in multiple sclerosis (MS). A trophy measures on MRI may be a useful surrogate marker of worsening disability in MS, but the published studies are of relatively short duration. C hange in brain volume (atrophy) was measured over a four-year period in 20 patients with relapsing-remitting (RR) and 18 with secondary progressive (SP) MS using three-dimensional (3D) MRI acquired during treatment trials of interferon-beta-1a (Rebif®). Brain parenchymal and lateral ventricle volume changes were determined and correlated with clinical measures. O ver four years, brain parenchymal volume (BPV) decreased in RRMS and SPMS patients by 0.9% (P-0.006) and 0.3% (P-0.118), respectively, and the lateral ventricle volumes increased by 15% (P-0.0001) and 13% (P-0.0001), respectively. In RRMS patients both lateral ventricle volume (r-0.63, P-0.004) and BPV change (r-/0.47, P-0.037) were related to disability change, as measured by the Expanded Disability Status Scale. Even though a small study and despite the possible confounding effects of interferon treatment, this study demonstrated an association between measures of cerebral atrophy and worsening disability. The data also provides evidence that brain atrophy can be detected early in the disease course and central white matter atrophy as reflected by ventricle enlargement appears to be a continuous process.
Development and validation of a self-efficacy measure for people with multiple sclerosis: the Multiple Sclerosis Self-efficacy Scale
Authors: Rigby S A , Domenech C , Thornton E W , Tedman S , Young C A
Published: November 2003

The aim of this study is to develop and validate a brief measure of self-efficacy specifically for use with people with multiple sclerosis (MS). Self-efficacy is the subjective belief that one can overcome challenges that one is faced with. In order to incorporate the subjective experiences of individuals with MS, a ‘patient-fo cused’ methodology has been adopted. O pen-ended interviews were used to generate potential scale items. Items were piloted on an initial sample of individuals with MS and reduced to 14 items on the basis of their perceived relevance to this patient group. The final 14-item scale was then used with a further 142 individuals in order to assess its psychometric properties. The scale demonstrated high internal consistency (C ronbach’s alpha-0.81) and test-retest reliability (r-0.81, P-0.001) and acceptable validity. Issues concerning the assessment of validity are discussed in terms of the scale’s relevancy to individuals with MS and the theoretical issues around the construct of self-efficacy. The scale has shown sensitivity to detect change following a brief therapeutic intervention, with an effect size of 0.502. This MS Self-efficacy Scale could, therefore, be a useful tool in the assessment of psychological adjustment and quality-of-life of individuals with MS.
Correlation of sexual dysfunction and brain magnetic resonance imaging in multiple sclerosis
Authors: Zorzon M , Zivadinov R , Locatelli L , Stival B , Nasuelli D , Bratina A , Bosco A , Tommasi M A , Pozzi Mucelli R S , Ukmar M , Cazzato G
Published: November 2003

Sixty-two patients (40 women and 22 men) with multiple sclerosis (MS) were examined with 1.5 tesla magnetic resonance imaging (MRI) of the brain. Information on sexual and sphincteric disturbances has been collected, and data on disability, independence, cognitive performances and psychological functioning have been assessed. C alculations of T1- and T2-lesion load (LL) of total brain, frontal lobes and pons have been performed using a reproducible semiautomated technique. Whole brain, frontal and pontine atrophies were estimated using a normalized measure, the brain parenchymal fraction (BPF), obtained with a computerized interactive program. When comparing patients with and without sexual dysfunction (SD), there were no differences in total brain, frontal and pontine T1- and T2-LL, as well as in measures of whole brain and frontal atrophy. The only significant difference was in the pontine BPF (P-0.026). In linear multiple regression analysis, SD was associated with depression (R-0.56, P-0.001) and, after adjusting for depression and anxiety, with bladder dysfunction (R-0.43, P-0.003) and pontine BPF (R-0.56, P-0.001). No association between SD and any of the measures of T1- and T2-LL was found. The findings showed a relationship between SD and pontine atrophy, confirmed the correlation of SD with bladder dysfunction and highlighted the role of psychological factors in determining SD.
Multiple sclerosis: report on 200 cases from Iran
Authors: Kalanie Hossein , Gharagozli Kurosh , Kalanie Amir Reza
Published: November 2003

C linical findings of 200 patients in Iran with definite multiple sclerosis (MS) according to Poser et al.’s criteria and positive findings on magnetic resonance imaging (MRI) have been reviewed. The clinical course was relapsing-remitting (RR) for 88%, primary progressive (PP) for 7% and secondary progressive (SP) for 5% of cases. The mean age of onset was 27±7.4 years for the whole group and 37.1±8.8 years for PPMS. The gender ratio was 2.5:1 female:male. Involvement of the pyramidal system was the most common mode of presentation. Five per cent of patients had positive family history for the disease, 14% of patients had benign MS and 12% with disease duration longer than five years had an Expanded Disability Status Scale-2. The optico-spinal form was not a common form of presentation in the group.
A novel and rapid assay for the detection of neutralizing antibodies against interferon-beta
Authors: Kob M , Harvey J , Schautzer F , Kascha S , Bibl D , Egg R , Reindl M , Berger T , Deisenhammer F
Published: November 2003

There is evidence that neutralizing antibodies (NA B) have a negative influence on the clinical and magnetic resonance imaging effects of interferon-beta (IFNb) in multiple sclerosis (MS) patients. The current methods for NA B detectio n are restricted to specialized laboratories because they require a cell culture and sometimes a viral culture. Results are typically obtained after several weeks. Therefore, the development of a simple and rapid assay for the detectio n of NA B was sought. Whole blood samples from 28 NAB-positive patients and 110 NAB-negative patients (52 with IFNb and 58 without IFNb therapy) were incubated with IFNb 976 IU/mL for 24 hours. MxA protein levels-a specific marker of class 1 IFN bioactivity-were measured in paired samples with and without IFNb incubatio n and the difference in MxA levels was calculated. The mean increase of MxA levels after stimulation with IFNb in the NAB-positive group was 8 ng/mL (range 0-44 ng/mL) and in the NA B-negative group was 84 ng/mL (range 0-302 ng/mL). Using an increase of 22.5 ng/mL as cut-off, the specificity of the MxA stimulation assay was 81.2% and the sensitivity was 96.4%. The whole blood MxA stimulation assay is virtually as sensitive as the conventional NA B assay but somewhat less specific. However, this is outweighed by the procedural advantage of the assay, which is simpler, quicker and much less expensive.
Rapid onset Mitoxantrone-induced cardiotoxicity in secondary progressive multiple sclerosis
Authors: Avasarala Jagannadha R , Cross Anne H , Clifford David B , Singer Barry A , Siegel Barry A , Abbey Elliot E
Published: November 2003

Mitoxantrone is a recently appro ved drug for patients with secondary progressive multiple sclerosis (SPMS). However, cardiac side effects limit Mitoxantrone use in SPMS and its lifetime cumulative dose should not exceed 140 mg/m2. A dditionally, Mitoxantrone is contraindicated for use in SPMS patients with a baseline left ventricular ejectio n fraction (LVEF) of-50%. The goal of this study was to monitor LVEF more frequently than ordinarily recommended since experience with Mitoxantrone use in SPMS patients is limited. A n unexpected decline in LVEF in one of the SPMS patients being treated with Mitoxantrone prompted further investigation into this finding. In our clinic, 47 patients on Mitoxantrone were followed prospectively; 28 of 47 patients had received a minimum of three doses and underwent a repeat LVEF evaluation prior to their fourth dose of Mitoxantrone. O f these 28 patients, five of 28 (17.8%) had a significant decline in LVEF from baseline. It is suggested that more stringent cardiac monitoring guidelines than current Food and Drug A dministration (FDA) recommendations be used to avert potential cardiac complications in SPMS patients on Mitoxantrone.
Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration
Authors: Bø L , Vedeler C A , Nyland H , Trapp B D , Mørk S J
Published: November 2003

The present study examined the extent and distribution of lymphocyte infiltration in demyelinated lesions in the cerebral cortex of multiple sclerosis (MS) patients. Tissue sections from the brain of 10 MS patients and five patients without neurological disease were double labeled for myelin basic protein and the lymphocyte markers C D3, C D4, C D8, C D45RO, and C D20. The highest density of C D3- positive T cells was found in MS white matter lesions (40.4/10 high power fields (hpf)). Fewer T cells were detected in cortical lesions that extended through both white and gray matter (12.1/10 hpf; P B-0.001). The lowest number of T cells was detected in intracortical demyelinated lesions (1.1/10 hpf). This was equal to the lymphocyte density in nondemyelinated cerebral cortex within the same tissue block (1.1/10 hpf) or cerebral cortex in control brains (1.8/10 hpf). A similar distribution was found using the C D4, C D8, and C D45RO markers. C D20-positive B cells were scarce in all specimens examined. These data indicate that areas of intracortical demyelination in chronic MS are not associated with an increased number of lymphocytes, or an altered distribution of lymphocyte subsets, when compared with control areas in MS and control patients. This finding indicates that the extent of lymphocyte infiltration in MS lesions is dependent on lesion location.
The amount of sonic hedgehog in multiple sclerosis white matter is decreased and cleavage to the signaling peptide is deficient
Authors: Mastronardi Fabrizio G , daCruz Luis AG , Wang Huimin , Boggs Joan , Moscarello Mario A
Published: November 2003

We have demonstrated that sonic hedgehog (Shh), vital for oligodendrocyte development, is present in both gray and white matter of normal human brain. Both the 45 kDa precursor protein and the 20 kDa N-terminal sonic hedgehog signaling portion (ShhN) were demonstrated by immunoblot and a partial purification has been achieved. In gray matter from brains of multiple sclerosis (MS) victims, the total amount of Shh was less than normals and the signaling 20 kDa protein was greatly reduced. In white matter homogenates, prepared from MS victims, only the 45 kDa precursor protein was found. None of the 20 kDa signaling protein was detected, suggesting that the 45 kDa signaling protein was not cleaved in the autocatalytic reaction carried out by the C -terminal portion. The 45 kDa protein and a small amount of the 20 kDa ShhN was detected in isolated MS myelin by Western blot, demonstrating some cleavage was possible. The cleavage of the 45 kDa protein was demonstrated in normal myelin in vitro, but not in myelin prepared from MS brain.
A role for hypertrophic astrocytes and astrocyte precursors in a case of rapidly progressive multiple sclerosis
Authors: Morcos Yvette , Lee Sang Min , Levin Michael C
Published: November 2003

The purpose of this study was to examine the roles played by astrocytes in a case of rapidly progressive multiple sclerosis (MS). Within early-active and active lesions, hypertrophic astrocytes played an important role in lesion patho logy through the phagocytosis of myelin and axonal debris and through the internalization of other glial cells, including astrocytes. In addition to this critical role, hypertrophic astrocytes, in areas that lack significant inflammation (within the adjacent normal appearing white matter and within late remyelinating lesions) were found to be active in myelin and axonal debris phagocytosis with no evidence of cellular internalization. Hypertrophic astrocytes therefore not only play an important role in the patho genesis of MS lesions but also exert a continued deleterio us effect upon tissue in the absence of significant inflammation. In addition, we found evidence for a significant population of vimentin-positive, glial fibrillary acidic protein (GFA P)-negative, bipolar, astrocyte precursors within the late remyelinating lesions. Their significance is not known but a possible role may include their participatio n in the successful remyelination of the lesion.
Polymorphisms of apolipoprotein E and Japanese patients with multiple sclerosis
Authors: Niino M , Kikuchi S , Fukazawa T , Yabe I , Tashiro K
Published: November 2003

The relation between apolipoprotein (A PO E) gene polymorphisms and disease progression of multiple sclerosis (MS) is controversial. The present study was designed to investigate the relation between A PO E gene polymorphisms and Japanese patients with MS. We analysed the frequencies of A PO E gene polymorphisms in 135 MS patients and 134 healthy controls, using PC R-RFLP. The results showed no significant differences in the distribution of A PO E gene polymorphisms between MS patients and controls. With regard to disease progression, there was no association between A PO E gene polymorphisms and ε4 allele positivity and disease progression index (EDSS/years). Furthermore, in patients with more than 10 years of disease onset, there were no significant differences between the frequencies of ε4 allele and patients with EDSS of more than 6. A lthough the low rate of ε4 allele in Japan should be taken into consideration, our results showed no relation between APO E gene polymorphisms and Japanese patients with MS.