bluuebunny/crossref_metadata_2025 huggingface dataset:
A nxiety and depression influence the relation between disability status and quality of life in multiple sclerosis
Authors: Janssens A CJW , van Doorn P A , de Boer J B , Kalkers N F , van der Meché F GA , Passchier J , Hintzen R Q
Published: November 2003

Disability status, depression and anxiety are important determinants of quality of life (Q oL) in patients with multiple sclerosis (MS). We investigated whether anxiety and depression influence the relation between disability status and Q oL in our cohort of recently diagnosed patients. Disability status [Expanded Disability Status Scale (EDSS)], anxiety and depression [Hospital A nxiety and Depression Scale (HADS)], and Q oL (SF-36) were prospectively obtained in 101 MS patients. The relation between EDSS and SF-36 scales was examined using regression analyses, without and with adjustment for anxiety and depression. Interaction effects were investigated by comparing the relation between EDSS and Q oL in patients with high and low anxiety and depression. In the unadjusted analyses, EDSS was significantly related to all SF-36 physical and mental health scales. A fter adjustment for anxiety and depression, EDSS was significantly related only to the SF-36 physical functioning, role-physical functioning and bodily pain scales. The relation between EDSS and these SF-36 scales was consistently higher in patients with more symptoms of anxiety or depression, suggesting that anxiety and depression strengthened the association of EDSS in these SF-36 physical health scales. A fter adjustment for anxiety and depression, EDSS was not significantly related to the SF-36 mental health scales and the general health scale. This finding is compatible with the hypothesis that anxiety and depression are intermediate factors in the association of EDSS with these SF-36 scales. Screening for symptoms of anxiety and depression is recommended in studies that use Q oL as an outcome measure of treatment or intervention efficacy.
Effects of glatiramer acetate on relapse rate and accumulated disability in multiple sclerosis: meta-analysis of three double-blind, randomized, placebo-controlled clinical trials
Authors: Boneschi Filippo Martinelli , Rovaris Marco , Johnson Kenneth P , Miller Aaron , Wolinsky Jerry S , Ladkani David , Shifroni Galia , Comi Giancarlo , Filippi Massimo
Published: November 2003

Three randomized, double-blind, placebo-controlled trials have shown that glatiramer acetate (GA) is effective in reducing relapse rate in patients with relapsing-remitting (RR) multiple sclerosis (MS). Using raw data pooled from 540 patients, we performed a meta-analysis of these three trials, to investigate whether the extent of G A efficacy varies according to disease-related variables at study entry. Three regression models were developed to assess the efficacy of G A on the annualized relapse rate (primary outcome measure), on the total number of on-trial relapses and on the time to first relapse. We also explored the efficacy of G A on accumulated disability and the potential role of baseline clinical variables as predicto rs of relapse-rate variables and treatment efficacy. The mean adjusted annualized relapse rate on study was 1.14 in the pooled placebo -treated subjects and 0.82 in the pooled GA group (P =0.004), indicating an average reductio n in annualized relapse rate of 28%. A bout a one third reductio n of the total number of on-trial relapses was also observed in patients receiving GA (P B-0.0001), who had a median time to the first relapse of 322 days versus a median time to the first relapse of 219 days seen in those receiving placebo (P =0.01). A beneficial effect on accumulated disability was also found (risk ratio of 0.6; 95%; C I =0.4-0.9; P =0.02). The drug assignment (P =0.004), baseline EDSS score (P =0.02) and number of relapses during the two years prior to study entry (P =0.002) were significant predicto rs of on-trial annualized relapse rate. No other demographic or clinical variable at baseline significantly influenced the treatment effect. This meta-analysis reaffirms the effectiveness of G A in reducing relapse rate and disability accumulatio n in RRMS, at a magnitude comparable to that of other available immunomodulating treatments. It also suggests that G A efficacy is not significantly influenced by the patients’ clinical characteristics at the time of treatment initiation.
Necrotizing skin lesions and NA Bs development in a multiple sclerosis patient treated with IFNβ 1b
Authors: Casoni Federica , Merelli Elisa , Bedin Roberta , Martella Alessandro , Cesinaro Anna , Bertolotto Antonio
Published: November 2003

A case of a severe necrotizing vasculopathic skin lesions occurred in a 43 year old women affected by multiple sclerosis (MS) submitted to IFNb-lb has been described. A fter two months of therapy the patient presented, in injection sites of the abdomen, arms and legs, numerous ulcers. A biopsy of the lesions was performed and evidenced confluent necro sis of the superficial and deep skin tissue with mild infiltration by inflammatory cells and thrombosis in deep blood vessels. The IFNb-lb was immediately discontinued and therapy with corticosteroids was started. A fter 12 months from the onset of the adverse reaction, the skin vasculopathic lesions cicatrised leaving sclerotic areas on the abdomen. Neutralizing antibodies against IFNb-lb (NA Bs) were strongly positive at the onset of the skin ulcers and slowly decreased until the recovery. A possible role of NA Bs in the development of the skin lesions has been considered.
The ‘Impact on Participation and A utonomy’: acceptability of the English version in a multiple sclerosis outpatient setting
Authors: Vazirinejad Reza , Lilley Jeanette M , Ward Christopher D
Published: November 2003

To elicit the opinion of multiple sclerosis (MS) patients about the acceptability of a newly designed participation questionnaire - the ‘Impact on Participatio n and A utonomy’ (IPA), 35 MS outpatients who had completed an English version of the IPA questionnaire (IPA-E) were interviewed. Patients were recruited consecutively from outpatients attending the MS clinic. They were invited to answer 15 short questions during a 20-minute interview after signing a consent form and completing the IPA -E questionnaire. C ompletion time of the IPA -E questionnaire was 19.3 ± 4.7 minutes. Most respondents believed that the IPA -E items were easy or very easy to understand (83%), relevant (more than 74%), not embarrassing (more than 97%) and 94% considered that no items should be removed. Three additional topics were suggested: ‘looking after children’, ‘the extent of information on current services’ and information about ‘treatment progress’. A mong the eight domains of the IPA, most respondents considered mobility to be the most important and education the least important. The IPA -E was found to be acceptable and relevant to a sample of MS outpatients, although it could have been enhanced by items on parental or family roles.
Diagnosis of MS: a comparison of three different clinical settings
Authors: Porter B , Keenan E , Record E , Thompson A J
Published: November 2003

In order to compare a newly established diagnostic clinic with two existing clinical settings in the management of the diagnostic phase of multiple sclerosis (MS), a retrospective audit was performed over a 12-month period comparing the length of time, adherence to recently published standards and price charged in diagnosing MS in three different clinical diagnostic settings operating within the same hospital: a specifically designed demyelinating disease diagnostic clinic (DDC), a general neurology clinic (GNC) and an inpatient investigation unit (IIU). A n audit tool was created to measure the standards advocated by the UK MS Society on management of the diagnostic phase of MS. The costing tool was the price charged to health authorities. A randomized retrospective case note and referral letter review method was used. The entry criterion was a confirmed diagnosis of MS documented in the medical notes following investigation during the period A pril 1999-A pril 2001. The time between referral and first appointment favoured the DDC with a mean time of 5.9 weeks, compared to 7.7 weeks for the G NC and 10.0 weeks for the IIU. The mean times between the first appointment and receipt of results were 4.7 weeks (DDC), 18.8 weeks (GNC) and 21.2 weeks (IIU). Prices ranged from £395-£790 (DDC), £95-£380 (GNC) and £1940-£2700 (IIU). This study suggests that the UK MS Society standards are achievable in most areas without excessive additional costs and provides evidence that the DDC offers a better service than other existing models.
Fatigue and its association with sociodemographic variables among multiple sclerosis patients
Authors: Lerdal A , Celius E G , Moum T
Published: November 2003

Objective: To explore the relationship between fatigue, sociodemographic and clinical variables in a population of patients with multiple sclerosis (MS). Rationale: There is a need to identify empirical relationships with possible antecedents of fatigue among patients with MS. Methods: A mailed questionnaire designed to survey sociodemographic variables and the Fatigue Severity Scale (FSS) was mailed to 502 individuals from the population of patients with definite MS in the city of O slo. A total of 368 (73%) responded. C linical data were collected from the O slo C ity MS-Registry. Results: The prevalence of fatigue in this population was 60.1%. The FSS score showed a negative correlation with education (r =-0.15, P <0.01) and a positive correlation with age (r =0.20, P B-0.001) and time since disease onset (r =0.11, P B-0.05). When controlled for gender, level of education and time since disease onset, the data showed a positive relationship between fatigue and age (P B-0.001) among patients with primary progressive (PP) disease. This relationship between age and fatigue was not found among patients with relapsing-remitting/secondary progressive (RR/SP) disease. Conclusion: The negative relationship between level of formal educatio n (FE) and fatigue among individuals with RR/SP disease suggests that behavioral factors may be among the antecedents of fatigue in this patient group. In contrast to normative data from the general population, our findings revealed no differences in fatigue related to gender. Thus, this study supports the hypothesis that there are disease-specific antecedents of fatigue among patients with MS.
An MRI study of Chlamydia pneumoniae infection in Italian multiple sclerosis patients
Authors: Grimaldi L ME , Pincherle A , Martinelli-Boneschi F , Filippi M , Patti F , Reggio A , Franciotta D , Allegra L , Comi G , Blasi F
Published: November 2003

We amplified sequences of the Chlamydia pneumoniae (C P) major-outer membrane protein in the cerebrospinal fluid (CSF) from 23 of 107 (21.5%) relapsing-remitting or secondary progressive multiple sclerosis (MS) patients and two of 77 (2.6%) patients with other neurological diseases (OND) (P =0.00022). C P+ patients showed magnetic resonance imaging (MRI) evidence of more active disease (P =0.02) compared to CP-MS patients and tended to have an anticipation of age at disease onset (32.39-12 versus 28.59-10 years; P =ns) causing a longer disease duration (7.59-5 versus 4.49-4 years; P =0.016) at the time of clinical evaluation. These findings, although indirectly, suggest that C P infection of the central nervous system (C NS) might affect disease course in a subgroup of MS patients.
Interferon beta in relapsing-remitting multiple sclerosis: an independent postmarketing study in southern Italy
Authors: Trojano Maria , Liguori Maria , Paolicelli Damiano , Zimatore Giovanni Bosco , De Robertis Francesca , Avolio Carlo , Giuliani Fabrizio , Fuiani Aurora , Livrea Paolo ,   Southern Italy MS Group
Published: November 2003

This independent, population-based surveillance study monitored the efficacy and safety of interferon beta (IFNb) products in 1033 patients with relapsing -remitting multiple sclerosis (RRMS) from 15 centres in Italy. Relapses, Expanded Disability Status Scale (EDSS) scores, and adverse events were evaluated for up to 24 months. Data of patients with a baseline EDSS score 5-3.5 are reported. The proportions of relapse-free patients were similar among the groups at 12 and 24 months (P =0.10). IFNb products produced significant reductio ns from baseline in relapse rates at 12 and 24 months (P B-0.001), with no differences among treatments (P =0.2). There were no significant differences in mean EDSS change among groups at 12 or 24 months. The IFNb-1b group showed a higher incidence of adverse events during the first year of treatment (P B-0.05) than IFNb-1a groups, and more withdrawals (10%) compared with Avonex (5%) at 24 months. IFNb products are equally effective in low disability RRMS, but IFNb-1a may have a more favorable efficacy/tolerability ratio.
Lack of apolipoprotein-E exacerbates experimental allergic encephalomyelitis
Authors: Karussis D , Michaelson D M , Grigoriadis N , Korezyn A D , Mizrachi-Koll R , Chapman S , Abramsky O , Chapman J
Published: November 2003

Experimental autoimmune encephalomyelitis (EAE) was found to have a chronic and significantly worse course in apolipoprotein-E (apoE) deficient female mice when compared with matched controls. Disease measures compared included incidence of EAE (64% versus 31%, P <0.05, x2 test), maximal clinical score (average ±SD 2.81±2.5 versus 0.75±1.1, P <0.01, Mann -Whitney test) and mortality (27.3% versus 0%, P =0.02, Mann -Whitney test and x2 test). A poE deficient mice had significantly increased lymphocyte proliferation responses to both myelin antigens and mitogens and significantly more infiltrating lesions in the central nervous system (CNS) in histopatho logy. Defective neuronal repair mechanisms and enhanced immune reactivity in apoE deficient mice may explain our findings. C linical implications for MS are discussed.
Predictors of alternative medicine use by multiple sclerosis patients
Authors: Marrie Ruth Ann , Hadjimichael Olympia , Vollmer Timothy
Published: November 2003

Objective: To determine the frequency of alternative medicine use among multiple sclerosis (MS) patients, and the factors which predict such use. Methods: We examined 20778 MS patients enrolled in the North A merican Research C onsortium on Multiple Sclerosis (NARC O MS) Patient Registry, residing in the USA. We used demographic and clinical data to create multivariate logistic regression models for i) lifetime use of any alternative medicine, ii) lifetime use of any alternative provider (A P), and iii) lifetime use of each of the three most common A P. Results: 20387 patients provided data regarding alternative medicine use. Lifetime use of any alternative medicine was 54% and current use was 30%. C hiropractors (51%), massage therapists (34%), and nutritionists (24%) were the most commonly used A P. In all five models, use of alternative medicine was most strongly predicted by use of a conventional provider, and more modestly by disease factors indicating more severe or prolonged disease. Predictive power of the models was poor (c-index =0.62-0.68), despite good fits for the data. Conclusions: Demographic factors play only a minimal role in predicting the use of alternative medicine in this MS population while disease factors play a slightly stronger role. There must be other factors involved that may include accessibility, social acceptability and cultural factors. G iven the frequency of alternative medicine use by this patient population, further characterization of these factors is important.
Improved resolution of human cerebrospinal fluid proteins on two-dimensional gels
Authors: Hammack B N , Owens G P , Burgoon M P , Gilden D H
Published: November 2003

Proteomics combines two-dimensional gel electro phoresis and peptide mass fingerprinting and can potentially identify a protein(s) unique to disease. Such proteins can be used either for diagnosis or may be relevant to the pathogenesis of disease. Because patients with multiple sclerosis (MS) have increased amounts of immunoglobulin (Ig) G in their cerebrospinal fluid (C SF) that is directed against an as yet unidentified protein, we are applying proteomics to MS C SF, studies that require optimal separation of proteins in human C SF. We found that recovery of proteins from C SF of MS patients was improved using ultrafiltration, rather than dialysis, for desalting. Resolution of these proteins was enhanced by aceto ne precipitatio n of desalted C SF before electrophoresis and by fractionation of C SF using C ibacron Blue sepharose affinity chromatography. Improved protein recovery and resolution will facilitate excision from gels for analysis by peptide mass fingerprinting.
Interobserver agreement on Poser’s and the new McDonald’s diagnostic criteria for multiple sclerosis
Authors: Zipoli V , Portaccio E , Siracusa G , Pracucci G , Sorbi S , Amato M P
Published: November 2003

We assessed the interobserver agreement on the diagnosis of multiple sclerosis (MS) in a study sample consisting of 41 MS (15 relapsing -remitting, two secondary progressive, five primary progressive and 19 presenting their first clinical attack) and three non-MS cases. C linical and paraclinical information was recorded in standardized forms. Four neurologists were asked to make a diagnosis using Poser’s and McDonald’s criteria and to assess MRI scans according to the McDonald’s guidelines. In terms of the kappa statistic (k), we found a moderate agreement on the overall diagnosis using both Poser’s and McDonald’s criteria (k, respectively, 0.57 and 0.52). A s for distinct diagnostic categories, we observed a moderate to substantial agreement for the three McDonald categories (range of k values 0.49-0.64) and a fair to substantial agreement for the nine Poser categories (range of k values 0.37-0.67). Taking into account clinical information, the agreement on dissemination over time was substantially higher (k=0.69) than that found on dissemination over space (k=0.46). In contrast, for MRI assessment, the agreement for spatial dissemination was substantial (k=0.74) compared with the fair agreement (k=0.25) yielded by dissemination over time. The new McDonald’s criteria yield a good overall diagnostic reliability, and compare favourably with Poser’s classification in terms of agreement on distinct diagnostic categories.
Symptomatic medication use in multiple sclerosis
Authors: Brichetto G , Uccelli M Messmer , Mancardi G L , Solaro C
Published: November 2003

Multiple sclerosis (MS) is one of the most studied neurological diseases, although scarce attention has been placed on symptomatic therapy. The aim of the study was to evaluate the frequency of medication prescription for the major symptoms related to MS in order to better understand the needs of patients. The study was conducted during an epidemiological survey in the province of G enoa, Italy. O ut of 856 patients with MS in the study area, 665 agreed to participate in a structured interview. Two hundred and forty-nine (37%) subjects, with a mean age of 53 years and a mean Expanded Disability Status Scale (EDSS) score of 5.2, were taking at least one symptomatic medication. Four hundred and sixteen (63%) subjects, with a mean age of 49 years and a mean EDSS score of 4.5, were not using symptomatic therapy. The most commonly treated symptoms were pain (28%), spasticity (27%) and mood disorder (16%), while bladder dysfunction (8%) and fatigue (3%) were less frequently treated with medicatio n. Seventy-seven patients (12%) were taking medicatio ns for reasons not directly related to MS. This cross-sectional study underlines the frequency of medication prescription for symptoms such as spasticity and pain, while other common symptoms, such as bladder dysfunction and fatigue, may perhaps be undertreated. The present findings also underline the need for clinical trials on symptomatic therapies.
A cute verbal dyspraxia, a rare presentation in multiple sclerosis: a case report with MRI localization
Authors: Jaffe Stephen L , Glabus Michael F , Kelley Roger E , Minagar Alireza
Published: November 2003

C ortical speech disorders rarely occur in multiple sclerosis (MS). We report a patient with relapsing-remitting MS, who presented with acute verbal dyspraxia. Magnetic resonance imaging (MRI) demonstrated an acute T2/Flair hyperintense, primarily white matter lesion underlying the middle third of the inferior frontal gyrus. The verbal dyspraxia cleared beginning 48 hours after the initiation of iv dexamethasone. Follow-up MRI demonstrated qualitative and quantitative diminution of the hyperintensity. This is the first report of a clinically definite MS patient with acute verbal dyspraxia. Moreover, there was a suggestive localization of verbal praxis to Brodmann areas 44/45.
Depressive symptoms in a treated multiple sclerosis cohort
Authors: Patten Scott B , Fridhandler Shanika , Beck Cynthia A , Metz Luanne M
Published: November 2003

Background: Recent side effect data from clinical trials of interferon beta in multiple sclerosis (MS) have failed to confirm that these medications are associated with an increased risk of depression. However, these studies have used highly selected samples and the results may not be generalizable to real world settings. Methods: C linical data on subjects from southern A lberta who have applied for, or are receiving, public reimbursement for MS treatment are maintained in a database at the University of C algary Multiple Sclerosis C linic. Depression ratings obtained using the C enter for Epidemiological Studies Depression Rating Scale (C ES-D) are included in this database. In the current analysis, these longitudinal data were used to determine whether depressive symptoms were associated with disease-modifying treatments. Results: A t baseline, ratings were available for 163 subjects. Those choosing interferon beta resembled those choosing glatiramer acetate in most respects. During follow-up, no differences were observed in the prevalence or incidence of depression and C ES-D scores were not found to differ between the treatment groups. Conclusions: The failure to identify higher rates of depression both in previous intervention studies and in the current observational study provides confirmation that these drugs are not substantially associated with the occurrence of depression.
Towards a European Network for Multiple Sclerosis Trials (ENMST)
Authors: Kappos L , Polman C , Thompson A J , Duda P , Clanet M , Comi G , Hartung H P , Montalban X
Published: November 2003

Quality standards for clinical studies in the field of multiple sclerosis (MS) have improved significantly, to the great benefit of patients. This development has been accompanied by soaring costs and ever increasing complexity, with industry-independent trials having become virtually impossible. We propose establishing a European network that would include expertise in all the relevant aspects of MS treatment trials. In a stepwise approach, all interested active centres across Europe should be recruited into the network, based on agreement upon common scientific standards and quality requirements. Three main goals are discussed: • to facilitate identification of potentially useful agents for MS treatment; • to establish protocols for the interactio n between investigators and industry; and • to identify common standards and a core set of data to allow for comparisons of MS trials. Collaboration with existing international organizations and institutions, especially the Sylvia Lawry Centre for MS Research, as well as with similar initiatives in North A merica and other parts of the world is envisaged.
Co-occurrence of multiple sclerosis and myasthenia gravis in British C olumbia
Authors: Isbister C M , Mackenzie P J , Anderson D , Wade N K , Oger J
Published: November 2003

We describe eight patients with associated multiple sclerosis (MS) and myasthenia gravis (MG). Patients were less than 50 years old at the time of onset, and seven were female. The clinical course of both MS and MG was mild in most patients. To our knowledge, this represents the largest reported series. We provide further evidence for a nonrandom association of these two diseases and discuss common mechanisms of patho genesis.
Blood-brain barrier disruption in multiple sclerosis
Authors: Minagar Alireza , Alexander J Steven
Published: November 2003

The blood-brain barrier (BBB) is a complex organization of cerebral endothelial cells (C EC), pericytes and their basal lamina, which are surrounded and supported by astrocytes and perivascular macrophages. C ollectively these cells separate and form the compartments of the cerebral vascular space and the cerebral interstitium under normal conditions. Without the BBB, the ‘interior milieu’ of the central nervous system (CNS) would be flooded by humoral neurotransmitters and formed blood elements that upset normal C NS functions and lead to vascular/neural injury. Dysregulation of the BBB and transendo thelial migration of activated leukocytes are among the earliest cerebrovascular abnormalities seen in multiple sclerosis (MS) brains and parallel the release of inflammatory cytokines/chemokines. Mechanisms for breakdown of the BBB in MS are incompletely understood, but appear to involve direct effects of these cytokines/chemokines on endothelial regulation of BBB components, as well as indirect cytokine/chemokine-dependent leukocyte mediated injury.

Unique endothelial structural features of the BBB include highly organized endothelial tight junctions, the absence of class II major histocompatibility complex, abundant mitochondria and a highly developed transport system in C EC. Exposure of endothelium to proinflammatory cytokines (IFN-g, TNF-a and IL-1b) interrupts the BBB by disorganizing cell-cell junctions, decreases the brain solute barrier, enhances leukocyte endothelial adhesion and migration as well as increases expression of class II MHC and promotes shedding of endothelial ‘microparticles’ (EMP). In this review we examine interactions between cytokines/chemokines, activated leukocytes, adhesion molecules and activated C EC in the pathogenesis of BBB failure in MS.
Bone status in multiple sclerosis: beyond corticosteroids
Authors: Tüzün Şansin , AltWntaş Ayşe , Karacan İlhan , Tangürek Saliha , Saip Sebahattin , Siva Aksel
Published: November 2003

The aim of this study was to determine the possible factors affecting bone mineral density (BMD) in multiple sclerosis (MS). In this cross-sectional study, 65 clinically definite MS patients and 72 comparable controls were prospectively evaluated. To assess bone mineral metabolism in MS, the BMD of the lumbar spine and hip (femoral neck, trochanter and total) was measured by dual-energy X-ray absorptiometry, and serum vitamin D and parathyroid hormone levels and biochemical markers of bone turnover were also evaluated. MS patients had significantly lower BMD values than the control group at all measurement sites. There was a significant correlation between the disease duration and BMD values at the trochanter in women with MS. A correlation between femoral BMD values and functional status in women was also detected. There was no relationship between bone biochemical markers and BMD, except a negative correlation between bone alkaline phosphatase and trochanter BMD. Both disability and disease duration have an influence on BMD of the MS patients, whereas no significant correlation between glucocorticoid use and BMD was observed.
Cytapheresis with a filter for selective removal of CD4+ T cells in experimental autoimmune encephalomyelitis
Authors: Nakane Shunya , Matsuo Hidenori , Goto Hirofumi , Yoshinaga-Matsumoto Megumi , Ohtsuru Izumi , Ichinose Katsuhiro , Onodera Hirokazu , Yoshida Makoto , Shibuya Noritoshi
Published: November 2003

Experimental autoimmune encephalomyelitis (EAE) is a major animal model of human multiple sclerosis (MS). CD4+ T cells are thought to play a pivotal role in the patho genesis of EAE and MS. In order to investigate the depletio n of CD4+ T cells from the systemic circulation as an effective strategy for the treatment of MS, we performed extracorporeal CD4+ T cell adsorption, using a filter to which anti-CD4+ antibody is immobilized as a ligand, in adoptively transferred EAE. Rats treated with CD4+ T cell removal filter (C D4RF) exhibited milder clinical signs of EAE and earlier recovery than those receiving sham treatment. Moreover, the thymic cells from EAE rats treated with C D4RF exhibited a suppressed proliferative response and IFN-g production to myelin basic protein. These results suggest that depletion of CD4+ T cells from the systemic circulation by extracorporeal treatment is a potentially useful strategy for treatment of acute phase and relapsing MS.
Phosphodiesterase inhibitors suppress IL-12 production with microglia and T helper 1 development
Authors: Suzumura Akio , Ito Atsushi , Mizuno Tetsuya
Published: November 2003

The effects of phosphodiesterase inhibitors (PDEIs) on interleukin (IL)-12 production by microglia, antigen-presenting cells in the central nervous system (C NS), were examined to learn how they affect T cell differentiatio n in the C NS. PDEIs significantly suppressed the microglial IL-12 production, as determined by reverse transcriptase-po lymerase chain reaction for IL-12 p35 and p40 mRNA expression and by an ELISA specific for IL-12 functional hetero dimer, p70. In addition, the PDEI ibudilast also suppressed interferon-g, but not IL-4 or IL-10, production by myelin oligodendro cyte glycoprotein (MO G)-specific T cells reactivated with MO G in the presence of microglia. Thus, PDEIs may also suppress differentiatio n of T helper 1 (Th1) in the C NS. PDEIs can be of use for future therapeutic strategy to treat Th1-mediated diseases, such as multiple sclerosis.
Rapid-onset endothelial dysfunction with adriamycin: evidence for a dysfunctional nitric oxide synthase
Authors: Duquaine Damon , Hirsch Glenn A , Chakrabarti Anjan , Han Zhenguo , Kehrer Chris , Brook Robert , Joseph Joy , Schott Anne , Kalyanaraman B , Vasquez-Vivar Jeanette , Rajagopalan Sanjay
Published: November 2003

Adriamycin (ADR) is a commonly used chemotherapeutic agent that is believed to exert its effects through the generation of oxygen free radicals. We hypothesized that administration of a single dose of ADR results in endothelial nitric oxide synthase (eNOS)-dependent generation of superoxide (O2·-) and acute endothelial dysfunction. A single dose of ADR (10 mg/kg i.v.) administered to rabbits resulted in rapid attenuation of agonist-dependent responses to acetylcholine and calcium ionophore (A23187). In vitro exposure of ring segments to ADR for <30 min resulted in O2·- generation measured by electron spin resonance (ESR) with the spin trap segments 5-tert-butoxycarbonyl-5-methyl-1-pyrroline N-oxide (BMPO) that was abolished by endothelial denudation and incubation with diphenyliodonium (DPI) (10 mM) but not L-NMMA (10 mM). Brachial artery flow-mediated dilation (FMD) in patients undergoing chemotherapy with ADR was markedly attenuated after a single dose of ADR (6.5 6 1.0 to 2.5 6 1.1% (p = 0.0004, time to end of infusion 27 6 8 min) while endothelial-independent dilatation with nitroglycerin was unchanged (16.3 6 3.1 and 14.33 6 2.1% respectively, p = 0.36). Serum nitrite and nitrate concentrations fell from 50 6 6 mmol/l pre-ADR to 33 6 6 mmol/l post-ADR infusion (p = 0.0005) while serum concentrations of CD141 thrombomodulin and von Wille-brand factor (vWF) activity remained unchanged after ADR infusion (36 6 13 to 52 6 22% ng/ml versus 3.25 6 0.98 to 3.01 6 0.91%, respectively, p = NS for pre versus post for both). Doppler indices of diastolic function (IVRT, DT and E/A ratios) were not altered in response to ADR. In conclusion, ADR administration results in rapid depletion of systemic NO· levels and attenuation of agonist-dependent responses in rabbits and flow-mediated dilation in the brachial artery of humans. ESR measurements in rabbit ring suggest an endothelial origin for radical production via flavin-containing oxido-reductases such as eNOS or NADPH cytochrome P450 reductase. These fi ndings may have implications for cardiovascular complications noted with ADR.
Penetrating neck injury: a review
Authors: MacFarlane Campbell , Benn Carol Ann
Published: November 2003

Penetrating injury to the neck has inspired considerable controversy with regard to its management, owing to the large number of important, susceptible structures contained in this area. Mandatory exploration of all wounds has generally given way to selective operative management. Clinical assessment has, once again, become the prime diagnostic tool. This review describes the evolution of management and the value of various diagnostic modalities. It concludes with a summary of appropriate operative techniques.
A role for recombinant activated factor VII in trauma?
Authors: Sapsford W
Published: November 2003

It is possible that recombinant activated factor VII (rFVIIa) could revolutionize the medical and surgical management of haemorrhage following trauma due to its ease of administration and mechanism of action. This article reviews the evidence for the use of rFVIIa as a procoagulant, its mechanism of action and its potential role in blunt and penetrating trauma. The role of rFVIIa in the emergency room or operating theatre and in the pre-hospital environment is discussed. Administration of rFVIIa `at the roadside’ may have signifi cant potential implications, especially for the trauma surgeon and even for strategic planners. Finally, the areas where further research is needed to provide objective evidence of its effi cacy are elaborated.
New techniques in facial trauma reconstruction
Authors: Amin M , Manisali M , Hopper C , Newman L
Published: November 2003

Over the last few decades there have been major advances in the management of patients with maxillofacial injuries in the Western world. Improvements in primary care, prompt recognition and treatment of life-threatening injuries and a multi-disciplinary approach to patients with severe cranio-maxillofacial trauma have all resulted in improved outcomes. Major advancements in diagnostic imaging, earlier surgical intervention, better instrumentation, a change from closed to open reduction and internal xation of facial fractures and improvements in secondary correction of deformities have also resulted in superior aesthetic and functional results. This article reviews some of the recent advances in this eld.
Peripheral nerve injuries
Authors: Waldram Michael
Published: November 2003

Peripheral nerve injuries are common. Most are caused by lacerating or penetrating injuries. Failure to diagnose early leads to permanent disability. In the accident department absent two point discrimination or loss of sweating on the affected nger are clues to nerve injury. Primary surgery can be performed up to three weeks from injury with approximately 60% return of nerve function. Late reconstruction with interposition nerve grafts (usually sural) can also result in useful return of nerve function. Rehabilitation after any nerve repair is slow and may require extensive hand therapy input for up to two years.
Consensus on the prehospital approach to burns patient management
Authors: Allison Keith , Porter Keith
Published: November 2003

Burns patients form a large group of trauma patients cared for by rst-aiders, ambulance staff, nurses and doctors before reaching specialist care in hospital. Guidance for these important carers is often poor or confused and this engenders anxiety and detracts from optimal patient care. This paper outlines nine key steps in the initial management of burn patients in the prehospital environment based on current available evidence and a consensus of specialists of all disciplines caring for burns patients. The basis of care should be that simple things should always be performed well.
Femoral shaft fractures
Authors: Gaffey A , Blakemore ME
Published: November 2003

Femoral shaft fractures are not only significant injuries in their own right but also often a marker for multiple, serious injuries elsewhere. The treatment in adults is usually surgical. The results are for the most part good, but are dependent on the degree of injury to the local soft tissues and on the presence or absence of other distant injuries.
Ketamine: prehospital and in-hospital use
Authors: Wood PR
Published: November 2003

Ketamine is a unique anaesthetic drug which produces dissociative anaesthesia. In this condition the patient is insensible, with excellent analgesia but with minimal depression of respiration and circulation. The analgesia can be maintained at subanaesthetic doses. The pharmacology and practical use of ketamine is discussed with practical emphasis on its use in trauma patients, for whom it has special advantages.
Resuscitation fluids and hyperchloraemic metabolic acidosis
Authors: Stephens R , Mythen M
Published: November 2003

Until recently, saline and Hartmann’s solution were used almost interchangeably, while interest in colloids was mainly focused on the colloid component (gelatin, dextran or starch) rather than the carrier solution. Some clinicians are still not aware that almost all colloids are suspended in saline. There are no studies examining clinical outcomes after trauma or ICU resuscitation that compare saline-based fluids with ‘balanced’ fluids such as Hartmann’s solution. Recent evidence from volunteer and surgical studies suggest that the use of saline-based fluids (both the crystalloid saline and when used as a carrier solution for a colloid) can cause a hyperchloraemic metabolic acidosis. Although this may not be directly harmful, it may result in incorrect treatment of the acidosis such as more saline-based fluid. Increasing awareness of the ‘Stewart hypothesis’ has led to new ways of managing acid-base balance.
Trauma and critical care - I Orthopaedic trauma and critical care: an overview
Authors: Parry-Jones AJD
Published: November 2003

The aim in this rst article of the series is to examine aspects of intensive care in relation to orthopaedic trauma. Spinal injuries create their own special problems for intensive care management and will be covered later with neurological injuries. A case report of a gentleman with a traumatic pelvic fracture is used to illustrate and guide the discussion of several key points.
Reforming emergency care: implications for the trauma patient
Authors: Robertson-Steel Iain
Published: November 2003

Published in October 2001, Reforming Emergency Care (REC) recognized the need to reorganize unscheduled care. It identified the need for radical restructuring and reform of emergency care by the use of an integrated system with common triage, prioritization and streaming. REC forms part of the modernization process for the National Health Service (NHS) in the UK. It will result in major change in primary care, accident and emergency care, and ambulance services. Local care systems combining emergency, elective, primary care and GP out of hours are a possible solution. The opportunity to improve trauma care by developing a network of 24-hour emergency hospitals for the critically ill and injured will improve the delivery of definitive care in minimum time, by passing the ‘baton of care’ the minimum number of times. Reforming emergency care represents a unique window of opportunity to improve the care of the critically ill and injured.
Developmental lessons of the Vietnamese transitional economy
Authors: Dixon Chris
Published: November 2003

The emergence of the transitional economies (TEs) in Eastern Europe and Pacific Asia have brought a new dimension to the development debate. Initially, events in Eastern Europe were depicted as confirming that there was no viable alternative to the market economy and the neoliberal perspective on development. However, the transition in Eastern Europe has proved to be a complex and problematic process, with recurrent economic and political crises and a wide range of situations and trajectories. More significantly, in Pacific Asia the Asian transitional economies (ATEs) of Vietnam and the People’s Republic of China (PRC) have experienced high rates of economic growth and large-scale inflows of investment with programmes of limited and gradual reform. These have taken place in the context of the continuation of single party rule, high levels of state intervention and significant direct control of production through the State Owned Enterprises (SOEs). Economic growth has been heavily concentrated in and around the state sectors. It is argued that a significant proportion of the growth has resulted from the party-states’ promotion of growth, establishment of incentives and encouragement of more localized activity. However, the changes set in motion by rapid growth and reform have started to undermine the developmental effectiveness of the party-state systems.
Globalization: understanding complexity
Authors: Cole Ken
Published: November 2003

With the increasing availability of relatively cheap computer technology, and the development of sophisticated, nonlinear mathematical techniques, the ‘science’ of complexity emerged in the 1990s. The intellectual concern is the process by which systems composed of interdependent components change, and order is restored, while not tending to equilibrium or stability. Initially concerned with order in ‘natural’ processes (chemical reactions, biological evolution, etc.), recently there has been interest in the study of a complex, emerging order within the process of globalization. This paper reviews the debate, concluding that a process of democracy is the feedback mechanism for establishing order in a complex, globalized world.
A kernel-based spectral model for non-Gaussian spatio-temporal processes
Authors: Wikle Christopher K
Published: November 2003

Spatio-temporal processes can often be written as hierarchical state-space processes. In situations with complicated dynamics such as wave propagation, it is difficult to parameterize state transition functions for high-dimensional state processes. Although in some cases prior understanding of the physical process can be used to formulate models for the state transition, this is not always possible. Alternatively, for processes where one considers discrete time and continuous space, complicated dynamics can be modeled by stochastic integro-difference equations in which the associated redistribution kernel is allowed to vary with space and/or time. By considering a spectral implementation of such models, one can formulate a spatio-temporal model with relatively few parameters that can accommodate complicated dynamics. This approach can be developed in a hierarchical framework for non-Gaussian processes, as demonstrated on cloud intensity data.
A mixed model formulation for designing cluster randomized trials with binary outcomes
Authors: Braun Thomas M
Published: November 2003

Cluster randomized trials (CRTs) are unlike traditional individually randomized trials because observations within the same cluster are positively correlated and the sample size (number of clusters) is relatively small. Although formulae for sample size and power estimates of CRT designs do exist, these formulae rely upon first-order asymptotic approximations for the distribution of the average intervention effect and are inaccurate for CRTs that have a small number of clusters. These formulae also assume that the intracluster correlation (ICC) is the same for each cluster in the CRT. However, for CRTs in which the clusters are classrooms or medical practices, the degree of ICC is often a factor of how many students are in each classroom or how many patients are in each practice. Specifically, smaller clusters are expected to have larger ICC than larger clusters. A weighted sum of the cluster means, D, is the statistic often used to estimate the average intervention effect in a CRT. Therefore, we propose that a saddlepoint approximation is a natural choice to approximate the distributions of the cluster means more precisely than a standard large-sample approximation. We parameterize the ICC for each cluster as a random effect with a predefined prior distribution that is dependent upon the size of each cluster. After integrating over the range of the random effect, we use Monte Carlo methods to generate sample cluster means, which are in turn used to approximate the distribution of D with saddlepoint methods. Through numerical examples and an actual application, we show that our method has accuracy that is equal to or better than that of existing methods. Futhermore, our method accommodates CRTs in which the correlation within cluster is expected to diminish with the cluster size.
Modelling paired release-recovery data in the presence of survival and capture heterogeneity with application to marked juvenile salmon
Authors: Newman Ken B
Published: November 2003

Products of multinomial models have been the standard approach to analysing animal release-recovery data. Two alternatives, a pseudo-likelihood model and a Bayesian nonlinear hierarchical model, are developed. Both approaches can to some degree account for heterogeneity in survival and capture probabilities over and above that accounted for by covariates. The pseudo-likelihood approach allows for recovery period specific overdispersion. The hierarchical approach treats survival and capture rates as a sum of fixed and random effects. The standard and alternative approaches were applied to a set of paired release-recovery salmon data. Marked juvenile chinook salmon ( Oncorhynchus tshawytscha) were released, with some recovered in freshwater as juveniles and others in marine waters as adults. Interest centered on modelling freshwater survival rates as a function of biological and hydrological covariates. Under the product multinomial formulation, most covariates were statistically significant. In contrast, under the pseudo-likelihood and hierarchical formulations, the standard errors for the coefficients were considerably larger, with pseudo-likelihood standard errors five to eight times larger, and fewer coefficients were statistically significant. Covariates, significant under all formulations, with important management implications included water temperature, water flow and amount of water exported for human use. The hierarchical model was considerably more stable with regard to estimated coefficients of training subsets used in a cross-validation.
Negative binomial loglinear mixed models
Authors: Booth James G , Casella George , Friedl Herwig , Hobert James P
Published: November 2003

The Poisson loglinear model is a common choice for explaining variability in counts. However, in many practical circumstances the restriction that the mean and variance are equal is not realistic. Overdispersion with respect to the Poisson distribution can be modeled explicitly by integrating with respect to a mixture distribution, and use of the conjugate gamma mixing distribution leads to a negative binomial loglinear model. This paper extends the negative binomial loglinear model to the case of dependent counts, where dependence among the counts is handled by including linear combinations of random effects in the linear predictor. If we assume that the vector of random effects is multivariate normal, then complex forms of dependence can be modelled by appropriate specification of the covariance structure. Although the likelihood function for the resulting model is not tractable, maximum likelihood estimates (and standard errors) can be found using the NLMIXED procedure in SAS or, in more complicated examples, using a Monte Carlo EM algorithm. An alternate approach is to leave the random effects completely unspecified and attempt to estimate them using nonparametric maximum likelihood. The methodologies are illustrated with several examples.