bluuebunny/crossref_metadata_2025 huggingface dataset:
Oprelvekin (Neumega®)
Authors: Adams Val R , Brenner Timothy L
Published: January 2007

Objective. Our objective was to review oprelvekin, which is a new thrombopoietic cytokine approved in the United States to prevent severe thrombocytopenia and reduce the number of platelet transfusions after myelosuppressive chemotherapy. This article focuses on oprelvekin’s pharmacology, pharmacokinetics, and place in therapy.

Data Sources. A search of the National Cancer Institute-sponsored Cancerlit database from 1963 to 1999 was completed. Subject mesh headings that were searched included interleukin-11, oprelvekin, breast cancer, chemotherapy dose intensity, and cancer pharmacoeconomics. Data were also collected from the package insert and from Genetics Institute (Cambridge, MA) publications.

Study Selection. Searches were limited to studies with humans, which included clinical trials, news articles, and review articles. After reading all of the human clinical trials, additional pertinent citations were obtained and read.

Data Synthesis. Oprelvekin has been studied in both adults and children, with the bulk of the data coming from the treatment of women with breast cancer. A phase I study in adults evaluated doses of 10, 25, 50, 75, and 100 mg/kg/day and determined the maximum tolerated dose to be 50 mg/kg/day. The toxicity seen with the 75 and 100 mg/kg/day doses includes constitutional symptoms (arthralgias, myalgias, fatigue, nausea, and headache) and a cerebral vascular accident. Phase II and III trials showed that 25-50 mg/kg/day effectively reduced the number of patients requiring platelet transfusions and decreased the number of platelet transfusions after chemotherapy.

Pharmacokinetics performed with the 50 mg/kg/day subcutaneous (s.c.) dose resulted in a maximum sera concentration of 17.4 6 5.4 ng/mL, which occurred at 3.2 6 2.4 hours. The terminal half-life was 6.9 6 1.7 hours. Clearance decreases with increasing age, and pediatric patients have a 1.2- to 1.6-fold higher clearance than adults. These pharmacokinetic parameters led to a dosing recommendation of 75- 100 mg/kg/day in pediatric patients.

Due to the high cost of oprelvekin and the lack of data demonstrating that it affects mortality, its role in current therapies is unclear. It is currently being promoted to maintain dose intensity in patients with breast cancer, testicular cancer, and lymphoma. Depending upon institutional platelet and oprelvekin costs, it may also be useful in patients receiving a large number of platelet transfusions. Thus far, it has not demonstrated efficacy in bone marrow transplant patients.

Conclusion. Oprelvekin can effectively prevent the need for platelet transfusion in nontransplant patients receiving myelosuppressive chemotherapy. Due to its high cost, it will most likely be used to maintain chemotherapy dose intensity, which may translate into a survival advantage.
Beneficial clinical outcomes resulting from pharmacist interventions
Authors: McLennan Danielle N , Dooley Michael J , Brien Jo-anne E
Published: January 2007

Objective. To assess the contribution pharmacists make to patient care by determining the clinical outcomes associated with pharmacist interventions.

Methods. A 2-month prospective intervention study was conducted at Peter MacCallum Cancer Institute, a tertiary referral center. During the study, clinical pharmacists documented intervention episodes, patient demographical details, and the drug(s) involved. Clinical outcomes resulting from pharmacist-initiated changes to drug therapy and patient management were assessed by an independent pharmacist according to defined criteria. Outcomes were determined through review of patient medical progress notes and discussion with members of the health care team.

Results. A total of 674 interventions were documented during the data collection period. Outcomes could be assessed for 10% of the interventions reported, and 90% of these interventions resulted in documented clinical benefit. The drug classes most frequently associated with pharmacist interventions were antiemetics, antimicrobials, and analgesics.

Conclusion. This prospective study demonstrated a high rate of beneficial outcomes achieved by pharmacist interventions.
Audit of efficacy of 3 mg versus 1 mg of intravenous granisetron as antiemetic prophylaxis against acute emesis caused by cisplatin or melphalan
Authors: Hole Alison , Conway Alison , Quadir Suraya
Published: January 2007

Objective. In the United Kingdom, granisetron is licensed at an adult dose of 3 mg for prophylaxis of emesis due to cytotoxic chemotherapy. In the United States, however, the licensed dose is 10 mg/kg, which, for most adults, equates to 1 mg. In view of the cost implications of this difference in dosage recommendations, the local drug and therapeutics advisory committee supported a proposal to evaluate the use of the 1-mg dose for our own patients. We report the results of this evaluation in patients receiving the highly emetic drugs cisplatin and melphalan, given alone or in combination with other cytotoxics.

Design. Prospective, open, non-randomised study of patients receiving 3 mg and 1 mg of granisetron as part of their antiemetic regimen. Data collection was carried out before and after a change in hospital antiemetic policy.

Setting. A specialist oncology hospital in England.

Patients. A total of 57 patients received 3 mg of granisetron, and 70 patients received 1 mg of granisetron.

Results. There was a small increase in the incidence of nausea and vomiting following the change in the granisetron dose from 3 mg to 1 mg, but this increase was not big enough to be significant.

Conclusion. Guidelines recommending the use of granisetron at a dose of 1 mg were successfully implemented at the Royal Marsden Hospital with the potential to save the Trust over £50,000 per year without detriment to patient care.
Social Investment and Personality: A Meta-Analysis of the Relationship of Personality Traits to Investment in Work, Family, Religion, and Volunteerism
Authors: Lodi-Smith Jennifer , Roberts Brent W.
Published: January 2007

Investing in normative, age-graded social roles has broad implications for both the individual and society. The current meta-analysis examines the way in which personality traits relate to four such investments—work, family, religion, and volunteerism. The present study uses meta-analytic techniques (K = 94) to identify the cross-sectional patterns of relationships between social investment in these four roles and the personality trait domains of agreeableness, conscientiousness, and emotional stability. Results show that the extent of investment in social roles across these domains is positively related to agreeableness, conscientiousness, emotional stability, and low psychoticism. These findings are more robust when individuals are psychologically committed to rather than simply demographically associated with the investment role.
TNF-α polymorphisms in multiple sclerosis: no association with −238 and −308 promoter alleles, but the microsatellite allele all is associated with the disease in French patients
Authors: Lucotte Gérard , Bathelier Christian , Mercier Géraldine
Published: January 2007

Tumor necrosis faaor-α (TNF-α), a proinflammatory cytokine, is believed to play an important role in multiple sclerosis (MS) pathogenesis. The objective of this study was to determine whether sequence variation in the TNF-α gene is associated with MS. Bi-allelic polymorphisms in the TNF-α promoter region (TNF-α −238 and −308) and microsatellite TNF-α were previously reported. We investigated these polymorphisms in 74 French patients with MS, compared with 75 controls. No significant differences regarding the TNF-α −238 and −308 polymorphisms were observed between MS patient and controls Allele frequency for the all allele is in very significant association (P < 0.0001) with MS, due in part to the assoiation of the all allele with the HLA-DRBI*15 allele in patients.
Diagnostic brain MRI findings in primary progressive multiple sclerosis
Authors: Kremenchutzky M , Lee D , Rice G P A , Ebers G C
Published: January 2007

The clinical course of multiple sclerosis can be classified as relapsing from onset (relapsing-remitting), or progressive from onset (primary progressive -PPMS). These clinical phenotypes have been based on historical and clinical observations. It has been reported that PPMS patients tend to have quantitatively less MRI activity and disease burden. We evaluated the sensitivity and diagnostic value of conventional brain MRI scan in 143 PPMS patients. Brain MRIs were blindly evaluated to determine if they satisfied Paty and/or Fazekas diagnostic criteria. Patient were divided into those with typical atypical or normal scans. They satisfied brain MRI criteria in 92% cases. Findings included: 131 typical four atypical, and eight normal scans. All 12 non-typical scans' subject had spinal onset; spinal MRI scans were positive in four of seven cases. Sex, age of onset, site and number of symptoms involved at onset among those groups were not significantly different but accumulation of disability had a tendency to be slower in these few individuals with normal or atypical head MRI's. Although there may be quantitative differences in lesion activity/burden, MRI scanning in PPMS unexpectedly has diagnostic sensitivity very similar to that seen in RRMS. A normal brain MRI is unusual in PPMS patients.
Antinuclear antibodies and response to IFNβ-1a therapy in relapsing-remitting multiple sclerosis
Authors: Ciccarelli O , Bagnato F , Mainero C , Salvetti M , Paolillo A , Gasperini C , Bastianello S , Pozzilli C
Published: January 2007

We determined whether positive ANA was related to response to rIFNû-1a in 62 relapsing-remitting MS patients. According to the presence of antinuclear antibodies (ANA) at baseline and during the first 6 months of treatment, patients were sorted in different groups. The clinical and MRI outcome during short-term (6 months) and long-term (24 months) treatment period was not statistically different between the groups. Therefore, the response to IFNb-1a seems not to be influenced by ANA occurrence either before or during treatment. When the analysis was extended to other autoantibodies (i.e. antithyroid, anticardiolipin) similar results were obtained.
1H MRSI comparison of white matter and lesions in primary progressive and relapsing-remitting MS
Authors: Suhy J , Rooney W D , Goodkin D E , Capizzano A A , Soher B J , Maudsley A A , Waubant E , Andersson P B , Weiner M W
Published: January 2007

Objective: To compare brain metabolite levels in patients with primary progressive (PP) and relapsing remitting (RR) MS and controls. Hypotheses: (1) creatine (Cr), a putative marker of gliosis, is elevated and N-acetylaspartate (NAA), a putative marker of axonal density and functional integrity, is reduced in PPMS lesions and normal appearing white matter (NAWM) compared to control white matter; (2) The pattern of metabolite change in PPMS is different than in RRMS. Methods: MRI and proton magnetic resonance spectroscopic imaging (1H MRSI) were collected from 15 PPMS patients, 13 RRMS patients, and 20 controls. Results: Cr was increased in PPMS NAWM compared to controls (P=0.035), and compared to RRMS NAWM (P=0.038). Cr was increased in focal MRI lesions from PPMS compared to lesions from RRMS (P=0.044) and compared to control white matter (P=0.041). NAA was similarly reduced in PPMS and RRMS NAWM compared to control. NAA was similarly reduced in PPMS and RRMS lesions, compared to control white matter. Conclusions: Creatine is higher in PPMS than RRS NAWM and focal lesions. This observation is consistent with the notion that progressive disability in PPMS reflects increased gliosis and axonal loss whereas disability in RRMS reflects the cumulative effects of acute inflammatory lesions and axonal loss.
Confabulation and multiple sclerosis: a rare association
Authors: Feinstein Anthony , Levine Brian , Protzner Andrea
Published: January 2007

Background: Fantastic confabulation in the context of Multiple Sclerosis (MS) has not previously been reported in the literature. The association is of interest because clearly demonstrable brain pathology in MS together with other cognitive and behavioural correlates may further our understanding of the neural basis underlying confabulation. Methods: A single case report with magnetic resonance imaging of the brain and detailed neuropsychological evaluation. Results: Confabulation occurred together with disinhibited and stimulus bound behaviour. While the patient's physical and emotional state limited the range of psychometric tests administered, the results revealed an inability to maintain focused, regulated information processing. Although memory difficulties were present, they were not in the nature of a severe amnesic disorder. The patient appeared to have a broad fund of knowledge, but the associations binding the information together and putting it into context were loose. All three features of a triad of responses previously described in confabulating patients were present, namely an inability to withhold answers, to monitor one's own responses and provide verbal self corrections. MRI of the brain showed bilateral periventricular lesions and discrete frontal lesions with 53% of the total lesion volume distributed in frontal areas. Cortical atrophy, most marked in frontal regions also was conspicuous. Conclusions: Confabulation linked to frontal lobe involvement may occur as part of the changes in mentation found in MS. It is, however, rare and although associated with impaired memory, may be found in the absence of a severe amnesic disorder. This conclusion is discussed in the light of observations from the literature suggesting that frontal involvement is a prerequisite before fantastic confabulation occurs.
Importance of paraclinical and CSF studies in the diagnosis of MS in patients presenting with partial cervical transverse myelopathy and negative cranial MRI
Authors: Bashir K , Whitaker J N
Published: January 2007

Patients presenting with isolated partial cervical myelopathy are at high risk for development of multiple sclerosis (MS), especially if lesions suggestive of demyelination are present on cranial magnetic resonance imaging (MRI). This risk is lower, though not precisely known, in patients whose cranial MRI is normal. This clinical issue was addressed by examining the role of paraclinical studies in establishing a diagnosis of MS at the time of initial presentation. Twelve consecutive patients, mean age of 32.2 years, seen over 6.5 years were identified prospectively and included in this study. Numbness was the presenting symptom in 11 of these patients. Symptoms completely resolved in nine patients regardless of treatment with glucocorticoids. Evoked potential (EP) and cerebrospinal fluid (CSF) examinations assisted in establishing a diagnosis of laboratory-supported definite (LSDMS) or clinically probable (CPMS) MS in six patients at the time of presentation. During a clinical follow-up period of 4.1 years, four developed recurrent neurologic deficits leading to the establishment of a diagnosis of clinically definite MS (CDMS). The presence of a solitary, non-specific lesion on cranial MRI resulted in an increased risk for the development of definite MS. In patients with a clinically isolated cervical partial transverse myelitis (TM) and normal cranial MRI, an accurate diagnosis of MS can usually be made. Revision of the diagnostic criteria for LSDMS is warranted.
MTR and T1 provide complementary information in MS NAWM, but not in lesions
Authors: Griffin C M , Parker G JM , Barker G J , Thompson A J , Miller D H
Published: January 2007

MTR and T1 relaxation times are abnormal in MS lesions and NAWM, and may reflect tissue damage such as demyelination and axonal loss. Their relationship and potential to provide complementary information in tissue characterisation is explored. The aim of this study was to document the relationship between magnetisation transfer ratio (MTR) and T1 relaxation time in Multiple Sclerosis (MS) lesions and normal appearing white matter (NAWM) in order to determine whether the combination provides a more comprehensive tissue characterisation than either parameter in isolation. Ten patients with relapsing remitting MS and 10 age matched healthy controls underwent imaging using a protocol which included the measurement of both MTR and T1 relaxation times. The MTR and T1 values were compared statistically using a commonly adopted correlation approach and a mixed-model regression approach. There was a strong correlation between MTR and T1 in MS lesions (r=0.74). The correlation was seen equally in T1 hypointense and isointense lesions. The relationship was much weaker in MS NAWM (r=0.24) and no correlation was found in control white matter (r=0.06). Mixed-model regression analysis confirmed that the relationship between T1 and MTR is strongly dependent upon tissue type (MS lesion, MS NAWM, or control white matter). The relationship between MTR and T1 relaxation time measurements varies markedly between pathological and normal tissue types. In MS, the complementary information obtained from MTR and T1 is most apparent in NAWM. The results emphasise the potential for combinations of MR parameters to improve tissue characterisation, which in turn should improve understanding of disease pathology and treatment monitoring.
A longitudinal study of ventricular volume in early relapsing-remitting multiple sclerosis
Authors: Luks T L , Goodkin D E , Nelson S J , Majumdar S , Bacchetti P , Portnoy D , Sloan R
Published: January 2007

The specific aim of this study was to determine whether progressive brain atrophy could be detected within 18 months of establishing a diagnosis of relapsing-remitting multiple sclerosis (RRMS). Fifteen patients with clinically definite RRMS (mean disease duration from first symptom=6 months, mean EDSS=1.2) completed 6-14 monthly quantitative MRI sessions. The volume of the lateral ventricles was determined each month using a semi-automated thresholding technique from T1-weighted axial images. The number of new monthly gadolinium-enhancing (Gd+) lesions and EDSS scores were also recorded. Lateral ventricular volumes increased significantly during this study. When individual data were examined, statistically significant changes were observed in six of 15 patients. Monthly change in ventricular volume was related to baseline EDSS and total number of new Gd+ lesions. These observations indicate brain atrophy, a putative imaging marker of diffuse demyelination and axonal loss, can occur as early as 18 months after first symptons of RRMS, and is related to the baseline level of disability and to the number of new Gd+ lesions.
Increase in serum levels of uric acid, an endogenous antioxidant, under treatment with glatiramer acetate for multiple sclerosis
Authors: Constantinescu C S , Freitag P , Kappos L
Published: January 2007

Free radicals including peroxynitrite are induced in Multiple Sclerosis (MS). Antioxidant and peroxynitrite inhibitor uric acid (UA), suppresses the MS animal model experimental autoimmune encephalomyelitis (EAE). MS patients have lower average serum UA than controls. An inverse relationship exists between MS and gout. Glatiramer acetate (GA) suppresses EAE and is beneficial in relapsing MS. We investigated serum UA changes during open-label treatment of relapsing MS with GAA. Ten patients (six females, four males, aged 19 to 39 years, mean age 32 years) completed 6 months of GAA (Copaxone® 20 mg s.c. daily). Of these, nine completed 12 months. After 6 months on GAA, serum UA (normal, 173-359 mmol/ml for women, 258-491 mmol/ml for men) increased in nine and marginally decreased (302 to 300 mmol/ml) in a single patient. Mean UA significantly increased from 240 to 303 mol/ml (P=0.0014). At 12 months, UA remained significantly higher than at start (P=0.006) decreasing in only one patient. In contrast, we found no significant UA changes after 6 and 12 months of treatment in 21 MS patients treated with interferon b1-a (Avonex®), or in 11 treated with interferon b1-a (Rebif®), or in five placebo-treated controls. Increasing UA, a natural inhibitor of free radicals, may represent a mechanism of action of glatiramer acetate in MS.
Neuropsychological counseling improves social behavior in cognitively-impaired multiple sclerosis patients
Authors: Benedict R HB , Shapiro A , Priore Roger , Miller C , Munschauer F , Jacobs L
Published: January 2007

We studied the effectiveness of a newly-developed cognitive-behavioral intervention in 15 patients with marked cognitive impairment and behavior disorder. The design was a single-blind test of a neuropsychological intervention, with pre- and post-treatment assessments of personality and social behavior. MS patients underwent neurological examination and neuropsychological testing at baseline. The patients were then randomly assigned to neuropsychological counseling or standard, non-specific supportive psychotherapy. The active 12-week treatment emphasized enhancement of insight through education, social skills training, and behavior modification. All patients were re-examined within 2 weeks of the termination of treatment. Neuropsychological technicians were blind to treatment condition. Both groups showed evidence of cognitive impairment and personality/behavior disorder prior to treatment and were well matched on demographic, disability, and cognitive measures. Patients who underwent neuropsychological counseling showed significant positive response on measures of social behavior (e.g. excessive ego-centric speech) compared to those who underwent standard counseling. We conclude that these data support the use of non-pharmacological, neuropsychological counseling in patients with acquired, MS-associated behavior disorder.
Chlamydia pneumoniae in multiple sclerosis: humoral immune responses in serum and cerebrospinal fluid and correlation with disease activity marker
Authors: Krametter D , Niederwieser G , Berghold A , Birnbaum G , Strasser-Fuchs S , Hartung H-P , Archelos J J
Published: January 2007

Humoral immune responses to Chlamydia pneumoniae (C. pneumoniae) were studied in paired sera and cerebrospinal fluid (CSF) of patients with definite multiple sclerosis (MS) and other inflammatory and non-inflammatory neurological diseases. Seropositivity was not significantly different between these groups. However, C. pneumoniae-specific IgG titers were significantly higher in CSF of MS than in controls. Sixteen out of 52 seropositive MS patients (30.8%) showed intrathecal synthesis of C. pneumoniae-specific IgG but only one of 43 seropositive controls (2.3%). In MS, this was strongly associated with intrathecal synthesis of polyclonal IgG in 13/16 patients. However, these elevated C. pneumoniae antibody titers in CSF did not significantly correlate with disease duration, disease course, clinical or MRI disease activity, disability or presence of oligoclonal IgG in MS.
Interferon beta-1b and intravenous methylprednisolone promote lesion recovery in multiple sclerosis
Authors: Richert N D , Ostuni J L , Bash C N , Leist T P , McFarland H F , Frank J A
Published: January 2007

Objective: To determine whether lesion evolution in relapsing-remitting multiple sclerosis (RRMS) patients is altered by treatment with interferonβ-1b (IFNb-1b) or by intravenous methylprednisolone (IVMP) as measured by magnetization transfer imaging. Methods: Magnetization transfer ratios (MTR) of 225 contrast enhancing lesions (CEL), in four RRMS patients were serially determined for 12 months before and 12-18 months after contrast enhancement in a baseline vs treatment trial with IFNβ-1b. During the baseline period, 185 new CEL were identified: 76 were treated with IVMP (1 giday x 5 days) and designated steroid CEL (S-CEL); the remaining 109 were considered baseline lesions (B-CEL). During IFNβ-1b treatment, 40 CEL (IFN-CEL) were identified. After image co-registration, regions of interest (ROIs) defining new CEL were transferred to the MTR image set to determine the mean lesion MTR on each monthly exam. The lesion MTR was compared to MTR of normal appearing white matter (NAWM) on the same exam. Results: As early as 12 months prior to enhancement, the MTR of CEL was reduced compared to NAWM (mean 9.43±3.2%; P<0.001). The further reduction in MTR (28%±4.0) at the time of contrast enhancement was not significantly different for B-CEL, S-CEL or IFN-CEL. Following enhancement, lesion recovery for IFN-CEL (P=0.02) and S-CEL (P=0.002) was significantly higher than B-CEL. Conclusion: IFNβ-1b and IVMP reduce tissue damage and promote lesion recovery in RRMS patients. The additional benefit of IVMP compared to IFNβ-1b may be related to its inhibitory effect on demyelination.
Quantitative contrast-enhanced magnetic resonance imaging to evaluate blood-brain barrier integrity in multiple sclerosis: a preliminary study
Authors: Silver N C , Tofts P S , Symms M R , Barker G J , Thompson A J , Miller D H
Published: January 2007

Gadolinium enhanced magnetic resonance imaging detects focal blood-brain barrier breakdown in new inflammatory multiple sclerosis lesions, but such lesions do not correlate with disease progression. To explore whether the latter might relate to subtle but widespread blood-brain barrier (BBB) breakdown with low grade inflammation mediating tissue damage, quantitative techniques were used to detect subtle gadolinium enhancement within otherwise normal-appearing white matter and within lesions not showing visible enhancement. T1-weighted imaging was performed prior to and at 5, 20 and 40 min following injection of 0.3 mmol/kg gadopentate dimeglumine in 33 patients with multiple sclerosis and five healthy control subjects. In healthy controls, a significant increase in white matter signal 5 min following contrast injection was observed (1.8%, P < 0.0005); the signal returned to baseline values by 20 min. In multiple sclerosis patients, a non-significant trend was noted for signal to remain elevated in normal-appearing white matter at the 20 and 40 min post-contrast time points; this was most apparent in primary progressive multiple sclerosis. Significant increases in signal intensity were noted at all time points post contrast in apparent non-enhancing lesions. The transient post contrast signal increase in controls is likely due to intravascular gadopentate dimeglumine. The persistent increases in signal intensity in non-enhancing lesions suggest more widespread abnormalities in BBB than is visually apparent, but substantiation of BBB leakage in normal appearing white matter will require further study using more sensitive methods.
Uric acid levels in patients with multiple sclerosis: analysis in mono- and dizygotic twins
Authors: Spitsin S , Hooper D C , Mikheeva T , Koprowski H
Published: January 2007

Presence of nitrotyrosine in cells surrounding plaques indicates that peroxynitrite may be the cause of brain lesions in multiple sclerosis. Low levels of uric acid, a natural scavenger of peroxynitrite, were demonstrated in blood of patients with multiple sclerosis in comparison with control individuals. These observations were now extended to 132 sets of twins with one sibling affected by multiple sclerosis. In blood of both mono- and dizygotic twins the uric acid levels were lower in the twin with the disease than in the healthy twin.
Ring-enhancement in multiple sclerosis: marker of disease severity
Authors: Morgen K , Jeffries N O , Stone R , Martin R , Richert N D , Frank J A , McFarland H F
Published: January 2007

Correlations between conventional MRI measures of disease activity and clinical disability in multiple sclerosis (MS) have been disappointing. Because ring-enhancing lesions may reflect a more destructive pathology, we tested their potential association with disease severity. We evaluated active lesions with regard to their enhancement pattern on serial magnetic resonance images in a cohort of 28 patients with relapsing-remitting MS. The percentage of ring-enhancing lesions correlated with EDSS, T2 lesion load and duration of disease and predicted the occurrence of relapses during the baseline period of observation as well as after 3 years of follow-up in multiple logistic regression analysis. The findings suggest that the pathological process reflected by ring-enhancing lesions may contribute to more severe clinical disease.
Double-blind randomized multicenter dose-comparison study of interferon-β-1a (AVONEX): rationale, design and baseline data
Authors:   European Study Group on Interferon-Beta-1a in MS
Published: January 2007

We describe the rationale and design of a double-blind, randomized, multicenter, dose-comparison study of interferon-beta-1a (IFN-β-1a; Avonex®), in the treatment of relapsing multiple sclerosis (MS). The study is expected to provide quantitative insights on the dose range for optimal clinical benefits in MS. The study involves 802 patients in 10 European countries who have EDSS scores 2.0-5.5, and who have experienced at least two relapses within the 3 years prior to enrolment. Patients are randomized to receive once-weekly intramuscular injections of IFN-β-1a 30 or 60 mcg for at least 3 years. The primary endpoint of the study is the effect of IFN-β-1a therapy on the time to sustained progression of disability. For patients with a baseline EDSS ≤44.5, sustained progression of disability is defined as a 1 point increase in EDSS from baseline, maintained for 6 months. For patients with baseline EDSS ≥55, sustained progression of disability is defined as reaching an EDSS ≥56.0, maintained for 6 months. EDSS scores will be determined every 3 months. A series of prospectively defined secondary and tertiary efficacy endpoints will be examined. Safety will be monitored throughout the study. Magnetic resonance imaging (MRI) with and without gadolinium-enhancement has been performed in at least 358 patients at baseline and repeated annually after enrolment. In a subset of these patients, a frequent MRI study is also being performed.
Effect of monthly intravenous cyclophosphamide in rapidly deteriorating multiple sclerosis patients resistant to conventional therapy
Authors: Khan Omar A , Zvartau-Hind Marina , Caon Christina , Din Moeen U , Cochran Mickey , Lisak Deena , Tselis Alexandros C , Kamholz John A , Garbern James Y , Lisak Robert P
Published: January 2007

Fourteen consecutive clinically definite relapsing-remitting multiple sclerosis (MS) patients were treated with monthly intravenous cyclophosphamide (CTX) for 6 months. All had experienced severe clinical deterioration during the 12 months prior to treatment with CTX despite treatment with conventional immunomodulating agents and intravenous methylprednisolone. Treatment with CTX led to improvement and neurologic stability within 6 months which was sustained for at least 18 months after the onset of treatment with CTX. Therapy with CTX was well tolerated. CTX may be of benefit in MS patients who experience rapid clinical worsening and are resistant to conventional therapy.
Profiles of nursing home residents with multiple sclerosis using the minimum data set
Authors: Buchanan Robert J , Wang Suojin , Huang Chunfeng , Graber David
Published: January 2007

This paper profiles nursing home residents with multiple sclerosis (MS) at the time of admission, including sociodemographic characteristics, health status measures, and treatments received. Admission assessments from the Minimum Data Set are used to create these profiles of residents with MS. There are 9013 admission assessments in the MDS for residents with MS between June 22, 1998 and January 17, 2000 analyzed for this study. Residents with MS are distinctly younger at admission than most nursing home residents, averaging 57.98 years of age. Recently admitted residents with MS are more physically dependent than other nursing home residents and tend to have limited range of motion and loss of voluntary movement. About one in three newly admitted residents with MS had some degree of impaired cognitive function. Over one third of residents with MS were depressed at admission, yet only 11.7% of recently admitted residents with MS were evaluated by a licensed mental health specialist. This prompts concern about the psychosocial well-being of MS residents in nursing homes.
Grey matter abnormalities in multiple sclerosis: proton magnetic resonance spectroscopic imaging
Authors: Sharma Rakesh , Narayana Ponnada A , Wolinsky Jerry S
Published: January 2007

Pathologically defined abnormalities in the cortical gray matter (GM) are well described in multiple sclerosis (MS) but are infrequently seen by conventional magnetic resonance imaging (MRI). We systematically evaluated 52 relapsing - remitting MS patients and 20 normal volunteers with high resolution MRI and short echo proton magnetic resonance spectroscopic imaging (MRSI). Individual tissue contributions to the spectroscopic voxels were estimated based on MRI that incorporated both CSF suppression and magnetization transfer, or double inversion images in which both CSF and GM were suppressed. Strong resonances in the 0.8 to 1.5 p.p.m. spectral region were observed in 13 MS patients. Image segmentation based on the MRI characteristics of tissues contributing to the spectroscopic voxels showed that these additional peaks originated mainly from GM. The presence of these additional peaks suggests that the normal appearance GM on MRI, is biochemically abnormal in a substantial proportion of relapsing-remitting MS patients.
Clinical features of multiple sclerosis in a genetically homogeneous tropical population
Authors: Sánchez J L , Palacio L G , Uribe C S , Londoño A C , Villa A , Jiménez M , Anaya J M , Jiménez I , Camargo M , Arcos-Burgos M
Published: January 2007

Individuals affected with multiple sclerosis (MS) from a genetically homogeneous Caucasian population in Antioquia, a tropical region of Colombia, were evaluated in order to observe the clinical behavior of the disease. The frequency of clinical manifestations in 65 patients with definite MS from Antioquia was compared with those reported from temperate regions. The most common manifestations were optic neuritis and motor symptoms with absence of cerebellar symptoms. This presentation is significantly different from the frequency distribution at onset in series from temperate regions. These differences suggest that environmental factors could modify the clinical expression of MS in this population.
Reduced quality of life among multiple sclerosis patients with sexual disturbance and bladder dysfunction
Authors: Nortvedt M W , Riise T , Myhr K-M , Landtblom A-M , Bakke A , Nyland H I
Published: January 2007

Objective: Physical disability explains only part of the reduced quality of life found among multiple sclerosis (MS) patients. Bladder dysfunction and sexual disturbance are frequent and distressing problems for MS patients. We therefore estimated the relationship between the presence and degree of sexual disturbance/bladder dysfunction and the patients' quality of life as measured by the SF-36 Health Survey. Methods: We performed a cross-sectional study of all individuals with the onset of MS between 1976 and 1986 in Hordaland County, Norway. The disease duration at examination was 9-19 years; 194 patients (94%) participated. Results: Fifty-three per cent of the patients with low physical disability (Expanded Disability Status Scale (EDSS)≤44.0) reported disease-related sexual disturbance and 44% had bladder dysfunction according to the Incapacity Status Scale. The corresponding figures for the patients with a high physical disability (EDSS>44.0) were 86 and 81% respectively. The patients with sexual disturbance had markedly and significantly reduced scores on all eight SF-36 scales, this was after adjustment for disease development measured by the EDSS. The patients without sexual disturbance scored 0.5 s.d. lower than a normal population on the social functioning scale, whereas those with marked sexual disturbance scored 1.5 s.d. lower. Similar results were found for the patients with bladder dysfunction. Conclusion: Bladder and sexual problems are associated with a marked reduction in the quality of life, also among patients with otherwise low disability. This underlines the need for identifying and treating these problems.
Depression during exacerbations in multiple sclerosis: the importance of uncertainty
Authors: Kroencke Dawn C , Denney Douglas R , Lynch Sharon G
Published: January 2007

The following correlates of depression were examined in a sample of 166 patients with clinically definite relapsing-remitting (n=140) or secondary progressive (n=26) multiple sclerosis: (a) the present state of the patients' illness (i.e., whether or not they were currently experiencing an exacerbation of their symptoms); (b) their level of uncertainty concerning their illness; and (c) their strategies for coping with their illness. A current exacerbation in symptoms, greater uncertainty of illness, and greater use of emotion-centered forms of coping were all related to depression. Multivariate analyses revealed that uncertainty of illness played a pivotal role as a mediating variable. Exacerbations in illness appeared to heighten patients' levels of uncertainty, and it was largely through this heightened uncertainty that the increases in depression came about.
Glial toxicity in urine and multiple sclerosis
Authors: Malcus-Vocanson C , Giraud P , Micoud F , Janin V , Charles M H , Broussolle E , Chazot G , Mandrand B , Perron H
Published: January 2007

The biochemical and biological characterization of a cytotoxic activity targeting macroglial cells (oligodendrocytes and astrocytes), in moncyte cultures and in CSF of a patient with multiple sclerosis, has previously been described. In further studies, cell-based tests have shown a good correlation between this glial cytotoxic (gliotoxic) activity, in CSF or in urine, and MS. We now present results obtained with urine samples from 102 MS patients, 51 patients with other neurological disease and 35 healthy subjects using a bioassay set up for the detection of an apoptosis-like effect induced in a glial cell-line. Significant gliotoxicity was detected in urine from 74/102 MS patients while only 4/51 neurological controls (P40.001) and never in healthy subjects (P40.001). Given the statistical tendency provided by this bioassay and its technical limitations for routine testing, it is now used for monitoring the molecular characterization of this `gliotoxic factor'. Its replacement by a specific immunoassay could provide more accurate routine techniques for the detection of this biological marker in MS.
Factors related to agreement between self-reported and conventional Expanded Disability Status Scale (EDSS) scores
Authors: Cheng E M , Hays R D , Myers L W , Ellison G W , Beckstrand M , Vickrey B G
Published: January 2007

Background: Although the Expanded Disability Status Scale (EDSS) remains a widely used scale for evaluating impairments in people with multiple sclerosis (MS), EDSS assessments are infeasible in certain situations. A self-administered version of the EDSS would be potentially usefulif it yielded similar results as the conventional physician-based version. Methods: We developed a self-administered patient questionnaire to obtain ratings of neurologic impairments, and developed algorithms to estimate EDSS scores. We mailed the questionnaires to all new consecutive patients scheduled to be seen at an MS clinic. Questionnaires were completed prior to the visit, and traditional EDSS ratings were made by one of two neurologists at the visit. One hundred and forty-six pairs of patient questionnaires and physician EDSS assessments were obtained. Results: Kappa values for agreement between the physician's EDSS scores and the questionnaire-derived scores were 0.13 (for exact agreement), 0.39 (+0.5 EDSS steps), and 0.56 (+1.0 EDSS steps). A scatterplot showed that agreement was best at EDSS scores 53.0 and 45.0. Better agreement was obtained when patients had a higher level of education, and when the physician was more certain of the diagnosis of MS. Conclusions: While the self-assessed EDSS scores do not agree highly enough to take the place of conventional EDSS scores, they may be sufficient for MS trial screening or for assessing outcomes across broad categories of disability.
Rehabilitation of intimacy and sexual dysfunction in couples with multiple sclerosis
Authors: Foley Frederick W , LaRocca Nicholas G , Sanders Audrey Sorgen , Zemon Vance
Published: January 2007

Sexual dysfunction is a highly prevalent symptom of multiple sclerosis (MS), with little published research on effective treatments. This pilot study tested the efficacy of a counseling intervention in nine couples utilizing a quasi-experimental research design. The intervention consisted of 12 counseling sessions, communication with the MS medical treatment team, education, and tailoring symptomatic treatments so they interfere less with sexual function. Repeated measures analysis of variance indicated significant improvements in affective and problem-solving communication, marital satisfaction, and sexual satisfaction during the treatment vs. the waiting list phase of the study (F=1.7, P5.001). MS patients and their spouses reported similar levels of improvement.
Abnormalities of biogenic amines affecting the metabolism of serotonin and catecholamines
Authors: Lamers Karel JB , Wevers Ron A
Published: January 2007

This paper describes the relevance of measuring biogenic amine metabolites in cerebrospinal fluid in order to detect inborn errors affecting catecholamines and serotonin biosynthesis. Defects in tetrahydrobiopterin and a deficiency of aromatic L-amino acid decarboxylase, tyrosine hydroxylase or dopamine-b-hydroxylase are candidate inborn errors for neurotransmitter matabolites screening. This investigation has to be considered in any child with motor retardation and extrapyramidal signs.
Toxicity in a double-blind, placebo-controlled pilot trial with D-penicillamine and metacycline in secondary progressive multiple sclerosis
Authors: Dubois B , D'Hooghe M B , De Lepeleire K , Ketelaer P , Opdenakker G , Carton H
Published: January 2007

The serine proteinase tissue-type plasminogen activator (t-PA) and the metalloproteinase gelatinase B (MMP-9) have recently been demonstrated in MS lesions. Both enzymes are interconnected in an enzyme cascade which contributes to destruction of the blood brain barrier and demyelination and both enzymes are inhibited by D-penicillamine. Metacycline was shown in in vitro experiments to inhibit gelatinase B. The combination of peroral D-penicillamine plus metacycline was evaluated in a double-blind placebo-controlled way in two groups of 10 patients suffering from secondary progressive multiple sclerosis. The major objectives of this pilot trial were to examine the safety of this combination and the possibility of blinding, while the effect on disease progression was considered as a secondary endpoint. Over a follow-up period of 1 year and in this selected patient group, there was no significant improvement in the Expanded Disability Status Scale score (EDSS) as compared with that of the placebo-control group. Toxicity was too high to consider additional trials with this combination of metalloproteinase inhibitors. Although peroral treatment is by most MS patients acknowledged as a major improvement in treatment compliance, one has to await the development of more selective and efficaceous protease inhibitors than those used in the combination therapy described here.
Neuropathology in multiple sclerosis: new concepts
Authors: Lassmann Hans
Published: January 2007

Multiple sclerosis lesions are characterized by inflammation, demyelination and a variable degree of axonal loss. The patterns of inflammation in MS lesions are compatible with a T-lymphocyte mediated immune reaction. The formation of demyelinated plaques, however, seem to require additional immunological mechanisms. In this review evidence is discussed for a pathogenetic role of demyelinating antibodies, toxic macrophage products, cytotoxic T-cells as well as metabolic disturbances of oligodendrocytes. It is suggested that the pathological heterogeneity regarding the patterns and extent of demyelination, remyelination and axonal loss may be the outcome of variable dominant immunopathogenetic mechanisms in different multiple sclerosis patients.
CSF-enriched antibodies do not share specificities among MS patients
Authors: Cortese I , Capone S , Luchetti S , Grimaldi L ME , Nicosia A , Cortese R
Published: January 2007

The specificity of the oligoclonal immunoglobulins found in MS CSF is unknown. We have previously shown that random peptide libraries displayed on phage can be used to identify specific ligands for CSF antibodies. Here we describe the use of this tool in the attempt to identify MS-specific CSF-enriched antibody reactivities with potential pathogenic, diagnostic or prognostic value. Applying different experimental strategies, several ligands reacting with CSF-enriched antibodies were identified. When tested against a panel of 55 MS patients, none of the ligands found were recognized by antibodies shared by any two patients. We used the selected peptides to demonstrate the stability in time of CSF-enriched antibodies notwithstanding disease progression.
Time-course analysis of CD25 and HLA-DR expression on lymphocytes in interferon-β1b-treated multiple sclerosis patients
Authors: Ferrarini A M , Sivieri S , Buttarello M , Facchinetti A , Perini P , Gallo P
Published: January 2007

To identify immunological markers that could be used to monitor relapsing-remitting multiple sclerosis (RRMS) course/activity during interferon beta 1b (IFNβ1b) therapy, we longitudinally studied HLA-DR and CD25 expression by T lymphocytes in 15 IFNβ1b-treated RRMS patients. Peripheral blood T cell subsets were analysed before therapy (T0), and after 1 (T1), 2 (T2), 3 (T3), 6 (T4) and 12 (T5) months after therapy initiation. HLADR expression and the CD3+HLA-DR+ T cell number showed a peculiar trend in almost all (14/15) the patients: a significant decrease at T1 and T2 followed by a return to pre-treatment levels from T3 to T5. At T1 and T2, eight patients showed an up-regulation of CD25 on CD4, as well as an increase in the CD4+CD25+ cell number. However, a marked, significant reduction of this T cell subset was observed in all the patients at T3, followed by the progressive return to pre-treatment values from T4 to T5. All the patients developed anti-IFNβ1b `binding' antibodies within the first three months of therapy. Our findings demonstrate that: (1) the expression of HLA-DR and CD25 on T cells, as well as the number of circulating CD3+HLA-DR+ and CD4+CD25+ cells, are only transiently reduced in vivo in IFNβ1b-treated RRMS patients, (2) the expression of HLA-DR and CD25 on T lymphocytes cannot be used to monitor MS course/activity during IFNβ1b therapy, (3) the long-lasting beneficial effect of IFNβ1b on RRMS reported in the literature cannot be explained by the down-regulation of MHC class II antigens and/or interleukin-2 receptor expression induced by this cytokine.
Free light chains in multiple sclerosis urine
Authors: Mehta P D , Cook S D , Coyle P K , Troiano R A , Constantinescu C S , Rostami A M
Published: January 2007

We measured free kappa (k) and lambda (l) light chains in urine from patients with definite multiple sclerosis (MS), other neurologic diseases (OND), and normal controls by using an enzyme linked immunosorbent assay. Both k and l light chains were higher in MS than OND or controls. In seven of eight relapsing-remitting (R-R) MS patients serial studies showed that urinary k chains were elevated during periods of worsening, and decreased during clinical recovery. In contrast, the levels of k chains did not correlate with clinical activity in 10 progressive (P) MS patients. Further correlation of urinary light chains with neurologic evaluations in R-R and P MS patients over a longer period are needed to determine their clinical and biological relevance.