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[Scintigraphic diagnosis of esophageal involvement in systemic sclerosis (scleroderma)].

Motor function disturbances (MFD) of the esophagus occur in the majority (90%) of patients with systemic sclerosis. We have tested the diagnostic value of esophagus scintigraphy in 20 patients with systemic sclerosis (12 CREST and 8 with diffuse form) and 18 controls (11 normals and 7 with pyrosis and/or regurgitation), in order to establish sensitivity, specificity, effects of body posture, and use of a liquid or solid meal in the evaluation of MFD of the esophagus. The patients drank 4 ml of fruit juice marked with 500 microCi of 99mTc-sulfur-colloid and afterwards 10 g of an equally marked and scrambled egg. Pictures were made with a Gamma-Camera until 180 s. Radioactivity was plotted against time and separately analysed for the upper, middle and distal esophagus. 65% of the systemic sclerosis patients had dysphagia and 70% had abnormal barium meal transit in the esophagus. The scintigrams were altered in all the patients with systemic sclerosis (p less than 0.001). Sensitivity using fluids was 95%, and specificity was 89%; with solid food 100% and 50%, respectively. Tests done in the upright position showed a better clearance of the esophagus in patients with systemic sclerosis and control patients, with loss of sensitivity. The qualitative analysis yielded little benefit to the reported results. The quantitative analysis under use of 2 indices (total transit time and clearance rate) permitted a clear distinction among patients and control individuals with and without upper digestive symptoms in the first 15 s of the test. The esophagus scintigraphy is a simple, quantitative and very sensitive method for the diagnosis of MFD of the esophagus in patients with systemic sclerosis.

Adult↗
PubMed2001

Matrix metalloproteinases and their tissue inhibitors as markers of disease subtype and response to interferon-beta therapy in relapsing and secondary-progressive multiple sclerosis patients.

Matrix metalloproteinases (MMPs) have recently been implicated in the pathogenesis of multiple sclerosis. Their suggested role includes the disruption of the blood-brain barrier, immune cell transmigration into the central nervous system, and myelin degradation. The present study characterized the mRNA level of a wide spectrum of MMPs and tissue inhibitors of metalloproteinases (TIMPs) expressed by peripheral blood leukocytes from relapsing-remitting (n = 16) and secondary-progressive (n = 12) multiple sclerosis patients. The expression of the same MMPs and TIMPs was evaluated also in a prospective 12-month follow-up of 6 patients randomly chosen from each of the 2 groups during interferon beta-1a treatment. Reverse transcription-polymerase chain reaction assessment demonstrated elevated levels of MT1-MMP and MMP-7 mRNA levels in both groups of patients, and no significant differences in MMP-9 levels, compared with healthy controls. Divergent expression of MMP-2 between relapsing-remitting and secondary-progressive patients compared with controls was observed. Interferon-beta treatment was associated with significant suppression of MMP-9 and MMP-7 mRNA in relapsing-remitting patients, though no significant changes were observed in the secondary-progressive group. These results contribute to the understanding of the IFN-beta-mediated immunomodulatory and therapeutic effects in multiple sclerosis patients and also support evidence for distinct immune mechanism(s) underlying relapsing-remitting versus secondary-progressive multiple sclerosis. The study also suggests that MMPs may be considered as potential biomarkers for response to treatment as well as targets for immunotherapy in multiple sclerosis.

Adjuvants, Immunologic↗
PubMed1997

Tuberin immunohistochemistry in brain, kidneys and heart with or without tuberous sclerosis.

We have studied immunohistochemically the expression of tuberin, the protein product of the TSC2 gene, in cerebral, renal and cardiac tissues obtained from patients with tuberous sclerosis and from control patients. Tuberin immunoreactivity was moderate to strong in neurons and reactive astrocytes of control brains, but was reduced in brains with tuberous sclerosis. Staining intensity of abnormal giant cells varied from negative to moderate in cortical tubers, subependymal nodules and subependymal giant cell astrocytomas. In control kidneys, uriniferous and collecting tubules showed positive immunoreactivity, whereas a focal decrease in their staining intensity was noted in kidneys with tuberous sclerosis. Renal angiomyolipomas were negative for tuberin. In the heart, cardiac muscles in both control and tuberous sclerosis patients were strongly immunoreactive. Cardiac rhabdomyomas in the latter were stained less intensely. These results provide histological evidence for the loss of tuberin in tuberous sclerosis tissues, which is associated with the development of hamartomas in an organ-specific manner.

Adolescent↗
PubMed2000

No evidence for transmission disequilibrium between a new marker at the myelin basic protein locus and multiple sclerosis in French patients.

The myelin basic protein (MBP) gene is a candidate locus for susceptibility to multiple sclerosis. Several groups have tested a complex (TGGA)n repeat in the 5' region of this gene for association/linkage with multiple sclerosis, with divergent results. This region of tandem repetitive sequence has been subjected to complex rearrangements, and there is a possibility that alleles of the same size have different internal structures, which reduces the interest of this marker for linkage disequilibrium studies and may at least partly explain the conflicting results obtained so far. To overcome this problem, we isolated a new polymorphic (CA)n repeat within the Golli-MBP locus. The limited number of alleles identified makes this other marker suitable for transmission disequilibrium studies. We tested this marker for linkage with multiple sclerosis, using the transmission-disequilibrium test (TDT) on a sample of 196 nuclear families in which the genotypes of both parents could be unambiguously defined. We found no evidence of transmission disequilibrium between multiple sclerosis and any of the three alleles of this marker, even when the patients were subdivided according to their HLA-DRB1*1501 status. The present data thus provide no evidence for a contribution of the MBP gene to multiple sclerosis susceptibility in French patients.

Base Sequence↗
PubMed1986

[Clinical variants of amyotrophic lateral sclerosis: hemiplegic type of ALS and Mills syndrome. A critical review].

According to the clinical classification of amyotrophic lateral sclerosis by Hemmer its "hemiplegic type" is described from two observations in 37 personal cases. The peculiar difficulties of differential diagnosis especially with the hemiplegic type of multiple sclerosis in two further cases are discussed in detail. Four cases of "Mills' syndrome" are compared. "Mills' syndrome" has been assumed to be a slowly progressive, unilateral ascending or descending variant of amyotrophic lateral sclerosis. A study of Mills' original papers and evaluation of personal observations leads to a more critical assessment. In Mills' original cases, widely different entities such as multiple sclerosis, syphilis, and parkinsonism are included besides amyotrophic lateral sclerosis. In the light of the investigations presented here, Mills' syndrome seems to be merely an obsolete clinical term.

Adult↗
PubMed1997

Renal cystic disease in tuberous sclerosis: role of the polycystic kidney disease 1 gene.

Tuberous sclerosis is an autosomal dominant trait characterized by the development of hamartomatous growths in many organs. Renal cysts are also a frequent manifestation. Major genes for tuberous sclerosis and autosomal dominant polycystic kidney disease, TSC2 and PKD1, respectively, lie adjacent to each other at chromosome 16p13.3, suggesting a role for PKD1 in the etiology of renal cystic disease in tuberous sclerosis. We studied 27 unrelated patients with tuberous sclerosis and renal cystic disease. Clinical histories and radiographic features were reviewed, and renal function was assessed. We sought mutations at the TSC2 and PKD1 loci, using pulsed field- and conventional-gel electrophoresis and FISH. Twenty-two patients had contiguous deletions of TSC2 and PKD1. In 17 patients with constitutional deletions, cystic disease was severe, with early renal insufficiency. One patient with deletion of TSC2 and of only the 3' UTR of PKD1 had few cysts. Four patients were somatic mosaics; the severity of their cystic disease varied considerably. Mosaicism and mild cystic disease also were demonstrated in parents of 3 of the constitutionally deleted patients. Five patients without contiguous deletions had relatively mild cystic disease, 3 of whom had gross rearrangements of TSC2 and 2 in whom no mutation was identified. Significant renal cystic disease in tuberous sclerosis usually reflects mutational involvement of the PKD1 gene, and mosaicism for large deletions of TSC2 and PKD1 is a frequent phenomenon.

Adolescent↗
PubMed2006

Multiple sclerosis, natalizumab therapy, and progressive multifocal leukoencephalopathy.

PURPOSE OF REVIEW: Multiple sclerosis affects many people, often in early adulthood, and causes significant disability. Natalizumab is a novel agent to be evaluated for multiple sclerosis and Crohn's disease that has demonstrated unique efficacy but has unfortunately been implicated in three cases of progressive multifocal leukoencephalopathy. This review covers the mechanism of action of natalizumab and efficacy for multiple sclerosis, the three cases of natalizumab-associated progressive multifocal leukoencephalopathy, our understanding of progressive multifocal leukoencephalopathy, and the mechanisms that may account for these events. RECENT FINDINGS: Natalizumab, an anti-alpha4-integrin antibody, binds to T-cell surface receptors to prevent migration from the circulation into the brain tissue. Phase II and III trials have been completed and demonstrate previously unseen efficacy in preventing relapses and disease progression. The cases of progressive multifocal leukoencephalopathy, two fatal and one disabling, resulted in the voluntary suspension of natalizumab and bring this entire class of agents into doubt. It is important to determine what led to the development of progressive multifocal leukoencephalopathy in the natalizumab-associated cases and to advance understanding and continue to develop therapies for the treatment of multiple sclerosis. SUMMARY: With ongoing safety evaluations, natalizumab is being reevaluated by the US Food and Drug Administration for possible reapproval and return to the market. If natalizumab is reapproved, challenging questions and issues will remain in treating patients with multiple sclerosis.

Adult↗
PubMed1965

OBSERVATIONS ON VITAMIN B12 IN SERUM AND CEREBROSPINAL FLUID IN MULTIPLE SCLEROSIS.

There are several claims that B(12) concentrations in serum and cerebrospinal fluid are grossly abnormal in multiple sclerosis, but results are conflicting. This paper reports measurements of these concentrations in 40 serum samples and 23 samples of lumbar cerebrospinal fluid from cases of multiple sclerosis, and in appropriate controls, using Euglena gracilis, z strain. The serum concentrations were found to be normal; the mean concentration in cerebrospinal fluid was slightly reduced, but all values were within the control range. In both control samples and samples from cases of multiple sclerosis, the B(12) concentration in lumbar cerebrospinal fluid was correlated with the concentration in serum. There was no correlation between B(12) concentration and total protein in cerebrospinal fluid.A number of estimations of serum B(12) were also made with Lactobacillus leichmannii, after extraction in the presence and absence of cyanide. These showed a difference between cases of multiple sclerosis and controls, one interpretation of which might be that the serum in multiple sclerosis contains an abnormally low concentration of hydroxocobalamin.

Blood↗
PubMed1996

Identification of a nonsense mutation at the 5' end of the TSC2 gene in a family with a presumptive diagnosis of tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited disease with a high mutation rate. It is clinically a very variable disorder and hamartomas can occur in many different organs. TSC shows genetic heterogeneity; one gene, TSC1, is on chromosome 9q34, and the second gene, TSC2, on chromosome 16p13.3. Clinical criteria for diagnosis have been established, but diagnosis of patients with minimal expression of the disease can be very difficult. In children the phenotype is often incomplete or not fully assessable. Hence mildly affected subjects, at risk for severely affected offspring, may remain undiagnosed. The detection of (small) mutations in the tuberous sclerosis gene located on chromosome 16 (TSC2) has recently become possible and may be helpful in the diagnosis of ambiguous cases. To our knowledge, this is the first report of a point mutation in the TSC2 gene in a familial case of tuberous sclerosis. A nonsense mutation was detected in a family in which the father had only minor signs hinting at tuberous sclerosis. The son had multiple cardiac tumours and white patches, but full clinical investigation was impossible in this child. This case illustrates that mutation analysis can contribute to a diagnosis of tuberous sclerosis in families with an incomplete phenotype.

Adult↗
PubMed2003

Standardized, reproducible, high resolution global measurements of T1 relaxation metrics in cases of multiple sclerosis.

BACKGROUND AND PURPOSE: We herein present a methodology for standardized and clinically applicable measurement of T1 relaxation maps with high resolution and volumetric coverage by using the commercially available 3D spoiled gradient-echo sequence. The reproducibility of the T1 metrics derived from these maps and their sensitivity to distinguish between control participants and patients with multiple sclerosis are evaluated. METHODS: Axial view 3D RF spoiled data sets with two flip angles were acquired at 1.5 T to generate the T1 maps, with all other imaging parameters (27/6 ms [TR/TE]; field of view, 180 x 240 x 186 mm(3); matrix, 192 x 256 x 124) kept identical between the two acquisitions. T1 maps were collected from 20 normal control participants and 32 patients with multiple sclerosis. An automated and operator-independent method was developed to segment the relaxation maps and define T1 metrics. RESULTS: We showed that the metrics derived from these maps to represent tissue characteristics were highly reproducible (coefficient of variation, approximately 1% to 4%) and were significantly different between normal control participants and patients with multiple sclerosis (P <.001) for the small cohort of patients in this study. CONCLUSION: The commercially accessible 3D spoiled gradient-echo sequence can be used to generate T1 relaxation maps with high resolution and volumetric coverage. The metrics derived from the relaxation maps are reproducible and have been shown to be sensitive to qualitative and quantitative differences between subgroups of patients with multiple sclerosis and control participants, with strong statistical significance. The use of a commercially available sequence enables the standardization and comparison of T1 metrics across different multiple sclerosis centers.

Artifacts↗
PubMed2007

Mitoxantrone reduced disability in Iranian patients with multiple sclerosis.

BACKGROUND: Multiple sclerosis is a leading cause of disability in young adults. Mitoxantrone has recently been shown to be effective in ameliorating multiple sclerosis activity and reducing the relapse rate. This study aimed to assess the efficacy of mitoxantrone on disease activity and decreasing relapse rate in patients with multiple sclerosis in Iran. METHODS: This was a clinical trial on patients who received intravenous mitoxantrone, 12 mg/m2 every 3 months. The study was performed at Isfahan Multiple Sclerosis Clinics, affiliated to Isfahan University of Medical Sciences. This clinical trial was conducted from October 2003 through April 2005. One hundred and forty-seven patients with worsening relapsing-remitting and secondary progressive multiple sclerosis received mitoxantrone, 12 mg/m(2) every 3 months. Clinical assessment was made every 3 months for one year. RESULTS: Of the 147 patients, 129 (93 females and 36 males) could successfully complete the course of our study. A significant therapeutic effect (P < 0.0001) was detected for the attack rate before and after treatment. The Mean attack rate 12 months before treatment was 1.10 (SD = 0.95), which reduced to 0.09 (SD = 0.29) during treatment. The Mean expanded disability status scale at the beginning of the treatment was 4.32, which declined to 3.62 (P < 0.0001) after one year. CONCLUSION: Mitoxantrone was generally well tolerated and reduced progression of disability and clinical exacerbation in our patients. Physicians must be careful about the complications of mitoxantrone especially cardiotoxicity.

Adolescent↗
PubMed1988

Genetic susceptibility to multiple sclerosis. A co-twin study of a nationwide series.

The problems of differentiation between environmental and genetic influences on the development of multiple sclerosis are well known. Twin studies may provide valuable information on this question. However, most published twin series are selected and no through clinical twin studies based on epidemiologic series have been carried out. In this study, all available same-sex twin pairs with clinically definite multiple sclerosis derived from the Finnish Twin Cohort of 15815 pairs were studied by clinical evaluation, magnetic resonance imaging, and visual and auditory evoked responses. The mean length of follow-up of the pairs after the onset of symptoms of multiple sclerosis was 20 years. Two of the seven monozygotic pairs were concordant; one was definitely so, and in the other, the co-twin of the index case had, in addition to clinical findings, white matter changes suggestive of multiple sclerosis in magnetic resonance imaging and abnormal visual evoked responses. All six dizygotic pairs were discordant. The frequency of the HLA antigen DR2 in probands (69%) was significantly increased, but the distribution among the healthy subjects and patients showed nonsignificant differences. The results indicate a genetic influence on the susceptibility to multiple sclerosis, although still unknown genetic determinants are possible involved.

Adult↗
PubMed1991

Incidence and prevalence of amyotrophic lateral sclerosis in Harris County, Texas, 1985-1988.

The incidence of amyotrophic lateral sclerosis was determined in Harris County, Texas, for the period 1985 through 1988. Amyotrophic lateral sclerosis cases were ascertained from four sources: area neurologists, hospitals, death certificates, and the Muscular Dystrophy Association. The age-adjusted incidences of 1.27 per 100,000 person-years in males and 1.03 per 100,000 person-years in females were lower than recent rates in the northern US, Canadian, and northern European studies but higher than rates in southern European studies. Comparisons with other recent incidence studies show less uniformity in occurrence of amyotrophic lateral sclerosis, in both the overall rates and in the age- and sex-specific patterns, than was suggested by mortality studies. The incidence of amyotrophic lateral sclerosis among blacks and whites was similar. Hispanic males had incidences similar to white males, although a deficit of female Hispanic cases was found in Harris County. The prevalence of amyotrophic lateral sclerosis peaked in the 65- to 74-year age group at 33 per 100,000 population among males and 19 per 100,000 population for females.

Adolescent↗
PubMed1992

Increased metallothionein in the liver and kidney of patients with amyotrophic lateral sclerosis.

To evaluate the putative role of metals and trace elements in the pathogenesis of classic amyotrophic lateral sclerosis, we studied the metallothionein levels in liver and kidney samples obtained at autopsy from 24 patients with amyotrophic lateral sclerosis and 18 controls. To assay metallothioneins and copper, cadmium, and zinc bound to metallothioneins, we used high-performance liquid chromatography directly coupled to flame atomic absorption spectrometry. Total cadmium, zinc, and copper concentrations were determined separately with the use of graphite furnace atomic absorption spectrometry with Zeeman background correction. The median liver metallothionein level was 60.3 mg/kg (range, 9 to 318 mg/kg) in the patients with amyotrophic lateral sclerosis and 12.6 mg/kg (range, 0 to 104.5 mg/kg) in the controls. In the kidney, median metallothionein levels were 126.9 mg/kg (range, 44 to 387 mg/kg) in the patients with amyotrophic lateral sclerosis and 64 mg/kg (range, 13.1 to 187 mg/kg) in the controls. Total zinc, cadmium, and copper concentrations, as measured by atomic absorption spectrometry, were not significantly different in patients vs controls. Our finding of elevated metallothionein levels in organs from patients with amyotrophic lateral sclerosis may indicate an increased exposure to metals.

Adolescent↗
PubMed1994

Survival in amyotrophic lateral sclerosis. The role of psychological factors.

OBJECTIVE: Examining the relationship between psychological status and survival in amyotrophic lateral sclerosis. Our hypothesis is that psychological distress is associated with greater mortality and shorter survival time than psychological well-being. DESIGN: Cross-sectional, longitudinal. The baseline evaluations used were disease severity and 10 psychometric tests. A psychological status score was derived from these tests. Survival status was monitored for 3.5 years. Interviewers were blinded to other interviews and data analysis. SETTING: Patient's residence. PATIENTS: The criteria for eligibility were diagnosis of amyotrophic lateral sclerosis by a neurologist, dementia or alcoholism absent, communication in English, and any severity or length of disease. It was a volunteer sample consisting of 144 patients from amyotrophic lateral sclerosis clinics or community-based amyotrophic lateral sclerosis support groups. In this sample 66% were men, 94% were white, mean age at diagnosis was 55 years, 79% were married, 60% had some college education, and 61% died during the study. INTERVENTIONS: None. MAIN OUTCOME MEASURES END POINTS: mortality during study, survival time from intake to last follow-up. RESULTS: Comparison between high and low psychological score groups: 32% of high and 82% of low died; survival curves were significantly different. Controlling for confounding factors (length of illness, disease severity, age), patients with psychological distress had a greater risk of mortality (relative risk, 6.76; 95% confidence limits, 1.69 to 27.12) and greater likelihood of dying in any given time period (relative risk, 2.24; 95% confidence limits, 1.08 to 4.64) than those with psychological well-being. CONCLUSION: Adjusting for confounding factors, psychological status is strongly related to outcome in amyotrophic lateral sclerosis. Further studies on psychological status should be done to confirm its prognostic value.

Amyotrophic Lateral Sclerosis↗
PubMed1995

Cognitive impairment in early-onset multiple sclerosis. Pattern, predictors, and impact on everyday life in a 4-year follow-up.

OBJECTIVES: To assess the evolution of cognitive dysfunction in early-onset multiple sclerosis, to identify clinical predictors of mental decline, and to determine its impact on a patient's everyday life. DESIGN: The cognitive performance of 50 patients with multiple sclerosis on a neuropsychological battery was compared with that of 70 control subjects initially and again after a 4-year interval. Clinical predictors of cognitive impairment and its effect on daily life were analyzed by stepwise linear regression. SETTING: The research clinic of a university department of neurology. PARTICIPANTS: A consecutive sample of 50 inpatients and outpatients with multiple sclerosis (mean disease duration, 1.58 years) and 70 demographically matched healthy control subjects selected from the patients' relatives and friends. MAIN OUTCOME MEASURES: Mean psychometric test scores of both groups at the initial and follow-up testing. Regression coefficients measuring the relationship between clinical parameters and cognitive capacity and between mental decline and performance of common tasks measured by the Environmental and the Incapacity Status scales. RESULTS: Multiple sclerosis-related deficits in verbal memory and abstract reasoning on initial testing remained more or less stable on the retest, at which time linguistic disturbances on the Set and Token tests also emerged. A patient's initial disability level predicted decreased performance on only four of 13 cognitive variables, and disease duration did so on only two. Extent of intellectual decline on initial testing, initial disability level, and progressive course were independent determinants of handicap in a patient's work and social activities. CONCLUSIONS: Cognitive and neurological deficits appear not to develop in parallel. Yet cognitive dysfunction proves to be a predictor of handicap in everyday life, even in patients in the incipient phase of multiple sclerosis.

Adolescent↗
PubMed2000

Clinical significance of the multiple sclerosis functional composite: relationship to patient-reported quality of life.

BACKGROUND: The Multiple Sclerosis Functional Composite (MSFC) was recommended by a task force of the National Multiple Sclerosis Society as a new clinical outcome measure for clinical trials. The task force recommended that the MSFC be validated against other measures of the disease, such as patient-reported quality of life. METHODS: Three hundred patients with multiple sclerosis (MS) representing the spectrum of disease severity were included in this cross-sectional study. The MSFC and Kurtzke Expanded Disability Status Scale (EDSS) were used as measures of disease severity. Clinical relevance of the disease severity scores was analyzed using measures included in the Multiple Sclerosis Quality of Life Inventory. The MSFC and EDSS scores were correlated with self-reported employment status, the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and the Sickness Impact Profile (SIP). RESULTS: The MSFC and EDSS scores were strongly correlated (r = -0.80, P<.001). The MSFC scores were correlated with patient-reported physical functioning (SIP Physical Summary Scale: r = -0.71, P<.001; SF-36 Physical Component Score: r = -0.41, P<.001). The MSFC scores were significantly but more weakly correlated with emotional functioning (SIP Psychosocial Summary Scale: r = -0.34, P<.001). After controlling for EDSS scores, there were significant residual correlations between the MSFC scores and measures of health-related quality of life, suggesting that the MSFC accounts for the variability in health-related quality of life measures not reflected by the EDSS. CONCLUSIONS: The observed strong correlations between MSFC scores and validated measures of self-reported quality of life indicate that the MSFC scores are clinically relevant. This study supports a recommendation by the National Multiple Sclerosis Society Task Force to use the MSFC as a clinical outcome measure.

Adult↗
PubMed2001

Oligoclonal band number as a marker for prognosis in multiple sclerosis.

The natural course of disease in multiple sclerosis varies. Multiple sclerosis that is clinically apparent but causes minimal disability over time has been labeled benign multiple sclerosis. The ability to predict the subsequent clinical course of multiple sclerosis on the basis of clinical and other supportive data at presentation would be invaluable. In this article we report our findings based on a retrospective analysis of 1800 patients diagnosed as having multiple sclerosis, of which 44 patients met our inclusion criteria. There was a suggestion that a low or absent number of oligoclonal bands in the cerebrospinal fluid at the time of diagnosis predicts a better prognosis. However, quantification of oligoclonal bands in cerebrospinal fluid remains an insensitive prognostic indicator and must not be used to influence decisions regarding therapeutic options.

Adult↗