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Biomedical subjects

C H Polman

Publications and source records attributed to C H Polman.

At least 19 recordsLinked to original sources
PubMed1997

TNF-alpha promoter polymorphisms, production and susceptibility to multiple sclerosis in different groups of patients.

TNF-alpha production in whole blood cultures upon stimulation with LPS was determined in 179 individuals from 61 families in order to characterise the magnitude of inherited differences in TNF-alpha production. The three families characterised by highest TNF production showed 7.1 +/- 0.3 ng TNF/ml upon culture with 10 ng LPS and 10.2 +/- 0.2 ng TNF/ml upon culture with 1000 ng LPS. in contrast to the three families characterised by the lowest TNF production that showed a production of 1.6 +/- 0.1 ng TNF upon culture with 10 ng and 2.5 +/- 0.2 ng/ml upon culture with 1000 ng LPS/ml. This difference could not be attributed to the promoter polymorphisms -308 G to A. -238 G to A or -376 G to A, although the -238 GA donors produced 2.1 +/- 0.9 ng TNF upon culture with 10 ng endotoxin compared to 3.2 +/- 2.2 ng TNF for the -238 GG donors. In line with these results the frequency of the -238 GG genotype was increased in hospitalized MS patients in a nursing home (100% 238GG, n = 57) compared to MS patients in an outpatient's clinic (94% 238GG, n = 98) or Dutch controls (90% 238GG, n = 180). These results suggest that the -238 GG genotype is differently distributed in hospitalized MS patients in a nursing home.

Disease Susceptibility↗
PubMed1997

Specific power calculations for magnetic resonance imaging (MRI) in monitoring active relapsing-remitting multiple sclerosis (MS): implications for phase II therapeutic trials.

Inhomogeneous patient samples have been used in previous studies to determine the power of magnetic resonance imaging (MRI) for trial monitoring in multiple sclerosis (MS). These power-calculations might not be applicable to the active relapsing-remitting patient who is preferably included in trials. In order to reevaluate the power-calculations for MRI in the monitoring of treatment in strictly relapsing-remitting MS and to compare the power of different trial designs we studied 12 relapsing-remitting MS patients prospectively for a median period of 12 months using monthly clinical assessments and gadolinium-enhanced MRI. A median number of two clinical relapses/patient occurred of which a median of one was treated with steroids. A median of 1.59 new lesions/scan/patient was detected (range 0-8). The total number of new active lesions correlated significantly with study period relapses (SRCC = 0.72, P = 0.023). Computer simulations using the bootstrap technique yielded mostly lower power values for a parallel groups design than in previous studies except for short follow-periods in larger samples. In this-sample the open cross-over design was found to be between 20 and 40% more powerful. Results of power-calculations are clearly sample dependent implying that for treatment trial monitoring using MRI in relapsing-remitting MS conservative sample size estimates are to be used. In an active patient group open cross-over trial designs could be a very powerful alternative to parallel groups design.

Adult↗
PubMed1996

Quality of life in multiple sclerosis: the disability and impact profile (DIP).

Seventy-three Dutch and Flemish patients with definite multiple sclerosis (MS) were assessed by means of the Disability and Impact Profile (DIP), which is a 2 x 39 item, self-administered questionnaire with parallel questions about disabilities and their importance for or impact on the patient, resulting in a profile of weighted scores. It was designed as a tool for clinical assessment of quality of life (QoL) domains in MS patients. Group data showed more than 50% loss on weighted scores for "walk", "clean home", "work" and "worry about deterioration". In individual patients a median of 7 (range 0-23) major disruptions of quality of life (MD-QoL: loss on weighted score more than 50%) was found. Prevalence of MD-QoL in more than 10% of the patients was found for as many as 31 disabilities and > 50% for 3 ("clean home", "work" and "worry about deterioration"). Results in the MS group were compared with available data from 25 patients with rheumatoid arthritis (RA) and 25 patients with a spinal cord lesion (SCl). Weighted scores of "read", "memory" and "concentration" were significantly lower in the MS group than in the RA and SCl groups. Significantly lower weighted scores in both the MS and RA groups were found for "worry about deterioration", "physical endurance", "clean home", "work", "see" and "write". In conclusion, major disruptions in many domains of QoL were found in MS patients. Weighted score profiles for MS were in accordance with clinical manifestations. Unlike Kurtzke's Extended Disability Status Scale, DIP assesses a wide range of potentially MS-affected human activities, and also takes into account the subjective perception of disabilities.

Adult↗
PubMed1996

The effect of the 21-aminosteroid U74006F on the clinical course of acute experimental allergic encephalomyelitis.

We evaluated the clinical effect of several doses of the 21-aminosteroid U74006F in acute experimental autoimmune encephalomyelitis (EAE) and compared it with the administration of methylprednisolone (MP). There was no significant change in the clinical course of EAE with the dosages we used, whereas the effect of MP was unquestionably beneficial. Based on these results U74006F does not seem to be a promising drug for the treatment of exacerbations of multiple sclerosis.

Acute Disease↗
PubMed1996

A pilot study investigating the effects of orally administered pentoxifylline on selected immune variables in patients with multiple sclerosis.

Multiple sclerosis is probably mainly mediated by T-helper 1 (TH1)-lymphocytes. TH1-function can be down-regulated in vitro and in animal experiments by pentoxifylline. Therefore, we included 20 multiple sclerosis patients in an open label pilot trial of pentoxifylline. Outcome parameter was the effect of treatment on levels of various cytokines and adhesion molecules in cerebrospinal fluid and serum, on production of TH1- and TH2-cytokines using cell stimulation assays, as well as on measures of T-cell activation and proliferation. Kurtzke's EDSS was a secondary efficacy parameter. A convincing and consistent effect of pentoxifylline could not be demonstrated.

Administration, Oral↗
PubMed1996

Recombinant interferon-beta blocks proliferation but enhances interleukin-10 secretion by activated human T-cells.

Results from recent clinical trials have indicated that recombinant interferon-beta (rIFN-beta) is a promising drug for the treatment of Multiple Sclerosis (MS), a disease of supposed autoimmune etiology. To gain insight into the immunoregulatory properties of this cytokine, we analyzed effects of interferon-beta (IFN-beta) on T-cell functions in vitro. Interferon-beta inhibited T-cell proliferation, as well as T-cell-dependent immunoglobulin secretion, in a dose-dependent manner. IFN-beta did not inhibit upregulations of CD40L on activated T-cells, but blocked induction of CD25 on stimulated T- and B-lymphocytes. Secretion of interferon-gamma (IFN-gamma), tumour necrosis alpha (TNF-alpha) and IL-13 was inhibited by the addition of IFN-beta, whereas IL-4 secretion was unaffected. Interestingly, IFN-beta enhanced secretion of IL-2 about two-fold and secretion of IL-10 nearly four-fold. In summary, these findings suggest that IFN-beta may exert direct effects on T- and beta-cell function in vivo. In addition, enhanced secretion of IL-10 by activated T-cells may interfere with newly initiated and ongoing inflammatory immune reactions.

B-Lymphocytes↗
PubMed1996

Disappearance of multiple sclerosis lesions with severely prolonged T1 on images obtained by a FLAIR pulse sequence.

Although the superiority of FLAIR over conventional T2-weighted spin-echo (SE) is still unclear, one potential advantage would be its use in quantitative lesion load measurements. We have observed a potential pitfall regarding the use of FLAIR in image quantification. We report a case where a part of the hyperintense lesions on T2 SE, which was hypointense on T1 SE, subsequently was found to be isointense to brain on FLAIR images. Therefore, quantification of lesion load by means of FLAIR might underestimate the "true" lesion load, as seen on T2 SE.

Brain↗
PubMed1996

Accumulation of hypointense lesions ("black holes") on T1 spin-echo MRI correlates with disease progression in multiple sclerosis.

MRI findings are increasingly used as outcome measures in therapeutic trials in MS. The discrepancy between the extent of the lesions on conventional T2 images and the clinical condition of the patient is one of the problems encountered in such studies. This clinical-radiological paradox prevents the use of MRI data as surrogate markers of disability in MS. A recent pilot study suggested a relationship between hypointense lesions on T1 MRI and disability. To assess in more detail the correlation of changes in hypointense lesion load on T1-weighted spin-echo MR images ("black holes") with changes in disability in MS, we studied 46 patients with clinically definite MS at baseline and after a median follow-up of 40 months. There was a significant correlation between baseline disability and hypointense lesion load (Spearman rank correlation coefficient [SRCC] = 0.46, p = 0.001). In secondary progressive patients, the rate of accumulation of these "black holes" was significantly related to progression rate (SRCC = 0.81, p < 0.0001). We speculate that the appearance of hypointense lesions is the MRI equivalent of a failure of remission. Overall, T1 lesion load measurements correlated better with clinical assessments than T2 lesion load measurements. Quantification of hypointense lesion load on T1-weighted spin-echo MRI helps to resolve the clinical-radiological paradox between disability and MRI and has the potential to be a surrogate marker of disability in MS.

Adult↗
PubMed1996

Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2.

There is evidence that treatment with an antibody to tumor necrosis factor alpha (TNF alpha) improves an animal model of multiple sclerosis (MS) and is beneficial in two systemic inflammatory disease in humans, but there are no reports about anti-TNF treatment of MS. Therefore, we treated two rapidly progressive MS patients with intravenous infusions of a humanized mouse monoclonal anti-TNF antibody (cA2) in an open-label phase I safety trial and monitored their clinical status, gadolinium-enhanced brain magnetic resonance imaging (MRI), and peripheral blood and cerebrospinal fluid (CSF) immunologic status. We did not notice any clinically significant neurologic changes in either patient. The number of gadolinium-enhancing lesions increased transiently after each treatment in both patients. CSF leukocyte counts and IgG index increased after each treatment. The transient increase in the number of gadolinium-enhancing lesions that followed each infusion of cA2 together with the increase in cells and immunoglobulin in the CSF of each patient suggest that the treatment caused immune activation and an increase in disease activity. These results suggest that further use of cA2 in MS is not warranted and that studies of other agents that antagonize TNF alpha should be carried out with frequent monitoring of gadolinium-enhanced MRIs.

Adult↗
PubMed1995

The small heat-shock protein alpha B-crystallin as candidate autoantigen in multiple sclerosis.

The identification of key antigens in human autoimmune diseases is a crucial step towards the development of specific intervention. The autoantigen(s) relevant to multiple sclerosis (MS) probably reside in myelin of the central nervous system, the target of the disease. Here we examine proliferative responses of human peripheral blood T cells to the complete collection of myelin proteins fractionated by reversed-phase high-performance liquid chromatography. Myelin isolated from MS-affected brain contained a single protein fraction to which T cells from MS patients and from healthy controls showed dominant responses. This highly immunogenic protein was identified as alpha B-crystallin, a small heat-shock protein. Immunohistochemical examination of MS lesions revealed the presence of oligodendrocytes and astrocytes with raised alpha B-crystallin expression, which were not found in unaffected myelin. Our findings indicate that alpha B-crystallin serves as immunodominant myelin antigen to human T cells when expressed at the elevated levels found in active MS lesions.

Astrocytes↗
PubMed1995

Analysis of CD27 surface expression on T cell subsets in MS patients and control individuals.

Within the peripheral blood, CD4+CD27- T cells only reside within the CD45RA- (memory or primed) T cell subset. Cells with this phenotype have characteristics of specialized effector T cells according to their cytokine secretion profiles and the expression of tissue-specific adhesion molecules. This subset was previously found to be increased in certain diseases that are associated with immune activation. Therefore we analyzed CD27 expression of peripheral blood and CSF T cells in MS patients. Within the CD4+ T cell subset no differences were seen between MS patients and controls in proportions of CD45RA-CD27- cells. However, when the CD3+ T cell compartment was analyzed, CD27- cells were also found within the CD45RA+ subset. These cells, most likely CD8+, are significantly reduced in PBL and CSF of MS patients as compared with OND patients. In MS and OND groups the level of CD27- cells in peripheral blood correlated significantly with that in CSF, indicating a balanced migration of CD27- cells between the two compartments. In OIND patients, however, this equilibrium was lost. The correlation of the level of CD27+ cells with the amount of intrathecally produced IgG in MS patients may suggest that CD27+ cells are responsible for B cell help in this disease.

Adult↗
PubMed1995

The treatment of multiple sclerosis: current and future.

During the past year observations have been published that might lead to further improvement in the design of future clinical trials. At the same time, results of clinical trials have become available that suggest that a number of treatments could be of benefit in the care of patients in the various phases of multiple sclerosis. Future multiple sclerosis clinical trials should involve a blinded investigator restricted to assessing the clinical outcome variables, and because current evidence suggests that magnetic resonance imaging gives an objective and sensitive reflection of the biological evolution of the disease, such scanning should also be included. The use of a composite outcome variable in a trial of chronic progressive multiple sclerosis should also be considered in order to increase the percentage of patients reaching the clinical endpoint. In 1994 recommendations were published for the selection of relapsing-remitting patients for treatment with interferon beta-1b; furthermore, large and well performed clinical trials demonstrated that interferon beta-1a and copolymer-1 are also partially effective, though not curative, for these patients. Two smaller studies suggested that low-dose methotrexate and cladribine might have a beneficial effect on the course of the disease in patients with secondary chronic progressive multiple sclerosis, the former drug probably being less toxic. Unfortunately, therapeutic perspectives for patients with primary progressive multiple sclerosis are less promising at present. Several studies suggest that 4-aminopyridine and tizanidine have therapeutic potential for symptomatic treatment; the former by improving neurological deficits, the latter by relieving troublesome spasticity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adjuvants, Immunologic↗
PubMed1995

Increased number of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of patients with multiple sclerosis.

Observations in experimental allergic encephalomyelitis (EAE), a model for multiple sclerosis (MS), have indicated that a low activity of the hypothalamo-pituitary-adrenal (HPA) system is accompanied by a high susceptibility for EAE in rat strains and that elevated corticosteroid levels are necessary for spontaneous recovery from EAE. The HPA axis activity is regulated by both corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). Both types of neurons are localized in the paraventricular nucleus (PVN) of the hypothalamus. We determined the number of immunocytochemically identified CRH-immunoreactive (CRH-IR) and AVP-immunoreactive (AVP-IR) neurons in the PVN of the human hypothalamus of 8 MS patients, aged 34-63 years, and 8 age-matched control subjects without any primary neurological or psychiatric disorders, aged 30-59 years. In addition, the number of oxytocin (OXT) immunoreactive (OXT-IR) neurons was determined, since these neurons innervate brain stem nuclei and might thus be related to autonomic disturbances in MS. In MS the staining intensity for AVP was clearly lower and for OXT slightly lower. For CRH, the staining intensity was similar in both groups, and, moreover, in MS patients the number of CRH-IR cells in the PVN was found to be about 2.4 times higher than that in the control group. The number of OXT-IR or AVP-IR cells in the PVN of MS patients was not significantly different from that of the control group. Our results point to an activation of the neuroendocrine HPA axis which may be compatible with the idea that the HPA axis is involved in recovery from MS.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Correlating MRI and clinical disease activity in multiple sclerosis: relevance of hypointense lesions on short-TR/short-TE (T1-weighted) spin-echo images.

Magnetic resonance imaging (MRI) is being used as an outcome criterion in therapeutic trials in multiple sclerosis (MS) on the assumption that it, as a sensitive marker of biologic disease activity, could serve as a surrogate marker of disability. We evaluated the relation between MRI findings and disability in a quantitative follow-up study of 48 MS patients. Median duration of follow-up was 24 months (range, 10 to 42 months). Computer-assisted volume measurements employing a seed-growing technique yielded a standard error of measurement of 0.275 cm2. The median total area of the hyperintense lesions on the initial T2-weighted images was 8.4 cm2. The median increase was 0.76 cm2/yr (9%). In a subgroup (n = 19) with short-TR/short-TE spin-echo (SE) images, we measured the hypointense lesion load. The median total area of the lesions at entry was 0.70 cm2, with a median increase of 0.28 cm2/yr (40%). The total area of the hyperintense lesions on the initial T2-weighted images showed a weak correlation with the Expanded Disability Status Scale score at entry (Spearman rank correlation coefficient [SRCC] = 0.30; 0.02 < p < 0.05). The increase in disability showed a positive correlation (SRCC = 0.19) with the increase in hyperintense lesion load on the T2-weighted SE images, but this correlation did not reach statistical significance (p = 0.09), probably because of lack of clinical progression.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Multiple sclerosis therapy. A practical guide.

A growing amount of evidence suggests that a disturbance of immunological function is of importance in the pathogenesis of multiple sclerosis. This is reflected in the drugs used to slow progression and to treat relapses. Immunosuppressive drugs such as azathioprine, cyclophosphamide and cyclosporin might have some potential to slow down progression of multiple sclerosis, but their use is limited by potentially serious adverse effects. Recently, it was shown that interferon-beta-1b can diminish the exacerbation rate in multiple sclerosis without leading to unacceptable adverse effects. Nevertheless, symptomatic treatment remains of crucial importance in the management of multiple sclerosis patients. Spasticity, depression, fatigue and urinary, paroxysmal and sensory symptoms can all be alleviated to some extent with pharmacological interventions, although rehabilitation procedures and psychosocial consultations are no less important. Further therapeutic approaches to multiple sclerosis will be directed at either the specificity of the immune response or the grade of activation of the immune response. Magnetic resonance imaging techniques will play an important role in the evaluation of efficacy of new therapeutic agents.

Adjuvants, Immunologic↗
PubMed1995

The effect of gadolinium on the sensitivity and specificity of MR in the initial diagnosis of multiple sclerosis.

PURPOSE: To determine whether gadolinium can improve the sensitivity and specificity of MR imaging for the initial diagnosis of multiple sclerosis. METHODS: Patients (n = 57) with neurologic symptoms suggesting multiple sclerosis were studied prospectively. MR imaging consisted of T2-weighted and gadolinium-enhanced T1-weighted spin-echo images. Lumbar puncture was performed for cerebrospinal fluid analysis in 34 patients. RESULTS: After imaging, 17 patients (35%) had clinically definite multiple sclerosis. Cerebrospinal fluid examination had a sensitivity of 69% and specificity of 38%. Using liberal criteria, the sensitivity of T2-weighted MR imaging was 94% and the specificity 55%; using more strict criteria, the specificity increased to 65% with a sensitivity of 88%. Gadopentetate dimeglumine enhancement increased the specificity further to 80% with a loss of sensitivity (59%). CONCLUSION: Gadolinium enhancement increases the specificity of MR imaging in the early diagnosis of multiple sclerosis.

Adult↗