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Biomedical subjects

Ariel Miller

Publications and source records attributed to Ariel Miller.

At least 19 recordsLinked to original sources
PubMed2006

Chronotherapy using corticosteroids for multiple sclerosis relapses.

BACKGROUND: The activity of the immune system displays a circadian rhythm. In diseases characterised by aberrant immune activity, chronotherapy (a treatment regimen tailored to diurnal body rhythms) may increase the efficiency, safety and tolerability of drugs. AIM: To compare the outcomes of intravenous corticosteroid administration during the day or night, for treatment of acute multiple sclerosis relapses. METHODS: 17 patients with multiple sclerosis were included in the study. Clinical assessment of disability was performed at trial entry, and at days 7 and 30 from the initiation of treatment. Adverse events and preference of night-time versus daytime treatment were assessed at the end of the treatment course. RESULTS: After night-time treatment, clinical recovery was significantly (p<0.001) enhanced and the mean number of side effects was significantly (p = 0.007) lower. Furthermore, most patients expressed a preference for night-time versus daytime treatment. CONCLUSIONS: The study suggests a potential benefit for implementation of chronotherapy using steroid treatment for acute multiple sclerosis relapse, with implications for other immune-mediated disorders.

Acute Disease↗
PubMed2006

Modulation of matrix metalloproteinase-9 (MMP-9) secretion in B lymphopoiesis.

The matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade the extracellular matrix, thus involved in cellular migration. The extent and role of MMPs secretion in primary non-transformed B cells, and specifically during early stages of development in the bone marrow (BM), has been barely unveiled. Herein, we investigated the secretion of MMP-9 during B lymphopoiesis and its modulation in response to different mitogens and cytokines. To do so, we used our BM culture system and well-studied mutated mouse models to isolate the different B cell populations. Our results show that MMP-9 is spontaneously secreted throughout B lymphopoiesis, and that the level of secreted MMP-9 is developmentally regulated. Using reverse transcription-PCR, we found that IFNbetaR is expressed throughout B cell development, while tumor necrosis factor (TNF)-alphaR-p55 and IFNgammaR expressions are initiated only at the pre-B stage. We found that TNFalpha stimulates MMP-9 secretion in transitional cells, whereas IFNs suppress MMP-9 secretion in immature cells. LPS and phorbol 12-myristate 13-acetate suppressed MMP-9 secretion in transitional cells, whereas LPS and concanavalin A stimulated MMP-9 secretion in mature B cells. We conclude that B lymphocyte development is accompanied with MMP-9 secretion and the developing cells are competent to modify this secretion upon different immune stimuli.

Animals↗
PubMed2006

Oral CD3-specific antibody suppresses autoimmune encephalomyelitis by inducing CD4+ CD25- LAP+ T cells.

A major goal of immunotherapy for autoimmune diseases and transplantation is induction of regulatory T cells that mediate immunologic tolerance. The mucosal immune system is unique, as tolerance is preferentially induced after exposure to antigen, and induction of regulatory T cells is a primary mechanism of oral tolerance. Parenteral administration of CD3-specific monoclonal antibody is an approved therapy for transplantation in humans and is effective in autoimmune diabetes. We found that orally administered CD3-specific antibody is biologically active in the gut and suppresses autoimmune encephalomyelitis both before induction of disease and at the height of disease. Orally administered CD3-specific antibody induces CD4+ CD25- LAP+ regulatory T cells that contain latency-associated peptide (LAP) on their surface and that function in vitro and in vivo through a TGF-beta-dependent mechanism. These findings identify a new immunologic approach that is widely applicable for the treatment of human autoimmune conditions.

Administration, Oral↗
PubMed2006

Pseudobulbar affect in multiple sclerosis: toward the development of innovative therapeutic strategies.

Pseudobulbar affect (PBA), a condition involving involuntary and uncontrollable episodes of crying and/or laughing, occurs frequently in patients with a variety of neurological disorders, including amyotrophic lateral sclerosis (ALS), stroke, traumatic brain injury, dementia including Alzheimer's disease, and multiple sclerosis (MS). Although PBA results in considerable distress for patients and caretakers, it is underrecognized and undertreated. Agents used to treat psychiatric disorders--particularly tricyclic antidepressants and selective serotonin reuptake inhibitors--are useful in alleviating PBA, but act on diffuse neural networks rather than targeting those involved in emotional motor expression. As a result of their nonspecific activity, these agents are associated with a range of unwanted effects that preclude many patients from using them. Dextromethorphan, a common cough suppressant, specifically targets sigma(1) receptors concentrated in the brainstem and cerebellum, thus providing the possibility of targeting regions implicated in emotional expression. When administered in a fixed combination with quinidine, dextromethorphan is effective in treating PBA in patients with ALS, and preliminary results suggest that this therapy also is effective in treating MS-related PBA.

Adrenergic alpha-Antagonists↗
PubMed2006

Multiple sclerosis frequency in Israel's diverse populations.

BACKGROUND: Israel has served for almost half a century as a site for epidemiologic studies of multiple sclerosis (MS). Its small geographic size, well-equipped, accessible, and subsidized health facilities, trained physicians, detailed census data, and a National MS Register, maintained since 1960, offer advantages for accurate determinations of MS frequency in its diverse populations. METHOD: The authors calculated age-specific prevalence of MS in Israeli-born Jewish inhabitants, immigrant Jews from Europe/America and from North Africa/Asia, Israeli-born Christian and Moslem Arabs, Druze, and Bedouins. RESULTS: Prevalence rate of MS per 10(5) population on June 30, 2000, for each of these groups in the order listed was 61.6, 53.7, and 27.9 for the Jewish groups and 35.3, 14.7, 10.9, and 17.3 for the non-Jewish groups. Three tiers in MS prevalence were apparent. The highest rates were in Israeli-born Jews and in Jewish immigrants from Europe/America (significantly higher in the former than the latter). Jewish immigrants from African/Asian countries and Christian Arabs had intermediate MS rates (significantly lower than in the first two groups but not significantly different from each other). Moslem Arabs, Druze, and Bedouins had the lowest rates of MS (significantly lower than in the intermediate group but not significantly different from each other). CONCLUSION: Diverse ethnic groups living in the same geographic area may have significantly different frequencies of MS.

Adolescent↗
PubMed2006

Cytokine-mediated modulation of MMPs and TIMPs in multipotential neural precursor cells.

Recent studies have implicated the inflammatory process during experimental allergic encephalomyelitis (EAE) in triggering migration and differentiation of transplanted neural precursors cells (NPCs) into the inflamed white matter. The pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma are key factors in the pathogenesis of brain inflammation in EAE and were shown to enhance NPCs migration in vitro. As cell migration is dependent on extracellular matrix remodeling, involving proteolytic enzyme members of the matrix metalloproteinase (MMPs) family, we characterized the profile of expression of MMPs and their endogenous inhibitors (TIMPs) in rat NPCs, and evaluated the effects of TNF-alpha, IFN-gamma and IFN-beta, a clinically proven modulator of brain inflammation, on the expression of these molecules. Newborn rat striatal NPCs were expanded in spheres as nestin+, PSA-NCAM+ and NG2(-) cells, which can differentiate into astrocytes, oligodendrocytes and neurons. NPCs' gelatinase activities of MMP-2 and MMP-9, as determined by zymography, were increased by TNF-alpha, and to a lesser extent by IFN-gamma. Semi-quantitative RT-PCR indicated that TNF-alpha also upregulated MMP-9 mRNA levels. IFN-beta suppressed the TNF-alpha-induced levels of secreted MMP-9 and MMP-2, while enhancing the expression of TIMP-1 and TIMP-2 mRNA. These results suggest that MMPs activity is induced in NPCs by pro-inflammatory cytokines to mobilize them for promoting reparative processes. IFN-beta, on the other hand, appears to have an anti-proteolytic influence that may attenuate such NPC-mediated repair processes.

Animals↗
PubMed2006

Serum anti-Glc(alpha1,4)Glc(alpha) antibodies as a biomarker for relapsing-remitting multiple sclerosis.

There is an unmet need to develop specific biomarkers for multiple sclerosis (MS) to aid in the diagnosis, improve the management of patients and the monitoring of the effectiveness of treatment. We have screened serum from patients with relapsing-remitting MS (RRMS, n = 107) against a library of glycans on a glycan chip, and have found significantly higher levels of IgM anti-Glc(alpha1,4)Glc(alpha) antibodies (anti-Galpha4Galpha antibodies) than in patients suffering from other neurological diseases (OND, n = 50, p < 0.0001), and other autoimmune diseases (OAD, n = 27, p = 0.02). No significant differences were found relative to patients having primary progressive MS (n = 16). No significant differences were detected between the levels of IgM anti-Galpha4Galpha antibodies in sera from patients with RRMS in relapsing versus remitting state, and in patients treated with immunotherapy versus untreated patients. To test whether the highly significant difference in the levels of IgM anti-Galpha4Galpha between RRMS and OND group is due to general increase in IgM levels, we have measured total serum IgM in a subgroup of 62 MS and 48 OND patients. Although the total IgM was significantly lower in the OND than the RRMS group (p = 0.0007), analysis of covariance (ANCOVA) reveled no statistically significant relationship to the covariate (total IgM). Furthermore, following normalizing the values to total IgM the difference in the levels of IgM anti-Galpha4Galpha between the MS and OND groups was found highly significant (p < < 0.0001). The present findings support further assessment of serum anti-Galpha4Galpha antibodies as a potential biomarker for MS, which may confirm disease diagnosis and aid in its management.

Adult↗
PubMed2006

Virtual reality cues for improvement of gait in patients with multiple sclerosis.

OBJECTIVE: To study the effects of visual cues, provided through a portable visual-feedback virtual reality (VR) apparatus, on the walking abilities of patients with multiple sclerosis (MS). METHODS: On-line (display-on) and residual short-term therapeutic effects on walking speed and stride length were measured in 16 randomly selected patients with gait disturbances predominantly due to cerebellar ataxia. RESULTS: Patients whose baseline walking speed (BWS) was below the median showed an average on-line improvement of 13.46% in their walking speed, while patients whose BWS was above the median improved their speed by 1.47%. The average short-term residual therapeutic improvement in walking speed was 24.49% in patients with BWS below the median, and 9.09% in patients with BWS above the median. Similar results were obtained for improvements in stride length. These results of improved functions in patients are particularly noteworthy when compared with the lack of change in healthy control subjects. CONCLUSIONS: Patients with multiple sclerosis showed improvement in walking abilities using virtual reality visual-feedback cues.

Adult↗
PubMed2006

Randomized, controlled trial of dextromethorphan/quinidine for pseudobulbar affect in multiple sclerosis.

OBJECTIVE: To evaluate the efficacy and safety of DM/Q (capsules containing dextromethorphan [DM] and quinidine [Q]) compared with placebo, taken twice daily, for the treatment of pseudobulbar affect over a 12-week period in multiple sclerosis patients. METHODS: A total of 150 patients were randomized in a double-blind, placebo-controlled study to assess pseudobulbar affect with the validated Center for Neurologic Study-Lability Scale. Each patient also recorded the number of episodes experienced between visits, estimated quality of life and quality of relationships on visual analog scales, and completed a pain rating scale. RESULTS: Patients receiving DM/Q had greater reductions in Center for Neurologic Study-Lability Scale scores than those receiving placebo (p < 0.0001) at all clinic visits (days 15, 29, 57, and 85). All secondary end points also favored DM/Q, including the number of crying or laughing episodes (p <or= 0.0077), quality of life (p < 0.0001), quality of relationships (p = 0.0001), and pain intensity score (p = 0.0271). DM/Q was well tolerated; only dizziness occurred with greater frequency than with placebo. INTERPRETATION: Results in multiple sclerosis patients were similar to those of a previous study in amyotrophic lateral sclerosis, demonstrating that DM/Q may be beneficial in treating potentially disabling pseudobulbar affect in a variety of neurological disorders.

Affect↗
PubMed2006

Health-related quality of life in multiple sclerosis: The impact of disability, gender and employment status.

OBJECTIVES: (1) Evaluate the impact of the patient characteristics of disability, gender and employment status on health-related quality of life (HRQOL) in multiple sclerosis (MS) and (2) Characterize the functional relationship between HRQOL and disability overall, and by gender and employment status. METHODS: We assessed the HRQOL of 215 MS outpatients in our clinic using the MSQOL-54 and Fatigue Severity Scale (FSS), and that of 172 healthy controls, using the SF-36 (a subset of MSQOL-54). We compared QOL between MS subgroups defined by disability, gender and employment, and computed the linear and non-linear relationships between disability level measured by the Expanded Disability Status Scale (EDSS) and MSQOL-54 dimensions. RESULTS: QOL of MS patients measured by SF-36 is lower than controls, varying by QOL dimension with the greatest difference emerging for physical aspects of the disease. The relationship of physical disability, measured by EDSS, and all 14 MSQOL-54 dimensions and FSS is negative; for 12 of the 14 dimensions and FSS it is also non-linear. Non-linearity is most pronounced among women, who show a weak EDSS/QOL relationship at higher levels of physical disability, suggesting women better able to "psychologically buffer" the debilitating aspects of MS. While employed have higher QOL than unemployed, the former are more affected by physical disability. CONCLUSIONS: Multiple attributes, including disability, gender and employment status, affect QOL. QOL's relationship with disability is complex, displaying non-linearity and interacting with patient characteristics. This has implication for QOL research methodology and provides insight into factors affecting patients' perceptions of well-being.

Adolescent↗
PubMed2006

Emerging therapeutic targets in multiple sclerosis.

PURPOSE OF REVIEW: The aim of this review is to describe the recent findings regarding the pathogenesis of multiple sclerosis and their translation to new therapies. RECENT FINDINGS: Basic research is providing new insights into the immune elements involved in the pathogenesis of multiple sclerosis, both in the periphery as well as in the central nervous system. Unveiling the complex interplay of the molecules involved in the immunological cascade of the disease supplies new targets for the development of new immunotherapeutic strategies. Similarly, clinical studies and identification of distinct subgroups of patients based on their responsiveness to immunotherapies provides support for the existence of immunopathological disease subtypes that seem to require different therapeutic approaches. These studies extend the theoretical basis that facilitates development of neuroprotective and repair-promoting therapeutic strategies. SUMMARY: The application of novel and cutting-edge technologies in the fields of genomics and proteomics is providing a better understanding of the genetic and environmental factors involved in multiple sclerosis susceptibility and progression, as well as the detection of biomarkers for disease activity and response to therapy. Implementation of these facilitates identification of new targets for therapy towards tailoring treatment to the individual patient with multiple sclerosis.

Antigens↗
PubMed2005

Vitamin B12, demyelination, remyelination and repair in multiple sclerosis.

Multiple Sclerosis (MS) and vitamin B12 deficiency share common inflammatory and neurodegenerative pathophysiological characteristics. Due to similarities in the clinical presentations and MRI findings, the differential diagnosis between vitamin B12 deficiency and MS may be difficult. Additionally, low or decreased levels of vitamin B12 have been demonstrated in MS patients. Moreover, recent studies suggest that vitamin B12, in addition to its known role as a co-factor in myelin formation, has important immunomodulatory and neurotrophic effects. These observations raise the questions of possible causal relationship between the two disorders, and suggest further studies of the need to close monitoring of vitamin B12 levels as well as the potential requirement for supplementation of vitamin B12 alone or in combination with the immunotherapies for MS patients.

Animals↗
PubMed2005

Gelatinases (MMP-2 and MMP-9) are preferentially expressed by Th1 vs. Th2 cells.

T helper subsets, Th1 and Th2, which are associated with different types of immune reactions, are distinguished by their cytokines' profiles and expression of different chemokine receptors, that may differentially influence their migratory capacity. The present study examined the expression of matrix metalloproteinases, (MMP)-2 and MMP-9, by the two CD4+ Th cell subsets and the role of these proteases in their migration. We observed that migration of CD4+ T cells is dependent on the gelatinases, and that the migratory capacity of Th1 is higher than Th2 cells. In addition, Th1 in comparison to Th2 cells, from both human (healthy subjects and multiple sclerosis (MS) patients) as well as from murine origin, secrete higher levels of MMP-2 and MMP-9. These novel findings contribute to the understanding of the physiological Th1 and Th2 immune responses as well as the enhanced Th1 reactivity in immune-mediated diseases, such as MS, in which enhanced levels of MMP-2 and MMP-9 are associated with disease processes.

Adult↗
PubMed2005

Hypoxia of endothelial cells leads to MMP-2-dependent survival and death.

Exposure of endothelial cells (ECs) to hypoxia has separately been shown to induce their angiogenesis or death. Matrix metalloproteinase (MMP)-2 is associated with EC angiogenesis, although recent studies also implicate this molecule in EC death. We studied the effect of hypoxia in the absence or presence of TNF-alpha (characteristic of the inflammatory microenvironment accompanying hypoxia) on MMP-2 expression and its role in angiogenesis (proliferation, migration, and tube formation) and in the death of primary human umbilical vein endothelial cells (HUVECs). Hypoxia alone (24-48 h in 0.3% O(2) in the hypoxic chamber) and furthermore, when combined with TNF-alpha, significantly enhanced MMP-2 expression and activity. Hypoxia also led to a reduction in membrane type 1 MMP (MT1-MMP) and tissue inhibitor of metalloproteinase-2 mRNA and protein while enhancing the expression of alpha(v)beta(3) integrin and the cytoskeletal protein phosphopaxillin. Moreover, hypoxia led to colocalization of alpha(v)beta(3) and MMP-2, but not MT1-MMP, with phosphopaxillin in ECs. These results suggest MT1-MMP-independent activation of MMP-2 during hypoxia and support interactions between the ECM, integrins, and the cytoskeleton in hypoxia-induced MMP-2-related functions. Hypoxia enhanced EC migration in an MMP-2-dependent manner while leading to a reduction of cell number via their apoptosis, which was also dependent on MMP-2. In addition, hypoxia caused an aberrant tubelike formation on Matrigel that appeared to be unaffected by MMP-2. The hypoxia-induced, MMP-2-dependent migration of ECs is in accordance with the proangiogenic role ascribed to MMP-2, while the involvement of this protease in the hypoxia-related death of ECs supports an additional apoptotic role for this protease. Hence, in the hypoxic microenvironment, MMP-2 appears to have a dual autocrine role in determining the fate of ECs.

Cell Death↗
PubMed2005

Health-related quality of life in multiple sclerosis: psychometric analysis of inventories.

OBJECTIVE: Measuring health-related quality of life (HRQoL) enables attainment of a comprehensive picture of chronic patients' conditions. The aim was to gain insight into HRQoL as viewed by Israeli multiple sclerosis (MS) patients, with an eye to its cross-cultural applicability, using psychometric analysis and a regression-based procedure. METHODS: The reliability and validity of the MSQoL-54 was assessed in 215 Israeli MS patients. Subsequently a novel method in QoL research for assessing the relative importance to patients of different aspects of the construct, comparing these between males and females, was applied. Using factor analysis, the degree to which the MSQoL-54 dimensions are applicable in our population and the existence of a separate dimension of Fatigue were tested. Finally, structural equation modelling (SEM) was used to examine relationships between QoL dimensions. RESULTS: The MSQoL-54 showed reliabilities and validities comparable to those found in other populations. Females attach importance to emotional aspects of QoL, while males are more concerned with physical aspects. The distinction between Emotional and Physical dimensions emerged from SEM, as did a distinction between Fatigue and Energy, the former being primarily Physical, and the latter Emotional. SEM indicated a reciprocal causality between Physical and Emotional dimensions. CONCLUSIONS: Based on internal structure, reliability and validity, the MSQoL-54 is applicable to Israeli MS patients. However, the scale's Social Function dimension is indecisively defined, which requires further study. QoL research in MS should distinguish between emotional and physical Fatigue. Assessing importance of QoL dimensions should inform clinicians in tailoring treatment to the individual patient.

Adolescent↗
PubMed2005

Emotional responses of children and adolescents to parents with multiple sclerosis.

The effect of a chronic illness of one parent on children is determined by a complicated interaction of various emotional components. Our focus was on the children's and adolescent's emotional reactions and feelings towards their multiple sclerosis (MS)-affected parents, including: degree of responsibility, obligation and concern, yielding behaviour and active protection, fear and anxiety related to the state of illness, their sense of burden in connection with household tasks and errands, and anger. Fifty-six children, ages 10-18, each having a parent with MS, were examined. The results were compared to a control group of 156 age-matched children with healthy parents. Feelings were examined by means of a questionnaire previously constructed by us. We found that children of parents with MS felt more responsibility and obligation than children of healthy parents. They also exhibited more yielding behaviour, more fear and anxiety related to states of illness, a greater sense of burden and a greater degree of anger. We consider the interaction between the sex of the parent and the sex of the child in connection with these feelings and discuss the implications of the 'parental child' role of these children.

Adolescent↗