Izabella Lejbkowicz

Detection of Multiple Sclerosis from Exhaled Breath Using Bilayers of Polycyclic Aromatic Hydrocarbons and Single-Wall Carbon Nanotubes

A cross-reactive array of polycyclic aromatic hydrocarbons and single wall carbon nanotube bilayers was designed for the detection of volatile organic compounds (tentatively, hexanal and 5-methyl-undecane) that identify the presence of disease in the exhaled breath of patients with multiple sclerosis. The sensors showed excellent discrimination between hexanal, 5-methyl-undecane, and other confounding volatile organic compounds. Results obtained from a clinical study consisting of 51 volunteers showed that the sensors could discriminate between multiple sclerosis and healthy states from exhaled breath samples with 85.3% sensitivity, 70.6% specificity, and 80.4% accuracy. These results open new frontiers in the development of a fast, noninvasive, and inexpensive medical diagnostic tool for the detection and identification of multiple sclerosis. The results could serve also as a launching pad for the discrimination between different subphases or stages of multiple sclerosis as well as for the identification of multiple sclerosis patients who would respond well to immunotherapy.

Diagnosis and Classification of 17 Diseases from 1404 Subjects via Pattern Analysis of Exhaled Molecules

We report on an artificially intelligent nanoarray based on molecularly modified gold nanoparticles and a random network of single-walled carbon nanotubes for noninvasive diagnosis and classification of a number of diseases from exhaled breath. The performance of this artificially intelligent nanoarray was clinically assessed on breath samples collected from 1404 subjects having one of 17 different disease conditions included in the study or having no evidence of any disease (healthy controls). Blind experiments showed that 86% accuracy could be achieved with the artificially intelligent nanoarray, allowing both detection and discrimination between the different disease conditions examined. Analysis of the artificially intelligent nanoarray also showed that each disease has its own unique breathprint, and that the presence of one disease would not screen out others. Cluster analysis showed a reasonable classification power of diseases from the same categories. The effect of confounding clinical and environmental factors on the performance of the nanoarray did not significantly alter the obtained results. The diagnosis and classification power of the nanoarray was also validated by an independent analytical technique, i.e., gas chromatography linked with mass spectrometry. This analysis found that 13 exhaled chemical species, called volatile organic compounds, are associated with certain diseases, and the composition of this assembly of volatile organic compounds differs from one disease to another. Overall, these findings could contribute to one of the most important criteria for successful health intervention in the modern era, viz. easy-to-use, inexpensive (affordable), and miniaturized tools that could also be used for personalized screening, diagnosis, and follow-up of a number of diseases, which can clearly be extended by further development.

Internet usage by patients with multiple sclerosis: implications to participatory medicine and personalized healthcare.

Online health information and services for patients were suggested to improve symptom management and treatment adherence, thereby contributing to healthcare optimization. This paper aimed to characterize multiple sclerosis (MS) patients Internet usage. Information regarding browsing habits, Internet reliability, and the medical teams attitude to information collected online was obtained by questionnaires from MS patients. Data was compared between nonbrowsers, browsers on MS topics, and browsers on non-MS topics only. From the 96 patients recruited, 61 (63.5%) performed MS-related searches. The most viewed topics were “understanding the disease” and “treatments”. Patients reported that the information helped coping with MS and assured them of the appropriateness of their therapy. Shorter disease duration was correlated with higher Internet activity. Disabled patients were more interested in online interaction with specialists and support groups. This paper suggests that MS patients benefit from online information, and it emphasizes the importance of resources tailored to patients needs.

Telemedicine for multiple sclerosis patients: assessment using Health Value Compass

Background: Telemedicine carries the potential of improving accessibility to health services, especially for disabled people. Objective: To assess the health-related outcomes of short-term implementation of telemedicine (telemed) for MS patients. Methods: A prospective study of 40 MS patients divided into a control group and a telemed group was conducted, in two stages: A. Six months’ follow-up for measurement of baseline health-related variables; B. Implementation stage, adding home telecare to the telemed group. A Health Value Compass was applied to assess the outcomes of home telecare implementation. Clinical status, cost data, patients’ self-assessment of Health Related Quality of Life (HRQoL) and satisfaction with telecare were studied. Results: Patients in the telemed group demonstrated improved clinical outcome measured by symptoms severity. There was a decrease of at least 35% in the medical costs for 67% of the telemed group patients. Satisfaction with telecare was high and most patients would recommend this service to others. Conclusions: The present pilot study, applying Health Value Compass-based analysis, suggests that telecare is a powerful tool for monitoring MS patients at home, carries the potential to improve health care while reducing costs, and should be considered for implementation as part of the management of chronic neurological diseases.

Participatory medicine and patient empowerment towards personalized healthcare in multiple sclerosis.

The current understanding that the key for successful healthcare is an integrated approach, involving predictive, preventive, personalized and participatory medicine, is leading major changes. These are: a shift from medical decisions based on ‘trial and error’ to informed therapeutics based on diagnostics (theranostics); a shift from a ‘disease-centered’ to a ‘patient-centered’ approach; and a shift from a ‘reactive’ to ‘proactive’ medical approach. It is essential that not only the physician, but also the patient, becomes proactive. Therefore, beyond the integration of genomic medicine and predictive biomarkers into practice, patient empowerment and participatory medicine are gaining increasing attention. This requires, besides appropriate sharing of information between patients and healthcare providers, new insights in patient involvement, such as patient-reported outcomes, both at the clinical trial stage of drug development and during post-marketing follow-up assessments. Patient empowerment and participatory medicine, as part of predictive, preventive, personalized and participatory medicine, are especially crucial in paving the way towards optimized healthcare in complex and chronic neurological diseases, such as multiple sclerosis.

Mediterranean weather conditions and exacerbations of multiple sclerosis.

Background: Previous studies provide increasing support for the impact of environmental factors on disease incidence and activity in multiple sclerosis (MS). Objectives: The purpose of this research was to assess the relationship between the incidence of MS relapses and weather conditions in Israel. Methods: Clinical data, including occurrence of relapses in 235 patients, during 3 consecutive years (2001–2003) were assessed against the general daily meteorological variables. Initially, the relationship between the relapses and their mode of distribution was evaluated. Second, the relationship between the number of relapses on a specific date and the meteorological variables was assessed. Third, the tendency to seasonality in the occurrence of relapses was examined. Results: No significant correlation was found between the number of relapses and a specific season, month or day. Moreover, no clear relationship was found between certain meteorological variables or a combination of variables and the frequency of the relapses. Conclusion: The meteorological parameters studied were not found to have a significant impact on the occurrence of relapses in this group of patients. These findings raise questions regarding the clinical significance of the impact of weather conditions, at least in the context of the Mediterranean climate, on the disease course of patients with MS.

Gene expression profiling of the response to interferon beta in Epstein-Barr-transformed and primary B cells of patients with multiple sclerosis.

The effects of interferon-beta (IFN-β), one of the key immunotherapies used in multiple sclerosis (MS), on peripheral blood leukocytes and T cells have been extensively studied. B cells are a less abundant leukocyte type, and accordingly less is known about the B cell-specific response to IFN-β. To identify gene expression changes and pathways induced by IFN-β in B cells, we studied the in vitro response of human Epstein Barr-transformed B cells (lymphoblast cell lines-LCLs), and validated our results in primary B cells. LCLs were derived from an MS patient repository. Whole genome expression analysis identified 115 genes that were more than two-fold differentially up-regulated following IFN-β exposure, with over 50 previously unrecognized as IFN-β response genes. Pathways analysis demonstrated that IFN-β affected LCLs in a similar manner to other cell types by activating known IFN-β canonical pathways. Additionally, IFN-β increased the expression of innate immune response genes, while down-regulating many B cell receptor pathway genes and genes involved in adaptive immune responses. Novel response genes identified herein, NEXN, DDX60L, IGFBP4, and HAPLN3, B cell receptor pathway genes, CD79B and SYK, and lymphocyte activation genes, LAG3 and IL27RA, were validated as IFN-β response genes in primary B cells. In this study new IFN-β response genes were identified in B cells, with possible implications to B cell-specific functions. The studys results emphasize the applicability of LCLs for studies of human B cell drug response. The usage of LCLs from patient-based repositories may facilitate future studies of drug response in MS and other immune-mediated disorders with a B cell component.

Effect of Fampridine-PR (prolonged released 4-aminopyridine) on the manual functions of patients with Multiple Sclerosis

BACKGROUND Persons with MS (PwMS) commonly present ambulatory and manual dysfunctions. While ambulation is recognized as important to PwMS, manual dysfunction is only lately gaining attention. Fampridine-PR was approved for MS ambulatory impairments. Anecdotal evidences indicate possible therapeutic effects on manual function. OBJECTIVE To comprehensively assess the effect of Fampridine-PR on manual functions of PwMS. METHODS Twenty six PwMS with ambulatory and manual dysfunction assessed before, 1 and 3months after treatment with Fampridine-PR, applying Timed 25-Foot Walk (T25FW) for ambulation while manual functions were evaluated by several tools addressing the International Classification of Functioning (ICF) concepts. This includes hand grip and pinch strength, 9 Hole Peg Test (9HPT), Arthritis Hand Function Test (AHFT), activities of daily life (ADL) tests, ABILHAND questionnaire and Computerized Penmanship Evaluation Tool (ComPET). RESULTS Fampridine-PR increased dominant hand grip and pinch strength 1month following treatment initiation by 12% and 10% (p<0.05), respectively. 9HPT improved by 11.3% after 3months of treatment (p<0.05%) and ABILHAND improved by 16% and 31% (p<0.05%) after 1 and 3months of treatment. Mean stroke duration in air of the name writing task improved by 21% (p<0.05) following 3months of treatment. T25FW results were similar to previous reports. CONCLUSION The results of this pilot study suggest that Fampridine-PR improves manual function of PwMS. Methods herein indicate that an integrative approach may be useful for evaluation of manual function in MS and in additional neurological diseases.

Multiple sclerosis in diverse populations: characteristics in distinct Arab ethnicities in Israel.

Background: Multiple sclerosis (MS) prevalence and genetic susceptibility varies among the different ethnic groups of Jews and Arabs in Israel. Objective: Characterization of MS disease course in Christian, Muslim and Druze Arabs in Israel. Methods: Historical cohort and three-year follow-up cohort analyses based on interviews and clinical charts of 149 Arab MS patients (78 Muslims, 49 Christians and 22 Druze) from three MS centers in Israel. Significant findings were adjusted for use of disease modifying therapy. Results: Age of onset (means between 30 and 31 years) and incomplete recovery rates after the first relapse (~50%) were similar for Christian, Muslim and Druze patients. Low rates of primary progressive MS (≤1%) were observed. Differences between the ethnicities in the time from onset to the second neurological episode were observed among females, but not males. Druze and Muslim women were more likely to have a second event within two years from the first event compared with Christians (odds ratios =8.8, p= 0.02; odds ratio=6.6, p=0.007 respectively). Trends for higher annual relapse rates, annual disability progression rates and MS Severity Scores were observed among the Druze. Conclusions: Among the Israeli Arab female MS patients, Druze and Muslims exhibit a more rapid disease course in comparison with Christians. Further elucidation of population-specific MS phenotypes may contribute to improved disease management.

Exhaled Breath Markers for Nonimaging and Noninvasive Measures for Detection of Multiple Sclerosis

Multiple sclerosis (MS) is the most common chronic neurological disease affecting young adults. MS diagnosis is based on clinical characteristics and confirmed by examination of the cerebrospinal fluids (CSF) or by magnetic resonance imaging (MRI) of the brain or spinal cord or both. However, neither of the current diagnostic procedures are adequate as a routine tool to determine disease state. Thus, diagnostic biomarkers are needed. In the current study, a novel approach that could meet these expectations is presented. The approach is based on noninvasive analysis of volatile organic compounds (VOCs) in breath. Exhaled breath was collected from 204 participants, 146 MS and 58 healthy control individuals. Analysis was performed by gas-chromatography mass-spectrometry (GC-MS) and nanomaterial-based sensor array. Predictive models were derived from the sensors, using artificial neural networks (ANNs). GC-MS analysis revealed significant differences in VOC abundance between MS patients and controls. Sensor data analysis on training sets was able to discriminate in binary comparisons between MS patients and controls with accuracies up to 90%. Blinded sets showed 95% positive predictive value (PPV) between MS-remission and control, 100% sensitivity with 100% negative predictive value (NPV) between MS not-treated (NT) and control, and 86% NPV between relapse and control. Possible links between VOC biomarkers and the MS pathogenesis were established. Preliminary results suggest the applicability of a new nanotechnology-based method for MS diagnostics.