ABSTRACT
BACKGROUND: In general, late side effects after salvage radiotherapy (RT) for prostate cancer are below 10%. Patients with impaired DNA repair ability and genetic instability can have significantly increased reactions after RT. CASE, CLINICAL FOLLOW-UP, AND EXAMINATION: We present a patient who experienced severe side effects after additive RT for prostate cancer and died from the complications 25 months after RT. Imaging (MR) is shown as well as three-color fluorescence in situ hybridization. The blood sample testing revealed that radiosensitivity was increased by 35-55%. We undertook a review of the literature to give an overview over the tests established that are currently considered useful. CONCLUSION: This case highlights that the identification of patients with increased radiosensitivity is an important task in radiation protection. Groups of patients who should be screened have to be found and corresponding research facilities have to be set up.
Subject(s)
Pelvis/radiation effects , Prostatic Neoplasms/radiotherapy , Radiation Injuries/etiology , Radiation Injuries/pathology , Radiation Tolerance , Radiotherapy, Adjuvant/adverse effects , Salvage Therapy/adverse effects , Adult , Aged , Aged, 80 and over , Combined Modality Therapy , Fatal Outcome , Female , Humans , Male , Middle Aged , Neoplasm Grading , Neoplasm Staging , Prostatectomy , Prostatic Neoplasms/pathology , Prostatic Neoplasms/surgery , Radiation Injuries/diagnosis , Radiotherapy, Intensity-Modulated/adverse effectsABSTRACT
BACKGROUND: Despite pleiotropic immunomodulatory effects of apolipoprotein E (apoE) in vitro, its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial. As sex hormones modify immunomodulatory apoE functions, they may explain contentious findings. This study aimed to investigate sex-specific effects of apoE on disease course of EAE and MS. METHODS: MOG(35-55) induced EAE in female and male apoE-deficient mice was assessed clinically and histopathologically. apoE expression was investigated by qPCR. The association of the MS severity score (MSSS) and APOE rs429358 and rs7412 was assessed across 3237 MS patients using linear regression analyses. RESULTS: EAE disease course was slightly attenuated in male apoE-deficient (apoE (-/-) ) mice compared to wildtype mice (cumulative median score: apoE (-/-) = 2 [IQR 0.0-4.5]; wildtype = 4 [IQR 1.0-5.0]; n = 10 each group, p = 0.0002). In contrast, EAE was more severe in female apoE (-/-) mice compared to wildtype mice (cumulative median score: apoE (-/-) = 3 [IQR 2.0-4.5]; wildtype = 3 [IQR 0.0-4.0]; n = 10, p = 0.003). In wildtype animals, apoE expression during the chronic EAE phase was increased in both females and males (in comparison to naïve animals; p < 0.001). However, in MS, we did not observe a significant association between MSSS and rs429358 or rs7412, neither in the overall analyses nor upon stratification for sex. CONCLUSIONS: apoE exerts moderate sex-specific effects on EAE severity. However, the results in the apoE knock-out model are not comparable to effects of polymorphic variants in the human APOE gene, thus pinpointing the challenge of translating findings from the EAE model to the human disease.
Subject(s)
Apolipoproteins E/genetics , Encephalomyelitis, Autoimmune, Experimental/genetics , Multiple Sclerosis/genetics , Animals , Apolipoproteins E/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Fluorescent Antibody Technique , Genotype , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Real-Time Polymerase Chain Reaction , Sex FactorsABSTRACT
BACKGROUND: Despite highly divergent time scales of disease evolution in multiple sclerosis (MS) and ischemic stroke, clear analogies are apparent that may point the way to optimization of MS treatment. Inflammatory disease activity and neurodegeneration may induce potentially irreversible damage to central nervous system structures and thus lead to permanent disability. For the treatment of MS early detection of disease activity and early immunotherapy or treatment optimization are pivotal determinants of long-term outcomes. Such therapeutic concepts may be described with the catchy phrase "time is brain" as coined for the acute thrombolytic treatment of ischemic stroke. RESULTS AND DISCUSSION: For MS a "time is brain" concept would comprise an early initiation of first line therapy as well as sensitive and structured monitoring of disease activity under therapy in conjunction with a low threshold for timely treatment optimization to achieve sustained freedom from measurable disease activity. This approach may substantially improve the long-term outcome in patients who show insufficient response to platform therapies. The intersectorial collaboration in regional MS care networks involving office-based neurologists and specialized MS centers may facilitate the timely use of highly active therapies with their specific benefit-risk profiles thus supporting sustained stabilization of patient quality of life.
Subject(s)
Immunosuppressive Agents/administration & dosage , Immunotherapy/methods , Immunotherapy/trends , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Multiple Sclerosis, Relapsing-Remitting/therapy , Early Diagnosis , Evidence-Based Medicine , HumansABSTRACT
Parkinson's disease (PD) is caused by degeneration of the dopaminergic neurons in the substantia nigra (SN) and a resulting dysfunction of the nigrostriatal pathways including the basal ganglia. Beside motor symptoms, different types of pain (e.g., dystonic musculoskeletal pain or central pain) occur in a considerable number of patients. In addition, abnormalities in pain processing have been observed in PD patients, which may present as increased pain sensitivity. The pathophysiological mechanisms involved in disturbed pain processing of PD, however, are still poorly understood. The present article gives an overview of the relevant experimental studies, investigating the abnormalities of pain processing in PD by means of electrophysiological [electroencephalography (EEG), sympathetic skin response (SSR)] and psychophysical methods [quantitative sensory testing (QST), RIII reflex threshold]. Based on a review of the literature, it is postulated that dysfunction in endogenous pain inhibition caused by dopaminergic deficiency in the basal ganglia, especially in the striatum, but also in mesolimbic areas is a main pathophysiological mechanism involved in nociceptive abnormalities in PD.
Subject(s)
Brain/physiopathology , Chronic Pain/epidemiology , Chronic Pain/physiopathology , Neural Inhibition/physiology , Nociceptors/physiology , Pain Threshold/physiology , Parkinson Disease/epidemiology , Parkinson Disease/physiopathology , Basal Ganglia/physiopathology , Cross-Sectional Studies , Dopamine/physiology , Humans , Limbic System/physiopathology , Mesencephalon/physiopathology , Neural Pathways/physiopathologyABSTRACT
BACKGROUND: Cladribine is a synthetic deoxyadenosine analogue in development as an oral multiple sclerosis (MS) therapy. OBJECTIVE: To report in detail the safety findings from the 96-week, phase III, double-blind CLARITY study, which evaluated treatment with cladribine tablets in relapsing-remitting MS. METHODS: A total of 1,326 patients were randomized 1:1:1 to two short-course regimens of cladribine tablets (3.5 or 5.25 mg/kg cumulative dose over 96 weeks) or placebo. Safety assessments included monitoring for adverse events (AEs), routine physical and neurologic examinations and frequent laboratory parameter assessments. RESULTS: Of the randomized patients, 88.6% completed treatment with cladribine tablets versus 86.3% with placebo. Lymphopenia was the most commonly reported AE in patients treated with cladribine tablets and was anticipated based on the mechanism of action. The incidence of infections was 48.3% with cladribine tablets and 42.5% with placebo, with 99.1% and 99.0% rated mild-to-moderate by investigators. Herpes zoster infections developed in 20 (2.3%) cladribine-treated patients; all cases were dermatomal. There were no herpes zoster infections in the placebo group. Nine (1.0%) patients experienced events related to uterine leiomyomas in the cladribine tablets groups versus one (0.2%) with placebo. Three isolated cases of malignancy were reported in cladribine-treated patients during the study; a fourth was reported during post-study surveillance. A pre-malignant cervical carcinoma in situ was also reported. The incidence of malignancies during the study did not exceed the expected rate in a population standardized for country, gender and age. CONCLUSION: The safety and tolerability profile observed in the CLARITY study together with the reported efficacy support the potential for cladribine tablets as an MS therapy.
Subject(s)
Cladribine/adverse effects , Immunosuppressive Agents/adverse effects , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Administration, Oral , Adult , Cladribine/administration & dosage , Disability Evaluation , Double-Blind Method , Europe , Herpes Zoster/chemically induced , Humans , Immunosuppressive Agents/administration & dosage , Lymphopenia/chemically induced , Male , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Neoplasms/chemically induced , Neurologic Examination , Physical Examination , Risk Assessment , Risk Factors , Time Factors , Treatment Outcome , United States , Young AdultABSTRACT
BACKGROUND: Patient-reported quality of life (QOL) is an outcome measure in clinical trials in multiple sclerosis (MS), but translated QOL instruments may affect the actual comparability of data. OBJECTIVES: We aimed to investigate possible differences in QOL in MS between cultures and countries. We employed the Functional Assessment of Multiple Sclerosis (FAMS) Version 4 questionnaire, which is a state-of-the-art QOL instrument. METHODS: Some 484 MS patients from Austria (145), Germany (144), and Poland (195) aged 20-60 years, and stratified for sex and disease severity as measured by the Expanded Disability Status Scale (EDSS) score completed the respective FAMS translation and a socio-demographic questionnaire. RESULTS: Analysis of variance and post-hoc Scheffé-test showed that 64% of the FAMS items were answered significantly differently (p < 0.001) between the three countries. A multivariate regression analysis including all the available disease-related and socio-demographic variables revealed the factors age, EDSS score, employment, social contacts, MS course, and country to be significant predictors of both the total FAMS score and the score for items answered differently between the three countries. CONCLUSIONS: Differences exist in the QOL of MS patients from Austria, Germany, and Poland which seem to lie beyond the impact of disease severity. They appear to be related to culture or other country-specific factors, as country was an independent predictor of differently answered items of the FAMS and thus also of the whole FAMS. QOL instruments should consider this aspect to faithfully reflect subjective information such as patient-reported benefit of treatment in multinational clinical trials.
Subject(s)
Cross-Cultural Comparison , Multiple Sclerosis/psychology , Quality of Life/psychology , Adult , Analysis of Variance , Austria , Chi-Square Distribution , Cross-Sectional Studies , Disability Evaluation , Female , Germany , Humans , Male , Middle Aged , Poland , Severity of Illness Index , Surveys and QuestionnairesABSTRACT
OBJECTIVES: Recently, associations of several single-nucleotide polymorphisms (SNPs) within the CLEC16A gene with multiple sclerosis (MS), type-I diabetes, and primary adrenal insufficiency were reported. METHODS: We performed linkage disequilibrium (LD) fine mapping with 31 SNPs from this gene, searching for the region of highest association with MS in a German sample consisting of 603 patients and 825 controls. RESULTS: Four SNPs located in intron 19 of the CLEC16A gene were found associated. We could replicate the finding for SNP rs725613 and were able to show for the first time the association of rs2041670, rs2080272 and rs998592 with MS. CONCLUSION: All described base polymorphisms are mapping to one LD block of approximately 50 kb within intron 19 of the CLEC16A gene, suggesting a pivotal role of this region for susceptibility of MS and possibly also for other autoimmune diseases.
Subject(s)
Genetic Predisposition to Disease/genetics , Genetic Variation , Lectins, C-Type/genetics , Monosaccharide Transport Proteins/genetics , Multiple Sclerosis/genetics , Polymorphism, Single Nucleotide/genetics , Adolescent , Adult , Aged , Female , Genetic Testing/methods , Humans , Linkage Disequilibrium , Male , Middle Aged , Multiple Sclerosis/epidemiology , Young AdultABSTRACT
BACKGROUND: The existing health-related quality of life questionnaires on multiple sclerosis (MS) only partially reflect the patient's point of view on the reduction of activities of daily living. Their development and validation was not performed in different languages. That is what prompted the development of the Multiple Sclerosis International Quality of Life (MusiQoL) Questionnaire as an international multidimensional measurement instrument. This paper presents this new development and the results of the German subgroup versus the total international sample. PATIENTS AND METHODS: A total of 1,992 MS patients from 15 countries, including 209 German patients, took part in the study between January 2004 and February 2005. The patients took the MusiQoL survey at baseline and at 21±7 days as well as completing a symptom-related checklist and the SF-36 short form survey. Demographics, history and MS classification data were also generated. Reproducibility, sensitivity, convergent and discriminant validity were analysed. RESULTS: Convergent and discriminant validity and reproducibility were satisfactory for all dimensions of the MusiQoL. The dimensional scores correlated moderately but significantly with the SF-36 scores, but showed a discriminant validity in terms of gender, socioeconomic status and health status that was more pronounced in the overall population than in the German subpopulation. The highest correlations were observed between the MusiQoL dimension of activities of daily living and the Expanded Disability Status Scale (EDSS). CONCLUSION: The results of this study confirm the validity and reliability of MusiQoL as an instrument for measuring the quality of life of German and international MS patients.
Subject(s)
Cross-Cultural Comparison , Multiple Sclerosis, Chronic Progressive/psychology , Multiple Sclerosis, Relapsing-Remitting/psychology , Quality of Life/psychology , Surveys and Questionnaires , Activities of Daily Living/psychology , Adult , Checklist , Female , Germany , Humans , Male , Middle Aged , Psychometrics/statistics & numerical dataABSTRACT
Multiple sclerosis is an autoimmune disease with a plethora of potentially arising impairments and a coarse standard clinical estimation of severity, the expanded disability status scale (EDSS). In this study, we introduced the Watzmann Severity Scale (WSS), a sensorimotor function based statistical model of the EDSS of 113 patients. Using the WSS, we examined the rehabilitation course of 87 patients. The WSS revealed to be a reliable estimate of the EDSS with an R²adjusted of 0.81, although lower EDSS grades were systematically overestimated. Further, patients slightly improved during their inpatient stay of in average 17d by 0.21 on the WSS, with changes in gait performance being the driving factor (|ß|-weight of 0.84). We were not able to reliably predict changes in the WSS and found no association with the duration of hospitalization. We conclude and advise that rehabilitation should start earlier, if lower EDSS grades were not overestimated, to emphasize gait less in rehabilitation, and to change from a perspective of impairment and disability to performance in order to maximize patient rehabilitation.
Subject(s)
Disabled Persons , Multiple Sclerosis , Disability Evaluation , Gait , Humans , Inpatients , Severity of Illness IndexABSTRACT
Freshly isolated B lymphocytes from patients infected with human immunodeficiency virus (HIV), in contrast to B cells from normal controls, were shown to induce viral expression in two cell lines: ACH-2, a T cell line, and U1, a promonocytic cell line, which are chronically infected with HIV, as well as in autologous T cells. In 10 out of 10 HIV-infected individuals with hypergammaglobulinemia, spontaneous HIV-inductive capacity was found with highly purified peripheral blood B cells, whereas peripheral blood or tonsillar B cells from six healthy, HIV-negative donors did not induce HIV expression unless the cells were stimulated in vitro. The induction of HIV expression was observed in direct coculture experiments of B lymphocytes and HIV-infected cells, and could also be mediated by supernatants from cultures of B cells. Significantly higher amounts of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) were detected in the B cell culture supernatants from HIV-infected patients with hypergammaglobulinemia (IL-6: mean = 536 pg/ml; TNF-alpha: mean = 493 pg/ml), as compared with normal uninfected controls (IL-6: mean = 18 pg/ml; TNF-alpha: mean = 23 pg/ml). Antibodies against these cytokines abolished the HIV-inductive capacity of B cells. We conclude that in vivo activated B cells in HIV-infected individuals can upregulate the expression of virus in infected cells by secreting cytokines such as TNF-alpha and IL-6, and, therefore, may play a role in the progression of HIV infection.
Subject(s)
B-Lymphocytes/physiology , HIV Infections/immunology , HIV-1/growth & development , Monocytes/microbiology , T-Lymphocytes/microbiology , B-Lymphocytes/metabolism , Cell Line , Cells, Cultured , HIV Infections/microbiology , Humans , Interleukin-6/metabolism , Lymphocyte Activation , Tumor Necrosis Factor-alpha/metabolism , Virus Activation/immunologyABSTRACT
Endothelins are peptides, originally isolated from endothelial cells, with potent vasoactive and mitogenic properties. In this study, we demonstrate that human macrophages synthesize and secrete endothelins. Cultured human macrophages were found by immunocytochemistry to stain positively for endothelin 1 and endothelin 3. Their capability to produce and release these peptides was confirmed by a combination of reverse-phase high-performance liquid chromatography and radioimmunoassays, specific for endothelin 1 and 3, respectively. Immunoreactive peptides were identified both in cellular extracts and in macrophage-conditioned medium. The secretion of endothelin 1, but not of endothelin 3, from macrophages could be stimulated 6-10-fold by lipopolysaccharide or phorbol myristate acetate (PMA). Northern blot analysis of total macrophage RNA using an endothelin 1 cDNA probe revealed induction of endothelin mRNA in PMA-treated macrophages. Furthermore, immunoreactive endothelin 1 and 3 were found in U937 cells, a human promonocytic line, and in freshly isolated human monocytes. In contrast, no immunoreactive endothelin was detected in cell extracts from human neutrophils and lymphocytes. The expression of endothelins in tissue macrophages was demonstrated in paraffin sections of human lung using immunohistochemistry. In conclusion, the finding that human macrophages produce endothelins suggests an important role for these peptides in the microenvironment of tissue macrophages. Macrophage-derived endothelins may have an essential function in blood vessel physiology, and aberrant production may contribute to vessel pathology.
Subject(s)
Endothelins/biosynthesis , Macrophages/physiology , Cells, Cultured , Chromatography, High Pressure Liquid , Culture Media , Endothelins/analysis , Endothelins/genetics , Granulomatosis with Polyangiitis/pathology , Granulomatosis with Polyangiitis/physiopathology , Humans , Immunohistochemistry , Lung/pathology , Macrophages/cytology , Macrophages/drug effects , RNA/genetics , RNA/isolation & purification , Tetradecanoylphorbol Acetate/pharmacologyABSTRACT
BACKGROUND: Glatiramer acetate, approved for the treatment of relapsing-remitting multiple sclerosis, reduces relapses and disease activity and burden monitored by MRI. We assessed the efficacy of early treatment with glatiramer acetate in delaying onset of clinically definite multiple sclerosis. METHODS: In this randomised, double-blind trial, undertaken in 80 sites in 16 countries, 481 patients presenting with a clinically isolated syndrome with unifocal manifestation, and two or more T2-weighted brain lesions measuring 6 mm or more, were randomly assigned to receive either subcutaneous glatiramer acetate 20 mg per day (n=243) or placebo (n=238) for up to 36 months, unless they converted to clinically definite multiple sclerosis. The randomisation scheme used SAS-based blocks stratified by centre, and patients and all personnel were masked to treatment assignment. The primary endpoint was time to clinically definite multiple sclerosis, based on a second clinical attack. Analysis was by intention to treat. A preplanned interim analysis was done for data accumulated from 81% of the 3-year study exposure. This study was registered with ClinicalTrials.gov, number NCT00666224. FINDINGS: All randomly assigned participants were analysed for the primary outcome. Glatiramer acetate reduced the risk of developing clinically definite multiple sclerosis by 45% compared with placebo (hazard ratio 0.55, 95% CI 0.40-0.77; p=0.0005). The time for 25% of patients to convert to clinically definite disease was prolonged by 115%, from 336 days for placebo to 722 days for glatiramer acetate. The most common adverse events in the glatiramer acetate group were injection-site reactions (135 [56%] glatiramer acetate vs 56 [24%] placebo) and immediate post-injection reactions (47 [19%] vs 12 [5%]). INTERPRETATION: Early treatment with glatiramer acetate is efficacious in delaying conversion to clinically definite multiple sclerosis in patients presenting with clinically isolated syndrome and brain lesions detected by MRI. FUNDING: Teva Pharmaceutical Industries, Israel.
Subject(s)
Immunosuppressive Agents/therapeutic use , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Peptides/therapeutic use , Adult , Analysis of Variance , Disease Progression , Double-Blind Method , Female , Glatiramer Acetate , Humans , Immunosuppressive Agents/adverse effects , Injections, Subcutaneous , Kaplan-Meier Estimate , Magnetic Resonance Imaging , Male , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Peptides/adverse effects , Proportional Hazards Models , Secondary Prevention , Syndrome , Treatment OutcomeABSTRACT
The pathophysiology of primary progressive (PP) multiple sclerosis (MS) involves diffuse axonal degeneration which is believed to start early in the disease process, even before the onset of clinical symptoms. Symptomatic onset then occurs when this process reaches a threshold after which the axonal loss can no longer be compensated. A preliminary study showed that patients with familial PPMS had an earlier clinical onset than patients with sporadic disease, suggesting a hereditary component to the disease process of PPMS. In this study, we combined data from two large, population-based, longitudinal MS databases to investigate disease onset in familial and sporadic PPMS. We examined 411 patients with PPMS. There were no differences in gender distribution or onset symptoms between familial and sporadic PPMS. Patients with familial PPMS were significantly younger at disease onset (n = 84, median age: 37.6 years) than patients with sporadic disease (n = 327, median age: 42.7, p = 0.007). This difference was due to a greater proportion of familial cases with a disease onset before the age of 30 and a smaller proportion with disease onset between 40 and 50 years of age (p = 0.002). Gender had no significant effect on the age at disease onset. Further analyses showed that these findings were unlikely to be due to ascertainment bias towards an earlier diagnosis in familial cases. Our findings suggest a hereditary component to the disease process of PPMS. It would be worthwhile to identify patients with familial PPMS for future research on disease modifying genes in MS.
Subject(s)
Multiple Sclerosis, Chronic Progressive/epidemiology , Age of Onset , Databases, Factual , Disease Progression , Female , Humans , Longitudinal Studies , Male , Multiple Sclerosis, Chronic Progressive/genetics , Risk Factors , Sex Factors , Statistics, NonparametricABSTRACT
Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) inhibits T-cell activation and interleukin-2 (IL-2) production. The PTPN22(gain-of-function)+1858T(+) genotypes predispose to multiple autoimmune diseases, including early-onset (non-thymomatous) myasthenia gravis (MG). The disease association and the requirement of IL-2/IL-2 receptor signaling for intrathymic, negative T-cell selection have suggested that these genotypes may weaken T-cell receptor (TCR) signaling and impair the deletion of autoreactive T cells. Evidence for this hypothesis is missing. Thymoma-associated MG, which depends on intratumorous generation and export of mature autoreactive CD4(+) T cells, is a model of autoimmunity because of central tolerance failure. Here, we analyzed the PTPN22 +1858C/T single nucleotide polymorphism in 426 German Caucasian individuals, including 125 thymoma patients (79 with MG), and investigated intratumorous IL-2 expression levels. Unlike two previous studies on French and Swedish patients, we found strong association of PTPN22 +1858T(+) genotypes not only with early-onset MG (P=0.00034) but also with thymoma-associated MG (P=0.0028). IL-2 expression in thymomas with PTPN22 +1858T(+) genotypes (P=0.028) was lower, implying weaker TCR signaling. We conclude that the PTPN22(gain-of-function) variant biases towards MG in a subgroup of thymoma patients possibly by impeding central tolerance induction.
Subject(s)
Interleukin-2/immunology , Myasthenia Gravis/immunology , Polymorphism, Single Nucleotide , Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 22/immunology , Thymoma/immunology , Thymus Neoplasms/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Antigens, CD/genetics , Antigens, CD/immunology , CTLA-4 Antigen , Female , Genetic Predisposition to Disease , Genotype , Humans , Male , Middle Aged , Myasthenia Gravis/complications , Myasthenia Gravis/genetics , Thymoma/complications , Thymoma/genetics , Thymus Neoplasms/complications , Thymus Neoplasms/genetics , White People/genetics , Young AdultABSTRACT
Multiple sclerosis (MS) is the most common chronic inflammatory neurologic disorder diagnosed in young adults and, due to its chronic course, is responsible for a substantial economic burden. MS is considered to be a multifactorial disease in which both genetic and environmental factors intervene. The well-established human leukocyte antigen (HLA) association does not completely explain the genetic impact on disease susceptibility. However, identification and validation of non-HLA-genes conferring susceptibility to MS has proven to be difficult probably because of the small individual contribution of each of these genes. Recently, associations with two single nucleotide polymorphisms (SNPs) in the IL2RA gene (rs12722489, rs2104286) and one SNP in the IL7RA gene (rs6897932) have been reported by several groups. These three SNPs were genotyped in a French and a German population of MS patients using the hME assay by the matrix-assisted laser desorption/ionization time of flight technology (Sequenom, San Diego, CA, USA). We show that these SNPs do contribute to the risk of MS in these two unrelated European MS patient populations with odds ratios varying from 1.1 to 1.5. The discovery and validation of new genetic risk factors in independent populations may help toward the understanding of MS pathogenesis by providing valuable information on biological pathways to be investigated.
Subject(s)
Genetic Predisposition to Disease/genetics , Interleukin-2 Receptor alpha Subunit/genetics , Multiple Sclerosis/genetics , Receptors, Interleukin-7/genetics , Adult , Aged , Female , France , Gene Frequency , Genotype , Germany , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Spectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationABSTRACT
In Helicobacter pylori gastritis gastric epithelium plays a central role in the innate immunity to H. pylori. However, epithelial receptors interacting with H. pylori have been poorly characterized so far. Recently a new triggering receptor expressed on myeloid cells-1 (TREM-1) has been identified on human neutrophils and monocytes. On these cells TREM-1 triggers innate immunity by stimulating the secretion of interleukin (IL)-8 and tumour necrosis factor (TNF)-alpha and thus amplifies bacterial-induced inflammation. In this study expression and function of TREM-1 in gastric epithelium exposed to H. pylori has been investigated. TREM-1 mRNA and protein were expressed on gastric epithelial cell lines as demonstrated by reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence activated cell sorter analysis. Gastric epithelial TREM-1 expression was up-regulated directly by H. pylori and was independent of epithelial IL-8 induced by H. pylori. Immunohistochemistry and tissue RT-PCR demonstrated significantly stronger TREM-1 expression in H. pylori gastritis compared with the non-inflamed gastric mucosa supporting in vivo that epithelial TREM-1 is up-regulated during H. pylori infection. Stimulation of gastric epithelial TREM-1 receptor resulted in IL-8 up-regulation on mRNA and protein level, as shown by real-time PCR and immunoassay. This is the first study localizing TREM-1 on gastric epithelium. Functional data suggest that TREM-1 expressed on gastric epithelium amplifies inflammation of the underlying gastric mucosa by up-regulation of IL-8.
Subject(s)
Gastric Mucosa/immunology , Helicobacter Infections/immunology , Helicobacter pylori , Membrane Glycoproteins/metabolism , Receptors, Immunologic/metabolism , Cell Line , Epithelial Cells/immunology , Gastritis/immunology , Gastritis/microbiology , Gene Expression/immunology , Humans , Immunity, Innate , Interleukin-8/immunology , Lipopolysaccharides/immunology , Membrane Glycoproteins/genetics , RNA, Messenger/genetics , Receptors, Immunologic/genetics , Reverse Transcriptase Polymerase Chain Reaction/methods , Triggering Receptor Expressed on Myeloid Cells-1 , Up-Regulation/immunologyABSTRACT
Several lines of evidence support early immunomodulatory treatment of relapsing multiple sclerosis with either recombinant beta-interferons or glatiramer acetate and positive results from phase III trials encourage start of treatment even in patients with clinical isolated syndrome (CIS). However, currently available drugs for basic therapy are only partially effective and patients may still encounter relapses or disease progression. As treatment-refractory, clinically active MS can quickly lead to irreversible neurological disability there is an urgent need for more effective therapeutic strategies.The major goal is to reduce the damage, protect the tissue and enhance repair. In order to achieve these goals we not only need effective and safe drugs but also the appropriate study designs to really detect the most relevant outcomes [2, 7].
Subject(s)
Clinical Trials as Topic/methods , Clinical Trials as Topic/standards , Immunotherapy/methods , Multiple Sclerosis/therapy , Humans , Immunotherapy/adverse effectsABSTRACT
This review updates and extends earlier Consensus Reports related to current basic and escalating immunomodulatory treatments in multiple sclerosis (MS). The recent literature has been extracted for new evidence from randomized controlled trials, open treatment studies and reported expert opinion, both in original articles and reviews, and evaluates indications and safety issues based on published data. After data extraction from published full length publications and critically weighing the evidence and potential impact of the data, the review has been drafted and circulated within the National MS Societies and the European MS Platform to reach consensus within a very large group of European experts, combining evidence-based criteria and expert opinion where evidence is still incomplete. The review also outlines a few areas of controversy and delineates the need for future research.
Subject(s)
Health Planning Guidelines , Immunologic Factors/therapeutic use , Multiple Sclerosis/therapy , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Azathioprine/pharmacology , Azathioprine/therapeutic use , Europe , Glatiramer Acetate , Humans , Immunoglobulins, Intravenous/pharmacology , Immunoglobulins, Intravenous/therapeutic use , Immunologic Factors/administration & dosage , Interferon-beta/pharmacology , Interferon-beta/therapeutic use , Magnetic Resonance Imaging , Mitoxantrone/pharmacology , Mitoxantrone/therapeutic use , Multiple Sclerosis/diagnosis , Natalizumab , Peptides/pharmacology , Peptides/therapeutic use , Plasmapheresis , Randomized Controlled Trials as Topic , Societies/standardsABSTRACT
Objectives - The use of telencephalin as a possible marker for altered cortical function as demonstrated by functional MRI was investigated in a pilot study with 16 patients with localization-related epilepsy and secondarily generalized seizures. Materials and methods - Functional MRI of verbal working memory performance (Sternberg paradigm) and self-regulatory control processes (Stroop paradigm) was used to examine cortical activation in 16 patients with localization-related epilepsy and secondarily generalized seizures. Additionally, blood serum concentrations of soluble telencephalin (marker for neuronal damage) were determined. Results - In three patients (one temporal and two frontal focus), telencephalin was detected. All three patients had lower functional MRI activation in the frontotemporal region (P = 0.04), but not in other regions (P > 0.35) compared with patients without detectable telencephalin. Additionally, an association of levetiracetam and frontotemporal activation was observed. Conclusions - These preliminary data in a heterogeneous group suggest an association between decreased frontotemporal activation on fMRI and both detectable telencephalin serum levels and levetiracetam use. Future longitudinal studies with larger patient groups are required to confirm these observations. It is hypothesized that altered local function of the frontotemporal cortex in localization-related epilepsy might be better predicted by the biochemical marker telencephalin than epilepsy characteristics such as seizure focus.
Subject(s)
Brain/pathology , Cell Adhesion Molecules/blood , Epilepsies, Partial/blood , Epilepsies, Partial/pathology , Magnetic Resonance Imaging , Nerve Tissue Proteins/blood , Adult , Anticonvulsants/therapeutic use , Biomarkers/blood , Brain/drug effects , Epilepsies, Partial/drug therapy , Female , Humans , Levetiracetam , Male , Middle Aged , Neuropsychological Tests , Pilot Projects , Piracetam/analogs & derivatives , Piracetam/therapeutic useABSTRACT
In multiple sclerosis patients, infection is often associated with disease deterioration. Lipopolysaccharide (LPS) from gram-negative bacteria signals via the toll-like receptor 4 (TLR-4) pathway. Therefore, we investigated the role of an Asp299Gly mutation in the TLR-4 receptor in 890 MS patients with multiple sclerosis and 350 healthy controls. No association of different genotypes with MS susceptibility, MS subtypes, or disease severity was found. In vitro LPS stimulation studies showed a significantly lower proliferation of PBMCs from donors heterozygous for the Asp299Gly mutation in comparison to PBMCs from individuals with the wild-type genotype (p=0.01). However, these functional changes seem not to have any impact on the clinical presentation of MS patients with different TLR-4 genotypes.