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Definitions and measures of asthma control used in clinical trials and practice often vary, as highlighted in the manuscript, “Is asthma control more than just an absence of symptoms? An expert consensus statement”. Furthermore, the authors discussed differences between patients and healthcare professionals (HCPs) in terms of understanding and managing asthma. Given these disparities, there is a need for consensus regarding what constitutes well-controlled asthma and, especially, how best it can be measured and recorded. In the current work, we describe our data and provide more detail on the methodology from a two-stage Delphi survey and a structured literature review, which were designed to reach a consensus definition of asthma control and alleviate misalignments between patients and HCPs. Survey data were collected using a two-stage Delphi technique; a method used to collate expert opinions over a series of sequential questionnaires to reach a consensus. The collated Delphi survey data were compared with results from a comprehensive, structured literature review of 216 publications, to assess if there was a correlation between existing guidance and measures of asthma control used in clinical trials and standard clinical practice. In order to collate and interpret findings from the Delphi survey, responses from 82 panelists (73 HCPs and 9 authors) were qualitatively analyzed, quantitatively categorized, and presented as percentages or counts in Excel databases, which are detailed in the current work. Searches conducted using PubMed and Cochrane identified 664 manuscripts, and Embase was used to identify 89 congress abstracts. After applying a stringent screening method using predefined key words, the structured literature review consisted of 185 peer-reviewed manuscripts and 31 congress abstracts, and assessed existing guidance and measures of asthma control used in clinical trials. In this publication, we provide further insight into the predefined keywords, search strings, and strategy applied to identify manuscripts and congress abstracts for inclusion/exclusion, and detail methods for data extraction. Together, the data from the Delphi survey and structured literature review aimed to provide greater insights into challenges and approaches in achieving asthma control in clinical practice, with the potential for results to be used to guide a universally accepted definition and measure of asthma control that can be used and understood by patients, HCPs, and researchers. Qualitative and quantitative methodology and analysis from the Delphi survey and literature review search strategy can potentially be used to identify disparities and explore expert opinion and relevant literature in other therapeutic areas to guide a consensus where disparities exist.

Objective: It is well known that abnormal automatic postural responses impair balance control in patients with multiple sclerosis (PwMS) and these responses can be ameliorated with training. However, the difference between patients with MS and the healthy population on the adaptation capacity of postural responses to perturbations remains unclear. The aim of the present study was to evaluate the adaptation capability to postural perturbations in PwMS and to reveal differences between healthy controls. Materials and Methods: Sixty-nine ambulatory PwMS with Expanded Disability Status Scale (EDSS) scores below or equal to 5.5, and 61 healthy subjects were recruited for the study. Adaptation Test with NeuroCom Smart Balance Master System, Berg Balance Scale (BBS), and EDSS were administered. The adaptation test was performed in the toes-up and toes-down directions; five consecutive perturbations were given for each direction. The sway energy score was calculated for postural sway that were released during these perturbations. Results: According to the adaptation test results, healthy volunteers’ sway energy scores were significantly lower than those of PwMS in five consecutive perturbations (toes-up p

Inguinal hernia repair is one of the most common operations performed in worldwide. The success of the hernia repair is judged mainly by the recurrence rate after following the operation. Different techniques have different recurrence rates. Open hernia repairs have recurrence rate between 10% and 30%. Lichtenstein's tension-free open hernia repair heralded a new era the reported recurrence after this repair in around 0%–1.7%.

Autoantibodies to myelin oligodendrocytes glycoprotein (MOG) are found in a fraction of patients with inflammatory demyelination and are detected with MOG-transfected cells. While the prototype anti-MOG mAb 8-18C5 and polyclonal anti-MOG responses from different mouse strains largely recognize the FG loop of MOG, the human anti-MOG response is more heterogeneous and human MOG-Abs recognizing different epitopes were found to be pathogenic. The aim of this study was to get further insight into details of antigen-recognition by human MOG-Abs focusing on the impact of glycosylation. MOG has one known N-glycosylation site at N31 located in the BC loop linking two beta-sheets. We compared the reactivity to wild type MOG with that toward two different mutants in which the neutral asparagine of N31 was mutated to negatively charged aspartate or to the neutral alanine. We found that around 60% of all patients (16/27) showed an altered reactivity to one or both of the mutations. We noted seven different patterns of recognition of the two glycosylation-deficient mutants by different patients. The introduced negative charge at N31 enhanced recognition in some, but reduced recognition in other patients. In 7/27 patients the neutral glycosylation-deficient mutant was recognized stronger. The folding of the extracellular domain of MOG with the formation of beta-sheets did not depend on its glycosylation as seen by circular dichroism. We determined the glycan structure of MOG produced in HEK cells by mass spectrometry. The most abundant glycoforms of MOG expressed in HEK cells are diantennary, contain a core fucose, an antennary fucose, and are decorated with α2,6 linked Neu5Ac, while details of the glycoforms of MOG in myelin remain to be identified. Together, we (1) increase the knowledge about heterogeneity of human autoantibodies to MOG, (2) show that the BC loop affects recognition in about 60% of the patients, (3) report that all patients recognized the unglycosylated protein backbone, while (4) in about 20% of the patients the attached sugar reduces autoantibody binding presumably via steric hindrance. Thus, a neutral glycosylation-deficient mutant of MOG might enhance the sensitivity to identify MOG-Abs.

Background: Acute disseminated encephalomyelitis (ADEM) is a rare demyelinating disease of the central nervous system, commonly attributed to infections or vaccinations. Toxic or allergenic compounds can also trigger a response in the immune system and may cause demyelination. We present a case with ADEM after using oral herbal medications. Case Report: A 25 year-old male developed bilateral central facial palsy and severe quadriparesis after taking herbal drugs (containing echinacea and many other herbal ingredients) for two weeks. He had used the extract to increase his potency and reproductivity. He had no past history of recent immunization or viral infection. The clinical findings, cerebrospinal fluid (CSF) analysis and brain magnetic resonance imaging (MRI) were compatible with ADEM. The neurological findings were improved after seven doses of pulse methylprednisolone treatment. To our knowledge, this is the third report in the literature that links herbal therapy and demyelinating disease. Conclusion: Most of the ADEM cases related to herbal therapy in the literature similarly used echinacea. It is our opinion that other ingredients of the herbal extract used by our case, besides echinacea, could have the potential to cause a trigger in the immune system. Further studies are needed to clarify the immunological effects of different kinds of herbal compounds, as well as the effects of different parts of the plants and the results of various dosages. Moreover, ingredients should also be tested for toxicity, adverse effects and drug interactions.

PURPOSECigarette smoking has been associated with increased occurrence of multiple sclerosis (MS), as well as clinical disability and disease progression in MS. We aimed to assess the effects of smoking on the white matter (WM) in patients with clinically isolated syndrome (CIS) using diffusion tensor imaging.METHODSSmoker patients with CIS (n=16), smoker healthy controls (n=13), nonsmoker patients with CIS (n=17) and nonsmoker healthy controls (n=14) were included. Thirteen regions-of-interest including nonenhancing T1 hypointense lesion and perilesional WM, and 11 normal-appearing white matter (NAWM) regions were drawn on color-coded fractional anisotropy (FA) maps. Lesion load was determined in terms of number and volume of WM hyperintensities.RESULTSA tendency towards greater lesion load was found in smoker patients. T1 hypointense lesions and perilesional WM had reduced FA and increased mean diffusivity to a similar degree in smoker and nonsmoker CIS patients. Compared with healthy smokers, smoker CIS patients had more extensive NAWM changes shown by increased mean diffusivity. There was no relationship between diffusion metrics and clinical disability scores, duration of the disease and degree of smoking exposure.CONCLUSIONSmoker patients showed a tendency towards having greater number of WM lesions and displayed significantly more extensive NAWM abnormalities.

Multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy is characterized by asymmetric multifocal motor and sensory loss and conduction blocks in peripheral nerves. Peripheral demyelinating diseases may be accompanied by demyelination in central nervous system (CNS). In this report, a MADSAM patient with a solitary tumefactive demyelinating lesion in brain is presented. Neuroimaging due to a visual field defect revealed a right parietooccipital lesion, which was initially misdiagnosed as a tumor. Pathological examination showed that it was demyelinating in nature. Peripheral nervous symptoms of the patient developed two years later and she was then diagnosed with MADSAM. There was prominent clinical and electrophysiological response to steroid treatment. Tumefactive brain involvement was not previously reported for MADSAM neuropathy, although it was documented in a single case with typical chronic inflammatory demyelinating polyneuropathy (CIDP). CNS involvement should therefore be considered in MADSAM patients.

Asli Kurne1, Rana Karabudak1, Gul Yalcin-Cakmakli1, Yasemin Gursoy-Ozdemir1, Pinar Aydin3, Ayse Ilksen-Colpak1, Sevda Lule2, Tulay Kansu11Department of Neurology, 2Institute of Neurological Sciences and Psychiatry, Faculty of Medicine, Hacettepe University, Ankara, Turkey; 3Special Eye Clinic, Ankara, TurkeyBackground and aim: Optic neuritis (ON) can be recurrent, with unilateral or bilateral presentation. Diagnosis of recurrent cases may be challenging. In this study long-term follow-up of recurrent and/or bilateral ON patients is reported in an effort to guide differential diagnosis and treatment.Methods: The study included 474 optic neuropathy patients. Of these, 70 patients with recurrent unilateral or bilateral, and nonrecurrent bilateral ON were assessed. The characteristics of each ON attack, laboratory and magnetic resonance imaging (MRI) findings, associated diseases and response to treatment were noted for each patient. Most of the patients were reevaluated in the outpatient clinic. Seven patients were investigated for neuromyelitis optica (NMO)-immunoglobulin G (IgG) seropositivity.Results: Forty-seven patients had recurrent unilateral ON and 23 had bilateral ON. Mean follow-up was 7.55 years. Final diagnoses for recurrent unilateral group were multiple sclerosis (MS) (n = 29), chronic relapsing inflammatory optic neuritis (CRION) (n = 11), NMO (n = 4), or autoimmune thyroid disease (n = 3); and for bilateral ON group, MS (n = 4), vasculitis (n = 13), postinfectious ON (n = 4), and sarcoidosis (n = 2). Three patients were positive for NMO antibodies.Conclusion: Based on the data collected, we conclude when recurrent ON causes moderate to severe visual loss in the absence of cranial MRI findings typical of MS, other diagnoses should be considered, including NMO.Keywords: optic neuritis, recurrent, bilateral, multiple sclerosis, neuromyelitis optica

OBJECTIVE: To report the clinical follow-up, side effects, and magnetic resonance imaging (MRI) findings of mitoxantrone treatment in patients in the early phase of secondary progressive and exacerbating relapsing-remitting multiple sclerosis. METHODS: Patients that completed and/or were undergoing treatment between 2001 and 2008 were included in the study. All patients were definitive progressive multiple sclerosis patients and met ‘non-responder’ criteria for immunomodulatory the- rapy. They did not have active infection, cardiac disease, or any contraindication for immunosuppressive treatment. Baseline comp- lete blood count, liver function tests, and transthoracic echocardiography were performed. Mitoxantrone was given as induction the- rapy (1 dose per month for 3 months) and then as maintenance therapy (with 3 month periods, 12 mg/m2 until to the cumulative dose was reached). Patients were followed-up regularly for the appearance of any side effects. RESULTS: The study included 33 female and 15 male patients. Mean age was 36.6 ± 7.8 years, mean disease duration was 9.38 ± 4.8 years, mean expanded disease severity scale (EDSS) score was 5.8, and mean treatment duration was 11.16 ± 7.4 months. Fol- lowing the end of treatment, 17 patients were stabilized, 10 improved, and 14 progressed. There were no side effects observed du- ring or after treatment in 16 patients. Among the other 32 patients, the observed side effects were as follows: nausea (n= 18), per- manent leucopenia (n= 1), transient thrombocytopenia (n= 4), alopecia (n= 13), neutropenic fever (n= 1), and amenorrhea (n= 18). MRI follow-up was performed in a subgroup of patients and showed that the lesion loads were stabilized. CONCLUSION: We reported the efficacy, and clinical and MRI follow-up results of multiple sclerosis patients treated with mitoxantro- ne. Patient selection and therapy timing was very important for maximum efficacy. Patients that responded to mitoxantrone treat- ment benefited beginning with the induction phase and their disability was limited or improved

OBJECTIVE: Multiple Sclerosis (MS) is an autoimmune disease that could be seen simultaneously with other diseases with autoimmune origin. OBJECTIVE: In this descriptive study, it was aimed to evaluate the relationship between MS and other autoimmune diseases among MS patients and their first degree relatives in two different centers, Ankara and Samsun. METHODS: 784 MS were included in the study. The data was gathered via interviews and patient record reviews. MS patients and their first degree relatives were asked for 13 specific autoimmune diseases which have been supposed to occur more frequently in MS patients. Data was evaluated seperately as patient record reviews and questionare interview. Ankara and Samsun center results were compared with each other. RESULTS: Among the interviewed subjects, 9 (5.3%) had co-occurrent autoimmune disease while the relatives of 26 (15.3%) was found to have autoimmune disease in Ankara. These figures were respectively 8 (17.4%) and 21 (45.7%) in Samsun. Both comorbid autoimmune disease among patients and autoimmune disease among relatives were observed to be higher in Samsun. Psoriasis was the mostly seen disease in Samsun and one of the mostly seen diseases in Ankara (1.2% in Ankara, 8.7% in Samsun). Multiple sclerosis (5.9%) and rheumatoid arthritis (32.6%) were the mostly seen diseases among relatives in Ankara and Samsun, respectively. According to the patient record reviews, the proportion of comorbid autoimmune disease in MS patients was 2.9% in Ankara and 5.2% in Samsun. In the whole group the proportion of the autoimmune diseases among female patients (17.4%) and their relatives was higher than male patients (5.3%) and their relatives. In Ankara, autoimmune thyroid disease (Graves and Hashimoto disease) was mostly seen whereas Behçet's disease was the most prominent in Samsun. CONCLUSION: In the study it was observed that among MS patients the percentage of having a comorbid disease was high. Besides, among the patients’ relatives, percentage of autoimmnue diseases, especially MS was observed to be high. Psoriasis was among the mostly seen diseases in both groups. MS and rheumatoid arthritis were observed to be the mostly seen autoimmune diseases among relatives

Scientific background: Neurodegeneration following inflammatory in- jury is considered to be a pathological correlate of irreversible disability in patients with multiple sclerosis (MS). The presence of amyloid precur- sor protein in active lesions, oxidative injury of mitochondrial DNA, dis/inactivation of mitochondrial enzymes, loss of axonal density in nor- mal appearing white matter, reduction of N-acetylaspartate (NAA)/cre- atinin ratio in magnetic resonance spectroscopy (MRS) and the correla- tion between reduced NAA levels and disability have been determined as evidences of neurodegeneration in MS. In the disease immunopatho- genesis some biological indicators of axonal transsection as NAA, ac- tin, tubulin, L-neurofilaments, anti-axolemma IgG, antigangliozide anti- bodies, glial fibrillary acid protein, S-100 protein, nitric oxide, neuronal specific enolase, 14-3-3 protein, apoprotein E have been described and put in association with the clinicial status. The description of axonal transsection which is a main cause of disabi- lity has been made in the very early times when the first histopatholo- gic signs of multiple sclerosis were discovered. Although it has a long past, the role of neurodegenerative mechanisms in the axonal transsec- tion has been recently described. Genetic factors, excitotoxicity, apop- tosis, depletion of growth factors and energy, inducible demyelination are the other mechanisms that cause neurodegeneration. Recent studies have shown that glutamate excitotoxicity may be a com- ponent in the pathogenesis of MS. Glutamate transporters determine the levels of extracellular glutamate and are essential to prevent excitotoxicity. In MS, the evident association between insidious and prolonged microglial activation and glutamate excitotoxicity has been emphasized and in addition glutamate excitotoxicity is considered to be responsible due to progressive loss of oligodendrocytes (OLG). Excitotoxicity in OLGs begins as Ca + + influx via AMPA/kainat receptors. The number of AMPA re- ceptors increased on postsynaptic membrane and apoptotic cellular death occur because of prolonged activation of these receptors. Proinflamma- tory cytokines such as interlukine-1 and tumor necrosis-· as increasing receptor expression on OLGs cause to be prone to excitotoxic death. The gradual loss of axons is thought to underlie irreversible clinical defi- cits in this disease. The precise mechanisms of axonopathy are poorly understood, but likely involve excess accumulation of Ca ions. In healthy fibers, ATP-dependent pumps support homeostasis of ionic gradients. When energy supply is limited, either due to inadequate delivery (e.g., ischemia, mitochondrial dysfunction) and/or excessive utilization (e.g., conduction along demyelinated axons), ion gradients break down, unleashing a variety of aberrant cascades, ultimately leading to Ca overload. During Na pump dysfunction, Na can enter axons through non-inactivating Na channels, promoting axonal Na overload. This will gate voltage-sensitive Ca channels and stimulate reverse Na-Ca exchan- ge, leading to further Ca entry. Energy failure will also promote Ca release from intracellular stores. Also, after demyelination a new orga- nisation of different types of sodium channels has been shown to ap- pear on axons and inflammatory cells. In this manuscript the role of voltage-gated sodium channels and glu- tamate excitotoxicity, and interactions of glutamate with receptors and cytokines on the immunopathogenesis of multiple sclerosis are revie- wed and discussed

Background: Inflammation has been described as a deleterious factor in MS immunopathogenesis for a long time. However, recent studies have proved the neuronal protective and efficacious effects of inflammation. Inflammation in the brain is a double-edged process that may be beneficial in promoting homeostasis and repair, but can also result in tissue injury through the damaging potential of inflammatory mediators. Control mechanisms that minimize the extent of the inflammatory reaction are necessary in order to preserve brain architecture and restore function. The end result of the inflammatory process, neurotoxicity and/or neuroprotection, is a function of the fine balance between the two cellular systems and of the complex signaling relationships between anti-inflammatory neuroprotective factors. In central nervous system inflammation the extent of tissue injury depends on both native and adaptive elements of the immune system. Besides, inflammation is not limited with the invasion of exogeneus cells infiltrating from the blood brain barrier. Astrocytes and microglial cells as being endogeneous also play an important role in the process. Secondary inflammatory mediators from these cells trigger the unique local inflammation of central nervous system. In the active MS plaques distinct cytokines and chemokines have been determined. C o n c l u s i o n: Inflammation has different aspects and some proof of beneficial roles can be summarized: Before the clinical signs of /during the experimental allergic encephalomyelitis (EAE) the presence of IFN-g h a s been shown as a limitting factor for the progression, the delivery of anti- I F N -g monoclonal antibodies have increased the morbidity in EAE. CD4+ T cells stimulate microglial cells to secrete some mediators as interleukin E2 that can supress IL-12 and the same cells can also secrete neruprotective factors as brain derived neurotrophic factor. Another group of cells, macrophages trigger remyelinization by clearing myelin debris. This review discusses about the contradictory effects of inflammation on the immunopathogenesis of multiple sclerosis. It outlines the cells responsible for the inflammatory cascade, both beneficial and detrimental effects of inflammation on myelin and axonal integrity and additional relation for demyelination and axonal transsection.

Byline: Rana Karabudak (1), AslA+- Kurne (1), Dicle Guc (2), Meltem Sengelen (3), Hande Canpinar (2), Emin Kansu (2) Keywords: multiple sclerosis; IFN [beta]1a; matrix metalloproteinases; tissue inhibitors of MMPs; MMP-9; TIMP-1 Abstract: Abstract. There is emerging evidence that matrix metalloproteinases (MMPs) might be involved in blood brain barrier (BBB) breakdown in multiple sclerosis. A group of natural tissue inhibitors of metalloproteinases (TIMPS) regulates proteolytic activity to prevent tissue damage. TIMP-1 and MMP-9 are known to be secreted as heterodimers and TIMP-1 preferentially functions to inhibit MMP-9 activity. In this present study, the effects of IFN[beta]-1a on serum MMP-9 and TIMP-1 were evaluated longitudinally during a one-year period. The MMP-9 levels showed no significant changes while TIMP-1 levels gradually and significantly increased during 3.sup.rd and 6.sup.th months of therapy compared with pretreatment levels. Author Affiliation: (1) Hacettepe University, Faculty of Medicine, Department of Neurology Neuroimmunology Unit, 06100, Ankara, Turkey (2) Hacettepe University, Oncology Institute, Department of Basic Oncology, Ankara, Turkey (3) Hacettepe University, Oncology Institute, Department of Preventive Oncology, Ankara, Turkey Article History: Registration Date: 01/01/2004 Received Date: 05/11/2002 Accepted Date: 24/09/2003