Long-term adherence to IFN beta-1a treatment when using rebismart1device in patients with relapsing-remitting multiple sclerosis

The effectiveness of disease-modifying drugs in the treatment of multiple sclerosis is associated with adherence. RebiSmart® electronic device provides useful information about adherence to the treatment with subcutaneous (sc) interferon (IFN) ß-1a (Rebif®). The aim of the study was to determine long-term adherence to this treatment in patients with relapsing- remitting multiple sclerosis (RRMS). This retrospective multicentre observational study analysed 258 patients with RRMS who were receiving sc IFN ß-1a (Rebif®) treatment by using RebiSmart® until replacement (36 months maximum lifetime) or treatment discontinuation. Adherence was calculated with data (injection dosage, time, and date) automatically recorded by RebiSmart®. Patients in the study had a mean age of 41 years with a female proportion of 68%. Mean EDSS score at start of treatment was 1.8 (95% CI, 1.6-1.9). Overall adherence was 92.6%(95% CI, 90.6-94.5%). A total of 30.2% of patients achieved an adherence rate of 100%, 80.6% at least 90%, and only 13.2% of patients showed a suboptimal adherence (<80%). A total of 59.9% of subjects were relapse-free after treatment initiation. Among 106 subjects (41.1%) who experienced, on average, 1.4 relapses, the majority were mild (40.6%) or moderate (47.2%). Having experienced relapses from the beginning of the treatment was the only variable significantly related to achieving an adherence of at least 80% (OR = 3.06, 1.28-7.31). Results of this study indicate that sc IFN ß-1a administration facilitated by RebiSmart® could lead to high rates of adherence to a prescribed dose regimen over 36 months

Pain as a First Manifestation of Paraneoplastic Neuropathies: A Systematic Review and Meta-Analysis.

INTRODUCTION: Paraneoplastic neurological syndromes (PNS) consist of a heterogeneous group of neurological disorders triggered by cancer. The aim of this systematic review is to estimate the reported prevalence of pain in patients with paraneoplastic peripheral neuropathy (PPN). METHODS: A systematic computer-based literature search was conducted on PubMed database. RESULTS: Our search strategy resulted in the identification of 126 articles. After the eligibility assessment, 45 papers met the inclusion criteria. Full clinical and neurophysiological data were further extracted and involved 92 patients with PPN (54.5% males, mean age 60.0 ± 12.2 years). The commonest first manifestation of PPN is sensory loss (67.4%), followed by pain (41.3%), weakness (22.8%), and sensory ataxia (20.7%). In 13.0% of the cases, pain was the sole first manifestation of the PPN. During the course of the PPN, 57.6% of the patients may experience pain secondary to the neuropathy. CONCLUSIONS: Pain is very prevalent within PPN. Pain specialists should be aware of this. Detailed history-taking, full clinical examination, and requesting nerve conduction studies might lead to an earlier diagnosis of an underlying malignancy

Next-gen sequencing identifies non-coding variation disrupting miRNA-binding sites in neurological disorders

Understanding the genetic factors underlying neurodevelopmental and neuropsychiatric disorders is a major challenge given their prevalence and potential severity for quality of life. While large-scale genomic screens have made major advances in this area, for many disorders the genetic underpinnings are complex and poorly understood. To date the field has focused predominantly on protein coding variation, but given the importance of tightly controlled gene expression for normal brain development and disorder, variation that affects non-coding regulatory regions of the genome is likely to play an important role in these phenotypes. Herein we show the importance of 3 prime untranslated region (3'UTR) non-coding regulatory variants across neurodevelopmental and neuropsychiatric disorders. We devised a pipeline for identifying and functionally validating putatively pathogenic variants from next generation sequencing (NGS) data. We applied this pipeline to a cohort of children with severe specific language impairment (SLI) and identified a functional, SLI-associated variant affecting gene regulation in cells and post-mortem human brain. This variant and the affected gene (ARHGEF39) represent new putative risk factors for SLI. Furthermore, we identified 3'UTR regulatory variants across autism, schizophrenia and bipolar disorder NGS cohorts demonstrating their impact on neurodevelopmental and neuropsychiatric disorders. Our findings show the importance of investigating non-coding regulatory variants when determining risk factors contributing to neurodevelopmental and neuropsychiatric disorders. In the future, integration of such regulatory variation with protein coding changes will be essential for uncovering the genetic causes of complex neurological disorders and the fundamental mechanisms underlying health and disease

Trends and outcome of neoadjuvant treatment for rectal cancer: A retrospective analysis and critical assessment of a 10-year prospective national registry on behalf of the Spanish Rectal Cancer Project

Introduction: Preoperative treatment and adequate surgery increase local control in rectal cancer. However, modalities and indications for neoadjuvant treatment may be controversial. Aim of this study was to assess the trends of preoperative treatment and outcomes in patients with rectal cancer included in the Rectal Cancer Registry of the Spanish Associations of Surgeons. Method: This is a STROBE-compliant retrospective analysis of a prospective database. All patients operated on with curative intention included in the Rectal Cancer Registry were included. Analyses were performed to compare the use of neoadjuvant/adjuvant treatment in three timeframes: I)2006–2009; II)2010–2013; III)2014–2017. Survival analyses were run for 3-year survival in timeframes I-II. Results: Out of 14, 391 patients, 8871 (61.6%) received neoadjuvant treatment. Long-course chemo/radiotherapy was the most used approach (79.9%), followed by short-course radiotherapy ± chemotherapy (7.6%). The use of neoadjuvant treatment for cancer of the upper third (15-11 cm) increased over time (31.5%vs 34.5%vs 38.6%, p = 0.0018). The complete regression rate slightly increased over time (15.6% vs 16% vs 18.5%; p = 0.0093); the proportion of patients with involved circumferential resection margins (CRM) went down from 8.2% to 7.3%and 5.5% (p = 0.0004). Neoadjuvant treatment significantly decreased positive CRM in lower third tumors (OR 0.71, 0.59–0.87, Cochrane-Mantel-Haenszel P = 0.0008). Most ypN0 patients also received adjuvant therapy. In MR-defined stage III patients, preoperative treatment was associated with significantly longer local-recurrence-free survival (p < 0.0001), and cancer-specific survival (p < 0.0001). The survival benefit was smaller in upper third cancers. Conclusion: There was an increasing trend and a potential overuse of neoadjuvant treatment in cancer of the upper rectum. Most ypN0 patients received postoperative treatment. Involvement of CRM in lower third tumors was reduced after neoadjuvant treatment. Stage III and MRcN + benefited the most

Estudio del efecto del tratamiento con inmunoglobulinas por vía intravenosa en la neuromielitis óptica

Resumen: Objetivo: Evaluar la seguridad y tolerancia de las inmunoglobulinas por vía intravenosa (IgIV) para el tratamiento de la neuromielitis óptica (NMO). Métodos: Ocho pacientes que cumplían los criterios diagnósticos revisados de Wingerchuk fueron tratados con IgIV cada 2 meses (0,7 g por kg de peso y día durante 3 días). Las medidas de resultado principales fueron los eventos adversos graves, definidos de acuerdo con las directrices NIH para los ensayos clínicos. Las medidas de resultado secundarias fueron los cambios en la tasa anualizada de brotes y la discapacidad neurológica medida con la Expanded Disability Status Scale (EDSS). Resultados: Ocho pacientes fueron tratados: 5 con episodios recidivantes de neuritis óptica y/o mielitis y 3 pacientes con mielitis transversa longitudinal extensa recurrente. La edad media de inicio fue de 20,5 años (rango 7-31), el 87,5% mujeres. El tiempo medio de duración de la enfermedad al inicio del tratamiento fue de 9,0 años (rango 3-17). Tras 83 infusiones (rango 4-21) y una media de seguimiento de 19,3 meses (rango 6-39), hubo eventos adversos menores (dolor de cabeza en 3 pacientes y erupción cutánea leve en un paciente). La tasa de recaídas se redujo de 1,8 en el año anterior a 0,006 en el seguimiento (z = –2,5, p = 0,01). La EDSS se redujo de 3,3 ± 1,3 a 2,6 ± 1,5 (z = –2,0, p = 0,04). Conclusiones: El tratamiento con IgIV es seguro y bien tolerado y podría ser una alternativa de tratamiento para los trastornos del espectro de la NMO. Abstract: Objective: Evaluate safety and tolerance levels for intravenous immunoglobulins (IVIG) as treatment for neuromyelitis optica (NMO). Methods: Eight patients meeting Wingerchuk's revised diagnostic criteria were treated with IVIG every 2 months (0.7 g per kg body weight per day for 3 days). The primary outcome measure was the occurrence of serious adverse effects, defined according to NIH guidelines for clinical trials. Secondary outcome measures were changes in the yearly rate of attacks and in the degree of neurological disability measured with the Expanded Disability Status Scale (EDSS). Results: All 8 patients were treated; 5 had relapsing optic neuritis with or without myelitis and 3 had recurrent longitudinally extensive transverse myelitis. The mean age of onset was 20.5 years (range, 7-31 years) and 87,5% were female. The mean duration of the disease before beginning treatment was 9.0 years (range, 3-17 years). Following 83 infusions (range, 4-21 per patient) and a mean follow-up time of 19.3 months (range, 6-39 months), minor adverse events had occurred (headache in 3 patients and a mild cutaneous eruption in a single patient). The relapse rate decreased from 1.8 in the previous year to 0.006 during follow-up (z= 2,5, P=.01). The EDSS score fell from 3.3 ± 1.3 to 2.6 ± 1.5 (z = −2.0, P=.04). Conclusions: Treatment with IVIG is safe and well-tolerated, and it may be used as a treatment alternative for NMO spectrum disorders. Palabras clave: Tratamiento con inmunoglobulinas, Neuromielitis óptica, Seguridad, Keywords: Immunoglobulin treatment, Neuromyelitis optica, Safet

The effect of intravenous immunoglobulin on neuromyelitis optica

Objective: Evaluate safety and tolerance levels for intravenous immunoglobulins (IVIG) as treatment for neuromyelitis optica (NMO). Methods: Eight patients meeting Wingerchuk's revised diagnostic criteria were treated with IVIG every 2 months (0.7 g/kg body weight per day for 3 days). The primary outcome measure was the occurrence of serious adverse effects, defined according to NIH guidelines for clinical trials. Secondary outcome measures were changes in the yearly rate of attacks and in the degree of neurological disability measured with the Expanded Disability Status Scale (EDSS). Results: All 8 patients were treated; 5 had relapsing optic neuritis with or without myelitis and 3 had recurrent longitudinally extensive transverse myelitis (LETM). The mean age of onset was 20.5 years (range, 7–31 years) and 87.5% were female. The mean duration of the disease before beginning treatment was 9.0 years (range, 3–17 years). Following 83 infusions (range, 4–21 per patient) and a mean follow-up time of 19.3 months (range, 6–39 months), minor adverse events had occurred (headache in 3 patients and a mild cutaneous eruption in a single patient). The relapse rate decreased from 1.8 in the previous year to 0.006 during follow-up (z = −2.5, P = .01). The EDSS score fell from 3.3 [SD 1.3] to 2.6 [SD 1.5] (z = −2.0, P = .04). Conclusions: Treatment with IVIG is safe and well-tolerated, and it may be used as a treatment alternative for NMO spectrum disorders. Resumen: Objetivo: Evaluar la seguridad y tolerancia de las inmunoglobulinas intravenosas (IgIV) para el tratamiento de la neuromielitis óptica (NMO). Métodos: Ocho pacientes que cumplían los criterios diagnósticos revisados de Wingerchuk fueron tratados con IgIV cada dos meses (0,7 gr por kg de peso y día durante tres días). Las medidas de resultado principales fueron los eventos adversos graves, definidos de acuerdo con las directrices NIH para los ensayos clínicos. Las medidas de resultado secundarias fueron los cambios en la tasa anualizada de brotes y la discapacidad neurológica medida con la Expanded Disability Status Scale (EDSS). Resultados: Ocho pacientes fueron tratados: 5 con episodios recidivantes de neuritis óptica y/o mielitis, y 3 pacientes con mielitis transversa longitudinal extensa recurrente. La edad media de inicio fue de 20,5 años (rango 7–31), 87,5% mujeres. El tiempo medio de duración de la enfermedad al inicio del tratamiento fue de 9,0 años (rango 3–17). Tras 83 infusiones (rango 4–21), y una media de seguimiento de 19,3 meses (rango 6–39), hubo eventos adversos menores (dolor de cabeza en tres pacientes y erupción cutánea leve en un paciente). La tasa de recaídas se redujo de 1,8 en el año anterior a 0.006 en el seguimiento (z = −2.5, p = 0,01). La EDSS se redujo de 3,3 (DE 1,3) y 2,6 (DE 1,5) (z = −2.0, p = 0,04). Conclusiones: El tratamiento con IgIV es seguro y bien tolerado y podría ser una alternativa de tratamiento para los trastornos del espectro de la NMO. Keywords: Immunoglobulin treatment, Neuromyelitis optica, Safety, Palabras clave: Tratamiento con inmunoglobulinas, Neuromielitis óptica, Segurida

Intrathecal somatic hypermutation of IgM in multiple sclerosis and neuroinflammation

Intrathecal oligoclonal bands of the cerebrospinal fluid are considered the most important immunological biomarkers of multiple sclerosis. They typically consist of clonally expanded IgG antibodies that underwent affinity maturation during sustained stimulation by largely unknown antigens. In addition, similar to 40% of patients with multiple sclerosis have oligoclonal bands that consist of expanded IgM antibodies. We investigated the molecular composition of IgM- and IgG-chains from cerebrospinal fluid of 12 patients with multiple sclerosis, seven patients with other neurological diseases, and eight healthy control subjects by high-throughput deep-sequencing and single-cell PCR. Further, we studied the expression of activation-induced cytidine deaminase, the key enzyme for affinity maturation of antibodies, in cerebrospinal fluid samples of 16 patients. From the cerebrospinal fluid of two multiple sclerosis patients we isolated single B cells and investigated the co-expression of antibody chains with activation-induced cytidine deaminase. In striking contrast to IgM-chains from peripheral blood, IgM-chains from cerebrospinal fluid of patients with multiple sclerosis or neuroborreliosis showed a high degree of somatic hypermutation. We found a high content of mutations that caused amino acid exchanges as compared to silent mutations. In addition, more mutations were found in the complementarity determining regions of the IgM-chains, which interact with yet unknown antigens, as compared to framework regions. Both observations provide evidence for antigen-driven affinity maturation. Furthermore, single B cells from the cerebrospinal fluid of patients with multiple sclerosis co-expressed somatically hypermutated IgM-chains and activation-induced cytidine deaminase, an enzyme that is crucial for somatic hypermutation and class switch recombination of antibodies and is normally expressed during activation of B cells in germinal centres. Clonal tracking of particular IgM(+) B cells allowed us to relate unmutated ancestor clones in blood to hypermutated offspring clones in CSF. Unexpectedly, however, we found no evidence for intrathecal isotype switching from IgM to IgG. Our data suggest that the intrathecal milieu sustains a germinal centre-like reaction with clonal expansion and extensive accumulation of somatic hypermutation in IgM-producing B cells

Afrika van Kaap tot Caïro

Afrika heeft ons veel te leren. Het is niet overdreven om te stellen dat we hier in Nederland knap onderontwikkeld zijn in onze algemene kennis omtrent dat continent. Ons beeld van Afrika is gevormd vanuit ons eigen verleden en de geschiedschrijving daarover. Daarin was Afrika een continent dat werd bewoond door mensen zonder beschaving. Een continent zonder eigen geschiedenis. Die begon pas toen heldhaftige ontdekkingsreizigers de donkere binnenlanden exploreerden en missionarissen de zegeningen van het christendom en de Europese beschaving brachten. Natuurlijk, er waren ook wel slechte aspecten aan onze bemoeienissen met Afrika. Slavernij en koloniale uitbuiting en Apartheidssystemen in Zuid- Afrika en Rhodesië. Een beeld van Afrika waarin de Europeaan de hoofdrol speelt en de Afrikaan slechts ter sprake komt als lijdend voorwerp. Met dit beeld van de Afrikaan zijn we nog onlangs indringend geconfronteerd door de tentoonstelling Wit over Zwart in het Tropenmuseum. De scherpste kantjes van dit eurocentrische denken zijn tegenwoordig wel verdwenen. We weten nu dat Afrika een rijke geschiedenis heeft met prachtige hoogtepunten. We weten inmiddels wel dat er een fantastische rijkdom is aan volken en culturen, waar we heel wat van kunnen leren