Тактика ведения пациентов при синдроме Мэллори-Вейсса

МЭЛЛОРИ-ВЕЙСА СИНДРОМ /диагн /терПИЩЕВОДА ПЕРФОРАЦИЯ /диагн /терЖЕЛУДОЧНО-КИШЕЧНОЕ КРОВОТЕЧЕНИЕГЕМОСТАЗ ЭНДОСКОПИЧЕСКИ

Fluoxetine in Progressive Multiple Sclerosis (FLUOX-PMS) : study protocol for a randomized controlled trial

Background: Currently available disease-modifying treatments acting by modifying the immune response are ineffective in progressive multiple sclerosis (MS), which is caused by a widespread axonal degeneration. Mechanisms suspected to be involved in this widespread axonal degeneration are reduced axonal energy metabolism, axonal glutamate toxicity, and reduced cerebral blood flow. Fluoxetine might theoretically reduce axonal degeneration in MS because it stimulates energy metabolism through enhancing glycogenolysis, stimulates the production of brain-derived neurotrophic factor, and dilates cerebral arterioles. The current document presents the protocol of a clinical trial to test the hypothesis that fluoxetine slows down the progressive phase of MS. Methods/Design: The FLUOX-PMS trial is a multi-center, randomized, controlled and double-blind clinical study. A total of 120 patients with the diagnosis of either secondary or primary progressive MS will be treated either by fluoxetine (40 mg daily) or placebo for a total period of 108 weeks. The primary endpoint is the time to confirmed disease progression defined as either at least a 20% increase in the timed 25-Foot Walk or at least a 20% increase in the 9-Hole Peg Test. Secondary endpoints include the Hauser ambulation index, cognitive changes, fatigue, magnetic resonance imaging of the brain, and in a small subgroup optical coherence tomography. Discussion: The FLUOX-PMS trial will gives us information as to whether fluoxetine has neuroprotective effects in patients with progressive MS

Loss of DPP6 in neurodegenerative dementia : a genetic player in the dysfunction of neuronal excitability

Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal firing as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family significantly linked to 7q36. We identified and validated a chromosomal inversion of ca. 4Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6 resequencing identified significantly more rare variants-nonsense, frame-shift, and missense-in early-onset Alzheimer's disease (EOAD, p value = 0.03, OR = 2.21 95% CI 1.05-4.82) and frontotemporal dementia (FTD, p = 0.006, OR = 2.59, 95% CI 1.28-5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and is mainly expressed in brain, where it binds to the potassium channel K(v)4.2 enhancing its expression, regulating its gating properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the missense variants found in patients destabilize DPP6 and reduce its membrane expression (p < 0.001 and p < 0.0001) leading to a loss of protein. Reduced DPP6 and/or K(v)4.2 expression was also detected in brain tissue of missense variant carriers. Loss of DPP6 is known to cause neuronal hyperexcitability and behavioral alterations in Dpp6-KO mice. Taken together, the results of our genomic, genetic, expression and modeling analyses, provided direct evidence supporting the involvement of DPP6 loss in dementia. We propose that loss of function variants have a higher penetrance and disease impact, whereas the missense variants have a variable risk contribution to disease that can vary from high to low penetrance. Our findings of DPP6, as novel gene in dementia, strengthen the involvement of neuronal hyperexcitability and alteration in the homeostasis of neuronal firing as a disease mechanism to further investigate

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Neurological outcome after minimally invasive coronary artery bypass surgery (NOMICS): An observational prospective cohort study.

Background/objectivesEndoscopic coronary artery bypass grafting (Endo-CABG) is a minimally invasive CABG procedure with retrograde arterial perfusion. The main objective of this study is to assess neurocognitive outcome after Endo-CABG.Methods/designIn this prospective observational cohort study, patients were categorised into: Endo-CABG (n = 60), a comparative Percutaneous Coronary Intervention (PCI) group (n = 60) and a healthy volunteer group (n = 60). A clinical neurological examination was performed both pre- and postoperatively, delirium was assessed postoperatively. A battery of 6 neurocognitive tests, Quality of life (QoL) and the level of depressive feelings were measured at baseline and after 3 months. Patient Satisfaction after Endo-CABG was assessed at 3-month follow-up. Primary endpoints were incidence of postoperative cognitive dysfunction (POCD), stroke and delirium after Endo-CABG. Secondary endpoints were QOL, patient satisfaction and the incidence of depressive feelings after Endo-CABG.ResultsIn total, 1 patient after Endo-CABG (1.72%) and 1 patient after PCI (1.67%) suffered from stroke during the 3-month follow-up. POCD in a patient is defined as a Reliable Change Index ≤-1.645 or Z-score ≤-1.645 in at least two tests, and was found in respectively 5 and 6 patients 3 months after Endo-CABG and PCI. Total incidence of POCD/stroke was not different (PCI: n= 7 [15.9%]; Endo-CABG: n= 6 [13.0%], p = 0.732). ICU delirium after Endo-CABG was found in 5 (8.6%) patients. QoL increased significantly three months after Endo-CABG and was comparable with QoL level after PCI and in the control group. Patient satisfaction after Endo-CABG and PCI was comparable. At follow-up, the level of depressive feelings was decreased in all groups.ConclusionsThe incidence of poor neurocognitive outcome, including stroke, POCD and postoperative ICU delirium until three months after Endo-CABG is low and comparable with PCI.Trial registrationRegistered on ClinicalTrials.gov (NCT02979782)

Effectiveness and safety of safinamide in routine clinical practice in a Belgian Parkinson's disease population: an open-label, levodopa add-on study.

Safinamide is a recent multimodal antiparkinsonian drug that inhibits monoamine oxidase B and modulates the glutamatergic system with positive effects on motor and nonmotor symptoms of Parkinson's disease (PD). This post-hoc analysis of the European SYNAPSES study provides first-time data on the use of safinamide in routine clinical practice in Belgium. To describe the efficacy and safety of safinamide in Belgian PD patients in real-life conditions. Post-hoc analysis of the Belgian cohort from the European SYNAPSES trial, which was an observational, multicenter, retrospective-prospective cohort study. Patients were followed up to 12 months. Analyses were performed in the overall population and according to different criteria such as the age limit (> 75 years), presence or absence of relevant comorbidities, presence or absence of psychiatric conditions such as depression and anxiety, patients on levodopa monotherapy or levodopa in combination with other treatments, patients on rasagiline before inclusion or not. Of the 172 patients included, 29.2% were > 75 years, 58.9% had relevant comorbidities and 32.7% had psychiatric conditions. Almost all the patients reported motor (98.8%) or non-motor (86.3%) symptoms. During the study, 36.3% of patients reported drug-related reactions. The adverse drug reactions were those already described in the patients' information leaflet. The majority were mild or moderate and completely resolved and no differences were detected between the subgroups of patients. Almost 35% of the patients demonstrated a clinically significant improvement in the UPDRS and 50% of the patients with wearing-off at baseline, did not report wearing-off anymore after one year of treatment. Patients under levodopa monotherapy compared to patients receiving levodopa combined with other antiparkinsonian treatments benefit more from safinamide treatment. Patients switched from rasagiline to safinamide seemed also to benefit more from safinamide treatment. The study confirms the excellent safety and efficacy profile of safinamide, particularly in more vulnerable groups of patients such as the elderly and patients with significant comorbidities or psychiatric conditions such as depression or anxiety

A 2-year observational study of patients with relapsing-remitting multiple sclerosis converting to glatiramer acetate from other disease-modifying therapies: the COPTIMIZE trial

Studies suggest that patients with relapsing-remitting multiple sclerosis (RRMS) who do not benefit from other disease-modifying treatments (DMTs) may benefit from converting to glatiramer acetate (GA). COPTIMIZE was a 24-month observational study designed to assess the disease course of patients converting to GA 20 mg daily from another DMT. Eligible patients had converted to GA and had received prior DMT for 3-6 months, depending on the reasons for conversion. Patients were assessed at baseline and at 6, 12, 18, and 24 months. In total, 672 patients from 148 centers worldwide were included in the analysis. Change of therapy to GA was prompted primarily by lack of efficacy (53.6 %) or intolerable adverse events (AEs; 44.8 %). Over a 24-month period, 72.7 % of patients were relapse free. Mean annual relapse rate decreased from 0.86 [95 % confidence interval (CI) 0.81-0.91] before the change to 0.32 (95 % CI 0.26-0.40; p less than 0.0001) at last observation, while the progression of disability was halted, as the Kurtzke Expanded Disability Status Scale (EDSS) scores remained stable. Patients improved significantly (p less than 0.05) on measures of fatigue, quality of life, depression, and cognition; mobility scores remained stable. The results indicate that changing RRMS patients to GA is associated with positive treatment outcomes.Funding Agencies|Teva Pharmaceuticals Industries Ltd., Petach Tikva, Israel</p