Revue de la littérature récente sur les neuropathies périphériques : actualités thérapeutiques

Improvement of therapeutic strategies for peripheral neuropathies requires multicentric clinical trials. For chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a randomized controlled multicentric study compared IgIV to pulses of methylprednisolone (MP) given for 6 months. The primary endpoint was treatment discontinuation due to inefficacy or intolerance; 45 patients were enrolled: more patients had interrupted MP than IVIg, usually because of inefficacy. A multicentric randomized clinical trial (PREDICT) evaluated long-term remission of CIDP after short-term corticosteroid therapy (pulses of dexamethasone or prednisolone); 39 patients were enrolled: 26% achieved cure or remission, a relapse occurred in 50% after a delay of 11 to 17 months. Differential diagnosis was identified in 58% of patients who had not responded to any therapy. For refractory CIDP, a retrospective study showed the possibility of functional improvement in 24% of cases after adjunction of animmunomodulatory agent; cyclosporine was associated with the highest rate of adverse events or side effects. In familial amyloidotic polyneuropathy, a multicentric controlled study against placebo with tafamidis, an akinetic stabilizer of transthyretin (TTR) 20 mg/d, in early stage of Val30MetTTR showed efficiency in the evaluable group and led to marketing authorization by the EMA in stage 1 to slow the progression of the neuropathy. A Cochrane database system review showed that there are no randomized or quasi-randomized controlled clinical trials of treatment for POEMS syndrome, for neuropathies with anti-MAG antibodies, or multifocal motor neuropathy on which to base practice. This review underlines the usefulness of multicentric randomized trials to assess treatments in peripheral neuropathies.     

SIV/Macaque Model of HIV Infection in Cocaine Users: Minimal Effects of Cocaine on Behavior, Virus Replication, and CNS Inflammation

Studies of the effects of drugs of abuse on HIV immune status, disease progression, and neuroAIDS have produced conflicting data and have not definitively shown whether this combination promotes cognitive impairment or disease progression. Using a consistent SIV?Cmacaque model, we investigated the effects of cocaine on behavior, virologic parameters, and CNS inflammation. Macaques received either vehicle or chronic administration of behaviorally active doses of cocaine (1.7 or 3.2?mg/kg/day). Chronic cocaine administration reduced CD8+ T cell counts during acute and late stage infection but had no effect on CD4+ T cell counts. Low-dose cocaine-treated animals had lower CSF vRNA levels late in infection, but cocaine did not alter plasma viral load or vRNA or protein in brain. There were no differences in CSF CCL-2 or interleukin (IL)-6 levels or severity of encephalitis in cocaine-treated as compared to vehicle-treated macaques. There were no differences in brain inflammation or neurodegeneration markers, as determined by interferon (IFN)-??, MxA, CCL2, IL-6, TNF??, IFN??, and indolamine 2,3-deoxygenase mRNA levels. APP levels also were not altered. The executive function of inhibitory control was not impaired in cocaine-treated or control animals following SIV infection. However, animals receiving 3.2?mg/kg/day cocaine performed more slowly in a bimanual motor test. Thus, chronic administration of cocaine produced only minor changes in behavior, encephalitis severity, CNS inflammation/neurodegeneration, and virus replication in SIV-infected pigtailed macaques, suggesting that cocaine would have only modest effects on the progression of neuroAIDS in HIV-infected individuals.     

Ca2+ release-activated Ca2+ channel blockade as a potential tool in antipancreatitis therapy

Alcohol-related acute pancreatitis can be mediated by a combination of alcohol and fatty acids (fatty acid ethyl esters) and is initiated by a sustained elevation of the Ca²⁺ concentration inside pancreatic acinar cells ([Ca²⁺]_i), due to excessive release of Ca²⁺ stored inside the cells followed by Ca²⁺ entry from the interstitial fluid. The sustained [Ca²⁺]_i elevation activates intracellular digestive proenzymes resulting in necrosis and inflammation. We tested the hypothesis that pharmacological blockade of store-operated or Ca²⁺ release-activated Ca²⁺ channels (CRAC) would prevent sustained elevation of [Ca²⁺]_i and therefore protease activation and necrosis. In isolated mouse pancreatic acinar cells, CRAC channels were activated by blocking Ca²⁺ ATPase pumps in the endoplasmic reticulum with thapsigargin in the absence of external Ca²⁺. Ca²⁺ entry then occurred upon admission of Ca²⁺ to the extracellular solution. The CRAC channel blocker developed by GlaxoSmithKline, GSK-7975A, inhibited store-operated Ca²⁺ entry in a concentration-dependent manner within the range of 1 to 50 μM (IC₅₀ = 3.4 μM), but had little or no effect on the physiological Ca²⁺ spiking evoked by acetylcholine or cholecystokinin. Palmitoleic acid ethyl ester (100 μM), an important mediator of alcohol-related pancreatitis, evoked a sustained elevation of [Ca²⁺]_i, which was markedly reduced by CRAC blockade. Importantly, the palmitoleic acid ethyl ester-induced trypsin and protease activity as well as necrosis were almost abolished by blocking CRAC channels. There is currently no specific treatment of pancreatitis, but our data show that pharmacological CRAC blockade is highly effective against toxic [Ca²⁺]_i elevation, necrosis, and trypsin/protease activity and therefore has potential to effectively treat pancreatitis.     

An implementation model for managing cloud-based longitudinal care plans for children with medical complexity

ObjectiveWe aimed to iteratively refine an implementation model for managing cloud-based longitudinal care plans (LCPs) for children with medical complexity (CMC).Materials and MethodsWe conducted iterative 1-on-1 design sessions with CMC caregivers (ie, parents/legal guardians) and providers between August 2017 and March 2019. During audio-recorded sessions, we asked participants to walk through role-specific scenarios of how they would create, review, and edit an LCP using a cloud-based prototype, which we concurrently developed. Between sessions, we reviewed audio recordings to identify strategies that would mitigate barriers that participants reported relating to 4 processes for managing LCPs: (1) taking ownership, (2) sharing, (3) reviewing, and (4) editing. Analysis informed iterative implementation model revisions.ResultsWe conducted 30 design sessions, with 10 caregivers and 20 providers. Participants emphasized that cloud-based LCPs required a team of owners: the caregiver(s), a caregiver-designated clinician, and a care coordinator. Permission settings would need to include universal accessibility for emergency providers, team-level permission options, and some editing restrictions for caregivers. Notifications to review and edit the LCP should be sent to team members before and after clinic visits and after hospital encounters. Mitigating double documentation barriers would require alignment of data fields between the LCP and electronic health record to maximize interoperability.DiscussionThese findings provide a model for how we may leverage emerging Health Insurance Portability and Accountability Act–compliant cloud computing technologies to support families and providers in comanaging health information for CMC.ConclusionsUtilizing these management strategies when implementing cloud-based LCPs has the potential to improve team-based care across settings.     

An Evaluation of the Clinical Utility of the OPIE-3 as an Estimate of Premorbid WAIS-III FSIQ

The clinical utility of the Oklahoma Premorbid Intelligence Estimate – 3 (OPIE-3; Schoenberg, Scott, Duff, & Adams, 2002) in estimating premorbid FSIQ was investigated with the WAIS-III standardization sample. The OPIE-3 algorithms combine Vocabulary, Information, Matrix Reasoning, and Picture Completion subtest raw scores with demographic variables to predict FSIQ. Estimated WAIS-III FSIQ scores are presented for patients’ diagnosed with dementia, traumatic brain injury, Huntington’s disease, Korsakoff’s disease, chronic alcohol use, temporal lobectomy, and schizophrenia. A group of patients with depression was employed as a clinical control group. The OPIE-3Vand OPIE-3MR algorithms performed well, with the average predicted FSIQ of the combined clinical sample approximating the mean FSIQ of healthy adults. The OPIE-3(Best), which is a procedure that employs either the OPIE-3V, OPIE-3MR, or OPIE-3(2ST) algorithms in a best performance method, is presented. Recommendations in the application of the OPIE-3 are made and future research is proposed.     

Nipple discharge and the efficacy of duct cytology in evaluating breast cancer risk

BackgroundNipple discharge accounts for up to 5% of referrals to breast surgical services. With the vast majority of breast carcinomas originating in the ductal system, symptomatic dysfunction of this system often raises disproportionate clinical concern. The aim of this study is firstly, to evaluate the clinical importance of nipple discharge as an indicator of underlying malignancy and secondly, to assess the diagnostic application of duct cytology in patients presenting with nipple discharge.Study designWe performed a retrospective analysis of all patients presenting with nipple discharge as their primary symptom to the symptomatic breast unit at a tertiary referral center over a 30-month period (n = 313). The Hospital Inpatient Enquiry (HIPE) System and BreastHealth database were used to identify our study cohort. Parameters evaluated included patient demographics, clinical presentation, clinical evaluation, radiological assessment and histological/cytological analysis.ResultsThree-hundred and thirteen patients presented with nipple discharge as their primary complaint. Invasive breast carcinoma was diagnosed by Triple Assessment in 5% of patients. 24% of patients presenting with nipple discharge underwent nipple aspiration and cytological analysis. Duct cytology was diagnostic of the underlying breast carcinoma in 50% of triple assessment diagnosed carcinoma. Four risk factors were identified as having a significant association with breast carcinoma, these included (a) age >50 years (p < 0.0001), (b) bloody nipple discharge (p < 0.008), (c) presence of a breast lump (p < 0.0001) and (d) single duct discharge (p < 0.006).ConclusionsNipple discharge is a poor indicator of an underlying malignancy. Use of nipple aspiration and duct cytology for the assessment of nipple discharge is of limited diagnostic benefit. However, by utilizing the systematic, gold standard approach of Triple Assessment (clinical, radiological and cytological evaluation), the risk of underlying carcinoma can be accurately defined.     

Factors affecting the apparent efficacy and safety of tissue plasminogen activator in thrombotic occlusion models of stroke: systematic review and meta-analysis

Thrombolysis with recombinant tissue plasminogen activator (rtPA) improves outcome in animal models of stroke and in clinical trial, but is associated with increased intracranial hemorrhage. Here, we explore the impact of biologic and experimental design factors on efficacy and bleeding. We conducted a systematic review of studies describing the effect of tPA in thrombotic occlusion models of ischemic stroke followed by random effects meta-analysis, meta-regression, and trim and fill. We identified 202, 66, 128, and 54 comparisons reporting infarct volume, neurobehavioral score, hemorrhage, and mortality, respectively. The rtPA reduced infarct volume by 25.2% (95% confidence interval=21.8 to 28.6, 3388 animals), improved neurobehavioral score by 18.0% (12.6% to 23.3%, n=1243), increased the risk of hemorrhage (odds ratio=1.71, 1.42 to 2.07, n=2833) and had no significant effect on mortality (odds ratio=0.82, 0.62 to 1.08, n=1274). There was an absolute reduction in efficacy of 1.1% (0.7% to 1.4%) for every 10 minutes delay to treatment. Cumulative meta-analysis showed that the estimate of efficacy fell as more data became available. Publication bias inflated efficacy by 5.1% (infarct volume) and 8.1% (neurobehavioral score). This data set was large enough to be adequately powered to estimate with precision the impact of biologic and experimental factors on the efficacy and safety of rtPA.