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2.
Cochrane Database Syst Rev ; 1: CD008630, 2020 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-31981368

RESUMO

BACKGROUND: Plasma exchange and intravenous immunoglobulin, but not corticosteroids, are beneficial in Guillain-Barré syndrome (GBS). The efficacy of other pharmacological agents is unknown. This review was first published in 2011 and previously updated in 2013, and 2016. OBJECTIVES: To assess the effects of pharmacological agents other than plasma exchange, intravenous immunoglobulin and corticosteroids for GBS. SEARCH METHODS: On 28 October 2019, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, and Embase for treatments for GBS. We also searched clinical trials registries. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) or quasi-RCTs of acute GBS (within four weeks from onset) of all types and degrees of severity, and in individuals of all ages. We discarded trials that investigated only corticosteroids, intravenous immunoglobulin or plasma exchange. We included other pharmacological treatments or combinations of treatments compared with no treatment, placebo or another treatment. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. MAIN RESULTS: We found six trials of five different interventions eligible for inclusion in this review. The trials were conducted in hospitals in Canada, China, Germany, Japan and the UK, and included 151 participants in total. All trials randomised participants aged 16 years and older (mean or median age in the trials ranged from 36 to 57 years in the intervention groups and 34 to 60 years in the control groups) with severe GBS, defined by the inability to walk unaided. One trial also randomised patients with mild GBS who were still able to walk unaided. We identified two new trials at this update.The primary outcome measure for this review was improvement in disability grade four weeks after randomisation. Four of six trials had a high risk of bias in at least one respect. We assessed all evidence for the outcome mean improvement in disability grade as very low certainty, which means that we were unable to draw any conclusions from the data. One RCT with 19 participants compared interferon beta-1a (IFNb-1a) and placebo. It is uncertain whether IFNb-1a improves disability after four weeks (mean difference (MD) -0.1; 95% CI -1.58 to 1.38; very low-certainty evidence). A trial with 10 participants compared brain-derived neurotrophic factor (BNDF) and placebo. It is uncertain whether BDNF improves disability after four weeks (MD 0.75; 95% CI -1.14 to 2.64; very low-certainty evidence). A trial with 37 participants compared cerebrospinal fluid (CSF) filtration and plasma exchange. It is uncertain whether CSF filtration improves disability after four weeks (MD 0.02; 95% CI -0.62 to 0.66; very low-certainty evidence). One trial that compared the Chinese herbal medicine tripterygium polyglycoside with corticosteroids with 43 participants did not report the risk ratio (RR) for an improvement by one or more disability grade after four weeks, but did report improvement after eight weeks. It is uncertain whether tripterygium polyglycoside improves disability after eight weeks (RR 1.47; 95% CI 1.02 to 2.11; very low-certainty evidence). We performed a meta-analysis of two trials comparing eculizumab and placebo with 41 participants. It is uncertain whether eculizumab improves disability after four weeks (MD -0.23; 95% CI -1.79 to 1.34; very low-certainty evidence). Serious adverse events were uncommon in each of the trials and evidence was graded as either low or very low. It is uncertain whether serious adverse events were more common with IFNb-1a versus placebo (RR 0.92, 95% CI 0.23 to 3.72; 19 participants), BNDF versus placebo (RR 1.00, 95% CI 0.28 to 3.54; 10 participants) or CSF filtration versus plasma exchange (RR 0.13, 95% CI 0.01 to 2.25; 37 participants). The trial of tripterygium polyglycoside did not report serious adverse events. There may be no clear difference in the number of serious adverse events after eculizumab compared to placebo (RR 1.90, 0.34 to 10.50; 41 participants). We found no clinically important differences in any of the outcome measures selected for this review in any of the six trials. However, sample sizes were small and therefore clinically important benefit or harm cannot be excluded. AUTHORS' CONCLUSIONS: All six RCTs were too small to exclude clinically important benefit or harm from the assessed interventions. The certainty of the evidence was low or very low for all interventions and outcomes.

3.
J Neurol Neurosurg Psychiatry ; 91(2): 111-112, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31924731
4.
J Neurol Neurosurg Psychiatry ; 91(2): 113-121, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31586949

RESUMO

OBJECTIVE: To compare disease course in patients with Guillain-Barré syndrome (GBS) with a poor prognosis who were treated with one or with two intravenous immunoglobulin (IVIg) courses. METHODS: From the International GBS Outcome Study, we selected patients whose modified Erasmus GBS Outcome Score at week 1 predicted a poor prognosis. We compared those treated with one IVIg course to those treated with two IVIg courses. The primary endpoint, the GBS disability scale at 4 weeks, was assessed with multivariable ordinal regression. RESULTS: Of 237 eligible patients, 199 patients received a single IVIg course. Twenty patients received an 'early' second IVIg course (1-2 weeks after start of the first IVIg course) and 18 patients a 'late' second IVIg course (2-4 weeks after start of IVIg). At baseline and 1 week, those receiving two IVIg courses were more disabled than those receiving one course. Compared with the one course group, the adjusted OR for a better GBS disability score at 4 weeks was 0.70 (95%CI 0.16 to 3.04) for the early group and 0.66 (95%CI 0.18 to 2.50) for the late group. The secondary endpoints were not in favour of a second IVIg course. CONCLUSIONS: This observational study did not show better outcomes after a second IVIg course in GBS with poor prognosis. The study was limited by small numbers and baseline imbalances. Lack of improvement was likely an incentive to start a second IVIg course. A prospective randomised trial is needed to evaluate whether a second IVIg course improves outcome in GBS.

5.
Transpl Int ; 33(3): 310-320, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31729770

RESUMO

Ganciclovir (GCV) inhibits spermatogenesis in preclinical studies but long-term effects on fertility in renal transplant patients are unknown. In a prospective, multicenter, open-label, nonrandomized study, male patients were assigned to Cohort A [valganciclovir (VGCV), a prodrug of GCV] (n = 38) or B (no VGCV) (n = 21) by cytomegalovirus prophylaxis requirement. Changes in semen parameters and DNA fragmentation were assessed via a mixed-effects linear regression model accounting for baseline differences. Sperm concentration increased post-transplant, but between baseline and treatment end (mean 164 days Cohort A, 211 days Cohort B), the model-based change was lower in Cohort A (difference: 43.82 × 106 /ml; P = 0.0038). Post-treatment, sperm concentration increased in Cohort A so that by end of follow-up (6 months post-treatment) changes were comparable between cohorts (difference: 2.09 × 106 /ml; P = 0.92). Most patients' sperm concentration improved by end of follow-up; none with normal baseline concentrations (≥20 × 106 /ml) were abnormal at end of follow-up. Changes in seminal volume, sperm motility/morphology, DNA fragmentation, and hormone levels were comparable between cohorts at end of follow-up. Improvement in semen parameters after renal transplant was delayed in men receiving VCGV, but 6 months post-treatment parameters were comparable between cohorts.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31700690

RESUMO

Introduction: Ganglion impar block (GIB) is a well-recognised treatment for chronic coccydynia. Several side effects have previously been described with this procedure, including transient motor dysfunction, bowel, bladder, and sexual dysfunction, neuritis, rectal perforation, impingement of the sciatic nerve, cauda equina syndrome, and infection. Case presentation: We describe the first report of imaging-documented conus infarction after an unguided-GIB performed in theatre using particulate steroids for a 17-year-old patient with coccydynia. Immediately post-GIB, patient developed transient neurological deficits in her lower limbs of inability to mobilise her legs that lasted for 24 h. These include back and leg pain, decreased power and movement, increased tone, brisk reflexes, reduced light touch sensation and proprioception of legs up to the T10 level. Urgent MRI spine showed intramedullary hyperintense signal within the conus and mild restricted diffusion on the distal cord and conus, suggestive of an acute conus infarction. On follow-up, the GIB did not result in symptom improvement of coccydynia and there was persistent altered sensation of her legs. Discussion: Various approaches of ganglion impar block have been described and performed in the past with different imaging techniques and injectants. A few cases of unusual neurological complications have been reported with the use of epidural steroid injections and ganglion impar block. Clinicians should be aware of the possible neurological complications following ganglion impar blocks and the risk of inadvertent intravascular injection of particulate steroids can potentially to be minimised by using imaging guidance.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31632723

RESUMO

Introduction: Chiari malformation is characterized by caudal descent of the cerebellar tonsils through the foramen magnum. Acquired Chiari malformations (ACM) have previously been described after a variety of pathologies including lumbar puncture, cerebrospinal fluid (CSF) drainage, lumboperitoneal shunts, and conditions causing craniocephalic disproportion. Case presentation: We present four cases of ACM following spinal cord injury (SCI), which has not previously been described in the literature. Discussion: ACM is rare and typically associated with abnormalities in CSF pressure or space-occupying lesions. This case series describes the potential association of SCI with ACM. We discuss the imaging findings and clinical management of these patients. Early recognition and intervention may be important to prevent progressive neurology in this vulnerable patient group.

8.
Nat Rev Neurol ; 15(11): 671-683, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31541214

RESUMO

Guillain-Barré syndrome (GBS) is a rare, but potentially fatal, immune-mediated disease of the peripheral nerves and nerve roots that is usually triggered by infections. The incidence of GBS can therefore increase during outbreaks of infectious diseases, as was seen during the Zika virus epidemics in 2013 in French Polynesia and 2015 in Latin America. Diagnosis and management of GBS can be complicated as its clinical presentation and disease course are heterogeneous, and no international clinical guidelines are currently available. To support clinicians, especially in the context of an outbreak, we have developed a globally applicable guideline for the diagnosis and management of GBS. The guideline is based on current literature and expert consensus, and has a ten-step structure to facilitate its use in clinical practice. We first provide an introduction to the diagnostic criteria, clinical variants and differential diagnoses of GBS. The ten steps then cover early recognition and diagnosis of GBS, admission to the intensive care unit, treatment indication and selection, monitoring and treatment of disease progression, prediction of clinical course and outcome, and management of complications and sequelae.


Assuntos
Gerenciamento Clínico , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/terapia , Variação Genética/genética , Síndrome de Guillain-Barré/epidemiologia , Humanos , Infecção por Zika virus/diagnóstico , Infecção por Zika virus/epidemiologia , Infecção por Zika virus/terapia
9.
Int J Clin Pharmacol Ther ; 57(10): 506-519, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31397274

RESUMO

OBJECTIVE: Mycophenolate mofetil (MMF) is widely used as an immunosuppressant for the prophylaxis of acute organ rejection in recipients of solid organ transplants. MATERIALS AND METHODS: We have compared, in healthy subjects, the pharmacokinetics of mycophenolic acid when MMF was administered in the form of the innovator product CellCept (F. Hoffmann-La Roche Ltd.) or one of three commercially available generics, Renodapt (Biocon Ltd.), Mycept (Panacea Biotec), or Cellmune (Cipla Ltd.). The study was powered to detect a 20% difference in mean formulation performance measures, but not to formally evaluate bioequivalence. Geometric mean ratios of maximum concentrations (Cmax) and areas under plasma concentration-time curves were calculated. RESULTS: Comparing generics against each other, the differences in point estimates of the geometric mean ratios of Cmax of two of the comparisons were either borderline within (Renodapt/Cellmune) or clearly outside (Mycept/Cellmune) a region of 80 - 125% around the reference mean, indicating that bioequivalence between these generics may be difficult to show. CONCLUSION: Physicians in the field of transplantation should be aware of the potential risk of altering the therapeutic outcome when switching from one preparation of MMF to another. ClinicalTrials.gov identifier: NCT02981290.


Assuntos
Medicamentos Genéricos/farmacocinética , Imunossupressores/farmacocinética , Ácido Micofenólico/farmacocinética , Equivalência Terapêutica , Estudos Cross-Over , Rejeição de Enxerto , Humanos
10.
PLoS One ; 14(8): e0221226, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31461469

RESUMO

Plant NLRs are modular immune receptors that trigger rapid cell death in response to attempted infection by pathogens. A highly conserved nucleotide-binding domain shared with APAF-1, various R-proteins and CED-4 (NB-ARC domain) is proposed to act as a molecular switch, cycling between ADP (repressed) and ATP (active) bound forms. Studies of plant NLR NB-ARC domains have revealed functional similarities to mammalian homologues, and provided insight into potential mechanisms of regulation. However, further advances have been limited by difficulties in obtaining sufficient yields of protein suitable for structural and biochemical techniques. From protein expression screens in Escherichia coli and Sf9 insect cells, we defined suitable conditions to produce the NB-ARC domain from the tomato NLR NRC1. Biophysical analyses of this domain showed it is a folded, soluble protein. Structural studies revealed the NRC1 NB-ARC domain had co-purified with ADP, and confirmed predicted structural similarities between plant NLR NB-ARC domains and their mammalian homologues.

11.
PLoS Biol ; 17(7): e3000373, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31329577

RESUMO

Autophagy-related protein 8 (ATG8) is a highly conserved ubiquitin-like protein that modulates autophagy pathways by binding autophagic membranes and a number of proteins, including cargo receptors and core autophagy components. Throughout plant evolution, ATG8 has expanded from a single protein in algae to multiple isoforms in higher plants. However, the degree to which ATG8 isoforms have functionally specialized to bind distinct proteins remains unclear. Here, we describe a comprehensive protein-protein interaction resource, obtained using in planta immunoprecipitation (IP) followed by mass spectrometry (MS), to define the potato ATG8 interactome. We discovered that ATG8 isoforms bind distinct sets of plant proteins with varying degrees of overlap. This prompted us to define the biochemical basis of ATG8 specialization by comparing two potato ATG8 isoforms using both in vivo protein interaction assays and in vitro quantitative binding affinity analyses. These experiments revealed that the N-terminal ß-strand-and, in particular, a single amino acid polymorphism-underpins binding specificity to the substrate PexRD54 by shaping the hydrophobic pocket that accommodates this protein's ATG8-interacting motif (AIM). Additional proteomics experiments indicated that the N-terminal ß-strand shapes the broader ATG8 interactor profiles, defining interaction specificity with about 80 plant proteins. Our findings are consistent with the view that ATG8 isoforms comprise a layer of specificity in the regulation of selective autophagy pathways in plants.


Assuntos
Família da Proteína 8 Relacionada à Autofagia/metabolismo , Autofagia , Proteínas de Plantas/metabolismo , Plantas/metabolismo , Família da Proteína 8 Relacionada à Autofagia/química , Família da Proteína 8 Relacionada à Autofagia/genética , Imunoprecipitação/métodos , Espectrometria de Massas/métodos , Filogenia , Proteínas de Plantas/química , Proteínas de Plantas/genética , Plantas/classificação , Plantas/genética , Plantas Geneticamente Modificadas , Ligação Proteica , Conformação Proteica em Folha beta , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteômica/métodos , Solanum tuberosum/genética , Solanum tuberosum/metabolismo , Tabaco/genética , Tabaco/metabolismo
13.
Dysphagia ; 34(5): 698-707, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30612234

RESUMO

Oropharyngeal dysphagia is prevalent in several at-risk populations, including post-stroke patients, patients in intensive care and the elderly. Dysphagia contributes to longer hospital stays and poor outcomes, including pneumonia. Early identification of dysphagia is recommended as part of the evaluation of at-risk patients, but available bedside screening tools perform inconsistently. In this study, we developed algorithms to detect swallowing impairment using a novel accelerometer-based dysphagia detection system (DDS). A sample of 344 individuals was enrolled across seven sites in the United States. Dual-axis accelerometry signals were collected prospectively with simultaneous videofluoroscopy (VFSS) during swallows of liquid barium stimuli in thin, mildly, moderately and extremely thick consistencies. Signal processing classifiers were trained using linear discriminant analysis and 10,000 random training-test data splits. The primary objective was to develop an algorithm to detect impaired swallowing safety with thin liquids with an area under receiver operating characteristic curve (AUC) > 80% compared to the VFSS reference standard. Impaired swallowing safety was identified in 7.2% of the thin liquid boluses collected. At least one unsafe thin liquid bolus was found in 19.7% of participants, but participants did not exhibit impaired safety consistently. The DDS classifier algorithms identified participants with impaired thin liquid swallowing safety with a mean AUC of 81.5%, (sensitivity 90.4%, specificity 60.0%). Thicker consistencies were effective for reducing the frequency of penetration-aspiration. This DDS reached targeted performance goals in detecting impaired swallowing safety with thin liquids. Simultaneous measures by DDS and VFSS, as performed here, will be used for future validation studies.

14.
JAMA Surg ; 154(1): 65-72, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30347089

RESUMO

Importance: There has been significant debate in the surgical and medical communities regarding the appropriateness of using aspirin alone for venous thromboembolism (VTE) prophylaxis following total knee arthroplasty (TKA). Objective: To determine the acceptability of aspirin alone vs anticoagulant prophylaxis for reducing the risk of postoperative VTE in patients undergoing TKA. Design, Setting, and Participants: Noninferiority study of a retrospective cohort of TKA cases submitted to the Michigan Arthroplasty Registry Collaborative Quality Initiative at 29 member hospitals, ranging from small community hospitals to large academic and nonacademic medical centers in Michigan. The study included 41 537 patients who underwent primary TKA between April 1, 2013, and October 31, 2015. Clinical events were monitored for 90 days after surgery. Data were analyzed between September and October 2016. Exposures: The method of pharmacologic prophylaxis: neither aspirin nor anticoagulants for 668 patients (1.6%), aspirin only for 12 831 patients (30.9%), anticoagulant only (eg, low-molecular-weight heparin, warfarin, and Xa inhibitors) for 22 620 patients (54.5%), and both aspirin/anticoagulant for 5418 patients (13.0%). Most patients were also using intermittent pneumatic compression stockings. Main Outcome and Measures: The primary composite outcome was the first occurrence of VTE or death. The noninferiority margin was specified as 0.3. The secondary outcome was bleeding events. Results: Of the 41 537 patients, 14 966 were men (36%), and the mean age was 65.8 years. A VTE event occurred in 573 of 41 537 patients (1.38%); 32 of 668 (4.79%) who received no pharmacologic prophylaxis, 149 of 12 831 (1.16%) treated with aspirin alone, 321 of 22 620 (1.42%) with anticoagulation alone, and 71 of 5418 (1.31%) prescribed both aspirin and anticoagulation. Aspirin only was noninferior for the composite VTE outcome compared with those receiving other chemoprophylaxis (adjusted odds ratio, 0.85; 95% CI, 0.68-1.07, P for inferiority = .007). Bleeding occurred in 457 of 41 537 patients (1.10%), 10 of 668 (1.50%) without prophylaxis, 116 of 12 831 (0.90%) in the aspirin group, 258 of 22 620 (1.14%) with anticoagulation, and 73 of 5418 (1.35%) of those receiving both. Aspirin alone was also noninferior for bleeding complications (adjusted odds ratio, 0.80; 95% CI, 0.63-1.00, P for inferiority <.001). Conclusions and Relevance: In this study of patients undergoing TKA, aspirin was not inferior to other anticoagulants in the postoperative rate of VTE or death. Aspirin alone may provide similar protection from postoperative VTE compared with other anticoagulation treatments.


Assuntos
Anticoagulantes/administração & dosagem , Artroplastia do Joelho/métodos , Aspirina/administração & dosagem , Inibidores da Agregação de Plaquetas/uso terapêutico , Tromboembolia Venosa/prevenção & controle , Administração Oral , Idoso , Feminino , Humanos , Masculino , Sistema de Registros , Estudos Retrospectivos
15.
Skeletal Radiol ; 48(8): 1269-1274, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30446788

RESUMO

OBJECTIVE: To describe and evaluate the outcome following shoulder manipulation under rotator interval block for the treatment of adhesive capsulitis. MATERIALS AND METHODS: Patients with adhesive capsulitis referred by our local orthopaedic shoulder surgeons consented to targeted ultrasound-guided injection of the glenohumeral joint via the rotator interval. Inclusion criteria included a failure to respond to conservative treatment and the absence of a full-thickness rotator cuff tear. Twelve millilitres of a mixture of local anaesthetic and steroid was injected into the rotator interval using a 21-gauge needle, with a small volume of the same solution instilled into the subacromial bursa. Following injection, under local anaesthetic block, patients were gently manipulated into abduction, external rotation and internal rotation as far as they could comfortably tolerate. Patients were assessed pre-injection with documented pain scores from 0 to 10 on a visual analogue scale (VAS) and the Oxford Shoulder Score (OSS) questionnaire. Initial follow-up comprised a VAS pain score at 1 h, 24 h and 2 weeks. Clinical review by the referring orthopaedic surgeon was performed at 2 months post-injection. Long-term follow-up involved a VAS pain score and the OSS questionnaire at 5 months. RESULTS: Forty patients were suitable for inclusion in the study. Twenty-three were female (57.5%) and 17 were male. The mean age was 52 years (range, 31-73 years). Twelve patients were post-operative. The duration of symptoms ranged from 3 months to 18 months. Mean pre-procedure OSS was recorded as 23.3 (range, 4-36). The mean VAS pain score was 7.7 before the procedure (range, 4 - 10), 3.4 at 1 h (range, 0-8), 2.9 at 24 h (range, 0-8), and 1.8 at 2 weeks (range 1-4). Orthopaedic follow-up at an average of 66 days post-injection was recorded in 18 patients. All patients reported initial improvement of their shoulder pain and return to near full range of movement; however, recurrence of adhesive capsulitis symptoms was recorded in 5 patients. One case of rupture of the long head of the biceps tendon was reported, but the patient remained asymptomatic. Long-term follow-up at 5 months was obtained in 31 patients, with a mean OSS of 42 (range, 21-60) and VAS of 2.3 (range, 0-7). CONCLUSION: Manipulation under general anaesthesia is a well-recognised treatment for adhesive capsulitis. We report that targeted ultrasound-guided injection of the rotator interval and manipulation of the shoulder under local anaesthetic blockade result in good outcomes in reducing shoulder pain and symptoms of adhesive capsulitis with low recurrence and complication rates.


Assuntos
Bursite/diagnóstico por imagem , Bursite/terapia , Manipulação Ortopédica/métodos , Adulto , Idoso , Anestésicos Locais/administração & dosagem , Estudos de Coortes , Feminino , Humanos , Injeções Intra-Articulares , Masculino , Pessoa de Meia-Idade , Bloqueio Nervoso , Amplitude de Movimento Articular , Ultrassonografia
16.
New Phytol ; 222(1): 438-454, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30536576

RESUMO

The potato blight agent Phytophthora infestans secretes a range of RXLR effectors to promote disease. Recent evidence indicates that some effectors suppress early pattern-triggered immunity (PTI) following perception of microbe-associated molecular patterns (MAMPs). Phytophthora infestans effector PiSFI3/Pi06087/PexRD16 has been previously shown to suppress MAMP-triggered pFRK1-Luciferase reporter gene activity. How PiSFI3 suppresses immunity is unknown. We employed yeast-two-hybrid (Y2H) assays, co-immunoprecipitation, transcriptional silencing by RNA interference and virus-induced gene silencing (VIGS), and X-ray crystallography for structure-guided mutagenesis, to investigate the function of PiSFI3 in targeting a plant U-box-kinase protein (StUBK) to suppress immunity. We discovered that PiSFI3 is active in the host nucleus and interacts in yeast and in planta with StUBK. UBK is a positive regulator of specific PTI pathways in both potato and Nicotiana benthamiana. Importantly, it contributes to early transcriptional responses that are suppressed by PiSFI3. PiSFI3 forms an unusual trans-homodimer. Mutation to disrupt dimerization prevents nucleolar localisation of PiSFI3 and attenuates both its interaction with StUBK and its ability to enhance P. infestans leaf colonisation. PiSFI3 is a 'WY-domain' RXLR effector that forms a novel trans-homodimer which is required for its ability to suppress PTI via interaction with the U-box-kinase protein StUBK.


Assuntos
Phytophthora infestans/metabolismo , Proteínas Quinases/metabolismo , Proteínas/metabolismo , Solanum tuberosum/imunologia , Solanum tuberosum/microbiologia , Transcrição Genética , Apoptose/efeitos dos fármacos , Nucléolo Celular/metabolismo , Núcleo Celular/metabolismo , Flagelina/farmacologia , Inativação Gênica , Proteínas de Fluorescência Verde/metabolismo , Mutação/genética , Phytophthora infestans/patogenicidade , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/microbiologia , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos , Proteínas Quinases/química , Multimerização Proteica , Solanum tuberosum/efeitos dos fármacos , Solanum tuberosum/genética , Virulência
17.
J Bone Joint Surg Am ; 100(22): e143, 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30480606

RESUMO

The Michigan Arthroplasty Registry Collaborative Quality Initiative (MARCQI) is a regional quality improvement effort that is focused on hip and knee arthroplasty. From its inception in 2012, MARCQI has grown to include data from 66 hospitals and surgery centers, and contains over 209,000 fully abstracted cases in its database. Using high-quality risk-standardized outcomes data, MARCQI drives quality improvement through a collaborative and nonpunitive structure. Quality improvement initiatives have included transfusion reduction, infection prevention, venous thromboembolism reduction, and reduction of discharge to nursing homes. In addition, MARCQI focuses on postmarket surveillance of implants by computing revision-risk estimates based on the cases that were registered prior to the end of 2016. This paper describes the impact of MARCQI on the quality of hip and knee arthroplasty care in the state of Michigan since its inception in 2012, and it briefly summarizes the recently released 5-year report.


Assuntos
Artroplastia de Quadril/normas , Artroplastia do Joelho/normas , Melhoria de Qualidade , Sistema de Registros , Humanos , Michigan
18.
Brain ; 141(10): 2866-2877, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30247567

RESUMO

Guillain-Barré syndrome is a heterogeneous disorder regarding the clinical presentation, electrophysiological subtype and outcome. Previous single country reports indicate that Guillain-Barré syndrome may differ among regions, but no systematic comparative studies have been conducted. Comparative studies are required to identify factors determining disease susceptibility, variation and prognosis, and to improve diagnostic criteria. The International Guillain-Barré Syndrome Outcome Study is a prospective, observational cohort study including all patients within the diagnostic spectrum, aiming to describe the heterogeneity of Guillain-Barré syndrome worldwide. The current study was based on the first 1000 inclusions with a follow-up of at least 1 year and confirmed the variation in clinical presentation, course and outcome between patients. The full clinical spectrum of Guillain-Barré syndrome was observed in patients from all countries participating in the International Guillain-Barré Syndrome Outcome Study, but the frequency of variants differed between regions. We compared three regions based on geography, income and previous reports of Guillain-Barré syndrome subtypes: 'Europe/Americas', 'Asia' (without Bangladesh), and 'Bangladesh'. We excluded 75 (8%) patients because of alternative diagnoses, protocol violations, or missing data. The predominant clinical variant was sensorimotor in Europe/Americas (n = 387/562, 69%) and Asia (n = 27/63, 43%), and pure motor in Bangladesh (n = 74/107, 69%). Miller Fisher syndrome and Miller Fisher-Guillain-Barré overlap syndrome were more common in Asia (n = 14/63, 22%) than in the other two regions (Europe/Americas: n = 64/562, 11%; Bangladesh: n = 1/107, 1%) (P < 0.001). The predominant electrophysiological subtype was demyelinating in all regions (Europe/Americas: n = 312/573, 55%; Asia: n = 29/65, 45%; Bangladesh: n = 38/94, 40%). The axonal subtype occurred more often in Bangladesh (n = 34/94, 36%) than in Europe/Americas (n = 33/573, 6%) and other Asian countries (n = 4/65, 6%) (P < 0.001). In all regions, patients with the axonal subtype were younger, had fewer sensory deficits, and showed a trend towards poorer recovery compared to patients with the demyelinating subtype. The proportion of patients able to walk unaided after 1 year varied between Asia (n = 31/34, 91%), Europe/Americas (n = 334/404, 83%) and Bangladesh (n = 67/97, 69%) (P = 0.003). A similar variation was seen for mortality, being higher in Bangladesh (n = 19/114, 17%) than in Europe/Americas (n = 23/486, 5%) and Asia (n = 1/45, 2%) (P < 0.001). This study showed that factors related to geography have a major influence on clinical phenotype, disease severity, electrophysiological subtype, and outcome of Guillain-Barré syndrome.


Assuntos
Síndrome de Guillain-Barré/epidemiologia , Síndrome de Guillain-Barré/fisiopatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
J Neurosci ; 38(32): 7088-7099, 2018 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-29976621

RESUMO

Methods to promote myelin regeneration in response to central myelin loss are essential to prevent the progression of clinical disability in demyelinating diseases. The neurotrophin brain-derived neurotrophic factor (BDNF) is known to promote myelination during development via oligodendrocyte expressed TrkB receptors. Here, we use a structural mimetic of BDNF to promote myelin regeneration in a preclinical mouse model of central demyelination. In female mice, we show that selective targeting of TrkB with the BDNF-mimetic enhances remyelination, increasing oligodendrocyte differentiation, the frequency of myelinated axons, and myelin sheath thickness after a demyelinating insult. Treatment with exogenous BDNF exerted an attenuated effect, increasing myelin sheath thickness only. Further, following conditional deletion of TrkB from premyelinating oligodendrocytes, we show the effects of the BDNF-mimetic on oligodendrocyte differentiation and remyelination are lost, indicating these are dependent on oligodendrocyte expression of TrkB. Overall, these studies demonstrate that targeting oligodendrocyte TrkB promotes in vivo remyelination in the brain.SIGNIFICANCE STATEMENT Novel strategies to promote myelin regeneration are required to prevent progressive neurodegeneration and clinical disability in patients with central demyelinating disease. Here, we test whether selectively targeting the TrkB receptor on the myelin-producing oligodendrocytes, can promote remyelination in the brain. Using a structural mimetic of its native ligand, BDNF, we show that stimulation of TrkB enhances remyelination, increasing oligodendrocyte differentiation, the frequency of myelinated axons and thickness of the myelin sheath following a demyelinating insult. Further, we show that these effects are dependent on the phosphorylation of oligodendrocyte expressed TrkB receptors in vivo Overall, we demonstrate that selective targeting of TrkB has therapeutic potential to promote remyelination in the brain.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/uso terapêutico , Encéfalo/efeitos dos fármacos , Doenças Desmielinizantes/tratamento farmacológico , Glicoproteínas de Membrana/agonistas , Terapia de Alvo Molecular , Bainha de Mielina/metabolismo , Oligodendroglia/efeitos dos fármacos , Remielinização/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Divisão Celular/efeitos dos fármacos , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/patologia , Feminino , Bombas de Infusão Implantáveis , Infusões Intraventriculares , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Básica da Mielina/biossíntese , Células-Tronco Neurais/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/uso terapêutico , Fosforilação , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Tirosina Quinases/metabolismo , Organismos Livres de Patógenos Específicos
20.
Lancet Neurol ; 17(8): 689-698, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30001923

RESUMO

BACKGROUND: Fingolimod is approved for the treatment of relapsing-remitting multiple sclerosis and was effective in experimental autoimmune neuritis in rats, a possible model for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We aimed to evaluate the efficacy of fingolimod in delaying disability progression in patients with CIDP who withdrew from currently effective treatments (intravenous immunoglobulin [IVIg] or corticosteroids). METHODS: This double-blind, multicentre, randomised, placebo-controlled, parallel-group, event-driven study was done at 48 neurology centres in Australia, Canada, Israel, Japan, the USA, and nine countries in Europe. Participants with CIDP who were receiving IVIg or corticosteroids were randomly assigned (1:1) to once-daily oral fingolimod 0·5 mg or placebo. Owing to the event-driven design, treatment duration was flexible and could be up to 4·5 years. Randomisation was done with an automated interactive voice response-web response system and was stratified by Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale scores. Previous IVIg treatment was discontinued after one final course ending the day before the first dose of fingolimod or placebo was given, whereas corticosteroids were tapered off over 8 weeks after randomisation. The primary endpoint was time to first confirmed worsening (≥1 point increase on the adjusted INCAT disability scale score versus baseline) and was assessed in the full analysis set, which consisted of all patients who underwent randomisation and had at least one efficacy assessment for the primary analysis. The survival distribution functions of time to first worsening were estimated within each treatment group according to the Kaplan-Meier survival distribution function and compared with a stratified log-rank test. The trial is registered with ClinicalTrials.gov, number NCT01625182. FINDINGS: Of 106 participants randomly assigned between Jan 24, 2013, and March 10, 2016, 54 received fingolimod (41 who had been receiving IVIg and 13 who had been receiving corticosteroids) and 52 received placebo (41 who had been receiving IVIg and 11 who had been receiving corticosteroids). The trial ended for futility as recommended by an independent data monitoring committee after an interim analysis when 44 confirmed worsening events had occurred. At the end of the study, the survival estimate of the proportion of participants free from confirmed worsening was not significantly different between the fingolimod group (42%, 95% CI 23-60) and the placebo group (43%, 28-59; p=0·91). Adverse events occurred in 41 (76%) participants receiving fingolimod and 44 (85%) on placebo, and serious adverse events occurred in nine (17%) and four (8%) patients, respectively. The most common adverse events with fingolimod were headache (12 [22%] patients), hypertension (ten [19%]), and extremity pain (seven [13%]). Adverse events leading to study discontinuation occurred in seven (13%) participants on fingolimod and none on placebo. INTERPRETATION: Fingolimod 0·5 mg once-daily was not better than placebo for the treatment of CIDP. Future trial designs should take account of the possibility that if IVIg is stopped abruptly, some patients might relapse soon afterwards whereas others might remain in remission. FUNDING: Novartis Pharma.


Assuntos
Cloridrato de Fingolimode/administração & dosagem , Imunossupressores/administração & dosagem , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/tratamento farmacológico , Administração Oral , Corticosteroides/uso terapêutico , Adulto , Idoso , Avaliação da Deficiência , Método Duplo-Cego , Eletrocardiografia , Feminino , Seguimentos , Força da Mão/fisiologia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Resultado do Tratamento
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