Citations

Hyperphosphorylation and aggregation of tau are observed in multiple neurodegenerative diseases termed tauopathies. Tau has also been implicated in the pathogenesis of Parkinson's disease (PD) and parkinsonisms. Some PD patients with mutations in the leucine‐rich repeat kinase 2 (LRRK2) gene exhibit tau pathology. Mutations in LRRK2 are a major risk factor for PD, but LRRK2 protein function remains unclear. The most common mutation, G2019S, is located in the kinase domain of LRRK2 and enhances kinase activity in vitro. This suggests that the kinase activity of LRRK2 may underlie its cellular toxicity. Recently, in vitro studies have suggested a direct interaction between tubulin‐bound tau and LRRK2 that results in tau phosphorylation at one identified site. Here we present data suggesting that microtubules (MTs) enhance LRRK2‐mediated tau phosphorylation at three different epitopes. We also explore the effect of divalent cations as catalytic cofactors for G2019S LRRK2‐mediated tau phosphorylation and show that manganese does not support kinase activity but inhibits the efficient ability of magnesium to catalyze LRRK2‐mediated phosphorylation of tau. These results suggest that cofactors such as MTs and cations in the cellular milieu have an important impact on LRRK2‐tau interactions and resultant tau phosphorylation. © 2015 Wiley Periodicals, Inc.

Background Despite the significant decline in smoking rates in the USA over the last 50 years, 42 million Americans continue to smoke. Although the combination of behavioural counselling with FDA-approved medications offers the best evidence-based treatment approach, 12-month relapse rates remain at >60%. Both healthcare providers and patients are searching for alternative treatment options. Most acupuncture trials have yielded poor results for smoking cessation; however, most trials have not used an intense treatment protocol and maintained treatment for at least 12 weeks. Methods We designed a pilot study to address these methodological problems. Twenty-eight smokers were recruited to attend two 1 h acupuncture sessions weekly for 12 weeks. Primary endpoints included completion rate, acceptability of the protocol and side effects. Secondary endpoints included carbon monoxide (CO)-confirmed, 7-day point prevalence quit rates at 12 weeks and 26 weeks. Results Sixteen of the 28 patients enrolled (57%) completed 12 weeks of treatment. Of the 17 patients who completed the end-of-study questionnaire, 94% (16/17) rated the programme as helpful, and 82% noted they would recommend it to friends for smoking cessation. Three of the 28 who initially enrolled in the study were confirmed abstinent at 12 weeks (10.7%); one of the 28 (3.6%) was abstinent at 26 weeks. Conclusions A larger study with a slightly less rigorous and more acceptable treatment protocol is feasible and should be considered.

Background: With patients living a decade or longer post-procedure, long-term data are needed to assess the durability of carotid artery stenting versus carotid endarterectomy. Identifying characteristics of those consenting or declining to continue in long-term follow-up may suggest strategies to improve retention in clinical trials. Purpose: This report describes differences between patients choosing or declining to continue follow-up for up to 10 years in the Carotid Revascularization Endarterectomy versus Stenting Trial. Methods: Following completion of the primary outcome, patients who were in active Carotid Revascularization Endarterectomy versus Stenting Trial follow-up were asked to continue beyond their original 4-year commitment for a maximum of 10 years. The characteristics of those who consented were compared with those who declined. Univariate and multivariable logistic regression were used for analysis, and backwards stepwise logistic regression (the most parsimonious model) was used to determine the factors associated with continuation. Results: Of the 1921 active Carotid Revascularization Endarterectomy versus Stenting Trial participants for whom consent to extend follow-up was requested, 1695 (88%; mean age: 68.4) consented; 226 (12%; mean age: 69.6) declined. Of those who did not consent versus those who consented, 66% versus 48% were symptomatic at baseline (p < 0.0001), at follow-up 28% versus 20% were smokers (p = 0.009), 85% versus 90% were hypertensive (p = 0.01), and 84% versus 94% were dyslipidemic (p < 0.0001). Additional factors that differed between those who did not consent and those who consented included the mean number of years in the study at time of consent (4.8 years vs 3.7 years (p = <0.0001)) and patients from sites that enrolled <30 patients compared to sites randomizing 30 or more (70% vs 52% (p < 0.0001)). Multivariable logistic regression indicated that those with lesser odds of consenting to the extended follow-up were older (odds ratio: 0.80; 95% confidence interval: 0.67, 0.96), more likely to be symptomatic (odds ratio: 0.58; 95% confidence interval: 0.42, 0.80), smokers (odds ratio: 0.48; 95% confidence interval: 0.34, 0.70), were in the study 5+ years versus <3 (odds ratio: 0.21; 95% confidence interval: 0.13, 0.34), and at a site that randomized <30 patients (odds ratio: 0.46; 95% confidence interval: 0.33, 0.63), while patients with dyslipidemia at follow-up had increased odds of consenting (odds ratio: 2.28 (1.47, 3.54)). Conclusion: Symptomatic status, increasing age, randomized at lower volume centers, and longer time in follow-up were associated with reduced odds of consenting to long-term follow-up. Identifying factors associated with reduced willingness to extend participation long-term can suggest targeted strategies to improve retention in future clinical trials.

Introduction The objective of this review is to provide an evidence-based discussion of different treatment strategies for medication-overuse headache (MOH). Method We searched PubMed for articles discussing the treatment and prognosis of MOH published between 2004 and August 2014. Titles, abstract and articles were reviewed systematically. The level of evidence provided by each study of the included articles was determined according to the American Academy of Neurology Clinical practice guideline manual. We discuss the level of evidence to support the early discontinuation/withdrawal of overused medications, the level of evidence to support the use of preventive treatment, the short- and long-term prognosis, and the outcome according to the class of drug overused in patients diagnosed with MOH. Results The initial search resulted in 1313 articles; 68 articles met our inclusion criteria and were discussed. The level of evidence to support early discontinuation of overused medications alone is low due to the absence of controlled studies. Adding preventive medication to early discontinuation led to a better outcome than early discontinuation alone. For patients with chronic migraine (CM) and medication overuse (MO), there are large randomized control trials supporting the use of onabotulinumtoxinA and topiramate without early discontinuation of overuse; however, the evidence is limited since data were obtained from post hoc analysis. Conclusion Considering current available evidence and the systemic toxicity of overusing acute headache medication, we suggest discontinuation of the overused medication with the addition of preventive medication. Appropriately sized, randomized controlled trials evaluating the safety and long-term efficacy of preventive medication plus early discontinuation of overuse vs preventive medication alone vs early discontinuation of overuse alone are needed.

Background: Understanding the effect size, variability, and underlying physiology of the dawn phenomenon is important for next-generation closed-loop control algorithms for type 1 diabetes (T1D). Subjects and Methods: We used an iterative protocol design to study 16 subjects with T1D on individualized insulin pump therapy for two successive nights. Endogenous glucose production (EGP) rates at 3 a.m. and 7 a.m. were measured with [6,6- 2 H 2 ]glucose as a single tracer, infused from midnight to 7 a.m. in all subjects. To explore possibility of tracer recycling due to prolonged [6,6- 2 H 2 ]glucose infusion, which was highly probable after preplanned interim data analyses, we infused a second tracer, [6- 3 H]glucose, from 4 a.m. to 7 a.m. in the last seven subjects to measure EGP at 7 a.m. Results: Cortisol concentrations increased during both nights, but changes in glucagon and insulin concentration were inconsistent. Although the plasma glucose concentrations rose from midnight to 7 a.m. during both nights, EGP measured with [6,6- 2 H 2 ]glucose between 3 a.m. and 7 a.m. did not differ during Night 1 but fell in Night 2. However, EGP measured with [6- 3 H]glucose at 7 a.m. was higher than that measured with [6,6- 2 H 2 ]glucose during both nights, thereby suggesting tracer recycling probably underestimating EGP calculated at 7 a.m. with [6,6- 2 H 2 ]glucose. Likewise, EGP was higher at 7 a.m. with [6- 3 H]glucose than at 3 a.m. with [6,6- 2 H 2 ]glucose during both nights. Conclusions: The data demonstrate a consistent overnight rise in glucose concentrations through increased EGP, mediated likely by rising cortisol concentrations. The observations with the dual tracer approach imply significant tracer recycling leading to underestimation of EGP measured by longer-duration tracer infusion.

A 64-year-old previously healthy man presented with a 4-week history of vague right upper quadrant abdominal pain. Imaging studies revealed extensive portal, splenic, superior and inferior mesenteric vein thrombosis with mosaic perfusion and wedge-shaped areas of liver perfusion abnormalities. An extensive thrombophilia workup including tests for factor V Leiden, prothrombin G20210A, lupus anticoagulant, paroxysmal nocturnal haemoglobinuria, protein C and S, homocysteine and antinuclear antibody titres were all negative. Other laboratory testing revealed an elevated alkaline phosphatase (340 IU/L). Surgical exploration and catheter-directed thrombolysis were not felt to be feasible given the extensive clot burden. He was started on anticoagulation therapy. Over the next 10 days, he required intensive care unit admission due to progressive hepatic encephalopathy and fulminant liver failure. He continued to decline and eventually died of multiorgan failure. Autopsy revealed extensive, diffuse intrahepatic cholangiocarcinoma that had almost entirely replaced his normal liver parenchyma.