Citations

Aims: Determine the mechanism by which C-terminus of HSC70-interacting protein (CHIP) induction alters neuronal survival under conditions of mitochondrial stress induced by oxygen glucose deprivation. Results: We report that animals deficient in the E3 ubiquitin ligase, CHIP, have high baseline levels of central nervous system protein oxidation and lipid peroxidation, reduced antioxidant defenses, and decreased energetic status. Stress-associated molecules typically linked to Parkinson's disease such as the mitochondrial kinase, PTEN-inducible putative kinase 1 (PINK1), and another E3 ligase, Parkin, are upregulated in brains from CHIP knockout (KO) animals. Utilizing a novel biotin–avidin capture technique, we found that the oxidation status of Parkin and the mitochondrial fission protein, dynamin-related protein 1 (Drp1), are altered in a CHIP-dependent manner. We also found that following oxygen–glucose deprivation (OGD), the expression of CHIP, PINK1, and the autophagic marker, LC3, increase and there is activation of the redox-sensitive kinase p66 shc . Under conditions of OGD, CHIP relocalizes from the cytosol to mitochondria. Mitochondria from CHIP KO mice have profound impairments in stress response induced by calcium overload, resulting in accelerated permeability transition activity. While CHIP-deficient neurons are morphologically intact, they are more susceptible to OGD consistent with a previously unknown neuroprotective role for CHIP in maintaining mitochondrial homeostasis. Innovation: CHIP relocalization to the mitochondria is essential for the regulation of mitochondrial integrity and neuronal survival following OGD. Conclusions: CHIP is an essential regulator of neuronal bioenergetics and redox tone. Altering the expression of this protein has profound effects on neuronal survival when cells are exposed to OGD. Antioxid. Redox Signal . 23, 535–549.

Objective Takayasu arteritis is a rare large vessel vasculitis with incompletely understood etiology. This study was undertaken to perform the first unbiased genome‐wide association analysis of Takayasu arteritis. Methods Two independent cohorts of patients with Takayasu arteritis from Turkey and North America were included in our study. The Turkish cohort consisted of 559 patients and 489 controls, and the North American cohort consisted of 134 patients and 1,047 controls of European ancestry. Genotyping was performed using the Omni1‐Quad and Omni2.5 genotyping arrays. Genotyping data were subjected to rigorous quality control measures and subsequently analyzed to discover genetic susceptibility loci for Takayasu arteritis. Results We identified genetic susceptibility loci for Takayasu arteritis with a genome‐wide level of significance in IL6 (rs2069837) (odds ratio [OR] 2.07, P = 6.70 × 10 −9 ), RPS9 / LILRB3 (rs11666543) (OR 1.65, P = 2.34 × 10 −8 ), and an intergenic locus on chromosome 21q22 (rs2836878) (OR 1.79, P = 3.62 × 10 −10 ). The genetic susceptibility locus in RPS9 / LILRB3 lies within the leukocyte receptor complex gene cluster on chromosome 19q13.4, and the disease risk variant in this locus correlates with reduced expression of multiple genes including the inhibitory leukocyte immunoglobulin‐like receptor gene LILRB3 ( P = 2.29 × 10 −8 ). In addition, we identified candidate susceptibility genes with suggestive levels of association ( P < 1 × 10 −5 ) with Takayasu arteritis, including PCSK5, LILRA3, PPM1G/NRBP1 , and PTK2B . Conclusion Our findings indicate novel genetic susceptibility loci for Takayasu arteritis and uncover potentially important aspects of the pathophysiology of this form of vasculitis.

The study aims to provide an updated assessment of the evidence for individual pharmacological therapies for acute migraine treatment. Pharmacological therapy is frequently required for acutely treating migraine attacks. The A merican A cademy of N eurology G uidelines published in 2000 summarized the available evidence relating to the efficacy of acute migraine medications. This review, conducted by the members of the G uidelines S ection of the A merican H eadache S ociety, is an updated assessment of evidence for the migraine acute medications. A standardized literature search was performed to identify articles related to acute migraine treatment that were published between 1998 and 2013. The A merican A cademy of N eurology G uidelines D evelopment procedures were followed. Two authors reviewed each abstract resulting from the search and determined whether the full manuscript qualified for review. Two reviewers studied each qualifying full manuscript for its level of evidence. Level A evidence requires at least 2 C lass I studies, and L evel B evidence requires 1 C lass I or 2 C lass II studies. The specific medications – triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan [oral, nasal spray, injectable, transcutaneous patch], zolmitriptan [oral and nasal spray]) and dihydroergotamine (nasal spray, inhaler) are effective ( L evel A ). Ergotamine and other forms of dihydroergotamine are probably effective ( L evel B ). Effective nonspecific medications include acetaminophen, nonsteroidal anti‐inflammatory drugs (aspirin, diclofenac, ibuprofen, and naproxen), opioids (butorphanol nasal spray), sumatriptan/naproxen, and the combination of acetaminophen/aspirin/caffeine ( L evel A ). Ketoprofen, intravenous and intramuscular ketorolac, flurbiprofen, intravenous magnesium (in migraine with aura), and the combination of isometheptene compounds, codeine/acetaminophen and tramadol/acetaminophen are probably effective ( L evel B ). The antiemetics prochlorperazine, droperidol, chlorpromazine, and metoclopramide are probably effective ( L evel B ). There is inadequate evidence for butalbital and butalbital combinations, phenazone, intravenous tramadol, methadone, butorphanol or meperidine injections, intranasal lidocaine, and corticosteroids, including dexamethasone ( L evel C ). Octreotide is probably not effective ( L evel B ). There is inadequate evidence to refute the efficacy of ketorolac nasal spray, intravenous acetaminophen, chlorpromazine injection, and intravenous granisetron ( L evel C ). There are many acute migraine treatments for which evidence supports efficacy. Clinicians must consider medication efficacy, potential side effects, and potential medication‐related adverse events when prescribing acute medications for migraine. Although opioids, such as butorphanol, codeine/acetaminophen, and tramadol/acetaminophen, are probably effective, they are not recommended for regular use.

Introduction Acetabular component position can be an important determinant of joint stability and bearing surface wear after THA. Nonetheless, the incidence of malpositioning is high. Patient obesity, low surgeon volume, and minimally invasive approaches are known risk factors for malposition. As the incidence of obesity continues to increase, it is important to recognise its effect on intraoperative component positioning in THA. Objectives Our goal was to assess the impact of obesity on component position for a high-volume surgeon using a standard postero-lateral approach. Methods A consecutive series of 120 obese (BMI >30, mean BMI 34.4) and 120 non-obese patients (mean BMI 25.4), who had undergone primary THA by a single surgeon, were included in our retrospective study. AP pelvis and cross-table radiographs obtained at the first postoperative visit were analysed using EBRA software to determine inclination and anteversion angles. Optimal position was defined as 30-45° of inclination and 5-25° of anteversion. Results Mean inclination and anteversion were 40.6 (+/-5.4°) and 16.6 (+/-5.5°) respectively, in the obese group and 39° (+/-5.0°) and 16.2° (+/-7.5°) in the non-obese group. In the obese group 89 (74%) patients were within the desired range for both measurements, 31 (26%) were out of range in at least one, compared to 91 (76%) and 29 (24%) in the non-obese group, respectively. The overall incidence of malpositioning was 25% for both groups. Among outliers, mean deviation from the optimal range was ≤3.8° in both groups. Conclusions The risk of component malpositioning in THA may be reduced when surgery is performed by an experienced, high volume surgeon utilising a standard posterolateral approach. In this setting the deleterious effect of obesity may be overcome.

Abstract Cigarette smoking is a major risk factor in the development of non–small cell lung cancer (NSCLC), which accounts for 80% of all lung cancers. Nicotine, the major addictive component of tobacco smoke, can induce proliferation, invasion, and epithelial-to-mesenchymal transition (EMT) in NSCLC cell lines and promote metastasis of NSCLC in mice. Here, we demonstrate that the scaffolding protein β-arrestin-1 is necessary for nicotine-mediated induction of mesenchymal genes vimentin and fibronectin as well as EMT regulators ZEB1 and ZEB2. Nicotine induced changes in cell morphology and ablate tight junctions consistent with EMT; β-arrestin-1, but not β-arrestin-2, was required for these changes. β-Arrestin-1 promoted the expression of the mesenchymal genes, as well as ZEB1 and ZEB2, through the mediation of the E2F1 transcription factor; this required Src kinase activity. Stimulation of multiple NSCLC cell lines with nicotine led to enhanced recruitment of β-arrestin-1 and E2F1 on vimentin, fibronectin, and ZEB1 and ZEB2 promoters. Furthermore, there was significantly more β-arrestin-1 and E2F1 associated with these promoters in human NSCLC tumors, and β-arrestin-1 levels correlated with vimentin and fibronectin levels in human NSCLC samples. A549-luciferase cells lacking β-arrestin-1 showed a significantly reduced capacity for tumor growth and metastasis when orthotopically implanted into the lungs of SCID-beige mice. Taken together, these studies reveal a novel role for β-arrestin-1 in the growth and metastasis of NSCLC. Cancer Res; 75(6); 1009–20. ©2015 AACR.