Glycans in Sera of Amyotrophic Lateral Sclerosis Patients and Their Role in Killing Neuronal Cells

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by degeneration of upper and lower motor neurons. To date, glycosylation patterns of glycoproteins in fluids of ALS patients have not been described. Moreover, the aberrant glycosylation related to the pathogenesis of other neurodegenerative diseases encouraged us to explore the glycome of ALS patient sera. We found high levels of sialylated glycans and low levels of core fucosylated glycans in serum-derived N-glycans of patients with ALS, compared to healthy volunteer sera. Based on these results, we analyzed the IgG Fc N297-glycans, as IgG are major serum glycoproteins affected by sialylation or core fucosylation and are found in the motor cortex of ALS patients. The analyses revealed a distinct glycan, A2BG2, in IgG derived from ALS patient sera (ALS-IgG). This glycan increases the affinity of IgG to CD16 on effector cells, consequently enhancing Antibody-Dependent Cellular Cytotoxicity (ADCC). Therefore, we explore whether the Fc-N297-glycans of IgG may be involved in ALS disease. Immunostaining of brain and spinal cord tissues revealed over-expression of CD16 and co-localization of intact ALS-IgG with CD16 and in brain with activated microglia of G93A-SOD1 mice. Intact ALS-IgG enhanced effector cell activation and ADCC reaction in comparison to sugar-depleted or control IgG. ALS-IgG were localized in the synapse between brain microglia and neurons of G93A-SOD1 mice, manifesting a promising in vivo ADCC reaction. Therefore, glycans of ALS-IgG may serve as a biomarker for the disease and may be involved in neuronal damage

Meta-analysis of the heritability of human traits based on fifty years of twin studies

Despite a century of research on complex traits in humans, the relative importance and specific nature of the influences of genes and environment on human traits remain controversial. We report a meta-analysis of twin correlations and reported variance components for 17,804 traits from 2,748 publications including 14,558,903 partly dependent twin pairs, virtually all published twin studies of complex traits. Estimates of heritability cluster strongly within functional domains, and across all traits the reported heritability is 49%. For a majority (69%) of traits, the observed twin correlations are consistent with a simple and parsimonious model where twin resemblance is solely due to additive genetic variation. The data are inconsistent with substantial influences from shared environment or non-additive genetic variation. This study provides the most comprehensive analysis of the causes of individual differences in human traits thus far and will guide future gene-mapping efforts. All the results can be visualized using the MaTCH webtool

New Pharmacological Agents to Aid Smoking Cessation and Tobacco Harm Reduction: What has been Investigated and What is in the Pipeline?

A wide range of support is available to help smokers to quit and aid attempts at harm reduction, including three first-line smoking cessation medications: nicotine replacement therapy, varenicline and bupropion. Despite the efficacy of these, there is a continual need to diversify the range of medications so that the needs of tobacco users are met. This paper compares the first-line smoking cessation medications to: 1) two variants of these existing products: new galenic formulations of varenicline and novel nicotine delivery devices; and 2) twenty-four alternative products: cytisine (novel outside of central and eastern Europe), nortriptyline, other tricyclic antidepressants, electronic cigarettes, clonidine (an anxiolytic), other anxiolytics (e.g. buspirone), selective 5-hydroxytryptamine (5-HT) reuptake inhibitors, supplements (e.g. St John’s wort), silver acetate, nicobrevin, modafinil, venlafaxine, monoamine oxidase inhibitors (MAOI), opioid antagonist, nicotinic acetylcholine receptors (nAChR) antagonists, glucose tablets, selective cannabinoid type 1 receptor antagonists, nicotine vaccines, drugs that affect gamma-aminobutyric acid (GABA) transmission, drugs that affect N-methyl-D-aspartate receptors (NMDA), dopamine agonists (e.g. levodopa), pioglitazone (Actos; OMS405), noradrenaline reuptake inhibitors, and the weight management drug lorcaserin. Six criteria are used: relative efficacy, relative safety, relative cost, relative use (overall impact of effective medication use), relative scope (ability to serve new groups of patients), and relative ease of use (ESCUSE). Many of these products are in the early stages of clinical trials, however, cytisine looks most promising in having established efficacy and safety and being of low cost. Electronic cigarettes have become very popular, appear to be efficacious and are safer than smoking, but issues of continued dependence and possible harms need to be considered

Associations among height, body mass index and intelligence from age 11 to age 78 years

BACKGROUND: Intelligence is related to both height and body mass index (BMI) at various stages of life. Several studies have demonstrated longitudinal relationships between these measures, but none has established whether height and intelligence, or BMI and intelligence are linked from childhood through to older age. METHODS: We assessed the relations between these measures over an interval of up to 67 years using data from the 36-Day Sample, an initially-representative sample of Scottish people born in 1936, assessed at age 11 years (N = 6,291) and again at 77-78 years (N = 722). This paper focuses on the 423 participants (6.7 % of the original sample) who provided relevant data in late adulthood. RESULTS: Height and intelligence were significantly positively associated in childhood (β = .23) and late adulthood (β = .21-.29). Longitudinal correlations also showed that childhood intelligence predicted late-adulthood height (β = .20), and childhood height predicted late-adulthood cognitive ability (β = .12-.14). We observed no significant relationship between BMI and intelligence either in childhood or in late adulthood, nor any longitudinal association between the two in this sample. CONCLUSIONS: Our results on height and intelligence are the first to demonstrate that their relationship spans almost seven decades, from childhood through to late adulthood, and they call for further investigation into the mechanisms underlying this lifelong association

Interspinous process decompression is associated with a reduction in opioid analgesia in patients with lumbar spinal stenosis

Pierce D Nunley,1 Timothy R Deer,2 Ramsin M Benyamin,3 Peter S Staats,4 Jon E Block5 1Spine Institute of Louisiana, Shreveport, LA 71101, USA; 2Center for Pain Relief, Charleston, WV 25301, USA; 3Millennium Pain Center, Bloomington, IL 61704, USA; 4National Spine and Pain Centers, Rockville, MD 20852, USA; 5Jon Block, San Francisco, CA 94115, USA Background: Lumbar spinal stenosis (LSS) causes significant pain and functional impairment, and medical management has increasingly included the prescription of opioid-based analgesics. Interspinous process decompression (IPD) provides a minimally-invasive treatment option for LSS.Methods: This study estimated the type, dosage, and duration of opioid medications through 5 years of follow-up after IPD with the Superion Indirect Decompression System (Vertiflex Inc., Carlsbad, CA USA). Data were obtained from the Superion-treatment arm of a randomized controlled noninferiority trial. The prevalence of subjects using opiates was determined at baseline through 60 months. Primary analysis included all 190 patients randomized to receive the Superion device. In a subgroup of 98 subjects, we determined opioid-medication prevalence among subjects with a history of opioid use.Results: At baseline, almost 50% (94 of 190) of subjects were using opioid medication. Thereafter, there was a sharp decrease in opioid-medication prevalence from 25.2% (41 of 163) at 12 months to 13.3% (20 of 150) at 24 months to 7.5% (8 of 107) at 60 months. Between baseline and 5 years, there was an 85% decrease in the proportion of subjects using opioids. A similar pattern was also observed among subjects with a history of opiates prior to entering the trial.Conclusion: Stand-alone IPD is associated with a marked decrease in the need for opioid medications to manage symptoms related to LSS. In light of the current opiate epidemic, such alternatives as IPD may provide effective pain relief in patients with LSS without the need for opioid therapy. Keywords: interspinous spacer, Superion, lumbar spinal stenosis, opioids, neurogenic claudication, indirect decompressio