Interaction of HLA Class II rs9272219 and TMPO rs17028450 (Arg690Cys) Variants Affects Neuromyelitis Optica Spectrum Disorder Susceptibility in an Admixed Mexican Population

Neuromyelitis Optica Spectrum Disorder (NMOSD) is a demyelinating autoimmune disease of the central nervous system, more prevalent in individuals of non-European ancestry. Few studies have analyzed genetic risk factors in NMOSD, and HLA class II gene variation has been associated NMOSD risk in various populations including Mexicans. Thymopoietin (TMPO) has not been tested as a candidate gene for NMOSD or other autoimmune disease, however, experimental evidence suggests this gene may be involved in negative selection of autoreactive T cells and autoimmunity. We thus investigated whether the missense TMPO variant rs17028450 (Arg630Cys, frequent in Latin America) is associated with NMOSD, and whether this variant shows an interaction with HLA-class II rs9272219, previously associated with NMOSD risk. A total of 119 Mexican NMOSD patients, 1208 controls and 357 Native Mexican individuals were included. The HLA rs9272219 "T" risk allele frequency ranged from 21 to 68%, while the rs17028450 "T" minor allele frequency was as high as 18% in Native Mexican groups. Both rs9272219 and rs17028450 were significantly associated with NMOSD risk under additive models (OR = 2.48; p = 8 × 10(-10) and OR = 1.59; p = 0.0075, respectively), and a significant interaction between both variants was identified with logistic regression models (p = 0.048). Individuals bearing both risk alleles had an estimated 3.9-fold increased risk of NMOSD. To our knowledge, this is the first study reporting an association of TMPO gene variation with an autoimmune disorder and the interaction of specific susceptibility gene variants, that may contribute to the genetic architecture of NMOSD in admixed Latin American populations

Improved functionalization of oleic acid-coated iron oxide nanoparticles for biomedical applications

Superparamagnetic iron oxide nanoparticles can providemultiple benefits for biomedical applications in aqueous environments such asmagnetic separation or magnetic resonance imaging. To increase the colloidal stability and allow subsequent reactions, the introduction of hydrophilic functional groups onto the particles’ surface is essential. During this process, the original coating is exchanged by preferably covalently bonded ligands such as trialkoxysilanes. The duration of the silane exchange reaction, which commonly takes more than 24 h, is an important drawback for this approach. In this paper, we present a novel method, which introduces ultrasonication as an energy source to dramatically accelerate this process, resulting in high-quality waterdispersible nanoparticles around 10 nmin size. To prove the generic character, different functional groups were introduced on the surface including polyethylene glycol chains, carboxylic acid, amine, and thiol groups. Their colloidal stability in various aqueous buffer solutions as well as human plasma and serum was investigated to allow implementation in biomedical and sensing applications.status: publishe

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Survey on the use of premix insulin analogues in diabetes mellitus type 1 and 2 in Mexico [Encuesta sobre el uso de premezclas de an�logos de insulinas en pacientes con diabetes en M�xico]

Background: There are several publications related to the use of premixed insulin analogs in Type 1 and 2 Diabetes Mellitus, however, there was no information about its use in the Mexican clinical practice. Materials and methods: A survey was conducted to 48 physicians experts in Diabetes Mellitus. They were endocrinologists (62%), Internists (32) and diabetologists (6%). Results: Twenty-four percent of the specialists pointed out that more than half of the patients who consult by the first time do not respond to treatment with oral hypoglycemic medication. A high number of patients treated with insulin reach glycemic control goals. Most of the experts treat more than half of their patients with insulin. Sixty-six percent of the experts use premixed insulin analogs in their patients with type 1 Diabetes, and a high percentage use them in type 2 Diabetes. Most of the expert physicians recommend the use of premixed insulin analogs as the first line treatment in their patients diagnosed with Type 2 Diabetes. Conclusions: Premixed insulin analogs are widely accepted by patients because they offer a complete coverage of their metabolic requirements, reducing the number of daily injections. In type 1 Diabetes, premixed insulin analogs will be used to improve metabolic control and to strengthen compliance. This document describes the use of premixed insulin analogs in the treatment of Diabetes Mellitus in Mexico

Survey on the use of premix insulin analogues in diabetes mellitus type 1 and 2 in Mexico [Encuesta sobre el uso de premezclas de análogos de insulinas en pacientes con diabetes en México]

Background: There are several publications related to the use of premixed insulin analogs in Type 1 and 2 Diabetes Mellitus, however, there was no information about its use in the Mexican clinical practice. Materials and methods: A survey was conducted to 48 physicians experts in Diabetes Mellitus. They were endocrinologists (62%), Internists (32) and diabetologists (6%). Results: Twenty-four percent of the specialists pointed out that more than half of the patients who consult by the first time do not respond to treatment with oral hypoglycemic medication. A high number of patients treated with insulin reach glycemic control goals. Most of the experts treat more than half of their patients with insulin. Sixty-six percent of the experts use premixed insulin analogs in their patients with type 1 Diabetes, and a high percentage use them in type 2 Diabetes. Most of the expert physicians recommend the use of premixed insulin analogs as the first line treatment in their patients diagnosed with Type 2 Diabetes. Conclusions: Premixed insulin analogs are widely accepted by patients because they offer a complete coverage of their metabolic requirements, reducing the number of daily injections. In type 1 Diabetes, premixed insulin analogs will be used to improve metabolic control and to strengthen compliance. This document describes the use of premixed insulin analogs in the treatment of Diabetes Mellitus in Mexico

The complete mitogenome of the invasive Japanese mud snail Batillaria attramentaria (Gastropoda: Batillariidae) from Elkhorn Slough, California, USA

Genomic analysis of the invasive marine snail Batillaria attramentaria from Elkhorn Slough, Moss Landing, California, USA using 150 bp paired-end Illumina sequences resulted in the assembly of its complete mitogenome. The mitogenome is 16,095 bp in length and contains 2 rRNA, 13 protein-coding, and 22 tRNA genes (GenBank Accession MN557850). Gene content and organization of B. attramentaria are identical to the Turritellidae and Pachychilidae. The phylogenetic analysis of B. attramentaria resolves it in a fully supported clade with these same two families in the superfamily Cerithioidea. Nucleotide BLAST searches of the Elkhorn Slough cox1 gene of B. attramentaria yielded identical sequences from invasive populations from California and British Columbia, and native populations from northeastern and central Japan. These data show that mitogenome sequencing is a useful tool for studying the classification and phylogenetic history Cerithioidea

Evolution from free-living bacteria to endosymbionts of insects: Genomic changes and the importance of the chaperonin GroEL

Major insect lineages have independently acquired bacterial species, mainly from Gamma-proteobacteria and Bacteroidetes class, which could be nutritional mutualistic factories, facultative mutualists that protect against biotic and abiotic stresses, or reproductive manipulators (which alter the fertility of the host species in its benefit). Some of them are enclosed in bacteriocytes to assure their maternal transmission over generations. All of them show an increased level of genetic drift due to the small population size and the continuous population bottlenecking at each generation, processes that have shaped their genome, proteome, and morphology. Depending on the nature of the relationship, the degree of genome plasticity varies, i.e., obligate nutritional mutualistic symbionts have extremely small genomes lacking mobile elements, bacteriophages, or recombination machinery. Under these conditions, endosymbionts face high mutational pressures that may drive to extinction or symbiont replacement. How do then they survive for such long evolutionary time, and why do they show a genome stasis? In this chapter, after a brief introduction to the problem, we will focus on the genome changes suffered by these endosymbionts, and on the mutational robustness mechanisms, including the moonlighting chaperone GroEL that could explain their long prevalence from an evolutionary perspective by comparing them with free-living bacteria.Peer reviewe