Bench Scale Application of the Hybridized Zero Valent Iron Process for the Removal of Dissolved Silica From Water

Dissolved silica in water is notorious for precipitating on industrial equipment. Scale formation can occur within tubes of a boiler, heat exchangers, and cooling towers, turbine blades are susceptible to deposit formation, and reverse osmosis membranes are susceptible to glass like scaling all leading to reduced efficiency. Conventional chemical treatment methods such as hot lime, activated alumina, and MgO require heavy dosage of chemicals and have limited pH ranges for which removal is effective. A more robust and cost-effective dissolved silica removal technique is desirable. The hybridized zero-valent iron (hZVI) process, now commercially available as Pironox™, uses zero-valent iron (Fe^0 ) as its main reactive media developed to remove heavy metals/metalloids, reactive oxyanions, and impurities from water/wastewater. The distinctive feature of this novel chemical treatment platform is the controlled formation of magnetite as the main iron corrosion product in the presence of aqueous Fe^2+. The hZVI system was shown to reduce dissolved silica from 70 mg/L to below 5 mg/L in a pilot scale demonstration for treating flue-gas desulfurization wastewater. In this study bench scale tests were performed using a single stage, continuously stirred tank reactor to optimize the removal efficiency of dissolved silica (100 mg/L as SiO2) using the hZVI process. It was demonstrated the continuous formation of magnetite in an hZVI system played a key role in achieving high system performance with respect to dissolved SiO2 removal. Using ZVI grains with an average diameter of 5 microns optimal reagent dosages were determined to be 27.9 mg/L (0.5 mM) Fe^2+ and 10 mg/L (0.72 mM) to 15 mg/L (1.07 mM) NO3-N. With added Fe^2+ and nitrate at these dosages or higher removal efficiency was 88% to 99% over a broad range of pH 6.8 to 9.8 offering a more flexible approach to removing dissolved silica from water when compared to conventional treatment methods. Using the optimal reagents the hZVI system sustained dissolved silica removal with >95% efficiency over an extended period. It was also shown that increasing the reactor temperature from 25°C to 90°C did not attenuate dissolved SiO2 removal in an hZVI system

Cranial expansion for shunt-induced craniostenosis. Case report

IntroductionLes dérivations ventriculo-péritonéales sont compliquées par ventricules fendues symptomatiques dans 1-5 % des cas. Quelques patients atteints de fentes ventriculaires développent une craniosténose shunt induite provoquant une augmentation de la pression intracrânienne pendant que le cerveau se développe peuvant être mal interprété comme un problème de dysfonctionnement de shunt. L’expansion de voûte crânienne a été décrit pour traiter cette craniosténose shunt-induite, mais il n’y a pas eu de rapports à ce jour de l’expansion crânienne dans les milieux pauvres en ressources .Présentation de casNous rapportons un enfant de trois mois qui a subi la reparation d’un myéloméningocèle et l’insertion d’un shunt ventriculo-péritonéal . Quand elle avait quatre ans , elle a développé des symptômes  d’hypertension intracrânienne avec une circonférence de 8 cm de la tête en deça de la normale. Les radiographies du crane ont démontré une apparence cuivre battu. Une opération d’expansion crânienne a été effectuée. En post-opératoire, les symptômes d’hypertension intracrânienne ont été résolus et ne se reproduirent plus avec deux ans plus tard des étapes normales de développement , une circonférence supérieure de 5.4cm par rapport au statut préopératoire , et l’amélioration des constats radiologiques .ConclusionLes craniosténose shunt induites doivent être pris en charge chez les enfants présentant les symptômes de syndrome ventricule fente. Le diagnostic peut être fait avec des critères cliniques et radiographiques , sans surveillance de la pression intracrânienne , dans les milieux pauvres en ressources , et traité efficacement avec l’expansion de la voûte crânienne

Role of spinal and peripheral HMGB1 in arthritis-induced pain

Chronic pain is one of the most debilitating and repeatedly reported symptoms by rheumatoid arthritis (RA) patients. Despite good disease control achieved with disease modifying antirheumatic drugs (DMARDs), joint pain remains a major problem for a subgroup of patients. Therefore, it appears episodes of joint inflammation can have long-term effects on the peripheral sensory nervous system. Additionally, changes in the central nervous system may contribute to chronification of RA pain. High mobility group box-1 protein (HMGB1) is an important molecule in the pathogenesis of RA, but the role of HMGB1 in RA associated pain has not been studied. Thus, the involvement of spinal and peripheral HMGB1 in rheumatoid arthritis-induced pain is the focus of this thesis. In Paper I, we characterized the collagen antibody-induced arthritis (CAIA) model from a pain perspective. As expected, injection of collagen type II antibodies induces transient joint inflammation and pain-like behavior. Surprisingly, pain-like behavior did not normalize when the inflammation resolved. We found that transient antibody-induced joint inflammation led to long-lasting mechanical hypersensitivity that outlasted the inflammation. Buprenorphine and gabapentin attenuated pain like behavior in both the inflammatory and late “postinflammatory” phase of the model, whereas diclofenac was antinociceptive only during the inflammatory phase. This indicates that there is a temporal shift in the mechanisms that maintain arthritis-induced nociception. The CAIA model can thus be used to explore mechanisms of persistent pain induced by inflammation in the articular joint. In Paper II and III, we investigated the spinal role of HMGB1 in arthritis-induced pain and sex-dependent microglial involvement in disulfide HMGB1 mediated nociception. Peripheral joint inflammation in the CAIA model increases expression and extranuclear levels of HMGB1 in the lumbar spinal cord. Blocking the endogenous action of HMGB1 with HMGB1 inhibitors attenuated CAIA-induced mechanical hypersensitivity in both male and female mice. A pronociceptive effect dependent on the redox state of HMGB1 was also revealed. The disulfide, but not the all-thiol or oxidized form, of HMGB1 induced nociception in male and female mice after intrathecal delivery. This effect was regulated via toll-like receptor 4 (TLR4) and associated with cytokine and chemokine production and elevated expression of factors related to increased glial cell reactivity. Intrathecal delivery of minocycline attenuated the disulfide HMGB1 induced hypersensitivity in male but not in female mice. Global protein analysis of lumbar spinal cords from male and female mice injected intrathecally with HMGB1 and vehicle or minocycline showed that 36 proteins were differentially expressed between male and female injected with HMGB1 and that 44 proteins in males and 8 in females were altered in mice receiving HMGB1 and minocycline. Interestingly, up-regulation of antinociceptive and anti-inflammatory molecules was found in male but not in female mice after intrathecal injection of HMGB1 and minocycline. This work points to a prominent and redox-dependent role of HMGB1 in spinal pain signal transmission. In Paper IV, we demonstrated that a repetitive systemic injection of a HMGB1 neutralizing antibody attenuates CAIA-induced nociception in male but not in female mice. Intraarticular injection of disulfide but not all-thiol HMGB1 induced mechanical hypersensitivity in both male and female mice, but with a more pronounced induction of cytokine and chemokine mRNA expression in male compared to female mice. Moreover, nociception induced by disulfide HMGB1 is mediated by TLR4 expressed on nociceptors and myeloid cells in male and female mice, with a stronger contribution of TLR4 on myeloid cells in male mice. In summary, we have described novel redox state and sex-dependent roles of HMGB1 in nociception at spinal and peripheral sites in a model of arthritis-induced pain. These results also reveal sex-dependent analgesic pharmacology and highlight the importance of taking sex into account in preclinical pain research. While further studies are warranted in order to further advance our knowledge on the role of HMGB1 in pain pathology, the work in this thesis highlights HMGB1 as an intriguing new target for pain relief

Using matrix assisted laser desorption ionisation mass spectrometry (MALDI-MS) profiling in order to predict clinical outcomes of patients with heart failure

Background Current risk prediction models in heart failure (HF) including clinical characteristics and biomarkers only have moderate predictive value. The aim of this study was to use matrix assisted laser desorption ionisation mass spectrometry (MALDI-MS) profiling to determine if a combination of peptides identified with MALDI-MS will better predict clinical outcomes of patients with HF. Methods A cohort of 100 patients with HF were recruited in the biomarker discovery phase (50 patients who died or had a HF hospital admission vs. 50 patients who did not have an event). The peptide extraction from plasma samples was performed using reversed phase C18. Then samples were analysed using MALDI-MS. A multiple peptide biomarker model was discovered that was able to predict clinical outcomes for patients with HF. Finally, this model was validated in an independent cohort with 100 patients with HF. Results After normalisation and alignment of all the processed spectra, a total of 11,389 peptides (m/z) were detected using MALDI-MS. A multiple biomarker model was developed from 14 plasma peptides that was able to predict clinical outcomes in HF patients with an area under the receiver operating characteristic curve (AUC) of 1.000 (p = 0.0005). This model was validated in an independent cohort with 100 HF patients that yielded an AUC of 0.817 (p = 0.0005) in the biomarker validation phase. Addition of this model to the BIOSTAT risk prediction model increased the predictive probability for clinical outcomes of HF from an AUC value of 0.643 to an AUC of 0.823 (p = 0.0021). Moreover, using the prediction model of fourteen peptides and the composite model of the multiple biomarker of fourteen peptides with the BIOSTAT risk prediction model achieved a better predictive probability of time-to-event in prediction of clinical events in patients with HF (p = 0.0005). Conclusions The results obtained in this study suggest that a cluster of plasma peptides using MALDI-MS can reliably predict clinical outcomes in HF that may help enable precision medicine in HF

Plasma proteomic approach in patients with heart failure:insights into pathogenesis of disease progression and potential novel treatment targets

Aims To provide insights into pathogenesis of disease progression and potential novel treatment targets for patients with heart failure by investigation of the plasma proteome using network analysis. Methods and results The plasma proteome of 50 patients with heart failure who died or were rehospitalised were compared with 50 patients with heart failure, matched for age and sex, who did not have an event. Peptides were analysed on two‐dimensional liquid chromatography coupled to tandem mass spectrometry (2D LC ESI‐MS/MS) in high definition mode (HDMSE). We identified and quantified 3001 proteins, of which 51 were significantly up‐regulated and 46 down‐regulated with more than two‐fold expression changes in those who experienced death or rehospitalisation. Gene ontology enrichment analysis and protein–protein interaction networks of significant differentially expressed proteins discovered the central role of metabolic processes in clinical outcomes of patients with heart failure. The findings revealed that a cluster of proteins related to glutathione metabolism, arginine and proline metabolism, and pyruvate metabolism in the pathogenesis of poor outcome in patients with heart failure who died or were rehospitalised. Conclusions Our findings show that in patients with heart failure who died or were rehospitalised, the glutathione, arginine and proline, and pyruvate pathways were activated. These pathways might be potential targets for therapies to improve poor outcomes in patients with heart failure

Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk

Glatiramer acetate is used therapeutically in multiple sclerosis but also known for adverse effects including elevated coronary artery disease (CAD) risk. The mechanisms underlying the cardiovascular side effects of the medication are unclear. Here, we made use of the chromosomal variation in the genes that are known to be affected by glatiramer treatment. Focusing on genes and gene products reported by drug-gene interaction database to interact with glatiramer acetate we explored a large meta-analysis on CAD genome-wide association studies aiming firstly, to investigate whether variants in these genes also affect cardiovascular risk and secondly, to identify new CAD risk genes. We traced association signals in a 200-kb region around genomic positions of genes interacting with glatiramer in up to 60 801 CAD cases and 123 504 controls. We validated the identified association in additional 21 934 CAD cases and 76 087 controls. We identified three new CAD risk alleles within the TGFB1 region on chromosome 19 that independently affect CAD risk. The lead SNP rs12459996 was genome-wide significantly associated with CAD in the extended meta-analysis (odds ratio 1.09, p = 1.58×10-12). The other two SNPs at the locus were not in linkage disequilibrium with the lead SNP and by a conditional analysis showed p-values of 4.05 × 10-10 and 2.21 × 10-6. Thus, studying genes reported to interact with glatiramer acetate we identified genetic variants that concordantly with the drug increase the risk of CAD. Of these, TGFB1 displayed signal for association. Indeed, the gene has been associated with CAD previously in both in vivo and in vitro studies. Here we establish genome-wide significant association with CAD in large human samples.This work was supported by grants from the Fondation Leducq (CADgenomics: Understanding CAD Genes, 12CVD02), the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (e:AtheroSysMed, grant 01ZX1313A-2014 and SysInflame, grant 01ZX1306A), and the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement no HEALTH-F2-2013-601456 (CVgenes-at-target). Further grants were received from the DFG as part of the Sonderforschungsbereich CRC 1123 (B2). T.K. was supported by a DZHK Rotation Grant. I.B. was supported by the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence ‘Inflammation at Interfaces’. F.W.A. is supported by a Dekker scholarship-Junior Staff Member 2014T001 - Netherlands Heart Foundation and UCL Hospitals NIHR Biomedical Research Centre

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis