Pyridoxamine Traps Intermediates in Lipid Peroxidation Reactions in Vivo: Evidence on the Role of Lipids in Chemical Modification of Protein and Development of Diabetic Complications

Maillard or browning reactions between reducing sugars and protein lead to formation of advanced glycation end products (AGEs) and are thought to contribute to the pathogenesis of diabetic complications. AGE inhibitors such as aminoguanidine and pyridoxamine (PM) inhibit both the formation of AGEs and development of complications in animal models of diabetes. PM also inhibits the chemical modification of protein by advanced lipoxidation end products (ALEs) during lipid peroxidation reactions in vitro. We show here that several PM adducts, formed in incubations of PM with linoleate and arachidonate in vitro, are also excreted in the urine of PM-treated animals. The PM adducts N-nonanedioyl-PM (derived from linoleate), N-pentanedioyl-PM, N-pyrrolo-PM, and N-(2-formyl)-pyrrolo-PM (derived from arachidonate), and N-formyl-PM and N-hexanoyl-PM (derived from both fatty acids) were quantified by liquid chromatography-mass spectrometry analysis of rat urine. Levels of these adducts were increased 5-10-fold in the urine of PM-treated diabetic and hyperlipidemic rats, compared with control animals. We conclude that the PM functions, at least in part, by trapping intermediates in AGE/ALE formation and propose a mechanism for PM inhibition of AGE/ALE formation involving cleavage of alpha-dicarbonyl intermediates in glycoxidation and lipoxidation reactions. We also conclude that ALEs derived from polyunsaturated fatty acids are increased in diabetes and hyperlipidemia and may contribute to development of long term renal and vascular pathology in these diseases

THE INTER-LABORATORY REPEATABILITY OF UNPLANNED SIDESTEPPING KINEMATICS

Anterior cruciate ligament (ACL) injury research has received much attention over the past 20 years. In this time, there have been many laboratory based clinical movement protocols developed to help characterise an individual’s injury risk in sport. Though many testing procedures exists, there is a paucity of research verifying the inter-lab reliability of these testing protocols. This places practical limitations on the ability to compare or share motion data between testing centres. The aim of this research was to help bridge this gap by assessing the inter-lab repeatability of an established sidestepping protocol. Results showed the inter-lab kinematics of unplanned sidestepping are repeatable ������������ ���� ��.02��) verifying this experimental protocol as a dependable between testing centres

Aged carbon mineralisation from headwater peatland floodplains in the Peak District, UK

Floodplains are dynamic ecosystems that cycle carbon, which is both delivered from upstream catchment sources and produced in-situ. These systems are being increasingly recognised as key environments of carbon processing, with the capacity for substantial carbon storage, in addition to acting as hotspots of carbon mineralisation. The balance of storage versus mineralisation is dependent on a number of controls including landscape position and environmental conditions. This study focuses on three headwater floodplains downstream of a highly eroded blanket bog peatland in the Peak District, UK. Previous research has shown that aged organic carbon from peatland sources, has been stored in floodplains in this area, and therefore, we aimed to understand whether allochthonous carbon was being mineralised in this context. We examined sediment cores and analysed the radiocarbon (14C) content of soil-respired CO2, using a partitioning approach to scrutinise the depth and age relations of respiration in the individual floodplains, and patterns of age distributions downstream. Aged organic carbon was released from the upper and mid floodplain sites (14C ages of 682 and 232 years BP, respectively), whereas only modern dates were recorded at the lower site. The geomorphic context and sedimentology supported these results, with the stratigraphy suggesting a dominance of allochthonous deposition at the upper sites, but primarily in-situ soil development at the lower site. There were no trends of radiocarbon age with depth in the individual floodplains, suggesting that floodplain sediments were well mixed and that aged organic matter was being processed both at the surface and at depth in the uppermost sites. An isotope mass balance mixing model indicated the dominance of two sources of CO2; recently fixed C3 organic matter (<10 years old) and CO2 produced by methanogenesis. The results indicate that floodplains in a relatively narrow halo around eroding headwater peatlands, could be important sites of aged carbon turnover originally derived from upstream sources. Reworked carbon does not transfer passively through the system and experiences periods of deposition where it can be subject to microbial action. This is an important consideration in other environments where organic carbon has previously been ‘locked up’ (e.g., permafrost regions) but is now under the threat of release due to climate change

Modeling of negative Poisson’s ratio (auxetic) crystalline cellulose Iβ

Energy minimizations for unstretched and stretched cellulose models using an all-atom empirical force field (Molecular Mechanics) have been performed to investigate the mechanism for auxetic (negative Poisson’s ratio) response in crystalline cellulose Iβ from kraft cooked Norway spruce. An initial investigation to identify an appropriate force field led to a study of the structure and elastic constants from models employing the CVFF force field. Negative values of on-axis Poisson’s ratios nu31 and nu13 in the x1-x3 plane containing the chain direction (x3) were realized in energy minimizations employing a stress perpendicular to the hydrogen-bonded cellobiose sheets to simulate swelling in this direction due to the kraft cooking process. Energy minimizations of structural evolution due to stretching along the x3 chain direction of the ‘swollen’ (kraft cooked) model identified chain rotation about the chain axis combined with inextensible secondary bonds as the most likely mechanism for auxetic response

WHO consultation on group B Streptococcus vaccine development: Report from a meeting held on 27-28 April 2016.

Globally, group B Streptococcus (GBS) remains a leading cause of sepsis and meningitis in infants in the first 90days of life. Intrapartum antibiotic prophylaxis (IAP) for women at increased risk of transmitting GBS to their newborns has been effective in reducing part, but not all, of the GBS disease burden in many high income countries (HICs). In low- and middle-income countries (LMICs), IAP use is low. Immunization of pregnant women with a GBS vaccine represents an alternative strategy to protecting newborns and young infants, through transplacental antibody transfer and potentially by reducing new vaginal colonization. This vaccination strategy was first suggested in the 1970s and several potential GBS vaccines have completed phase I/II clinical trials. During the 2015 WHO Product Development for Vaccines Advisory Committee meeting, GBS was identified as a high priority for the development of a vaccine for maternal immunization because of the major public health burden posed by GBS in LMICs, and the high technical feasibility for successful development. Following this meeting, the first WHO technical consultation on GBS vaccines was held on the 27th and 28th of April 2016, to consider development pathways for such vaccines, focused on their potential role in reducing newborn and young infant deaths and possibly stillbirths in LMICs. Discussion topics included: (1) pathophysiology of disease; (2) current gaps in the knowledge of global disease burden and serotype distribution; (3) vaccine candidates under development; (4) design considerations for phase III trials; and (5) pathways to licensure, policy recommendations and use. Efforts to address gaps identified in each of these areas are needed to establish the public health need for, the development and deployment of, efficacious GBS vaccines. In particular, more work is required to understand the global disease burden of GBS-associated stillbirths, and to develop quality-assured standardized antibody assays to identify correlates of protection

Safety and immunogenicity of a novel 10-valent pneumococcal conjugate vaccine candidate in adults, toddlers, and infants in The Gambia-Results of a phase 1/2 randomized, double-blinded, controlled trial.

BACKGROUND: A more affordable pneumococcal conjugate vaccine (PCV) that provides comparable protection to current PCVs is needed to ensure sustainable access in resource-limited settings. Serum Institute of India Pvt. Ltd.'s PCV candidate (SIIPL-PCV) has the potential to meet this need as manufacturing efficiency has been optimized and the vaccine targets the most prevalent disease-causing serotypes in Africa and Asia. We report SIIPL-PCV's safety, tolerability, and immunogenicity in adults, toddlers, and infants in The Gambia. METHODS: This phase 1/2, randomized, double-blind trial sequentially enrolled 34 PCV-naive adults (18-40?years old), 112 PCV (Prevenar 13® [PCV13])-primed toddlers (12-15?months old), and 200 PCV-naive infants (6-8?weeks old), who were randomized (1:1) to receive SIIPL-PCV or a licensed comparator vaccine. Infants received three-doses of SIIPL-PCV or PCV13 at 6, 10, and 14?weeks of age co-administered with routine Expanded Program on Immunization (EPI) vaccines. Reactogenicity was solicited through seven-days post-vaccination; unsolicited adverse events (AEs) were assessed throughout the study. The safety and immunogenicity of a matching booster at 10-14?months of age were evaluated in a subset of 96 infants. Immune responses were evaluated post-primary and pre- and post-booster vaccinations. RESULTS: Reactogenicity was primarily mild-to-moderate in severity. In infants, the most common solicited reactions were injection-site tenderness and fever, with no meaningful treatment-group differences. There were no serious or severe vaccine-related AEs and no meaningful trends in SAEs, vaccine-related AEs, or overall AEs. Infant post-primary seroresponse rates (IgG level???0.35?µg/mL) were ?89% for all serotypes except 6A (79%) in the SIIPL-PCV group. IgG GMCs were >1?µg/mL for all serotypes in both SIIPL-PCV and PCV13 groups. Post-booster GMCs were comparable between groups. CONCLUSION: SIIPL-PCV was well-tolerated, had an acceptable safety profile, and was immunogenic for all vaccine serotypes. Results support the evaluation of SIIPL-PCV in a phase 3 non-inferiority trial. Clinicaltrials.gov: NCT02308540

Surveillance and control of meningococcal disease in the COVID-19 era: A Global Meningococcal Initiative review

RevisiónThis review article incorporates information from the 4th Global Meningococcal Initiative summit meeting. Since the introduction of stringent COVID-19 infection control and lockdown measures globally in 2020, there has been an impact on IMD prevalence, surveillance, and vaccination compliance. Incidence rates and associated mortality fell across various regions during 2020. A reduction in vaccine uptake during 2020 remains a concern globally. In addition, several Neisseria meningitidis clonal complexes, particularly CC4821 and CC11, continue to exhibit resistance to antibiotics, with resistance to ciprofloxacin or beta-lactams mainly linked to modifications of gyrA or penA alleles, respectively. Beta-lactamase acquisition was also reported through horizontal gene transfer (blaROB-1) involving other bacterial species. Despite the challenges over the past year, progress has also been made on meningococcal vaccine development, with several pentavalent (serogroups ABCWY and ACWYX) vaccines currently being studied in late-stage clinical trial programmes.Medical writing support was funded by Sanofi Pasteur.S