A peptide mimic of the chemotaxis inhibitory protein of Staphylococcus aureus: towards the development of novel anti-inflammatory compounds

Complement factor C5a is one of the most powerful pro-inflammatory agents involved in recruitment of leukocytes, activation of phagocytes and other inflammatory responses. C5a triggers inflammatory responses by binding to its G-protein-coupled C5a-receptor (C5aR). Excessive or erroneous activation of the C5aR has been implicated in numerous inflammatory diseases. The C5aR is therefore a key target in the development of specific anti-inflammatory compounds. A very potent natural inhibitor of the C5aR is the 121-residue chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS). Although CHIPS effectively blocks C5aR activation by binding tightly to its extra-cellular N terminus, it is not suitable as a potential anti-inflammatory drug due to its immunogenic properties. As a first step in the development of an improved CHIPS mimic, we designed and synthesized a substantially shorter 50-residue adapted peptide, designated CHOPS. This peptide included all residues important for receptor binding as based on the recent structure of CHIPS in complex with the C5aR N terminus. Using isothermal titration calorimetry we demonstrate that CHOPS has micromolar affinity for a model peptide comprising residues 7–28 of the C5aR N terminus including two O-sulfated tyrosine residues at positions 11 and 14. CD and NMR spectroscopy showed that CHOPS is unstructured free in solution. Upon addition of the doubly sulfated model peptide, however, the NMR and CD spectra reveal the formation of structural elements in CHOPS reminiscent of native CHIPS

Incidence and Prevalence of Chronic Inflammatory Demyelinating Polyradiculoneuropathy: A Systematic Review and Meta-Analysis

Abstract Background: Prevalence and incidence rates of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are required to determine the impact of CIDP on society. We aimed to estimate the prevalence and incidence of CIDP worldwide and to determine the effect of diagnostic criteria on prevalence and incidence. Method: A systematic review was conducted for all published incidence and prevalence studies on CIDP until May 18, 2017. Methodological quality was assessed using the Methodological Evaluation of Observational Research checklist. We performed a random effect meta-analysis to estimate pooled prevalence and incidence rates. Results: Of the 907 studies, 11 were included in the systematic review, 5 in the meta-analysis of incidence (818 cases; 220,513,514 person-years) and 9 in the meta-analysis of prevalence (3,160 cases; 160,765,325 population). These studies had a moderate quality. The pooled crude incidence rate was 0.33 per 100,000 person-years (95% CI 0.21–0.53; I2 = 95.7%) and the pooled prevalence rate was 2.81 per 100,000 (95% CI 1.58–4.39; I 2 = 99.1%). Substantial heterogeneity in incidence and prevalence across studies seems to be partly explained by using different diagnostic criteria. Conclusion: These findings provide a starting point to estimate the social burden of CIDP and demonstrate the need to reach consensus on diagnostic criteria for CIDP

Mechanistic basis of the Cu(OAc)2 catalyzed azide-ynamine (3 + 2) cycloaddition reaction

R.P.B. and G.A.B. thank GSK and the Engineering and Physical Sciences Research Council (EPSRC) for an industrial CASE studentship (EP/P51066X/1). G.A.B., F.P., and A.J.B.W. thank the Leverhulme Trust (RP-2020-380). A.T.S. and G.A.B. thank the Biotechnology and Biological Research Council (BBSRC) for its support (BB/V017586/1; BB/T000627/1). A.J.B.W. and M.J.A. thank the EPSRC for its support (EP/R025754/1). A.J.B.W. thanks the Leverhulme Trust for a Research Fellowship (RF-2022-014).The Cu-catalyzed azide–alkyne cycloaddition (CuAAC) reaction is used as a ligation tool throughout chemical and biological sciences. Despite the pervasiveness of CuAAC, there is a need to develop more efficient methods to form 1,4-triazole ligated products with low loadings of Cu. In this paper, we disclose a mechanistic model for the ynamine-azide (3 + 2) cycloadditions catalyzed by copper(II) acetate. Using multinuclear nuclear magnetic resonance spectroscopy, electron paramagnetic resonance spectroscopy, and high-performance liquid chromatography analyses, a dual catalytic cycle is identified. First, the formation of a diyne species via Glaser–Hay coupling of a terminal ynamine forms a Cu(I) species competent to catalyze an ynamine-azide (3 + 2) cycloaddition. Second, the benzimidazole unit of the ynamine structure has multiple roles: assisting C–H activation, Cu coordination, and the formation of a postreaction resting state Cu complex after completion of the (3 + 2) cycloaddition. Finally, reactivation of the Cu resting state complex is shown by the addition of isotopically labeled ynamine and azide substrates to form a labeled 1,4-triazole product. This work provides a mechanistic basis for the use of mixed valency binuclear catalytic Cu species in conjunction with Cu-coordinating alkynes to afford superior reactivity in CuAAC reactions. Additionally, these data show how the CuAAC reaction kinetics can be modulated by changes to the alkyne substrate, which then has a predictable effect on the reaction mechanism.Peer reviewe

Reduced cardiovascular morbidity in patients with hemophilia:results of a 5-year multinational prospective study

Hemophilia is a congenital bleeding disorder caused by low levels of clotting factor VIII or IX. The life expectancy of people with hemophilia (PWH) has increased with the availability of clotting factor concentrates. At the same time, the incidence of cardiovascular disease (CVD) has increased; in retrospective studies, there are conflicting data regarding if, despite this increase, the incidence is still lower than in the general population. We prospectively compared the incidence of CVD in PWH vs the predicted incidence. This prospective, multicenter, observational study included adult PWH (aged &gt;30 years) from The Netherlands and United Kingdom. They were followed up for a 5-year period, and CVD incidence was compared with a predicted event rate based on the QRISK2-2011 CVD risk model. The primary end point was the observed fatal and nonfatal CVD incidence after 5 years compared with the estimated events and in relation to severity of hemophilia. The study included 709 patients, of whom 687 (96.9%) completed 5 years' follow-up or reached an end point. For 108 patients, the QRISK score could not be calculated at inclusion. For the remaining 579, fewer CVD events were observed than predicted: 9 vs 24 (relative risk, 0.38; 95% confidence interval, 0.18-0.80; P 5 .01), corresponding with an absolute risk reduction of 2.4%. Severe hemophilia treated on demand had the highest risk reduction. There was no statistically significant relation between severity of hemophilia and incidence of CVD. In hemophilia, a lower-than-predicted CVD incidence was found, supporting the theory that hemophilia protects against CVD. The study is registered at www.clinicaltrials.gov as #NCT01303900.</p

Socioeconomic participation of persons with hemophilia:Results from the sixth hemophilia in the Netherlands study

Background and objectives Treatment availability and comprehensive care have resulted in improved clinical outcomes for persons with hemophilia. Recent data on socioeconomic participation in the Netherlands are lacking. This study assessed participation in education, in the labor market, and social participation for persons with hemophilia compared with the general male population. Methods Dutch adults and children (5-75 years) of all hemophilia severities (n = 1009) participated in a questionnaire study that included sociodemographic, occupational, and educational variables. Clinical characteristics were extracted from electronic medical records. General population data were extracted from Statistics Netherlands. Social participation was assessed with the PROMIS Ability to Participate in Social Roles and Activities short form, with a minimal important difference set at 1.0. Results Data from 906 adults and children were analyzed. Participation in education of 20 to 24 year olds was 68% (general male population: 53%). Educational attainment was higher compared with Dutch males, especially for severe hemophilia. Absenteeism from school was more common than in the general population. The employment-to-population ratio and occupational disability were worse for severe hemophilia than in the general population (64.3% vs. 73.2% and 14.7% vs. 4.8%, respectively), but similar for nonsevere hemophilia. Unemployment was 5.4% (general male population: 3.4%). Absenteeism from work was less common (38% vs. 45.2%). Mean PROMIS score was similar to or higher than in the general population (54.2; SD 8.9 vs. 50; SD 10). Conclusion Socioeconomic participation of persons with nonsevere hemophilia was similar to the general male population. Some participation outcomes for persons with severe hemophilia were reduced

Hepatitis C virus in hemophilia:Health-related quality of life after successful treatment in the sixth Hemophilia in the Netherlands study

INTRODUCTION: Persons with hemophilia and hepatitis C virus (HCV) infection have a lower health‐related quality of life (HRQoL) than those never HCV infected. However, it is unknown whether HRQoL after HCV eradication is comparable to individuals never HCV infected. We aimed to compare HRQoL between HCV‐cured and never chronically HCV‐infected persons with hemophilia. METHODS: All persons with hemophilia in the Netherlands were invited for a nationwide study conducted in 2018–2019. For the current analysis, participants born before 1992 with data on HRQoL and HCV status were included. HCV status was collected from medical records. HRQoL was measured by RAND‐36 questionnaire, with a minimally important difference set at 4.0 points. Multivariable linear regression was used to adjust for age, hemophilia severity, HIV status, and self‐reported joint impairment. RESULTS: In total, 486 persons were eligible; 180 were HCV cured and 306 never chronically HCV infected. Compared with those never HCV infected, HCV‐cured individuals were older (57 vs. 53 years), more often had severe hemophilia (67% vs. 21%), and reported more impaired joints (median 3 vs. 0). Compared with those never HCV infected, adjusted RAND‐36 domain scores of HCV‐cured individuals cured were lower on all RAND‐36 domains except Pain, ranging from a difference of 4.5 (95% CI, −8.8 to −0.3) for Physical functioning to 11.3 (95% CI, −19.4 to −3.1) for Role limitations due to physical problems. CONCLUSION: Despite effective HCV treatment, HRQoL of HCV‐cured persons with hemophilia is still lower than HRQoL of those never chronically HCV‐infected on all RAND‐36 domains. This implies that careful psychosocial follow‐up and support are indicated

Predictors of and reasons for pacifier use in first-time mothers: an observational study

Background: The use of pacifiers is commonplace in Australia and has been shown to be negatively associated with breastfeeding duration. In order to influence behaviour related to the use of pacifiers it is important to understand the reasons for their use. The primary aim of this observational study was to investigate who (if anyone) advises first-time mothers to give a pacifier and the reasons for which they first give (or try to give) a pacifier to their infant. Additionally, this study investigated the predictors of pacifier use and the relationship between pacifier use and breastfeeding duration. Methods: In total, 670 Australian first-time mothers recruited as part of the NOURISH trial completed a questionnaire regarding infant feeding and pacifier use. Results: Pacifiers were introduced by 79% of mothers, of whom 28.7% were advised to use a pacifier by their mother/mother-in-law with a further 22.7% being advised by a midwife. The majority of mothers used a pacifier in order to soothe their infant (78.3%), to help put them to sleep (57.4%) and to keep them comforted and quiet (40.4%). Pacifiers given to infants before four weeks (adjHR 3.67; 95%CI 2.14–6.28) and used most days (adjHR 3.28; 95%CI 1.92–5.61) were significantly associated with shorter duration of breastfeeding. Conclusions: This study identifies an opportunity for educating new mothers and their support network, particularly their infant’s grandmothers, with regards to potential risks associated with the early and frequent use of a pacifier, and alternative methods for soothing their infant, in order to reduce the use of pacifiers and their potentially negative effect on breastfeeding duratio

Maternal and neonatal bleeding complications in relation to peripartum management in hemophilia carriers:A systematic review

Currently, there is no consensus on the optimal management to prevent postpartum hemorrhage (PPH) in hemophilia carriers. We aimed to evaluate peripartum management strategies in relation to maternal and neonatal bleeding outcomes by performing an extensive database search up to August 2020. Seventeen case-reports/series and 11 cohort studies were identified of overall 'poor' quality describing 502 deliveries. The PPH incidence in the individual patient data was 63%; 44% for those women receiving prophylaxis to correct coagulation and 77% for those without (OR 0.23, CI 0.09-0.58) and in cohort data 20.3% (26.8% (11/41) vs. 19.4% (55/284) (OR: 1.53, 95% CI: 0.72-3.24), respectively. Peripartum management strategies mostly consisted of clotting factor concentrates, rarely of desmopressin or plasma. Tranexamic acid appears promising in preventing secondary PPH, but was not used consistently. Neonatal bleeding was described in 6 affected male neonates, mostly after instrumental delivery or emergency CS, but insufficient information was provided to reliably investigate neonatal outcome in relation to management. The high PPH risk seems apparent, at most mildly attenuated by prophylactic treatment. Prospective cohort studies are needed to determine the optimal perinatal management in hemophilia.Thrombosis and Hemostasi

'Be active, eat right', evaluation of an overweight prevention protocol among 5-year-old children: design of a cluster randomised controlled trial

BACKGROUND: The prevalence of overweight and obesity in children has at least doubled in the past 25 years with a major impact on health. In 2005 a prevention protocol was developed applicable within Youth Health Care. This study aims to assess the effects of this protocol on prevalence of overweight and health behaviour among children. METHODS AND DESIGN: A cluster randomised controlled trial is conducted among 5-year-old children included by 44 Youth Health Care teams randomised within 9 Municipal Health Services. The teams are randomly allocated to the intervention or control group. The teams measure the weight and height of all children. When a child in the intervention group is detected with overweight according to the international age and gender specific cut-off points of BMI, the prevention protocol is applied. According to this protocol parents of overweight children are invited for up to three counselling sessions during which they receive personal advice about a healthy lifestyle, and are motivated for and assisted in behavioural change.The primary outcome measures are Body Mass Index and waist circumference of the children. Parents will complete questionnaires to assess secondary outcome measures: levels of overweight inducing/reducing behaviours (i.e. being physically active, having breakfast, drinking sweet beverages and watching television/playing computer games), parenting styles, parenting practices, and attitudes of parents regarding these behaviours, health-related quality of life of the children, and possible negative side effects of the prevention protocol. Data will be collected at baseline (when the children are aged 5 years), and after 12 and 24 months of follow-up. Additionally, a process and a cost-effectiveness evaluation will be conducted. DISCUSSION: In this study called 'Be active, eat right' we evaluate an overweight prevention protocol for use in the setting of Youth Health Care. It is hypothesized that the use of this protocol will result in a healthier lifestyle of the children and an improved BMI and waist circumference. TRIAL REGISTRATION: Current Controlled Trials ISRCTN04965410