Amino-terminal dimerization of an erythropoietin mimetic peptide results in increased erythropoietic activity

AbstractBackground: Erythropoietin (EPO), the hormone involved in red blood cell production, activates its receptor by binding to the receptor's extracellular domain and presumably dimerizing two receptor monomers to initiate signal transduction. EPO-mimetic peptides, such as EMP1, also bind and activate the receptor by dimerization. These mimetic peptides are not as potent as EPO, however. The crystal structure of the EPO receptor (EBP) bound to EMP1 reveals the formation of a complex consisting of two peptides bound to two receptors, so we sought to improve the biological activity of EPO-mimetic peptides by constructing covalent dimers of EMP1 and other peptide mimetics linked by polyethylene glycol (PEG).Results: The potency of the PEG-dimerized EPO peptide mimetics both in vitro and in vivo was improved up to 1,000-fold compared to the corresponding peptide monomers. The dinners were constructed using peptide monomers which have only one reactive amine per molecule, allowing us to conclude that the increase in potency can be attributed to a structure in which two peptides are linked through their respective amino termini to the difunctional PEG molecule. In addition, an inactive peptide was converted into a weak agonist by PEG-induced dimerization.Conclusions: The potency of previously isolated peptides that are modest agonists of the EPO receptor was dramatically increased by PEG-induced dimerization. The EPO receptor is thought to be dimerized during activation, so our results are consistent with the proposed 2:2 receptor : peptide stoichiometry. The conversion of an inactive peptide into an agonist further supports the idea that dimerization can mediate receptor activation

Prevalence and Determinants of Vitamin D Deficiency in 1825 Cape Town Primary Schoolchildren: A Cross-Sectional Study

Vitamin D deficiency (25-hydroxyvitamin D[25(OH)D] <50 nmol/L) is common among adults in Cape Town, South Africa, but studies investigating vitamin D status of children in this setting are lacking. We conducted a cross-sectional study to determine the prevalence and determinants of vitamin D deficiency in 1825 Cape Town schoolchildren aged 6–11 years. Prevalence of vitamin D deficiency was 7.6% (95% Confidence Interval [CI] 6.5% to 8.9%). Determinants of vitamin D deficiency included month of sampling (adjusted odds ratio [aOR] for July–September vs. January–March 10.69, 95% CI 5.02 to 22.77; aOR for October–December vs. January–March 6.73, 95% CI 2.82 to 16.08), older age (aOR 1.25 per increasing year, 95% CI: 1.01–1.53) and higher body mass index (BMI; aOR 1.24 per unit increase in BMI-for-age Z-score, 95% CI: 1.03–1.49). In a subset of 370 participants in whom parathyroid hormone (PTH) concentrations were measured; these were inversely related to serum 25(OH)D concentrations (p < 0.001). However, no association between participants with hyperparathyroidism (PTH >6.9 pmol/L) and vitamin D deficiency was seen (p = 0.42). In conclusion, we report that season is the major determinant of vitamin D status among Cape Town primary schoolchildren, with prevalence of vitamin D deficiency ranging from 1.4% in January–March to 22.8% in July–September

A systematic review of the effectiveness and cost-effectiveness of peer education and peer support in prisons.

BACKGROUND: Prisoners experience significantly worse health than the general population. This review examines the effectiveness and cost-effectiveness of peer interventions in prison settings. METHODS: A mixed methods systematic review of effectiveness and cost-effectiveness studies, including qualitative and quantitative synthesis was conducted. In addition to grey literature identified and searches of websites, nineteen electronic databases were searched from 1985 to 2012. Study selection criteria were: Population: Prisoners resident in adult prisons and children resident in Young Offender Institutions (YOIs). INTERVENTION: Peer-based interventions Comparators: Review questions 3 and 4 compared peer and professionally led approaches. OUTCOMES: Prisoner health or determinants of health; organisational/ process outcomes; views of prison populations. STUDY DESIGNS: Quantitative, qualitative and mixed method evaluations. RESULTS: Fifty-seven studies were included in the effectiveness review and one study in the cost-effectiveness review; most were of poor methodological quality. Evidence suggested that peer education interventions are effective at reducing risky behaviours, and that peer support services are acceptable within the prison environment and have a positive effect on recipients, practically or emotionally. Consistent evidence from many, predominantly qualitative, studies, suggested that being a peer deliverer was associated with positive effects. There was little evidence on cost-effectiveness of peer-based interventions. CONCLUSIONS: There is consistent evidence from a large number of studies that being a peer worker is associated with positive health; peer support services are also an acceptable source of help within the prison environment and can have a positive effect on recipients. Research into cost-effectiveness is sparse. SYSTEMATIC REVIEW REGISTRATION: PROSPERO ref: CRD42012002349

Influence of vitamin D supplementation on bone mineral content, bone turnover markers and fracture risk in South African schoolchildren: Multicentre double-blind randomised placebo-controlled trial (ViDiKids)

Randomised controlled trials (RCT) to determine the influence of vitamin D on bone mineral content (BMC) and fracture risk in children of Black African ancestry are lacking. We conducted a sub-study (n=450) nested within a Phase 3 RCT of weekly oral supplementation with 10,000 IU vitamin D3 vs. placebo for 3 years in HIV- uninfected Cape Town schoolchildren aged 6-11 years. Outcomes were BMC at the whole body less head (WBLH) and lumbar spine (LS) and serum 25-hydroxyvitamin D3 (25[OH]D3), parathyroid hormone (PTH), alkaline phosphatase, C-terminal telopeptide and procollagen type 1 N propeptide. Incidence of fractures was a secondary outcome of the main trial (n=1682). At baseline, mean serum 25(OH)D3 concentration was 70.0 nmol/L (s.d. 13.5), and 5.8% of participants had serum 25(OH)D3 concentrations <50 nmol/L. Among sub-study participants, end-trial serum 25(OH)D3 concentrations were higher for participants allocated to vitamin D vs. placebo (adjusted mean difference [aMD] 39.9 nmol/L, 95% CI 36.1 to 43.6) and serum PTH concentrations were lower (aMD -0.55 pmol/L, 95% CI -0.94 to -0.17). However, no interarm differences were seen for WBLH BMC (aMD -8.0 g, 95% CI - 30.7 to 14.7) or LS BMC (aMD -0.3 g, 95% CI -1.3 to 0.8) or serum concentrations of bone turnover markers. Fractures were rare among participants in the main trial randomised to vitamin D vs. placebo (7/755 vs. 10/758 attending at least one follow- up; adjusted odds ratio 0.70, 95% CI 0.27 to 1.85). In conclusion, a 3-year course of weekly oral vitamin D supplementation elevated serum 25(OH)D3 concentrations and suppressed serum PTH concentrations in HIV-uninfected South African schoolchildren of Black African ancestry but did not influence BMC or serum concentrations of bone turnover markers. Fracture incidence was low, limiting power to detect an effect of vitamin D on this outcome

Influence of vitamin D supplementation on growth, body composition, pubertal development and spirometry in South African schoolchildren: A randomised controlled trial (ViDiKids)

Objective: To determine whether weekly oral vitamin D supplementation influences growth, body composition, pubertal development or spirometric outcomes in South African schoolchildren.   Design: Phase 3 double-blind randomised placebo-controlled trial.   Setting: Socioeconomically disadvantaged peri-urban district of Cape Town, South Africa.   Participants: 1682 children of black African ancestry attending government primary schools and aged 6-11 years at baseline.   Interventions: Oral vitamin D 3 (10 000 IU/week) versus placebo for 3 years.   Main outcome measures: Height-for-age and body mass index-for-age, measured in all participants; Tanner scores for pubertal development, spirometric lung volumes and body composition, measured in a subset of 450 children who additionally took part in a nested substudy.   Results: Mean serum 25-hydroxyvitamin D 3 concentration at 3-year follow-up was higher among children randomised to receive vitamin D versus placebo (104.3 vs 64.7 nmol/L, respectively; mean difference (MD) 39.7 nmol/L, 95% CI 37.6 to 41.9 nmol/L). No statistically significant differences in height-for-age z-score (adjusted MD (aMD) -0.08, 95% CI -0.19 to 0.03) or body mass index-for-age z-score (aMD -0.04, 95% CI -0.16 to 0.07) were seen between vitamin D versus placebo groups at follow-up. Among substudy participants, allocation to vitamin D versus placebo did not influence pubertal development scores, % predicted forced expiratory volume in 1 s (FEV1), % predicted forced vital capacity (FVC), % predicted FEV1/FVC, fat mass or fat-free mass.   Conclusions: Weekly oral administration of 10 000 IU vitamin D 3 boosted vitamin D status but did not influence growth, body composition, pubertal development or spirometric outcomes in South African schoolchildren. Trial registration numbers ClinicalTrials.gov NCT02880982, South African National Clinical Trials Register DOH-27-0916-5527

Vitamin D supplementation to prevent tuberculosis infection in South African schoolchildren: multicentre phase 3 double-blind randomised placebo-controlled trial (ViDiKids)

BACKGROUND: Relationships between vitamin D status, parathyroid hormone (PTH), bone mineral content (BMC) and fracture risk differ between children of White European vs. Black African ancestry. However, randomised controlled trials (RCT) to determine the influence of vitamin D supplements on BMC and fracture risk in African children are lacking.   METHODS: We conducted a sub-study nested within a Phase 3 RCT of weekly oral supplementation with 10,000 IU vitamin D3 in Cape Town schoolchildren aged 6-11 years. Sub-study outcomes were BMC at the whole body minus head and lumbar spine sites, determined by dual-energy x-ray absorptiometry (DXA), serum concentrations of 25-hydroxyvitamin D3 (25[OH]D3), PTH, alkaline phosphatase (ALP), C-terminal telopeptide (CTX) and procollagen type 1 N propeptide (P1NP). Incidence of fractures was a secondary outcome of the main trial.   FINDINGS: 1682 children of Black African ancestry attending 23 schools were enrolled in the main trial (829 vs. 853 randomised to vitamin D vs. placebo, respectively) of whom 450 also participated in the nested sub-study (228 vs. 222 randomised to vitamin D vs. placebo, respectively). In the sub-study population, end-trial serum concentrations of 25(OH)D3 were higher for participants allocated to vitamin D vs. placebo (adjusted mean difference [aMD] 39.9 nmol/L, 95% CI 36.1 to 43.6 nmol/L, P<0.001) and serum PTH concentrations were lower (aMD -0.55 pmol/L, 95% CI -0.94 to -0.17, P=0.005). However, no interarm differences were seen for BMC at the whole body minus head (aMD -8.0 g, 95% CI -30.7 to 14.7) or the lumbar spine (aMD -0.3 g, 95% CI -1.3 to 0.8), or for serum concentrations of alkaline phosphatase, CTX or P1NP (P≥0.28). In the main trial population, allocation to vitamin D vs. placebo did not influence the proportion of participants reporting one or more fractures (adjusted odds ratio 0.70, 95% CI 0.27 to 1.85, P=0.48).   INTERPRETATION: Weekly oral supplementation with 10,000 IU vitamin D3 for 3 years elevated serum 25(OH)D3 concentrations and suppressed serum PTH concentrations among Cape Town schoolchildren of Black African ancestry but did not influence BMC, serum concentrations of bone turnover markers or fracture risk

Prevalence, incidence and determinants of quantiferon-positivity in South African schoolchildren

Background: Tuberculosis (TB) control requires the understanding and disruption of TB transmission. We describe prevalence, incidence and risk factors associated with childhood TB infection in Cape Town. Methods: We report cross-sectional baseline and prospective incidence data from a large trial among primary school children living in high TB-burden communities. Prevalent infection was defined as QuantiFERON-TB Gold Plus (QFT-Plus) positivity as assessed at baseline. Subsequent conversion to QFT-Plus positivity was measured 3 years later among those QFT-Plus-negative at baseline. Multivariable logistic regression models examined factors associated with TB infection. Results: QuantiFERON-positivity at baseline (prevalence: 22.6%, 95% Confidence Interval [CI]: 20.9 – 24.4), was independently associated with increasing age (adjusted odds ratio [aOR] 1.24 per additional year, 95% CI: 1.15 – 1.34) and household exposure to TB during the participant’s lifetime (aOR 1.87, 95% CI: 1.46 – 2.40). QFT-Plus conversion at year 3 (12.2%, 95% CI: 10.5-14.0; annual infection rate: 3.95%) was associated with household exposure to an index TB case (aOR 2.74, 95% CI: 1.05 to 7.18). Conclusion: Rates of QFT-diagnosed TB infection remain high in this population. The strong association with household TB exposure reinforces the importance of contact tracing, preventative treatment and early treatment of infectious disease to reduce community transmission

Influence of vitamin D supplementation on growth, body composition, pubertal development and spirometry in South African schoolchildren: a randomised controlled trial (ViDiKids)

Objective: to determine whether weekly oral vitamin D supplementation influences growth, body composition, pubertal development or spirometric outcomes in South African schoolchildren.Design: phase 3 double-blind randomised placebo-controlled trial.Setting: socioeconomically disadvantaged peri-urban district of Cape Town, South Africa.Participants: 1682 children of black African ancestry attending government primary schools and aged 6–11 years at baseline.Interventions: oral vitamin D3 (10 000 IU/week) versus placebo for 3 years.Main outcome measures: height-for-age and body mass index-for-age, measured in all participants; Tanner scores for pubertal development, spirometric lung volumes and body composition, measured in a subset of 450 children who additionally took part in a nested substudy.Results: mean serum 25-hydroxyvitamin D3 concentration at 3-year follow-up was higher among children randomised to receive vitamin D versus placebo (104.3 vs 64.7 nmol/L, respectively; mean difference (MD) 39.7 nmol/L, 95% CI 37.6 to 41.9 nmol/L). No statistically significant differences in height-for-age z-score (adjusted MD (aMD) −0.08, 95% CI −0.19 to 0.03) or body mass index-for-age z-score (aMD −0.04, 95% CI −0.16 to 0.07) were seen between vitamin D versus placebo groups at follow-up. Among substudy participants, allocation to vitamin D versus placebo did not influence pubertal development scores, % predicted forced expiratory volume in 1 s (FEV1), % predicted forced vital capacity (FVC), % predicted FEV1/FVC, fat mass or fat-free mass.Conclusions: weekly oral administration of 10 000 IU vitamin D3 boosted vitamin D status but did not influence growth, body composition, pubertal development or spirometric outcomes in South African schoolchildren.Trial registration numbers: ClinicalTrials.gov NCT02880982, South African National Clinical Trials Register DOH-27-0916-5527