The Influence of Salivary Statherin, Histatin-1 and Their 21 N-terminal Peptides Individually and When in Combination on the Demineralisation of Hydroxyapatite and Enamel. The Effect of Peptides Adsorption, Aggregation, Surface Charge and Secondary Structure

PhDSalivary proteins such as statherin (STN) are known to be involved in enamel de/remineralisation, the inhibition of crystal growth, and spontaneous precipitation of calcium phosphate salts. The active N-terminal of STN (STN21) is involved in binding with Ca2+ and in reducing HA demineralisation. In addition, salivary Histatin-1 (HTN) inhibits crystal growth of calcium phosphate salts but does not inhibit their spontaneous precipitation. These salivary peptides do not occur as individual molecules in saliva, they are part of a complex salivary system. The aims were to investigate the effect of salivary STN, HTN and their 21 N-terminal peptides (STN21, and HTN21) individually and when in combination on the demineralisation rates of HA and enamel using scanning microradiography. In addition, to understand their effect on HA and enamel demineralisation, peptide adsorption onto HA and enamel was measured spectrophotometrically. Also, peptide aggregation, surface charge and, conformation in solution were investigated. The adsorption and demineralisation reduction of non-human STN was also investigated. STN, HTN and STN21 individually showed similar adsorption and demineralisation reduction efficacy in HA but not in enamel. HTN21 showed the lowest demineralisation reduction of all peptides. STN21 when in combination with either HTN, or HTN21, showed the greatest demineralisation reduction of all peptides.The increase in peptides demineralisation reduction efficacy when in combination suggests co-operative efficacy, which is further increased with the removal of the C-terminal. All individual peptides were found to adopt an α-helical conformation at the N-terminal, which is important in peptide adsorption onto HA surfaces. When in combination conformational changes led to peptide interaction and caused an increase in their net negative charges. In conclusion, it was found that the degree to which demineralisation is reduced by peptides is correlated with the amount of peptide adsorbed

Rhabdomyolysis reported for children and adolescents treated with antipsychotic medicines: a case series analysis

published_or_final_versio

Rhabdomyolysis reported for children and adolescents treated with antipsychotic medicines: a case series analysis

published_or_final_versio

Associations between the LEP -2548G/A Promoter and Baseline Weight and between LEPR Gln223Arg and Lys656Asn Variants and Change in BMI z Scores in Arab Children and Adolescents Treated with Risperidone

Data on baseline (antipsychotic-naïve) age, weight, and height and change in these over three subsequent follow up time points up to 313.6 days (CI 303.5-323.7), were collected from 181 risperidone-treated children and adolescents (mean age 12.58 years, SD 4.99, range 2.17-17.7) attending a pediatric neurology clinic in Saudi Arabia. Owing to differences in genotypic distributions in subsamples, results are reported from the white Arabs (N=144). Age and gender-normed BMI-standardised z scores (BMI z) were calculated (lmsgrowth program). Linear regression was performed for baseline weight and BMI z, while change in BMI z was assessed using random effects ordered logistic regression. The following SNPs were analyzed: rs7799039 in the LEP promoter, rs1805094 (previously rs8179183), rs1137100 and rs1137101 in the LEPR, and rs1414334 in HTR2C. We found a nominally significant association between rs7799309 and baseline weight, adjusting for height, age, gender and diagnosis (A/G, P=0.035, β=-3.62, compared to G/G). rs1137101 (G/G, P=0.018, OR=4.13 compared to A/A) and rs1805094 C-allele carriers (P=0.019, OR=0.51) showed nominally significant associations with change in BMI z categories. Our data support and replicate previous relevant associations for these variants including with weight gain on risperidone, whilst being the first to report such associations in those of Arab ethnicity

Factors Influencing Weight Gain in Young People Treated with Antipsychotics

Atypical antipsychotic treatment in both children and adults carries significant risk for excessive weight gain that varies widely across individuals. This variation suggests genetic and/or environmental factors are involved in antipsychotic-induced weight gain. This thesis aimed to: 1) provide a systematic review and meta-analysis of the effects of atypical antipsychotics in children and adolescents on weight gain; 2) genotype three specific genes (HTR2C receptors, LEP and LEPR) which are thought to be likely candidates for association between risperidone and weight gain in young people; 3) assess the association between the genotypes of each gene and weight gain. A genetic study was conducted in outpatient mental health clinics/hospitals in the UK and the Kingdom of Saudi Arabia. In this study we investigated the association of 5 single nucleotide polymorphisms (SNPs) with weight gain in a cohort composed of 200 children and adolescents undergoing first treatment with the antipsychotic risperidone over 36 weeks. Of the 200 patients, DNA samples were successfully collected from 197 patients. For all genes we found no significant association with risperidone–induced weight gain after controlling for baseline weight, age, gender, diagnosis and ethnicity. A significant association was found between baseline body mass index (BMI)-standardised z scores (BMIz) and age at the onset of risperidone treatment and weight gain, patients with a lower baseline BMI gained more weight, (p<0.001), and younger patients tended to gain more weight (p<0.001) for all 5 SNPs tested. There was a significant association between weight gain and ethnicity, with individuals of Arab origin being more likely to gain weight than young British for all SNPs. No association between weight gain and gender was found. In this sample no significant association between risperidone-induced weight gain and any of the genotypes tested was found. The novel aspects of this study are the ethnicity of the sample and the age group. Future directions will include genotyping of other relevant variants, such as in MC4R and FTO. The goal of such work includes identifying segments of patient groups for appropriate targeted clinical interventions