N-terminally modified glucagon-like peptide-1(7-36) amide exhibits resistance to enzymatic degradation while maintaining its antihyperglycaemic activity in vivo

Glucagon-like peptide-1 (7-36)amide (tGLP-1) is inactivated by dipeptidyl peptidase (DPP) IV by removal of the NH2-terminal dipeptide His(7)-Ala(8). We examined the degradation of NH2-terminally modified His(7)-glucitol tGLP-1 and its insulin-releasing and antihyperglycaemic activity in vivo, tGLP-1 was degraded by purified DPP IV after 4 h (43% intact) and after 12 hi 89% was converted to GLP-1(9-36)amide. In contrast > 99% of His(7)-glucitol tGLP-1 remained intact at 12 h. His(7)-glucitol tGLP-1 was similarly resistant to plasma degradation in vitro. His7-glucitol tGLP-1 showed greater resistance to degradation in vivo (92% intact) compared to tGLP-1 (27% intact) 10 min after i.p. administration to Wistar rats. Glucose homeostasis was examined following i.p. injection of both peptides (12 nmol/kg) together with glucose (18 mmol/kg). Plasma glucose concentrations were significantly reduced and insulin concentrations elevated following peptides administration compared with glucose alone. The area under the curve (AUC) for glucose for controls (AUC 691 +/- 35 mM/min) was significantly lower after administration of tGLP-1 and His7-glucitol tGLP-1 (36 and 49% less; AUC; 440 +/- 40 and 353 +/- 31 mM/min, respectively; P

Caesarean section is associated with an increased risk of childhood-onset type 1 diabetes: A meta-analysis of observational studies

Aims/hypothesis: The aim of this study was to investigate the evidence of an increased risk of childhood-onset type 1 diabetes in children born by Caesarean section by systematically reviewing the published literature and performing a meta-analysis with adjustment for recognised confounders.
Methods: After MEDLINE, Web of Science and EMBASE searches, crude ORs and 95% CIs for type 1 diabetes in children born by Caesarean section were calculated from the data reported in each study. Authors were contacted to facilitate adjustments for potential confounders, either by supplying raw data or calculating adjusted estimates. Meta-analysis techniques were then used to derive combined ORs and to investigate heterogeneity between studies.
Results: Twenty studies were identified. Overall, there was a significant increase in the risk of type 1 diabetes in children born by Caesarean section (OR 1.23, 95% CI 1.15-1.32, p<0.001). There was little evidence of heterogeneity between studies (p=0.54). Seventeen authors provided raw data or adjusted estimates to facilitate adjustments for potential confounders. In these studies, there was evidence of an increase in diabetes risk with greater birthweight, shorter gestation and greater maternal age. The increased risk of type 1 diabetes after Caesarean section was little altered after adjustment for gestational age, birth weight, maternal age, birth order, breast-feeding and maternal diabetes (adjusted OR 1.19, 95% CI 1.04-1.36, p=0.01).
Conclusions/interpretation: This analysis demonstrates a 20% increase in the risk of childhood-onset type 1 diabetes after Caesarean section delivery that cannot be explained by known confounders.

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.

A school based study of psychological disturbance in children following the Omagh bomb

Objective
To assess the extent and nature of psychiatric morbidity among children (aged 8 to 13 years) 15 months after a car bomb explosion in the town of Omagh, Northern Ireland.

Method
A survey was conducted of 1945 school children attending 13 schools in the Omagh district. Questionnaires included demographic details, measures of exposure, the Horowitz Impact of Events Scale, the Birleson Self-Rating Depression Scale, and the Spence Children’s Anxiety Scale.

Results
Children directly exposed to the bomb reported higher levels of probable PTSD (70%), and psychological distress than those not exposed. Direct exposure was more closely associated with an increase in PTSD symptoms than in general psychiatric distress. Significant predictors of increased IES scores included being male, witnessing people injured and reporting a perceived life threat but when co-morbid anxiety and depression are included as potential predictors anxiety remains the only significant predictor of PTSD scores.

Conclusions
School-based studies are a potentially valuable means of screening and assessing for PTSD in children after large-scale tragedies. Assessment should consider type of exposure, perceived life threat and other co-morbid anxiety as risk factors for PTSD.

Mode of prostate cancer detection is associated with the psychological wellbeing of survivors: results from the PiCTure study

Purpose: Many men with prostate cancer are asymptomatic, diagnosed following prostate specific antigen (PSA) testing. We investigate whether mode of detection, i.e. ‘PSA detected’ or ‘clinically detected’, was associated with psychological wellbeing among prostate cancer survivors. Methods: A cross-sectional postal questionnaire was administered in 2012 to 6559 prostate cancer (ICD10 C61) survivors up to 18 years post-diagnosis, identified through population-based cancer registries in Ireland. Psychological wellbeing was assessed using the Depression Anxiety Stress Scale-21. Logistic regression was used to investigate associations between mode of detection and depression, anxiety and stress, adjusting for socio-demographic and clinical confounders. Results: The response rate was 54 % (3348/6262). Fifty-nine percent of survivors were diagnosed with asymptomatic PSA-tested disease. Prevalence of depression (13.8 vs 20.7 %; p < 0.001), anxiety (13.6 vs 20.9 %; p < 0.001) and stress (8.7 vs 13.8 %; p < 0.001) were significantly lower among survivors diagnosed with PSA-detected, than clinically detected disease. After adjusting for clinical and socio-demographic factors, survivors with clinically detected disease had significantly higher risk of depression (odds ratio (OR) = 1.46 95 % CI 1.18, 1.80; p = 0.001), anxiety (OR = 1.36 95 % CI 1.09, 1.68; p = 0.006) and stress (OR = 1.43 95 % CI 1.11, 1.85; p = 0.006) than survivors with PSA-detected disease. Conclusions: These findings contribute to the ongoing debate on benefits and risks of PSA testing and may be considered by policy makers formulating population-based prostate cancer screening policies. The relatively high prevalence of negative psychological states among survivors means that a ‘risk-adapted approach’ should be implemented to screen survivors most at risk of psychological morbidity for psychological health, and mode of detection could be considered as a risk stratum.

Isotope Shift in the Dielectronic Recombination of Three-Electron ANd57+

Isotope shifts in dielectronic recombination spectra were studied for Li-like ^ANd⁵⁷⁺ ions with A=142 and A=150. From the displacement of resonance positions energy shifts dE^142?150(2s-2p_1/2)=40.2(3)(6)??meV [(stat)(sys)] and dE^142?150(2s-2p_3/2)=42.3(12)(20)??meV of 2s-2p_jtransitions were deduced. An evaluation of these values within a full QED treatment yields a change in the mean-square charge radius of ^142?150d?r²?=-1.36(1)(3)??fm². The approach is conceptually new and combines the advantage of a simple atomic structure with high sensitivity to nuclear size.

Nature or nurture BMI and blood pressure at 90. Findings from the Belfast Elderly longitudinal free-living aging study Belfast

Hypertension is a key risk factor for stroke, cardiovascular disease and dementia. Although the link between weight, sodium and hypertension is established in younger people, little is known about their inter-relationship in people beyond 80 years of age. Associations between blood pressure, anthropometric indices and sodium were investigated in 495 apparently healthy, community-living participants (age 90, SD 4.8; range 80–106), from the cross-sectional Belfast Elderly Longitudinal Free-living Aging STudy (BELFAST) study. In age-sex-adjusted logistic regression models, blood pressure =140/90 mmHg significantly associated with body mass index (BMI) [odds ratio (OR)?=?1.28/ kg/m2], with weight (OR?=?1.22/kg) approaching significance (P?=?0.07). In further age-sex-adjusted models, blood pressure above the 120/80 mmHg normotensive reference value significantly associated with BMI (OR?=?1.44/kg/m2), weight (OR?=?1.36/kg), skin-fold-thickness (OR?=?1.33/mm) and serum sodium (OR?=?1.37 mmol/l). In BELFAST participants over 80 years old, blood pressure =140/90 mmHg is associated with BMI, in apparently similar ways to younger groups.

A GREM1 gene variant associates with diabetic nephropathy

Gremlin, a cell growth and differentiation factor, promotes the development of diabetic nephropathy in animal models, but whether GREM1 gene variants associate with diabetic nephropathy is unknown. We comprehensively screened the 5' upstream region (including the predicted promoter), all exons, intron-exon boundaries, complete untranslated regions, and the 3' region downstream of the GREM1 gene. We identified 31 unique variants, including 24 with a minor allele frequency exceeding 5%, and 9 haplotype-tagging single nucleotide polymorphisms (htSNPs). We selected one additional variant that we predicted to alter transcription factor binding. We genotyped 709 individuals with type 1 diabetes of whom 267 had nephropathy (cases) and 442 had no evidence of kidney disease (controls). Three individual SNPs significantly associated with nephropathy at the 5% level, and two remained significant after adjustment for multiple testing. Subsequently, we genotyped a replicate population comprising 597 cases and 502 controls: this population supported an association with one of the SNPs (rs1129456; P = 0.0003). Combined analysis, adjusted for recruitment center (n = 8), suggested that the T allele conferred greater odds of nephropathy (OR 1.69; 95% CI 1.36 to 2.11). In summary, the GREM1 variant rs1129456 associates with diabetic nephropathy, perhaps explaining some of the genetic susceptibility to this condition.

Methods to increase response to postal and electronic questionnaires

Background: Postal and electronic questionnaires are widely used for data collection in epidemiological studies but non-response reduces the effective sample size and can introduce bias. Finding ways to increase response to postal and electronic questionnaires would improve the quality of health research. Objectives: To identify effective strategies to increase response to postal and electronic questionnaires. Search strategy: We searched 14 electronic databases to February 2008 and manually searched the reference lists of relevant trials and reviews, and all issues of two journals. We contacted the authors of all trials or reviews to ask about unpublished trials. Where necessary, we also contacted authors to confirm methods of allocation used and to clarify results presented. We assessed the eligibility of each trial using pre-defined criteria. Selection criteria: Randomised controlled trials of methods to increase response to postal or electronic questionnaires. Data collection and analysis: We extracted data on the trial participants, the intervention, the number randomised to intervention and comparison groups and allocation concealment. For each strategy, we estimated pooled odds ratios (OR) and 95% confidence intervals (CI) in a random-effects model. We assessed evidence for selection bias using Egger's weighted regression method and Begg's rank correlation test and funnel plot. We assessed heterogeneity among trial odds ratios using a Chi 2 test and the degree of inconsistency between trial results was quantified using the I 2 statistic. Main results: Postal We found 481 eligible trials.The trials evaluated 110 different ways of increasing response to postal questionnaires.We found substantial heterogeneity among trial results in half of the strategies. The odds of response were at least doubled using monetary incentives (odds ratio 1.87; 95% CI 1.73 to 2.04; heterogeneity P < 0.00001, I 2 = 84%), recorded delivery (1.76; 95% CI 1.43 to 2.18; P = 0.0001, I 2 = 71%), a teaser on the envelope - e.g. a comment suggesting to participants that they may benefit if they open it (3.08; 95% CI 1.27 to 7.44) and a more interesting questionnaire topic (2.00; 95% CI 1.32 to 3.04; P = 0.06, I 2 = 80%). The odds of response were substantially higher with pre-notification (1.45; 95% CI 1.29 to 1.63; P < 0.00001, I 2 = 89%), follow-up contact (1.35; 95% CI 1.18 to 1.55; P < 0.00001, I 2 = 76%), unconditional incentives (1.61; 1.36 to 1.89; P < 0.00001, I 2 = 88%), shorter questionnaires (1.64; 95%CI 1.43 to 1.87; P < 0.00001, I 2 = 91%), providing a second copy of the questionnaire at follow up (1.46; 95% CI 1.13 to 1.90; P < 0.00001, I 2 = 82%), mentioning an obligation to respond (1.61; 95% CI 1.16 to 2.22; P = 0.98, I 2 = 0%) and university sponsorship (1.32; 95% CI 1.13 to 1.54; P < 0.00001, I 2 = 83%). The odds of response were also increased with non-monetary incentives (1.15; 95% CI 1.08 to 1.22; P < 0.00001, I 2 = 79%), personalised questionnaires (1.14; 95% CI 1.07 to 1.22; P < 0.00001, I 2 = 63%), use of hand-written addresses (1.25; 95% CI 1.08 to 1.45; P = 0.32, I 2 = 14%), use of stamped return envelopes as opposed to franked return envelopes (1.24; 95% CI 1.14 to 1.35; P < 0.00001, I 2 = 69%), an assurance of confidentiality (1.33; 95% CI 1.24 to 1.42) and first class outward mailing (1.11; 95% CI 1.02 to 1.21; P = 0.78, I 2 = 0%). The odds of response were reduced when the questionnaire included questions of a sensitive nature (0.94; 95% CI 0.88 to 1.00; P = 0.51, I 2 = 0%). Electronic: We found 32 eligible trials. The trials evaluated 27 different ways of increasing response to electronic questionnaires. We found substantial heterogeneity among trial results in half of the strategies. The odds of response were increased by more than a half using non-monetary incentives (1.72; 95% CI 1.09 to 2.72; heterogeneity P < 0.00001, I 2 = 95%), shorter e-questionnaires (1.73; 1.40 to 2.13; P = 0.08, I 2 = 68%), including a statement that others had responded (1.52; 95% CI 1.36 to 1.70), and a more interesting topic (1.85; 95% CI 1.52 to 2.26). The odds of response increased by a third using a lottery with immediate notification of results (1.37; 95% CI 1.13 to 1.65), an offer of survey results (1.36; 95% CI 1.15 to 1.61), and using a white background (1.31; 95% CI 1.10 to 1.56). The odds of response were also increased with personalised e-questionnaires (1.24; 95% CI 1.17 to 1.32; P = 0.07, I 2 = 41%), using a simple header (1.23; 95% CI 1.03 to 1.48), using textual representation of response categories (1.19; 95% CI 1.05 to 1.36), and giving a deadline (1.18; 95% CI 1.03 to 1.34). The odds of response tripled when a picture was included in an e-mail (3.05; 95% CI 1.84 to 5.06; P = 0.27, I 2 = 19%). The odds of response were reduced when "Survey" was mentioned in the e-mail subject line (0.81; 95% CI 0.67 to 0.97; P = 0.33, I 2 = 0%), and when the e-mail included a male signature (0.55; 95% CI 0.38 to 0.80; P = 0.96, I 2 = 0%). Authors' conclusions: Health researchers using postal and electronic questionnaires can increase response using the strategies shown to be effective in this systematic review. Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.


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Fluorobenzoyl dipeptidyl derivatives as inhibitors of the Fasciola hepatica cysteine protease cathepsin L1

Cathepsins are known to have many important physiological roles and provide a viable target for inhibition. Fluorobenzoyl dipeptide derivatives were synthesized and tested for biological activity in an effort to find an efficient inhibitor of the cysteine protease cathepsin L. Thirty-six novel inhibitors (1-36) were synthesized from protected amino acids via the standard DCC/HOBt coupling protocol, containing a benzyl ester or a nitrile as an electrophilic warhead. The activity of the inhibitors was evaluated against cathepsin L and IC50 values calculated. Modification of both amino acids and terminal groups afforded compounds with single digit micromolar inhibition. Results utilizing the benzoyl-L-leucine-glycine nitrile backbone are comparable to that for the commercially available inhibitor 39.

Lipoprotein composition in HNF1A-MODY: Differentiating between HNF1A-MODY and Type 2 diabetes.

INTRODUCTION:

The young-onset diabetes seen in HNF1A-MODY is often misdiagnosed as Type 2 diabetes. Type 2 diabetes, unlike HNF1A-MODY, is associated with insulin resistance and a characteristic dyslipidaemia. We aimed to compare the lipid profiles in HNF1A-MODY, Type 2 diabetes and control subjects and to determine if lipids can be used to aid the differential diagnosis of diabetes sub-type.
METHODS:

1) 14 subjects in each group (HNF1A-MODY, Type 2 diabetes and controls) were matched for gender and BMI. Fasting lipid profiles and HDL lipid constituents were compared in the 3 groups. 2) HDL-cholesterol was assessed in a further 267 patients with HNF1A-MODY and 297 patients with a diagnosis of Type 2 diabetes to determine its discriminative value.

RESULTS:

1) In HNF1A-MODY subjects, plasma-triglycerides were lower (1.36 vs. 1.93 mmol/l, p = 0.07) and plasma-HDL-cholesterol was higher than in subjects with Type 2 diabetes (1.47 vs. 1.15 mmol/l, p = 0.0008), but was similar to controls. Furthermore, in the isolated HDL; HDL-phospholipid and HDL-cholesterol ester content were higher in HNF1A-MODY, than in Type 2 diabetes (1.59 vs. 1.33 mmol/L, p = 0.04 and 1.10 vs. 0.83 mmol/L, p = 0.019, respectively), but were similar to controls (1.59 vs. 1.45 mmol/L, p = 0.35 and 1.10 vs. 1.21 mmol/L, p = 0.19, respectively). 2) A plasma-HDL-cholesterol > 1.12 mmol/L was 75% sensitive and 64% specific (ROC AUC = 0.76) at discriminating HNF1A-MODY from Type 2 diabetes.

CONCLUSION:

The plasma-lipid profiles of HNF1A-MODY and the lipid constituents of HDL are similar to non-diabetic controls. However, HDL-cholesterol was higher in HNF1A-MODY than in Type 2 diabetes and could be used as a biomarker to aid in the identification of patients with HNF1A-MODY.