Bisphosphonates alter trabecular bone collagen cross-linking and isomerization in beagle dog vertebra

Changes in organic matrix may contribute to the anti-fracture efficacy of anti-remodeling agents. Following one year of treatment in beagle dogs, bisphosphonates alter the organic matrix of vertebral trabecular bone, while raloxifene had no effect. These results show that pharmacological suppression of turnover alters the organic matrix component of bone. INTRODUCTION: The collagen matrix contributes significantly to a bone's fracture resistance yet the effects of anti-remodeling agents on collagen properties are unclear. The goal of this study was to assess changes in collagen cross-linking and isomerization following anti-remodeling treatment. METHODS: Skeletally mature female beagles were treated for one year with oral doses of vehicle (VEH), risedronate (RIS; 3 doses), alendronate (ALN; 3 doses), or raloxifene (RAL; 2 doses). The middle dose of RIS and ALN and the lower dose of RAL approximate doses used for treatment of post menopausal osteoporosis. Vertebral trabecular bone matrix was assessed for collagen isomerization (ratio of alpha/beta C-telopeptide [CTX]), enzymatic (pyridinoline [PYD] and deoxypyridinoline [DPD]), and non-enzymatic (pentosidine [PEN]) cross-links. RESULTS: All doses of both RIS and ALN increased PEN (+34-58%) and the ratio of PYD/DPD (+14-26%), and decreased the ratio of alpha/beta CTX (-29-56%) compared to VEH. RAL did not alter any collagen parameters. Bone turnover rate was significantly correlated to PEN (R = -0.664), alpha/beta CTX (R = 0.586), and PYD/DPD (R = -0.470). CONCLUSIONS: Bisphosphonate treatment significantly alters properties of bone collagen suggesting a contribution of the organic matrix to the anti-fracture efficacy of this drug class.The authors thank Dr. Keith Condon, Diana Jacob, Mary Hooser, and Lauren Waugh for histological preparation. This work was supported by NIH Grants AR047838 and AR007581 and research grants from The Alliance for Better Bone Health (Procter & Gamble Pharmaceuticals and sanofi-aventis), and Lilly Research Laboratories, as well as an unrestricted grant from Eli Lilly to INSERM. Merck and Co. kindly provided the alendronate. This investigation utilized an animal facility constructed with support from Research Facilities Improvement Program Grant Number C06 RR10601-01 from the National Center for Research Resources, National Institutes of Health

Harmonic Superspaces in Low Dimensions

Harmonic superspaces for spacetimes of dimension $d\leq 3$ are constructed. Some applications are given.Comment: 16, kcl-th-94-15. Two further references have been added (12 and 13) and a few typographical errors have been correcte

Excessive collagen turnover products are released during colorectal cancer progression and elevated in serum from metastatic colorectal cancer patients

During cancer progression, the homeostasis of the extracellular matrix becomes imbalanced with an excessive collagen remodeling by matrix metalloproteinases. As a consequence, small protein fragments of degraded collagens are released into the circulation. We have investigated the potential of protein fragments of collagen type I, III and IV as novel biomarkers for colorectal cancer. Specific fragments of degraded type I, III and IV collagen (C1M, C3M, C4M) and type III collagen formation (Pro-C3) were assessed in serum from colorectal cancer patients, subjects with adenomas and matched healthy controls using well-characterized and validated ELISAs. Serum levels of the biomarkers were significantly elevated in colorectal cancer patients compared to subjects with adenomas (C1M, Pro-C3, C3M) and controls (C1M, Pro-C3). When patients were stratified according to their tumour stage, all four biomarkers were able to differentiate stage IV metastatic patients from all other stages. Combination of all markers with age and gender in a logistic regression model discriminated between metastatic and non-metastatic patients with an AUROC of 0.80. The data suggest that the levels of these collagen remodeling biomarkers may be a measure of tumour activity and invasiveness and may provide new clinical tools for monitoring of patients with advanced stage colorectal cancer

Dietary influence on systolic and diastolic blood pressure in the TwinsUK cohort

Nutrition plays a key role in blood pressure (BP) regulation. Here, we examine associations between nutrient intakes and BP in a large predominantly female population-based cohort. We assessed the correlation between 45 nutrients (from food frequency questionnaires) and systolic BP/diastolic BP (SBP/DBP) in 3889 individuals from TwinsUK not on hypertensive treatments and replicated in an independent subset of monozygotic twins discordant for nutrient intake (17–242 pairs). Results from both analyses were meta-analysed. For significant nutrients, we calculated heritability using structural equation modelling. We identified and replicated 15 nutrients associated with SBP, 9 also being associated with DBP, adjusting for covariates and multiple testing. 14 of those had a heritable component (h2: 27.1–57.6%). Strong associations with SBP were observed for riboflavin (Beta(SE) = −1.49(0.38), P = 1.00 × 10−4) and tryptophan (−0.31(0.01), P = 5 × 10−4), while with DBP for alcohol (0.05(0.07), P = 1.00 × 10−4) and lactose (−0.05(0.0), P = 1.3 × 10−3). Two multivariable nutrient scores, combining independently SBP/DBP-associated nutrients, explained 22% of the variance in SBP and 13.6% of the variance in DBP. Moreover, bivariate heritability analysis suggested that nutrients and BP share some genetic influences. We confirm current understanding and extend the panel of dietary nutrients implicated in BP regulation underscoring the value of nutrient focused dietary research in preventing and managing hypertension

The community paediatric respiratory infection surveillance study protocol:a feasibility, prospective inception cohort study

INTRODUCTION: Paediatric respiratory tract infections (RTIs) are common reasons for primary care consultations and antibiotic prescribing. Locally relevant syndromic and microbiological surveillance information has the potential to improve the care of children with RTIs by normalising illness (parents) and reducing uncertainty (clinicians). Currently, most RTI studies are conducted at the point of healthcare service consultation, leaving the community burden, microbiology, symptom duration and proportion consulting largely unknown. This study seeks to establish the feasibility of (mainly online) participant recruitment and retention, and the acceptability/comparability of parent versus nurse-collected microbiological sampling, to inform the design of a future surveillance intervention study. Evidence regarding consultation rates and symptom duration is also sought. METHODS AND ANALYSIS: A community-based, feasibility prospective inception cohort study, recruiting children aged ≥3 months and <16 years and their parents via general practitioner surgery invitation letter, aiming to collect data on 300 incident RTIs by July 2016. Following informed consent, parents provide baseline (demographic) data online, and respond to weekly emails to confirm the absence/presence of new RTI symptoms. Once symptomatic, parents provide daily data online (RTI symptoms, school/day-care attendance, time off work, health service use, medication), and a research nurse visits to collect clinical examination data and microbiological (nasal and saliva) swabs. Parents are invited to provide symptomatic (at nurse visit, but without nurse assistance) and asymptomatic (alone) swabs on recovery. A review of primary care medical notes will gather medical history, health service utilisation, referral and antibiotic prescribing rates. Feasibility will be assessed using recruitment and retention rates, data completeness; and acceptability by quantitative survey and qualitative interviews. Symptomatic parent and nurse swab pairs will be compared for microbe isolation

Reconstructing ‘the Alcoholic’: Recovering from Alcohol Addiction and the Stigma this Entails

Public perception of alcohol addiction is frequently negative, whilst an important part of recovery is the construction of a positive sense of self. In order to explore how this might be achieved, we investigated how those who self-identify as in recovery from alcohol problems view themselves and their difficulties with alcohol and how they make sense of others’ responses to their addiction. Semi-structured interviews with six individuals who had been in recovery between 5 and 35 years and in contact with Alcoholics Anonymous were analysed using Interpretative Phenomenological Analysis. The participants were acutely aware of stigmatising images of ‘alcoholics’ and described having struggled with a considerable dilemma in accepting this identity themselves. However, to some extent they were able to resist stigma by conceiving of an ‘aware alcoholic self’ which was divorced from their previously unaware self and formed the basis for a new more knowing and valued identity

Protonation Isomers of Highly Charged Protein Ions Can Be Separated in FAIMS-MS

High-field asymmetric waveform ion mobility spectrometry-mass spectrometry (FAIMS-MS) can resolve over an order of magnitude more conformers for a given protein ion than alternative methods. Such an expansion in separation space results, in part, from protein ions with masses of \u3e29 kDa undergoing dipole alignment in the high electric field of FAIMS, and the resolution of ions that adopt pendular vs free rotor states. In this study, FAIMS-MS, collision-induced dissociation (CID), and travelling wave (TW) IMS-MS were used to investigate the pendular and free rotor states of protonated carbonic anhydrase II (CAII, 29 kDa). The electrospray ionization additive 1,2-butylene carbonate was used to increase protein charge states and ensure extended ion conformations were formed. For relatively high charge states in which dipole alignment occurs (30e38þ), FAIMS-MS can baseline resolve the isobaric pendular and free rotor ion populations. For TWIMS-MS, these same charge states resulted in monomodal arrival time distributions with collision cross sections corresponding to highly extended ion conformations. Interestingly, CID of FAIMS-selected pendular and free rotor ion populations resulted in significantly different frag-mentation patterns. For example, CID of the dipole aligned CAII 37þ resulted in cleavages C-terminal to residue 183, 192 and 196, whereas cleavage sites for the free rotor population occurred near residues 12 and 238. Given that the cleavage sites are ’directed’ by protonation sites in the CID of protein ions, and highly charged protein ions adopt extended conformations with the same or very similar collision cross sections, these results indicate that the pendular and free rotor populations separated in FAIMS can be attributed to protonation isomers. Moreover, the extent of protein ion charging in FAIMS-MS decreased substantially as the carrier gas flow rate decreased, indicating that ion charging in FAIMS-MS can be limited by proton-transfer reactions. Given that the total mass of proton charge carriers corresponds to less than 0.2% the mass of CAII, we anticipate that FAIMS-MS can be used to separate intact isobaric proteoforms with masses of at least ~29 kDa that result from alternative sites of post-translational modifications

Assessment of suspended sediment export and dynamics using in‐line turbidity sensors and time series statistical models

The Coln is an ecologically sensitive river in a limestone dominated catchment with no major tributaries. Three in-line turbidity sensors were installed to monitor changes in the dynamics of suspended sediment transport from headwaters to the confluence. The aims were to (i) provide estimates of yield (t km−2 year−1) and likely drivers of suspended sediment over ~3 years and (ii) assess turbidity dynamics during storm events in different parts of the catchment. In addition, the sensor installation allowed a novel wavelet analysis based on identifying groups of turbidity peaks to estimate transport times of suspended sediment through the catchment. Yearly suspended sediment yields calculated for the upper catchment were typically less than 4 t ha−1 year−1 being similar to other UK limestone or chalk-based rivers. Time series autoregressive integrated moving average models including explanatory variable regression modelling indicated that river discharge, groundwater level and water temperature were all significant predictors of turbidity levels throughout the year. However, high model residuals demonstrate that the models failed to capture random turbidity events. Five parts of the time series data were used to examine sediment dynamics. Plots of scaled discharge verses turbidity demonstrated that in the upper catchment, after initial suspended sediment generation, sediment quickly became limited. In the lower catchment, hysteresis analysis suggested that sediment dilution occurred, due to increasing base flow. The novel wavelet analysis demonstrated that during winter ‘sediment events’ identified as groups of turbidity peaks, took ~18 h to pass from the first sensor in the upper catchment to the second sensor (10.3 km downstream of sensor 1) and 24 h to the third sensor (23.3 km from sensor 1). The work demonstrates the potential for using multiple turbidity sensors and time series statistical techniques in developing greater understanding of suspended sediment dynamics and associated poor water quality in ecologically sensitive rivers