Interleukin-6 receptor pathways in abdominal aortic aneurysm

We conducted a systematic review and meta-analysis of studies reporting circulating IL-6 in AAA, and new investigations of the association between a common non-synonymous functional variant (Asp358Ala) in the IL-6R gene (IL6R) and AAA, followed the analysis of the variant both in vitro and in vivo. Inflammation may play a role in the development of abdominal aortic aneurysms (AAA). Interleukin-6 (IL-6) signalling through its receptor (IL-6R) is one pathway that could be exploited pharmacologically. We investigated this using a Mendelian randomization approach

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Audit of maternal and fetal outcomes in women treated for glucose intolerance during pregnancy

Objective To determine whether one should aim for glycaemia that is statistically 'normal' or for levels of glycaemia low enough to prevent macrosomia (if such a threshold exists) when glucose intolerance is detected during pregnancy Design An audit of pregnancy outcomes in women with impaired glucose tolerance in pregnancy as compared to a local age-matched reference group with normal glucose tolerance. Results Our study suggests that for most patients, more intensive therapy would not have been justified. Maternal smoking appeared to convey some 'advantages' in terms of neonatal outcomes, with reduction in large-for-gestational-age (LGA) infants and jaundice in babies of impaired glucose tolerance (IGT) mothers. Conclusions These observations demonstrate the importance of considering risk factors other than GTT results in analysing pregnancy outcomes, while emphasising that 'normalisation' of fetal size should not be our only therapeutic endpoint. Our detailed outcome review allows us to reassure patients with GDM that with current treatment protocols, they should have every expectation of a positive pregnancy outcome

Design of erosion/abrasion studies - insights and rational concepts

In vitro and in situ studies modelling the wear of dental hard tissues due to erosion and abrasion are characterised by a high variation in study designs and experimental parameters. Based on a summary of the existing protocols, the present review aimed to describe and discuss the parameters which must be carefully considered in erosion-abrasion research, especially when it is intended to simulate clinical conditions. Experimental characteristics and parameters were retrieved from a total of 42 in vitro and 20 in situ studies. The key experimental characteristics included parameters of erosion (duration and pH) and abrasion (duration, kinds of toothbrush and toothpaste, brushing force, and time point) as well as co-factors (e.g. dental hard tissue). The majority of studies used models with alternating erosion/abrasion treatments intended to simulate clinical conditions, while other studies exaggerated clinical conditions intentionally, often using only a single erosion/abrasion treatment. Both in vitro and in situ models shared a high level of standardisation, but several studies showed a trend to severe erosion (e.g. >5 min/cycle) or extensive brushing (e.g. >100 brushing strokes/cycle) at a high frequency and repetition rate. Thus, studies often tend to produce a higher amount of wear than in the clinical situation, especially as modifying biological factors (e.g. the dilution of the erosive solution by saliva and the protective effect of the pellicle) cannot be simulated adequately. With respect to the existing models, it seems advisable to diminish duration and frequency of erosion and abrasion to more realistic clinical conditions when the everyday situation is to be simulated. Experimental parameters must be chosen with care to ensure that the problem is investigated in an appropriate mode at standardised conditions and with adequate measuring systems to allow prediction of clinical outcomes

The Dutch founder mutation SDHD.D92Y shows a reduced penetrance for the development of paragangliomas in a large multigenerational family

Germline mutations in SDHD predispose to the development of head and neck paragangliomas, and phaeochromocytomas. The risk of developing a tumor depends on the sex of the parent who transmits the mutation: paragangliomas only arise upon paternal transmission. In this study, both the risk of paraganglioma and phaeochromocytoma formation, and the risk of developing associated symptoms were investigated in 243 family members with the SDHD.D92Y founder mutation. By using the Kaplan–Meier method, age-specific penetrance was calculated separately for paraganglioma formation as defined by magnetic resonance imaging (MRI) and for paraganglioma-related signs and symptoms. Evaluating clinical signs and symptoms alone, the penetrance reached a maximum of 57% by the age of 47 years. When MRI detection of occult paragangliomas was included, penetrance was estimated to be 54% by the age of 40 years, 68% by the age of 60 years and 87% by the age of 70 years. Multiple tumors were found in 65% and phaeochromocytomas were diagnosed in 8% of paraganglioma patients. Malignant paraganglioma was diagnosed in one patient (3%). Although the majority of carriers of a paternally inherited SDHD mutation will eventually develop head and neck paragangliomas, we find a lower penetrance than previous estimates from studies based on predominantly index cases. The family-based study described here emphasizes the importance of the identification and inclusion of clinically unaffected mutation carriers in all estimates of penetrance. This finding will allow a more accurate genetic counseling and warrants a ‘wait and scan' policy for asymptomatic paragangliomas, combined with biochemical screening for catecholamine excess in SDHD-linked patients

Risks of Lynch Syndrome Cancers for MSH6 Mutation Carriers

Background: Germline mutations in MSH6 account for 10%–20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene mutations. Because there have been only a few studies of mutation carriers, their cancer risks are uncertain. Methods: We identified 113 families of MSH6 mutation carriers from five countries that we ascertained through family cancer clinics and population-based cancer registries. Mutation status, sex, age, and histories of cancer, polypectomy, and hysterectomy were sought from 3104 of their relatives. Age-specific cumulative risks for carriers and hazard ratios (HRs) for cancer risks of carriers, compared with those of the general population of the same country, were estimated by use of a modified segregation analysis with appropriate conditioning depending on ascertainment. Results: For MSH6 mutation carriers, the estimated cumulative risks to ages 70 and 80 years, respectively, were as follows: for colorectal cancer, 22% (95% confidence interval [CI] = 14% to 32%) and 44% (95% CI = 28% to 62%) for men and 10% (95% CI = 5% to 17%) and 20% (95% CI = 11% to 35%) for women; for endometrial cancer, 26% (95% CI = 18% to 36%) and 44% (95% CI = 30% to 58%); and for any cancer associated with Lynch syndrome, 24% (95% CI = 16% to 37%) and 47% (95% CI = 32% to 66%) for men and 40% (95% CI = 32% to 52%) and 65% (95% CI = 53% to 78%) for women. Compared with incidence for the general population, MSH6 mutation carriers had an eightfold increased incidence of colorectal cancer (HR = 7.6, 95% CI = 5.4 to 10.8), which was independent of sex and age. Women who were MSH6 mutation carriers had a 26-fold increased incidence of endometrial cancer (HR = 25.5, 95% CI = 16.8 to 38.7) and a sixfold increased incidence of other cancers associated with Lynch syndrome (HR = 6.0, 95% CI = 3.4 to 10.7). Conclusion: We have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers.Laura Baglietto... Dutch Lynch Syndrome Study Group... Graeme Suthers... et al