Could recombinant insulin compounds contribute to adenocarcinoma progression by stimulating local angiogenesis?

Negative effects on the progression of adenocarcinomas by hyperinsulinaemia and the insulin analogue glargine (A21Gly,B31Arg,B32Arg human insulin) have recently been suggested. Most actions of this insulin analogue have hitherto been explained by direct stimulation of growth potential of neoplastic cells and by its IGF-1 related properties. However, insulin-stimulated angiogenesis could be an additional factor involved in tumour progression and clinical outcomes associated with cancer. Five types of human adenocarcinoma (breast, colon, pancreas, lung and kidney) were evaluated for the presence of insulin receptors (IRs) on angiogenic structures. In an in vitro angiogenesis assay, various commercially available insulin compounds were evaluated for their potential to increase capillary-like tube formation of human microvascular endothelial cells (hMVEC). Insulin compounds used were: human insulin, insulin lispro (B28Lys,B29Pro human insulin), insulin glargine and insulin detemir (B29Lys[e-tetradecanoyl],desB30 human insulin). Insulin receptors were found to be strongly expressed on the endothelium of microvessels in all evaluated adenocarcinomas, in addition to variable expression on tumour cells. Low or no detectable expression of IRs was seen on microvessels in extratumoral stroma. Incubation with commercially available insulin compounds increased capillary-like tube formation of hMVEC in vitro. Our results suggest that all tested insulin compounds may stimulate tumour growth by enhancing local angiogenesis. Future studies need to confirm the association between insulin therapy in type 2 diabetes and tumour progressio

Intrauterine environmental and genetic influences on the association between birthweight and cardiovascular risk factors: studies in twins as a means of testing the fetal origins hypothesis

Evidence has accumulated that low birthweight is associated with several risk factors for cardiovascular disease. However, it is not known whether or not these associations are due to a programmed response to intrauterine malnutrition or genetic factors influencing both birthweight and cardiovascular risk factors. Twin studies offer a unique opportunity to distinguish between intrauterine and genetic origins of the association between birthweight and cardiovascular risk. In our twin cohort, low birthweight was associated with insulin resistance, lower HDL and shorter height within both dizygotic and monozygotic twin pairs, suggesting that these associations are, at least in part, independent of genetic factors. In contrast, low birthweight was associated with blood pressure, total and LDL cholesterol, fibrinogen and sympathetic activation within dizygotic twin pairs, but not within monozygotic twin pairs. These differences between dizygotic and monozygotic twins suggest that these associations are, at least in part, due to genetic factors. Therefore, both intrauterine environmental and genetic factors appear to play a role in the association between birthweight and cardiovascular risk factors. In the future, strategies may be developed targeted at improving or preventing impaired intrauterine growth. However, the effects of interventions that comprise changes in environment within the normal range may be limited due to the possible important role of genetic factor

Predisposition to Obesity: Should We Target Those Most Susceptible?

Obesity prevention should remain a priority, even if there is some suggestion that the epidemic may presently have reached a stable level. However, previous interventions have not been effective in preventing overweight and obesity, and at the same time studies suggest that some subgroups are more predisposed to future obesity. The purpose of this paper is to review interventions on obesity prevention published during the past year, and to examine if interventions targeting predisposed groups or individuals seem more efficient in preventing obesity than studies targeting general populations. Among 15 identified studies, 7 targeted predisposed children or adolescents. More of the studies targeting predisposed individuals were able to show significant effects than the studies targeting general populations. Most studies targeting predisposed defined the predisposition based on ethnicity or socioeconomic status. Thus, we may be more successful in preventing obesity when targeting predisposed individuals, but more studies are needed before a firm conclusion can be drawn

A Genome-Wide Association Study on Obesity and Obesity-Related Traits

Large-scale genome-wide association studies (GWAS) have identified many loci associated with body mass index (BMI), but few studies focused on obesity as a binary trait. Here we report the results of a GWAS and candidate SNP genotyping study of obesity, including extremely obese cases and never overweight controls as well as families segregating extreme obesity and thinness. We first performed a GWAS on 520 cases (BMI>35 kg/m2) and 540 control subjects (BMI<25 kg/m2), on measures of obesity and obesity-related traits. We subsequently followed up obesity-associated signals by genotyping the top ∼500 SNPs from GWAS in the combined sample of cases, controls and family members totaling 2,256 individuals. For the binary trait of obesity, we found 16 genome-wide significant signals within the FTO gene (strongest signal at rs17817449, P = 2.5×10−12). We next examined obesity-related quantitative traits (such as total body weight, waist circumference and waist to hip ratio), and detected genome-wide significant signals between waist to hip ratio and NRXN3 (rs11624704, P = 2.67×10−9), previously associated with body weight and fat distribution. Our study demonstrated how a relatively small sample ascertained through extreme phenotypes can detect genuine associations in a GWAS

Identification of a Shared Genetic Susceptibility Locus for Coronary Heart Disease and Periodontitis

Recent studies indicate a mutual epidemiological relationship between coronary heart disease (CHD) and periodontitis. Both diseases are associated with similar risk factors and are characterized by a chronic inflammatory process. In a candidate-gene association study, we identify an association of a genetic susceptibility locus shared by both diseases. We confirm the known association of two neighboring linkage disequilibrium regions on human chromosome 9p21.3 with CHD and show the additional strong association of these loci with the risk of aggressive periodontitis. For the lead SNP of the main associated linkage disequilibrium region, rs1333048, the odds ratio of the autosomal-recessive mode of inheritance is 1.99 (95% confidence interval 1.33–2.94; P = 6.9×10−4) for generalized aggressive periodontitis, and 1.72 (1.06–2.76; P = 2.6×10−2) for localized aggressive periodontitis. The two associated linkage disequilibrium regions map to the sequence of the large antisense noncoding RNA ANRIL, which partly overlaps regulatory and coding sequences of CDKN2A/CDKN2B. A closely located diabetes-associated variant was independent of the CHD and periodontitis risk haplotypes. Our study demonstrates that CHD and periodontitis are genetically related by at least one susceptibility locus, which is possibly involved in ANRIL activity and independent of diabetes associated risk variants within this region. Elucidation of the interplay of ANRIL transcript variants and their involvement in increased susceptibility to the interactive diseases CHD and periodontitis promises new insight into the underlying shared pathogenic mechanisms of these complex common diseases

EuraHS: the development of an international online platform for registration and outcome measurement of ventral abdominal wall hernia repair

Background Although the repair of ventral abdominal wall hernias is one of the most commonly performed operations, many aspects of their treatment are still under debate or poorly studied. In addition, there is a lack of good definitions and classifications that make the evaluation of studies and meta-analyses in this field of surgery difficult. Materials and methods Under the auspices of the board of the European Hernia Society and following the previously published classifications on inguinal and on ventral hernias, a working group was formed to create an online platform for registration and outcome measurement of operations for ventral abdominal wall hernias. Development of such a registry involved reaching agreement about clear definitions and classifications on patient variables, surgical procedures and mesh materials used, as well as outcome parameters. The EuraHS working group (European registry for abdominal wall hernias) comprised of a multinational European expert panel with specific interest in abdominal wall hernias. Over five working group meetings, consensus was reached on definitions for the data to be recorded in the registry. Results A set of well-described definitions was made. The previously reported EHS classifications of hernias will be used. Risk factors for recurrences and co-morbidities of patients were listed. A new severity of comorbidity score was defined. Post-operative complications were classified according to existing classifications as described for other fields of surgery. A new 3-dimensional numerical quality-of-life score, EuraHS-QoL score, was defined. An online platform is created based on the definitions and classifications, which can be used by individual surgeons, surgical teams or for multicentre studies. A EuraHS website is constructed with easy access to all the definitions, classifications and results from the database. Conclusion An online platform for registration and outcome measurement of abdominal wall hernia repairs with clear definitions and classifications is offered to the surgical community. It is hoped that this registry could lead to better evidence-based guidelines for treatment of abdominal wall hernias based on hernia variables, patient variables, available hernia repair materials and techniques

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Do Gene Variants Influencing Adult Adiposity Affect Birth Weight? A Population-Based Study of 24 Loci in 4,744 Danish Individuals

Several obesity risk alleles affecting adult adiposity have been identified by the recent wave of genome wide association studies. We aimed to examine the potential effect of these variants on fetal body composition by investigating the variants in relation to birth weight and ponderal index of the newborn.Midwife records from the Danish State Archives provided information on mother's age, parity, as well as birth weight, birth length and prematurity of the newborn in 4,744 individuals of the population-based Inter99 study. Twenty-four risk alleles showing genome-wide associations with adult BMI and/or waist circumference were genotyped. None of the 24 risk variants tested showed an association with birth weight or ponderal index after correction for multiple testing. Birth weight was divided into three categories low (≤10(th) percentile), normal (10(th)-90(th) percentile) and high birth weight (≥90th percentile) to allow for non-linear associations. There was no difference in the number of risk alleles between the groups (p = 0.57). No interactions between each risk allele and birth weight in the prediction of adult BMI were observed. An obesity risk score was created by summing up risk alleles. The risk score did not associate with fetal body composition. Moreover there was no interaction between the risk score and birth weight/ponderal index in the prediction of adult BMI.24 common variants associated with adult adiposity did not affect or interact with birth weight among Danes suggesting that the effects of these variants predominantly arise in the post-natal life

International guidelines for groin hernia management

Worldwide, more than 20 million patients undergo groin hernia repair annually. The many different approaches, treatment indications and a significant array of techniques for groin hernia repair warrant guidelines to standardize care, minimize complications, and improve results. The main goal of these guidelines is to improve patient outcomes, specifically to decrease recurrence rates and reduce chronic pain, the most frequent problems following groin hernia repair. They have been endorsed by all five continental hernia societies, the International Endo Hernia Society and the European Association for Endoscopic Surgery. An expert group of international surgeons (the HerniaSurge Group) and one anesthesiologist pain expert was formed. The group consisted of members from all continents with specific experience in hernia-related research. Care was taken to include surgeons who perform different types of repair and had preferably performed research on groin hernia surgery. During the Group's first meeting, evidence-based medicine (EBM) training occurred and 166 key questions (KQ) were formulated. EBM rules were followed in complete literature searches (including a complete search by The Dutch Cochrane database) to January 1, 2015 and to July 1, 2015 for level 1 publications. The articles were scored by teams of two or three according to Oxford, SIGN and Grade methodologies. During five 2-day meetings, results were discussed with the working group members leading to 136 statements and 88 recommendations. Recommendations were graded as "strong" (recommendations) or "weak" (suggestions) and by consensus in some cases upgraded. In the Results and summary section below, the term "should" refers to a recommendation. The AGREE II instrument was used to validate the guidelines. An external review was performed by three international experts. They recommended the guidelines with high scores. The risk factors for inguinal hernia (IH) include: family history, previous contra-lateral hernia, male gender, age, abnormal collagen metabolism, prostatectomy, and low body mass index. Peri-operative risk factors for recurrence include poor surgical techniques, low surgical volumes, surgical inexperience and local anesthesia. These should be considered when treating IH patients. IH diagnosis can be confirmed by physical examination alone in the vast majority of patients with appropriate signs and symptoms. Rarely, ultrasound is necessary. Less commonly still, a dynamic MRI or CT scan or herniography may be needed. The EHS classification system is suggested to stratify IH patients for tailored treatment, research and audit. Symptomatic groin hernias should be treated surgically. Asymptomatic or minimally symptomatic male IH patients may be managed with "watchful waiting" since their risk of hernia-related emergencies is low. The majority of these individuals will eventually require surgery; therefore, surgical risks and the watchful waiting strategy should be discussed with patients. Surgical treatment should be tailored to the surgeon's expertise, patient- and hernia-related characteristics and local/national resources. Furthermore, patient health-related, life style and social factors should all influence the shared decision-making process leading up to hernia management. Mesh repair is recommended as first choice, either by an open procedure or a laparo-endoscopic repair technique. One standard repair technique for all groin hernias does not exist. It is recommended that surgeons/surgical services provide both anterior and posterior approach options. Lichtenstein and laparo-endoscopic repair are best evaluated. Many other techniques need further evaluation. Provided that resources and expertise are available, laparo-endoscopic techniques have faster recovery times, lower chronic pain risk and are cost effective. There is discussion concerning laparo-endoscopic management of potential bilateral hernias (occult hernia issue). After patient consent, during TAPP, the contra-lateral side should be inspected. This is not suggested during unilateral TEP repair. After appropriate discussions with patients concerning results tissue repair (first choice is the Shouldice technique) can be offered. Day surgery is recommended for the majority of groin hernia repair provided aftercare is organized. Surgeons should be aware of the intrinsic characteristics of the meshes they use. Use of so-called low-weight mesh may have slight short-term benefits like reduced postoperative pain and shorter convalescence, but are not associated with better longer-term outcomes like recurrence and chronic pain. Mesh selection on weight alone is not recommended. The incidence of erosion seems higher with plug versus flat mesh. It is suggested not to use plug repair techniques. The use of other implants to replace the standard flat mesh in the Lichtenstein technique is currently not recommended. In almost all cases, mesh fixation in TEP is unnecessary. In both TEP and TAPP it is recommended to fix mesh in M3 hernias (large medial) to reduce recurrence risk. Antibiotic prophylaxis in average-risk patients in low-risk environments is not recommended in open surgery. In laparo-endoscopic repair it is never recommended. Local anesthesia in open repair has many advantages, and its use is recommended provided the surgeon is experienced in this technique. General anesthesia is suggested over regional in patients aged 65 and older as it might be associated with fewer complications like myocardial infarction, pneumonia and thromboembolism. Perioperative field blocks and/or subfascial/subcutaneous infiltrations are recommended in all cases of open repair. Patients are recommended to resume normal activities without restrictions as soon as they feel comfortable. Provided expertise is available, it is suggested that women with groin hernias undergo laparo-endoscopic repair in order to decrease the risk of chronic pain and avoid missing a femoral hernia. Watchful waiting is suggested in pregnant women as groin swelling most often consists of self-limited round ligament varicosities. Timely mesh repair by a laparo-endoscopic approach is suggested for femoral hernias provided expertise is available. All complications of groin hernia management are discussed in an extensive chapter on the topic. Overall, the incidence of clinically significant chronic pain is in the 10-12% range, decreasing over time. Debilitating chronic pain affecting normal daily activities or work ranges from 0.5 to 6%. Chronic postoperative inguinal pain (CPIP) is defined as bothersome moderate pain impacting daily activities lasting at least 3 months postoperatively and decreasing over time. CPIP risk factors include: young age, female gender, high preoperative pain, early high postoperative pain, recurrent hernia and open repair. For CPIP the focus should be on nerve recognition in open surgery and, in selected cases, prophylactic pragmatic nerve resection (planned resection is not suggested). It is suggested that CPIP management be performed by multi-disciplinary teams. It is also suggested that CPIP be managed by a combination of pharmacological and interventional measures and, if this is unsuccessful, followed by, in selected cases (triple) neurectomy and (in selected cases) mesh removal. For recurrent hernia after anterior repair, posterior repair is recommended. If recurrence occurs after a posterior repair, an anterior repair is recommended. After a failed anterior and posterior approach, management by a specialist hernia surgeon is recommended. Risk factors for hernia incarceration/strangulation include: female gender, femoral hernia and a history of hospitalization related to groin hernia. It is suggested that treatment of emergencies be tailored according to patient- and hernia-related factors, local expertise and resources. Learning curves vary between different techniques. Probably about 100 supervised laparo-endoscopic repairs are needed to achieve the same results as open mesh surgery like Lichtenstein. It is suggested that case load per surgeon is more important than center volume. It is recommended that minimum requirements be developed to certify individuals as expert hernia surgeon. The same is true for the designation "Hernia Center". From a cost-effectiveness perspective, day-case laparoscopic IH repair with minimal use of disposables is recommended. The development and implementation of national groin hernia registries in every country (or region, in the case of small country populations) is suggested. They should include patient follow-up data and account for local healthcare structures. A dissemination and implementation plan of the guidelines will be developed by global (HerniaSurge), regional (international societies) and local (national chapters) initiatives through internet websites, social media and smartphone apps. An overarching plan to improve access to safe IH surgery in low-resource settings (LRSs) is needed. It is suggested that this plan contains simple guidelines and a sustainability strategy, independent of international aid. It is suggested that in LRSs the focus be on performing high-volume Lichtenstein repair under local anesthesia using low-cost mesh. Three chapters discuss future research, guidelines for general practitioners and guidelines for patients. The HerniaSurge Group has developed these extensive and inclusive guidelines for the management of adult groin hernia patients. It is hoped that they will lead to better outcomes for groin hernia patients wherever they live. More knowledge, better training, national audit and specialization in groin hernia management will standardize care for these patients, lead to more effective and efficient healthcare and provide direction for future research

Replicating genotype-phenotype associations

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62757/1/447655a.pd