Genetic background influences tumour development in heterozygous Men1 knockout mice

Multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder caused by MEN1 germline mutations, is characterised by parathyroid, pancreatic and pituitary tumours. MEN1 mutations also cause familial isolated primary hyperparathyroidism (FIHP), a milder condition causing hyperparathyroidism only. Identical mutations can cause either MEN1 or FIHP in different families, thereby implicating a role for genetic modifiers in altering phenotypic expression of tumours. We therefore investigated the effects of genetic background and potential for genetic modifiers on tumour development in adult Men1+/- mice, which develop tumours of the parathyroids, pancreatic islets, anterior pituitary, adrenal cortex and gonads, that had been backcrossed to generate C57BL/6 and 129S6/SvEv congenic strains. A total of 275 Men1+/- mice, aged 5–26 months were macroscopically studied, and this revealed that genetic background significantly influenced the development of pituitary, adrenal and ovarian tumours, which occurred in mice over 12 months of age and more frequently in C57BL/6 females, 129S6/SvEv males and 129S6/SvEv females, respectively. Moreover, pituitary and adrenal tumours developed earlier, in C57BL/6 males and 129S6/SvEv females, respectively, and pancreatic and testicular tumours developed earlier in 129S6/SvEv males. Furthermore, glucagon-positive staining pancreatic tumours occurred more frequently in 129S6/SvEv Men1+/- mice. Whole genome sequence analysis of 129S6/SvEv and C57BL/6 Men1+/- mice revealed >54,000 different variants in >300 genes. These included, Coq7, Dmpk, Ccne2, Kras, Wnt2b, Il3ra and Tnfrsf10a, and qRT-PCR analysis revealed that Kras was significantly higher in pituitaries of male 129S6/SvEv mice. Thus, our results demonstrate that Kras and other genes could represent possible genetic modifiers of Men1

Tracking seabird migration in the tropical Indian Ocean reveals basin-scale conservation need

Summary Understanding marine predator distributions is an essential component of arresting their catastrophic declines.1,2,3,4 In temperate, polar, and upwelling seas, predictable oceanographic features can aggregate migratory predators, which benefit from site-based protection.5,6,7,8 In more oligotrophic tropical waters, however, it is unclear whether environmental conditions create similar multi-species hotspots. We track the non-breeding movements and habitat preferences of a tropical seabird assemblage (n = 348 individuals, 9 species, and 10 colonies in the western Indian Ocean), which supports globally important biodiversity.9,10,11,12 We mapped species richness from tracked populations and then predicted the same diversity measure for all known Indian Ocean colonies. Most species had large non-breeding ranges, low or variable residency patterns, and specific habitat preferences. This in turn revealed that maximum species richness covered >3.9 million km2, with no focused aggregations, in stark contrast to large-scale tracking studies in all other ocean basins.5,6,7,13,14 High species richness was captured by existing marine protected areas (MPAs) in the region; however, most occurred in the unprotected high seas beyond national jurisdictions. Seabirds experience cumulative anthropogenic impacts13 and high mortality15,16 during non-breeding. Therefore, our results suggest that seabird conservation in the tropical Indian Ocean requires an ocean-wide perspective, including high seas legislation.17 As restoration actions improve the outlook for tropical seabirds on land18,19,20,21,22 and environmental change reshapes the habitats that support them at sea,15,16 appropriate marine conservation will be crucial for their long-term recovery and whole ecosystem restoration

Reliability of the TekScan MatScan® system for the measurement of plantar forces and pressures during barefoot level walking in healthy adults

<p>Abstract</p> <p>Background</p> <p>Plantar pressure systems are increasingly being used to evaluate foot function in both research settings and in clinical practice. The purpose of this study was to investigate the reliability of the TekScan MatScan^®system in assessing plantar forces and pressures during barefoot level walking.</p> <p>Methods</p> <p>Thirty participants were assessed for the reliability of measurements taken one week apart for the variables maximum force, peak pressure and average pressure. The following seven regions of the foot were investigated; heel, midfoot, 3^rd-5^thmetatarsophalangeal joint, 2^ndmetatarsophalangeal joint, 1^stmetatarsophalangeal joint, hallux and the lesser toes.</p> <p>Results</p> <p>Reliability was assessed using both the mean and the median values of three repeated trials. The system displayed moderate to good reliability of mean and median calculations for the three analysed variables across all seven regions, as indicated by intra-class correlation coefficients ranging from 0.44 to 0.95 for the mean and 0.54 to 0.97 for the median, and coefficients of variation ranging from 5 to 20% for the mean and 3 to 23% for the median. Selecting the median value of three repeated trials yielded slightly more reliable results than the mean.</p> <p>Conclusions</p> <p>These findings indicate that the TekScan MatScan^®system demonstrates generally moderate to good reliability.</p

Inherited germline TP53 mutation encodes a protein with an aberrant C-terminal motif in a case of pediatric adrenocortical tumor

Childhood adrenocortical tumor (ACT), a very rare malignancy, has an annual worldwide incidence of about 0.3 per million children younger than 15 years. The association between inherited germline mutations of the TP53 gene and an increased predisposition to ACT was described in the context of the Li-Fraumeni syndrome. In fact, about two-thirds of children with ACT have a TP53 mutation. However, less than 10% of pediatric ACT cases occur in Li-Fraumeni syndrome, suggesting that inherited low-penetrance TP53 mutations play an important role in pediatric adrenal cortex tumorigenesis. We identified a novel inherited germline TP53 mutation affecting the acceptor splice site at intron 10 in a child with an ACT and no family history of cancer. The lack of family history of cancer and previous information about the carcinogenic potential of the mutation led us to further characterize it. Bioinformatics analysis showed that the non-natural and highly hydrophobic C-terminal segment of the frame-shifted mutant p53 protein may disrupt its tumor suppressor function by causing misfolding and aggregation. Our findings highlight the clinical and genetic counseling dilemmas that arise when an inherited TP53 mutation is found in a child with ACT without relatives with Li-Fraumeni-component tumors

Non-invasive imaging of atherosclerotic plaque macrophage in a rabbit model with F-18 FDG PET: a histopathological correlation

BACKGROUND: Coronary atherosclerosis and its thrombotic complications are the major cause of mortality and morbidity throughout the industrialized world. Thrombosis on disrupted atherosclerotic plaques plays a key role in the onset of acute coronary syndromes. Macrophages density is one of the most critical compositions of plaque in both plaque vulnerability and thrombogenicity upon rupture. It has been shown that macrophages have a high uptake of (18)F-FDG (FDG). We studied the correlation of FDG uptake with histopathological macrophage accumulation in atherosclerotic plaques in a rabbit model. METHODS: Atherosclerosis was induced in rabbits (n = 6) by a combination of atherogenic diet and balloon denudation of the aorta. PET imaging was performed at baseline and 2 months after atherogenic diet and coregistered with magnetic resonance (MR) imaging. Normal (n = 3) rabbits served as controls. FDG uptake by the thoracic aorta was expressed as concentration (μCi/ml) and the ratio of aortic uptake-to-blood radioactivity. FDG uptake and RAM-11 antibody positive areas were analyzed in descending aorta. RESULTS: Atherosclerotic aortas showed significantly higher uptake of FDG than normal aortas. The correlation of aortic FDG uptake with macrophage areas assessed by histopathology was statistically significant although it was not high (r = 0.48, p < 0.0001). When uptake was expressed as the ratio of aortic uptake-to-blood activity, it correlated better (r = 0.80, p < 0.0001) with the macrophage areas, due to the correction for residual blood FDG activity. CONCLUSION: PET FDG activity correlated with macrophage content within aortic atherosclerosis. This imaging approach might serve as a useful non-invasive imaging technique and potentially permit monitoring of relative changes in inflammation within the atherosclerotic lesion

Early-Life Determinants of Total and HDL Cholesterol Concentrations in 8-Year-Old Children; The PIAMA Birth Cohort Study

BACKGROUND: Adult cholesterol concentrations might be influenced by early-life factors, such as breastfeeding and birth weight, referred to as "early programming". How such early factors exert their influence over the life course is still poorly understood. Evidence from studies in children and adolescents is scarce and conflicting. We investigated the influence of 6 different perinatal risk factors on childhood total and HDL cholesterol concentrations and total-to-HDL cholesterol ratio measured at 8 years of age, and additionally we studied the role of the child's current Body Mass Index (BMI). METHODS: Anthropometric measures and blood plasma samples were collected during a medical examination in 751 8-year-old children participating in the prospective Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort study. Linear and logistic regression were performed to estimate associations of total and HDL cholesterol concentrations with breastfeeding, birth weight, infant weight gain, maternal overweight before pregnancy, gestational diabetes and maternal smoking during pregnancy, taking into account the child's current BMI. RESULTS: Linear regressions showed an association between total-to-HDL cholesterol ratio and maternal pre-pregnancy overweight (β = 0.15, Confidence Interval 95% (CI): 0.02, 0.28), rapid infant weight gain (β = 0.13, 95%CI: 0.01, 0.26), and maternal smoking during pregnancy (β = 0.14, 95%CI: 0.00, 0.29). These associations were partly mediated by the child's BMI. CONCLUSION: Total-to-HDL cholesterol ratio in 8-year-old children was positively associated with maternal pre-pregnancy overweight, maternal smoking during pregnancy and rapid infant weight gain

Особливості формування самостійної пізнавальної діяльності майбутніх учителів математики

(uk) У статті зроблено спробу розкрити особливості самостійної пізнавальної діяльності майбутніх вчителів; досліджуються різні підходи до цього поняття; розкриваються такі його складові, як самостійність, пізнавальна самостійність, пізнавальна діяльність.(ru) В статье сделана попытка раскрыть особенности самостоятельной познавательной деятельности будущих учителей; исследуются различные подходы к этому понятию; раскрываются такие его составляющие, как самостоятельность, познавательная самостоятельность, познавательная деятельность

Panton-Valentine Leukocidin Does Play a Role in the Early Stage of Staphylococcus aureus Skin Infections: A Rabbit Model

Despite epidemiological data linking necrotizing skin infections with the production of Panton-Valentine leukocidin (PVL), the contribution of this toxin to the virulence of S. aureus has been highly discussed as a result of inconclusive results of in vivo studies. However, the majority of these results originate from experiments using mice, an animal species which neutrophils - the major target cells for PVL - are highly insensitive to the action of this leukocidin. In contrast, the rabbit neutrophils have been shown to be as sensitive to PVL action as human cells, making the rabbit a better experimental animal to explore the PVL role. In this study we examined whether PVL contributes to S. aureus pathogenicity by means of a rabbit skin infection model. The rabbits were injected intradermally with 108 cfu of either a PVL positive community-associated methicillin-resistant S. aureus isolate, its isogenic PVL knockout or a PVL complemented knockout strain, and the development of skin lesions was observed. While all strains induced skin infection, the wild type strain produced larger lesions and a higher degree of skin necrosis compared to the PVL knockout strain in the first week after the infection. The PVL expression in the rabbits was indirectly confirmed by a raise in the serum titer of anti-LukS-PV antibodies observed only in the rabbits infected with PVL positive strains. These results indicate that the rabbit model is more suitable for studying the role of PVL in staphylococcal diseases than other animal models. Further, they support the epidemiological link between PVL producing S. aureus strains and necrotizing skin infections