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Type 2 diabetes (T2D) is a chronic disease that disproportionately affects Indigenous Australians. We have previously reported the localization of a novel T2D locus by linkage analysis to chromosome 2q24 in a large admixed Indigenous Australian pedigree (Busfield et al. (2002). American Journal of Human Genetics, 70, 349–357). Here we describe fine mapping of this region in this pedigree, with the identification of SNPs showing strong association with T2D: rs3845724 (diabetes p = 7 × 10−4), rs4668106 (diabetes p = 9 × 10−4) and rs529002 (plasma glucose p = 3 × 10−4). These associations were successfully replicated in an independent collection of Indigenous Australian T2D cases and controls. These SNPs all lie within the gene encoding ceramide synthase 6 (CERS6) and thus may regulate ceramide synthesis.
Necrotising enterocolitis (NEC) is a devastating disease that typically affects formula-fed premature infants, suggesting that dietary components may influence disease pathogenesis. TAG are the major fat components of infant formula, and their digestion requires pancreatic lipases, which may be naturally deficient in premature neonates. We hypothesise that NEC develops partly from the accumulation of incompletely digested long-chain TAG-containing unsaturated fatty acids within the intestinal epithelial cells, leading to oxidative stress and enterocyte damage. We further hypothesise that the administration of a formula that contains reduced TAG (‘pre-digested fat’) that do not require lipase action may reduce NEC severity. To test these hypotheses, we induced NEC in neonatal mice using three different fat formulations, namely ‘standard fat’, ‘pre-digested fat’ or ‘very low fat’, and determined that mice fed ‘standard fat’ developed severe NEC, which was significantly reduced in mice fed ‘pre-digested fat’ or ‘very low fat’. The expression level of the critical fat-digesting enzyme carboxyl ester lipase was significantly lower in the newborn compared with older pups, leading to impaired fat digestion. The accumulation of mal-digested fat resulted in the significant accumulation of fat droplets within the intestinal epithelium of the distal ileum, resulting in the generation of reactive oxygen species and intestinal inflammation. Strikingly, these changes were prevented in pups fed ‘pre-digested fat’ or ‘very low fat’ formulas. These findings suggest that nutritional formula containing a pre-digested fat system may overcome the natural lipase deficiency of the premature gut, and serve as a novel approach to prevent NEC.
Based on seven measured sections from Svalbard, the marine strata of the Permian Kapp Starostin Formation are arranged into seven transgressive–regressive sequences (TR1–TR7) of c. 4–5 Ma average duration, each bound by a maximum regressive surface. Facies, including heterozoan-dominated limestones, spiculitic cherts, sandstones, siltstones and shales, record deposition within inner, middle and outer shelf areas. The lowermost sequence, TR1, comprises most of the basal Vøringen Member, which records a transgression across the Gipshuken Formation following a hiatus of unknown duration. Temperate to cold, storm-dominated facies established in inner to middle shelf areas between the latest Artinskian and Kungurian. Prolonged deepening during sequences TR2 and TR3 was succeeded by a long-term shallowing-upward trend that lasted until the latest Permian (TR4–TR7). A major depocentre existed in central and western Spitsbergen while to the north, Dickson Land remained a shallow platform, leading to a shallow homoclinal ramp in NE Spitsbergen and Nordaustlandet. The Middle Permian extinction (late Capitanian) is recorded near the base of TR6 in deeper parts of the basin only; elsewhere this sequence is not recorded. Likewise the youngest sequence, TR7, extending to the upper formational contact of latest Permian age, is found only in the basin depocentre. Comparison with age-equivalent strata in the Sverdrup Basin of Canada reveals a remarkably similar depositional history, with, for example, two (third-order) sea-level cycles recorded in the Late Permian of both regions, in keeping with the global record. Sequence stratigraphy may therefore be a powerful correlative tool for onshore and offshore Permian deposits across NW Pangaea.
Necrotising enterocolitis (NEC) is a common disease in premature infants characterised by intestinal ischaemia and necrosis. The only effective preventative strategy against NEC is the administration of breast milk, although the protective mechanisms remain unknown. We hypothesise that an abundant human milk oligosaccharide (HMO) in breast milk, 2′-fucosyllactose (2′FL), protects against NEC by enhancing intestinal mucosal blood flow, and we sought to determine the mechanisms underlying this protection. Administration of HMO-2′FL protected against NEC in neonatal wild-type mice, resulted in a decrease in pro-inflammatory markers and preserved the small intestinal mucosal architecture. These protective effects occurred via restoration of intestinal perfusion through up-regulation of the vasodilatory molecule endothelial nitric oxide synthase (eNOS), as administration of HMO-2′FL to eNOS-deficient mice or to mice that received eNOS inhibitors did not protect against NEC, and by 16S analysis HMO-2′FL affected the microbiota of the neonatal mouse gut, although these changes do not seem to be the primary mechanism of protection. Induction of eNOS by HMO-2′FL was also observed in cultured endothelial cells, providing a link between eNOS and HMO in the endothelium. These data demonstrate that HMO-2′FL protects against NEC in part through maintaining mesenteric perfusion via increased eNOS expression, and suggest that the 2′FL found in human milk may be mediating some of the protective benefits of breast milk in the clinical setting against NEC.
In this study, we conduct a cost-effectiveness analysis of nine air quality regulations recently issued by the U.S. Environmental Protection Agency (EPA). Taking emission reductions in the Regulatory Impact Analyses (RIAs) for these regulations as given, we independently assess uncertainty about the compliance costs of the regulations and the lives the regulations are estimated to save. The latter evaluation is based on a formal uncertainty analysis that integrates expert judgments about the effects of fine particle exposures on mortality risks. These expert judgments were given in an EPA-sponsored elicitation study conducted in 2006. The integrated judgments are used to generate probability distributions for several types of cost-effectiveness ratios, including the gross and net cost per life saved, net cost per life year saved, and net cost per quality-adjusted life year (QALY) gained. The results show that the cost-effectiveness ratios exhibit considerable uncertainty individually and also vary widely across regulations. Within a simulated 90% confidence interval for the gross cost per life saved, for example, there is both the possibility that benefits from lifesavings alone are sufficient to cover the rules’ costs and the possibility that no lives will be saved and cost-effectiveness ratios will be infinite. The wide ranges for the confidence intervals suggest the need for better information about the effects of fine particle exposures on mortality risks.
The miconia (Miconia calvescens) invasion of the East Maui Watershed (EMW) started from a single introduction over 40 yr ago, establishing a nascent patch network spread across 20,000 ha. In 2012, an accelerated intervention strategy was implemented utilizing the Herbicide Ballistic Technology (HBT) platform in a Hughes 500D helicopter to reduce target densities of seven nascent patches in the EMW. In a 14-mo period, a total of 48 interventions eliminated 4,029 miconia targets, with an estimated 33% increase in operations and 168% increase in recorded targets relative to the adjusted means from 2005 to 2011 data (prior to HBT adoption). This sequence of interventions covered a total net area of 1,138 ha, creating a field mosaic of overlapping search coverage (saturation) for each patch (four to eight interventions per patch). Target density reduction for each patch fit exponential decay functions (R2 > 0.88, P < 0.05), with a majority of the target interventions spatially assigned to the highest saturation fields. The progressive decay in target density led to concomitant reductions in search efficiency (min ha−1) and herbicide use rate (grams ae ha−1) in subsequent interventions. Mean detection efficacy (± SE) between overlapping interventions (n = 41) was 0.62 ± 0.03, matching closely with the probability of detection for a random search operation and verifying imperfect (albeit precise) detection. The HBT platform increases the value of aerial surveillance operations with 98% efficacy in target elimination. Applying coverage saturation with an accelerated intervention schedule to known patch locations is an adaptive process for compensating imperfect detection and building intelligence with spatial and temporal relevance to the next operation.
David J. Good, Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, BC, Canada,
Randy D. Gascoyne, Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, BC, Canada
The non-Hodgkin lymphomas (NHLs) encompass a wide spectrum of disorders with varying clinical and biologic features. The appropriate diagnosis and classification forms the basis of clinical patient management and the choice of treatment protocol. The diagnosis of lymphoma begins by a thorough evaluation of the histologic and cytologic features. However, this is often inadequate for accurate classification as there is often significant overlap between these entities. Immunophenotyping studies, either by flow cytometry or immunohistochemical staining, are often initially done to determine lineage and possibly clonality. Molecular techniques are of increasing practical importance as they provide an additional level of testing. This is particularly useful in cases where the histologic features or the immunophenotypic findings are not conclusive, or the biopsy is small, hampering an accurate assessment. As well, molecular testing can detect specific lymphomas that have distinctive molecular abnormalities. Figure 14.1 describes an algorithm, outlining how ancillary testing can be utilized in the diagnosis of lymphoma.
This chapter attempts to summarize the basic molecular biology, principles of the molecular techniques, common molecular aberrations, and the application of molecular diagnostics as a key ancillary tool in the diagnosis and classification of lymphoma.
IG and TCR gene rearrangements
Human lymphocytes have the ability to specifically recognize millions of different antigens and antigenic epitopes. This is based on the enormous diversity of their antigen-specific receptors, known as immunoglobulin (IG) and T-cell receptor (TCR) molecules. Each single B or T lymphocyte has a distinct IG or TCR and expresses approximately 105 molecules with identical antigen specificity.
Objective/Introduction: We sought to characterize the impact of the 90-item Symptom Checklist (SCL-90) subscales for paranoid ideation (PI) and psychoticism (P) in patients with major depressive disorder (MDD), on acute anti-depressant response and on relapse prevention.
Methods: Subjects with Structured Clinical Interview for DSM Disorders-diagnosed non-psychotic MDD were recruited into a clinical trial of open-label fluoxetine 10–60 mg/day for 12 weeks, followed by double-blind randomization of responders (n=262) to fluoxetine continuation or placebo for 12 months. PI and P were assessed with the patient-rated SCL-90. The association of these symptoms with response to treatment was assessed by logistic regression.
Results: We found significant decreases in PI and P during acute treatment phase for fluoxetine responders and nonresponders, although only 10.3% and 7.5% of patients experienced a ≥50% reduction in PI and P scores, respectively. Neither PI nor P scores significantly predicted time to relapse. P scores predicted a lower response rate to treatment with fluoxetine.
Discussion: The results of the present study suggest that there is a significant relationship between the presence of psychoticism in patients with nonpsychotic MDD, and the likelihood of overall depressive symptom improvement following a trial of monotherapy with fluoxetine.
Conclusion: An increased burden of psychoticism in depressed subjects may confer poorer response to fluoxetine, but not increased risk of relapse among fluoxetine responders.
The chromosome 8q24 region (specifically, 8q24.21.a) is known to harbor variants associated with risk of breast, colorectal, prostate, and bladder cancers. In 2008, variants rs10505477 and rs6983267 in this region were associated with increased risk of invasive ovarian cancer (p < 0.01); however, three subsequent ovarian cancer reports of 8q24 variants were null. Here, we used a multi-site case-control study of 940 ovarian cancer cases and 1,041 controls to evaluate associations between these and other single-nucleotide polymorphisms (SNPs) in this 8q24 region, as well as in the 9p24 colorectal cancer associated-region (specifically, 9p24.1.b). A total of 35 SNPs from previous reports and additional tagging SNPs were assessed using an Illumina GoldenGate array and analyzed using logistic regression models, adjusting for population structure and other potential confounders. We observed no association between genotypes and risk of ovarian cancer considering all cases, invasive cases, or invasive serous cases. For example, at 8q24 SNPs rs10505477 and rs6983267, analyses yielded per-allele invasive cancer odds ratios of 0.95 (95% confidence interval (CI) 0.82–1.09, p trend 0.46) and 0.97 (95% CI 0.84–1.12, p trend 0.69), respectively. Analyses using an approach identical to that of the first positive 8q24 report also yielded no association with risk of ovarian cancer. In the 9p24 region, no SNPs were associated with risk of ovarian cancer overall or with invasive or invasive serous disease (all p values > 0.10). These results indicate that the SNPs studied here are not related to risk of this gynecologic malignancy and that the site-specific nature of 8q24.21.a associations may not include ovarian cancer.
Fibroblast growth factor (FGF)-2 (basic) is a potent angiogenic molecule involved in tumor progression, and is one of several growth factors with a central role in ovarian carcinogenesis. We hypothesized that common single nucleotide polymorphisms (SNPs) in the FGF2 gene may alter angiogenic potential and thereby susceptibility to ovarian cancer. We analyzed 25 FGF2 tgSNPs using five independent study populations from the United States and Australia. Analysis was restricted to non-Hispanic White women with serous ovarian carcinoma (1269 cases and 2829 controls). There were no statistically significant associations between any FGF2 SNPs and ovarian cancer risk. There were two nominally statistically significant associations between heterozygosity for two FGF2 SNPs (rs308379 and rs308447; p < .05) and serous ovarian cancer risk in the combined dataset, but rare homozygous estimates did not achieve statistical significance, nor were they consistent with the log additive model of inheritance. Overall genetic variation in FGF2 does not appear to play a role in susceptibility to ovarian cancer.