This Perspective provides a brief history of intrahepatic alloislet and autoislet transplantation in humans and an update of the recent success rates. It also examines the important role that ...hypoglycemia plays in clinical outcomes. On the one hand, recurrent serious hypoglycemic episodes related to insulin therapy are a major criterion for alloislet transplantation. On the other hand, spontaneous clinical hypoglycemia, perhaps related to the accompanying Roux-en-Y procedure for total pancreatectomy, is a complication of autoislet transplantation. Complex alterations in glucagon secretion compromise counter-regulation of hypoglycemia in both situations. The glucagon response to hypoglycemia is intrinsically defective in type 1 diabetes before transplant because of the absence of physiological regulation of α-cell secretion by neighboring β-cells. Glucagon secretion from intrahepatic islets during systemic hypoglycemia is also defective, although β-cells in the graft are normally regulated by glucose and arginine. My personal perspective is that the latter is caused by intrahepatic glycogenolysis stimulated by systemic hypoglycemia with consequent increases in intrahepatic glucose flux, which incorrectly signals intrahepatic α-cells to be quiescent. This defect is liver-specific, which strongly suggests modifying the current approach to islet transplantation by placing a portion of allo- and autoislets in nonhepatic sites in addition to hepatic sites to ensure physiological glucagon secretion as a strategy to ameliorate post-transplant hypoglycemia.
Molecular mechanisms involving oxidative stress have been increasingly implicated in the pathogenesis of type 2 diabetes. These implications have arisen from reports that glucolipotoxicity of the ...pancreatic islet and non-islet tissues can lead to deterioration of islet function and insulin sensitivity, as well as structural abnormalities in tissues adversely affected by diabetes. Co-incident with these changes are profound alterations in insulin gene expression, which involve greatly diminished levels of two transcription factors, MafA and Pdx-1.
A substantial proportion of echinococcosis transmission to humans via contamination of food has been assumed. However, the relative importance of food as a transmission vehicle has previously been ...estimated through expert opinion rather than empirical data.
To find and evaluate empirical data that could be used to estimate the source attribution of echinococcosis, in particular the proportion that is transmitted through contaminated food.
A systematic review was undertaken to identify reports on the risk factors for human cystic (CE) and alveolar (AE) echinococcosis. Data bases searched included PubMed, Scopus, Web of Knowledge, Cab Direct, Science Direct, Google Scholar, eLIBRARY.RU, CyberLeninka, CNKI and VIP. Search terms included Echinococc*, hydatid, epidemiology, logistic regression, risk factors, odds ratio, relative risk, risk factors. Reports, including grey literature where available, that had suitable data were selected and data were extracted. The main pathways of transmission were hypothesised to be contact with the definitive host, contaminated water, contaminated food and contaminated environment (other than food). For each study the attributable fraction for these potential sources of infection was calculated from the data presented. A meta-analysis was then undertaken to obtain pooled estimates for the relative contribution of these transmission pathways.
Data from 28 cross-sectional studies and 14 case-control studies were extracted. There was strong evidence for transmission by direct contact with dogs for both CE and AE. The estimated attributable fractions were 26.1% (CI 13.8%-39.6%) and 34.4% (CI 20.7% -48.2%) respectively. Transmission through contaminated water was estimated to be responsible for approximately 29.4% (CI 12.1%-51.7%) for CE and 24.8% (CI 10.6% to 42.6%) for AE. Contaminated food may be responsible for approximately 23.4% of CE cases (CI 2.1%-47.3%). Globally, there was insufficient evidence to conclude AE can be transmitted by food, although case control studies from low human incidence areas suggested that possibly 32.5% (CI 10.0%-53.2%) could be transmitted by food. There was also insufficient evidence that direct contact with foxes was a significant source of human disease. There were no suitable studies with a risk of environmental contact reported, but the residual attributable fraction thatwould likely include this pathway was approximately 21.1% for CE and 11.1% for AE.
The results support the hypothesis that dog contact and drinking contaminated water are major pathways of transmission of both CE and AE. For contaminated food, the results are less consistent, but suggest that it is an important transmission pathway and provide better evidence than expert elicitations as previously used.
Abstract Multiplanet systems exhibit a diversity of architectures that diverge from the solar system and contribute to the topic of exoplanet demographics. Radial velocity (RV) surveys form a crucial ...component of exoplanet surveys, as their long observational baselines allow for searches for more distant planetary orbits. This work provides a significantly revised architecture for the multiplanet system HD 134606 using both HARPS and UCLES RVs. We confirm the presence of previously reported planets b, c, and d with periods of 12.0897 − 0.0018 + 0.0019 , 58.947 − 0.054 + 0.056 , and 958.7 − 5.9 + 6.3 days and masses of 9.14 − 0.63 + 0.65 , 11.0 ± 1, and 44.5 ± 2.9 Earth masses, respectively, with the planet d orbit significantly revised to over double that originally reported. We report two newly detected super-Earths, e and f, with periods of 4.31943 − 0.00068 + 0.00075 and 26.9 − 0.017 + 0.019 days and masses of 2.31 − 0.35 + 0.36 and 5.52 − 0.73 + 0.74 Earth masses, respectively. In addition, we identify a linear trend in the RV time series, and the cause of this acceleration is deemed to be a newly detected massive companion with a very long orbital period. HD 134606 now displays four low-mass planets in a compact region near the star, one gas giant further out in the habitable zone, an additional companion in the outer regime, and a low-mass M dwarf stellar companion at large separation, making it an intriguing target for system formation/evolution studies. The location of planet d in the habitable zone proves to be an exciting candidate for future space-based direct imaging missions, whereas continued RV observations of this system are recommended for understanding the nature of the massive, long-period companion.
Abstract Glucocorticoid (cort) hormones are increasingly applied in studies of free-ranging animals, with elevated baseline cort levels generally assumed to indicate individuals or populations in ...worse condition and with lower fitness (the Cort-Fitness Hypothesis ). The relationship between cort and fitness is rarely validated and studies investigating the cort-fitness relationship often find results inconsistent with the Cort-Fitness Hypothesis. The inconsistency of these studies may result in part from variation in the cort-fitness relationship across life history stages. Here we address the following questions in a two-year study in free-ranging tree swallows ( Tachycineta bicolor ): (1) Do baseline cort levels correlate with fitness within a life history stage? (2) Does the cort-fitness relationship vary across different life history stages? (3) Does the cort-fitness relationship vary across life history stages within an individual? (4) Does reproductive effort influence cort levels, and do cort levels influence reproductive effort? We measured baseline cort and fitness components in female birds of known breeding stages. We find correlations between baseline cort levels and fitness within some life history stages, but the relationship shifts from negative during early breeding to positive during late breeding, even within the same individuals. A positive relationship between baseline cort and fitness components during the nestling period suggests that reproductive investment may elicit higher cort levels that feedback to reallocate more effort to reproduction during critical periods of nestling provisioning. Our findings provide reason to question the Cort-Fitness Hypothesis, and have implications for the application of cort measures in monitoring the condition of populations of conservation concern.
...the risk ratio for dog ownership is 9.79 and the OR is 88.91. ...dog owners have a massively increased risk of echinococcosis compared with non-owners of dogs. ...the AF to dog ownership is just ...0.0808 or approximately 8.1%. ...being a dog owner has a high odds of being infected, but a low AF. For both AE and CE there is the theoretical possibility that food maybe contaminated with Echinococcus eggs resulting in the foodborne pathway of human infection. Because of this, there is a common tendency to state that food is a major pathway of human infection; this is perhaps also a result of several publications 5–7 that indicate that a substantial proportion of echinococcosis is foodborne. Where E. multilocularis is endemic there is usually a stable wildlife lifecycle. ...for AE, knowledge of the source attribution is important for identifying the most appropriate measures to implement for the prevention of transmission to people.
Chronic exposure to hyperglycemia can lead to cellular dysfunction that may become irreversible over time, a process that is termed glucose toxicity. Our perspective about glucose toxicity as it ...pertains to the pancreatic beta-cell is that the characteristic decreases in insulin synthesis and secretion are caused by decreased insulin gene expression. The responsible metabolic lesion appears to involve a posttranscriptional defect in pancreas duodenum homeobox-1 (PDX-1) mRNA maturation. PDX-1 is a critically important transcription factor for the insulin promoter, is absent in glucotoxic islets, and, when transfected into glucotoxic beta-cells, improves insulin promoter activity. Because reactive oxygen species are produced via oxidative phosphorylation during anaerobic glycolysis, via the Schiff reaction during glycation, via glucose autoxidation, and via hexosamine metabolism under supraphysiological glucose concentrations, we hypothesize that chronic oxidative stress is an important mechanism for glucose toxicity. Support for this hypothesis is found in the observations that high glucose concentrations increase intraislet peroxide levels, that islets contain very low levels of antioxidant enzyme activities, and that adenoviral overexpression of antioxidant enzymes in vitro in islets, as well as exogenous treatment with antioxidants in vivo in animals, protect the islet from the toxic effects of excessive glucose levels. Clinically, consideration of antioxidants as adjunct therapy in type 2 diabetes is warranted because of the many reports of elevated markers of oxidative stress in patients with this disease, which is characterized by imperfect management of glycemia, consequent chronic hyperglycemia, and relentless deterioration of beta-cell function.
Abstract Description Diabetes and glucose intolerance are common complications of chronic pancreatitis, yet clinical guidance on their detection, classification, and management is lacking. Methods A ...working group reviewed the medical problems, diagnostic methods, and treatment options for chronic pancreatitis-associated diabetes for a consensus meeting at PancreasFest 2012. Results Guidance Statement 1.1 : Diabetes mellitus is common in chronic pancreatitis. While any patient with chronic pancreatitis should be monitored for development of diabetes, those with long-standing duration of disease, prior partial pancreatectomy, and early onset of calcific disease may be at higher risk. Those patients developing diabetes mellitus are likely to have co-existing pancreatic exocrine insufficiency. Guidance Statement 1.2 : Diabetes occurring secondary to chronic pancreatitis should be recognized as pancreatogenic diabetes (type 3c diabetes). Guidance Statement 2.1 : The initial evaluation should include fasting glucose and HbA1c. These tests should be repeated annually. Impairment in either fasting glucose or HbA1c requires further evaluation. Guidance Statement 2.2 : Impairment in either fasting glucose or HbA1c should be further evaluated by a standard 75 g oral glucose tolerance test. Guidance Statement 2.3 : An absent pancreatic polypeptide response to mixed-nutrient ingestion is a specific indicator of type 3c diabetes. Guidance Statement 2.4 : Assessment of pancreatic endocrine reserve, and importantly that of functional beta-cell mass, should be performed as part of the evaluation and follow-up for total pancreatectomy with islet autotransplantation (TPIAT). Guidance Statement 3 : Patients with pancreatic diabetes shall be treated with specifically tailored medical nutrition and pharmacologic therapies. Conclusions Physicians should evaluate and treat glucose intolerance in patients with pancreatitis.
Abstract
Galleria mellonella (greater wax moth) larvae are used widely as surrogate infectious disease models, due to ease of use and the presence of an innate immune system functionally similar to ...that of vertebrates. Here, we review G. mellonella–human intracellular bacteria pathogen infection models from the genera Burkholderia, Coxiella, Francisella, Listeria, and Mycobacterium. For all genera, G. mellonella use has increased understanding of host–bacterial interactive biology, particularly through studies comparing the virulence of closely related species and/or wild-type versus mutant pairs. In many cases, virulence in G. mellonella mirrors that found in mammalian infection models, although it is unclear whether the pathogenic mechanisms are the same. The use of G. mellonella larvae has speeded up in vivo efficacy and toxicity testing of novel antimicrobials to treat infections caused by intracellular bacteria: an area that will expand since the FDA no longer requires animal testing for licensure. Further use of G. mellonella–intracellular bacteria infection models will be driven by advances in G. mellonella genetics, imaging, metabolomics, proteomics, and transcriptomic methodologies, alongside the development and accessibility of reagents to quantify immune markers, all of which will be underpinned by a fully annotated genome.
Infection of larvae of the insect Galleria mellonella (greater wax moth) with bacteria that reside inside human cells and cause disease (intracellular pathogens) is valuable in screening for new antibiotics and identifying bacterial factors necessary to cause disease.
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