Gestational diabetes as a risk factor for pancreatic cancer: a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>Diabetes is known to be associated with cancer of the pancreas, though there is some debate as to whether it is a cause or a consequence of the disease. We investigated the incidence of pancreatic cancer in a cohort of 37926 Israeli women followed for 28–40 years for whom information on diabetes had been collected at the time they gave birth, in 1964–1976, in Jerusalem. There were 54 cases of pancreatic cancer ascertained from the Israel Cancer Registry during follow-up.</p> <p>Methods</p> <p>We used Cox proportional hazards models to adjust for age at baseline and explore effects of other risk factors, including ethnic groups, preeclampsia, birth order and birth weight of offspring.</p> <p>Results</p> <p>We observed no cases of pancreatic cancer in the women with insulin dependent diabetes; however, there were five cases in the women with gestational diabetes. The interval between the record of diabetes in pregnancy and the diagnosis of pancreatic cancer ranged from 14–35 years. Women with a history of gestational diabetes showed a relative risk of pancreatic cancer of 7.1 (95% confidence interval, 2.8–18.0).</p> <p>Conclusion</p> <p>We conclude that gestational diabetes is strongly related to the risk of cancer of the pancreas in women in this population, and that gestational diabetes can precede cancer diagnosis by many years.</p

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance.

INTRODUCTION: 2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance. METHODS: This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009-2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence). RESULTS: Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60-1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14-2.28) when Hr genotype was included, but this analysis lacked power (p=0.42). CONCLUSIONS: In a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations

Digestibility of resistant starch containing preparations using two in vitro models

BACKGROUND: Resistant starch (RS) is known for potential health benefits in the human colon. To investigate these positive effects it is important to be able to predict the amount, and the structure of starch reaching the large intestine. AIM OF THE STUDY: The aim of this study was to compare two different in vitro models simulating the digestibility of two RS containing preparations. METHODS: The substrates, high amylose maize (HAM) containing RS type 2, and retrograded long chain tapioca maltodextrins (RTmd) containing RS type 3 were in vitro digested using a batch and a dynamic model, respectively. Both preparations were characterized before and after digestion by using X-Ray and DSC, and by measuring their total starch, RS and protein contents. RESULTS: Using both digestion models, 60-61 g/100 g of RTmd turned out to be indigestible, which is very well in accordance with 59 g/100 g found in vivo after feeding RTmd to ileostomy patients. In contrast, dynamic and batch in vitro digestion experiments using HAM as a substrate led to 58 g/100 g and 66 g/100 g RS recovery. The degradability of HAM is more affected by differences in experimental parameters compared to RTmd. The main variations between the two in vitro digestion methods are the enzyme preparations used, incubation times and mechanical stress exerted on the substrate. However, for both preparations dynamically digested fractions led to lower amounts of analytically RS and a lower crystallinity. CONCLUSIONS: The two in vitro digestion methods used attacked the starch molecules differently, which influenced starch digestibility of HAM but not of RTmd

Is there a protective effect of normal to high intellectual function on mental health in children with chronic illness?

<p>Abstract</p> <p>Background</p> <p>High intellectual function is considered as a protective factor for children's mental health. Few studies have investigated the effect of intellectual function on mental health in children with chronic illness (CI). The aim of the present study was twofold: First, we asked if <it>normal to high </it>intellectual function (IQ) has a protective effect on mental health in children with CI, and secondly, if this effect is more substantial than in their peers (NCI).</p> <p>Methods</p> <p>The participants were selected among children who participated in the Bergen Child Study (BCS): 96 children with CI (the CI-group) and 96 children without CI (the NCI-group). The groups were matched on intellectual function as measured by the WISC-III by selecting the same number of children from three levels of the Full Scale IQ Score (FSIQ): "very low" (<70),"low" (70 to 84), or "normal to high" (>84). CI was reported by parents as part of a diagnostic interview (Kiddie-SADS-PL) that also generated the mental health measures used in the present study: the presence of a DSM-IV psychiatric diagnosis and the score on the Children's Global Assessment Scale.</p> <p>Results</p> <p>The risk of a psychiatric diagnosis was significantly lower for children with a normal to high FSIQ-level than for children with a very low and low FSIQ-level in the CI-group as well as in the NCI-group. The group differences were statistically non-significant for all three FSIQ-levels, and the effect of the interaction between the group-variable (CI/NCI) and the FSIQ-level was non-significant on both measures of mental health.</p> <p>Conclusion</p> <p>The present study showed a protective effect of normal to high intellectual function on children's mental health. This protective effect was not more substantial in children with CI than in children without CI.</p

Serine phosphorylation regulates paxillin turnover during cell migration

BACKGROUND: Paxillin acts as an adaptor protein that localizes to focal adhesion. This protein is regulated during cell migration by phosphorylation on tyrosine, serine and threonine residues. Most of these phosphorylations have been implicated in the regulation of different steps of cell migration. The two major phosphorylation sites of paxillin in response to adhesion to an extracellular matrix are serines 188 and 190. However, the function of this phosphorylation event remains unknown. The purpose of this work was to determine the role of paxillin phosphorylation on residues S188 and S190 in the regulation of cell migration. RESULTS: We used NBT-II epithelial cells that can be induced to migrate when plated on collagen. To examine the role of paxillin serines 188/190 in cell migration, we constructed an EGFP-tagged paxillin mutant in which S188/S190 were mutated into unphosphorylatable alanine residues. We provide evidence that paxillin is regulated by proteasomal degradation following polyubiquitylation of the protein. During active cell migration on collagen, paxillin is protected from proteasome-dependent degradation. We demonstrate that phosphorylation of serines 188/190 is necessary for the protective effect of collagen. In an effort to understand the physiological relevance of paxillin protection from degradation, we show that cells expressing the paxillin S188/190A interfering mutant spread less, have reduced protrusive activity but migrate more actively. CONCLUSION: Our data demonstrate for the first time that serine-regulated degradation of paxillin plays a key role in the modulation of membrane dynamics and consequently, in the control of cell motility

Pleuro-pulmonary tumours detected by clinical and chest X-ray analyses in rats transplanted with mesothelioma cells

New strategies for cancer therapy must be developed, especially in severe neoplasms such as malignant pleural mesothelioma. Animal models of cancer, as close as possible to the human situation, are needed to investigate novel therapeutical approaches. Orthotopic transplantation of cancer cells is then relevant and efforts should be made to follow up tumour evolution in animals. In the present study, we developed a method for the orthotopic growth of mesothelioma cells in the pleural cavity of Fischer 344 and nude rats, along with a procedure for clinical survey. Two mesothelioma cell lines, of rat and human origin, were inoculated by transthoracic puncture. Body weight determination and chest X-ray analyses permitted the follow-up of tumour evolution by identifying different stages. Autopsies showed that tumours localized on the whole pleural cavity (diaphragm, parietal pleura), mediastinum and pericardium. Tumour morphology and antigenic characteristics were consistent with those of the inoculated cells and were similar in both types of rats inoculated with the same cell type. These results demonstrate that mesothelioma formation in rats can be followed up by clinical and radiographic survey after gentle intrathoracic inoculation of mesothelioma cells, thus allowing the definition of stages of interest for further experimental trials. © 1999 Cancer Research Campaig

Predicting the demand of physician workforce: an international model based on "crowd behaviors"

<p>Abstract</p> <p>Background</p> <p>Appropriateness of physician workforce greatly influences the quality of healthcare. When facing the crisis of physician shortages, the correction of manpower always takes an extended time period, and both the public and health personnel suffer. To calculate an appropriate number of Physician Density (PD) for a specific country, this study was designed to create a PD prediction model, based on health-related data from many countries.</p> <p>Methods</p> <p>Twelve factors that could possibly impact physicians' demand were chosen, and data of these factors from 130 countries (by reviewing 195) were extracted. Multiple stepwise-linear regression was used to derive the PD prediction model, and a split-sample cross-validation procedure was performed to evaluate the generalizability of the results.</p> <p>Results</p> <p>Using data from 130 countries, with the consideration of the correlation between variables, and preventing multi-collinearity, seven out of the 12 predictor variables were selected for entry into the stepwise regression procedure. The final model was: PD = (5.014 - 0.128 × proportion under age 15 years + 0.034 × life expectancy)², with R²of 80.4%. Using the prediction equation, 70 countries had PDs with "negative discrepancy", while 58 had PDs with "positive discrepancy".</p> <p>Conclusion</p> <p>This study provided a regression-based PD model to calculate a "norm" number of PD for a specific country. A large PD discrepancy in a country indicates the needs to examine physician's workloads and their well-being, the effectiveness/efficiency of medical care, the promotion of population health and the team resource management.</p

Inducible expression of Pisum sativum xyloglucan fucosyltransferase in the pea root cap meristem, and effects of antisense mRNA expression on root cap cell wall structural integrity

Mitosis and cell wall synthesis in the legume root cap meristem can be induced and synchronized by the nondestructive removal of border cells from the cap periphery. Newly synthesized cells can be examined microscopically as they differentiate progressively during cap development, and ultimately detach as a new population of border cells. This system was used to demonstrate that Pisum sativum L. fucosyl transferase (PsFut1) mRNA expression is strongly expressed in root meristematic tissues, and is induced >2-fold during a 5-h period when mitosis in the root cap meristem is increased. Expression of PsFut1 antisense mRNA in pea hairy roots under the control of the CaMV35S promoter, which exhibits meristem localized expression in pea root caps, resulted in a 50–60% reduction in meristem localized endogenous PsFut1 mRNA expression measured using whole mount in situ hybridization. Changes in gross levels of cell wall fucosylated xyloglucan were not detected, but altered surface localization patterns were detected using whole mount immunolocalization with CCRC-M1, an antibody that recognizes fucosylated xyloglucan. Emerging hairy roots expressing antisense PsFut1 mRNA appeared normal macroscopically but scanning electron microscopy of tissues with altered CCRC-M1 localization patterns revealed wrinkled, collapsed cell surfaces. As individual border cells separated from the cap periphery, cell death occurred in correlation with extrusion of cellular contents through breaks in the wall

Circumstellar disks and planets. Science cases for next-generation optical/infrared long-baseline interferometers

We present a review of the interplay between the evolution of circumstellar disks and the formation of planets, both from the perspective of theoretical models and dedicated observations. Based on this, we identify and discuss fundamental questions concerning the formation and evolution of circumstellar disks and planets which can be addressed in the near future with optical and infrared long-baseline interferometers. Furthermore, the importance of complementary observations with long-baseline (sub)millimeter interferometers and high-sensitivity infrared observatories is outlined.Comment: 83 pages; Accepted for publication in "Astronomy and Astrophysics Review"; The final publication is available at http://www.springerlink.co

The N–Terminal Tail of hERG Contains an Amphipathic α–Helix That Regulates Channel Deactivation

The cytoplasmic N–terminal domain of the human ether–a–go–go related gene (hERG) K+ channel is critical for the slow deactivation kinetics of the channel. However, the mechanism(s) by which the N–terminal domain regulates deactivation remains to be determined. Here we show that the solution NMR structure of the N–terminal 135 residues of hERG contains a previously described Per–Arnt–Sim (PAS) domain (residues 26–135) as well as an amphipathic α–helix (residues 13–23) and an initial unstructured segment (residues 2–9). Deletion of residues 2–25, only the unstructured segment (residues 2–9) or replacement of the α–helix with a flexible linker all result in enhanced rates of deactivation. Thus, both the initial flexible segment and the α–helix are required but neither is sufficient to confer slow deactivation kinetics. Alanine scanning mutagenesis identified R5 and G6 in the initial flexible segment as critical for slow deactivation. Alanine mutants in the helical region had less dramatic phenotypes. We propose that the PAS domain is bound close to the central core of the channel and that the N–terminal α–helix ensures that the flexible tail is correctly orientated for interaction with the activation gating machinery to stabilize the open state of the channel