Associations between weight loss history and factors related to type 2 diabetes risk in the Stop Diabetes study.

BACKGROUND: Frequent weight loss attempts are related to maladaptive eating behaviours and higher body mass index (BMI). We studied associations of several type 2 diabetes (T2D) risk factors with weight loss history, defined as the frequency of prior weight loss attempts, among Finnish adults at increased risk for T2D. METHODS: This study (n = 2684, 80% women) is a secondary analysis of the 1-year StopDia lifestyle intervention with digital intervention group, digital intervention + face-to-face counselling group, or control group. The frequency of prior weight loss attempts was categorized into five groups: no attempts/no attempts to lose weight, but trying to keep weight stable/1-2 attempts/3 or more attempts/ continuous attempts. Data on emotional eating and social/emotional nutrition self-efficacy were collected with a digital questionnaire. We assessed baseline differences between categories of weight loss history as well as the intervention effects. RESULTS: Altogether 84% of participants had attempted weight loss. Those with one or more weight loss attempts had higher BMI, larger waist circumference, and more emotional eating compared to 'no attempts' and 'no attempts to lose weight, but trying to keep weight stable' categories. The 'no attempts' category had the highest baseline fasting insulin, whereas it showed the largest decrease in this measure with the intervention. This change in fasting insulin in the 'no attempts' category was significantly different from all the other categories. Emotional nutrition self-efficacy slightly improved in the 'no attempts' category, which was significantly different from its concomitant decrease in the categories '1-2 attempts' and '3 or more attempts'. The intervention group assignment did not affect the results. CONCLUSIONS: Multiple attempts to lose weight may unfavourably affect T2D risk factors as well as lifestyle intervention outcomes. More research is needed on how weight loss frequency could affect T2D risk factors and how to design lifestyle interventions for individuals with frequent previous weight loss attempts.

Serum proteomic profiling at diagnosis predicts clinical course, and need for intensification of treatment in inflammatory bowel disease.

BACKGROUND: Success in personalized medicine in complex disease is critically dependent on biomarker discovery. We profiled serum proteins using a novel proximity extension assay [PEA] to identify diagnostic and prognostic biomarkers in inflammatory bowel disease [IBD]. METHODS: We conducted a prospective case-control study in an inception cohort of 552 patients [328 IBD, 224 non-IBD], profiling proteins recruited across six centres. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. Nested leave-one-out cross-validation was used to examine the performance of diagnostic and prognostic proteins. RESULTS: A total of 66 serum proteins differentiated IBD from symptomatic non-IBD controls, including matrix metallopeptidase-12 [MMP-12; Holm-adjusted p = 4.1 × 10-23] and oncostatin-M [OSM; p = 3.7 × 10-16]. Nine of these proteins are associated with cis-germline variation [59 independent single nucleotide polymorphisms]. Fifteen proteins, all members of tumour necrosis factor-independent pathways including interleukin-1 (IL-1) and OSM, predicted escalation, over a median follow-up of 518 [interquartile range 224-756] days. Nested cross-validation of the entire data set allowed characterization of five-protein models [96% comprising five core proteins ITGAV, EpCAM, IL18, SLAMF7 and IL8], which define a high-risk subgroup in IBD [hazard ratio 3.90, confidence interval: 2.43-6.26], or allowed distinct two- and three-protein models for ulcerative colitis and Crohn's disease respectively. CONCLUSION: We have characterized a simple oligo-protein panel that has the potential to identify IBD from symptomatic controls and to predict future disease course. Further prospective work is required to validate our findings.

Faecal microbiota signatures of IBD and their relation to diagnosis, disease phenotype, inflammation, treatment escalation and anti-TNF response in a European Multicentre Study (IBD-Character).

METHOD: We examined faecal samples, using the GA-map™ Dysbiosis Test, to associate gut microbiota composition with Crohn's disease (CD) and ulcerative colitis (UC) and to identify markers for future biomarker identification. We conducted a prospective case-control study (EU-ref. no. 305676) in an inception cohort of 324 individuals (64 CD, 84 UC, 116 symptomatic non-IBD controls and 44 healthy controls) across five European centres and examined 54 predetermined bacterial markers. We categorized patients according to the Montreal Classification and calculated the dysbiosis index (DI). Non-parametric tests were used to compare groups and the Bonferroni correction to adjust for multiple comparisons. RESULTS: The fluorescent signals (FSSs) for Firmicutes and Eubacterium hallii were lower in inflammatory bowel disease (IBD) vs. symptomatic controls (p<.05). FSS for Firmicutes, Lachnospiraceae, Eubacterium hallii and Ruminococcus albus/bromii were lower, whereas the signal for Bacteroides Fragilis was higher in UC vs. symptomatic controls (p<.05). FSS was higher for Bifidobacterium spp., Eubacterium hallii, Actinobacteria and Firmicutes among patients with ulcerative proctitis, compared to extensive colitis (p<.05). In CD, we observed no association with disease location. The DI correlated with faecal-calprotectin in both CD and in UC (p<.001). In terms of treatment escalation and anti-TNF response, differences were observed for some bacterial markers, but none of these associations were statistically significant. CONCLUSION: Our data reveal that the GA-map™ Dysbiosis Test holds the potential to characterize the faecal microbiota composition and to assess the degree of dysbiosis in new-onset IBD. On the other hand, our results cannot demonstrate any proven diagnostic or predictive value of this method to support clinical decision making.

Life Style Intervention Improves Retinopathy Status-The Finnish Diabetes Prevention Study.

The aim of the study was to find out whether participation in earlier intervention had an effect on the occurrence of retinopathy in study participants. We also examined risk factors (age, sex, weight, fasting and 2 h glucose, fasting insulin, blood pressure, serum lipids) for early retinal changes. The study included 522 individuals (mean 55 years old, range 40-64 years) with impaired glucose tolerance who were randomized into intervention (weight loss, healthy diet, and physical activity, N = 265) and control groups (N = 257). Intervention lasted for median of four years in 1993-2000, after which annual follow-up visits at study clinics were conducted. In the years 2002-2006 (at least five years after stopping intervention), fundus photography was offered for all study participants in four of five study clinics. Photographs were assessed by two experienced ophthalmologists (A.A. and K.K.), masked for the group assignment. After exclusion of poor quality photographs, the data of 211 individuals (N = 113 for intervention and N = 98 for control group) were included in the present study. The occurrence of microaneurysms was significantly higher in the control (37/98, 38%) than in the intervention group (27/113, 24%; p = 0.029). In the model, including age, sex, diabetes diagnosis before the retinal assessment, body mass index (BMI), and treatment group, the odds ratio for microaneurysms was markedly lower in intervention group (OR 0.52; 0.28-0.97, p = 0.039). The only risk factor that predicted the occurrence of microaneurysms was serum triglycerides at baseline (mean ± SD 1.9 ± 0.9 vs. 1.6 ± 0.7, mmol/L, with and without microaneurysms, respectively, p = 0.003). Triglycerides associated with decreased microaneurysms in regression analysis for age, sex, fasting glucose, and intervention group (OR 1.92, p = 0.018). Lifestyle intervention in overweight and obese individuals with impaired glucose tolerance showed decreased occurrence of retinal microaneurysms. Elevated serum triglycerides were associated to the development of early diabetic microangiopathy.

The effect of pre-pregnancy lifestyle counselling on food intakes and association between food intakes and gestational diabetes in high-risk women: results from a randomised controlled trial.

BACKGROUND: Healthy diets before and during pregnancy have been suggested to reduce the risk of gestational diabetes (GDM). Several lifestyle intervention studies for pregnant women have reported dietary improvements after counselling. However, evidence concerning the effect of counselling initiated before pregnancy on diets is limited. METHODS: This randomised controlled study explored whether pre-pregnancy lifestyle counselling influenced food intakes, as well as whether changes in food intakes were associated with GDM. The participants comprised 75 women with prior GDM and/or a body mass index ≥ 30 kg m-2 . Women were randomised into a control or an intervention group, and their food intakes were followed from pre-pregnancy to early pregnancy using a food frequency questionnaire. The control and intervention groups were combined to assess the association between changes in food intakes and GDM. The diagnosis of GDM was based on a 75-g oral glucose tolerance test conducted in the first and second trimester of pregnancy. RESULTS: Pre-pregnancy lifestyle counselling showed no major overall effect on food intakes. The intake of low-fat cheese increased significantly in women who did not develop GDM compared to women who did after adjusting for potential confounders (P = 0.028). This association was not observed for regular-fat cheese. CONCLUSIONS: The findings obtained in the present study suggest that an increased intake of low-fat but not regular-fat cheese between pre-pregnancy and early pregnancy is associated with a lower risk of GDM in high-risk women.

Alterations in fatty acid metabolism in response to obesity surgery combined with dietary counseling.

BACKGROUND: The effects of obesity surgery on serum and adipose tissue fatty acid (FA) profile and FA metabolism may modify the risk of obesity-related diseases. METHODS: We measured serum (n=122) and adipose tissue (n=24) FA composition and adipose tissue mRNA expression of genes regulating FA metabolism (n=100) in participants of the Kuopio Obesity Surgery Study (KOBS, age 47.2±8.7 years, BMI 44.6±6.0, 40 men, 82 women) before and one year after obesity surgery. As part of the surgery protocol, all the subjects were instructed to add sources of unsaturated fatty acids, such as rapeseed oil and fatty fish, into their diet. The results were compared with changes in serum FA composition in 122 subjects from the Finnish Diabetes Prevention study (DPS) (age 54.3±7.1 years, BMI 32.2±4.6, 28 men, 94 women). RESULTS: The proportion of saturated FAs decreased and the proportion of n-3 and n-6 FAs increased in serum triglycerides after obesity surgery (all P<0.002). Weight loss predicted changes in quantitative amounts of saturated FAs, monounsaturated FAs, n-3 and n-6 FAs in triglycerides (P<0.002 for all). Moreover, the changes in adipose tissue FAs reflected the changes in serum FAs, and some of the changes were associated with mRNA expression of elongases and desaturases in adipose tissue (all P<0.05). In line with this the estimated activity of elongase (18:1 n-7/16:1 n-7) increased significantly after obesity surgery in all lipid fractions (all P<4 × 10-7) and the increase in the estimated activity of D5D in triglycerides was associated with higher weight loss (r=0.415, P<2 × 10-6). Changes in serum FA profile were similar after obesity surgery and lifestyle intervention, except for the change in the absolute amounts of n-3 FAs between the two studies (P=0.044). CONCLUSIONS: Beneficial changes in serum and adipose tissue FAs after obesity surgery could be associated with changes in endogenous metabolism and diet.

Association between diet quality measured by the Healthy Food Intake Index and later risk of gestational diabetes-a secondary analysis of the RADIEL trial.

This corrects the article DOI: 10.1038/ejcn.2016.275.

An integrated analysis of micro- and macro-habitat features as a tool to detect weather-driven constraints: A case study with cavity nesters.

The effects of climate change on animal populations may be shaped by habitat characteristics at both micro- and macro-habitat level, however, empirical studies integrating these two scales of observation are lacking. As analyses of the effects of climate change commonly rely on data from a much larger scale than the microhabitat level organisms are affected at, this mismatch risks hampering progress in developing understanding of the details of the ecological and evolutionary responses of organisms and, ultimately, effective actions to preserve their populations. Cavity nesters, often with a conservation status of concern, are an ideal model because the cavity is a microenvironment potentially different from the macroenvironment but nonetheless inevitably interacting with it. The lesser kestrel (Falco naumanni) is a cavity nester which was until recently classified by as Vulnerable species. Since 2004, for nine years, we collected detailed biotic and abiotic data at both micro- and macro-scales of observation in a kestrel population breeding in the Gela Plain (Italy), a Mediterranean area where high temperatures may reach lethal values for the nest content. We show that macroclimatic features needed to be integrated with both abiotic and biotic factors recorded at a microscale before reliably predicting nest temperatures. Among the nest types used by lesser kestrels, we detected a preferential occupation of the cooler nest types, roof tiles, by early breeders whereas, paradoxically, late breeders nesting with hotter temperatures occupied the overheated nest holes. Not consistent with such a suggested nest selection, the coolest nest type did not host a higher reproductive success than the overheated nests. We discussed our findings in the light of cavity temperatures and nest types deployed within conservation actions assessed by integrating selected factors at different observation scales.

Association between diet quality measured by the Healthy Food Intake Index and later risk of gestational diabetes-a secondary analysis of the RADIEL trial.

The aim of this study was to find the association between adherence to the Nordic Nutrition Recommendations (NNR) and glucose metabolism. Participants were 137 pregnant obese women or women with a history of gestational diabetes (GDM) from the Finnish Gestational Diabetes Prevention Study. Adherence to the NNR was assessed by the Healthy Food Intake Index (HFII) calculated from the first trimesters' food frequency questionnaires. Higher HFII scores reflected higher adherence to the NNR (score range 0-17). Regression models with linear contrasts served for the main analysis. The mean HFII score was 10.0 (s.d. 2.8). The odds for GDM decreased toward the higher HFII categories (P=0.067). Fasting glucose (FG) and 2hG concentrations showed inverse linearity across the HFII categories (P(FG)=0.030 and P(2hG)=0.028, adjusted for body mass index, age and GDM/pregnancy history). Low adherence to the NNR is associated with higher antenatal FG and 2hG concentrations and possibly GDM.

Role of TRP Channels in Dinoflagellate Mechanotransduction.

Transient receptor potential (TRP) ion channels are common components of mechanosensing pathways, mainly described in mammals and other multicellular organisms. To gain insight into the evolutionary origins of eukaryotic mechanosensory proteins, we investigated the involvement of TRP channels in mechanosensing in a unicellular eukaryotic protist, the dinoflagellate Lingulodinium polyedra. BLASTP analysis of the protein sequences predicted from the L. polyedra transcriptome revealed six sequences with high similarity to human TRPM2, TRPM8, TRPML2, TRPP1, and TRPP2; and characteristic TRP domains were identified in all sequences. In a phylogenetic tree including all mammalian TRP subfamilies and TRP channel sequences from unicellular and multicellular organisms, the L. polyedra sequences grouped with the TRPM, TPPML, and TRPP clades. In pharmacological experiments, we used the intrinsic bioluminescence of L. polyedra as a reporter of mechanoresponsivity. Capsaicin and RN1734, agonists of mammalian TRPV, and arachidonic acid, an agonist of mammalian TRPV, TRPA, TRPM, and Drosophila TRP, all stimulated bioluminescence in L. polyedra. Mechanical stimulation of bioluminescence, but not capsaicin-stimulated bioluminescence, was inhibited by gadolinium (Gd3+), a general inhibitor of mechanosensitive ion channels, and the phospholipase C (PLC) inhibitor U73122. These pharmacological results are consistent with the involvement of TRP-like channels in mechanosensing by L. polyedra. The TRP channels do not appear to be mechanoreceptors but rather are components of the mechanotransduction signaling pathway and may be activated via a PLC-dependent mechanism. The presence and function of TRP channels in a dinoflagellate emphasize the evolutionary conservation of both the channel structures and their functions.

Bowel function and quality of life after superior mesenteric nerve plexus transection in right colectomy with D3 extended mesenterectomy.

BACKGROUND: The aim of this study was to ascertain the impact of injury to the superior mesenteric nerve plexus caused by right colectomy with D3 extended mesenterectomy as performed in the prospective multicenter trial: "Safe Radical D3 Right Hemicolectomy for Cancer through Preoperative Biphasic Multi-detector Computed Tomography" in which all soft tissue surrounding the superior mesenteric vessels from the level of the middle colic artery to that of the ileocolic artery was removed. METHODS: Bowel function and gastrointestinal quality of life in two consecutive cohorts that underwent right colectomy with and without D3 extended mesenterectomy were compared. Main outcome measures were the Diarrhea Assessment Scale (DAS) and Gastrointestinal Quality of Life Index (GIQLI). The data were collected prospectively through telephone interviews. RESULTS: Forty-nine patients per group, comparable for age, sex, length of bowel resected but with significantly shorter follow-up time in the experimental group, were included. There was no difference in total DAS scores, subscores or additional questions except for higher bowel frequency scores in the D3 group (p = 0.02). Comparison of total GIQLI scores and subscales showed no difference between groups. Regression analysis with correction for confounding factors showed 0.48 lower bowel frequency scores in the D2 group (p = 0.022). Within the D3 group presence of jejunal arteries cranial to the D3 dissection area showed 1.78 lower DAS scores and 0.7 lower bowel frequency scores. CONCLUSIONS: Small bowel denervation after right colectomy with D3 extended mesenterectomy leads to increased bowel frequency but does not impact gastrointestinal quality of life. Individual anatomical variants can affect postoperative bowel function differently despite standardized surgery.

Association of Long-Term Dietary Fat Intake, Exercise, and Weight with Later Cognitive Function in the Finnish Diabetes Prevention Study.

OBJECTIVES: To investigate associations of long-term nutrient intake, physical activity and obesity with later cognitive function among the participants in the Finnish Diabetes Prevention Study, in which a lifestyle intervention was successful in diabetes prevention. DESIGN: An active lifestyle intervention phase during middle age (mean duration 4 years) and extended follow-up (additional 9 years) with annual lifestyle measurements, followed by an ancillary cognition assessment. SETTING: 5 research centers in Finland. PARTICIPANTS: Of the 522 middle-aged, overweight participants with impaired glucose tolerance recruited to the study, 364 (70%) participated in the cognition assessment (mean age 68 years). MEASUREMENTS: A cognitive assessment was executed with the CERAD test battery and the Trail Making Test A on average 13 years after baseline. Lifestyle measurements included annual clinical measurements, food records, and exercise questionnaires during both the intervention and follow-up phase. RESULTS: Lower intake of total fat (p=0.021) and saturated fatty acids (p=0.010), and frequent physical activity (p=0.040) during the whole study period were associated with better cognitive performance. Higher BMI (p=0.012) and waist circumference (p=0.012) were also associated with worse performance, but weight reduction prior to the cognition assessment predicted worse performance as well (decrease vs. increase, p=0.008 for BMI and p=0.002 for waist). CONCLUSIONS: Long-term dietary fat intake, BMI, and waist circumference have an inverse association with cognitive function in later life among people with IGT. However, decreases in BMI and waist prior to cognitive assessment are associated with worse cognitive performance, which could be explained by reverse causality.

The effect of dietary counselling on food intakes in pregnant women at risk for gestational diabetes: a secondary analysis of a randomised controlled trial RADIEL.

BACKGROUND/OBJECTIVES: The prevalence of gestational diabetes mellitus (GDM) is increasing worldwide. GDM may be prevented by improving the diets of pregnant women. The objective of this study was to evaluate the effect of dietary counselling on the diets of pregnant women at GDM risk. SUBJECTS/METHODS: This study was a secondary analysis of a randomised controlled trial the Finnish gestational diabetes prevention study (RADIEL) in which pre-pregnant and pregnant women with previous GDM or BMI ⩾30 kg/m(2) were allocated into two groups, namely the control and the intervention groups. The control group received standard antenatal dietary counselling according to the Finnish Nutrition Recommendations. The intervention group participated in one individual dietary counselling session and one group dietary counselling session in addition to the standard counselling. This study included women who were recruited during pregnancy. To assess changes in food intake, food-intake questionnaires were collected during the first and the second trimester of pregnancy. Bootstrap type analysis of covariance was used, and 242 participants were included in the final analysis to study changes in food intake. RESULTS: The intakes of low-fat cheese (baseline adjusted mean 0.09 times/day; 95% confidence interval (CI) 0.07, 0.24; P=0.040) and fish (baseline adjusted mean 0.28 times per week; 95% CI 0.08, 0.49; P=0.011) showed a significant increase in the intervention group compared with the control group. CONCLUSIONS: This study showed that dietary counselling in early pregnancy can lead to modest dietary improvements in pregnant women at GDM risk.

Markers of cholesterol metabolism as biomarkers in predicting diabetes in the Finnish Diabetes Prevention Study.

BACKGROUND AND AIMS: We examined the effect of serum markers of cholesterol synthesis and absorption on the incidence of type 2 diabetes (T2D) in the randomized Finnish Diabetes Prevention Study (DPS). We also explored a possible interaction of ABCG8 rs4299376 on sterol levels and lifestyle intervention. METHODS AND RESULTS: We conducted a prospective cohort study including overweight, middle-aged people with impaired glucose tolerance at baseline who participated in the randomized DPS. The primary outcome of the DPS was the diagnosis of T2D based on repeated oral glucose tolerance tests (OGTTs). After active intervention (median of four years, 1994-2001), non-T2D participants were further followed until T2D diagnosis, dropout or the end of 2009. Of these, 340 participants who had ß-sitosterol, campesterol, lathosterol and desmosterol measured by gas chromatography-mass spectrometry during the active four-year follow-up and who were not using cholesterol lowering medications were analysed. Surrogate indexes of insulin sensitivity (IS) and secretion were calculated from an OGTT. In adjusted models, plant sterols during the four-year follow-up were associated with lower T2D incidence during the extended eight-year follow-up (HR for 1-SD change in ß-sitosterol and campesterol: 0.76 [0.63-0.92], and 0.81 [0.67-0.99], respectively). Lathosterol levels were associated with higher T2D incidence (HR: 1.35 [1.13-1.62]). These associations, though, were not independent of IS. There was an interaction between rs4299376 and study group on ß-sitosterol (p = 0.001) and campesterol (p = 0.004) levels during the follow-up. CONCLUSIONS: Markers of low absorption and high synthesis of cholesterol were associated with the risk of developing T2D, mostly ascribed to IS.

National diabetes prevention program (DEHKO): awareness and self-reported lifestyle changes in Finnish middle-aged population.

OBJECTIVES: The national development programme for the prevention and care of diabetes was carried out in Finland during 2000-2010. One of the programme goals was to raise awareness of diabetes and its risk factors in the whole population through various activities, e.g. media campaigns and health fares. In addition, a targeted implementation project on the prevention of type 2 diabetes, FIN-D2D, was carried out in selected districts during 2003-2008. The aim of this analysis was to examine the changes in overall awareness of the programme and its association with self-reported lifestyle changes within the adult population during the FIN-D2D project period in the FIN-D2D area compared with the area not participating in the FIN-D2D (the control area). STUDY DESIGN: Health behaviour and health among the Finnish Adult Population -postal survey. METHODS: The structured questionnaire mailed to a random population sample included questions on participants' sociodemographic background, medical history, health habits, and recent lifestyle changes. Awareness of the national diabetes programme was also enquired. Data (n = 10 831) from the 2004-2008 postal surveys were used for this investigation. RESULTS: In the FIN-D2D area, 25% (347/1384) of men and 48% (797/1674) of women reported being aware of the programme. In the control area, the proportions were 20% (702/3551) and 36% (1514/4222), respectively. The overall awareness increased among both genders and in all areas during the project period, but the level of awareness was consistently higher in the FIN-D2D area. Female gender and higher age were associated with increasing awareness of the programme in both areas. Self-reported lifestyle changes were more common among women, but associated with the level of awareness of the programme more often among men than women. CONCLUSIONS: The awareness of diabetes and its risk factors increased among men and women in both implementation and control areas during the FIN-D2D project period. The activities of the implementation project may at least partly explain the differences in lifestyle changes between areas, especially among men. The results suggest that health promotion campaigns increase the population awareness about the prevention of chronic diseases and as a result, especially men may be prompted to make beneficial lifestyle changes.

Development of intestinal ion-transporting mechanisms during smoltification and seawater acclimation in Atlantic salmon Salmo salar.

This study investigated the expression of ion transporters involved in intestinal fluid absorption and presents evidence for developmental changes in abundance and tissue distribution of these transporters during smoltification and seawater (SW) acclimation of Atlantic salmon Salmo salar. Emphasis was placed on Na(+) , K(+) -ATPase (NKA) and Na(+) , K(+) , Cl(-) co-transporter (NKCC) isoforms, at both transcriptional and protein levels, together with transcription of chloride channel genes. The nka α1c was the dominant isoform at the transcript level in both proximal and distal intestines; also, it was the most abundant isoform expressed in the basolateral membrane of enterocytes in the proximal intestine. This isoform was also abundantly expressed in the distal intestine in the lower part of the mucosal folds. The protein expression of intestinal Nkaα1c increased during smoltification. Immunostaining was localized to the basal membrane of the enterocytes in freshwater (FW) fish, and re-distributed to a lateral position after SW entry. Two other Nka isoforms, α1a and α1b, were expressed in the intestine but were not regulated to the same extent during smoltification and subsequent SW transfer. Their localization in the intestinal wall indicates a house-keeping function in excitatory tissues. The absorptive form of the NKCC-like isoform (sub-apically located NKCC2 and/or Na(+) , Cl(-) co-transporter) increased during smoltification and further after SW transfer. The cellular distribution changed from a diffuse expression in the sub-apical regions during smoltification to clustering of the transporters closer to the apical membrane after entry to SW. Furthermore, transcript abundance indicates that the mechanisms necessary for exit of chloride ions across the basolateral membrane and into the lateral intercellular space are present in the form of one or more of three different chloride channels: cystic fibrosis transmembrane conductance regulator I and II and chloride channel 3.

Rare human nicotinic acetylcholine receptor α4 subunit (CHRNA4) variants affect expression and function of high-affinity nicotinic acetylcholine receptors.

Nicotine, the primary psychoactive component in tobacco smoke, produces its behavioral effects through interactions with neuronal nicotinic acetylcholine receptors (nAChRs). α4ß2 nAChRs are the most abundant in mammalian brain, and converging evidence shows that this subtype mediates the rewarding and reinforcing effects of nicotine. A number of rare variants in the CHRNA4 gene that encode the α4 nAChR subunit have been identified in human subjects and appear to be underrepresented in a cohort of smokers. We compared three of these variants (α4R336C, α4P451L, and α4R487Q) to the common variant to determine their effects on α4ß2 nAChR pharmacology. We examined [(3)H]epibatidine binding, interacting proteins, and phosphorylation of the α4 nAChR subunit with liquid chromatography and tandem mass spectrometry (LC-MS/MS) in HEK 293 cells and voltage-clamp electrophysiology in Xenopus laevis oocytes. We observed significant effects of the α4 variants on nAChR expression, subcellular distribution, and sensitivity to nicotine-induced receptor upregulation. Proteomic analysis of immunopurified α4ß2 nAChRs incorporating the rare variants identified considerable differences in the intracellular interactomes due to these single amino acid substitutions. Electrophysiological characterization in X. laevis oocytes revealed alterations in the functional parameters of activation by nAChR agonists conferred by these α4 rare variants, as well as shifts in receptor function after incubation with nicotine. Taken together, these experiments suggest that genetic variation at CHRNA4 alters the assembly and expression of human α4ß2 nAChRs, resulting in receptors that are more sensitive to nicotine exposure than those assembled with the common α4 variant. The changes in nAChR pharmacology could contribute to differences in responses to smoked nicotine in individuals harboring these rare variants.

Megaesophagus in a line of transgenic rats: a model of achalasia.

Megaesophagus is defined as the abnormal enlargement or dilatation of the esophagus, characterized by a lack of normal contraction of the esophageal walls. This is called achalasia when associated with reduced or no relaxation of the lower esophageal sphincter (LES). To date, there are few naturally occurring models for this disease. A colony of transgenic (Pvrl3-Cre) rats presented with megaesophagus at 3 to 4 months of age; further breeding studies revealed a prevalence of 90% of transgene-positive animals having megaesophagus. Affected rats could be maintained on a total liquid diet long term and were shown to display the classic features of dilated esophagus, closed lower esophageal sphincter, and abnormal contractions on contrast radiography and fluoroscopy. Histologically, the findings of muscle degeneration, inflammation, and a reduced number of myenteric ganglia in the esophagus combined with ultrastructural lesions of muscle fiber disarray and mitochondrial changes in the striated muscle of these animals closely mimic that seen in the human condition. Muscle contractile studies looking at the response of the lower esophageal sphincter and fundus to electrical field stimulation, sodium nitroprusside, and L-nitro-L-arginine methyl ester also demonstrate the similarity between megaesophagus in the transgenic rats and patients with achalasia. No primary cause for megaesophagus was found, but the close parallel to the human form of the disease, as well as ease of care and manipulation of these rats, makes this a suitable model to better understand the etiology of achalasia as well as study new management and treatment options for this incurable condition.

Improved lifestyle and decreased diabetes risk over 13 years: long-term follow-up of the randomised Finnish Diabetes Prevention Study (DPS).

AIMS/HYPOTHESIS: This study aimed to determine whether lifestyle intervention lasting for 4 years affected diabetes incidence, body weight, glycaemia or lifestyle over 13 years among individuals at high risk of type 2 diabetes. METHODS: Overweight, middle-aged men (n = 172) and women (n = 350) with impaired glucose tolerance were randomised in 1993-1998 to an intensive lifestyle intervention group (n = 265), aiming at weight reduction, dietary modification and increased physical activity, or to a control group (n = 257) that received general lifestyle information. The primary outcome was a diagnosis of diabetes based on annual OGTTs. Secondary outcomes included changes in body weight, glycaemia, physical activity and diet. After active intervention (median 4 years, range 1-6 years), participants still free of diabetes and willing to continue their participation (200 in the intervention group and 166 in the control group) were further followed until diabetes diagnosis, dropout or the end of 2009, with a median total follow-up of 9 years and a time span of 13 years from baseline. RESULTS: During the total follow-up the adjusted HR for diabetes (intervention group vs control group) was 0.614 (95% CI 0.478, 0.789; p < 0.001). The corresponding HR during the post-intervention follow-up was 0.672 (95% CI 0.477, 0.947; p = 0.023). The former intervention group participants sustained lower absolute levels of body weight, fasting and 2 h plasma glucose and a healthier diet. Adherence to lifestyle changes during the intervention period predicted greater risk reduction during the total follow-up. CONCLUSIONS/INTERPRETATION: Lifestyle intervention in people at high risk of type 2 diabetes induces sustaining lifestyle change and results in long-term prevention of progression to type 2 diabetes.

Delaying progression to type 2 diabetes among high-risk Spanish individuals is feasible in real-life primary healthcare settings using intensive lifestyle intervention.

AIMS/HYPOTHESIS: To assess the feasibility and effectiveness of an active real-life primary care lifestyle intervention in preventing type 2 diabetes within a high-risk Mediterranean population. METHODS: A prospective cohort study was performed in the setting of Spanish primary care. White-European individuals without diabetes aged 45-75 years (n = 2,054) were screened using the Finnish Diabetes Risk Score (FINDRISC) and a subsequent 2 h OGTT. Where feasible, high-risk individuals who were identified were allocated sequentially to standard care, a group-based or an individual level intervention (intensive reinforced DE-PLAN [Diabetes in Europe-Prevention using Lifestyle, Physical Activity and Nutritional] intervention). The primary outcome was the development of diabetes according to WHO criteria. Analyses after 4-year follow-up were performed based on the intention-to-treat principle with comparison of standard care and the combined intervention groups. RESULTS: The standard care (n = 219) and intensive intervention (n = 333) groups were comparable in age (62.0/62.2 years), sex (64.4/68.2% women), BMI (31.3/31.2 kg/m(2)), FINDRISC score (16.2/15.8 points), fasting (5.3/5.2 mmol/l), 2 h plasma glucose (7.1/6.9 mmol/l) and self-reported interest to make lifestyle changes at baseline. Diabetes was diagnosed in 124 individuals: 63 (28.8%) in the standard care group and 61 (18.3%) in the intensive intervention group. During a 4.2-year median follow-up, the incidences of diabetes were 7.2 and 4.6 cases per 100 person-years, respectively (36.5% relative risk reduction, p < 0.005). The number of participants needed to be treated by intensive intervention for 4 years to reduce one case of diabetes was 9.5. CONCLUSIONS/INTERPRETATION: Intensive lifestyle intervention is feasible in a primary care setting and substantially reduces diabetes incidence among high-risk individuals. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov NCT01519505. FUNDING: Commission of the European Communities, Institute of Health Carlos III, Spanish Ministry of Health and Department of Health, Generalitat de Catalunya.