Overweight, hyperglycemia and tobacco use are modifiable risk factors for onset of retinopathy 9 and 17years after the diagnosis of diabetes - A retrospective observational nation-wide cohort study.

BACKGROUND: The aims of this study were to estimate the risk for diabetic retinopathy (DR) and to identify risk factors. We investigated a nationwide population-based cohort with diabetes diagnosed at age 15-34years. PATIENTS AND METHODS: Of 794 patients registered 1987-1988 in the Diabetes Incidence Study in Sweden (DISS) 444 (56%) patients with retinal photos available for classification of retinopathy participated in a follow-up study 15-19 (median 17) years after diagnosis. Mean age was 42.3±5.7years, BMI 26.1±4.1kg/m2, 62% were male and 91% had type 1 diabetes. A sub-study was performed in 367 patients with retinal photos from both the 9 and 17year follow up and the risk for development of retinopathy between 9 and 17years of follow up was calculated. RESULTS: After median 17years 324/444 (73%, 67% of T1D and 71% of T2D), had developed any DR but only 5.4% proliferative DR. Male sex increased the risk of developing retinopathy (OR 1.9, 95% CI 1.2-2.9). In the sub-study obesity (OR 1.2, 95% CI 1.04-1.4), hyperglycemia (OR 2.5, 95% CI 1.6-3.8) and tobacco use (OR 2.9, 95% CI 1.1-7.3) predicted onset of retinopathy between 9 and 17years after diagnosis of diabetes. CONCLUSION: The number of patients with severe retinopathy after 17years of diabetes disease was small. The risk of developing retinopathy with onset between 9 and 17years after diagnosis of diabetes was strongly associated to modifiable risk factors such as glycemic control, obesity and tobacco use.

Membrane interactions and antimicrobial effects of layered double hydroxide nanoparticles.

Membrane interactions are critical for the successful use of inorganic nanoparticles as antimicrobial agents and as carriers of, or co-actives with, antimicrobial peptides (AMPs). In order to contribute to an increased understanding of these, we here investigate effects of particle size (42-208 nm) on layered double hydroxide (LDH) interactions with both bacteria-mimicking and mammalian-mimicking lipid membranes. LDH binding to bacteria-mimicking membranes, extraction of anionic lipids, as well as resulting membrane destabilization, was found to increase with decreasing particle size, also translating into size-dependent synergistic effects with the antimicrobial peptide LL-37. Due to strong interactions with anionic lipopolysaccharide and peptidoglycan layers, direct membrane disruption of both Gram-negative and Gram-positive bacteria is suppressed. However, LDH nanoparticles cause size-dependent charge reversal and resulting flocculation of both liposomes and bacteria, which may provide a mechanism for bacterial confinement or clearance. Taken together, these findings demonstrate a set of previously unknown behaviors, including synergistic membrane destabilization and dual confinement/killing of bacteria through combined LDH/AMP exposure, of potential therapeutic interest.

Barriers and facilitators experienced in collaborative prospective research in orthopaedic oncology: A qualitative study.

OBJECTIVES: As tumours of bone and soft tissue are rare, multicentre prospective collaboration is essential for meaningful research and evidence-based advances in patient care. The aim of this study was to identify barriers and facilitators encountered in large-scale collaborative research by orthopaedic oncological surgeons involved or interested in prospective multicentre collaboration. METHODS: All surgeons who were involved, or had expressed an interest, in the ongoing Prophylactic Antibiotic Regimens in Tumour Surgery (PARITY) trial were invited to participate in a focus group to discuss their experiences with collaborative research in this area. The discussion was digitally recorded, transcribed and anonymised. The transcript was analysed qualitatively, using an analytic approach which aims to organise the data in the language of the participants with little theoretical interpretation. RESULTS: The 13 surgeons who participated in the discussion represented orthopaedic oncology practices from seven countries (Argentina, Brazil, Italy, Spain, Denmark, United States and Canada). Four categories and associated themes emerged from the discussion: the need for collaboration in the field of orthopaedic oncology due to the rarity of the tumours and the need for high level evidence to guide treatment; motivational factors for participating in collaborative research including establishing proof of principle, learning opportunity, answering a relevant research question and being part of a collaborative research community; barriers to participation including funding, personal barriers, institutional barriers, trial barriers, and administrative barriers and facilitators for participation including institutional facilitators, leadership, authorship, trial set-up, and the support of centralised study coordination. CONCLUSIONS: Orthopaedic surgeons involved in an ongoing international randomised controlled trial (RCT) were motivated by many factors to participate. There were a number of barriers to and facilitators for their participation. There was a collective sense of fatigue experienced in overcoming these barriers, which was mirrored by a strong collective sense of the importance of, and need for, collaborative research in this field. The experiences were described as essential educational first steps to advance collaborative studies in this area. Knowledge gained from this study will inform the development of future large-scale collaborative research projects in orthopaedic oncology.Cite this article: J. S. Rendon, M. Swinton, N. Bernthal, M. Boffano, T. Damron, N. Evaniew, P. Ferguson, M. Galli Serra, W. Hettwer, P. McKay, B. Miller, L. Nystrom, W. Parizzia, P. Schneider, A. Spiguel, R. Vélez, K. Weiss, J. P. Zumárraga, M. Ghert. Barriers and facilitators experienced in collaborative prospective research in orthopaedic oncology: A qualitative study. Bone Joint Res 2017;6:-314. DOI: 10.1302/2046-3758.65.BJR-2016-0192.R1.

Blood plasma lipidome profile of dairy cows during the transition period.

BACKGROUND: The transition period of dairy cows, around parturition and the onset of lactation, involves endocrine and metabolic changes to compensate for an increased energy requirement aggravated by reduced feed intake. Transition cows adjust to the resulting negative energy balance with the mobilization of lipids from the adipose tissues yielding increased blood levels of non-esterified fatty acids and ketone bodies like ß-hydroxybutyrate. RESULTS: To study the biochemical adaptations underlying this physiologic adjustment and possible pathologic derangements, we analyzed the blood plasma lipidome of transition cows by ultra-pressure liquid chromatography coupled to high-resolution quadrupole time-of-flight mass spectrometry. The resulting data were processed by principal component analysis, revealing over 60 lipid masses that change in abundance over the test period ranging from two weeks before calving to four weeks postpartum. Further characterization of analytes by tandem mass spectrometry demonstrated that the concentration of triacylglycerides in plasma drops at the day of parturition whereas the plasma level of many phosphatidylcholines and two sphingomyelins increases steadily during early lactation. CONCLUSION: This newly identified shift in phospholipid composition delivers a potential biomarker to detect aberrant metabolic pathways in transition cows and also provides insights into how to prevent and treat associated disorders like fatty liver disease.

Zebrafish: A possible tool to evaluate bioactive ions.

Zebrafish is a well-established model organism with a skeletal structure that highly resembles mammalian bone. Yet its use in the research field of biomaterials has been limited. One area that could benefit from this model system is the evaluation of ionic dissolution products from different materials. As a proof of concept we have evaluated the effect of silicate ions on the zebrafish larvae and compared it to a well-known osteoblastic cell line, MC3T3-E1 subclone 14. We have shown that sodium metasilicate (125 µM and 625 µM) induces more mineralisation in a dose-dependent manner in zebrafish larvae, 9 days post fertilisation as compared to the non-treated group. Moreover the same trends were seen when adding sodium metasilicate to MC3T3-E1 cultures, with more mineralisation and higher ALP levels with higher doses of silicate (25, 125 and 625 µM). These results indicate the feasibility of zebrafish larvae for ionic dissolution studies. The zebrafish model is superior to isolated cell cultures in the aspect that it includes the whole bone remodelling system, with osteoblasts, osteoclasts and osteocytes. Zebrafish could thus provide a powerful in vivo tool and be a bridge between cell culture systems and mammalian models.

The risk for diabetic nephropathy is low in young adults in a 17-year follow-up from the Diabetes Incidence Study in Sweden (DISS). Older age and higher BMI at diabetes onset can be important risk factors.

AIMS: The main objective of this study was to estimate the occurrence of diabetic nephropathy in a population-based cohort of patients diagnosed with diabetes as young adults (15-34 years). METHODS: All 794 patients registered 1987-1988 in the Diabetes Incidence Study in Sweden (DISS) were invited to a follow-up study 15-19 years after diagnosis, and 468 (58%) participated. Analysis of islet antibodies was used to classify type of diabetes. RESULTS: After median 17 years of diabetes, 15% of all patients, 14% T1DM and 25% T2DM, were diagnosed with diabetic nephropathy. Ninety-one percent had microalbuminuria and 8.6% macroalbuminuria. Older age at diagnosis (HR 1.05; 95% CI 1.01-1.10 per year) was an independent and a higher BMI at diabetes diagnosis (HR 1.04; 95% CI 1.00-1.09 per 1 kg/m²), a near-significant predictor of development of diabetic nephropathy. Age at onset of diabetes (p = 0.041), BMI (p = 0.012) and HbA1c (p < 0.001) were significant predictors of developing diabetic nephropathy between 9 and 17 years of diabetes. At 17 years of diabetes duration, a high HbA1c level (OR 1.06; 95% CI 1.03-1.08 per 1 mmol/mol increase) and systolic blood pressure (OR 1.08; 95% CI 1.05 1.12 per 1 mmHg increase) were associated with DN. CONCLUSIONS: Patients with T2DM diagnosed as young adults seem to have an increased risk to develop diabetic nephropathy compared with those with T1DM. Older age and higher BMI at diagnosis of diabetes were risk markers for development of diabetic nephropathy. In addition, poor glycaemic control but not systolic blood pressure at 9 years of follow-up was a risk marker for later development of diabetic nephropathy.

Production of folate in oat bran fermentation by yeasts isolated from barley and diverse foods.

AIMS: The focus of the research was to identify yeasts from barley kernels in order to study their folate production capability while maintaining high viscosity caused by soluble fibres in oat bran fermentation. METHODS AND RESULTS: The 65 isolated yeasts were characterized by API carbohydrate utilization tests, and assays for extracellular enzyme activities were the following: amylase, beta-glucanase, cellulase or CMCase, lipase, protease and xylanase. Yeasts were identified by partial DNA sequencing of the 25S D1/D2 and ITS1-5.8S-ITS2 regions. They belonged to the genera Aureobasidium, Cryptococcus, Pseudozyma and Rhodotorula. Folate production was determined from supernatant and cells grown in a rich laboratory medium or directly from oat bran solution inoculated with the appropriate yeast. Food yeasts, Saccharomyces cerevisiae, Candida milleri, Kluyveromyces marxianus and Galactomyces geotrichum, were used for comparison. Most of the yeasts isolated from barley destroyed the solid, viscous structure of the oat bran solution, indicating that they degraded the viscosity-generating soluble fibres, considered to be nutritionally advantageous. The best folate producers were S. cerevisiae, followed by Pseudozyma sp., Rhodotorula glutinis and K. marxianus. The yeasts maintaining high viscosity were used together with lactic acid bacteria (LAB) Streptococcus thermophilus or Lactobacillus rhamnosus to ferment oat bran solution. None of the yeasts isolated from barley, contrary to S. cerevisiae and C. milleri, produced together with LAB significant amounts of folate. CONCLUSIONS: Fermentative yeasts together with LAB are potential for use in developing novel high folate content healthy foods and snacks from oat bran. SIGNIFICANCE AND IMPACT OF THE STUDY: High soluble fibre content and high natural folate content but low energy content food and snack products with pleasant fermentation aroma provide possibilities for new developments in the food industry.

Assessment of beta-cell function in young patients with type 2 diabetes: arginine-stimulated insulin secretion may reflect beta-cell reserve.

OBJECTIVE: Simple methods for the evaluation of dynamic b-cell function in epidemiological and clinical studies of patients with type 2 diabetes (T2D) are needed. The aim of this study was to evaluate the dynamic beta-cell function in young patients with T2D with different disease durations and treatments. METHODS: Overall, 54 subjects with T2D from the Diabetes Incidence Study in Sweden (DISS) and 23 healthy control participants were included in this cross-sectional study. Beta-cell function was assessed by intravenous (i.v.) administration of arginine followed by i.v. glucose. The acute insulin and C-peptide responses to arginine (AIRarg and Ac-pepRarg, respectively) and to glucose (AIRglu and Ac-pepRglu, respectively)were estimated.Homeostasis model assessment of b-cell function(HOMA-b) andCpeptide assessments were also used for comparisons between patients with T2D and control participants. RESULTS: AIRarg and Ac-pepRarg, but not AIRglu and Ac-pepRglu, could differentiate between patients with different disease durations. AIRglu values were 89% (P < 0.001) lower and AIRarg values were 29% (P < 0.01) lower in patients with T2D compared with control participants. HOMA-b and fasting plasma C-peptide levels did not differ between the T2D and control groups. CONCLUSION: In young patients with T2D, the insulin secretory response to i.v. glucose is markedly attenuated, whereas i.v. arginine-stimulated insulin release is better preserved and can distinguish between patients with different disease duration and antidiabetic therapies. This suggests that the i.v. arginine stimulation test may provide an estimate of functional beta-cell reserve.

Worse glycaemic control in LADA patients than in those with type 2 diabetes, despite a longer time on insulin therapy.

AIMS/HYPOTHESIS: Our aim was to study whether glycaemic control differs between individuals with latent autoimmune diabetes in adults (LADA) and patients with type 2 diabetes, and whether it is influenced by time on insulin therapy. METHODS: We performed a retrospective study of 372 patients with LADA (205 men and 167 women; median age 54 years, range 35-80 years) from Swedish cohorts from Skåne (n = 272) and Västerbotten (n = 100). Age- and sex-matched patients with type 2 diabetes were included as controls. Data on the use of oral hypoglycaemic agents (OHAs), insulin and insulin-OHA combination therapy was retrieved from the medical records. Poor glycaemic control was defined as HbA(1c) ≥7.0% (≥53 mmol/mol) at follow-up. RESULTS: The individuals with LADA and with type 2 diabetes were followed for an average of 107 months. LADA patients were leaner than type 2 diabetes patients at diagnosis (BMI 27.7 vs 31.0 kg/m(2); p < 0.001) and follow-up (BMI 27.9 vs 30.2 kg/m(2); p < 0.001). Patients with LADA had been treated with insulin for longer than those with type 2 diabetes (53.3 vs 28.8 months; p < 0.001). There was no significant difference between the patient groups with regard to poor glycaemic control at diagnosis, but more patients with LADA (67.8%) than type 2 diabetes patients (53.0%; p < 0.001) had poor glycaemic control at follow-up. Patients with LADA had worse glycaemic control at follow-up compared with participants with type 2 diabetes (OR = 1.8, 95% CI 1.2, 2.7), adjusted for age at diagnosis, HbA(1c), BMI at diagnosis, follow-up time and duration of insulin treatment. CONCLUSIONS/INTERPRETATION: Individuals with LADA have worse glycaemic control than patients with type 2 diabetes despite a longer time on insulin therapy.

The impact of mammographic screening on breast cancer mortality in Europe: a review of trend studies.

OBJECTIVE: Analysing trends in population breast cancer mortality statistics appears a simple method of estimating the effectiveness of mammographic screening programmes. We reviewed such studies of population-based screening in Europe to assess their value. METHODS: A literature review identified 17 papers, of which 12 provided quantitative estimates of the impact of screening. Due to differences in comparisons and outcome measures, no pooled estimate of effectiveness was calculated. RESULTS: Comparisons included breast cancer mortality before and after the introduction of screening, trends in early and late starting areas and trends in age groups affected and unaffected by screening. Studies that calculated the percentage annual change after the start of screening found reductions of 1-9% per year (1%, 2.3-2.8% and 9% for those with adequate follow-up). Of studies that compared mortality in time periods before and after introduction of screening, three single country studies all had adequate follow-up and estimated mortality reductions ranging from 28% to 36%. Limitations of studies of population mortality rates include the inability to exclude deaths in women with breast cancer diagnosed before invitation to screening, diluting any observable impact of screening, and the gradual implementation of screening in a country or region. CONCLUSIONS: Although analysing population breast cancer mortality rates over time can be a first step in examining changes following the introduction of screening, this method is of limited value for assessment of screening impact. Other methods and individual data are necessary to properly quantify the effect.

EEG oscillations reveal neural correlates of evidence accumulation.

Recent studies have begun to elucidate the neural correlates of evidence accumulation in perceptual decision making, but few of them have used a combined modeling-electrophysiological approach to studying evidence accumulation. We introduce a multivariate approach to EEG analysis with which we can perform a comprehensive search for the neural correlate of dynamics predicted by accumulator models. We show that the dynamics of evidence accumulation are most strongly correlated with ramping of oscillatory power in the 4-9 Hz theta band over the course of a trial, although it also correlates with oscillatory power in other frequency bands. The rate of power decrease in the theta band correlates with individual differences in the parameters of drift diffusion models fitted to individuals' behavioral data.

Changing healthcare utilization patterns in diabetes mellitus: case-control studies 1 year and 8 years after diagnosis.

AIMS: To describe healthcare utilization patterns in young and middle-aged patients with diabetes 1 year and 8 years after diagnosis and to compare with the general population at two time points, 16 years apart. METHODS: Four cohorts with disease duration of 1 year or 8 years were selected from the Diabetes Incidence Study in Sweden, which registers all incident cases of diabetes in the 15- to 34-year age group. Control subjects were selected from the population register matched by age, sex and county of residence. A postal questionnaire was sent to the 1983 and 1992 cohorts in 1991 and 1993, and to the 1999 and 2008 cohorts in 2007 and 2009. Nine hundred and thirteen patients with diabetes and 1679 control subjects responded. RESULTS: One year after diagnosis, 49% of patients with diabetes in the 1992 cohort compared with 4.2% in the 2008 cohort reported visits to departments of internal medicine and endocrinology. A similar pattern was seen 8 years after diagnosis. The use of day care was 4-5 times higher among patients with diabetes compared with control subjects. Utilization of outpatient hospital care was higher among patients with diabetes compared with control subjects, even when excluding visits to diabetes clinics. CONCLUSIONS: Excess use of health care among patients with diabetes remained 16 years after the first follow-up. Utilization patterns were stable, except for a major decrease in inpatient care 1 year after diagnosis and an increase in day care 8 years after diagnosis. Observed changes probably reflect successive reforming of diabetes care in Sweden.

Proinsulin/C-peptide ratio, glucagon and remission in new-onset Type 1 diabetes mellitus in young adults.

AIMS: After initiation of treatment in Type 1 diabetes, a period with lower insulin requirement often follows, reflecting increased insulin sensitivity and improved insulin secretion. We explored if efficiency of proinsulin processing is associated with the remission phenomenon. METHODS: Seventy-eight patients with new-onset Type 1 diabetes were followed prospectively for 3 years. Daily insulin dosage, HbA(1c) , plasma glucose, proinsulin, C-peptide, glucagon concentrations and islet antibodies were determined at diagnosis and after 3, 6, 9, 12, 18, 24, 30 and 36 months. We studied remission, defined as an insulin dose ≤ 0.3 U kg(-1) 24 h(-1) and HbA(1c) within the normal range, in relation to the above-mentioned variables. RESULTS: A rise and subsequent decline in plasma proinsulin and C-peptide concentrations was observed. Forty-five per cent of the patients experienced remission at one or more times, characterized by higher proinsulin and C-peptide levels, and lower proinsulin/C-peptide ratios, indicating more efficient proinsulin processing, compared with those not in remission. Non-remission also tended to be associated with higher glucagon values. Patients entering remission were more often men, had higher BMI at diagnosis, but did not differ at baseline with respect to islet antibody titres compared with patients with no remission. CONCLUSIONS: Remissions after diagnosis of Type 1 diabetes were associated with lower proinsulin/C-peptide ratios, suggesting more efficient proinsulin processing, and tended to have lower glucagon release than non-remissions. This indicates that, in remission, the residual islets maintain a secretion of insulin and glucagon of benefit for control of hepatic glucose production.

Long-term detrimental consequences of the onset of type 1 diabetes on annual earnings--evidence from annual registry data in 1990-2005.

AIMS/HYPOTHESIS: Young adults in the early stages of their participation in the labour market may be particularly vulnerable to the effects of onset of a chronic disease. Our aim was to quantify the consequences of the onset of type 1 diabetes in young adults on annual earnings, using individual-level longitudinal data before and after the onset of diabetes. METHODS: The Econ-DISS database contains annual socioeconomic information for 1990-2005 from Statistics Sweden. Econ-DISS includes data for persons with diabetes onset at the age of 15-34 years between 1983 and 2005, registered in the national Diabetes Incidence Study in Sweden (DISS) database, and for controls. Considering the onset of type 1 diabetes as an unanticipated and significant life event, we compared the progression of annual earnings for 3,650 cases born between 1949 and 1970 before and after onset of diabetes with that of 14,629 controls. Possible confounders--education, participation in the labour market, sick leave and parental education--were analysed. RESULTS: We found no differences between the groups in annual earnings or participation in the labour market before onset of diabetes. After onset, persons with type 1 diabetes gradually lagged behind the controls. Their median annual earnings were lower in each year from 1995 to 2005 (p < 0.01). The difference in 2005 was euro (EUR) 1,411 (5.3%). Controlling for confounders, duration of type 1 diabetes > or = 10 years was associated with 4.2% (men) and 8.1% (women) lower average annual earnings for persons with upper secondary education only who were active in the labour market. CONCLUSION/INTERPRETATION: The onset of type 1 diabetes in young adults has long-term detrimental consequences on earnings that cannot be attributed to confounders.

Differences in endpoints between the Swedish W-E (two county) trial of mammographic screening and the Swedish overview: methodological consequences.

OBJECTIVES: To characterize and quantify the differences in the number of cases and breast cancer deaths in the Swedish W-E Trial compared with the Swedish Overview Committee (OVC) summaries and to study methodological issues related to trials in secondary prevention. SETTING: The study population of the W-E Trial of mammography screening was included in the first (W and E county) and the second (E-county) OVC summary of all Swedish randomized mammography screening trials. The OVC and the W-E Trial used different criteria for case definition and causes of death determination. METHOD: A Review Committee compared the original data files from W and E county and the first and second OVC. The reason for a discrepancy was determined individually for all non-concordant cases or breast cancer deaths. RESULTS: Of the 2615 cases included by the W-E Trial or the OVC, there were 478 (18%) disagreements. Of the disagreements 82% were due to inclusion/exclusion criteria, and 18% to disagreement with respect to cause of death or vital status at ascertainment. For E-County, the OVC inclusion rules and register based determination of cause of death (second OVC) rather than individual case review (W-E Trial and 1st OVC) resulted in a reduction of the estimate of the effect of screening, but for W-County the difference between the original trial and the OVC was modest. CONCLUSIONS: The conclusion that invitation to mammography screening reduces breast cancer mortality remains robust. Disagreements were mainly due to study design issues, while disagreements about cause of death were a minority. When secondary research does not adhere to the protocols of the primary research projects, the consequences of such design differences should be investigated and reported. Register linkage of trials can add follow-up information. The precision of trials with modest size is enhanced by individual monitoring of case status and outcome status such as determination of cause of death.

Common variants in the TCF7L2 gene help to differentiate autoimmune from non-autoimmune diabetes in young (15-34 years) but not in middle-aged (40-59 years) diabetic patients.

AIMS/HYPOTHESIS: Type 1 diabetes in children is characterised by autoimmune destruction of pancreatic beta cells and the presence of certain risk genotypes. In adults the same situation is often referred to as latent autoimmune diabetes in adults (LADA). We tested whether genetic markers associated with type 1 or type 2 diabetes could help to discriminate between autoimmune and non-autoimmune diabetes in young (15-34 years) and middle-aged (40-59 years) diabetic patients. METHODS: In 1,642 young and 1,619 middle-aged patients we determined: (1) HLA-DQB1 genotypes; (2) PTPN22 and INS variable-number tandem repeat (VNTR) polymorphisms; (3) two single nucleotide polymorphisms (rs7903146 and rs10885406) in the TCF7L2 gene; (4) glutamic acid decarboxylase (GAD) and IA-2-protein tyrosine phosphatase-like protein (IA-2) antibodies; and (5) fasting plasma C-peptide. RESULTS: Frequency of risk genotypes HLA-DQB1 (60% vs 25%, p = 9.4 x 10(-34); 45% vs 18%, p = 1.4 x 10(-16)), PTPN22 CT/TT (34% vs 26%, p = 0.0023; 31% vs 23%, p = 0.034), INS VNTR class I/I (69% vs 53%, p = 1.3 x 10(-8); 69% vs 51%, p = 8.5 x 10(-5)) and INS VNTR class IIIA/IIIA (75% vs 63%, p = 4.3 x 10(-6); 73% vs 60%, p = 0.008) was increased in young and middle-aged GAD antibodies (GADA)-positive compared with GADA-negative patients. The type 2 diabetes-associated genotypes of TCF7L2 CT/TT of rs7903146 were significantly more common in young GADA-negative than in GADA-positive patients (53% vs 43%; p = 0.0004). No such difference was seen in middle-aged patients, in whom the frequency of the CT/TT genotypes of TCF7L2 was similarly increased in GADA-negative and GADA-positive groups (55% vs 56%). CONCLUSIONS/INTERPRETATION: Common variants in the TCF7L2 gene help to differentiate young but not middle-aged GADA-positive and GADA-negative diabetic patients, suggesting that young GADA-negative patients have type 2 diabetes and that middle-aged GADA-positive patients are different from their young GADA-positive counterparts and share genetic features with type 2 diabetes.

Smoking worsens the prognosis in multiple sclerosis.

OBJECTIVE: To estimate the effect of smoking on the risk for progression in multiple sclerosis (MS). METHODS: Self-reported data were used on smoking habits in 122 incident cases with disability assessments made after a median of 6 years disease duration. RESULTS: Ever smokers were more likely to have progressive disease compared with never smokers (P < 0.01). This was most pronounced in ever smokers with early smoking debut (< or = 15 years of age) for whom progressive disease was significantly more likely and occurred at an earlier age, compared with those with later smoking debut (P < 0.01 for both) or never smokers (P < 0.01 for both). Earlys moking start also predisposed to a progressive disease from onset when compared with never smokers (P = 0.012). A multivariate Cox regression analysis of sex, age at disease onset (above vs. under median) and smoking (ever vs. never) status showed that cases with late disease onset had three times higher risk and ever smokers had twice as high a risk for progression. CONCLUSION: Past smoking is associated with a worsened prognosis in MS. The negative effect from smoking is most obvious in ever smokers with early smoking debut, which also affects MS phenotype significantly.

EBNA-1 reactivity and HLA DRB1*1501 as statistically independent risk factors for multiple sclerosis: a case-control study.

OBJECTIVES AND METHODS: The interaction between the two best documented risk factors (human leukocyte antigen [HLA] class II [DRB1*1501 positivity] and Epstein-Barr virus [elevated Epstein-Barr nuclear antigen 1 (EBNA-1) antibody reactivity]) for multiple sclerosis (MS) was studied in a case-control study of biobank samples from 109 MS cases and 212 matched referents. RESULTS: Multivariate logistic regression analysis showed that both were statistically significant in both sexes. HLA DRB1*1501-positive referents had higher EBNA-1 reactivity than HLA-negative referents. Less EBNA-1 reactivity was required to increase the MS risk in HLA DRB1*1501-positives than in HLA-negatives. CONCLUSION: We suggest that HLA DRB1*1501-positive individuals have an increased vulnerability to EBV-induced autoimmunity.

Smoke exposure increases the risk for multiple sclerosis.

PURPOSE AND METHODS: To estimate the effect of exposure to smoking on the risk for multiple sclerosis (MS), we analyzed nicotine metabolite (cotinine) levels in biobank samples from 109 MS cases and 218 matched referents. RESULTS: Elevated cotinine levels, even modest elevations, were associated with an increased risk for MS (all other categories versus lowest: OR = 2.9; 95% CI: 1.3-6.3). A similar but non-significant risk increase was observed also in the small subset of individuals with samples collected before the onset of MS (all other categories versus lowest: OR = 2.4; 95% CI: 0.26-21). Elevated cotinine was associated with an increased risk for MS predominantly in women (all other categories versus lowest category: OR = 3.9; 95% CI: 1.3-12), whereas the risk increase in men was smaller and non-significant. DISCUSSION: Smoke exposure is associated with a higher risk for MS than previously estimated. There seems to be a threshold effect present in the lower range of cotinine in its relation to MS. Modestly elevated cotinine levels suggestive of passive smoking are associated with an increased risk for MS. Smoke exposure may explain the higher incidence of MS in women. These preliminary findings need to be confirmed in an expanded material of prospectively collected samples.