Cellular immunological changes in patients with LADA are a mixture of those seen in patients with type 1 and type 2 diabetes.

There is currently scarce knowledge of the immunological profile of patients with latent autoimmune diabetes mellitus in the adult (LADA) when compared with healthy controls (HC) and patients with classical type 1 diabetes (T1D) and type 2 diabetes (T2D). The objective of this study was to investigate the cellular immunological profile of LADA patients and compare to HC and patients with T1D and T2D. All patients and age-matched HC were recruited from Uppsala County. Peripheral blood mononuclear cells were isolated from freshly collected blood to determine the proportions of immune cells by flow cytometry. Plasma concentrations of the cytokine interleukin (IL)-35 were measured by enzyme-linked immunosorbent assay (ELISA). The proportion of CD11c+ CD123- antigen-presenting cells (APCs) was lower, while the proportions of CD11c+ CD123+ APCs and IL-35+ tolerogenic APCs were higher in LADA patients than in T1D patients. The proportion of CD3- CD56high CD16+ natural killer (NK) cells was higher in LADA patients than in both HC and T2D patients. The frequency of IL-35+ regulatory T cells and plasma IL-35 concentrations in LADA patients were similar to those in T1D and T2D patients, but lower than in HC. The proportion of regulatory B cells in LADA patients was higher than in healthy controls, T1D and T2D patients, and the frequency of IL-35+ regulatory B cells was higher than in T1D patients. LADA presents a mixed cellular immunological pattern with features overlapping with both T1D and T2D.

Coffee consumption, genetic susceptibility and risk of latent autoimmune diabetes in adults: A population-based case-control study.

AIM: Coffee consumption is inversely related to risk of type 2 diabetes (T2D). In contrast, an increased risk of latent autoimmune diabetes in adults (LADA) has been reported in heavy coffee consumers, primarily in a subgroup with stronger autoimmune characteristics. Our study aimed to investigate whether coffee consumption interacts with HLA genotypes in relation to risk of LADA. METHODS: This population-based study comprised incident cases of LADA (n=484) and T2D (n=1609), and also 885 healthy controls. Information on coffee consumption was collected by food frequency questionnaire. Odds ratios (ORs) with 95% CIs of diabetes were calculated and adjusted for age, gender, BMI, education level, smoking and alcohol intake. Potential interactions between coffee consumption and high-risk HLA genotypes were calculated by attributable proportion (AP) due to interaction. RESULTS: Coffee intake was positively associated with LADA in carriers of high-risk HLA genotypes (OR: 1.14 per cup/day, 95% CI: 1.02-1.28), whereas no association was observed in non-carriers (OR: 1.04, 95% CI: 0.93-1.17). Subjects with both heavy coffee consumption (≥4 cups/day) and high-risk HLA genotypes had an OR of 5.74 (95% CI: 3.34-9.88) with an estimated AP of 0.36 (95% CI: 0.01-0.71; P=0.04370). CONCLUSION: Our findings suggest that coffee consumption interacts with HLA to promote LADA.

Family history of type 1 and type 2 diabetes and risk of latent autoimmune diabetes in adults (LADA).

BACKGROUND: A family history of diabetes (FHD) is a strong predictor of diabetes risk, yet has rarely been investigated in latent autoimmune diabetes in adults (LADA). This study therefore investigated the risk of LADA and type 2 diabetes (T2D) in relation to FHD, taking into account the type of diabetes in relatives. METHODS: Data from a population-based study were used, including incident cases of LADA [glutamic acid decarboxylase antibody (GADA)-positive, n=378] and T2D (GADA-negative, n=1199), and their matched controls (n=1484). First-degree relatives with disease onset at age<40 years and taking insulin treatment were classified as type 1 diabetes (T1D) or, if otherwise, as T2D. Odds ratios (ORs) were adjusted for age, gender, BMI, education and smoking. Cases were genotyped for high- and low-risk HLA genotypes. RESULTS: Both FHD-T1D (OR: 5.8; 95% CI: 3.2-10.3) and FHD-T2D (OR: 1.9; 95% CI: 1.5-2.5) were associated with an increased risk of LADA, whereas the risk of T2D was associated with FHD-T2D (OR: 2.7; 95% CI: 2.2-3.3), but not FHD-T1D. In LADA patients, FHD-T1D vs FHD-T2D was associated with higher GADA but lower C-peptide levels, lower prevalence of low-risk HLA genotypes (5.0% vs 28.6%, respectively; P=0.038) and a tendency for higher prevalence of high-risk genotypes (90.0% vs 69.1%, respectively; P=0.0576). CONCLUSION: The risk of LADA is substantially increased with FHD-T1D but also, albeit significantly less so, with FHD-T2D. This supports the idea of LADA as a mix of both T1D and T2D, but suggests that the genes related to T1D have greater impact. LADA patients with FHD-T1D had more T1D-like features, emphasizing the heterogeneity of LADA.

Serious life events and the risk of latent autoimmune diabetes in adults (LADA) and Type 2 diabetes.

AIM: It has been suggested that experiencing serious life events may promote Type 1 diabetes in children. Studies in adults are lacking, as are studies on the interaction of life events with genetic factors. We aimed to investigate life events and the risk of latent autoimmune diabetes in adults (LADA) and Type 2 diabetes while taking into account HLA genotype. METHODS: Analysis was based on 425 incident cases of LADA, 1417 incident cases of Type 2 diabetes and 1702 population-based controls recruited in Sweden between 2010 and 2016. Self-reported information on life events including conflicts, divorce, illness/accidents, death and financial problems experienced during the 5 years preceding diagnosis/index year was used. Odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated by logistic regression and adjusted for age, sex, BMI, family history of diabetes, smoking, physical activity and education. RESULTS: Overall there was no association between experience of any life event and either LADA (OR 0.86, 95% CI 0.68-1.08) or Type 2 diabetes (OR 1.00, 95% CI 0.83-1.21). The results were similar for individual events as well as in separate analysis of men and women. Similar results were seen in more autoimmune LADA (glutamic acid decarboxylase antibodies > median) [OR (any life event) 0.88, 95% CI 0.64-1.21] and in LADA carriers of the high-risk HLADR4-DQ8 genotype (OR 0.89, 95% CI 0.61-1.29). CONCLUSIONS: Our findings indicate that experience of a serious life event, including the death of a family member, divorce or financial problems, is not associated with an increased risk of LADA, overall or in genetically susceptible individuals.

Use of Swedish smokeless tobacco (snus) and the risk of Type 2 diabetes and latent autoimmune diabetes of adulthood (LADA).

AIMS: It has been suggested that moist snuff (snus), a smokeless tobacco product that is high in nicotine and widespread in Scandinavia, increases the risk of Type 2 diabetes. Previous studies are however few, contradictory and, with regard to autoimmune diabetes, lacking. Our aim was to study the association between snus use and the risk of Type 2 diabetes and latent autoimmune diabetes of adulthood (LADA). METHOD: Analyses were based on incident cases (Type 2 diabetes, n = 724; LADA, n = 200) and population-based controls (n = 699) from a Swedish case-control study. Additional analyses were performed on cross-sectional data from the Norwegian HUNT study (n = 21 473) with 829 prevalent cases of Type 2 diabetes. Odds ratios (OR) were estimated adjusted for age, BMI family history of diabetes and smoking. Only men were included. RESULTS: No association between snus use and Type 2 diabetes or LADA was seen in the Swedish data. For Type 2 diabetes, the OR for > 10 box-years was 1.00 [95% confidence interval (CI), 0.47 to 2.11] and for LADA 1.01 (95% CI, 0.45 to 2.29). Similarly, in HUNT, the OR for Type 2 diabetes in ever-users was estimated at 0.91 (95% CI, 0.75 to 1.10) and in heavy users at 0.92 (95% CI, 0.46 to 1.83). CONCLUSION: The risk of Type 2 diabetes and LADA is unrelated to the use of snus, despite its high nicotine content. This opens the possibility of the increased risk of Type 2 diabetes seen in smokers may not be attributed to nicotine, but to other substances in tobacco smoke.

Fatty fish consumption and risk of latent autoimmune diabetes in adults.

OBJECTIVE: It has been suggested that intake of fatty fish may protect against both type 1 and type 2 diabetes. Hypotheses rest on the high marine omega-3 fatty acid eicosapentaenoic acid+docosahexaenoic acid (EPA+DHA) and vitamin D contents, with possible beneficial effects on immune function and glucose metabolism. Our aim was to investigate, for the first time, fatty fish consumption in relation to the risk of latent autoimmune diabetes in adults (LADA). METHODS: Analyses were based on data from a Swedish case-control study with incident cases of LADA (n=89) and type 2 diabetes (n=462) and randomly selected diabetes-free controls (n=1007). Diabetes classification was based on the onset of age (⩾35), glutamic acid decarboxylase autoantibodies, and C-peptide. A validated food frequency questionnaire was used to derive information on previous intake of fish, polyunsaturated long-chain omega-3 fatty acids (n-3 PUFA) and supplementation of fish oil and vitamin D. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using logistic regression, adjusted for age, gender, body mass index (BMI), family history of diabetes, physical activity, smoking, education, and consumption of alcohol, fruit, vegetables and red meat. RESULTS: Weekly fatty fish consumption (⩾1 vs <1 serving per week), was associated with a reduced risk of LADA but not type 2 diabetes (OR 0.51, 95% CI 0.30-0.87, and 1.01, 95% CI 0.74-1.39, respectively). Similar associations were seen for estimated intake of n-3 PUFA (⩾0.3 g per day; LADA: OR 0.60, 95% CI 0.35-1.03, type 2 diabetes: OR 1.14, 95% CI 0.79-1.58) and fish oil supplementation (LADA: OR 0.47, 95% CI 0.19-1.12, type 2 diabetes: OR 1.58, 95% CI 1.08-2.31). CONCLUSIONS: Our findings suggest that fatty fish consumption may reduce the risk of LADA, possibly through effects of marine-originated omega-3 fatty acids.

Coffee consumption and the risk of latent autoimmune diabetes in adults--results from a Swedish case-control study.

AIMS: Coffee consumption is associated with a reduced risk of Type 2 diabetes. Our aim was to investigate if coffee intake may also reduce the risk of latent autoimmune diabetes in adults, an autoimmune form of diabetes with features of Type 2 diabetes. METHODS: We used data from a population-based case-control study with incident cases of adult onset (≥ 35 years) diabetes, including 245 cases of latent autoimmune diabetes in adults (glutamic acid decarboxylase antibody positive), 759 cases of Type 2 diabetes (glutamic acid decarboxylase antibody negative), together with 990 control subjects without diabetes, randomly selected from the population. Using questionnaire information on coffee consumption, we estimated the odds ratio of latent autoimmune diabetes in adults and Type 2 diabetes adjusted for age, sex, BMI, smoking, physical activity, alcohol, education and family history of diabetes. RESULTS: Coffee intake was inversely associated with Type 2 diabetes (odds ratio 0.92, 95% CI 0.87-0.98 per cup/day). With regard to latent autoimmune diabetes in adults, the general trend was weak (odds ratio 1.04, 95% CI 0.96-1.13), but stratification by degree of autoimmunity (median glutamic acid decarboxylase antibody levels) suggested that coffee intake may be associated with an increased risk of high glutamic acid decarboxylase antibody latent autoimmune diabetes in adults (odds ratio 1.11, 95% CI 1.00-1.23 per cup/day). Furthermore, for every additional cup of coffee consumed per day, there was a 15.2% (P = 0.0268) increase in glutamic acid decarboxylase antibody levels. CONCLUSIONS: Our findings confirm that coffee consumption is associated with a reduced risk of Type 2 diabetes. Interestingly, the findings suggest that coffee may be associated with development of autoimmunity and possibly an increased risk of more Type 1-like latent autoimmune diabetes in adults.

Time to insulin treatment and factors associated with insulin prescription in Swedish patients with type 2 diabetes.

AIMS: The purpose of this study was to investigate the time between the start of OAD treatment and the initiation of insulin therapy and to identify the factors associated with insulin prescription among Swedish patients with type 2 diabetes in Uppsala County. METHODS: Retrospective, population-based, primary-care data gathered within the Swedish RECAP-DM study were used to identify type 2 diabetic patients who initiated OAD treatment. A Kaplan-Meier survival estimate for time to initiation of insulin therapy was generated and factors associated with insulin prescription were tested using a Cox proportional-hazards model. RESULTS: Within 6 years of starting OAD treatment, an estimated 25% of Swedish patients with type 2 diabetes will be prescribed insulin (95% CI: 0.23-0.26) and, within 10 years, this figure will rise to 42% (95% CI: 0.39-0.45). The probability of insulin prescription was increased in patients aged less than 65 years (HR=1.24, 95% CI: 1.03-1.50) and in those who initiated OAD treatment with more than one agent (HR=2.71, 95% CI: 2.15-3.43). HbA(1c) at the time of starting OAD treatment was also related to the probability of insulin prescription (HR=1.20, 95% CI: 1.146-1.25). CONCLUSION: Many type 2 diabetic patients who begin treatment with an OAD will eventually be prescribed insulin. Age, disease severity and the type of prior treatment may affect the rate of the transition.

Prevalence and incidence of Type 2 diabetes and its complications 1996-2003--estimates from a Swedish population-based study.

AIMS: To determine the prevalence and incidence of Type 2 diabetes and its complications in Uppsala county, Sweden between 1996 and 2003. METHODS: Retrospective population-based study of patients with Type 2 diabetes identified in computerized medical records at 26 county primary care centres. Prevalence and incidence of Type 2 diabetes were estimated in the population aged 30-39, 40-49, 50-59, 60-69, 70-79 and > or = 80 years. Mortality, prevalence and incidence of complications in patients with Type 2 diabetes were determined through linkage to national inpatient, uraemia and cause-of-death registers. RESULTS: Crude prevalence of Type 2 diabetes increased from 2.2 to 3.5% between 1996 and 2003. In the population aged > or = 30 years, the age- and sex-adjusted period increase was 53%[odds ratio (OR) 1.53, 95% confidence interval (CI) 1.47-1.58]. Crude population incidence was approximately stable after 1997 (3.7 cases/1000 residents in 1997 compared with 3.8/1000 in 2003). Age- and sex-adjusted mortality rates in Type 2 diabetic patients decreased by 4% per year (OR 0.96, 95% CI 0.94-0.97). Prevalence rates of cardiovascular disease in Type 2 diabetic patients were essentially stable, affecting 13.8% of females and 18.0% of males in 2003. No trend was detected for prevalence of renal failure or incidence of acute myocardial infarction, stroke and amputation. CONCLUSIONS: Prevalence of Type 2 diabetes increased in Uppsala county between 1996 and 2003 as a consequence of approximately stable incidence since 1997 and declining mortality. Rates of diabetes-related complications, notably cardiovascular disease, continued to impose a substantial burden.

Resource use and costs of type 2 diabetes in Sweden - estimates from population-based register data.

AIMS: To examine medical resource use of Swedish patients with type 2 diabetes during 2000-2004 and to estimate annual costs of care. METHODS: Retrospective population-based cohort study of patients with type 2 diabetes identified in computerised medical records at 26 primary care centres in Uppsala county, Sweden. Annual quantities of medical resources were determined for prevalent cases during 2000-2004 using register data from outpatient primary care, outpatient hospital care, the National Inpatient Register and a national register for treatment of uraemia. Average costs of care of patients with type 2 diabetes were estimated based on year 2004 resource quantities of 8230 prevalent study cases. RESULTS: Annual quantities of medical resource use were stable in outpatient primary care and outpatient hospital care, with patients making an average of two General Practitioner visits and 3.5 outpatient hospital visits each year. Higher rates of hospitalisation [12% in 2000 (n = 6711) compared with 16% in 2004 (n = 8230)] led to an increase in the mean (SD) number of inpatient days from 2.3 (11.8) to 2.7 (11.9) (p = 0.040) between 2000 and 2004. Mean (SD) total costs of care in 2004 were EUR 3602 (EUR 9537). Inpatient care was the major contributor to costs, accounting for 57% of total costs while drug costs accounted for an average 7%. CONCLUSIONS: Swedish type 2 diabetic patients in this large sample from Uppsala county required steady annual amounts of outpatient care and increasing amounts of inpatient care during 2000-2004. The associated costs in 2004 were substantial, with inpatient care identified as the most important component.

Endocavitary patch repair for a left ventricular pseudoaneurysm: an alternative approach.

We present a case of postinfarction posterolateral left ventricular wall pseudoaneurysm with severe mitral regurgitation and poor left ventricular function. The patient had New York Heart Association (NYHA) class IV heart failure at the time of surgery, which was performed on an emergency basis. The surgical approach included coronary revascularization, surgical posterior mitral leaflet detachment with patch closure of the pseudoaneurysm neck from inside of the left ventricular cavity followed by mitral valve reconstruction, and subsequent implantation of a mitral annuloplasty ring.

Prodigiosin from the supernatant of Serratia marcescens induces apoptosis in haematopoietic cancer cell lines.

The effects of supernatant from the bacterial strain Serratia marcescens 2170 (CS-2170) on the viability of different haematopoietic cancer cell lines (Jurkat, NSO, HL-60 and Ramos) and nonmalignant cells (NIH-3T3 and MDCK) was studied. We examined whether this cytotoxic effect was due to apoptosis, and we purified the molecule responsible for this effect and determined its chemical structure. Using an MTT assay we showed a rapid (4 h) decrease in the number of viable cells. This cytotoxic effect was due to apoptosis, according to the fragmentation pattern of DNA, Hoechst 33342 staining and FACS analysis of the phosphatidylserine externalization. This apoptosis was blocked by using the caspase inhibitor Z-VAD.fmk, indicating the involvement of caspases. Prodigiosin is a red pigment produced by various bacteria including S. marcescens. Using mutants of S. marcescens (OF, WF and 933) that do not synthesize prodigiosin, we further showed that prodigiosin is involved in this apoptosis. This evidence was corroborated by spectroscopic analysis of prodigiosin isolated from S. marcescens. These results indicate that prodigiosin, an immunosuppressor, induces apoptosis in haematopoietic cancer cells with no marked toxicity in nonmalignant cells, raising the possibility of its therapeutic use as an antineoplastic drug.

[Pure alexia: presentation of three cases and review of the literature]. / Alexia pura: presentación de tres casos y revisión de la literatura.

INTRODUCTION: Pure alexia is a syndrome characterized by the inability to read aloud in the absence of agraphia or apnasia. CLINICAL CASES: Three clinical cases showing this syndrome are presented. Case I had a left occipital lesion compatible with a subacute haematoma. He had problems with reading, visuo-spatial recognition, digital gnosia and memorizing texts. One year later there was considerable improvement in most of the sub-tests evaluated. There was still deficient colour naming right/left orientation and understanding of letters and words. Case 2 presented with a right homonymous hemianopia and slight left paresis. He had a small left occipital ischaemic infarct. One year later there was improvement on testing, with some deficit still in visual recognition, naming colours and memory. Case 3 presented with right homonymous hemianopia, slight right paresis and a left occipito-parietal expansive lesion. He had defective reading, choosing and naming of colours, right/left orientation and memory. On later evaluation, considerable improvement was seen. There was still colour agnosia, although less severe and mild 'laziness' of the right side. CONCLUSIONS: In the review of the literature, the disorder and the contributions of various authors, from Déperine in 1892 to the present day, are considered in detail.

Rapid response to osmotic upshift by osmoregulated genes in Escherichia coli and Salmonella typhimurium.

The rapid in vivo response of both Escherichia coli and Salmonella typhimurium osmoregulated genes to an osmotic upshift was analyzed in detail by using chromosomal operon fusions. Within 10 min after the addition of 0.3 M NaCl to the culture medium, the differential rates of expression of both an S. typhimurium proU-lac fusion and a proP-lac fusion increased by 180- and 17-fold respectively, while an E. coli ompC-lac fusion increased by 3.4-fold. For all three stimulated promoters, the increased rate of expression was maintained until about 40 min after the osmotic upshift. Thereafter, proU expression continued at a steady-state rate that was 27-fold higher than that of the control, while proP and ompC expression fell to 1.4- and 2-fold of the control rates, respectively. In contrast, expression of an E. coli ompF-lac fusion decreased twofold within 2.5 min. For proU, the length of the lag phase, which preceded the onset of the rapid response, increased with the degree of osmotic upshift, above a threshold of 0.2 M NaCl; the onset of the rapid proU response also preceded the resumption of growth. The rapid response phase, which was first quantitated for proU, proP, ompC, and ompF in this study, is an important component of the osmoregulation of these promoters. The addition of the osmoprotectant glycine betaine at the time of osmotic upshift decreased both the length of the rapid response and the subsequent steady-state of expression of proU.