Immunological and clinical characteristics of latent autoimmune diabetes in the elderly

Background: Latent autoimmune diabetes in adults (LADA) is determined by both a noninsulin-dependent clinical presentation and an autoimmune pathogenic process. Glutamic acid decarboxylase antibody (GADA) constitutes the most important marker, although IA-2A and ZnT8A also define LADA presentation. Type 2 diabetes mellitus (T2DM) is the most prevalent type particularly over 65 years old. Studies about autoimmunity in this age group are scarce. Objective: The aim of this work was to determine whether three autoantibodies for diabetes autoimmunity were present in elderly T2DM patients, and to assess the distinctive clinical features of autoantibody-positive patients. Research Design and Methods: We recruited 153 patients with diabetes with onset of diabetes after 65 years of age and a BMI under 30 kg/m2. Results: The prevalence of at least one of the autoantibodies was 15.68% (24/153). The most prevalent autoantibody was GADA with 8.49% (13/153), followed by ZnT8A with 6.50% (10/153) and IA2A with 1.96% (3/153). The autoimmunity-positive group presented higher HbA1c (7.01 ± 1.98 vs 6.35 ± 1.01; P = 0.007) and more prevalent insulin therapy (25% vs 10.85%; P = 0.047). GADA-positive patients with diabetes presented higher FPG (7.79 ± 3.79 mmol/L vs 6.43 ± 1.6 mmol/L; P = 0.014) and insulin therapy more frequently (46% vs 10.71%; p = 0.015). GADA titre levels in the individuals with BMI under 27 kg/m2 were higher (35.00 ± 4.20) than those in the group with BMI over 27 kg/m2 (8.83 ± 3.041; P = 0.0005). Conclusion:: Autoantibodies GADA and Znt8A may be useful markers in identifying a subgroup of older patients with a clinical presentation of diabetes which could be characterized as latent autoimmune diabetes in the elderly.Fil: Yohena, Silvina. Hospital Sirio Libanés; Argentina. Fundación Barceló. Instituto Universitario de Ciencias de la Salud; ArgentinaFil: Penas Steinhardt, Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Barceló. Instituto Universitario de Ciencias de la Salud; Argentina. Universidad Nacional de Luján; ArgentinaFil: Muller, Clara. Hospital Sirio Libanés; ArgentinaFil: Faccinetti, Natalia Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Cerrone, Gloria Edith. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Lovecchio, Silvia. Hospital Sirio Libanés; Argentina. Fundación Barceló. Instituto Universitario de Ciencias de la Salud; ArgentinaFil: Ridner, Alberrto Edgardo. Fundación Barceló. Instituto Universitario de Ciencias de la Salud; ArgentinaFil: Valdez, Silvina Noemi. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Frechtel, Gustavo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Hospital Sirio Libanés; Argentina. Fundación Barceló. Instituto Universitario de Ciencias de la Salud; Argentin

Sufficient blood, safe blood: can we have both?

The decision in September 2011 in the UK to accept blood donations from non-practicing men who have sex with men (MSM) has received significant public attention. Will this rule change substantially boost the number of blood donations or will it make our blood less safe? Clearly, most European countries have a blood procurement problem. Fewer young people are donating, while the population is aging and more invasive therapies are requiring more blood. Yet if that was the reason for allowing non-practicing MSM to donate, clearly re-admission of some other, much larger populations that are currently deferred from donation should likewise be considered. As far as risks for blood safety are concerned, evidence has been provided that the current quality of infectious disease marker testing significantly mitigates against, although does not completely eradicate, risks associated with admission of donors with a high risk of carrying certain blood-transmissible agents. However, it could be argued that more effective recruitment of the non-donor pool, which is substantially larger than the group of currently ineligible donors, would be a better strategy. Recruitment of this group will benefit the availability of blood without jeopardizing the current excellent safety profile of blood

An integrated expression phenotype mapping approach defines common variants in LEP, ALOX15 and CAPNS1 associated with induction of IL-6

Interleukin-6 (IL-6) is an important modulator of inflammation and immunity whose dysregulation is associated with a number of disease states. There is evidence of significant heritability in inter-individual variation in IL6 gene expression but the genetic variants responsible for this remain to be defined. We adopted a combined approach of mapping protein and expression quantitative trait loci in peripheral blood mononuclear cells using high-density single-nucleotide polymorphism (SNP) typing for ∼2000 loci implicated in cardiovascular, metabolic and inflammatory syndromes to show that common SNP markers and haplotypes of LEP (encoding leptin) associate with a 1.7- to 2-fold higher level of lipopolysaccharide (LPS)-induced IL-6 expression. We subsequently demonstrate that basal leptin expression significantly correlates with LPS-induced IL-6 expression and that the same variants at LEP which associate with IL-6 expression are also major determinants of leptin expression in these cells. We find that variation involving two other genomic regions, CAPNS1 (encoding calpain small subunit 1) and ALOX15 (encoding arachidonate 15-lipoxygenase), show significant association with IL-6 expression. Although this may be a subset of all such trans-acting effects, we find that the same ALOX15 variants are associated with induced expression of tumour necrosis factor and IL-1beta consistent with a broader role in acute inflammation for ALOX15. This study provides evidence of novel genetic determinants of IL-6 production with implications for understanding susceptibility to inflammatory disease processes and insight into cross talk between metabolic and inflammatory pathways. It also provides proof of concept for use of an integrated expression phenotype mapping approach

Patients with chronic three-vessel disease in a 15-year follow-up study: genetic and non-genetic predictors of survival.

Genetic and non-genetic predictors of 15-year survival in patients with chronic three-vessel disease (3VD) were investigated. Coronary angiography was performed on 810 subjects with symptoms of stable ischemic heart disease in 1998. The patients with 3VD were genotyped for 23 candidate polymorphisms covering the PPAR-RXR pathway, matrix metalloproteinase-2, renin-angiotensin-aldosterone system, endothelin-1, cytokine genes, MTHFR and APO E variants. Fifteen-year survival data were obtained from the national insurance registry. All data were available in the case of 150 patients with 3VD. Statistical analysis used stepwise Cox regression with dominant, recessive, or additive mode of genetic expression. Involved variables included age, sex, BMI, blood pressure, diabetes, ejection fraction, left main stenosis, previously diagnosed coronary stenosis, myocardial infarction in personal history, and coronary bypass along with polymorphisms pre-selected by log-rank tests. Out of the 23 polymorphisms, four were included in the model construction. SNP in the IL-6 gene rs1800795 (-174 G/C) has been found to be a significant predictor of survival. This SNP was in a linkage disequilibrium with rs1800797 (-597 G/A) in the same gene (D=1.0), which was also found to constitute a significant predictor of survival when rs1800795 was not included in the model construction. Age, increased BMI, diabetes, low EF, and left main stenosis were also significant predictors in all models. Age, increased BMI, diabetes, low ejection fraction, left main stenosis, and genetic variation in the IL-6 promoter were established as significant independent risk factors for the survival of patients with three-vessel disease.Genetic and non-genetic predictors of 15-year survival in patients with chronic three-vessel disease (3VD) were investigated. Coronary angiography was performed on 810 subjects with symptoms of stable ischemic heart disease in 1998. The patients with 3VD were genotyped for 23 candidate polymorphisms covering the PPAR-RXR pathway, matrix metalloproteinase-2, renin-angiotensin-aldosterone system, endothelin-1, cytokine genes, MTHFR and APO E variants. Fifteen-year survival data were obtained from the national insurance registry. All data were available in the case of 150 patients with 3VD. Statistical analysis used stepwise Cox regression with dominant, recessive, or additive mode of genetic expression. Involved variables included age, sex, BMI, blood pressure, diabetes, ejection fraction, left main stenosis, previously diagnosed coronary stenosis, myocardial infarction in personal history, and coronary bypass along with polymorphisms pre-selected by log-rank tests. Out of the 23 polymorphisms, four were included in the model construction. SNP in the IL-6 gene rs1800795 (-174 G/C) has been found to be a significant predictor of survival. This SNP was in a linkage disequilibrium with rs1800797 (-597 G/A) in the same gene (D=1.0), which was also found to constitute a significant predictor of survival when rs1800795 was not included in the model construction. Age, increased BMI, diabetes, low EF, and left main stenosis were also significant predictors in all models. Age, increased BMI, diabetes, low ejection fraction, left main stenosis, and genetic variation in the IL-6 promoter were established as significant independent risk factors for the survival of patients with three-vessel disease

Treatment of hepatic encephalopathy by on-line hemodiafiltration: a case series study

<p>Abstract</p> <p>Background</p> <p>It is thought that a good survival rate of patients with acute liver failure can be achieved by establishing an artificial liver support system that reliably compensates liver function until the liver regenerates or a patient undergoes transplantation. We introduced a new artificial liver support system, on-line hemodiafiltration, in patients with acute liver failure.</p> <p>Methods</p> <p>This case series study was conducted from May 2001 to October 2008 at the medical intensive care unit of a tertiary care academic medical center. Seventeen consecutive patients who admitted to our hospital presenting with acute liver failure were treated with artificial liver support including daily on-line hemodiafiltration and plasma exchange.</p> <p>Results</p> <p>After 4.9 ± 0.7 (mean ± SD) on-line hemodiafiltration sessions, 16 of 17 (94.1%) patients completely recovered from hepatic encephalopathy and maintained consciousness for 16.4 ± 3.4 (7-55) days until discontinuation of artificial liver support (a total of 14.4 ± 2.6 [6-47] on-line hemodiafiltration sessions). Significant correlation was observed between the degree of encephalopathy and number of sessions of on-line HDF required for recovery of consciousness. Of the 16 patients who recovered consciousness, 7 fully recovered and returned to society with no cognitive sequelae, 3 died of complications of acute liver failure except brain edema, and the remaining 6 were candidates for liver transplantation; 2 of them received living-related liver transplantation but 4 died without transplantation after discontinuation of therapy.</p> <p>Conclusions</p> <p>On-line hemodiafiltration was effective in patients with acute liver failure, and consciousness was maintained for the duration of artificial liver support, even in those in whom it was considered that hepatic function was completely abolished.</p

Genetic polymorphisms of the RAS-cytokine pathway and chronic kidney disease

Chronic kidney disease (CKD) in children is irreversible. It is associated with renal failure progression and atherosclerotic cardiovascular (CV) abnormalities. Nearly 60% of children with CKD are affected since birth with congenital or inherited kidney disorders. Preliminary evidence primarily from adult CKD studies indicates common genetic risk factors for CKD and atherosclerotic CV disease. Although multiple physiologic pathways share common genes for CKD and CV disease, substantial evidence supports our attention to the renin angiotensin system (RAS) and the interlinked inflammatory cascade because they modulate the progressions of renal and CV disease. Gene polymorphisms in the RAS-cytokine pathway, through altered gene expression of inflammatory cytokines, are potential factors that modulate the rate of CKD progression and CV abnormalities in patients with CKD. For studying such hypotheses, the cooperative efforts among scientific groups and the availability of robust and affordable technologies to genotype thousands of single nucleotide polymorphisms (SNPs) across the genome make genome-wide association studies an attractive paradigm for studying polygenic diseases such as CKD. Although attractive, such studies should be interpreted carefully, with a fundamental understanding of their potential weaknesses. Nevertheless, whole-genome association studies for diabetic nephropathy and future studies pertaining to other types of CKD will offer further insight for the development of targeted interventions to treat CKD and associated atherosclerotic CV abnormalities in the pediatric CKD population