Lipoprotein metabolism in patients with type 1 diabetes under intensive insulin treatment

Background Type 1 diabetes (T1DM) is frequently accompanied by dyslipidemia related with insulin-dependent steps of the intravascular lipoprotein metabolism. T1DM dyslipidemia may predispose to precocious cardiovascular disease and the lipid status in T1DM under intensive insulin treatment has not been sufficiently explored. The aim was to investigate the plasma lipids and the metabolism of LDL and HDL in insulin-treated T1DM patients with high glycemic levels. Methods Sixteen male patients with T1DM (26 ± 7 yrs) with glycated hemoglobin >7%, and 15 control subjects (28 ± 6 yrs) were injected with a lipid nanoemulsion (LDE) resembling LDL and labeled with 14C-cholesteryl ester and 3H-free-cholesterol for determination of fractional clearance rates (FCR, in h-1) and cholesterol esterification kinetics. Transfer of labeled lipids from LDE to HDL was assayed in vitro. Results LDL-cholesterol (83 ± 15 vs 100 ± 29 mg/dl, p=0.08) tended to be lower in T1DM than in controls; HDL-cholesterol and triglycerides were equal. LDE marker 14C-cholesteryl ester was removed faster from plasma in T1DM patients than in controls (FCR=0.059 ± 0.022 vs 0.039 ± 0.022h-1, p=0.019), which may account for their lower LDL-cholesterol levels. Cholesterol esterification kinetics and transfer of non-esterified and esterified cholesterol, phospholipids and triglycerides from LDE to HDL were also equal. Conclusion T1DM patients under intensive insulin treatment but with poor glycemic control had lower LDL-cholesterol with higher LDE plasma clearance, indicating that LDL plasma removal was even more efficient than in controls. Furthermore, HDL-cholesterol and triglycerides, cholesterol esterification and transfer of lipids to HDL, an important step in reverse cholesterol transport, were all normal. Coexistence of high glycemia levels with normal intravascular lipid metabolism may be related to differences in exogenous insulin bioavailabity and different insulin mechanisms of action on glucose and lipids. Those findings may have important implications for prevention of macrovascular disease by intensive insulin treatment.

Influence of obesity and cardiometabolic makers on lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in adolescents: the healthy young cross-sectional study

Abstract Background Lipoprotein-associated phospholipase A2 activity (Lp-PLA2) is a good marker of cardiovascular risk in adults. It is strongly associated with stroke and many others cardiovascular events. Despite this, the impact of obesity on this enzyme activity and its relation to biomarkers of cardiovascular disease in adolescents is not very well investigated. The purpose of this article is to evaluate the influence of obesity and cardiometabolic markers on Lp-PLA2 activity in adolescents. Results This cross-sectional study included 242 adolescents (10–19 years) of both gender. These subjects were classified in Healthy Weight (n = 77), Overweight (n = 82) and Obese (n = 83) groups. Lipid profile, glucose, insulin, HDL size, LDL(−) and anti-LDL(−) antibodies were analyzed. The Lp-PLA2 activity was determined by a colorimetric commercial kit. Body mass index (BMI), waist circumference and body composition were monitored. Food intake was evaluated using three 24-hour diet recalls. The Lp-PLA2 activity changed in function to high BMI, waist circumference and fat mass percentage. It was also positively associated with HOMA-IR, glucose, insulin and almost all variables of lipid profile. Furthermore, it was negatively related to Apo AI (β = −0.137; P = 0.038) and strongly positively associated with Apo B (β = 0.293; P < 0.001) and with Apo B/Apo AI ratio (β = 0.343; P < 0.001). The better predictor model for enzyme activity, on multivariate analysis, included Apo B/Apo AI (β = 0.327; P < 0.001), HDL size (β = −0.326; P < 0.001), WC (β = 0.171; P = 0.006) and glucose (β = 0.119; P = 0.038). Logistic regression analysis demonstrated that changes in Apo B/Apo AI ratio were associated with a 73.5 times higher risk to elevated Lp-PLA2 activity. Conclusions Lp-PLA2 changes in function of obesity, and that it shows important associations with markers of cardiovascular risk, in particular with waist circumference, glucose, HDL size and Apo B/Apo AI ratio. These results suggest that Lp-PLA2 activity can be a cardiovascular biomarker in adolescence.

Effect of Echium oil compared with marine oils on lipid profile and inhibition of hepatic steatosis in LDLr knockout mice

Abstract Background In an effort to identify new alternatives for long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) supplementation, the effect of three sources of omega 3 fatty acids (algae, fish and Echium oils) on lipid profile and inflammation biomarkers was evaluated in LDL receptor knockout mice. Methods The animals received a high fat diet and were supplemented by gavage with an emulsion containing water (CON), docosahexaenoic acid (DHA, 42.89%) from algae oil (ALG), eicosapentaenoic acid (EPA, 19.97%) plus DHA (11.51%) from fish oil (FIS), and alpha-linolenic acid (ALA, 26.75%) plus stearidonic acid (SDA, 11.13%) from Echium oil (ECH) for 4 weeks. Results Animals supplemented with Echium oil presented lower cholesterol total and triacylglycerol concentrations than control group (CON) and lower VLDL than all of the other groups, constituting the best lipoprotein profile observed in our study. Moreover, the Echium oil attenuated the hepatic steatosis caused by the high fat diet. However, in contrast to the marine oils, Echium oil did not affect the levels of transcription factors involved in lipid metabolism, such as Peroxisome Proliferator Activated Receptor α (PPAR α) and Liver X Receptor α (LXR α), suggesting that it exerts its beneficial effects by a mechanism other than those observed to EPA and DHA. Echium oil also reduced N-6/N-3 FA ratio in hepatic tissue, which can have been responsible for the attenuation of steatosis hepatic observed in ECH group. None of the supplemented oils reduced the inflammation biomarkers. Conclusion Our results suggest that Echium oil represents an alternative as natural ingredient to be applied in functional foods to reduce cardiovascular disease risk factors.

Regional differences in clinical care among patients with type 1 diabetes in Brazil: Brazilian Type 1 Diabetes Study Group

Background To determine the characteristics of clinical care offered to type 1 diabetic patients across the four distinct regions of Brazil, with geographic and contrasting socioeconomic differences. Glycemic control, prevalence of cardiovascular risk factors, screening for chronic complications and the frequency that the recommended treatment goals were met using the American Diabetes Association guidelines were evaluated. Methods This was a cross-sectional, multicenter study conducted from December 2008 to December 2010 in 28 secondary and tertiary care public clinics in 20 Brazilian cities in north/northeast, mid-west, southeast and south regions. The data were obtained from 3,591 patients (56.0% females and 57.1% Caucasians) aged 21.2 ± 11.7 years with a disease duration of 9.6 ± 8.1 years (<1 to 50 years). Results Overall, 18.4% patients had HbA1c levels <7.0%, and 47.5% patients had HbA1c levels ≥ 9%. HbA1c levels were associated with lower economic status, female gender, age and the daily frequency of self-blood glucose monitoring (SBGM) but not with insulin regimen and geographic region. Hypertension was more frequent in the mid-west (32%) and north/northeast (25%) than in the southeast (19%) and south (17%) regions (p<0.001). More patients from the southeast region achieved LDL cholesterol goals and were treated with statins (p<0.001). Fewer patients from the north/northeast and mid-west regions were screened for retinopathy and nephropathy, compared with patients from the south and southeast. Patients from the south/southeast regions had more intensive insulin regimens than patients from the north/northeast and mid-west regions (p<0.001). The most common insulin therapy combination was intermediate-acting with regular human insulin, mainly in the north/northeast region (p<0.001). The combination of insulin glargine with lispro and glulisine was more frequently used in the mid-west region (p<0.001). Patients from the north/northeast region were younger, non-Caucasian, from lower economic status, used less continuous subcutaneous insulin infusion, performed less SBGM and were less overweight/obese (p<0.001). Conclusions A majority of patients, mainly in the north/northeast and mid-west regions, did not meet metabolic control goals and were not screened for diabetes-related chronic complications. These results should guide governmental health policy decisions, specific to each geographic region, to improve diabetes care and decrease the negative impact diabetes has on the public health system.

A behavioral intervention in a cohort of Japanese-Brazilians at high cardiometabolic risk

OBJECTIVE: To assess the effect of a health promotion program on cardiometabolic risk profile in Japanese-Brazilians. METHODS: A total of 466 subjects from a study on diabetes prevalence conducted in the city of Bauru, southeastern Brazil, in 2000 completed a 1-year intervention program (2005-2006) based on healthy diet counseling and physical activity. Changes in blood pressure and metabolic parameters in the 2005-2006 period were compared with annual changes in these same variables in the 2000-2005 period. RESULTS: During the intervention, there were greater annual reductions in mean (SD) waist circumference [-0.5(3.8) vs. 1.2(1.2) cm per year, p<0.001], systolic blood pressure [-4.6(17.9) vs. 1.8(4.3) mmHg per year, p<0.001], 2-hour plasma glucose [-1.2(2.1) vs. -0.2(0.6) mmol/L per year, p<0.001], LDL-cholesterol [-0.3(0.9) vs. -0.1(0.2) mmol/L per year, p<0.001] and Framingham coronary heart disease risk score [-0.25(3.03) vs. 0.11(0.66) per year, p=0.02] but not in triglycerides [0.2(1.6) vs. 0.1(0.42) mmol/L per year, p<0.001], and fasting insulin level [1.2(5.8) vs. -0.7(2.2) IU/mL per year, p<0.001] compared with the pre-intervention period. Significant reductions in the prevalence of impaired fasting glucose/impaired glucose tolerance and diabetes were seen during the intervention (from 58.4% to 35.4%, p<0.001; and from 30.1% to 21.7%, p= 0.004, respectively). CONCLUSIONS: A one-year community-based health promotion program brings cardiometabolic benefits in a high-risk population of Japanese-Brazilians.

Risco cardiovascular em profissionais de saúde de serviços de atendimento pré-hospitalar

Avaliar os fatores de risco cardiovascular, com ênfase na hipertensão, e estratificá-los de acordo com o Escore de Risco de Framingham (ERF). Estudo com 154 profissionais que atuavam em aten-dimento pré-hospitalar na cidade de São Paulo e rodovia Br-116. Foi considerado significante o valor de p<0,05. A prevalência de hipertensão foi de 33%, sendo que 20,1% eram tabagistas, 47% ingeriam bebidas alcoólicas, 64% eram sedentários, 66% apresentaram obesidade/sobrepeso e 70% cintura abdominal alterada, glicemia>110mg/dL- 11%, colesterol total>200mg/dL- 36%, LDL-c>130mg/dL- 33%, HDL-c<60mg/dL- 89%, triglicérides>150mg/dL- 30% e proteína C reativa>0,5mg/dL- 16%. O ERF foi médio em 10,3% e alto em 1,3%. Na análise de regressão logística verificou-se que a hipertensão associou-se com as variáveis: HDL-c (odds ratio: 0,257) e ERF (odds ratio: 23,159). Houve forte associação entre ERF e hipertensão. Os dados chamam a atenção, por se tratar principalmente de profissionais da área da saúde relativamente jovens.

Association of postalimentary lipemia with atherosclerotic manifestations

We identified different lipemic and metabolic responses after the ingestion of a standardized meal by healthy adults and related them to atherosclerotic markers. Samples from 60 normolipidemic adults were collected before and after a liquid meal (40 g fat/m² body surface) at 0, 2, 4, 6, and 8 h for measurements of lipids, free fatty acids (FFA), insulin, cholesteryl ester transfer protein (CETP), autoantibodies to epitopes of oxidized LDL (oxLDL Ab), lipolytic activities, and apolipoprotein E polymorphism. Mean carotid intima-media thickness (cIMT) was determined by Doppler ultrasound. The volunteers were classified into early (N = 39) and late (N = 31) triacylglycerol (TAG) responders to the test meal. Late responders showed lower HDL cholesterol concentration at fasting and in the TAG peak, lower insulin and higher FFA concentrations compared to early responders. Multivariate regression analyses showed that mean cIMT was associated with gender (male) and age in early responders and by cholesterol levels at the 6th hour in late responders. oxLDL Ab were explained by lipoprotein lipase and negatively by hepatic lipase and oxLDL Ab (fasting period) by CETP (negative) and FFA (positive). This study is the first to identify a postalimentary insulin resistance state, combined with a reduced CETP response exclusively among late responders, and the identification of the regulators of postalimentary atherogenicity. Further research is required to determine the metabolic mechanisms described in the different postalimentary phenotypes observed in this study, as well as in different pathological states, as currently investigated in our laboratory.

Avaliação de resultados em um serviço de atenção secundária para pacientes com Diabetes mellitus

OBJETIVO: Avaliar o componente resultado em um serviço de atenção secundária a usuários com Diabetes mellitus tipo 2, tomando como indicadores os controles de pressão arterial, hemoglobina glicada e lipoproteína de baixa densidade. MÉTODOS: Estudo do tipo documental e retrospectivo envolvendo a análise desses indicadores, obtidos nos anos entre 2007 e 2009, com base na consulta de 108 prontuários de usuários de um serviço de atenção secundária, realizada na avaliação de cuidados em saúde. RESULTADOS: Os resultados evidenciaram que 30,3% dos usuários alcançaram a meta para a hemoglobina glicada, 48,1%, para a pressão arterial e 42,3%, para a lipoproteína de baixa densidade. CONCLUSÃO: Os dados avaliados foram semelhantes aos encontrados em outras investigações internacionais e nacionais, com grande proporção de usuários com DM2 estudados, apresentando controle dos níveis hemoglobina A1c, PA e LDL-C, aquém do preconizado nos consensos.

Consenso 2012 da Sociedade Brasileira de Reumatologia sobre o manejo de comorbidades em pacientes com artrite reumatoide

OBJETIVO: Elaborar recomendações da Comissão de Artrite Reumatoide da Sociedade Brasileira de Reumatologia (SBR) para o manuseio das comorbidades em artrite reumatoide (AR). MÉTODOS: Revisão da literatura e opinião de especialistas da Comissão de AR da SBR. RESULTADOS E CONCLUSÕES: Recomendações: 1) Diagnosticar e tratar precoce e adequadamente as comorbidades; 2) O tratamento específico da AR deve ser adaptado às comorbidades; 3) Inibidores da enzima conversora da angiotensina (IECA) ou bloqueadores dos receptores de angiotensina II (BRA) são preferidos no tratamento da hipertensão arterial sistêmica; 4) Em pacientes com AR e diabetes mellitus, deve-se evitar o uso contínuo de dose cumulativa alta de corticoides; 5) Sugere-se o uso de estatinas para manter níveis de LDL menor que 100 mg/dL e índice aterosclerótico menor que 3,5 em pacientes com AR e comorbidades; 6) A síndrome metabólica deve ser tratada; 7) Recomenda-se a realização de exames para a investigação de aterosclerose subclínica; 8) Maior vigilância para um diagnóstico precoce de neoplasia oculta; 9) Medidas de prevenção para trombose venosa são sugeridas; 10) Recomenda-se a realização de densitometria óssea em pacientes com AR acima de 50 anos, e naqueles com idade menor com corticoide maior que 7,5 mg por mais de três meses; 11) Pacientes com AR e osteoporose devem evitar quedas, e devem ser aconselhados a aumentarem a ingestão de cálcio, aumentarem a exposição solar e fazerem atividade física; 12) Suplementação de cálcio e vitamina D é sugerida.Autilização de bisfosfonatos é sugerida para pacientes com escore T menor que -2,5 na densidade mineral óssea; 13) Recomenda-se equipe multidisciplinar, com participação ativa do médico reumatologista no tratamento das comorbidades.

Adhesion molecules of detrusor muscle cells are influenced by a hypercholesterolemic diet or bladder outlet obstruction in a wistar rat model

Abstract Background Cell adhesion molecules (CAMs) are essential for maintaining tissue integrity by regulating intercellular and cell to extracellular matrix interactions. Cadherins and catenins are CAMs that are located on the cell membrane and are important for adherens junction (AJ) function. This study aims to verify if hypercholesterolemic diet (HCD) or bladder outlet obstruction (BOO) promotes structural bladder wall modifications specific to alterations in the expression of cadherins and catenins in detrusor muscle cells. Methods Forty-five 4-week-old female Wistar rats were divided into the following three groups: group 1 was a control group that was fed a normal diet (ND); group 2 was the BOO model and was fed a ND; and group 3 was a control group that was fed a HCD (1.25% cholesterol). Initially, serum cholesterol, LDL cholesterol and body weight were determined. Four weeks later, groups 1 and 3 underwent a sham operation; whereas group 2 underwent a partial BOO procedure that included a suture tied around the urethra. Six weeks later, all rats had their bladders removed, and previous exams were repeated. The expression levels of N-, P-, and E-cadherin, cadherin-11 and alpha-, beta- and gamma-catenins were evaluated by immunohistochemistry with a semiquantitative analysis. Results Wistar rats fed a HCD (group 3) exhibited a significant increase in LDL cholesterol levels (p=0.041) and body weight (p=0.017) when compared to both groups that were fed a normal diet in a ten-week period. We found higher β- and γ-catenin expression in groups 2 and 3 when compared to group 1 (p = 0.042 and p = 0.044, respectively). We also observed Cadherin-11 overexpression in group 3 when compared to groups 1 and 2 (p = 0.002). Conclusions A HCD in Wistar rats promoted, in addition to higher body weight gain and increased serum LDL cholesterol levels, overexpression of β- and γ-catenin in the detrusor muscle cells. Similar finding was observed in the BOO group. Higher Cadherin-11 expression was observed only in the HCD-treated rats. These findings may be associated with bladder dysfunctions that occur under such situations.

Adaptive immunity is related to coronary artery disease severity after acute coronary syndrome in subjects with metabolic syndrome

Metabolic syndrome (MetS) is an inflammatory state associated with high coronary disease risk. Inflammation and adaptive immunity modulate atherosclerosis and plaque instability. We examined early changes in anti-oxidized lowdensity lipoprotein (LDL) (anti-oxLDL) autoantibodies (Abs) in patients with MetS after an acute coronary syndrome (ACS). Patients of both genders (n=116) with MetS were prospectively included after an acute yocardial infarction (MI) or hospitalization due to unstable angina. Anti-oxLDL Abs (IgG class) were assayed at baseline, three and six weeks after ACS. The severity of coronary disease was evaluated by the Gensini score. We observed a decrease in anti-oxLDL Abs titers (p<0.002 vs. baseline), mainly in males (p=0.01), in those under 65 y (p=0.03), and in subjects with Gensini score above median (p=0.04). In conclusion, early decrease in circulating anti-oxLDL Abs is associated with coronary disease severity among subjects with MetS.

Resultados da cirurgia bariátrica e metabólica: gastrectomia vertical versus gastroplastia vertical com derivação em Y-de-Roux. Ensaio clínico prospectivo

Objetivos: Avaliar a equivalência da operação gastrectomia vertical com anel (GVA), em relação à operação gastroplastia vertical com anel e derivação gástrica em Y-de-Roux (DGA), na indução de perda ponderal e modificação da composição corporal em obesas mórbidas. Verificar os impactos laboratoriais e clínicos da GVA sobre as principais doenças associadas à obesidade mórbida, e a ocorrência de complicações, em comparação à DGA. Métodos: Ensaio clínico prospectivo não-randomizado, incluindo 65 mulheres obesas mórbidas, distribuídas em dois grupos, GVA (n = 33) e DGA (n = 32). Operadas consecutivamente, pelo mesmo cirurgião, por via laparotômica. Os parâmetros avaliados foram antropométricos; composição corporal, por meio de bioimpedância elétrica; laboratoriais; efeitos sobre as doenças pré-existentes e complicações. Resultados: Ocorreu perda de peso expressiva (p = 0,0000), redução do índice de massa corporal - IMC (p = 0,0000) e cintura abdominal (p = 0,0000) em ambos grupos. O índice cintura/quadril diminuiu (p = 0,0000) após ambas intervenções. A perda do excesso de IMC foi de 86,05% ± 14,2 no grupo GVA e 85,91 ± 15,71 no grupo DGA. A variação da gordura corporal foi de -35,84% ± 8,66 no grupo GVA e de -37,64% ± 9,62 no grupo DGA. A redução dos níveis de triglicerídios (p = 0,0222) foi mais expressiva no grupo DGA. O grupo DGA atingiu os alvos terapêuticos para o colesterol-LDL com maior freqüência (p = 0,0005), que o grupo GVA. Intolerância à glicose, diabetes mellitus tipo 2, hipertensão arterial sistêmica, esteatose hepática e síndrome metabólica, foram controladas de forma semelhante entre as técnicas. Anemia foi mais prevalente no grupo DGA (p=0,0033) e a esofagite erosiva, no grupo GVA (p = 0,0032). Não houve diferença na formação de cálculos biliares entre os grupos. Conclusões: A GVA é tão efetiva quanto a DGA em induzir perda ponderal e modificação favorável da composição corporal. A GVA é menos efetiva no controle da dislipidemia, em relação à DGA. GVA acarreta anemia em menor freqüência e, esofagite erosiva de maneira mais freqüente, que a DGA. GVA não é mais segura que a DGA, mas deve ser considerada intervenção bariátrica efetiva como segunda opção.

Il craniofaringioma nel bambino e nell'adolescente. Luci ed ombre durante il follow-up

Introduction. Craniopharyngioma (CF) is a malformation of the hypothalamicpituitary region and it is the most common nonglial cerebral tumor in children with an high overall survival rate. In some case severe endocrinologic and metabolic sequelae may occur during follow up. 50% of patients (pts), in particular those with radical removal of suprasellar lesions, develop intractable hyperphagia and morbid obesity, with dyslypidemia and high cardiovascular risk. We studied the auxological and metabolic features of a series of 29 patients (18 males) treated at a mean age of 7,6 years, followed up in our Centre from 1973 to 2008 with a mean follow up of 8,3 years. Patients features at the onset. 62% of pts showed as first symptoms of disease visual impairment and neurological disturbancies (headache); 34% growth arrest; 24% signs of raised intracranial pressure and 7% diabetes insipidus. Diagnosis. Diagnosis of CF was reached finally by TC or MRI scans which showed endo-suprasellar lesion in 23 cases and endosellar tumour in 6 cases. Treatment and outcome. 25/29 pts underwent surgical removal of CF (19 by transcranial approach and 6 by endoscopic surgery); 4 pts underwent stereotactic surgery as first line therapy. 3 pts underwent local irradiation with yttrium-90, 5 pts post surgery radiotherapy. 45% of pts needed more than one treatment procedure. Results. After CF treatment all patients suffered from 3 or more pituitary hormone deficiencies and diabetes insipidus. They underwent promptly substitutive therapy with corticosteroids, l-thyroxine and desmopressin. In 28/29 pts we found growth hormone (GH) deficiency. 20/28 pts started GH substitutive therapy and 15 pts reached final height(FH) near target height(TH). 8 pts were not GH treated for good growth velocity, even without GH, or for tumour residual. They reached in 2 cases FH over TH showing the already known phenomenon of growth without GH. 38% of patients showed BMI SDS >2 SDS at last assessment, in particular pts not GH treated (BMI 2,5 SDS) are more obese than GH treated (BMI 1,2 SDS). Lipid panel of 16 examined pts showed significative differencies among GH treated (9 pts) and not treated (7 pts) with better profile in GH treated ones for Total Cholesterol/C-HDL and C-LDL/C-HDL. We examined intima media thickness of common carotid arteries in 11 pts. 3/4 not GH treated pts showed ultrasonographic abnormalities: calcifications in 2 and plaque in 1 case. Of them 1 pt was only 12,6 years old and already showed hypothalamic obesity with hyperphagia, high HOMA index and dyslipidemia. In the GH treated group (7) we found calcifications in 1 case and a plaque in another one. GH therapy was started in the young pt with carotid calcifications, with good improvement within 6 months of treatment. 5/29 pts showed hypothalamic obesity, related to hypothalamic damage (type of surgical treatment, endo-suprasellar primitive lesion, recurrences). 48% of patients recurred during follow up ( mean time from treatment: 3 years) and underwent, in some cases up to 4 transcranial surgical treatments. GH seems not to increase recurrence rate since 40% of GH treated recurred vs 66,6% of not GH treated pts. Discussion. Our data show the extereme difficulties that occur during follow up of craniopharyngioma treated patients. GH therapy should be offered to all patients even with good growth velocity after CF treatment, to avoid dislypidemia and reduce cardiovascular risk. The optimal therapy is not completely understood and whether gross tumor removal or partial surgery is the best option remains to be decided only on one patient tumour features and hypothalamic involvement. In conclusion the gold standard treatment of CF remains complete tumour removal, when feasible, or partial resection to preserve hypothalamic function in endosuprasellar large neoplasms.

Atherosklerose und Apoptose

Subendothelial in den Arterienwänden abgelagertes LDL kann einer enzymatischen Modifikation unterliegen, die es in einen cytotoxischen Partikel überführt. In vitro Behandlung von LDL mit Proteasen (Trypsin) und Cholesterinesterase führt zu einem dem läsionalen LDL ähnlichen Produkt. Die Behandlung von humanen Endothelzellen mit enzymatisch verändertem LDL (E-LDL), das einen hohen Gehalt an freiem Cholesterin und freien Fettsäuren aufweist, führt zur Auslösung der Apoptose via ASK1 (apoptosis signal-regulating kinase 1) –abhängiger p38-Phosphorylierung. Durch eine Aktivierung der Effektor-Caspasen-3/-7 kommt es zur Fragmentierung der DNA und zur Spaltung des nukleären Enzyms Poly-(ADP-ribose)-Polymerase. Phosphatidylserin ist an der äußeren Zellmembran mittels Annexin-Bindung detektierbar. Natives oder oxidiertes LDL induziert bei gleicher Konzentration keinen programmierten Zelltod. In Depletions- und Rekonstitutionsexperimenten wurden freie Fettsäuren aus E-LDL als Auslöser der Apoptose identifiziert. In nativem LDL ist der Anteil an freien Fettsäuren gering, deshalb ist das Lipoprotein nicht cytotoxisch. E-LDL induziert weiterhin eine Erhöhung bzw. eine Hemmung der transkriptionellen Aktivität eines AP-1- bzw. NF-κB-Luciferase Reporterplasmids. Die Ausschaltung von ASK1 mittels RNA-Interferenz bzw. die Hemmung von p38 mit dem Inhibitor SB203580 rettet die Zellen vor dem programmierten Zelltod. E-LDL kann in Endothelzellen oxidativen Stress auslösen. Durch Vorbehandlung mit N-Acetyl-Cystein wird die Aktivierung sowohl von ASK1 als auch von p38 unterdrückt.

Identificazione dei fenotipi clinici dell’insufficienza renale cronica che predicono la progressione della malattia. Un’applicazione della tecnica degli alberi decisionali

The primary aim of this dissertation to identify subgroups of patients with chronic kidney disease (CKD) who have a differential risk of progression of illness and the secondary aim is compare 2 equations to estimate the glomerular filtration rate (GFR). To this purpose, the PIRP (Prevention of Progressive Kidney Disease) registry was linked with the dialysis and mortality registries. The outcome of interest is the mean annual variation of GFR, estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. A decision tree model was used to subtype CKD patients, based on the non-parametric procedure CHAID (Chi-squared Automatic Interaction Detector). The independent variables of the model include gender, age, diabetes, hypertension, cardiac diseases, body mass index, baseline serum creatinine, haemoglobin, proteinuria, LDL cholesterol, tryglycerides, serum phoshates, glycemia, parathyroid hormone and uricemia. The decision tree model classified patients into 10 terminal nodes using 6 variables (gender, age, proteinuria, diabetes, serum phosphates and ischemic cardiac disease) that predict a differential progression of kidney disease. Specifically, age <=53 year, male gender, proteinuria, diabetes and serum phosphates >3.70 mg/dl predict a faster decrease of GFR, while ischemic cardiac disease predicts a slower decrease. The comparison between GFR estimates obtained using MDRD4 and CKD-EPI equations shows a high percentage agreement (>90%), with modest discrepancies for high and low age and serum creatinine levels. The study results underscore the need for a tight follow-up schedule in patients with age <53, and of patients aged 54 to 67 with diabetes, to try to slow down the progression of the disease. The result also emphasize the effective management of patients aged>67, in whom the estimated decrease in glomerular filtration rate corresponds with the physiological decrease observed in the absence of kidney disease, except for the subgroup of patients with proteinuria, in whom the GFR decline is more pronounced.