Prevalence and clinical features of celiac disease in 950 children with type 1 diabetes in France.

UNLABELLED: The prevalence of celiac disease is higher in children with type 1 diabetes mellitus (DM) than in the general pediatric population, but may vary widely across countries. Sensitive and specific antibody tests are available for detecting celiac disease. AIMS: To evaluate the prevalence in France of histologically documented celiac disease in a vast cohort of children with type 1 DM, and to describe the features of celiac disease and treatment response. METHODS: Retrospective cohort study of 950 children with type 1 diabetes seen between 1994 and 2001. Antibodies to gliadin, reticulin, endomysium and transglutaminase were looked for one to seven times in each patient. RESULTS: Fifteen patients (1.6%) had biopsy-confirmed celiac disease. Symptoms led to the diagnosis in six patients (mean age, 7 years) and screening tests in nine patients (mean age, 11 years). Anti-endomysium antibodies were consistently positive. Tests for HLA-DQB1 0201 and/or 0302 were positive. Anti-endomysium antibody seroconversion was seen in two patients, 2 and 6 years, respectively, after the diagnosis of diabetes. In another patient, the biopsy became abnormal 6 years after the first positive anti-endomysium antibody test (latent form). After a mean of 3 years on a gluten-free diet, significant increases were noted in body weight (P=0.04) and insulin dose (P=0.05); clinical symptoms completely resolved in five of the six symptomatic patients. CONCLUSIONS: The prevalence of celiac disease is higher in children with type 1 DM than in the general pediatric population. Serological screening is useful for diagnosing asymptomatic celiac disease, detecting seroconversion and monitoring latent forms of disease.

Advantages to using capillary blood beta-hydroxybutyrate determination for the detection and treatment of diabetic ketosis.

Ketone body determination is indicated in all diabetic patients when the risk of ketotic decompensation exists. New methods of screening for ketosis, in particular capillary blood ketone body determination, provide analytical, technical and clinical advantages compared to the conventional ketonuria. It is proposed that a diabetic patient with hyperglycaemia (capillary blood glucose > 2.50 g.l(-1)) and capillary blood ketone bodies exceeding 0.5 mmol.l(-1) requires therapeutic management. For values greater than 3 mmol.l(-1) or in case of more serious clinical symptoms, hospitalisation is indicated, considering the high probability of ketoacidotic decompensation. The advantages of capillary blood ketone body determination including easy use, and rapid and objective results may improve management of the diabetic patient, especially in emergency situations. However, prescription by a physician of capillary blood ketone body determination should be offered to targeted populations that have a high risk of ketoacidotic decompensation, after providing education to patients that is above all aimed at preventing this metabolic complication. In this context of determining ketone bodies in capillary blood, the term "capillary blood ketone bodies" is therefore preferable to the term "capillary blood beta-hydroxybutyrate determination". Indeed, it appears more appropriate, simple, descriptive and significant both for health-care staff and for patients.

Evaluation of clinical guidelines for the management of end-stage renal disease in europe: the EU BIOMED 1 study.

BACKGROUND: There are wide national and international variations in the management of patients with end-stage renal disease (ESRD). The aim of this study was to develop, harmonize, implement, and evaluate consensus-based clinical guidelines for the management of renal anaemia and renal bone disease in patients with ESRD, and for the prevention and management of cytomegalovirus disease in renal transplant recipients across six renal centres in Europe. METHODS: The trial was a prospective, multicentre, randomized balanced incomplete block design. Nephrologists from the six European renal units were randomized to develop and implement guidelines for two out of the three conditions and to act as a control for the third condition. Data were collected pre- (1 year) and post- (9 months) intervention on aspects of patient monitoring, management, and outcome. RESULTS: Eight hundred and twenty-nine dialysis patients from the six European dialysis centres were included in the study. Multivariate analysis (adjusting for case-mix and secular trends) showed a significant increase in the number of monitoring events in the guideline group compared with control group (6%, 95% CI, 1-11%). There was no concomitant increase in either appropriate management or the number of favourable patient outcomes. CONCLUSIONS: In the first European collaboration on renal guidelines, the introduction of the guidelines improved the monitoring of the patients, but did not improve patient management or outcome. This study suggests the potential for creating clinical guidelines with the aim of standardizing treatment protocols across international boundaries, and improving the quality of the medical care provided.

Comparing outcomes in renal replacement therapy: how should we correct for case mix?

The need to evaluate the effectiveness of clinical practice to justify expensive therapy in the face of financial constraints in all areas of health care delivery makes it necessary to identify groups of patients who are likely to benefit most from treatment. Various risk stratification methods have been used for analyzing survival probabilities for patients receiving renal replacement therapy. Complicated risk stratification methods produce large numbers of risk groups of small sizes, which makes comparison between individual centers difficult. We compared three simple methods of risk stratification, that divided patients into low-, medium-, and high-risk groups, in a cohort of 1,407 patients who commenced renal replacement therapy in five European countries during a 7-year period. Method 1 considered age (>55 years) and diabetes alone; method 2 used a higher age limit (>70 years) and comorbid illnesses, including those other than diabetes; and method 3 used only the number of comorbidities (none, 1, or > or =2) for stratification. Kaplan-Meier survival curves were constructed for comparison between risk groups and Cox's regression model used to assess strength of relationship with mortality. Although patient survival was significantly different between the low-, medium-, and high-risk groups using all three methods, Cox's regression analysis showed that method 2 provided the greatest discrimination between risk groups. In predicting mortality, method 2 (based on comorbidities and age) showed the highest sensitivity and specificity (84% and 80%, respectively) compared with method 1 (80% and 74%) and method 3 (64% and 82%). Validation of this approach in other populations in a prospective study is required before this method, which takes into account the influences of both age and comorbidity for risk stratification, can be used for comparing survival data and for presenting results of renal replacement therapy.

Survival on renal replacement therapy in Europe: is there a 'centre effect'?

OBJECTIVE: Survival is the ultimate outcome measure in renal replacement therapy (RRT) and may be used to compare performance among centres. Such comparison, however, is meaningless if the influences of comorbidity, age and early deaths are not considered. We therefore studied survival rates on RRT in seven centres in Europe after taking into account the influence of age, early deaths, primary renal diagnoses, and comorbidity. DESIGN: A retrospective survival analysis was carried out on 1407 patients who commenced RRT in seven centres across five European countries during a 7-year period. Patients were stratified into low-, medium- and high-risk groups based mainly on comorbidity and to a lesser extent on age at commencement of RRT. Kaplan-Meier survival and Cox's proportional hazards model were used to compare survival. RESULTS: Before risk stratification overall 2-year survival across the seven centres ranged from 60.2 to 85.3% (69.3-89.9%) after excluding early deaths) masking a range of survivals of 27.4% for the high-risk group with the worst survival to 100% in the low-risk group with the best survival. After excluding early deaths 2-year survival in the low risk groups (n=622) was greater than 90% in all centres. Multivariate analysis showed that the mortality risk increased four fold from low- to medium- and a further 1.6-fold from medium- to high-risk group. However, despite this adjustment for comorbidity and age there still remained a significant difference in survival among some centres, i.e. a 'centre effect' which ranked the centres. CONCLUSION: Risk stratification diminishes the variance in survival between centres but a centre effect remains despite adjusting for age and comorbidity. Multicentre prospective studies are urgently required to identify the reasons for this apparent centre effect.

Receptor-dependent and -independent catabolism of low-density lipoprotein in a kindred with familial hypobetalipoproteinemia.

Three affected members of a kindred with asymptomatic hypobetalipoproteinemia (HBL) were injected intravenously with 125I-labeled native low-density lipoproteins (LDL) and 131I-labeled cyclohexanedione (CHD)-treated LDL. Plasma and urine radioactivity data were collected for 15 days at regular intervals. A compartmental model using the SAAM program was built to fit simultaneously 125I and 131I plasma radioactivity decay and urine excretion data. This model allows precise calculation of the kinetic parameters of both receptor-independent (NR) and receptor-dependent (R) pathways. Compared with normal subjects, HBL patients show a 90% increased fractional catabolic rate (FCR) of LDL by both routes, more marked for the R pathway (215% increase), and an approximately 50% reduced production rate (PR). Structural analysis did not show significant abnormalities of apolipoprotein (apo) B in HBL patients compared with normal. These data suggest that the very reduced, LDL-apo B plasma levels result from a combination of two processes: (1) an increased activity of all catabolic routes, and (2) a reduced "synthesis" rate. The latter may result from a decreased conversion of very-low-density lipoprotein (VLDL) to LDL secondary to an increased direct removal of large VLDL, suggested by apo C-II and C-III turnover studies previously reported.

In vivo metabolism of apolipoproteins A-IV and A-I associated with high density lipoprotein in normolipidemic subjects.

The kinetics of apolipoprotein A-IV associated with high density lipoproteins (HDL) of plasma from fasting human subjects was followed for 15 days in five healthy normolipidemic volunteers. Purified apoA-IV and apoA-I were radioiodinated, respectively, with 125I and 131I, incubated in vitro with normal HDL, isolated at density 1.250 g/ml, and finally reinjected intravenously as HDL-125I-labeled apoA-IV and HDL-131I-labeled apoA-I. Blood samples were withdrawn at regular intervals for 15 days, and 24-h urine samples were collected. More than 93% (93.5 +/- 0.9%) of apoA-IV was recovered in apoA-I-containing lipoprotein particles after affinity chromatography on an anti-apoA-I column and 69.7 +/- 4.8% was bound to apoA-II in apoA-I:A-II particles separated on an anti-apoA-II column. 125I-labeled apoA-IV showed a much faster decay than 131I-labeled apoA-I for the first 5 days and thereafter the curves became parallel. Urinary/plasma ratios (U/P) for the 125I-labeled parallel. Urinary/plasma ratios (U/P) for the 125I-labeled apoA-IV were much higher than those for 131I-labeled apoA-I for the first days, but the U/P curves became parallel for the last 7 days, suggesting heterogeneity of apoA-IV metabolism. A heterogeneous multicompartmental model was constructed to describe the metabolism of lipoprotein particles containing apoA-IV and apoA-I and to calculate the kinetic parameters, fitting simultaneously all plasma and urine data for both tracers.(ABSTRACT TRUNCATED AT 250 WORDS)

Apolipoprotein C-II and C-III metabolism in a kindred of familial hypobetalipoproteinemia.

Three affected members of a kindred with asymptomatic hypobetalipoproteinemia (HBL) showed low levels of triglycerides, low-density lipoprotein (LDL)-cholesterol, and apolipoproteins (apo) B, C-II, and C-III. Turnover of iodine-labeled apo C-II and apo C-III associated in vitro to plasma lipoproteins was studied after intravenous injection. Radioactivity in plasma and lipoproteins (95% recovered in high-density lipoprotein [HDL] density range) and in 24-hour urine samples was observed for 16 days. A parallelism of the slowest slopes of plasma decay curves was observed between apo C-II and apo C-III, indicating a partial common catabolic route. Urine/plasma radioactivity ratio (U/P) varied with time, suggesting heterogeneity of metabolic pathways. A new compartmental model using the SAAM program was built, not only fitting simultaneously plasma and urine data, but also taking into account the partial common metabolism of lipoprotein particles (LP) containing apo C-II and apo C-III. The low apo C-II and C-III plasma concentrations observed in HBL compared with normal resulted from both an increased catabolism and a reduced synthesis, these changes being more marked for apo C-III. The modifications in the rate constants of the different pathways calculated from the new model are in favor of an increased direct removal of particles following the fast pathway, likely in the very-low-density lipoprotein (VLDL) density range.

Effect of simvastatin on receptor-dependent low density lipoprotein catabolism in normocholesterolemic human volunteers.

Simvastatin, an inhibitor of HMG-CoA reductase was given to 7 normolipidemic healthy volunteers for 1 month at a dose of 20 mg/day. Measurements of turnover of low density lipoprotein apolipoprotein B (LDL-apo B) were determined before and after drug treatment using intravenous injection of 125I-labeled LDL and 131I-labeled cyclohexanedione-treated LDL to quantify the receptor pathway. In addition to a 13% increase in HDL cholesterol and apolipoprotein A-I concentrations, plasma cholesterol was reduced by 20%, LDL-cholesterol by 32%, and apolipoprotein B by 23%. Assuming a heterogeneous pool of LDL, the new model presented in the companion paper was built to calculate the contribution of the receptor-dependent and the receptor-independent pathways and the corresponding fractional catabolic rates. Simvastatin did not modify constantly the synthetic rate of LDL-apo B but increased the fractional catabolic rate of the receptor-dependent pathway and the contribution of this pathway in the catabolism. The fall in LDL plasma levels observed in normocholesterolemic subjects can be then entirely explained by an enhanced fractional removal of LDL from the circulation by the receptor route.

Kinetics of a heterogeneous population of particles in low density lipoprotein apolipoprotein B.

This paper examines the kinetics of low density lipoprotein (LDL) metabolism following the in vivo injection of native and chemically-modified lipoproteins in an attempt to assess the relative importance of receptor-dependent and receptor-independent catabolic pathways. The shape of the urinary/plasma ratio curve suggested heterogeneity of the LDL-apolipoprotein B pool and excluded homogeneity. This heterogeneity required the building of a more complex model that allowed the simultaneous fitting of plasma and urinary data. This new model permits the precise quantification of both receptor and non-receptor pathways.

Apolipoproteins C-II and C-III metabolism in hypertriglyceridemic patients. Effect of a drastic triglyceride reduction by combined diet restriction and fenofibrate administration.

Four hypertriglyceridemic patients, who had received an equilibrated high calorie diet and no lipid lowering drug for 1 month, were injected intravenously with 125I-apo C-II and 131I-apo C-III labeled homologous lipoproteins. Plasma and urine radioactivity, lipid and apolipoprotein levels were followed at regular intervals for 15 days. At the end of this first kinetic study the patients were advised to adhere for 1 month to a more restricted diet, limited in fat, and were given additionally 300 mg fenofibrate daily. After this treatment, a new kinetic study involving intravenous injection (similar to the first one) was performed. The protocols of both studies were identical. Treatment (diet plus drug) (1) reduced total cholesterol by 26 +/- 8%, triglycerides by 56 +/- 15%, apo C-II by 36 +/- 14%, and apo C-III by 48 +/- 10%; (2) modified the distribution of radioactivity between lipoproteins proportionally to the change in their mass ratio (decrease in VLDL and increase in HDL); (3) changed the kinetics of both apoproteins by rising the fractional removal rate, shortening residence time and decreasing the synthesis rate of both apolipoproteins C-II and C-III. The treatment was, however, unable to reduce the synthesis rate of apo C-III to normal, suggesting a major role of the apoprotein overproduction in the triggering of hypertriglyceridemia.

Proposed folding pattern for apolipoprotein A-II based on a structural analogy with uteroglobin.

The tertiary structure observed in the crystalline state for uteroglobin, a small steroid binding protein, is used as a template to build an approximated model for apolipoprotein A-II. The presence of four proline residues and four hydrophobic clusters located at similar positions in apolipoprotein A-II and uteroglobin is taken as the major source of stability in such tertiary structures. A brief description of plausible specific binding sites appearing on the model of apolipoprotein A-II is given. It is suggested that the internal cavity and the four surface pockets observed for uteroglobin and postulated for apolipoprotein A-II might be used to insure specific binding of triglycerides, phospholipids, or cholesterol.

[Reversible acute renal failure with tubular oxalosis. Possible role of nutritional factors]. / Insuffisance rénale aiguë réversible avec oxalose tubulaire. Rôle possible de facteurs nutritionnels.

Intratubular deposits of calcium oxalate crystals can be responsible for acute renal failure. The present report concerns two cases for which none of the known causes of oxalate nephropathy were found. Both patients had common features: chronic alcoholism and denutrition. Except for early lumbar and abdominal pain, the renal failure picture was without any peculiarity. Renal biopsy showed tubular epithelium alterations with marked luminal deposition of birefringent crystals consistent with calcium oxalate. In one patient serum oxalate level was high, and in the other urinary oxalate excretion rose above normal when diuresis resumed. Renal function recovered spontaneously (follow-up of four years for one patient). Neither intoxication nor intestinal disease could be detected. Given the key role of pyridoxine in oxalate metabolism, we suggest that vitamin B6 deficiency secondary to alcoholism and denutrition could cause a rise in oxalemia leading to oxalate nephropathy. Experiments in animals support this hypothesis.

Metabolism of apolipoprotein C-III in normolipemic human subjects.

Radioiodinated apolipoprotein C-III labeled either by the iodine monochloride procedure or by the Bolton-Hunter reagent were incubated in vitro with normal HDL. The labeled HDL-apo C-III, after ultracentrifugation and dialysis, was injected intravenously in 8 normolipidemic subjects. The label was followed in VLDL, IDL + LDL, HDL, d = 1.225 g/ml infranate as well as in total plasma and urine for the first time over a period of 2 weeks. Apolipoprotein C-III distributes readily between the different lipoprotein classes, only a small amount being present in the non-lipoprotein fraction. The percent distribution of apo C-III radioactivity and mass was found similar in VLDL, IDL and HDL using 3 different separation methods. Residence time in the whole system was 2.45 +/- 0.33 days. Fractional catabolic rates calculated from the urine/plasma radioactivity ratios or from the plasma curve were 0.731 +/- 0.096 and 0.767 +/- 0.125 pools/day. Synthetic rate was 2.28 +/- 0.32 mg/day/kg. The parameters seem not affected by the labeling procedure. The shapes of the plasma curve and of the urine/plasma ratio curve suggest a kinetic heterogeneity in the metabolism of apo C-III-containing particles.

In vivo metabolism of apolipoprotein S in humans. Comparison with apolipoprotein A-I metabolism.

125I-labelled apolipoprotein (Apo) S and 131I-labelled apolipoprotein A-I were injected i.v. into healthy volunteers. Blood samples and daily urine collections were drawn periodically for 15 days. Ninety-eight percent of 131I radioactivity and greater than 95% of 125I radioactivity were found in HDL after Superose gel chromatography of plasma. About 10% of each radioactivity was recovered in the d 1.250 infranate after one ultracentrifugation. Affinity chromatography on monoclonal anti-Apo A-I Sepharose column separates two lipoprotein particles containing Apo S, one retained with Apo A-I (42.5%) and the other eluting without Apo A-I (57.5%). Kinetic parameters were calculated according to exponential curve fitting. Mean transit time was about 7.0 days for both Apo A-I and Apo S. FCR of Apo S was 50% higher than FCR of Apo A-I. Synthetic rate of Apo S was about 150 times smaller than for Apo A-I. As heterogeneity of HDL-S was suggested by both the results of affinity chromatography and the urinary data, a compartmental model was built which fitted adequately all data. Part of the model is common to HDL-A-I and HDL-S.