Asymmetric dimethylarginine in young people with Type 1 diabetes: a paradoxical association with HbA(1c).

AIMS: Asymmetric dimethylarginine (ADMA) is an independent risk factor for cardiovascular disease and its concentrations are increased in several diseases, including diabetes. However, there is limited information on this plasma marker in young people, particularly in those with Type 1 diabetes. The aim of the present study was therefore to perform a longitudinal evaluation of plasma ADMA and of its determinants in young people with childhood-onset Type 1 diabetes. METHODS: For measurement of ADMA using mass spectrometry, 1018 longitudinal stored blood samples were available from 330 young people with Type 1 diabetes followed in the Oxford Regional Prospective Study. Additional data concerning annual assessments of HbA(1c) , height, weight, insulin dose and three early morning urine samples for measurement of the albumin/creatinine ratio were available. RESULTS: ADMA levels were significantly higher in males than in females (mean ± SD: 0.477 ± 0.090 vs. 0.460 ± 0.089 µmol/l, P=0.002) and declined with chronological age (estimate ± SE: -0.0106 ± 0.0008, P<0.001). A significant inverse association was detected between ADMA and HbA(1c) (estimate ± SE:-0.0113 ± 0.001, P<0.001). ADMA levels were lower in subjects developing microalbuminuria (mean ± SD: 0.455 ± 0.093 vs. 0.476 ± 0.087 µmol/l, P=0.001) than in subjects with normoalbuminuria, but this difference disappeared after adjusting for HbA(1c) . CONCLUSIONS: In this longitudinal study, ADMA concentrations decreased with age and were significantly higher in males and lower in subjects developing microalbuminuria. These associations were largely explained by a paradoxical negative association between HbA(1c) and ADMA. We suggest that chronic hyperglycaemia might down-regulate mechanisms implicated in ADMA production or stimulate its metabolism confounding short-term associations with complications risk.

Reduced endogenous secretory receptor for advanced glycation end products (esRAGE) in young people with Type 1 diabetes developing microalbuminuria.

AIMS: The endogenous secretory receptor for advanced glycation end products (esRAGE) appears to work as a scavenger for AGEs and it has been implicated in the pathogenesis of diabetic complications. The aim of the present study was to perform a longitudinal evaluation of esRAGE in young people with Type 1 diabetes (T1D) in relation to the development of microalbuminuria (MA). METHODS: Serum esRAGE levels were measured in longitudinally collected blood samples from 49 T1D patients with MA (MA+) and 49 matched normoalbuminuric patients (MA-), followed in the Oxford Regional Prospective Study. esRAGE levels were compared between MA+ and MA- subjects in relation to the time of MA onset. RESULTS: Overall, esRAGE levels were significantly lower in MA+ than in MA- subjects (0.727 +/- 0.396 vs. 0.936 +/- 0.433 ng/ml; P = 0.015). These differences between the two groups were present both before (0.725 +/- 0.410 vs. 0.956 +/- 0.505 ng/ml, P = 0.038) and after the onset of MA (0.750 +/- 0.433 vs. 0.948 +/- 0.418 ng/ml, P = 0.04). In a longitudinal analysis there was no effect of age, duration, glycated haemoglobin (HbA(1c)) or body mass index standard deviation scores on esRAGE levels (all P > 0.05). In a Cox model, esRAGE levels significantly contributed to the probability of developing MA [Exp(B)(95% confidence interval): 0.34(0.12-0.98); P = 0.04), independently of HbA(1c). CONCLUSIONS: In this longitudinal study of young people with T1D, esRAGE levels were reduced in MA+ subjects, even before the onset of MA, and appeared to be related to its development, thus suggesting a potential role of esRAGE in the pathogenesis of this complication. Diabet. Med. 26, 815-819 (2009).

Ambulatory blood pressure measurements are related to albumin excretion and are predictive for risk of microalbuminuria in young people with type 1 diabetes.

AIMS/HYPOTHESIS: The relationship between BP and microalbuminuria in young people with type 1 diabetes is not completely clear. As microalbuminuria is preceded by a gradual rise in albumin excretion within the normal range, we hypothesised that ambulatory BP (ABP) may be closely related to albumin excretion and progression to microalbuminuria. METHODS: ABP monitoring (ABPM) was performed in 509 young people with type 1 diabetes (age median [range]: 15.7 [10.7-22.6] years) followed with annual assessments of three early morning urinary albumin:creatinine ratios (ACRs) and HbA(1c). Systolic BP (SBP) and diastolic BP (DBP) and the nocturnal fall in BP were analysed in relation to ACR. RESULTS: All ABPM variables were significantly related to baseline log(10) ACR (p < 0.001). After the ABPM evaluation, 287 patients were followed for a median of 2.2 (1.0-5.5) years. ABP at baseline was independently related to mean ACR during follow-up. Nineteen initially normoalbuminuric patients developed microalbuminuria after 2.0 (0.2-4.0) years and their baseline daytime DBP was higher than in normoalbuminuric patients (p < 0.001). After adjusting for baseline ACR and HbA(1c), there was an 11% increased risk of microalbuminuria for each 1 mmHg increase in daytime DBP. Forty-eight per cent of patients were non-dippers for SBP and 60% for DBP; however, ACR was not different between dippers and non-dippers and there were no differences in the nocturnal fall in BP between normoalbuminuric and future microalbuminuric patients. CONCLUSIONS/INTERPRETATION: In this cohort of young people with type 1 diabetes, ABP was significantly related to ACR, and daytime DBP was independently associated with progression to microalbuminuria. Increasing albumin excretion, even in the normal range, may be associated with parallel rises in BP.

Unchanged incidence of microalbuminuria in children with type 1 diabetes since 1986: a UK based inception cohort.

AIMS: To prospectively determine the change in prevalence of microalbuminuria in relation to changes in glycaemic control in children diagnosed with type 1 diabetes between 1986 and 1996. DESIGN: Prospective observational study of an inception cohort. SETTING: The geographically defined region of Oxfordshire, UK. PATIENTS: 527 children diagnosed with type 1 diabetes under 16 years of age, were divided into three groups based on year of diagnosis of diabetes: group A (1986-1989, n = 165), group B (1990-1993, n = 179) and group C (1994-1996, n = 183). Each group was followed prospectively for 10 years. MAIN OUTCOME MEASURES: Cumulative prevalence of microalbuminuria. RESULTS: After 4052 patient years of follow-up, in groups C versus B versus A, the cumulative prevalence of microalbuminuria was 31.7% (95% CI 20.9 to 42.5), 24.8% (17.8 to 31.8) and 23.2% (15.4 to 30.0) (log rank p = 0.22), and risk for development of microalbuminuria was not associated with year of onset of diabetes (hazard ratio 1.05 (0.99 to 1.12), p = 0.11). In groups C versus B versus A, glycaemic control improved after 10 years of diabetes (mean HbA1c 8.9% (1.5%) vs 9.4% (1.5%) vs 10.1% (1.7%), p value for ANOVA <0.001) and more children achieved an HbA1c level <7.5% (15.6% vs 5.9% vs 6.1%, p value for ANOVA = 0.032). CONCLUSION: In this UK based inception cohort of children diagnosed with type 1 diabetes, the adjusted prevalence of microalbuminuria was unchanged since 1986, despite some improvements in glycaemic control. This observation highlights the need for more proactive intervention with drugs such as angiotensin converting enzyme (ACE) inhibitors.

Can we identify adolescents at high risk for nephropathy before the development of microalbuminuria?

AIMS: To determine whether higher than average albumin excretion during early puberty identifies subjects who will subsequently develop microalbuminuria (MA) and clinical proteinuria. METHODS: Longitudinal data from the Oxford Regional Prospective Study of Childhood Diabetes (ORPS; n = 554, median duration of follow-up 10 years; range 3.0-16.7) with assessment of albumin/creatinine ratios in three early morning urine samples collected annually. An albumin excretion phenotype was derived from longitudinal data, for each individual, defining deviation from the mean of regression models, including covariates gender, age, duration of diabetes and age at assessment. Tracking of the phenotypes was confirmed in a second independent cohort from Perth, Australia. RESULTS: The albumin excretion phenotype showed reasonable correlation between age 11-15 years and age 16-18 years in both cohorts, indicative of good 'tracking'. In the ORPS cohort, tertiles of the albumin excretion phenotype at aged 11-15 years were predictive of subsequent risk for the development of MA. All of the subjects developing clinical proteinuria had an albumin excretion phenotype in the upper tertile or an HbA(1c) > 9% at aged 11-15 years. CONCLUSIONS: Identification of adolescents at risk of diabetic nephropathy using an albumin excretion phenotype is feasible. When combined with elevated HbA(1c), it may identify subjects for trial of early intervention with angiotensin-converting enzyme inhibitors/angiotensin-II receptor antagonists and statins to improve long-term prognosis in these subjects where sustained improvement in glycaemic control may be difficult to achieve.

The UK case-control study of cerebral oedema complicating diabetic ketoacidosis in children.

AIMS/HYPOTHESIS: Cerebral oedema complicating diabetic ketoacidosis (DKA) remains the major cause of morbidity and mortality in children with type 1 diabetes, but its aetiology remains unknown. Our objective was to determine the impact of baseline biochemical factors and of treatment-related variables on risk of the development of cerebral oedema in children with DKA. MATERIALS AND METHODS: This was a national UK case-control study. Through the British Paediatric Surveillance Unit we identified 43 cases of cerebral oedema. Through a parallel reporting system, we also identified 2,940 episodes of DKA and selected 169 control subjects on the basis of comparable age, sex, numbers of new or known cases of diabetes and date of admission. Baseline biochemical data and treatment-related variables were extracted from the clinical notes of cases and control subjects. RESULTS: Allowing for differences in age, sex and new or known diabetes, cases were more acidotic at diagnosis of DKA (odds ratio [OR] for events in the least acidotic compared with the most acidotic tertile=0.02 [95% CI: 0.002-0.15], p<0.001). In addition, cases had higher potassium and urea levels at baseline. Calculated osmolality and baseline glucose were not significantly different. After allowing for severity of acidosis, insulin administration in the first hour (OR 12.7 [1.41-114.5], p=0.02) and volume of fluid administered over the first 4 h (OR 6.55 [1.38-30.97], p=0.01) were associated with risk. Low baseline plasma sodium and an elevated p(a)CO(2) also contributed to risk in the final regression model. Bicarbonate administration was not associated with increased risk of an event when corrected for acidosis. CONCLUSIONS/INTERPRETATION: In this case-control study of DKA, baseline acidosis and abnormalities of sodium, potassium and urea concentrations were important predictors of risk of cerebral oedema. Additional risk factors identified were early administration of insulin and high volumes of fluid. These observations should be taken into account when designing treatment protocols.

Longitudinal relation between limited joint mobility, height, insulin-like growth factor 1 levels, and risk of developing microalbuminuria: the Oxford Regional Prospective Study.

AIMS: To determine risk factors for development of microalbuminuria (MA) in relation to detection of limited joint mobility (LJM+) of the interphalangeal joints in a longitudinal cohort of type 1 diabetic (T1DM) subjects. METHODS: A total of 479 T1DM subjects diagnosed <16 years were followed from diagnosis of diabetes with annual assessments consisting of assessment of LJM, measurement of HbA1c and insulin-like growth factor 1 (IGF-1), and three urine samples for albumin:creatinine ratio (ACR). RESULTS: After a median follow up of 10.9 years, 162 subjects (35.1%) developed LJM at median age 13.0 years and duration 5.2 years. More subjects developed LJM after compared to before puberty (67.6 v 32.4%). In LJM+ compared to LJM- subjects, HbA1c (mean 10.1 (SD 1.6) v 9.6 (1.4) %)) and ACR levels (median 1.1 (range 0.2-242.9) v 0.9 (0.4-70.7) mg/mmol) were higher, and in a Cox model probability of developing LJM was related to puberty and higher HbA1c levels. ACR levels were higher after detection of LJM compared to before (median 1.2 (range 0.4-102.6) v 0.8 (0.2-181.9) mg/mmol). Probability of developing MA was related to puberty, HbA1c, female sex, and presence of LJM (a 1.9-fold increased risk). Both LJM and MA were associated with lower height SDS (LJM: mean 0.0 (SD 1.0) v 0.2 (1.1); MA: 0.0 (1.0) v 0.2 (SD 1.0)) and lower IGF-1 levels. CONCLUSION: The development of LJM was associated with an increased risk of microalbuminuria, independent of glycaemic control. Risk for both microalbuminuria and LJM was associated with puberty, reduced growth, and reduced IGF-1 levels, and may indicate underlying shared pathogenic mechanisms.

Optimal planning target volume for stage I testicular seminoma: A Medical Research Council randomized trial. Medical Research Council Testicular Tumor Working Group.

PURPOSE: To compare relapse rates and toxicity associated with para-aortic (PA) strip or PA and ipsilateral iliac lymph node irradiation (dogleg [DL] field) (30 Gy/15 fractions/3 weeks) for stage I testicular seminoma. PATIENTS AND METHODS: Between July 1989 and May 1993, 478 men with testicular seminoma stage I (T1 to T3; no ipsilateral inguinoscrotal operation before orchiectomy) were randomized (PA, 236 patients; DL, 242 patients). RESULTS: Median follow-up time is 4.5 years. Eighteen relapses, nine in each treatment group, have occurred 4 to 35 months after radiotherapy; among these, four were pelvic relapses, all occurring after PA radiotherapy. However, the 95% confidence interval (CI) for the difference in pelvic relapse rates excludes differences of more than 4%. The 3-year relapse-free survival was 96% (95% CI, 94% to 99%) after PA radiotherapy and 96.6% (95% CI, 94% to 99%) after DL (difference, 0.6%; 95% confidence limits, -3.4%, +4.6%). One patient (PA field) has died from seminoma. Survival at 3 years was 99.3% for PA and 100% for DL radiotherapy. Acute toxicity (nausea, vomiting, leukopenia) was less frequent and less pronounced in patients in the PA arm. Within the first 18 months of follow-up, the sperm counts were significantly higher after PA than after DL irradiation. CONCLUSION: In patients with testicular seminoma stage I (T1 to T3) and with undisturbed lymphatic drainage, adjuvant radiotherapy confined to the PA lymph nodes is associated with reduced hematologic, gastrointestinal, and gonadal toxicity, but with a higher risk of pelvic recurrence, compared with DL radiotherapy. The recurrence rate is low with either treatment. PA radiotherapy is recommended as standard treatment in these patients.

Loss of normal thymic repertoire selection and persistence of autoreactive T cells in graft vs host disease.

To assess the influence of graft vs host disease (GVHD) on T cell development and thymic repertoire selection, a murine transplantation model was chosen, in which donor (B10.BR: Mls-1b, Mls-2b) and recipient (CBA/J: Mls-1a, Mls-2a) mice differ in their minor lymphocyte-stimulating Ag. Mature splenic T cells of donor origin were added to the T cell-depleted bone marrow cells to induce moderate GVHD. When analyzed 5 and 10 wk after transplantation, animals with GVHD, but not disease-free controls, demonstrated aberrant thymic maturation with an increase in single positive, TCRhigh+ thymocytes. Phenotypic analysis of TCR V beta expression in mature thymocytes and peripheral T cells revealed a disruption of negative thymic selection of Mls-reactive T cells with the subsequent emergence of V beta 3+ and V beta 6+ T cells in mice with GVHD but not in controls. Using retroviral-mediated gene transfer to tag mature T cells, these V beta 3+ and V beta 6+ T cells could be shown to be derived from donor bone marrow precursors. Thymocytes expressing V beta 3 and V beta 6 were efficiently activated upon cross-linking of their TCRs and peripheral T cells from mice with GVHD proliferated to host-derived splenocytes in a MLR. When transferred to sublethally irradiated CBA/J recipients, only T cells from mice with GVHD expanded dramatically. These data suggest that the lack of proper thymic selection after bone marrow transplantation results in the survival and persistence of self-reactive T cells, which might be responsible for the autoimmune manifestations of chronic GVHD.

Early action of nerve determines motor endplate differentiation in rat muscle.

The formation of a motor endplate is characterized by a complex series of changes in the properties of the subsynaptic acetylcholine receptors (AChRs). Among the last changes to occur are the shortening of the apparent mean open time of their ion channels from about 4 to 1 ms and an increase in the single-channel conductance. This conversion of channel gating at the endplate seems to be induced by the motor neurone. We report here that fast channel gating also develops at nerve-free endplate sites of fibres that had been denervated while gating was still slow. At such sites, junctional folds will develop in the absence of the nerve terminal. Although the conversion of channel gating and the formation of junctional folds are late events in endplate development, the neural signals inducing these changes must therefore act at the earliest stages of junctional development.

Serum electrolyte and acid base composition. The influence of graded degrees of chronic renal failure.

Data from 41 ambulatory patients with graded degrees of uncomplicated, chronic renal failure were used to define the quantitative relationship between serum acid-base and electrolyte composition and the serum creatinine level. Even in patients with only moderate renal insufficiency, serum total carbon dioxide (tCO2) content was reduced significantly. This early fall in tCO2 was offset by an increase in serum chloride (Cl-), serum undetermined anton concentration (A-) remaining normal. In patients with more severe degrees of renal insufficiency, further decrements in tCO2 occurred that were proportional to the increment in serum creatinine. These latter decrements in tCO2 were associated with equivalent increments in A-, serum Cl- remaining unchanged at the elevated level observed during moderate renal insufficiency. Confidence limits of 95% for tCO2 and A- were calculated from the data.

[Cooperation between private physician, regional hospital and oncologic center]. / Zusammenarbeit zwischen praktizierendem Arzt, Regionalspital und onkologischem Zentrum.

Due to numerical, socio-psychological, economic and geographic factors, not all tumor patients can be followed exclusively by specialized oncologic institutions. Institutionalized, well organized cooperation between private physician, community hospital and regional cancer center is mandatory in affording every patient speedy and adequate investigation and treatment. One model of regional oncologic cooperation which has been realized successfully for some years now in Eastern Switzerland is presented. Decentralized oncologic consulting clinics open for in- and out-patients are the cornerstone of this system, which guarantees the same quality of management for the tumor patient in hospital or at home and requires the active participation of family doctors.