A pharmacokinetic model for the glycation of albumin

Glycated haemoglobin (HbA1c) concentrations can be falsely lowered in circumstances when red blood cell (RBC) survival is reduced, e.g. in patients with chronic kidney disease (CKD). Glycated albumin (GA) has been suggested as an alternative marker of glycaemic control in these patients since it is independent of the RBC life span. The primary aim of this work was to develop a pharmacokinetic model that describes the time course of GA. The secondary aim was to assess the performance of GA as marker for glycaemic control in comparison to HbA1c based on simulations. For the second aim, three different scenarios were considered in the simulations: 1) assessment of the effect of large intra-day fluctuations in mean blood glucose on GA concentrations, 2) initiation of antidiabetic treatment on the GA profile, and 3) a hypothetical phase II study for a new antidiabetic compound. The GA model, as well as a previously developed HbA1c model described literature data well. GA concentrations appear to be stable even in the presence of high intra-day fluctuations in mean blood glucose concentrations. Simulation of a decrease in mean blood glucose concentrations resulted in a faster change in GA compared to HbA1c. GA also provided a time to 90?% power of the effect of a hypothetical antidiabetic drug that was 16?days shorter than when using HbA1c. These results indicate that GA could be used as alternative marker to assess blood glucose control in diabetic patients with CKD and also to follow an individual patient over time.     

Resynchronization or dyssynchronization--successful treatment with biventricular stimulation of a child with obstructive hypertrophic cardiomyopathy without dyssynchrony

CRT in a Child with Hypertrophic Cardiomyopathy. We present a case of a 10-year-old boy with hypertrophic cardiomyopathy, intraventricular pressure gradient of 104 mmHg, and indications for prophylactic ICD implantation. Based on intraoperative pressure measurements, the child was implanted with biventricular ICD. During 2.5 months of observation, the patient's functional status improved significantly, as shown by subjective and objective parameters and, moreover, the pressure gradient fell to 12 mmHg. Significant electrical and mechanical cardiac dyssynchrony appeared parallel to clinical improvement.     

Incidence and outcome of TCF3-PBX1-positive acute lymphoblastic leukemia in Austrian children

Lessons from the analysis of children with TCF3-PBX1 ALL could help to identify treatment components essential for this leukemia subtype. Of 859 children with ALL who were treated in ALL-BFM trials in Austria, 31 (3.6%) had a TCF3-PBX1 ALL. The 5-year event-free survival rate for these 31 patients was 90%+/-5%. Patients with TCF3-PBX1 ALL treated on the ALL-BFM 86 trial had a poorer outcome than patients with TCF3-PBX1 ALL treated on later trials. These data document that contemporary ALL-BFM treatment is highly effective in children with TCF3-PBX1 ALL. Implementation of early dose-intensified remission induction may be an essential treatment component.     

Different types of renal dysfunction in patients with acute myocardial infarction treated with percutaneous coronary intervention

BACKGROUND: The prognostic significance of different types of renal dysfunction in patients with acute myocardial infarction (AMI) treated with percutaneous coronary intervention (PCI) has not been well characterized. METHODS: The single-center AMI registry encompassed 1,486 consecutive AMI patients treated with PCI, who were followed by mean 29.7 months. Subjects with an estimated glomerular filtration rate <60 mL/min per 1.73 m2 at baseline were selected (n = 283, 19.0%) and incorporated into the chronic kidney disease (CKD) group. The control group consisted of 1,203 subjects with normal renal function (81.0%). The CKD patients were divided into subgroups: with contrast-induced nephropathy - CKD + CIN (n = 68, 4.6%) and without - CKD-CIN (n = 215, 14.5%). RESULTS: Remote mortality rate was significantly higher in CKD group (34.6%) and in particular subgroups: CKD + CIN (47.0%), CKD-CIN (31.0%) than in controls (9.1%, P < 0.001 for all study groups vs controls). Multivariate analysis identified CKD as an independent predictor of any-cause death in the whole population (hazard ratio [HR] 1.77, 95% confidence interval [CI] 1.60-1.94, P < 0.001). Similarly, CKD + CIN contrary to CKD-CIN had significant and independent influence on remote survival in study population (HR 2.16, 95% CI 1.95-2.37, P < 0.001). CONCLUSIONS: CKD and its types have significant, negative influence on long-term survival in AMI patients treated with PCI. It is especially strongly expressed in those CKD patients who develop contrast-induced nephropathy, which occurrence is an independent risk factor of mortality associated with over twofold increase of death hazard.     

Cerebrospinal fluid biomarkers predict decline in subjective cognitive function over 3 years in healthy elderly

OBJECTIVE: To investigate whether cerebrospinal fluid (CSF) biomarkers can predict cognitive decline in healthy, elderly individuals as they have been shown to do in cognitively impaired patient samples. METHODS: In this study, 57 controls were tested for CSF biomarkers at baseline and then cognitively followed over 3 years. RESULTS: Low levels of baseline beta-amyloid 1-42 (Abeta42) were associated with development of subjective memory impairment affecting quality of life (memQoL), with a worse Mini Mental Status Examination score and with inability to live in regular housing at follow-up (p < 0.05). The combination of baseline Abeta42 and phosphorylated tau (P-tau) was found to predict development of pathological memQoL with a sensitivity of 71.4% and a specificity of 75.7 (<0.01). CONCLUSION: Low Abeta42 and combined Abeta42 and P-tau predicted subjective cognitive decline in healthy individuals. In summary, this study shows that already in the clinically normal population Alzheimer-disease-related biological signs might be detectable.     

Prediction of Alzheimer's disease using the CSF Abeta42/Abeta40 ratio in patients with mild cognitive impairment

Evidence supports an important role for beta-amyloid (Abeta) in the pathogenesis of Alzheimer's disease (AD). Here, we investigate baseline levels of the 40- and 42-amino-acid-long Abeta peptides (Abeta40 and Abeta42) in cerebrospinal fluid (CSF) from a cohort of patients with mild cognitive impairment (MCI, n = 137) in relation to the final diagnosis after 4-6 years of follow-up time. CSF Abeta42 concentration at baseline and the Abeta42/Abeta40 ratio were significantly decreased in the MCI patients who developed AD as compared to cognitively stable MCI patients and MCI patients who developed other forms of dementia (p < 0.001). The baseline levels of Abeta40 were similar in all MCI groups but correlated with change in Mini Mental State Examination scores in converters to AD. The Abeta42/Abeta40 ratio was superior to Abeta42 concentration with regard to identifying incipient AD in MCI (p < 0.05). In conclusion, the data provide further support for the view that amyloid precursor protein metabolism is disturbed in early sporadic AD and points to the usefulness of the Abeta42/Abeta40 ratio as a predictive biomarker for AD.     

Elevated plasma levels of soluble CD40 in incipient Alzheimer's disease

CD40 is a member of the tumor necrosis factor receptor super-family and has been suggested to play a role in the metabolism of beta-amyloid (Abeta) in Alzheimer's disease (AD). However, the role of CD40-signalling in incipient AD has not yet been studied. We investigated the plasma levels of soluble CD40 (sCD40) and the soluble CD40 ligand (sCD40L) at baseline in 136 subjects with mild cognitive impairment (MCI) and 30 age-matched controls. Sixty of the 136 MCI cases converted to AD (MCI-AD) during a clinical follow-up period of 4-7 years. The baseline levels of sCD40, but not sCD40L, were elevated in MCI-AD cases when compared to age-matched controls (Mann-Whitney U-test, p=0.02). However, MCI patients who were cognitively stable or developed vascular dementia during follow-up did not have significantly increased levels of sCD40 or sCD40L when compared to controls. The levels of sCD40 correlated to decreased baseline performance on mini-mental state examination (MMSE) in both controls (r(s)=-0.37, p<0.05) and MCI-AD cases (r(s)=-0.29, p<0.05). Finally, the plasma levels of sCD40 correlated with the levels of soluble amyloid precursor protein-alpha (sAPP-alpha) (r(s)=0.28, p<0.01) and sAPP-beta (r(s)=0.23, p<0.05) in cerebrospinal fluid. In conclusion, CD40-signalling might play a role in the pathogenesis of early AD.     

Tenascin C in medullary thyroid microcarcinoma and C-cell hyperplasia

Tenascin C (Tn-C) is an extracellular matrix glycoprotein that is expressed early in carcinogenesis including intraepithelial neoplastic lesions of different organs. In this study, we analyze whether stroma reaction seen by Tn-C expression is detected early in tumorigenesis of medullary thyroid carcinoma (MTC) including medullary microcarcinoma and C-cell hyperplasia (CCH), which is accepted to be a precursor lesion of MTC in the setting of RET oncogene germ-line mutation. Tn-C was expressed in the stroma of all medullary microcarcinoma and in the stroma next to CCH. Stromal Tn-C expression was significantly more often seen in CCH with concomitant MTC than in isolated CCH of hereditary as well as nonhereditary cases (p = 0.001 and p = 0.016, respectively). We conclude that Tn-C expression and thus early stroma remodeling is seen in medullary microcarcinoma and CCH. Stromal Tn-C expression seems to be an indicator of a further step in carcinogenesis of MTC irrespective of a RET oncogene germ-line mutation.