Phosphatidylethanol: normalization during detoxification, gender aspects and correlation with other biomarkers and self-reports

Phosphatidylethanol (PEth) is a direct ethanol metabolite, and has recently attracted attention as biomarker of ethanol intake. The aims of the current study are: (1) to characterize the normalization time of PEth in larger samples than previously conducted; (2) to elucidate potential gender differences; and (3) to report the correlation of PEth with other biomarkers and self-reported alcohol consumption. Fifty-seven alcohol-dependent patients (ICD 10 F 10.25; 9 females, 48 males) entering medical detoxification at three study sites were enrolled. The study sample was comprised of 48 males and 9 females, with mean age 43.5. Mean gamma glutamyl transpeptidase (GGT) was 209.61 U/l, average mean corpuscular volume (MCV) was 97.35 fl, mean carbohydrate deficient transferrin (%CDT) was 8.68, and mean total ethanol intake in the last 7 days was 1653 g. PEth was measured in heparinized whole blood with a high-pressure liquid chromatography method, while GGT, MCV and %CDT were measured using routine methods. PEth levels at day 1 of detoxification ranged between 0.63 and 26.95 micromol/l (6.22 mean, 4.70 median, SD 4.97). There were no false negatives at day 1. Sensitivities for the other biomarkers were 40.4% for MCV, 73.1% for GGT and 69.2% for %CDT, respectively. No gender differences were found for PEth levels at any time point. Our data suggest that PEth is (1) a suitable intermediate term marker of ethanol intake in both sexes; and (2) sensitivity is extraordinary high in alcohol dependent patients. The results add further evidence to the data that suggest that PEth has potential as a candidate for a sensitive and specific biomarker, which reflects longer-lasting intake of higher amounts of alcohol and seemingly has the above mentioned certain advantages over traditional biomarkers.

Science to practice: Can diffusion-weighted MR imaging findings be used as biomarkers to monitor the progression of renal fibrosis?

In an experimental murine model of unilateral ureteral obstruction, Togao et al demonstrated that diffusion-weighted (DW) magnetic resonance (MR) imaging can depict and enable monitoring of abnormal changes in the progression of renal fibrosis; because these microstructural changes are complex and multifactorial, future studies focused on their specificity should be performed before they are applied in clinical trials.

Clinical and biochemical consequences of p450 oxidoreductase deficiency

Patients with P450 oxidoreductase (POR) deficiency typically present with adrenal insufficiency, genital anomalies and bony malformations resembling the Antley-Bixler craniosynostosis syndrome. Since our first report in 2004, more than 40 POR mutations have been identified in over 65 patients. POR is the obligate electron donor to all microsomal P450 enzymes, including the steroidogenic enzymes CYP17A1, CYP21A2 and CYP19A1. POR deficiency may cause disordered sexual development manifested as genital undervirilization in 46, XY newborns as well as overvirilization in those who are 46, XX. This may be explained by impaired aromatization of fetal androgens that may cause maternal virilization and low urinary estriol levels during pregnancy. In addition, the alternate 'backdoor' pathway of androgen biosynthesis, which leads to dihydrotestosterone production bypassing androstenedione and testosterone, may also play a role. Functional assays studying the effects of POR mutations on steroidogenesis showed that several POR variants impaired CYP17A1, CYP21A2 and CYP19A1 activities to different degrees, indicating that each POR variant must be studied separately for each potential target P450 enzyme. POR variants may also affect skeletal development and drug metabolism. As most drugs are metabolized by hepatic microsomal P450 enzymes, studies of the impact of POR mutations on drug-metabolizing P450s are particularly important.

High-level cytoplasmic cyclin D1 expression in lymph node metastases from prostate cancer independently predicts early biochemical failure and death in surgically treated patients

To test the prognostic significance of cyclin D1 in nodal-positive prostate cancer.

KPNA2 expression is an independent adverse predictor of biochemical recurrence after radical prostatectomy

To analyze rates of expression of karyopherin alpha 2 (KPNA2) in different prostate tissues and to evaluate the prognostic properties for patients with primary prostate cancer.

Are biochemical markers of neuroendocrine tumors coreleased with insulin following local calcium stimulation in patients with insulinomas?

The objective was to test whether chromogranin A (CgA), neuron-specific enolase (NSE), and pancreatic polypeptide (PP) are released from the pancreas during the selective arterial calcium stimulation and hepatic venous sampling test (ASVS) in patients with insulinomas.

Potential biomarkers for hepatoblastoma: Results from the SIOPEL-3 study

Hepatoblastoma (HB) is a rare malignant liver tumour found in infants. Many heterogenous histological tumour subtypes exist. Although survival rates have improved dramatically in recent years with the use of platinum-based chemotherapy, there still exists a subset of HB that does not respond to treatment. There are currently no tumour biomarkers in use and in this study we aim to evaluate potential biomarkers to aid identification of relapse cases that would otherwise be overlooked by current prognostication. This may identify patients that would benefit from more aggressive therapy and could improve overall survival rates. We used immunohistochemistry to analyse the expression of β-catenin, E-cadherin, Cyclin D1, Ki-67 and alpha-fetoprotein (AFP) protein in tumours from 91 patients prospectively enroled into the SIOPEL 3 clinical trial. The relationship between these biomarkers and clinicopathologic features and patient survival were statistically analysed. We identified one biomarker, Cyclin D1, which has a correlation with mixed epithelial/mesenchymal HB approaching significance (P=0.07). Survival analysis using these markers has revealed two potential prognostic indicators; Cyclin D1 and Ki-67 (P=0.01, 0.01).

A strategy combining imaging and laboratory biomarkers in comparison with a simplified clinical score for risk stratification of patients with acute pulmonary embolism

This study aimed to assess the performance of two prognostic models-the European Society of Cardiology (ESC) model and the simplified Pulmonary Embolism Severity Index (sPESI)-in predicting short-term mortality in patients with pulmonary embolism (PE).

Dietary intervention induces flow of changes within biomarkers of lipids, inflammation, liver enzymes, and glycemic control

To determine how changes in lipids, liver enzymes, and inflammatory and glycemia markers intercorrelate during prolonged dietary intervention in obese participants with or without type 2 diabetes (T2D).

Biochemical (T2, T2* and magnetisation transfer ratio) MRI of knee cartilage: feasibility at ultra-high field (7T) compared with high field (3T) strength

This study compares the performance and the reproducibility of quantitative T2, T2* and the magnetisation transfer ratio (MTR) of articular cartilage at 7T and 3T.

Morphological and biochemical T2 evaluation of cartilage repair tissue based on a hybrid double echo at steady state (DESS-T2d) approach

To use a new approach which provides, based on the widely used three-dimensional double-echo steady-state (DESS) sequence, in addition to the morphological information, the generation of biochemical T2 maps in one hybrid sequence.

Gadolinium diethylenetriaminepentaacetate enhancement kinetics in the menisci of asymptomatic subjects: a first step towards a dedicated dGEMRIC (delayed gadolinium-enhanced MRI of cartilage)-like protocol for biochemical imaging of the menisci

It was our aim to investigate the gadolinium diethylenetriaminepentaacetate (Gd-DTPA(2-) ) enhancement kinetics in the menisci of the knee joint over a prolonged period of time. Six asymptomatic volunteers (four men and two women; mean age, 25 ± 2.4 years) were enrolled. Sagittal, T(1) -weighted, spin-echo MR sequences of the right knee joint were obtained at 3 T. Imaging was performed before (baseline), 1 h after and in half-hour intervals up to 9 h after the intravenous administration of 0.2 mmol/kg of Gd-DTPA(2-) . To measure the rates of contrast enhancement relative to the baseline, regions of interest that covered the anterior and posterior horns of the medial and lateral meniscus were defined on each of two adjacent sections, and enhancement curves were constructed. An enhancement peak between 2.5 and 4.5 h after Gd-DTPA(2-) administration was observed, and analysis of variance also revealed no significant difference (p=0.94), in terms of enhancement, within this time interval. Pair-wise, post hoc testing also revealed no significant differences between 2.5 and 3, 3 and 3.5, 3.5 and 4, and 4 and 4.5 h post Gd-DTPA(2-) application. Our preliminary data therefore suggest that the time window suitable for a dGEMRIC (delayed gadolinium-enhanced MRI of cartilage)-like T(1) mapping of the menisci is relatively short, and lies between 2.5 and 4.5 h after Gd-DTPA(2-) injection.

Molecular and biochemical characterisation of a novel mutation in POLG associated with Alpers syndrome

Background DNA polymerase γ (POLG) is the only known mitochondrial DNA (mtDNA) polymerase. It mediates mtDNA replication and base excision repair. Mutations in the POLG gene lead to reduction of functional mtDNA (mtDNA depletion and/or deletions) and are therefore predicted to result in defective oxidative phosphorylation (OXPHOS). Many mutations map to the polymerase and exonuclease domains of the enzyme and produce a broad clinical spectrum. The most frequent mutation p.A467T is localised in the linker region between these domains. In compound heterozygote patients the p.A467T mutation has been described to be associated amongst others with fatal childhood encephalopathy. These patients have a poorer survival rate compared to homozygotes. Methods mtDNA content in various tissues (fibroblasts, muscle and liver) was quantified using quantitative PCR (qPCR). OXPHOS activities in the same tissues were assessed using spectrophotometric methods and catalytic stain of BN-PAGE. Results We characterise a novel splice site mutation in POLG found in trans with the p.A467T mutation in a 3.5 years old boy with valproic acid induced acute liver failure (Alpers-Huttenlocher syndrome). These mutations result in a tissue specific depletion of the mtDNA which correlates with the OXPHOS-activities. Conclusions mtDNA depletion can be expressed in a high tissue-specific manner and confirms the need to analyse primary tissue. Furthermore, POLG analysis optimises clinical management in the early stages of disease and reinforces the need for its evaluation before starting valproic acid treatment.