Subjects with Molecularly Defined Familial Hypercholesterolemia or Familial Defective apoB-100 Are Not Being Adequately Treated

To study whether subjects with a molecular genetic diagnosis of familial hypercholesterolemia (FH) or familial defective apoB-100 (FDB) are being adequately treated.A questionnaire regarding medical history was sent to 2611 subjects who had been provided with a molecular genetic diagnosis of FH or FDB, and a blood sample was obtained for lipid measurements.956 (36.6%) of the 2611 subjects participated. The mean age for starting lipid-lowering therapy was 33.4 (±12.1) years. Among those below 18 years of age, only 20.4% were on lipid-lowering drugs, whereas 89.1% of those aged 18 and above were on lipid-lowering drugs. The mean levels of total serum cholesterol and LDL-cholesterol were 5.7 (±1.5) mmol/l and 3.9 (±1.3) mmol/l, respectively. Among those who were on lipid-lowering drugs, 29.0% and 12.2% had levels of LDL cholesterol below 3.0 mmol/l and 2.6 mmol/l, respectively. Only 47.3% of the 956 subjects were considered as being adequately treated largely due to a failure to titrate their drug regimens. From the use of cholesterol-years score, lipid-lowering therapy must start before the age of 20 in order to prevent the subjects from contracting premature coronary heart disease.The majority of FH/FDB subjects are being diagnosed late in life and are not being adequately treated. In order to prevent them from contracting premature coronary heart disease, it is key that levels of LDL cholesterol are normalized from a young age and that sufficient doses of lipid-lowering drugs are being used

Regulation and the promotion of investment in next generation networks--A European dilemma

The paper discusses the dilemmas facing European regulators (the European Commission and the national regulatory authorities) over the promotion of investment in Next Generation Access Networks (NGANs). Whereas the US has adopted a deregulatory approach and parts of Asia takes an approach linked to industrial policy considerations, the EU has largely left the process to operators working subject to a framework of regulation of access. While this may be enough to elicit investment where there is competition among networks, the incentives to invest are weaker where there is only one fixed network, as is the case in most of the territory of the EU. In reaching this view, the paper examines the prospects for competition from both wireless and municipal networks. It recommends that steps be taken fully to mobilise incentives to invest in NGANs where there is competition. Elsewhere, it may be necessary to consider a broader range of policies to create conditions for investment.Telecommunication regulation Access network Investment Next generation networks

Regulation and the promotion of investment in next generation networks-A European dilemma

The paper discusses the dilemmas facing European regulators (the European Commission and the national regulatory authorities) over the promotion of investment in Next Generation Access Networks (NGANs). Whereas the US has adopted a deregulatory approach and parts of Asia takes an approach linked to industrial policy considerations, the EU has largely left the process to operators working subject to a framework of regulation of access. While this may be enough to elicit investment where there is competition among networks, the incentives to invest are weaker where there is only one fixed network, as is the case in most of the territory of the EU. In reaching this view, the paper examines the prospects for competition from both wireless and,municipal networks. It recommends that steps be taken fully to mobilise incentives to invest ill NGANs where there is competition. Elsewhere, it may be necessary to consider a broader range of policies to create conditions for investment. (C) 2008 Elsevier Ltd. All rights reserved

Sex differences in characteristics of atrial fibrillation recurrence post surgical pulmonary vein isolation

Background: Prior studies demonstrated that female sex is associated with arrhythmia recurrence after endovascular pulmonary vein isolation (PVI). However, it is unknown if the sexes differ in outcome after video assisted thoracoscopic (VATS) PVI. The aim of this study was therefore to compare characteristics of recurrent AF episodes in a matched male and female population, using implantable loop recorders for continuous rhythm monitoring. Methods: 40 matched (based on propensity score) males (age: 60.0 ± 7.71 (45–75)) and females (age: 62.0 ± 7.0 (37–74)) were retrieved from an existing database from a prior conducted study by the cardiothoracic department of the OLVG hospital (1) containing patients who received an implantable looprecorder and underwent a VATS PVI between 2012 and 2017. Patients were continuously monitored for a period of 12 months after VATS PVI and AF characteristics were compared. Results: An equal number of males and females had AF episodes during all periods (P > 0.05). The number of AF episodes was higher in females, during the first 6 months (P = 0.01, P = 0.034). During the entire follow up, the total AF duration was longer in females (P = 0.01, for all periods) with shorter inter - episode intervals (P = 0.001, P = 0001, P = 0.04) and a higher AF burden (P = 0.003, P = 0001, P = 0.006). After 3 months, AF recurrences during the night were more frequently observed in female patients (P = 0.001, P = 0.001). Conclusions: AF episodes occur frequently in both sexes after VATS PVI and warrant frequent rhythm monitoring. The observed sex differences in AF burden after VATS PVI, calls for intensive rhythm monitoring and aggressive treatment of recurrent AF epsiodes in females

Identification of Δ-1-pyrroline-5-carboxylate derived biomarkers for hyperprolinemia type II

Hyperprolinemia type II (HPII) is an inborn error of metabolism due to genetic variants in ALDH4A1, leading to a deficiency in Δ-1-pyrroline-5-carboxylate (P5C) dehydrogenase. This leads to an accumulation of toxic levels of P5C, an intermediate in proline catabolism. The accumulating P5C spontaneously reacts with, and inactivates, pyridoxal 5'-phosphate, a crucial cofactor for many enzymatic processes, which is thought to be the pathophysiological mechanism for HPII. Here, we describe the use of a combination of LC-QTOF untargeted metabolomics, NMR spectroscopy and infrared ion spectroscopy (IRIS) to identify and characterize biomarkers for HPII that result of the spontaneous reaction of P5C with malonic acid and acetoacetic acid. We show that these biomarkers can differentiate between HPI, caused by a deficiency of proline oxidase activity, and HPII. The elucidation of their molecular structures yields insights into the disease pathophysiology of HPII

Metabolite Identification Using Infrared Ion Spectroscopy – Novel Biomarkers for Pyridoxine-Dependent Epilepsy

Untargeted LC-MS based metabolomics strategies are being increasingly applied in metabolite screening for a wide variety of medical conditions. The long-standing “grand challenge” in the utilization of this approach is metabolite identification – confidently determining the chemical structures of m/z-detected unknowns. Here, we use a novel workflow based on the detection of molecular features of interest by high-throughput untargeted LC-MS analysis of patient body fluids combined with targeted molecular identification of those features using infrared ion spectroscopy (IRIS), effectively providing diagnostic IR fingerprints for mass-isolated targets. A significant advantage of this approach is that in silico predicted IR spectra of candidate chemical structures can be used to suggest the molecular structure of unknown features, thus mitigating the need for the synthesis of a broad range of physical reference standards. Pyridoxine dependent epilepsy (PDE-ALDH7A1) is an inborn error of lysine metabolism, resulting from a mutation in the ALDH7A1 gene that leads to an accumulation of toxic levels of α-aminoadipic semialdehyde (α-AASA), piperideine-6-carboxylate (P6C), and pipecolic acid in body fluids. While α-AASA and P6C are known biomarkers for PDE in urine, their instability makes them poor candidates for diagnostic analysis from blood, which would be required for application in newborn screening protocols. Here, we use combined untargeted metabolomics-IRIS to identify several new biomarkers for PDE-ALDH7A1 that can be used for diagnostic analysis in urine, plasma, and cerebrospinal fluids, and are compatible with analysis in dried blood spots for newborn screening. The identification of these novel metabolites has directly rendered novel insights in the pathophysiology of PDE-ALDH7A1

Metabolite Identification Using Infrared Ion Spectroscopy-Novel Biomarkers for Pyridoxine-Dependent Epilepsy

Untargeted liquid chromatography-mass spectrometry (LC-MS)-based metabolomics strategies are being increasingly applied in metabolite screening for a wide variety of medical conditions. The long-standing "grand challenge"in the utilization of this approach is metabolite identification-confidently determining the chemical structures of m/z-detected unknowns. Here, we use a novel workflow based on the detection of molecular features of interest by high-throughput untargeted LC-MS analysis of patient body fluids combined with targeted molecular identification of those features using infrared ion spectroscopy (IRIS), effectively providing diagnostic IR fingerprints for mass-isolated targets. A significant advantage of this approach is that in silico-predicted IR spectra of candidate chemical structures can be used to suggest the molecular structure of unknown features, thus mitigating the need for the synthesis of a broad range of physical reference standards. Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an inborn error of lysine metabolism, resulting from a mutation in the ALDH7A1 gene that leads to an accumulation of toxic levels of α-aminoadipic semialdehyde (α-AASA), piperideine-6-carboxylate (P6C), and pipecolic acid in body fluids. While α-AASA and P6C are known biomarkers for PDE in urine, their instability makes them poor candidates for diagnostic analysis from blood, which would be required for application in newborn screening protocols. Here, we use combined untargeted metabolomics-IRIS to identify several new biomarkers for PDE-ALDH7A1 that can be used for diagnostic analysis in urine, plasma, and cerebrospinal fluids and that are compatible with analysis in dried blood spots for newborn screening. The identification of these novel metabolites has directly provided novel insights into the pathophysiology of PDE-ALDH7A1

Metabolite Identification Using Infrared Ion Spectroscopy-Novel Biomarkers for Pyridoxine-Dependent Epilepsy

Untargeted liquid chromatography-mass spectrometry (LC-MS)-based metabolomics strategies are being increasingly applied in metabolite screening for a wide variety of medical conditions. The long-standing grand challenge in the utilization of this approach is metabolite identification-confidently determining the chemical structures of m/z-detected unknowns. Here, we use a novel workflow based on the detection of molecular features of interest by high-throughput untargeted LC-MS analysis of patient body fluids combined with targeted molecular identification of those features using infrared ion spectroscopy (IRIS), effectively providing diagnostic IR fingerprints for mass-isolated targets. A significant advantage of this approach is that in silico-predicted IR spectra of candidate chemical structures can be used to suggest the molecular structure of unknown features, thus mitigating the need for the synthesis of a broad range of physical reference standards. Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an inborn error of lysine metabolism, resulting from a mutation in the ALDH7A1 gene that leads to an accumulation of toxic levels of alpha-aminoadipic semialdehyde (alpha-AASA), piperideine-6-carboxylate (P6C), and pipecolic acid in body fluids. While alpha-AASA and P6C are known biomarkers for PDE in urine, their instability makes them poor candidates for diagnostic analysis from blood, which would be required for application in newborn screening protocols. Here, we use combined untargeted metabolomics-IRIS to identify several new biomarkers for PDE-ALDH7A1 that can be used for diagnostic analysis in urine, plasma, and cerebrospinal fluids and that are compatible with analysis in dried blood spots for newborn screening. The identification of these novel metabolites has directly provided novel insights into the pathophysiology of PDE-ALDH7A1

Amadori rearrangement products as potential biomarkers for inborn errors of amino-acid metabolism

The identification of disease biomarkers plays a crucial role in developing diagnostic strategies for inborn errors of metabolism and understanding their pathophysiology. A primary metabolite that accumulates in the inborn error phenylketonuria is phenylalanine, however its levels do not always directly correlate with clinical outcomes. Here we combine infrared ion spectroscopy and NMR spectroscopy to identify the Phe-glucose Amadori rearrangement product as a biomarker for phenylketonuria. Additionally, we find analogous amino acid-glucose metabolites formed in the body fluids of patients accumulating methionine, lysine, proline and citrulline. Amadori rearrangement products are well-known intermediates in the formation of advanced glycation end-products and have been associated with the pathophysiology of diabetes mellitus and ageing, but are now shown to also form under conditions of aminoacidemia. They represent a general class of metabolites for inborn errors of amino acid metabolism that show potential as biomarkers and may provide further insight in disease pathophysiology