Induction of hepatic aminolevulinate acid synthetase activity by isoflurane in a genetic model for erythropoietic protoporphyria

Erythropoietic Protoporphyria (EPP) is an inherited deficiency of ferrochelatase, the last enzyme of the heme pathway. Under general anaesthesia, some patients develop neurological dysfunction suggesting upregulation in heme biosynthesis similar to that described for acute porphyrias after xenobiotic administration. Our aim has been to evaluate whether Isoflurane induces alterations in the heme pathway in a mouse model for EPP. Administration of Isoflurane (a single dose of 2 ml/kg, i.p) to wild-type (+/+), heterozygous (+/Fechm1Pas) and homozygous (Fechm1Pas/Fech m1Pas) mice, was evaluated by measuring the activity of δ-Aminolevulinic acid synthetase (ALA-S) and Porphobilinogen-deaminase (PBG-D) in different tissues, as well as Heme oxygenase (HO), cytochrome P-450, CYP2E1 and glutathione levels in liver. Porphyrin precursors were measured in 24h-urine samples. Fechm1Pas/Fechm1Pas mice receiving anaesthesia show enhanced ALA-S and CYP2E1 activities in the liver and increased urinary excretion of porphyrin precursors. No alterations were found in either PBG-D or HO activities. Diminished glutathione levels suggest that anaesthesia may produce oxidative stress in these animals. In conclusion, Isoflurane induces ALA-S activity and increased excretion of porphyrin precursors in EPP mice. These findings appear to confirm our previous hypothesis and indicate that Isoflurane may be an unsafe anaesthetic not only for patients with acute porphyrias but also for individuals with non acute porphyrias. Copyright © 2009 C.M.B. Edition.Fil:Buzaleh, A.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Batlle, A.M.D.C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina

Tear fluid biomarkers in ocular and systemic disease: potential use for predictive, preventive and personalised medicine

In the field of predictive, preventive and personalised medicine, researchers are keen to identify novel and reliable ways to predict and diagnose disease, as well as to monitor patient response to therapeutic agents. In the last decade alone, the sensitivity of profiling technologies has undergone huge improvements in detection sensitivity, thus allowing quantification of minute samples, for example body fluids that were previously difficult to assay. As a consequence, there has been a huge increase in tear fluid investigation, predominantly in the field of ocular surface disease. As tears are a more accessible and less complex body fluid (than serum or plasma) and sampling is much less invasive, research is starting to focus on how disease processes affect the proteomic, lipidomic and metabolomic composition of the tear film. By determining compositional changes to tear profiles, crucial pathways in disease progression may be identified, allowing for more predictive and personalised therapy of the individual. This article will provide an overview of the various putative tear fluid biomarkers that have been identified to date, ranging from ocular surface disease and retinopathies to cancer and multiple sclerosis. Putative tear fluid biomarkers of ocular disorders, as well as the more recent field of systemic disease biomarkers, will be shown

Renal Failure Affects the Enzymatic Activities of the Three First Steps in Hepatic Heme Biosynthesis in the Acute Intermittent Porphyria Mouse

Chronic kidney disease is a long-term complication in acute intermittent porphyria (AIP). The pathophysiological significance of hepatic overproduction of the porphyrin precursors aminolevulinate acid (ALA) and porphobilinogen (PBG) in chronic kidney disease is unclear. We have investigated the effect of repetitive acute attacks on renal function and the effect of total or five-sixth nephrectomy causing renal insufficiency on hepatic heme synthesis in the porphobilinogen deaminase (PBGD)-deficient (AIP) mouse. Phenobarbital challenge in the AIP-mice increased urinary porphyrin precursor excretion. Successive attacks throughout 14 weeks led to minor renal lesions with no impact on renal function. In the liver of wild type and AIP mice, 5/6 nephrectomy enhanced transcription of the first and rate-limiting ALA synthase. As a consequence, urinary PBG excretion increased in AIP mice. The PBG/ALA ratio increased from 1 in sham operated AIP animals to over 5 (males) and over 13 (females) in the 5/6 nephrectomized mice. Total nephrectomy caused a rapid decrease in PBGD activity without changes in enzyme protein level in the AIP mice but not in the wild type animals. In conclusion, high concentration of porphyrin precursors had little impact on renal function. However, progressive renal insufficiency aggravates porphyria attacks and increases the PBG/ALA ratio, which should be considered a warning sign for potentially life-threatening impairment in AIP patients with signs of renal failure

Prevalence of porphyria cutanea tarda in Madrid, Spain, and association between porphyrinuria and alcohol intake in a linear multiple regression model Prevalencia de porfiria cutánea tarda en Madrid y asociación entre la porfirinuria y el consumo de etano

BACKGROUND: The application of a simple fluorometric analytical method enabled us to quantify the urinary porphyrin excretion and to establish the prevalence of porphyria cutanea tarda (PCT) in the town of Madrid, Spain, in a cross-sectional study. PATIENTS AND METHODS: The study assessed 1,613 subjects from three districts in Madrid, in whom further variables potentially related to porphyrinuria such as ethanol intake or -in women- oral contraceptive use were measured and recorded. RESULTS: The estimated prevalence of the disease was 1.24 cases per 1,000 inhabitants (95% confidence interval 0.15-4.47 per thousand). After excluding from the study sample all cases with existent disease, an analysis was performed to ascertain an unilateral tolerance interval for urinary porphyrin concentration in the adult population; this level was established at 181.2 μg/l. The effect of ethanol intake on porphyrinuria was considered significant using a multiple linear regression model adjusted for th

Energy-Efficient Indoor Localization WiFi-Fingerprint System: An Experimental Study

In order to apply indoor localization systems in real environments it is necessary to provide an accurate location without implying a high impact on the user’s normal behaviour. To achieve this goal, in this paper, a combination of battery saving techniques with a system based on WiFi fingerprinting is proposed. This is done by transferring the location calculation workload to the server, leaving user’s mobile devices the only responsibility of making periodic WiFi network scans at dynamic intervals based on user activity, through an application running on background. There are not many studies analyzing energy consumption of existing localization systems, even though it is an important factor in real applications. In this paper, both energy consumption and accuracy are analyzed, having an energy consumption of only 0.8 Wh (having a 3.7 V battery) during a 24-hour cycle and an average localization error of 4.51 meters. Worth to mention that as computation is done on server side the system can be expanded to multiple buildings and floors. Finally, the dataset used in this paper has been published making possible to test new algorithms in the same environment.This work was supported in part by the Spanish Ministry of Economy and Competitiveness through the VICTORY Project under Grant TIN2017-82113-C2-1-R MINECO/FEDER R&D, UE, and in part by the Spanish Ministry of Science, Innovation, and Universities through the MICROCEBUS Project under Grant RTI2018-095168-B-C55 MCIU/AEI/FEDER,UE.Peer reviewe

Induction of hepatic aminolevulinate acid synthetase activity by isoflurane in a genetic model for erythropoietic protoporphyria

Erythropoietic Protoporphyria (EPP) is an inherited deficiency of ferrochelatase, the last enzyme of the heme pathway. Under general anaesthesia, some patients develop neurological dysfunction suggesting upregulation in heme biosynthesis similar to that described for acute porphyrias after xenobiotic administration. Our aim has been to evaluate whether Isoflurane induces alterations in the heme pathway in a mouse model for EPP. Administration of Isoflurane (a single dose of 2 ml/kg, i.p) to wild-type (+/+), heterozygous (+/Fechm1Pas) and homozygous (Fechm1Pas/Fech m1Pas) mice, was evaluated by measuring the activity of δ-Aminolevulinic acid synthetase (ALA-S) and Porphobilinogen-deaminase (PBG-D) in different tissues, as well as Heme oxygenase (HO), cytochrome P-450, CYP2E1 and glutathione levels in liver. Porphyrin precursors were measured in 24h-urine samples. Fechm1Pas/Fechm1Pas mice receiving anaesthesia show enhanced ALA-S and CYP2E1 activities in the liver and increased urinary excretion of porphyrin precursors. No alterations were found in either PBG-D or HO activities. Diminished glutathione levels suggest that anaesthesia may produce oxidative stress in these animals. In conclusion, Isoflurane induces ALA-S activity and increased excretion of porphyrin precursors in EPP mice. These findings appear to confirm our previous hypothesis and indicate that Isoflurane may be an unsafe anaesthetic not only for patients with acute porphyrias but also for individuals with non acute porphyrias. Copyright © 2009 C.M.B. Edition.Fil:Buzaleh, A.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Batlle, A.M.D.C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina