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Defects in hydroxymethylbilane synthase (HMBS) can cause Acute Intermittent Porphyria (AIP), an acute neurological disease. Although sequencing-based diagnosis can be definitive, ~⅓ of clinical HMBS variants are missense variants, and most clinically-reported HMBS missense variants are designated as “variants of uncertain significance” (VUS). Using saturation mutagenesis,en masseselection, and sequencing, we applied a multiplexed validated assay to both the erythroid-specific and ubiquitous isoforms of HMBS, obtaining confident functional impact scores for >84% of all possible amino-acid substitutions. The resulting variant effect maps generally agreed with biochemical expectation. However, the maps showed variants at the dimerization interface to be unexpectedly well tolerated, and suggested residue roles in active site dynamics that were supported by molecular dynamics simulations. Most importantly, these HMBS variant effect maps can help discriminate pathogenic from benign variants, proactively providing evidence even for yet-to-be-observed clinical missense variants.

The global energy mix and cost structure of the power industry are experiencing a redefinition. Many countries are revamping electricity-pricing systems to guarantee fixed-cost recovery, often by raising the fixed charge of two-part tariff schemes. However, a key assumption of two-part tariff schemes and associated fixed-cost recoveries is that consumers discriminate fixed from marginal costs. We conduct a quasi-experiment with data from a major electricity price reform recently implemented in Spain and find robust evidence indicating that consumers fail to distinguish between fixed and marginal costs. As a result, policymakers are not achieving the goal of cost recovery.

The aim of this paper is to present a new, analytical, method for computing the exact number of relative equilibria in the planar, circular, restricted 4-body problem of celestial mechanics. The new approach allows for a very efficient computer-aided proof, and opens a potential pathway to proving harder instances of the n-body problem.

Patients with major forms of acute hepatic porphyria present acute neurological attacks with overproduction of porphobilinogen (PBG) and δ-aminolevulinic acid (ALA). Even if ALA is considered the most likely agent inducing the acute symptoms, the mechanism of its accumulation has not been experimentally demonstrated. In the most frequent form, acute intermittent porphyria (AIP), inherited gene mutations induce a deficiency in PBG deaminase; thus, accumulation of the substrate PBG is biochemically obligated but not that of ALA. A similar scenario is observed in other forms of acute hepatic porphyria (i.e., porphyria variegate, VP) in which PBG deaminase is inhibited by metabolic intermediates. Here, we have investigated the molecular basis of δ-aminolevulinate accumulation using

Background Hepatitis C virus (HCV) is a risk factor for porphyria cutanea tarda (PCT), a rare disease originating in the liver characterised by overproduction of porphyrins. Although hepatitis C infection is highly prevalent among patients with porphyria, only a minority of hepatitis C patients develop PCT. Aims To explore the presence of porphyrin abnormalities in a cohort of asymptomatic hepatitis C-infected patients and the impact of anti-viral therapy. Methods Eighty-four consecutive patients with HCV infection treated with direct-acting antivirals after 1 January 2018 were longitudinally evaluated for the presence of porphyrin abnormalities. Those patients with biochemical abnormalities at baseline were additionally evaluated at follow-up. Porphyrins in urine were screened by fluorometry and isomer separation was performed by liquid chromatography. Results In five patients, all of them asymptomatic, porphyrin profile abnormalities were detected: three presented significant increased urinary porphyrins with a typical PCT profile, and two showed normal levels of urinary porphyrins, but abnormal porphyria-like profiles. Urine evaluation after hepatitis C cure showed complete normalisation of the urinary porphyrins in all patients, confirming the biochemical cure of the disease. Conclusions We document the existence of rare cases of hepatitis C-infected patients with significant uroporphyrinuria in the absence of dermatological manifestations. Anti-viral therapy normalises the biochemical disorder, preventing patients from presenting PCT associated complications.

We consider the setting for the disappearance of uniform hyperbolicity as in Bjerklov and Saprykina (2008 Nonlinearity 21), where it was proved that the minimum distance between invariant stable and unstable bundles has a linear power law dependence on parameters. In this scenario we prove that the Lyapunov exponent is sharp \begin{document}$ \frac12 $\end{document} -Holder continuous. In particular, we show that the Lyapunov exponent of Schrodinger cocycles with a potential having a unique non-degenerate minimum is sharp \begin{document}$ \frac12 $\end{document} -Holder continuous below the lowest energy of the spectrum, in the large coupling regime.

Porphyria cutanea tarda (PCT) arises from a deficiency of uroporphyrinogen decarboxylase (UROD) in the liver. Several exogenous risk factors are associated with the acquired form of the disease. In Southern Europe, PCT is strongly linked to hepatitis C virus (HCV) infection to the point that a high prevalence of viral infection in some geographic areas generated an increase of PCT cases as a complication. In spite of the association, PCT is a rare complication of HCV infection, thus suggesting the existence of susceptibility factors operating in only some patients. Investigation of liver specimens of PCT patients showed iron accumulation, which albeit moderate, was higher in comparison with HCV-infected patients without PCT. Measurements of hepcidin in serum of HCV-infected patients with and without PCT and calculation of hepcidin/ferritin ratio were compatible with the hypothesis that HCV induced inadequate response of hepcidin to iron accumulation. Administration of direct-acting antivirals (DAA) to HCV-infected patients with active PCT showed that eradication of the virus was followed by resolution of PCT and rapid disappearance of urinary porphyrins. This suggests a direct participation of the virus in the oxidative mechanism leading to UROD inhibition. If clinical evolution of HCV- PCT-patients is placed within a time-frame, rapid PCT resolution by DAA is in striking contrast with a long-delay (in most cases of decades) between viral infection and appearance of overt porphyria. This could be explained if HCV infection (a): enhanced an oxidative environment in the vicinity of UROD and (b): facilitated iron accumulation through hepdicin down-regulation. Thus, only when iron accumulation reached a threshold, inhibition of UROD attained a critical level. However, the enigma is why only a minority of HCV-infected patients develop PCT. If additional risk factors (i.e. alcohol abuse) are not concurring, it should be concluded that modifier genes or epigenetic mechanisms related to iron homeostasis, facilitate iron progressive accumulation in only a minority susceptible patients.

Amphetamine urine drug screening by immunoassay is prone to cross-react with other compounds leading to false positive results. Tetracaine is a local anesthetic drug used in the clinical setting as an ointment during urinary catheterization. In our laboratory, tetracaine is often detected by gas chromatography-mass spectrometry in the urine of patients admitted in the emergency department with false positive amphetamine results. The objectives of this study were to investigate if there was cross-reactivity to tetracaine in an amphetamine immunoassay and to retrospectively evaluate the potential contribution of tetracaine to false positive amphetamine results.An interference study was conducted using negative urine samples spiked with increasing concentrations of tetracaine hydrochloride and analyzed with the CEDIA Amphetamine/Ecstasy immunoassay. Retrospectively, urine samples of patients which yielded positive amphetamine immunoassay results and were analyzed by gas chromatography-mass spectrometry were reviewed (Tetracaine caused false positive amphetamine results by immunoassay (cut-off 1000 µg/L) with a concentration of above 40 mg/L. Retrospective analysis of all positive amphetamine immunoassay samples showed that in 45 out of the 417 (10.8%) urine samples no amphetamine-like derivative was identified by gas chromatography - mass spectrometry. In 37 out of 45 (82.2%) of these false positive cases tetracaine was detected, of whom 59.5% (22/37) had an estimated tetracaine concentration of ≥40 mg/L.This study confirmed the interference of tetracaine in the CEDIA Amphetamine/Ecstasy immunoassay and that tetracaine may have contributed to around 80% of the false positive amphetamine cases in the urine samples of patients admitted to the emergency department at our institution.

Introduction: 6-Monoacetylmorphine (6-MAM) is a specific metabolite of heroin. Thus, the presence of 6-MAM in urine is a definitive indication of heroin intake. The possibility of having an immunoa...

A fundamental question in Dynamical Systems is to identify regions of phase/parameter space satisfying a given property (stability, linearization, etc). Given a family of analytic circle diffeomorphisms depending on a parameter, we obtain effective (almost optimal) lower bounds of the Lebesgue measure of the set of parameters that are conjugated to a rigid rotation. We estimate this measure using an a-posteriori KAM scheme that relies on quantitative conditions that are checkable using computer-assistance. We carefully describe how the hypotheses in our theorems are reduced to a finite number of computations, and apply our methodology to the case of the Arnold family. Hence we show that obtaining non-asymptotic lower bounds for the applicability of KAM theorems is a feasible task provided one has an a-posteriori theorem to characterize the problem. Finally, as a direct corollary, we produce explicit asymptotic estimates in the so called local reduction setting (\`a la Arnold) which are valid for a global set of rotations., Comment: 39 pages

We present numerical results and computer assisted proofs of the existence of periodic orbits for the Kuramoto-Sivashinky equation. These two results are based on writing down the existence of periodic orbits as zeros of functionals. This leads to the use of Newton's algorithm for the numerical computation of the solutions and, with some a posteriori analysis in combination with rigorous interval arithmetic, to the rigorous verification of the existence of solutions. This is a particular case of the methodology developed in [19] for several types of orbits. An independent implementation, covering overlapping but different ground, using different functional setups appears in [33]., Comment: 19 pages, 7 figures

With the advent of precision and genomic medicine, a critical issue is whether a disease gene variant is pathogenic or benign. Such is the case for the three autosomal dominant acute hepatic porphyrias (AHPs), including acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria, each resulting from the half-normal enzymatic activities of hydroxymethylbilane synthase, coproporphyrinogen oxidase, and protoporphyrinogen oxidase, respectively. To date, there is no public database that documents the likely pathogenicity of variants causing the porphyrias, and more specifically, the AHPs with biochemically and clinically verified information. Therefore, an international collaborative with the European Porphyria Network and the National Institutes of Health/National Center for Advancing Translational Sciences/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NCATS/NIDDK)-sponsored Porphyrias Consortium of porphyria diagnostic experts is establishing an online database that will collate biochemical and clinical evidence verifying the pathogenicity of the published and newly identified variants in the AHP-causing genes. The overall goal of the International Porphyria Molecular Diagnostic Collaborative is to determine the pathogenic and benign variants for all eight porphyrias. Here we describe the overall objectives and the initial efforts to validate pathogenic and benign variants in the respective heme biosynthetic genes causing the AHPs.

Deficiency of uroporphyrinogen III synthase (UROS) causes congenital erythropoietic porphyria (CEP). The disease, originating from the inheritance of mutations within the UROS gene, presents a recessive form of transmission. In a few patients, a late-onset CEP-like phenotype without UROS mutations appears to be associated with a myelodysplastic syndrome. We report a 60-year-old man with late-onset signs of cutaneous porphyria and accumulation in urine, plasma and faeces of type I porphyrin isomers characteristic of CEP. Analysis of DNA from peripheral leucocytes, skin and bone marrow aspirate showed that he was a heterozygous carrier of a Cys73Arg (c.217 T>C) mutation within UROS. Sequencing of cDNA from peripheral blood confirmed heterozygosity and expression of the normal allele. Measurement of UROS enzymatic activity in erythrocytes showed values ~70% of normal, indirectly indicating expression of the normal allele. Differently from other cases of late-onset uroporphyria, the patient did not present thrombocytopenia or any evidence of a myelodysplastic syndrome. Five years of clinical follow-up showed persistence of skin signs and increased excretion of porphyrins, independently of lifestyle factors or changes in medication regimes. We hypothesize acquired mosaicism (in the bone marrow) affecting the UROS gene. Thus, unstable cellular clones initiated overproduction of isomer I porphyrins leading to a CEP phenotype. This could be explained either by a clonal expansion of the porphyric (Cys73Arg) allele or by loss of function of the normal allele. Cellular turnover would facilitate release of uroporphyrins into circulation and subsequent skin lesions. This is the first case of a CEP heterozygous carrier presenting clinical manifestations.

An effective climate agreement is urgently required, yet conflict between parties prevails over cooperation. Thanks to advances in science it is now possible to quantify the global carbon budget, the amount of available cumulative CO2 emissions before crossing the 2 C-a similar to threshold (Meinshausen et al. Nature 458(7242):1158-1162, 2009). Countries carbon claims, however, exceed this. Historically such situations have been tackled with bankruptcy division rules. We argue that framing climate negotiations as a classical conflicting claims problem (O'Neill Math Soc Sci 2(4):345-371, 1982) may provide for an effective climate policy. We analyze the allocation of the global carbon budget among parties claiming the maximum emissions rights possible. Based on the selection of some desirable principles, we propose an efficient and sustainable allocation of the available carbon budget for the period 2000 to 2050 taking into account different risk scenarios. Generalitat de Catalunya Ministerio de Economia y Competitividad

SummaryBackground Human immunodeficiency virus (HIV) infection has been reported to be a risk factor for porphyria cutanea tarda (PCT). Purpose To assess the strength of the association between HIV infection and PCT in a large hospital setting. Methods All patients (N = 210) diagnosed of PCT between 1990 and 2014 were retrospectively investigated for HIV infection and co-precipitating factors. High-performance liquid chromatography was used to assess the appearance of pre-PCT urinary porphyrin abnormalities among a group (N = 22) of HIV-infected patients without PCT using the urine of patients co-infected with hepatitis C virus (HCV) without PCT for comparison. Results Twenty-six HIV-infected patients (19 males and seven females) were diagnosed of PCT. During the same interval of time, ~8000 different patients infected with HIV were attended in the hospital of infectious diseases department. Examination of risk factors showed that 25 out of 26 of the PCT patients with HIV were co-infected with HCV. No chromatographic abnormalities were found in the urine of non-PCT-HIV-infected patients, whereas 39% co-infected patients showed urinary porphyrin abnormalities. Conclusions In our large hospital series, the appearance of PCT among HIV-infected patients is low (

Mushroom poisoning with Amanita phalloides or similar species can lead to liver failure with 10-30% mortality rates. We aimed at defining the prognostic value of urinary amatoxin quantification in patients with hepatotoxic mushroom poisoning.Data from 32 patients with hepatotoxic mushroom poisoning (Hospital Clínic Barcelona, 2002-16) in whom urinary amatoxins were determined (ELISA) were retrospectively reviewed. Correlations between urinary amatoxin and collected baseline variables with outcomes including hepatotoxicity (ALT1000 U/L), severe acute liver injury (ALI, prothrombin50%), acute liver failure (ALF, ALI and encephalopathy), transplantation/death and hospital length-of-stay, were evaluated.12/32 patients developed increased aminotransferase activity. Among the 13/32 amatoxin negative patients, 1 developed ALI and 12/13 no hepatotoxicity. Among the 19/32 amatoxin positive patients, 8/19 (42%) developed hepatotoxicity, including 5 who progressed to severe ALI, of whom 3 developed ALF (2 deaths, 1 transplantation). Urinary amatoxin and prothrombin were independent predictors of hepatotoxicity, ALT peak values (along with age) and hospital length-of-stay. In positive amatoxins patients, urinary concentrations55 ng/ml (or a baseline prothrombin ≤ 83%), were associated to hepatotoxicity (presented by 8/9 patients with ALT1000 U/L). Among 5 patients with urinary amatoxin ≥ 70 ng/ml, 4 developed severe ALI.In patients with hepatotoxic mushroom poisoning, a negative urinary amatoxin quantification within 72h of intake ruled out the risk of hepatotoxicity in 92% of patients, whereas positive urinary amatoxins were associated with hepatotoxicity and severe ALI. Concentrations55 ng/ml and ≥ 70 ng/ml were predictive of hepatotoxicity and severe ALI, respectively.

Congenital erythropoietic porphyria is a rare autosomal recessive disease caused by a deficiency of uroporphyrinogen III synthase, owing to mutations in UROS in chromosome 10. Occasionally, patients show a mild, late-onset disease, without germline UROS mutations, associated with haematological malignancies. We report a 65-year-old patient with photosensitivity, overexcretion of porphyrins and thrombocytopenia. Bone marrow analysis gave a diagnosis of myelodysplastic syndrome (MDS) with the presence of a derivative chromosome 3, possibly due to an inversion including 3q21 and 3q26 break points. After allogeneic stem-cell transplantation, complete remission of MDS and uroporphyria was achieved. To our knowledge, this is the first reported case of acquired erythropoietic uroporphyria associated with MDS, with chromosome 3 alterations.

Resumen Fundamento y objetivos La porfiria aguda intermitente (PAI) es una enfermedad causada por un defecto en la enzima porfobilinogeno deaminasa que cataliza la tercera etapa de sintesis del hemo. Los portadores pueden presentar ataques neuroviscerales agudos tras sobreproduccion hepatica de precursores del hemo. Pacientes y metodo Se presentan las caracteristicas de todos los pacientes con PAI atendidos en el Hospital Clinic de Barcelona entre los anos 1993-2013, y su seguimiento a largo plazo. Resultados Treinta y cinco pacientes con PAI (33 mujeres y 2 varones) presentaron ataques agudos neuroviscerales. El tratamiento con hemina resolvio el cuadro agudo en todos los casos. Nueve pacientes presentaron polineuropatia y secuelas persistentes. El seguimiento permitio clasificar a los pacientes en: A, con sintomatologia aguda durante 1-2 anos y posterior remision duradera (n = 24) o bien alguna crisis puntual (n = 3), y B, con ataques recurrentes que requirieron administracion cronica de hemina (n = 8). En la mayoria de los pacientes del grupo A la concentracion urinaria de precursores del hemo fue disminuyendo progresivamente, mientras que en el grupo B esta se mantuvo elevada sin descenso observable a largo termino. Adicionalmente, el estudio familiar permitio identificar 44 portadores asintomaticos, la mayoria (70,5%) con valores normales de precusores del hemo en orina. Conclusiones Una mayoria de pacientes con PAI de nuestra serie logro una remision clinica duradera. Una minoria presenta ataques recurrentes, sin que el tratamiento cronico con hemina haga factible su interrupcion ni induzca remision bioquimica a largo plazo. El tipo de mutacion en el gen de la porfobilinogeno deaminasa, y tambien factores asociados al estilo de vida, pueden determinar el curso de la remision.

We document the presence of a previously unknown species in the urine of patients with acute intermittent porphyria (AIP). The compound was fully characterised by liquid chromatography tandem mass spectrometry. Interpretation of both full spectrum acquisition and product ion spectra acquired in positive and negative ionisation modes by quadrupole time of flight MS allowed for the identification of a condensation product arising from porphobilinogen (PBG, increased in the urine of AIP patients) and indolyl-3-acryloylglycine (IAG, derived from indolylacrylic acid and present in human urine). The structure was unequivocally confirmed through comparison between the selected reaction monitoring chromatograms obtained from the urinary species and the condensation product qualitatively synthesised in the laboratory. Owing to the large amounts of both PBG and IAG in urine of AIP patients, the possible ex vivo formation of PBG-IAG in urine samples was evaluated. The product was spontaneously formed at room temperature, at 4 °C and even during storage at -20 °C when spiking a control sample with PBG. A positive correlation was found between PBG and PBG-IAG in samples collected from AIP patients. However, no correlation was found between PBG-IAG and IAG. Purified PBG-IAG did not form the characteristic chromogen after application of p-dimethylaminobenzaldehyde in HCl, thus suggesting that the current techniques used to measure PBG in urine of AIP patients based on Ehlrich's reaction do not detect this newly characterised PBG-IAG fraction.

Resumen A traves de Internet recientemente se han comercializado algunas sustancias estimulantes estructuralmente parecidas a neurotransmisores derivadas de medicamentos ya retirados, que potencialmente pueden causar cuadros clinicos de diversa gravedad. Su efecto estimulante y el hecho de que aparecen antes de prohibirse su consumo explican la denominacion generica de legal highs. La exposicion a estas sustancias se manifiesta como cuadros parecidos a los del consumo de productos como fenciclidina, anfetaminas o cocaina, ya que muy probablemente compartan mecanismos de accion sobre la recaptacion de dopamina en los nucleos cerebrales implicados en el comportamiento de gratificacion. La escasez de informacion medica contrastada, y las dificultades para disponer de material de calibracion constituyen un reto diagnostico. El desoxipipradol, sintetizado hace mas de 6 decadas para el tratamiento del trastorno hipercinetico, fue relegado por el metilfenidato, un compuesto analogo. En 2009 reaparecio como droga recreativa responsable de algunos cuadros clinicos de intoxicacion.

Sporadic porphyria cutanea tarda (PCT) is strongly associated with HCV infection in our population 1,2,3,4. . Therapeutic options for PCT include phlebotomies and low-dose 4-aminoquinolines, which show high rates of disease remission. However, some PCT patients may present frequent relapses attributable to resistance/intolerability/poor adherence to conventional treatments and/or persistence of risk factors. In 2014 we reported the first case of a patient with active PCT and HCV-HIV co-infection cured with direct antiviral agents (DAAs) 5. Herein, we present a larger cohort of patients, demonstrating the rapid and persistent remission of PCT with DAAs regimes administered for HVC infection. This article is protected by copyright. All rights reserved.

Acute intermittent porphyria (AIP) is a rare metabolic disorder due to a deficiency of porphobilinogen deaminase, the third enzyme of the heme biosynthetic pathway. This low enzymatic activity may predispose to the appearance of acute neurological attacks. Seminal studies suggested that AIP was associated with changes in tryptophan homeostasis with inconclusive results. Therefore, the aim of this study was to analyze the urinary metabolome of AIP patients focusing on tryptophan metabolism using state-of-the-art technology.This was a case-control study including a group of 25 AIP patients with active biochemical disease and increased excretion of heme-precursors and 25 healthy controls. Tryptophan and related compounds and metabolites including: large neutral amino acids (LNAAs), serotonin, kynurenine, kynurenic acid and anthranilic acid were quantified in urine by liquid chromatography tandem-mass spectrometry (LC-MS/MS). Twenty-nine biological markers (including metabolic ratios and absolute concentrations) were compared between patients and controls.Significant differences were found in the tryptophan-kynurenine metabolic pathway. Compared to controls, AIP patients showed: (a) increased urinary excretion of kynurenine and anthranilic acid (P0.005); (b): elevation of the kynurenine/tryptophan ratio (P0.001) and (c): decrease of the kynurenic acid/kynurenine ratio (P=0.001). In contrast, no differences were found in the serotonin metabolic pathway independently of the markers and ratios used.The results of the study demonstrate that there is an imbalance in the kynurenine metabolic pathway in AIP patients, with an increase of the kynurenine/tryptophan ratio in urine and a reduction of the kynurenic acid/kynurenine ratio. The modified ratios suggest induction of indoleamine 2,3-deoxygenase and decreased activity of kynurenine aminotransferase in the liver. The results confirm that LC-MS/MS is useful for the characterization of the urinary metabolome of hepatic porphyrias.

We develop a theoretical framework for computer-assisted proofs of the existence of invariant objects in semilinear PDEs. The invariant objects considered in this paper are equilibrium points, traveling waves, periodic orbits and invariant manifolds attached to fixed points or periodic orbits. The core of the study is writing down the invariance condition as a zero of an operator. These operators are in general not continuous, so one needs to smooth them by means of preconditioners before classical fixed point theorems can be applied. We develop in detail all the aspects of how to work with these objects: how to precondition the equations, how to work with the nonlinear terms, which function spaces can be useful, and how to work with them in a computationally rigorous way. In two companion papers, we present two different implementations of the tools developed in this paper to study periodic orbits., 17 pages

Typically, conflicts in world environmental negotiations are related, amongst other aspects, to the level of polarization of the countries in groups with conflicting interests. Given the predictable relationship between polarization and conflict, it would seem logical to evaluate the degree to which the distribution of countries – for example, in terms of their CO 2 emissions per capita – would be structured through groups which in themselves are antagonistic, as well as their evolution over time. This paper takes the concept of polarization to explore this distribution for the period 1992–2010, looking at different analytic approaches related to the concept. Specifically, it makes a comparative evaluation of the results associated with endogenous multi-polarization measures (i.e. EGR and DER indices), exogenous measures (i.e. Z–K or multidimensional index) and strict bipolarization measures (i.e. Wolfson’s measure). Indeed, the interest lies not only in evaluating the global situation of polarization by comparing the different approaches and their temporal patterns, but also in examining the explanatory capacity of the different proxy groups used as a possible reference for designing global environmental policy from a group premise.

This paper analyses the international inequalities in $$\hbox {CO}_{2}$$ emissions intensity for the period 1971–2009 and assesses explanatory factors. Group, additive and multiplicative methodologies of inequality decomposition are employed. The first allows us to understand the role of regional groups; the second allows us to investigate the role of different fossil energy sources (coal, oil and gas); and the third allows us to clarify the separated role of the carbonisation index and the energy intensity in the pattern observed for inequalities in $$\hbox {CO}_{2}$$ intensities. The results show that, first, the reduction in global emissions intensity has coincided with a significant reduction in international inequality. Second, the bulk of this inequality and its reduction are attributed to differences between the groups of countries considered. Third, coal is the main energy source explaining these inequalities, although the growth in the relative contribution of gas is also remarkable. Fourth, the bulk of inequalities between countries and its decline are explained by differences in energy intensities, although there are significant differences in the patterns demonstrated by different groups of countries. The policy implications of these results are discussed.

The international allocation of natural resources is determined, not by any ethical or ecological criteria, but by the dominance of market mechanisms. From a core–periphery perspective, this allocation may even be driven by historically determined structural patterns, with a core group of countries whose consumption appropriates most available natural resources, and another group, having low natural resource consumption, which plays a peripheral role. This article consists of an empirical distributional analysis of natural resource consumption (as measured by Ecological Footprints) whose purpose is to assess how strongly countries cluster together based on their Ecological Footprints: this is the extent to which the distribution of consumption responds to polarization (as opposed to mere inequality). To assess this, we estimate and decompose different polarization indices for a balanced sample of 119 countries over the period 1961 to 2007. Our results point towards a polarized distribution which is consistent with a core–periphery framework.

Scarcities of environmental services are no longer merely a remote hypothesis. Consequently, analysis of their inequalities between nations becomes of paramount importance for the achievement of sustainability. This paper aims, on the one hand, at revising methodological aspects of the inequality measurement of certain environmental data and, on the other, at extending the scarce empirical evidence relating to the international distribution of Ecological Footprint (EF). Most of the techniques currently important in the literature are revised and then tested on EF data with interesting results. We consider the underlying properties of different inequality indices. Those indices which fit best with environmental inequality measurements are CV $$^{2}$$ and GE(2) because of their neutrality property. Subgroup and Source decompositions are also discussed from a methodological perspective. Empirically, this paper contributes to the environmental inequality measurement of EF: this inequality has been quite stable. Subgroup decomposition by using exogenous country groups (World Bank classification) conclude that between group inequality explains almost the totality of international EF-inequality. Source decomposition warns of the dangers of confining CO $$_2$$ emissions reduction to crop-based energies because of the implications for basic needs satisfaction.

Acute intermittent porphyria (AIP) is an autosomal dominant disease that results from a deficiency of hydroxymethylbilane synthase, the third enzyme of the heme biosynthetic pathway. AIP carriers may present acute neurovisceral attacks with hepatic overproduction of heme-precursors. In some patients, remission of the acute symptoms leads to long-term hepatic metabolic abnormalities. In this study, gas chromatography-mass spectrometry (GC/MS) was used to investigate urinary steroid metabolome of AIP patients.Steroid profiling in urine was performed in a group of AIP patients with biochemically active disease (n=22) and healthy controls (n = 20). Five asymptomatic AIP family carriers were also studied. Commonly used ratios for the evaluation of disturbances in the steroid metabolism were calculated.We found that etiocholanolone/androsterone and tetrahydrocortisol/5α-tetrahydrocortisol (THF/5α-THF) metabolic ratios were significantly increased in the urine of AIP patients compared to controls (2.3 ± 0.3 vs 0.8 ± 0.1; p0.001 and 2.9 ± 0.7 vs 0.9 ± 0.1; p0.01). The (THF+5α-THF)/tetrahydrocortisone ratio was reduced among the AIP patients (p0.01). Quantification of the steroid absolute concentrations showed that these variations were due to a decrease of the 5α metabolites. Other ratios, like cortisol/cortisone and 6β-hydroxycortisol/cortisol in the free steroid fraction did not show differences between patients and controls. All ratios were normal among the family carriers.A significant number of AIP patients present a basal decrease of steroid 5α-reductase activity in the liver. The deficiency may be related to malnutrition and hepatic energy misbalance associated with active AIP. Urinary steroid profiling by GC/MS may be a valuable tool to assess hepatic metabolome in AIP.

Congenital erythropoietic porphyria (CEP), or Günther's disease, is an inborn error of metabolism produced by a deficiency of uroporphyrinogen III synthase (UROS), the fourth enzyme of the heme biosynthesis pathway. This enzymatic defect induces the accumulation of isomer I porphyrins in erythrocytes, skin, and tissues, producing various clinical manifestations. Severe cases are characterized by extreme photosensitivity, causing scarring and mutilations, and by hemolytic anemia, reducing life expectancy. CEP is caused by mutations in the UROS gene, and one of the most severe forms of the disease is associated with a cysteine to arginine substitution at residue 73 of the protein (C73R). CEP has been successfully treated only by the transplantation of hematopoietic precursors. We report the case of a male infant with severe postdelivery symptoms diagnosed with CEP and found to be homozygous for the C73R mutation. He underwent successful allogeneic bone marrow transplantation from a matched unrelated donor at 7 months of age. The hemolytic anemia was corrected and the porphyrin overproduction was significantly reduced. The patient remained asymptomatic after 1 year. This new case confirms that patients with severe CEP can benefit from early postnatal hematopoietic stem cell transplantation.

We develop techniques for the verification of the Chebyshev property of Abelian integrals. These techniques are a combination of theoretical results, analysis of asymptotic behavior of Wronskians, and rigorous computations based on interval arithmetic. We apply this approach to tackle a conjecture formulated by Dumortier and Roussarie in [F. Dumortier, R. Roussarie, Birth of canard cycles, Discrete Contin. Dyn. Syst. 2 (2009) 723–781], which we are able to prove for q ≤ 2 .

We provide several explicit examples of 3D quasiperiodic linear skew-products with simple Lyapunov spectrum, that is with $3$ different Lyapunov multipliers, for which the corresponding Oseledets bundles are measurable but not continuous, colliding in a measure zero dense set.

In this paper we present and illustrate a general methodology to apply KAM theory in particular problems, based on an {\em a posteriori} approach. We focus on the existence of real-analytic quasi-periodic Lagrangian invariant tori for symplectic maps. The purpose is to verify the hypotheses of a KAM theorem in an a posteriori format: given a parameterization of an approximately invariant torus, we have to check non-resonance (Diophantine) conditions, non-degeneracy conditions and certain inequalities to hold. To check such inequalities we require to control the analytic norm of some functions that depend on the map, the ambient structure and the parameterization. To this end, we propose an efficient computer assisted methodology, using fast Fourier transform, having the same asymptotic cost of using the parameterization method for obtaining numerical approximations of invariant tori. We illustrate our methodology by proving the existence of invariant curves for the standard map (up to $\eps=0.9716$), meandering curves for the non-twist standard map and 2-dimensional tori for the Froeschl\'e map., Comment: 49 pages, 3 figures, 9 tables

The authors acknowledge support from XREAP (DGR) This paper analyses the international inequalities in (Formula presented.) emissions intensity for the period 1971-2009 and assesses explanatory factors. Group, additive and multiplicative methodologies of inequality decomposition are employed. The first allows us to understand the role of regional groups; the second allows us to investigate the role of different fossil energy sources (coal, oil and gas); and the third allows us to clarify the separated role of the carbonisation index and the energy intensity in the pattern observed for inequalities in (Formula presented.) intensities. The results show that, first, the reduction in global emissions intensity has coincided with a significant reduction in international inequality. Second, the bulk of this inequality and its reduction are attributed to differences between the groups of countries considered. Third, coal is the main energy source explaining these inequalities, although the growth in the relative contribution of gas is also remarkable. Fourth, the bulk of inequalities between countries and its decline are explained by differences in energy intensities, although there are significant differences in the patterns demonstrated by different groups of countries. The policy implications of these results are discussed.

Natural resource scarcity is no longer merely a remote possibility and governments increasingly seek information about the global distribution of resource use and related environmental pressures. This paper presents an international distributional analysis of natural resource use indicators. These encompass both territorial (national production) and footprint (national consumption) indicators for land-related pressures (human appropriation of net primary production, HANPP, and embodied HANPP), for material use (domestic material extraction and consumption and material footprint), and for carbon emissions (territorial carbon emissions and carbon footprints). Our main question is "What, both from a territorial and a footprint perspective, are the main driving factors of international environmental inequality?". We show that, for the environmental indicators we studied, inequality tends to be higher for footprint indicators than for territorial ones. The exception is land use intensity (as measured by HANPP), for which geographical drivers mainly determine the distribution pattern. The international distribution of material consumption is mainly a result of economic drivers whereas, for domestic extraction, demographic drivers can explain almost half of the distribution pattern. Finally, carbon emissions are the environmental pressure that shows the highest international inequality because of the larger contribution of economic drivers. (C) 2015 Elsevier Ltd. All rights reserved. Spanish research project [ECO2013-45380-P] Austrian National Science Fund FWF [P20812-G11, P21012-G11] FP7 project VOLANTE [265104] Economic and Social Research Council [ES/K006576/1]

This chapter developes the “from theory-to algorithms-to computations-to validations” program for response tori in quasi-periodically forced systems. First, it provides a full proof of a Kantorovich-like theorem for invariant tori in discrete quasi-periodic systems. The proof of this theorem leads to several algorithms for the computation of invariant tori in this context, that are also detailed. Next, it is explained a computer assisted methodology for the validation of numerical results based on the previous a posteriori theorem. The chapter ends with three examples: validation of saddle invariant tori on the verge of breakdown, computation of a rigorous upper bound of the measure of Cantor-like spectra of a discrete Schrodinger operator, and validation of an attracting torus that by direct double precision seems to be a strange nonchaotic attractor.

Introduction: Variegate porphyria (VP) is a rare metabolic disorder that may present as an acute predominantly motor neuropathy. Cranial nerves and brainstem functions have been only scarcely studied. Methods: Brainstem reflexes were examined in symptomatic and non-symptomatic VP mutation carriers of a single family. Results: Similar results were found in the 2 patients with a history of porphyric crises. The blink reflex showed an absence of late responses (R2 and R2c) to stimulation of both sides. The masseter inhibitory reflex showed reduced inhibition of the second phase. The jaw jerk was normal. The asymptomatic carriers did not show any of the abnormalities just noted. Conclusions: Our results are compatible with a central lower pons–upper medulla disorder in the brainstem. We hypothesize that brainstem dysfunction in VP patients with a history of porphyric crises may be due to neurotoxic effects of porphyrin precursors as well as subclinical osmolarity changes due to hyponatremia. Muscle Nerve 46: 426–433, 2012

Background Increased iron stores- are common in porphyria cutanea tarda (PCT) patients, but the pathophysiological pathways remain unknown. Down-regulation of hepcidin, a peptide which regulates systemic iron homeostasis, has been demonstrated in different conditions associated with PCT, such as haemochromatosis, chronic hepatitis C (CHC) and excessive alcohol intake. However, serum hepcidin levels have not yet been studied in PCT patients. Objective To measure the serum hepcidin levels in patients with PCT, CHC and control patients, and to assess the association of hepcidin with serum markers of inflammation, iron overload and oxidative stress. Methods Hepcidin levels were measured by a competitive enzyme-linked immunosorbent assay in serum samples of patients presenting PCT (n = 30), CHC (n = 31) and healthy volunteers (n = 52). Results The mean of serum hepcidin levels was significantly higher in the PCT group (129.6 ng/mL) in comparison with the mean values in the CHC (41.3 ng/mL) and control (70.8 ng/mL) groups. The serum concentration of ferritin and interleukin-6 (IL-6) was also significantly higher in the PCT group, and correlated strongly with the hepcidin levels. The PCT patients with hepatitis C virus (HCV) infection showed significantly higher hepcidin levels than the group of CHC patients without porphyria. Conclusion Serum hepcidin levels are increased in patients with PCT suggesting that the mechanisms regulating iron homeostasis in PCT differ from those involved in other related disorders, such as haemochromatosis, HCV infection or alcohol abuse.

Mutations in the uroporphyrinogen III synthase (UROS) gene cause congenital erythropoietic porphyria (CEP), an autosomal-recessive inborn error of erythroid heme biosynthesis. Clinical features of CEP include dermatologic and hematologic abnormalities of variable severity. The discovery of a new type of erythroid porphyria, X-linked dominant protoporphyria (XLDPP), which results from increased activity of 5-aminolevulinate synthase 2 (ALAS2), the rate-controlling enzyme of erythroid heme synthesis, led us to hypothesize that the CEP phenotype may be modulated by sequence variations in the ALAS2 gene. We genotyped ALAS2 in 4 unrelated CEP patients exhibiting the same C73R/P248Q UROS genotype. The most severe of the CEP patients, a young girl, proved to be heterozygous for a novel ALAS2 mutation: c.1757 A > T in exon 11. This mutation is predicted to affect the highly conserved and penultimate C-terminal amino acid of ALAS2 (Y586). The rate of 5-aminolevulinate release from Y586F was significantly increased over that of wild-type ALAS2. The contribution of the ALAS2 gain-of-function mutation to the CEP phenotype underscores the importance of modifier genes underlying CEP. We propose that ALAS2 gene mutations should be considered not only as causative of X-linked sideroblastic anemia (XLSA) and XLDPP but may also modulate gene function in other erythropoietic disorders.

Summary Background An association between porphyria cutanea tarda (PCT) and diabetes mellitus (DM) is widely reported, but the pathogenetic link remains unknown. Objectives To investigate the natural history of DM in the setting of PCT and to determine which PCT features and risk factors may be associated with the development of DM. Methods This retrospective longitudinal study included 81 Spanish patients with PCT with at least 10 years of strict follow-up. Patients attended our Porphyria Unit for follow-up visits and the data were collected in the period 2004–2008. We classified patients into two groups: patients with glucose metabolism alterations (GMA: DM or impaired fasting glucose), and patients without. PCT features and PCT and DM risk factors were retrieved from clinical charts and compared between groups. Results We identified 33 patients (41%) with GMA, of whom 27 (82%) developed GMA a long time after the diagnosis of PCT (mean 12·7 years). In bivariate analysis, these patients had significantly higher mean serum ferritin at diagnosis (651 vs. 405 ng mL−1; P = 0·005), a higher prevalence of persistently elevated serum ferritin (52% vs. 15%; P

Porphyria cutanea tarda (PCT) arises from decreased hepatic activity of uroporphyrinogen decarboxylase (UROD). Both genetic and environmental factors interplay in the precipitation of clinically overt PCT, but these factors may vary between different geographic areas. Decreased activity of UROD in erythrocytes was used to identify patients with UROD mutations among a group of 130 Spanish PCT patients. Nineteen patients (14.6%) were found to harbor a mutation in the UROD gene. Eight mutations were novel: M1I, 5del10, A22V, D79N, F84I, Q116X, T141I and Y182C. Five others were previously described: F46L, V134Q, R142Q, P150L and E218G. The new missense mutations and P150L were expressed in Escherichia coli. D79N and P150L resulted in proteins that were localized to inclusion bodies. The other mutations produced recombinant proteins that were purified and showed reduced activity (range: 2.3–73.2% of wild type). These single amino acid changes were predicted to produce complex structural alterations and/or reduced stability of the enzyme. Screening of relatives of the probands showed that 37.5% of mutation carriers demonstrated increased urinary porphyrins. This study emphasizes the role of UROD mutations as a strong risk factor for PCT even in areas where environmental factors (hepatitis C virus) have been shown to be highly associated with the disease.

4 pages, 4 tables.-- 18941586 [PubMed].-- PMCID: PMC2569103.-- Printed version published Oct 2008., Background Hexachlorobenzene (HCB) and other organochlorines induce porphyria cutanea tarda (PCT) in animal studies. Evidence in humans, however, is contradictory. In neonates and adults from a population historically highly exposed to HCB (Flix, Catalonia, Spain), no relation with PCT or with porphyrin excretion was found., Objectives We aimed to analyze the association between urinary porphyrin excretion and exposure to HCB and other organochlorinated compounds in children 4 years of age., Methods Our birth cohort included all newborns from Flix and the five surrounding towns (where no airborne pollution occurred). Among the 68 children with porphyrins we measured in cord blood, 52 children 4 years of age provided blood to measure organochlorine compounds, hair for methylmercury, and urine for porphyrin excretion pattern., Results Quantitative porphyrin excretion was within the normal values. However, total porphyrins, coproporphyrin I (CPI), and coproporphyrin III (CPIII) adjusted to creatinine excretion increased with increasing levels of HCB, 1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene (p,p′-DDE), 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (p,p′-DDT), and polychlorinated biphenyl congener 153 (PCB-153). We found no association with methylmercury. When we fitted multiple pollutant models, p,p′-DDE had the strongest association. We found these associations in children from both Flix and other towns, and they were independent of breast-feeding and of organochlorine and porphyrin levels at birth., Conclusion HCB at current levels did not induce porphyria or increase uroporphyrins. However, the increase of urinary coproporphyrins suggests an incipient toxic effect of the organochlorines, especially for p,p′-DDE, on the hepatic heme-synthesis pathway that differs from the major effects seen in PCT., This study was funded by the Spanish Ministry of Health (FIS-97/1102, FIS-PI041436, Red INMA G03/176, and CB06/02/0041), “Fundació La Caixa” (97/009-00 and 00/077-00), and Generalitat de Catalunya-CIRIT 1999SGR 00241.

Fundamento y objetivo El extasis liquido o acido γ-hidroxibutirico (GHB) es una nueva causa de sobredosis de droga de abuso en nuestro medio. El objetivo es describir el perfil epidemiologico y las caracteristicas clinicas de los intoxicados por GHB atendidos en los servicios de urgencies de 2 hospitales de Barcelona. Pacientes y metodo Durante 2 anos (2003-2004) se han estudiado los casos de intoxicacion o sobredosis por GHB atendidos en el Hospital del Mar y en el Hospital Clinic de Barcelona. El diagnostico fue clinico y/o por analisis toxicologico. Se analizaron variables epidemiologicas, clinicas, analiticas, terapeuticas y evolutivas. Resultados Se identifico a 339 pacientes. La edad media fue 23,5 anos y el 62% eran varones. Se atendio a la mayoria de pacientes de madrugada (89%) y durante un fin de semana (89%), y el inicio de los sintomas se produjo en un lugar publico (97%). La sintomatologia se caracterizo por la disminucion del grado de conciencia, ya que el 72% de los casos presentaba 12 puntos o menos en la escala de coma de Glasgow. El 70% de los pacientes reconocio el consumo combinado de GHB con otras drogas, entre las cuales las mas habituales fueron el alcohol etilico (53%) y la cocaina (16%). El 32% de los casos requirio algun tipo de tratamiento y a 20 de ellos se les administraron antidotos: naloxona (12 casos), flumazenilo (8 casos) o fisostigmina (6 casos). Cinco pacientes precisaron intubacion orotraqueal y soporte ventilatorio, y hubo de practicarse soporte vital avanzado en un caso. No se registraron fallecimientos. Conclusiones En los servicios de urgencias, la intoxicacion por GHB es una causa frecuente de consulta por disminucion del grado de conciencia, sobre todo en pacientes jovenes, en fin de semana y de madrugada. La intoxicacion por GHB debe descartarse en todo coma de origen desconocido.

The relative content of the four main bacteriochlorophyll (BChl) e homologs of several populations of brown-colored photosynthetic sulfur bacteria grown in different waterbodies have been measured by high performance liquid chromatography and statistically compared by principal component analysis. All the studied populations possessed representative pigment patterns enriched in highly alkylated bacteriochlorophyll e homologs, with average contents of 0.02±0.01%, 24.92±1.01%, 35.2±0.70%, and 39.9±0.71% for bacteriochlorophyll e1, e2, e3, and e4, respectively. These values clearly differ from those obtained for the same species growing under optimal conditions in laboratory batch cultures (4.99±1.11%, 50.34±1.73%, 28.99±0.63%, and 15.6±1.10% for bacteriochlorophyll e1, e2, e3, and e4, respectively). Multivariate statistical analyses grouped samples into two main clusters, both related to the developmental state of the population. Within these clusters, samples were arranged in several groups according to the physiological pigment response of bacterial populations to light limitation. Although bacteriochlorophyll homolog distribution cannot be considered a real taxonomic character, the data presented demonstrate that it can be useful in field studies since it reflects both the physiological status of the cells and the light regime under which the population has been growing.

We report a biochemical and genetic characterization of four cases of hereditary coproporphyria (HCP) in Spain. All patients showed a typical HCP porphyrin excretion pattern with a high concentration of coproporphyrins in feces and inverted I:III isomer ratio. The porphyrin precursors in urine were found elevated in two patients who showed acute symptoms. The analysis of the CPO gene showed that three cases harboured novel mutations: V135A (404T > C; exon 1); L214R (641T > G; exon 2); and P249R (746C > G; exon 3) and in the fourth, a previously described R426X mutation in exon 6.