Delivery of the 135 kb human frataxin genomic DNA locus gives rise to different frataxin isoforms.

Friedreich's ataxia (FRDA) is the most common form of hereditary ataxia caused by recessive mutations in the FXN gene. Recent results have indicated the presence of different frataxin isoforms due to alternative gene expression mechanisms. Our previous studies demonstrated the advantages of using high-capacity herpes simplex virus type 1 (HSV-1) amplicon vectors containing the entire FXN genomic locus (iBAC-FXN) as a gene-delivery vehicle capable of ensuring physiologically-regulated and long-term persistence. Here we describe how expression from the 135 kb human FXN genomic locus produces the three frataxin isoforms both in cultured neuronal cells and also in vivo. Moreover, we also observed the correct expression of these frataxin isoforms in patient-derived cells after delivery of the iBAC-FXN. These results lend further support to the potential use of HSV-1 vectors containing entire genomic loci whose expression is mediated by complex transcriptional and posttranscriptional mechanisms for gene therapy applications.

Comparison of gas exchange after lung resection with a Boussignac CPAP or Venturi mask.

BACKGROUND: Postoperative continuous positive airway pressure (CPAP) can improve lung function. The aim of our study was to assess the efficacy of prophylactic CPAP on the Pa(O2)/FI(O2) ratio measured the day after surgery in patients undergoing lung resection surgery (LRS). METHODS: The study population comprised 110 patients undergoing LRS. On arrival in the postanaesthesia care unit (PACU), patients were randomized to receive CPAP at 5-7 cm H2O during the first 6 h after surgery (CPAP group) or supplemental oxygen through a Venturi mask (Venturi group). The Pa(O2)/FI(O2) ratio was measured on arrival in the PACU, 7 h after admission, and the day after surgery. The Pa(O2)/FI(O2) ratio is the primary endpoint of our study. We also analysed the chest radiograph and assessed the postoperative course. We then analysed the impact of ventilatory management in the PACU depending on the respiratory risk of the patient. RESULTS: Baseline characteristics were similar in both groups. Patients who received CPAP had significantly higher Pa(O2)/FI(O2) at 24 h after surgery compared with patients managed conventionally (Venturi group) (48.6±14 vs 42.3±12, P=0.031), but there were no differences at 7 h. On subgroup analysis, we found that the benefits of CPAP were greater in higher risk patients. The incidence of postoperative pulmonary complications and stay in the PACU and hospital were similar in both groups. CONCLUSIONS: In patients undergoing LRS, prophylactic CPAP during the first 6 h after surgery with a pressure of 5-7 cm H2O improved the Pa(O2)/FI(O2) ratio at 24 h. This effect was more evident in patients with increased risk of postoperative pulmonary complications.

Anti­CGRP monoclonal antibodies in resistant migraine: preliminary real-world effectiveness and clinical predictors of response at two years.

BACKGROUND: Monoclonal antibodies targeting calcitonin gene-related peptide (anti-CGRP mAbs) have shown clinical effectiveness and safety in randomized clinical studies. However, long-term studies in clinical practice remain limited. AIM: To assess the long-term effectiveness, clinical predictors and safety of three anti-CGRP mAbs (erenumab, galcanezumab, fremanezumab) in resistant migraine patients. METHOD: A single-center retrospective study was conducted from December 2019 to June 2023 involving 120 resistant migraine patients who received at least a month of anti-CGRP mAbs treatment. Patients completed a headache diary that included monthly acute medication intake (MAM), monthly migraine days (MMD), adverse events as well as completed Patient-Reported Outcome questionnaires (MIDAS [Migraine Disability Assessment] and Headache Impact Test 6 [HIT-6]). The number of patients achieving a ≥ 50% reduction in monthly migraine days was determined and classified as ≥ 50% responders, and baseline parameters and logistic regression between responders and non-responders were analyzed to identify potential predictors of response. Adverse events were registered in every follow-up. RESULTS: Treatment with anti-CGRP mAbs led to reductions in MIDAS, HIT-6, MMD and MAM from baseline to 6-24 months. At 6-12 months, responders (61% and 57%, respectively) exhibited lower baseline MMD and MAM. Medication overuse  was associated with non-responders from 6 to 24 months and it was identified as a negative predictor of treatment effectiveness (OR 0.23, 95% CI 0.07-0.74; p = 0.014). CONCLUSION: Anti-CGRP mAbs prove effectiveness and safety over a 24-month period in a RM population. Patients with no medication overuse and lower basal MMDs and MAM may respond better to anti-CGRP mAbs.

Growth and ligninolytic system production dynamics of the Phanerochaete chrysosporium fungus A modelling and optimization approach.

The well-documented ability to degrade lignin and a variety of complex chemicals showed by the white-rot fungus Phanerochaete chrysosporium has made it the subject of many studies in areas of environmental concern, including pulp bioleaching and bioremediation technologies. However, until now, most of the work in this field has been focused on the ligninolytic sub-system but, due to the great complexity of the involved processes, less progress has been made in understanding the biochemical regulatory structure that could explain growth dynamics, the substrate utilization and the ligninolytic system production itself. In this work we want to tackle this problem from the perspectives and approaches of systems biology, which have been shown to be effective in the case of complex systems. We will use a top-down approach to the construction of this model aiming to identify the cellular sub-systems that play a major role in the whole process. We have investigated growth dynamics, substrate consumption and lignin peroxidase production of the P. chrysosporium wild type under a set of definite culture conditions. Based on data gathered from different authors and in our own experimental determinations, we built a model using a GMA power-law representation, which was used as platform to make predictive simulations. Thereby, we could assess the consistency of some current assumptions about the regulatory structure of the overall process. The model parameters were estimated from a time series experimental measurements by means of an algorithm previously adapted and optimized for power-law models. The model was subsequently checked for quality by comparing its predictions with the experimental behavior observed in new, different experimental settings and through perturbation analysis aimed to test the robustness of the model. Hence, the model showed to be able to predict the dynamics of two critical variables such as biomass and lignin peroxidase activity when in conditions of nutrient deprivation and after pulses of veratryl alcohol. Moreover, it successfully predicts the evolution of the variables during both, the active growth phase and after the deprivation shock. The close agreement between the predicted and observed behavior and the advanced understanding of its kinetic structure and regulatory features provides the necessary background for the design of a biotechnological set-up designed for the continuous production of the ligninolityc system and its optimization.

Metal Concentrations in Wild-Harvested Phaeophyta Seaweed from the Atlantic Ocean (Canary Islands, Spain).

Seaweeds are being consumed more often worldwide and are a source of essential minerals, fiber, vitamins, amino acids, and various bioactive compounds that have many beneficial effects on human health. However, marine pollution and the high capacity of seaweed to absorb metals may mean this food can also be dangerous to human health. The concentrations of some trace elements (B, Ba, Fe, Ni, Li, and V) and toxic metals (Al, Cd, and Pb) were determined in various species of wild seaweeds in the Phaeophyta group of brown algae from the Atlantic Ocean. Inductively coupled plasma atomic emission spectrometry revealed high concentrations of Al (256 mg/kg dry weight), Pb (3.92 mg/kg dry weight), and Cd (0.20 mg/kg dry weight) in Padina pavonica. Pb contributed the most to the tolerable daily intake (TDI) of toxic metals in these samples; 57.2 and 45.3% of the TDI for Pb was found in 5 g of dehydrated P. pavonica and Halopteris scoparia, respectively. This percent contribution is half of the recommended TDI for this metal, which is 34.24 µg/day; therefore, high consumption of these species is discouraged. The maximum TDIs established by various institutions for the other metals were not exceeded from the daily consumption of 5 g of the other dehydrated seaweeds evaluated in this study.

Antifungal stewardship in a tertiary-care institution: a bedside intervention.

Antifungal stewardship (AFS) programmes are needed in tertiary-care hospitals. Our aim is to describe a bedside non-restrictive AFS programme, and to evaluate its economic impact. During the first year of the AFS a bundle of non-interventional measures were implemented. During the second year an infectious diseases specialist visited 453 patients receiving candins, liposomal amphotericin B, voriconazole or posaconazole. Monthly costs were studied with an interrupted time series (ITS) analysis. The main prescribing departments were haematology (35%), medical departments (23%), and intensive care units (20%). Reasons to start antifungal therapy were: targeted therapy (36%), prophylaxis (32%), empirical therapy (20%) and pre-emptive therapy (12%). At the initial visit, diagnostic advice was provided in 40% of cases. The most common therapeutic recommendations were to de-escalate the antifungal drug (17%) or to suspend it (7%). Annual total antifungal expenditure was reduced from US$3.8 million to US$2.9 million over the first 2 years, generating net savings of US$407,663 and US$824,458 per year after considering the cost of additional staff required. The ITS analyses showed a significant economic impact after the first 12 months of the intervention (p 0.042 at month 13), which was enhanced in the following 24 months (p 0.006 at month 35). The number of defined daily doses decreased from 66.4 to 54.8 per 1000 patient-days. Incidence of candidaemia was reduced from 1.49 to 1.14 (p 0.08) and related mortality was reduced from 28% to 16% (p 0.1). A collaborative and non-compulsory AFS program based on bedside intervention is an efficacious and cost-effective approach that optimizes the use of AF drugs.

Lignan models as inhibitors of Phanerochaete chrysosporium lignin peroxidase.

The lignan 8,8'-bis-(methylenedioxy)cinnamic acid (BMDCA) is a powerful competitive inhibitor (K1 = 2.0 microM) of the lignin peroxidase (LiP) from Phanerochaete chrysosporium and of the extracellular peroxidase of Phlebia radiata (I0.5 = 10 microM). BMDCA derivatives with the same double bond system also inhibited these enzymes to some extent. If the double bonds were hydrogenated, the inhibitory effect was lost. HRP-VIII and HRP-XI were slightly inhibited by BMDCA (I0.5 > 50 microM) and two plant peroxidases described as efficient lignan synthesizers were unaffected. Liquid cultures of P chrysosporium did not discolour the dve Poly R478 when 250 microM of BMDCA was present.

Population data for Southern Spain and Canary Islands of HLADQA1, PM and D1S80 loci.

Allele frequencies for seven polymerase chain reaction (PCR)-based DNA genetic markers in two Spanish populations (Southern Spain and Canary Islands), were determined and compared. The loci analysed were HLADQA1, LDLR, GYPA, HBGG, D7S8,Gc, and D1S80.

[Fatal poisoning by the rupture of intestinal bags of cocaine]. / Intoxicación mortal por rotura de bolsas intestinales de cocaína.

We report a case of rupture of bags filled with cocaine into the digestive apparatus in a young man. He carried into his digestive tract one hundred of small bags containing 40 g of cocaine each one. The initial clinical picture was characterized by sympathetic hyperactivity, rectorrhagia, and psychosis that evolved in 72 h to neurologic coma, convulsions, rhabdomyolysis, hyperthermia, hypocalcemia, hyperdynamic picture with negative blood cultures, arterial hypotension, syndrome of adult respiratory distress, and multiorgan failure. Treatment with propranolol, mechanic ventilation, barbiturates and inotropic agents was ineffective and the patient died 7 days after.

[Risk Factors and extraneurological complications of stroke patients]. / Factores de riesgo y complicaciones extraneurológicas de pacientes internados por Accidente Cerebrovascular en el Hospital Nacional de Clínicas de Córdoba.

INTRODUCTION: Stroke is the third leading cause of death globally , act on modifiable risk factors is now the best prevention strategy. Medical complications are common in patients hospitalized for stroke , the valuation of income NIHSS , is associated with the final result in terms of duration of hospitalization, survival and discharge location. OBJETIVE: Determining risk factors ( RF) in patients hospitalized for stroke in Hospital Nacional de Clinicas de Córdoba (HNC) and characterize neurological complications NIHSS relative to income. MATERIAL AND METHODS: Prospective study of patients admitted to the Service of Neurology at HNC diagnosed with the first of September , 2010 to December 30, 2012 , we applied the admission NIHSS scale. Were determined cerebrovascular risk factors , we evaluated neurological complications during hospitalization. RESULTS: The total number of patients admitted for stroke was 200 , with 168 ischemic stroke ( 84%) and hemorrhagic stroke 32 (16 % ) . The FR Hypertension was the most frequent ( 83.5 %), over 40% had 3 or more FR for stroke. Had complications : 32 % of patients , the respiratory infection was the most frequent (14.5 % ). Patients with NIHSS greater than 10 points had a higher rate of complications. CONCLUSION: The multiple RF control is an effective strategy to decrease the incidence of stroke . Prevention of medical complications enable better patient care and reduce morbidity associated with stroke.

El Accidente cerebro vascular (ACV) constituye la tercera causa de muerte a nivel mundial; actuar sobre los factores de riesgo modificables constituye hoy la mejor estrategia de prevención. Las complicaciones médicas son frecuentes en los pacientes internados por ACV; la valoración del NIHSS de ingreso, está asociado al resultado final en términos de duración de internación, supervivencia y ubicación al alta. Objetivo. Determinar los factores de riesgo (FR) en pacientes internados por ACV en el HNC de Córdoba y caracterizar las complicaciones no neurológicas en relación al NIHSS de ingreso. Material y métodos. Estudio prospectivo de pacientes internados en el HNC con diagnóstico de ACV del primero de septiembre de 2010 al 30 de diciembre de 2012, se aplicó la escala de NIHSS al ingreso. Se determinaron los factores de riesgo cerebrovasculares; se evaluaron las complicaciones no neurológicas durante la internación. Resultados. El total de pacientes ingresados por ACV fue de 200, con ACV isquémico 168 (84%) y ACV hemorrágico 32(16%). La Hipertensión Arterial fue el FR más frecuente (83,5%); más del 40% tenía 3 o más FR para ACV. Tuvieron complicaciones: 32% de los pacientes, la Infección respiratoria fue la más frecuente (14.5%)Pacientes con NIHSS superior a 10 puntos presentaron mayor porcentaje de complicaciones. Conclusión. El control de FR múltiples constituye una estrategia efectiva para disminuir la incidencia de ACV. La prevención de las complicaciones médicas permiten un mejor cuidado del paciente y reducen la morbilidad relacionada al ACV.

Effect of polyethylene glycol on the in vitro production of L-lactate by rat liver under near physiological conditions.

The effect of polyethylene glycol (PEG) on lactate production from glucose by rat liver postmitochondrial fraction has been examined, using physiological concentrations of substrate and effectors. Addition of 10% polyethylene glycol (Mw 6000) resulted in an increase in lactate production, while the inhibition of lactate production by citrate and ATP was decreased. These results in conjunction with analysis of glycolytic intermediates suggest that PEG exerts its major action on phosphofructokinase.

Concentrations of Mercury in Fresh and Salted Marine Fish From the Canary Islands.

A statistical study of recovery has been carried out in five mineralization procedures: i) HNO3/H2SO4 (1:1), 45°C/15 h; ii) HNO3, 100°C (teflón pump)/l h.; iii) HNO3/H2SO4 (1:1), 100°C (teflon pump)/l h; iv) H2SO4/HCI (1:1), 100°C (teflon pump)/l h; and v) Lumaton, 45°C/24 h, for determination of mercury (cold vapor - A.A.S.) in muscle of fish. Only in method 1 there is no evidence of the systematic error (P > 0.05). This method was applied to 449 samples of fresh and salted fish. Mean concentrations of mercury ranged of 0.014 ppm ( Pagellus erythrinus ) to 0.970 ppm ( Lepidopus caudatus ) for fresh fish, and for salted fish between 0.043 ppm ( Diplodus sargus cadenati ) and 0.172 ppm ( Galeorhinus galeus ). One can conclude that the low mercury level of analyzed samples was lower than fish species from some polluted areas of the Mediterranean Sea. No significant differences were observed between the mean concentrations of fresh and salted fish.

Purification of a new peroxidase catalysing the formation of lignan-type compounds.

A novel peroxidase that catalyses the dimerization of ferulic acid or caffeic acid via oxidative coupling and formation of beta beta'-linkage to the lignan-type compounds 8,8'-bis(caffeic acid) or 8,8'-bis(ferulic acid) respectively was purified from the leaves of Bupleurum salicifolium. The enzyme, for which the name caffeate peroxidase is proposed, was purified 2700-fold. It is a glycoprotein and has an Mr of 38,000 as determined by gel filtration and SDS/PAGE. The Km values for ferulic acid and caffeic acid were 0.24 mM and for H2O2 0.04 mM with caffeic acid and 0.48 mM with ferulic acid. The purified peroxidase does not exhibit activity on other phenylpropanoids tested and has no detectable phenol oxidase or NADPH oxidase activity. The caffeate peroxidase could be involved in the biosynthesis of lignans.

Lesion of the internal carotid artery caused by a car safety belt.

A description is given of a case of complete obstruction of the internal carotid in a patient wearing a lap-shoulder belt. This was presumed due to direct contusion of the vessel at the C2 level.

The endogenous functional turkey erythrocyte and rat liver insulin receptor is an alpha 2 beta 2 heterotetrameric complex.

Previous studies have indicated that turkey erythrocyte and rat liver membranes contain endogenous alpha beta heterodimeric insulin receptors in addition to the disulphide-linked alpha 2 beta 2 heterotetrameric complexes characteristic of most cell types. We utilized 125I-insulin affinity cross-linking to examine the structural properties of insulin receptors from rat liver and turkey erythrocyte membranes prepared in the absence and presence of sulphydryl alkylating agents. Rat liver membranes prepared in the absence of sulphydryl alkylating agents displayed specific labelling of Mr 400,000 and 200,000 bands, corresponding to the alpha 2 beta 2 heterotetrameric and alpha beta heterodimeric insulin receptor complexes respectively. In contrast, affinity cross-linking of membranes prepared with iodoacetamide (IAN) or N-ethylmaleimide identified predominantly the alpha 2 beta 2 heterotetrameric insulin receptor complex. Similarly, affinity cross-linking and solubilization of intact turkey erythrocytes in the presence of IAN resulted in exclusive labelling of the alpha 2 beta 2 heterotetrameric insulin receptor complex, whereas in the absence of IAN both alpha 2 beta 2 and alpha beta species were observed. Turkey erythrocyte alpha 2 beta 2 heterotetrameric insulin receptors from IAN-protected membranes displayed a 3-4-fold stimulation of beta subunit autophosphorylation and substrate phosphorylation by insulin, equivalent to that observed in intact human placenta insulin receptors. Turkey erythrocyte alpha beta heterodimeric insulin receptors, prepared by defined pH/dithiothreitol treatment of IAN-protected membranes, were also fully competent in insulin-stimulated protein kinase activity compared with alpha beta heterodimeric human placenta receptors. In contrast, endogenous turkey erythrocyte alpha beta heterodimeric insulin receptors displayed basal protein kinase activity which was insulin-insensitive. These data indicate that native turkey erythrocyte and rat liver insulin receptors are structurally and functionally similar to alpha 2 beta 2 heterotetrameric human placenta insulin receptors. The alpha beta heterodimeric insulin receptors previously identified in these tissues most likely resulted from disulphide bond reduction and denaturation of the alpha 2 beta 2 holoreceptor complexes during membrane preparation.

A major isoform of the maize plasma membrane H(+)-ATPase: characterization and induction by auxin in coleoptiles.

The plasma membrane (PM) H(+)-ATPase has been proposed to play important transport and regulatory roles in plant physiology, including its participation in auxin-induced acidification in coleoptile segments. This enzyme is encoded by a family of genes differing in tissue distribution, regulation, and expression level. A major expressed isoform of the maize PM H(+)-ATPase (MHA2) has been characterized. RNA gel blot analysis indicated that MHA2 is expressed in all maize organs, with highest levels being in the roots. In situ hybridization of sections from maize seedlings indicated enriched expression of MHA2 in stomatal guard cells, phloem cells, and root epidermal cells. MHA2 mRNA was induced threefold when nonvascular parts of the coleoptile segments were treated with auxin. This induction correlates with auxin-triggered proton extrusion by the same part of the segments. The PM H(+)-ATPase in the vascular bundies does not contribute significantly to auxin-induced acidification, is not regulated by auxin, and masks the auxin effect in extracts of whole coleoptile segments. We conclude that auxin-induced acidification in coleoptile segments most often occurs in the nonvascular tissue and is mediated, at least in part, by increased levels of MHA2.

Factores de riesgo y complicaciones extraneurológicas de pacientes internados por Accidente Cerebrovascular en el Hospital Nacional de Clínicas de Córdoba / [Risk Factors and extraneurological complications of stroke patients].

INTRODUCTION: Stroke is the third leading cause of death globally , act on modifiable risk factors is now the best prevention strategy. Medical complications are common in patients hospitalized for stroke , the valuation of income NIHSS , is associated with the final result in terms of duration of hospitalization, survival and discharge location. OBJETIVE: Determining risk factors ( RF) in patients hospitalized for stroke in Hospital Nacional de Clinicas de Córdoba (HNC) and characterize neurological complications NIHSS relative to income. MATERIAL AND METHODS: Prospective study of patients admitted to the Service of Neurology at HNC diagnosed with the first of September , 2010 to December 30, 2012 , we applied the admission NIHSS scale. Were determined cerebrovascular risk factors , we evaluated neurological complications during hospitalization. RESULTS: The total number of patients admitted for stroke was 200 , with 168 ischemic stroke ( 84

) and hemorrhagic stroke 32 (16

) . The FR Hypertension was the most frequent ( 83.5

had 3 or more FR for stroke. Had complications : 32

of patients , the respiratory infection was the most frequent (14.5

). Patients with NIHSS greater than 10 points had a higher rate of complications. CONCLUSION: The multiple RF control is an effective strategy to decrease the incidence of stroke . Prevention of medical complications enable better patient care and reduce morbidity associated with stroke.