Low aerobic capacity in McArdle disease: A role for mitochondrial network impairment?

Aerobic capacity; Glycogen; McArdle diseaseCapacidad aeróbica; Glucógeno; Enfermedad de McArdleCapacitat aeròbica; Glicogen; Malaltia de McArdleBackground McArdle disease is caused by myophosphorylase deficiency and results in complete inability for muscle glycogen breakdown. A hallmark of this condition is muscle oxidation impairment (e.g., low peak oxygen uptake (VO2peak)), a phenomenon traditionally attributed to reduced glycolytic flux and Krebs cycle anaplerosis. Here we hypothesized an additional role for muscle mitochondrial network alterations associated with massive intracellular glycogen accumulation. Methods We analyzed in depth mitochondrial characteristics-content, biogenesis, ultrastructure-and network integrity in skeletal-muscle from McArdle/control mice and two patients. We also determined VO2peak in patients (both sexes, N = 145) and healthy controls (N = 133). Results Besides corroborating very poor VO2peak values in patients and impairment in muscle glycolytic flux, we found that, in McArdle muscle: (a) damaged fibers are likely those with a higher mitochondrial and glycogen content, which show major disruption of the three main cytoskeleton components-actin microfilaments, microtubules and intermediate filaments-thereby contributing to mitochondrial network disruption in skeletal muscle fibers; (b) there was an altered subcellular localization of mitochondrial fission/fusion proteins and of the sarcoplasmic reticulum protein calsequestrin-with subsequent alteration in mitochondrial dynamics/function; impairment in mitochondrial content/biogenesis; and (c) several OXPHOS-related complex proteins/activities were also affected. Conclusions In McArdle disease, severe muscle oxidative capacity impairment could also be explained by a disruption of the mitochondrial network, at least in those fibers with a higher capacity for glycogen accumulation. Our findings might pave the way for future research addressing the potential involvement of mitochondrial network alterations in the pathophysiology of other glycogenoses.The present study was funded by grants received from the Fondo de Investigaciones Sanitarias (FIS, PI17/02052, PI18/00139, PI19/01313, and PI20/00645) and cofunded by ‘Fondos FEDER’. Gisela Nogales-Gadea and Carmen Fiuza-Luces are supported by the Miguel Servet research contracts (ISCIII CD14/00032 and CP18/00034, respectively and cofounded by Fondos FEDER′). Research by Pedro L. Valenzuela is funded by a postdoctoral contract granted by Instituto de Salud Carlos III (Sara Borrell, CD21/00138). Monica Villarreal Salazar is supported by the Mexican National Council for Science and Technology (CONACYT)

2,2′-Dimethoxy-4,4′-[rel-(2R,3S)-2,3-di­methylbutane-1,4-diyl]diphenol

The title mol­ecule, C20H26O4, commonly known as meso-dihydro­guaiaretic acid, is a naturally occurring lignan extracted from Larrea tridentata and other plants. The mol­ecule has a noncrystallographic inversion center situated at the midpoint of the central C—C bond, generating the meso stereoisomer. The central C—C—C—C alkyl chain displays an all-trans conformation, allowing an almost parallel arrangement of the benzene rings, which make a dihedral angle of 5.0 (3)°. Both hydr­oxy groups form weak O—H⋯O—H chains of hydrogen bonds along [100]. The resulting supra­molecular structure is an undulating plane parallel to (010)

Dispositivo intrauterino parcialmente migrado e incrustado en serosa de rectosigmoides tras 8 años de inserción

It is shown the clinical case of an intrauterine device partially migrated to the pelvic cavity and embedded in the serous rectosigmoid eight years after insertion. The diagnosis was made by transvaginal ultrasound and laparoscopy removal of the device by laparoscopy. Suture of rectum serous and uterus were performed. The patient had an uneventful postoperative course.Se presenta el caso clínico de un dispositivo intrauterino parcialmente migrado a cavidad pélvica e incrustado en serosa de rectosigmoides luego de 8 años de su inserción. El diagnóstico se realizó mediante ecografía transvaginal y retiro del dispositivo por laparoscopia. Se realizó rafia de serosa rectal y de útero. La paciente tuvo un postoperatorio sin complicaciones

Dispositivo intrauterino parcialmente migrado e incrustado en serosa de rectosigmoides tras 8 años de inserción

It is shown the clinical case of an intrauterine device partially migrated to the pelvic cavity and embedded in the serous rectosigmoid eight years after insertion. The diagnosis was made by transvaginal ultrasound and laparoscopy removal of the device by laparoscopy. Suture of rectum serous and uterus were performed. The patient had an uneventful postoperative course.Se presenta el caso clínico de un dispositivo intrauterino parcialmente migrado a cavidad pélvica e incrustado en serosa de rectosigmoides luego de 8 años de su inserción. El diagnóstico se realizó mediante ecografía transvaginal y retiro del dispositivo por laparoscopia. Se realizó rafia de serosa rectal y de útero. La paciente tuvo un postoperatorio sin complicaciones

Phase I randomized dose-ascending placebo-controlled trials of ferroquine - a candidate anti-malarial drug - in adults with asymptomatic Plasmodium falciparum infection

<p>Abstract</p> <p>Background</p> <p>The development and spread of drug resistant <it>Plasmodium falciparum </it>strains is a major concern and novel anti-malarial drugs are, therefore, needed. Ferroquine is a ferrocenic derivative of chloroquine with proven anti-malarial activity against chloroquine-resistant and -sensitive <it>P. falciparum </it>laboratory strains.</p> <p>Methods</p> <p>Adult young male aged 18 to 45 years, asymptomatic carriers of <it>P. falciparum</it>, were included in two-dose escalation, double-blind, randomized, placebo-controlled Phase I trials, a single dose study and a multiple dose study aiming to evaluate oral doses of ferroquine from 400 to 1,600 mg.</p> <p>Results</p> <p>Overall, 54/66 patients (40 and 26 treated in the single and multiple dose studies, respectively) experienced at least one adverse event, 15 were under placebo. Adverse events were mainly gastrointestinal symptoms such as abdominal pain (16), diarrhoea (5), nausea (13), and vomiting (9), but also headache (11), and dizziness (5). A few patients had slightly elevated liver parameters (10/66) including two patients under placebo. Moderate changes in QTc and morphological changes in T waves were observed in the course of the study. However, no adverse cardiac effects with clinical relevance were observed.</p> <p>Conclusions</p> <p>These phase I trials showed that clinically, ferroquine was generally well-tolerated up to 1,600 mg as single dose and up to 800 mg as repeated dose in asymptomatic young male with <it>P. falciparum </it>infection. Further clinical development of ferroquine, either alone or in combination with another anti-malarial, is highly warranted and currently underway.</p

Direct venous inoculation of Plasmodium falciparum sporozoites for controlled human malaria infection: a dose-finding trial in two centres

BACKGROUND: Controlled human malaria infection (CHMI) accelerates development of anti-malarial interventions. So far, CHMI is done by exposure of volunteers to bites of five mosquitoes carrying Plasmodium falciparum sporozoites (PfSPZ), a technique available in only a few centres worldwide. Mosquito-mediated CHMI is logistically complex, exact PfSPZ dosage is impossible and live mosquito-based interventions are not suitable for further clinical development. METHODS: An open-labelled, randomized, dose-finding study in 18-45 year old, healthy, malaria-naive volunteers was performed to assess if intravenous (IV) injection of 50 to 3,200 aseptic, purified, cryopreserved PfSPZ is safe and achieves infection kinetics comparable to published data of mosquito-mediated CHMI. An independent study site verified the fully infectious dose using direct venous inoculation of PfSPZ. Parasite kinetics were assessed by thick blood smear microscopy and quantitative real time PCR. RESULTS: IV inoculation with 50, 200, 800, or 3,200 PfSPZ led to parasitaemia in 1/3, 1/3, 7/9, and 9/9 volunteers, respectively. The geometric mean pre-patent period (GMPPP) was 11.2 days (range 10.5-12.5) in the 3,200 PfSPZ IV group. Subsequently, six volunteers received 3,200 PfSPZ by direct venous inoculation at an independent investigational site. All six developed parasitaemia (GMPPP: 11.4 days, range: 10.4-12.3). Inoculation of PfSPZ was safe. Infection rate and pre-patent period depended on dose, and injection of 3,200 PfSPZ led to a GMPPP similar to CHMI with five PfSPZ-infected mosquitoes. The infectious dose of PfSPZ predicted dosage of radiation-attenuated PfSPZ required for successful vaccination. CONCLUSIONS: IV inoculation of PfSPZ is safe, well tolerated and highly reproducible. It shall further accelerate development of anti-malarial interventions through standardization and facilitation of CHMI. Beyond this, rational dose selection for whole PfSPZ-based immunization and complex study designs are now possible. TRIAL REGISTRATION: ClinicalTrials.gov NCT01624961 and NCT01771848

Reproductive and seminal characteristics of Pelibuey rams infected with Mycobacterium avium subsp. paratuberculosis in the subclinical stage

Objective: To evaluate the reproductive and seminal characteristics of Pelibuey rams infected with Mycobacterium avium subsp. paratuberculosis in the subclinical phase. Design/methodology/approach: In order to determine whether paratuberculosis (PTB) affects the reproductive variables and seminal quality in Pelibuey rams naturally infected with Mycobacterium avium subsp. paratuberculosis (MAP) in the subclinical phase, weekly evaluations were conducted, over a period of two months, of the variables live weight, scrotal circumference, ejaculation latency and seminal characteristics: volume, pH, masal motility and progressive individual motility, concentration, live spermatozoids and dead spermatozoids, in five rams infected by MAP and a further five uninfected rams, of average weight and age 53.58 kg (± 3.26) and 2.91 years (± 0.59), respectively. Results: PTB was not found to affect the reproductive and seminal variables evaluated. Limitations of the study/implications: It would have been convenient to carry out the evaluation of the seminal characteristics for a longer time, however, the sampling was stopped in order to ensure the animal welfare of the rams as far as possible, since they began to show signs of PTB. Findings/Conclusions: The Pelibuey rams diagnosed with PTB in subclinical phase did not present any effect on the reproductive and seminal characteristics. Meanwhile, reproductive management can be carried out with PTB-infected Pelibuey lambs in a subclinical phase.Objective: To evaluate the reproductive and seminal characteristics of Pelibuey rams infected with Mycobacterium avium subsp. paratuberculosis in the subclinical phase. Design/methodology/approach: In order to determine whether paratuberculosis (PTB) affects the reproductive variables and seminal quality in Pelibuey rams naturally infected with Mycobacterium avium subsp. paratuberculosis (MAP) in the subclinical phase, weekly evaluations were conducted, over a period of two months, of the variables live weight, scrotal circumference, ejaculation latency and seminal characteristics: volume, pH, masal motility and progressive individual motility, concentration, live spermatozoids and dead spermatozoids, in five rams infected by MAP and a further five uninfected rams, of average weight and age 53.58 kg (± 3.26) and 2.91 years (± 0.59), respectively. Results: PTB was not found to affect the reproductive and seminal variables evaluated. Limitations of the study/implications: It would have been convenient to carry out the evaluation of the seminal characteristics for a longer time, however, the sampling was stopped in order to ensure the animal welfare of the rams as far as possible, since they began to show signs of PTB. Findings/Conclusions: The Pelibuey rams diagnosed with PTB in subclinical phase did not present any effect on the reproductive and seminal characteristics. Meanwhile, reproductive management can be carried out with PTB-infected Pelibuey lambs in a subclinical phase

Enhanced wheat yield by biochar addition under different mineral fertilization levels

Climate change and global warming have worldwide adverse consequences. Biochar production and its use in agriculture can play a key role in climate change mitigation and help improve the quality and management of waste materials coming from agriculture and forestry. Biochar is a carbonaceous material obtained from thermal decomposition of residual biomass at relatively low temperature and under oxygen limited conditions (pyrolysis). Biochar is currently a subject of active research worldwide because it can constitute a viable option for sustainable agriculture due to its potential as a long-term sink for carbon in soil and benefits for crops. However, to date, the results of research studies on biochar effects on crop production show great variability, depending on the biochar type and experimental conditions. Therefore, it is important to identify the beneficial aspects of biochar addition to soil on crop yield in order to promote the adoption of this practice in agriculture. In this study, the effects of two types of biochar from agricultural wastes typical of Southern Spain: wheat straw and olive tree pruning, combined with different mineral fertilization levels on the growth and yield of wheat (Triticum durum L. cv. Vitron) were evaluated. Durum wheat was pot-grown for 2 months in a growth chamber on a soil collected from an agricultural field near Córdoba, Southern Spain. Soil properties and plant growth variables were studied in order to assess the agronomic efficiency of biochar. Our results show that biochar addition to a nutrientpoor, slightly acidic loamy sand soil had little effect on wheat yield in the absence of mineral fertilization. However, at the highest mineral fertilizer rate, addition of biochar led to about 20–30 % increase in grain yield compared with the use of the mineral fertilizer alone. Both biochars acted as a source of available P, which led to beneficial effects on crop production. In contrast, the addition of biochar resulted in decreases in available N and Mn. A maximum reduction in plant nutrient concentration of 25 and 80% compared to nonbiochar-treated soils for N and Mn, respectively, was detected. This fact was related to the own nature of biochar: low available nitrogen content, high adsorption capacity, and low mineralization rate for N; and alkaline pH and high carbonate content for Mn. Our results indicate that biochar-based soil management strategies can enhance wheat production with the environmental benefits of global warming mitigation. This can contribute positively to the viability and benefits of agricultural production systems. However, the nutrient–biochar interactions should receive special attention due to the great variability in the properties of biochar-type materials

Does social capital travel? Influences on the life satisfaction of young people living in England and Spain

<p>Abstract</p> <p>Background</p> <p>This study used a social capital framework to examine the relationship between a set of potential protective ('health assets') factors and the wellbeing of 15 year adolescents living in Spain and England. The overall purpose of the study was to compare the consistency of these relationships between countries and to investigate their respective relative importance.</p> <p>Methods</p> <p>Data were drawn from the 2002, English and Spanish components of the WHO Health Behaviour in School-Aged Children (HBSC) survey A total of 3,591 respondents (1884, Spain; 1707, England) aged 15, drawn from random samples of students in 215 and 80 schools respectively were included in the study. A series of univariate, bivariate and multivariate (general linear modelling and decision tree) analyses were used to establish the relationships.</p> <p>Results</p> <p>Results showed that the wellbeing of Spanish and English adolescents is similar and good. Three measures of social capital and 2 measures of social support were found to be important factors in the general linear model. Namely, family autonomy and control; family and school sense of belonging; and social support at home and school. However, there were differences in how the sub components of social capital manifest themselves in each country--feelings of autonomy of control, were more important in England and social support factors in Spain.</p> <p>Conclusions</p> <p>There is some evidence to suggest that social capital (and its related concept of social support) do travel and are applicable to young people living in Spain and England. Given the different constellation of assets found in each country, it is not possible to define exactly the precise formula for applying social capital across cultures. This should more appropriately be defined at the programme planning stage.</p