Immunomodulation of Oxidative Stress during Organ Donation Process: Preliminary Results

The objective was to quantify oxidative stress resulting from ischemia during the donation process, using malondialdehyde (MDA) measurement, and its modulation by the administration of melatonin. We designed a triple-blind clinical trial with donors randomized to melatonin or placebo. We collected donors by donation after brain death (DBD) and controlled donation after circulatory death (DCD), the latter maintained by normothermic regional perfusion (NRP). Melatonin or placebo was administered prior to donation or following limitation of therapeutic effort (LTE). Demographic variables and medical history were collected. We also collected serial measurements of MDA, at 60 and 90 min after melatonin or placebo administration. A total of 53 donors were included (32 from DBD and 21 from DCD). In the DBD group, 17 donors received melatonin, and 15 placebo. Eight DCD donors were randomized to melatonin and 13 to placebo. Medical history and cause for LTE were similar between groups. Although MDA values did not differ in the DBD group, statistical differences were observed in DCD donors during the 0–60 min interval: −4.296 (−6.752; −2.336) in the melatonin group and −1.612 (−2.886; −0.7445) in controls. Given the antioxidant effect of melatonin, its use could reduce the production of oxidative stress in controlled DCD

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Microbiota and organophosphates

Organophosphates (OPs) are important toxic compounds commonly used for a variety of purposes in agriculture, industry and household settings. Consumption of these compounds affects several central nervous system functions. Some of the most recognised consequences of organophosphate pesticide exposure in humans include neonatal developmental abnormalities, endocrine disruption, neurodegeneration, neuroinflammation and cancer. In addition, neurobehavioral and emotional deficits following OP exposure have been reported. It would be of great value to discover a therapeutic strategy which produces a protective effect against these neurotoxic compounds. Moreover, a growing body of preclinical data suggests that the microbiota may affect metabolism and neurotoxic outcomes through exposure to OPs. The human gut is colonised by a broad variety of microorganisms. This huge number of bacteria and other microorganisms which survive by colonising the gastrointestinal tract is defined as “gut microbiota”. The gut microbiome plays a profound role in metabolic processing, energy production, immune and cognitive development and homeostasis. The effects are not only localized in the gut, but also influence many other organs, such as the brain through the microbiome-gut-brain axis. Therefore, given the gut microbiota’s key role in host homeostasis, this microbiota may be altered or modified temporarily by factors such as antibiotics, diet and toxins such as pesticides. The aim of this review is to examine scientific articles concerning the impact of microbiota in OP toxicity. Studies focussed on the possible contribution the microbiota has on variable host pharmacokinetic responses such as absorption and biotransformation of xenobiotics will be evaluated. Microbiome manipulation by antibiotic or probiotic administration and faecal transplantation are experimental approaches recently proposed as treatments for several diseases. Finally, microbiota manipulation as a possible therapeutic strategy in order to reduce OP toxicity will be discussed.Peer reviewe

Analysis of Gut Characteristics and Microbiota Changes with Maternal Supplementation in a Neural Tube Defect Mouse Model

Adequate nutrient supply is crucial for the proper development of the embryo. Although nutrient supply is determined by maternal diet, the gut microbiota also influences nutrient availability. While currently there is no cure for neural tube defects (NTDs), their prevention is largely amenable to maternal folic acid and inositol supplementation. The gut microbiota also contributes to the production of these nutrients, which are absorbed by the host, but its role in this context remains largely unexplored. In this study, we performed a functional and morphological analysis of the intestinal tract of loop-tail mice (Vangl2 mutants), a mouse model of folate/inositol-resistant NTDs. In addition, we investigated the changes in gut microbiota using 16S rRNA gene sequencing regarding (1) the host genotype; (2) the sample source for metagenomics analysis; (3) the pregnancy status in the gestational window of neural tube closure; (4) folic acid and (5) D-chiro-inositol supplementation. We observed that Vangl2+/Lp mice showed no apparent changes in gastrointestinal transit time or fecal output, yet exhibited increased intestinal length and cecal weight and gut dysbiosis. Moreover, our results showed that the mice supplemented with folic acid and D-chiro-inositol had significant changes in their microbiota composition, which are changes that could have implications for nutrient absorption

Immunomodulation of Oxidative Stress during Organ Donation Process: Preliminary Results

The objective was to quantify oxidative stress resulting from ischemia during the donation process, using malondialdehyde (MDA) measurement, and its modulation by the administration of melatonin. We designed a triple-blind clinical trial with donors randomized to melatonin or placebo. We collected donors by donation after brain death (DBD) and controlled donation after circulatory death (DCD), the latter maintained by normothermic regional perfusion (NRP). Melatonin or placebo was administered prior to donation or following limitation of therapeutic effort (LTE). Demographic variables and medical history were collected. We also collected serial measurements of MDA, at 60 and 90 min after melatonin or placebo administration. A total of 53 donors were included (32 from DBD and 21 from DCD). In the DBD group, 17 donors received melatonin, and 15 placebo. Eight DCD donors were randomized to melatonin and 13 to placebo. Medical history and cause for LTE were similar between groups. Although MDA values did not differ in the DBD group, statistical differences were observed in DCD donors during the 0&ndash;60 min interval: &minus;4.296 (&minus;6.752; &minus;2.336) in the melatonin group and &minus;1.612 (&minus;2.886; &minus;0.7445) in controls. Given the antioxidant effect of melatonin, its use could reduce the production of oxidative stress in controlled DCD

Formation of intra-arc volcanosedimentary basins in the western flank of the central Peruvian Andes during Late Cretaceous oblique subduction: field evidence and constraints from U–Pb ages and Hf isotopes

During late Early to Late Cretaceous, the Peruvian coastal margin underwent fast and oblique subduction and was characterized by important arc plutonism (the Peruvian Coastal Batholith) and formation of volcanosedimentary basins known as the Western Peruvian Trough (WPT). We present high-precision U–Pb ages and initial Hf isotopic compositions of zircon from conformable volcanic and crosscutting intrusive rocks within submarine volcanosedimentary strata of the WPT hosting the Perubar massive sulfide deposit. Zircons extracted from both the volcanic and intrusive rocks yield concordant U–Pb ages ranging from 67.89±0.18 Ma to 69.71±0.18 Ma, indicating that basin subsidence, submarine volcanism and plutonic activity occurred in close spatial and temporal relationship within the Andean magmatic arc during the Late Cretaceous. Field observations, satellite image interpretation, and plate reconstructions, suggest that dextral wrenching movements along crustal lineaments were related to oblique subduction. Wrench tectonics is therefore considered to be the trigger for the formation of the WPT as a series of pull-apart basins and for the emplacement of the Coastal Batholith. The zircon initial εHf values of the dated magmatic rocks fall between 5.5 and 7.4, and indicate only very subordinate influence of a sedimentary or continental component. The absence of inherited cores in the zircons suggest a complete lack of old basement below the WPT, in agreement with previous U–Pb and Sr isotopic data for batholithic rocks emplaced in the WPT area. This is supported by the presence of a most likely continuous block of dense (~3.0 g/cm3) material observed beneath the WPT area on gravimetric crustal cross sections. We suggest that this gravimetric anomaly may correspond to a piece of lithospheric mantle and/or oceanic crust inherited from a possible Late Permian–Triassic rifting. Such young and mafic crust was the most probable source for arc magmatism in the WPT area

New Algorithms Improving PML Risk Stratification in MS Patients Treated With Natalizumab

none60siOverview: We assessed the role of age and disease activity as new factors contributing to establish the risk of progressive multifocal leucoencephalopathy in multiple sclerosis patients treated with natalizumab in 36 University Hospitals in Europe. We performed the study in 1,307 multiple sclerosis patients (70.8% anti-John Cunninghan virus positive antibodies) treated with natalizumab for a median time of 3.28 years. Epidemiological, clinical, and laboratory variables were collected. Lipid-specific IgM oligoclonal band status was available in 277 patients. Factors associated with progressive multifocal leucoencephalopathy onset were explored by uni- and multivariate logistic regression. Results: Thirty-five patients developed progressive multifocal leucoencephalopathy. The multivariate analysis identified anti-John Cunninghan virus antibody indices and relapse rate as the best predictors for the onset of this serious opportunistic infection in the whole cohort. They allowed to stratify progressive multifocal leucoencephalopathy risk before natalizumab initiation in individual patients [area under the curve (AUC) = 0.85]. The risk ranged from &lt;1/3,300 in patients with anti-John Cunninghan virus antibody indices &lt;0.9 and relapse rate &gt;0.5, to 1/50 in the opposite case. In patients with lipid-specific IgM oligoclonal bands assessment, age at natalizumab onset, anti-John Cunninghan virus antibody indices, and lipid-specific IgM oligoclonal band status predicted progressive multifocal leucoencephalopathy risk (AUC = 0.92). The absence of lipid-specific IgM oligoclonal bands was the best individual predictor (OR = 40.94). The individual risk ranged from &lt;1/10,000 in patients younger than 45 years at natalizumab initiation, who showed anti John Cunningham virus antibody indices &lt;0.9 and lipid-specific IgM oligoclonal bands to 1/33 in the opposite case. Conclusions: In a perspective of personalized medicine, disease activity, anti-lipid specific IgM oligoclonal bands, anti Jonh Cunninghan virus antibody levels, and age can help tailor natalizumab therapy in multiple sclerosis patients, as predictors of progressive multifocal leucoencephalopathy.mixedToboso, Inmaculada; Tejeda-Velarde, Amalia; Alvarez-Lafuente, Roberto; Arroyo, Rafael; Hegen, Harald; Deisenhammer, Florian; Sainz de la Maza, Susana; Alvarez-Cermeño, José C; Izquierdo, Guillermo; Paramo, Dolores; Oliva, Pedro; Casanova, Bonaventura; Agüera-Morales, Eduardo; Franciotta, Diego; Gastaldi, Matteo; Fernández, Oscar; Urbaneja, Patricia; Garcia-Dominguez, José M; Romero, Fernando; Laroni, Alice; Uccelli, Antonio; Perez-Sempere, Angel; Saiz, Albert; Blanco, Yolanda; Galimberti, Daniela; Scarpini, Elio; Espejo, Carmen; Montalban, Xavier; Rasche, Ludwig; Paul, Friedemann; González, Inés; Álvarez, Elena; Ramo, Cristina; Caminero, Ana B; Aladro, Yolanda; Calles, Carmen; Eguía, Pablo; Belenguer-Benavides, Antonio; Ramió-Torrentà, Lluis; Quintana, Ester; Martínez-Rodríguez, José E; Oterino, Agustín; López de Silanes, Carlos; Casanova, Luis I; Landete, Lamberto; Frederiksen, Jette; Bsteh, Gabriel; Mulero, Patricia; Comabella, Manuel; Hernández, Miguel A; Espiño, Mercedes; Prieto, José M; Pérez, Domingo; Otano, María; Padilla, Francisco; García-Merino, Juan A; Navarro, Laura; Muriel, Alfonso; Frossard, Lucienne Costa; Villar, Luisa MToboso, Inmaculada; Tejeda-Velarde, Amalia; Alvarez-Lafuente, Roberto; Arroyo, Rafael; Hegen, Harald; Deisenhammer, Florian; Sainz de la Maza, Susana; Alvarez-Cermeño, José C; Izquierdo, Guillermo; Paramo, Dolores; Oliva, Pedro; Casanova, Bonaventura; Agüera-Morales, Eduardo; Franciotta, Diego; Gastaldi, Matteo; Fernández, Oscar; Urbaneja, Patricia; Garcia-Dominguez, José M; Romero, Fernando; Laroni, Alice; Uccelli, Antonio; Perez-Sempere, Angel; Saiz, Albert; Blanco, Yolanda; Galimberti, Daniela; Scarpini, Elio; Espejo, Carmen; Montalban, Xavier; Rasche, Ludwig; Paul, Friedemann; González, Inés; Álvarez, Elena; Ramo, Cristina; Caminero, Ana B; Aladro, Yolanda; Calles, Carmen; Eguía, Pablo; Belenguer-Benavides, Antonio; Ramió-Torrentà, Lluis; Quintana, Ester; Martínez-Rodríguez, José E; Oterino, Agustín; López de Silanes, Carlos; Casanova, Luis I; Landete, Lamberto; Frederiksen, Jette; Bsteh, Gabriel; Mulero, Patricia; Comabella, Manuel; Hernández, Miguel A; Espiño, Mercedes; Prieto, José M; Pérez, Domingo; Otano, María; Padilla, Francisco; García-Merino, Juan A; Navarro, Laura; Muriel, Alfonso; Frossard, Lucienne Costa; Villar, Luisa

New Algorithms Improving PML Risk Stratification in MS Patients Treated With Natalizumab

Overview: We assessed the role of age and disease activity as new factors contributing to establish the risk of progressive multifocal leucoencephalopathy in multiple sclerosis patients treated with natalizumab in 36 University Hospitals in Europe. We performed the study in 1,307 multiple sclerosis patients (70.8% anti-John Cunninghan virus positive antibodies) treated with natalizumab for a median time of 3.28 years. Epidemiological, clinical, and laboratory variables were collected. Lipid-specific IgM oligoclonal band status was available in 277 patients. Factors associated with progressive multifocal leucoencephalopathy onset were explored by uni- and multivariate logistic regression. Results: Thirty-five patients developed progressive multifocal leucoencephalopathy. The multivariate analysis identified anti-John Cunninghan virus antibody indices and relapse rate as the best predictors for the onset of this serious opportunistic infection in the whole cohort. They allowed to stratify progressive multifocal leucoencephalopathy risk before natalizumab initiation in individual patients [area under the curve (AUC) = 0.85]. The risk ranged from 0.5, to 1/50 in the opposite case. In patients with lipid-specific IgM oligoclonal bands assessment, age at natalizumab onset, anti-John Cunninghan virus antibody indices, and lipid-specific IgM oligoclonal band status predicted progressive multifocal leucoencephalopathy risk (AUC = 0.92). The absence of lipid-specific IgM oligoclonal bands was the best individual predictor (OR = 40.94). The individual risk ranged from <1/10,000 in patients younger than 45 years at natalizumab initiation, who showed anti John Cunningham virus antibody indices <0.9 and lipid-specific IgM oligoclonal bands to 1/33 in the opposite case. Conclusions: In a perspective of personalized medicine, disease activity, anti-lipid specific IgM oligoclonal bands, anti Jonh Cunninghan virus antibody levels, and age can help tailor natalizumab therapy in multiple sclerosis patients, as predictors of progressive multifocal leucoencephalopath