Prediction of cognitive outcome based on the progression of auditory discrimination during coma.

To date, no clinical test is able to predict cognitive and functional outcome of cardiac arrest survivors. Improvement of auditory discrimination in acute coma indicates survival with high specificity. Whether the degree of this improvement is indicative of recovery remains unknown. Here we investigated if progression of auditory discrimination can predict cognitive and functional outcome. We prospectively recorded electroencephalography responses to auditory stimuli of post-anoxic comatose patients on the first and second day after admission. For each recording, auditory discrimination was quantified and its evolution over the two recordings was used to classify survivors as "predicted" when it increased vs. "other" if not. Cognitive functions were tested on awakening and functional outcome was assessed at 3 months using the Cerebral Performance Categories (CPC) scale. Thirty-two patients were included, 14 "predicted survivors" and 18 "other survivors". "Predicted survivors" were more likely to recover basic cognitive functions shortly after awakening (ability to follow a standardized neuropsychological battery: 86% vs. 44%; p=0.03 (Fisher)) and to show a very good functional outcome at 3 months (CPC 1: 86% vs. 33%; p=0.004 (Fisher)). Moreover, progression of auditory discrimination during coma was strongly correlated with cognitive performance on awakening (phonemic verbal fluency: rs=0.48; p=0.009 (Spearman)). Progression of auditory discrimination during coma provides early indication of future recovery of cognitive functions. The degree of improvement is informative of the degree of functional impairment. If confirmed in a larger cohort, this test would be the first to predict detailed outcome at the single-patient level

Ulcerative Colitis Induces Changes on the Expression of the Endocannabinoid System in the Human Colonic Tissue

Altres ajuts: Proyectos de Excelencia, Consejeria de Innovacion de la Junta de Andalucia; Marato TV3 2005/060; Beca Iniciacion a la Recerca 2008. Societat Catalana Digestologia.Recent studies suggest potential roles of the endocannabinoid system in gastrointestinal inflammation. Although cannabinoid CB receptor expression is increased in inflammatory disorders, the presence and function of the remaining proteins of the endocannabinoid system in the colonic tissue is not well characterized. Cannabinoid CB and CB receptors, the enzymes for endocannabinoid biosynthesis DAGLα, DAGLβ and NAPE-PLD, and the endocannabinoid-degradating enzymes FAAH and MAGL were analysed in both acute untreated active ulcerative pancolitis and treated quiescent patients in comparison with healthy human colonic tissue by immunocytochemistry. Analyses were carried out according to clinical criteria, taking into account the severity at onset and treatment received. Western blot and immunocytochemistry indicated that the endocannabinoid system is present in the colonic tissue, but it shows a differential distribution in epithelium, lamina propria, smooth muscle and enteric plexi. Quantification of epithelial immunoreactivity showed an increase of CB receptor, DAGLα and MAGL expression, mainly in mild and moderate pancolitis patients. In contrast, NAPE-PLD expression decreased in moderate and severe pancolitis patients. During quiescent pancolitis, CB, CB and DAGLα expression dropped, while NAPE-PLD expression rose, mainly in patients treated with 5-ASA or 5-ASA+corticosteroids. The number of immune cells containing MAGL and FAAH in the lamina propria increased in acute pancolitis patients, but dropped after treatment. Endocannabinoids signaling pathway, through CB receptor, may reduce colitis-associated inflammation suggesting a potential drugable target for the treatment of inflammatory bowel diseases

Prediction of awakening from hypothermic post anoxic coma based on auditory discrimination.

OBJECTIVE: Most of the available clinical tests for prognosis of post-anoxic coma are informative of poor outcome. Previous work has shown that an improvement in auditory discrimination over the first days of coma is predictive of awakening. Here, we aimed at evaluating this test on a large cohort of patients undergoing therapeutic hypothermia and at investigating its added value on existing clinical measures. METHODS: We recorded electroencephalography responses to auditory stimuli in 94 comatose patients, under hypothermia and after re-warming to normal temperature. Auditory discrimination was semi-automatically quantified by decoding electroencephalography responses to frequently repeated vs. rare sounds. Outcome prediction was based on the change of decoding performance from hypothermia to normothermia. RESULTS: An increase in auditory discrimination from hypothermia to normothermia was observed for 33 out of 94 patients. Among them, 27 awoke from coma, resulting in a positive predictive value of awakening of 82% (95% confidence interval: 0.65-0.93). Most non-survivors showing an improvement in auditory discrimination had incident status epilepticus. By excluding them, 27 out of 29 patients with improvement in auditory discrimination survived, resulting in a considerable improvement of the predictive value for awakening (93%, with 95% confidence interval: 0.77-0.99). Importantly, this test predicted the awakening of 13 out of 51 patients for which the outcome was uncertain based on current tests. INTERPRETATION: The progression of auditory discrimination from hypothermia to normothermia has a high predictive value for awakening. This quantitative measure provides an added value to existing clinical tests and encourages the maintenance of life support. This article is protected by copyright. All rights reserved

Evidence of trace conditioning in comatose patients revealed by the reactivation of EEG responses to alerting sounds.

Trace conditioning refers to a learning process occurring after repeated presentation of a neutral conditioned stimulus (CS+) and a salient unconditioned stimulus (UCS) separated by a temporal gap. Recent studies have reported that trace conditioning can occur in humans in reduced levels of consciousness by showing a transfer of the unconditioned autonomic response to the CS+ in healthy sleeping individuals and in vegetative state patients. However, no previous studies have investigated the neural underpinning of trace conditioning in the absence of consciousness in humans. In the present study, we recorded the EEG activity of 29 post-anoxic comatose patients while presenting a trace conditioning paradigm using neutral tones as CS+ and alerting sounds as UCS. Most patients received therapeutic hypothermia and all were deeply unconscious according to standardized clinical scales. After repeated presentation of the CS+ and UCS couple, learning was assessed by measuring the EEG activity during the period where the UCS is omitted after CS+ presentation. Specifically we assessed the 'reactivation' of the neural response to UCS omission by applying a decoding algorithm derived from the statistical model of the EEG activity in response to the UCS presentation. The same procedure was used in a group of 12 awake healthy controls. We found a reactivation of the UCS response in absence of stimulation in eight patients (five under therapeutic hypothermia) and four healthy controls. Additionally, the reactivation effect was temporally specific within trials since it manifested primarily at the specific latency of UCS presentation and significantly less before or after this period. Our results show for the first time that trace conditioning may manifest as a reactivation of the EEG activity related to the UCS and even in the absence of consciousness

Genotoxic evaluation of sludge from Matanza-Riachuelo basin under the influence of different uses of land

El Río Matanza-Riachuelo y sus afluentes atraviesan zonas con diferente grado de contaminación generada por lasactividades agrícola-ganaderas, urbana e industrial. Los contaminantes que llegan al agua y son depositados en los sedimentospueden ser liberados nuevamente al agua generando efectos tóxicos y/o genotóxicos sobre los organismos acuáticos. El objetivode este trabajo fue analizar la genotoxicidad de muestras de sedimentos de la cuenca Matanza-Riachuelo obtenidas dezonas con diferentes usos del suelo. Se seleccionaron cuatro sitios de muestreo. Se utilizaron 2 métodos de extracción de contaminantes(agitación y sonicación), 2 solventes orgánicos (metanol y diclorometano) y 2 solventes inorgánicos (agua y soluciónácida), obteniéndose un total de 5 extractos para cada muestra. Se realizaron mediciones de metales pesados e hidrocarburosaromáticos policíclicos (HAPs) mediante espectrofotometría de absorción atómica y CG/MS, respectivamente. La genotoxicidadse evaluó mediante el test de Ames con 2 cepas de Salmonella typhimurium (TA98 y TA100), con y sin fracción microsomal S9,y el test de Allium cepa. De los cuatro sitios estudiados, los sedimentos del Riachuelo mostraron mayores concentraciones demetales pesados y HAPs. Para el test de Ames, sólo los extractos obtenidos en diclorometano resultaron genotóxicos para laTA100 +S9 mix. Tanto los extractos inorgánicos como los orgánicos fueron citotóxicos y genotóxicos para A. cepa. Se observóuna correlación negativa entre algunos compuestos HAPs y la frecuencia de micronúcleos, indicando la presencia de efectosantagónicos con otros compuestos genotóxicos. Los extractos con mayor efecto tóxico y genotóxico fueron los obtenidos condiclorometano y solución ácida. Este estudio mostró que los contaminantes orgánicos e inorgánicos extraídos de muestras desedimento de la Cuenca Matanza-Riachuelo, con diferente grado de impacto, presentan un potencial riesgo tóxico y genotóxicopara el ecosistema acuático.The Matanza-Riachuelo River and its tributaries traverse areas with different degrees of contamination due to farming, urban and industrial activities. The pollutants entering the water are deposited in sediments, and can be released back into the water producing toxic and/or genotoxic effects on aquatic organisms. The aim of this study was to analyze the genotoxicity of sediment samples from the Matanza-Riachuelo Basin with different land uses. Four sampling sites according to the characteristics of land use were selected. Two methods of extraction (stirring and sonication), two organic solvents (methanol and dichloromethane) and two inorganic solvents (water and acid solution) were used, yielding a total of 5 extracts for each sample. Measurements of heavy metals and polycyclic aromatic hydrocarbons (PAHs) by atomic absorption spectrophotometry and GC/MS, respectively were performed. Genotoxicity was assessed using the Ames test with 2 strains of Salmonella typhimurium (TA98 and TA100) with and without S9 microsomal fraction, and the Allium cepa test. Taking into account the four sites, sediments from Riachuelo showed higher concentrations of heavy metals and PAHs. Only the dichloromethane extracts were genotoxic to the Ames test using the TA100 strain +S9 the mix. Both organic and inorganic extracts were cytotoxic and genotoxic to A. cepa. A negative correlation between some PAHs compounds and micronucleus frequency were observed, indicating the presence of antagonistic effects with other genotoxic compounds in samples. The extracts with high toxic and genotoxic effects were obtained with dichloromethane and acid solution. This study showed that organic and inorganic contaminants extracted from sediment samples from the Matanza-Riachuelo Basin, with varying degrees of impact, have potential toxic and genotoxic risk to the aquatic ecosystem.Fil: Biruk, Lucia Nadia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Investigaciones de las Zonas Áridas. Provincia de Mendoza. Instituto Argentino de Investigaciones de las Zonas Áridas. Universidad Nacional de Cuyo. Instituto Argentino de Investigaciones de las Zonas Áridas; ArgentinaFil: Moretton, Juan Agustin. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Filippetto, Javier. Instituto Nacional de Tecnología Industrial; ArgentinaFil: Etcheverry, Jimena. Instituto Nacional de Tecnología Industrial; ArgentinaFil: Weigant, Cristian. Universidad de Buenos Aires. Facultad de Agronomía; ArgentinaFil: Fabrizio de Iorio, Alicia Rosa. Universidad de Buenos Aires. Facultad de Agronomía; ArgentinaFil: Magdaleno, Anahí. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Tuberculosis Epidemiology and Badger (Meles meles) Spatial Ecology in a Hot-Spot Area in Atlantic Spain

: We provide a temporal overview (from 2012 to 2018) of the outcomes of tuberculosis (TB) in the cattle and badger populations in a hot-spot in Asturias (Atlantic Spain). We also study the badger's spatial ecology from an epidemiological perspective in order to describe hazardous behavior in relation to TB transmission between cattle and badgers. Culture and single intradermal tuberculin test (SITT) were available for cattle as part of the National Program for the Eradication of TB. A field survey was also carried out in order to determine the paddocks and buildings used by each farm, and the information obtained was stored by using geographic information systems. Moreover, eighty-three badgers were submitted for necropsy and subsequent bacteriological studies. Ten badgers were also tracked, using global positioning system (GPS) collars. The prevalence of TB in cattle herds in the hot-spot increased from 2.2% in 2012 to 20% in 2016; it then declined to 0.0% in 2018. In contrast, the TB prevalence in badgers increased notably (from 5.55% in 2012-2015 to 10.64% in 2016-2018). Both cattle and badgers shared the same strain of Mycobacterium bovis. The collared badgers preferred paddocks used by TB-positive herds in spring and summer (when they were more active). The males occupied larger home ranges than the females (Khr95: males 149.78 ± 25.84 ha and females 73.37 ± 22.91 ha; Kcr50: males 29.83 ± 5.69 ha and females 13.59 ± 5.00 ha), and the home ranges were smaller in autumn and winter than in summer. The averages of the index of daily and maximum distances traveled by badgers were 1.88 ± (SD) 1.20 km and 1.99 ± 0.71 km, respectively. One of them presented a dispersive behavior with a maximum range of 18.3 km. The most preferred habitat was apple orchards in all seasons, with the exception of winter, in which they preferred pastures. Land uses and landscape structure, which have been linked with certain livestock-management practices, provide a scenario of great potential for badger-cattle interactions, thus enhancing the importance of the badgers' ecology, which could potentially transmit TB back to cattle in the future.This work was funded by the Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA) projects (FEDER co-funded): RTA2011-00010-00-00, RTA2014-00002-C02-01; by the Agencia Estatal de Investigación (AEI) reference project RTI2018-096010-B-C21 (FEDER co-funded); and by PCTI 2018–2020 (GRUPIN: IDI2018-000237) and FEDER. We received funds from RTI2018-096010-B-C21 (FEDER co-funded) to cover publication costs.S

Ulcerative Colitis Impairs the Acylethanolamide-Based Anti-Inflammatory System Reversal by 5-Aminosalicylic Acid and Glucocorticoids

Studies in animal models and humans suggest anti-inflammatory roles on the N-acylethanolamide (NAE)-peroxisome proliferators activated receptor alpha (PPARα) system in inflammatory bowel diseases. However, the presence and function of NAE-PPARα signaling system in the ulcerative colitis (UC) of humans remain unknown as well as its response to active anti-inflammatory therapies such as 5-aminosalicylic acid (5-ASA) and glucocorticoids. Expression of PPARα receptor and PPARα ligands-biosynthetic (NAPE-PLD) and -degrading (FAAH and NAAA) enzymes were analyzed in untreated active and 5-ASA/glucocorticoids/immunomodulators-treated quiescent UC patients compared to healthy human colonic tissue by RT-PCR and immunohistochemical analyses. PPARα, NAAA, NAPE-PLD and FAAH showed differential distributions in the colonic epithelium, lamina propria, smooth muscle and enteric plexus. Gene expression analysis indicated a decrease of PPARα, PPARγ and NAAA, and an increase of FAAH and iNOS in the active colitis mucosa. Immunohistochemical expression in active colitis epithelium confirmed a PPARα decrease, but showed a sharp NAAA increase and a NAPE-PLD decrease, which were partially restored to control levels after treatment. We also characterized the immune cells of the UC mucosa infiltrate. We detected a decreased number of NAAA-positive and an increased number of FAAH-positive immune cells in active UC, which were partially restored to control levels after treatment. NAE-PPARα signaling system is impaired during active UC and 5-ASA/glucocorticoids treatment restored its normal expression. Since 5-ASA actions may work through PPARα and glucocorticoids through NAE-producing/degrading enzymes, the use of PPARα agonists or FAAH/NAAA blockers that increases endogenous PPARα ligands may yield similar therapeutics advantages

Advanced immunotherapies for glioblastoma: tumor neoantigen vaccines in combination with immunomodulators

Correction to: Advanced immunotherapies for glioblastoma: tumor neoantigen vaccines in combination with immunomodulators. Acta Neuropathol Commun. 2023 Jul 12;11(1):116. doi: 10.1186/s40478-023-01600-2. PMID: 37438824.Glial-origin brain tumors, including glioblastomas (GBM), have one of the worst prognoses due to their rapid and fatal progression. From an oncological point of view, advances in complete surgical resection fail to eliminate the entire tumor and the remaining cells allow a rapid recurrence, which does not respond to traditional therapeutic treatments. Here, we have reviewed new immunotherapy strategies in association with the knowledge of the immune micro-environment. To understand the best lines for the future, we address the advances in the design of neoantigen vaccines and possible new immune modulators. Recently, the efficacy and availability of vaccine development with different formulations, especially liposome plus mRNA vaccines, has been observed. We believe that the application of new strategies used with mRNA vaccines in combination with personalized medicine (guided by different omic's strategies) could give good results in glioma therapy. In addition, a large part of the possible advances in new immunotherapy strategies focused on GBM may be key improving current therapies of immune checkpoint inhibitors (ICI), given the fact that this type of tumor has been highly refractory to ICI.This study has been funded by Instituto de Salud Carlos III (ISCIII) through the project “CP21/00116 and PI22/0117” and co-funded by the European Union to RG, by “Asociación Española contra el Cancer (AECC) grant: INVES192GARG to RG and by Ministerio de Ciencia e Innovación and FEDER funds: PI21/01406 to JMSS.S