Pragmatic, open-label, single-center, randomized, phase II clinical trial to evaluate the efficacy and safety of methylprednisolone pulses and tacrolimus in patients with severe pneumonia secondary to COVID-19: The TACROVID trial protocol.

INTRODUCTION: Some COVID-19 patients evolve to severe lung injury and systemic hyperinflammatory syndrome triggered by both the coronavirus infection and the subsequent host-immune response. Accordingly, the use of immunomodulatory agents has been suggested but still remains controversial. Our working hypothesis is that methylprednisolone pulses and tacrolimus may be an effective and safety drug combination for treating severe COVID-19 patients. METHODS: and analysis: TACROVID is a randomized, open-label, single-center, phase II trial to evaluate the efficacy and safety of methylprednisolone pulses and tacrolimus plus standard of care (SoC) versus SoC alone, in patients at advanced stage of COVID-19 disease with lung injury and systemic hyperinflammatory response. Patients are randomly assigned (1:1) to one of two arms (42 patients in each group). The primary aim is to assess the time to clinical stability after initiating randomization. Clinical stability is defined as body temperature ≤37.5 °C, and PaO2/FiO2 > 400 and/or SatO2/FiO2 > 300, and respiratory rate ≤24 rpm; for 48 consecutive hours. DISCUSSION: Methylprednisolone and tacrolimus might be beneficial to treat those COVID-19 patients progressing into severe pulmonary failure and systemic hyperinflammatory syndrome. The rationale for its use is the fast effect of methylprednisolone pulses and the ability of tacrolimus to inhibit both the CoV-2 replication and the secondary cytokine storm. Interestingly, both drugs are low-cost and can be manufactured on a large scale; thus, if effective and safe, a large number of patients could be treated in developed and developing countries. TRIAL REGISTRATION NUMBER: NCT04341038 / EudraCT: 2020-001445-39.

Geographic patterns of stress in insular lizards reveal anthropogenic and climatic signatures.

Anthropization of insular ecosystems may have negative impacts on native populations of lizards, which provide core ecosystem services on islands. We aimed to identify environmental factors to explain the interlocal variation in faecal glucocorticoids, parasite intensity, and body condition in populations of insular lizards. A cross-sectional design during the summer of 2017 and 2018 was used to sample 611 adult lizards, Gallotia galloti. Interlocal variation of three stress indicators was analysed in response to environmental variables across a wide environmental gradient in Tenerife (Canary Islands): (i) concentration of faecal glucocorticoids, (ii) intensities of infection by hematic parasites, and (iii) body condition. The data, with low spatial autocorrelation, were analysed using multimodel inference and model cross-validation. Bioclimatic variables associated with the extreme hot and dry climate of summer were the most informative predictors. Interlocal variation in faecal corticosterone in males was best fitted to a model that included the maximum temperature of the warmest month, although the best predictor was habitat anthropization. The thermal annual range, associated with extreme thermal events, was positively related to faecal corticosterone in females. Extreme hot temperatures were positively related to the median parasite intensities in both sexes, while the highest mean intensities of infection were found in females from the most xeric coastal localities. None of the predictors tested, including faecal glucocorticoids, explained individual or interlocal variation in body condition. Effects of human pressure and climate change on insular populations of lizards can be additive. However, the uncoupled relationship found between body condition and the faecal glucocorticoid content suggests that current negative effects may be aggravated during drought periods in summer. Given the impact of climate change on islands, our results may be of application to other archipelagos, where lizards also play key ecological roles.

Plant growth-promoting traits of yeasts isolated from Spanish vineyards: benefits for seedling development.

It is known that some microorganisms can enhance plant development. However, the use of yeasts as growth-promoting agents has been poorly investigated. The aim of this study was the characterisation of a collection of 69 yeast strains isolated from Spanish vineyards. Phytobeneficial attributes such as solubilisation of nutrients, synthesis of active biomolecules and cell wall-degrading enzyme production were analysed. Strains that revealed multiple growth-promoting characteristics were identified. The in vitro co-culture of Nicotiana benthamiana with yeast isolates showed enhancement of plant growth in 10 strains (up to 5-fold higher shoot dry weight in the case of Hyphopichia pseudoburtonii Hp-54), indicating a beneficial direct yeast-plant interaction. In addition, 18 out of the 69 strains increased dry weight and the number of roots per seedling when tobacco seeds were inoculated. Two of these, Pichia dianae Pd-2 and Meyerozyma guilliermondii Mg-11, also increased the chlorophyll content. The results in tobacco were mostly reproduced in lettuce with these two strains, which demonstrates that the effect of the yeast-plant interaction is not species-specific. In addition, the yeast collection was evaluated in maize seedlings grown in soil in a phytotron. Three isolates (Debaryomyces hansenii Dh-67, Lachancea thermotolerans Lt-69 and Saccharomyces cerevisiae Sc-6) promoted seedling development (increases of 10 % in dry weight and chlorophyll content). In conclusion, our data confirm that several yeast strains can promote plant growth and could be considered for the development of biological fertiliser treatments.

Striatal Protection in nNOS Knock-Out Mice After Quinolinic Acid-Induced Oxidative Damage.

Under pathological conditions, nitric oxide can become a mediator of oxidative cellular damage, generating an unbalance between oxidant and antioxidant systems. The participation of neuronal nitric oxide synthase (nNOS) in the neurodegeneration mechanism has been reported; the activation of N-methyl-D-aspartate (NMDA) receptors by agonist quinolinic acid (QUIN) triggers an increase in nNOS function and promotes oxidative stress. The aim of the present work was to elucidate the participation of nNOS in QUIN-induced oxidative stress in knock-out mice (nNOS-/-). To do so, we microinjected saline solution or QUIN in the striatum of wild-type (nNOS +/+), heterozygote (nNOS+/-), and knock-out (nNOS-/-) mice, and measured circling behavior, GABA content levels, oxidative stress, and NOS expression and activity. We found that the absence of nNOS provides a protection against striatal oxidative damage induced by QUIN, resulting in decreased circling behavior, oxidative stress, and a partial protection reflected in GABA depletion. We have shown that nNOS-derived NO is involved in neurological damage induced by oxidative stress in a QUIN-excitotoxic model.

The Coyoacán Cohort Study: Design, Methodology, and Participants' Characteristics of a Mexican Study on Nutritional and Psychosocial Markers of Frailty.

BACKGROUND: "Frailty" has emerged as a condition associated with an increased risk of functional decline among the elderly, which may be differentiated from aging, disability, and co-morbidities. OBJECTIVE: The Mexican Study of Nutritional and Psychosocial Markers of Frailty among Community-Dwelling Elderly has emerged to help answer many questions about frailty among the older adults. This report presents the design of the study and baseline data of its participants. DESIGN: The "Coyoacan cohort" is a longitudinal observational study developed in Mexico City. PARTICIPANTS: A representative sample of 1,294 non-institutionalized men and women aged 70 years and older were randomly recruited to undergo a face-to-face interview and a comprehensive geriatric assessment (including clinical evaluations and blood samples) between 2008 and 2009. MEASUREMENTS: Data collected included socio-demographic and economic characteristics, medical history, oral health, drug use, cognitive function and mood, nutritional status, physical performance and functional status, physical activity, quality of life, social networks, and biological data. Frailty was defined as the presence of ≥3 of the following components: slowness, poor muscle strength, low physical activity, exhaustion and unintentional weight loss. RESULTS: A total of 1,124 participants completed the interview. The mean age was 79.5 ± 7.1 years, and 55.9% were female. Nine hundred and forty-five subjects completed the clinical evaluation and 743 blood samples were collected. The baseline prevalence of frailty was 14.1%. CONCLUSIONS: Understanding the medical, biological, and environmental factors that contribute to the phenomenon of frailty is the goal of the current research in the field.

Self-reported reading and writing skills in elderly who never attended school influence cognitive performances: results from the Coyoacán cohort study.

OBJECTIVES: Beyond the well-known effect of educational level on cognitive performances, the present study investigates the specific effect of literacy acquisition independently of education. DESIGN: A sample of 175 unschooled elderly participants was selected from a larger Mexican population-based cohort study. PARTICIPANTS: The sample of 175 subjects who never went to school was divided in two groups: 109 who never acquired literacy skills and 66 who declared having acquired reading and writing abilities. MEASUREMENTS: Cognitive performances on commonly used tests (mini mental state examination, Isaacs set test, free and cued selective reminding test and clock-drawing test) were compared between the two groups taking into account several potentially confounding factors. RESULTS: The participants with reading and writing skills performed better than their counterparts in most tests, even though no difference was observed for the Isaacs Set Test and the delayed recall of the free and cued selective reminding test. CONCLUSION: Writing and reading skills in elderly people with no formal education influence performances in very commonly used test. Not only educational level but also literacy acquisition should be taken into account when conducting cognitive assessment in very low educated elderly people.

Overweight and obesity as markers for the evaluation of disease risk in older adults.

OBJECTIVES: To explore disease risk through the measurement of BMI scores and waist circumferences in older Mexican adults with favorable health statuses and to determine how this risk is associated with sociodemographic characteristics. METHODS: Using data from the National Health and Nutrition Survey of 2006, we created a cross-sectional design and selected 878 participants (60 years or older) who had favorable health statuses. The demographic data, health status, body mass index (BMI), waist circumference (WC), and an estimation of disease risk (arterial hypertension, diabetes type 2, and metabolic syndrome) were obtained through the survey. RESULTS: The prevalence of overweight, obesity, and abdominal obesity were 42.1%, 29.7%, and 80.9%, respectively. Disease risks, which were classified as least, increased, high, or very high, were 14.7%, 17.5%, 38.7%, and 29.1%, respectively. We observed that younger age has a higher risk for disease and that this decreases as age increases until it becomes minimal. After controlling for some risk factors such as tobacco, alcohol, and physical activity, we observed that being female, younger, and married are all factors significantly associated with a high and very high risk for disease. On the other hand, being indigenous, having a low education level, living in a rural setting are all protective factors with a minimum disease risk. CONCLUSIONS: The prevalence rates of overweight, obesity, and abdominal obesity are high among older Mexican adults. We observed that as age increases, disease risk decreases, which also occurs with some lifestyle factors such as living in a rural setting, being indigenous, having a low education level, and being married.

Cognitive impairment and low physical activity are the components of frailty more strongly associated with disability.

OBJECTIVE: To determine the association of the five frailty criteria from the Cardiovascular Health Study, as well as cognitive impairment, with prevalent disability for the instrumental (IADL) and basic activities of daily living (ADL). DESIGN: Cross-sectional study of 475 community-dwelling subjects aged 70 and older, participating in the Mexican Study of Nutritional and Psychosocial Markers of Frailty. MEASUREMENTS: Six probable frailty criteria were considered: weight loss, poor endurance, low physical activity, slowness, weakness, and cognitive impairment. The association of each component of frailty for IADL and ADL disability as main outcomes was determined constructing multivariate logistic regression analyses. Final models were adjusted by socio-demographic factors and the presence of the other five frailty components as covariates. RESULTS: Mean age of participants was 78.1 (SD=6.2). The unadjusted results showed that each of the components of frailty, except weight loss, was associated with both IADL and ADL disability. However, after adjustment, only low physical activity [Odds ratio (OR) =3.27; 95% CI=1.56 to 6.85] and cognitive impairment (OR=2.06; 95% CI=1.04 to 4.06) remain independently associated with IADL disability. Regarding ADL disability, only a lower physical activity (OR=7.72; 95% CI=1.28 to 46.46) was associated with this outcome, whereas cognitive impairment was marginally associated but was not statistically significant (OR=5.45; 95% CI=0.91 to 32.57). CONCLUSIONS: Cognitive impairment and low physical activity are the main contributing factors of frailty phenotype to disability. Better understanding the independent contribution of each frailty subdimension to the different adverse-health outcomes may help to provide a more adequate management of frail elderly.

Valproic acid induces polarization, neuronal-like differentiation of a subpopulation of C6 glioma cells and selectively regulates transgene expression.

Glioblastoma is the most frequent primary brain tumor, and for which standard therapies have not significantly increased the survival of patients. Recently, chromatin alterations have been linked to the pathogenesis of cancer, and drugs that modify chromatin structure, such as inhibitors of histone deacetylases (iHDAC), are now considered as a valuable strategy for the treatment of cancer. For instance, valproic acid (VPA), an iHDAC originally used for the treatment of bipolar disorders and epilepsy, is now being used in cancer therapy. In this work we show that VPA induces morphological changes in murine astrocytoma C6 cells, which are associated with inhibition of cell proliferation, growth arrest, decreased cell migration, cell death and histone 4 hyperacetylation. VPA-treated cells extended processes with characteristics similar to the structure of a growth cone, and we also observed both a down-regulation of glial protein markers and increased expression of a neuronal specific protein after VPA treatment. Finally, there is an increase in the expression of a reporter transgene driven by a neuronal-specific promoter and a decrease of gene expression using a glial specific promoter in VPA-treated cells. These results indicate that VPA induces a specific differentiation of C6 cells toward a neuronal-like phenotype. The present data highlight the importance of epigenetic phenomena in the development and differentiation of the nervous system.

Targeted-simultaneous expression of Gas1 and p53 using a bicistronic adenoviral vector in gliomas.

The targeted expression of transgenes is one of the principal goals of gene therapy, and it is particularly relevant for the treatment of brain tumors. In this study, we examined the effect of the overexpression of human gas1 (growth arrest specific 1) and human p53 cDNAs, both under the transcriptional control of a promoter of the human glial fibrillary acidic protein (gfa2), employing adenoviral expression vectors, in glioma cells. We showed that the targeted overexpression of gas1 and p53 (AdSGas1 and AdSp53, respectively) in rat glioma cells (C6) reduced the number of viable cells and induced apoptosis. Moreover, the adenovirally targeted expression of these genes also reduced tumor growth in vivo. Unexpectedly, there was no additive effect when both gas1 and p53 were simultaneously expressed in the same cells using a bicistronic adenoviral vector. We suggest that Gas1 does not act in combination with p53 in the C6 and U373 glioma cell lines, inducing apoptosis and cell cycle arrest. Our results indicate that the targeted expression of tumor suppressor genes (gas1 and p53) regulated by the gfa2 promoter, together with adenoviral vectors may provide an interesting approach for adjuvant selective glioma gene therapy.

Inbreeding and reproduction in endangered ungulates: preservation of genetic variation through the Organization of Genetic Resource Banks.

There is a constant increase in the number of species suffering marked reductions in population size. This reduction in size and the lack of genetic flow may lead to a decrease in genetic variability and to matings between close relatives (i.e. inbreeding) with an ensuing reduction in fitness. It is thus important to understand the mechanism underlying the deleterious effects of inbreeding and to develop reproductive biotechnologies that will allow the reduction of inbreeding depression by facilitating gene exchange between populations. The study of three endangered species of gazelles, Cuvier's gazelle (Gazella cuvieri), Mohor gazelle (Gazella dama mhorr) and dorcas gazelle (Gazella dorcas neglecta) has revealed that inbreeding negatively affects several semen parameters (motility, sperm morphology, acrosome integrity). Semen cryopreservation has been achieved in the three species but success varies depending on the diluent employed and the level of inbreeding. Artificial insemination of Mohor gazelles have led to the birth of the first gazelle born using frozen-thawed semen but improvements are needed before this technology can be applied on a routine basis for the genetic management of the populations. Collection of oocytes after ovarian stimulation, followed by in vitro maturation, fertilization and culture has met with some initial success in the Mohor gazelle. These, together with other reproductive technologies, will offer an invaluable help in preserving the maximum of genetic diversity of these and related endangered ungulate species.

[Incidence of influenza and influenza vaccine effectiveness in the 2004-2005 season]. / Incidencia de la gripe y efectividad de la vacuna antigripal en la temporada 2004-2005.

BACKGROUND: To quantify the incidence of flu in different groups of the population of Navarra in the 2004-2005 season, and to evaluate the effectiveness of anti-flu vaccination. METHODS: The analysis of influenza cases in the system of compulsory notificable diseases was complemented by the individualised notifications in the network of sentinel doctors that covers a population of 22,339 inhabitants. The coverage and effectiveness of the vaccine was studied. RESULTS: Vaccine coverage in (3)65 year olds reached 62%. The incidence of influenza was 42.6 cases per 1,000 inhabitants. It reached a maximum in mid-January, exceeding 750 weekly cases per 100,000 inhabitants and 1,900 cases per 100,000 children. The highest rate of influenza was observed in under-15 year olds (49.4 cases per 1,000 inhabitants) and the lowest in non-institutionalised (3)65 year olds (2.6 per 1,000 inhabitants), although it was higher in geriatric residences (62.1 per 1,000; p<0.0001). Seventy-nine percent of the cases from 5 to 64 years resulted in absenteeism from school or work. The flu virus was identified in 42/65 (65%) nasopharyngeal smears, 90% being influenza virus A(H3). The incidence of influenza was 3.08% in the unvaccinated and 0.45% in the vaccinated (p<0.001). The global effectiveness of the anti-flu vaccine was 65%, and in (3)65 years old it was 73%. CONCLUSION: Although its effectiveness is not total, the vaccine is the main measure for preventing influenza. The network of sentinel doctors provide useful information for the coordination of care and public health activities against flu.

Incidencia de la gripe y efectividad de la vacuna antigripal en la temporada 2004-2005 / Incidence of influenza and influenza vaccine effectiveness in the 2004-2005 season

Fundamento. Cuantificar la incidencia de gripe en distintos grupos de la población de Navarra en la temporada 2004-2005 y evaluar la efectividad de la vacunación antigripal.Métodos. El análisis de los casos de gripe del sistema de enfermedades de declaración obligatoria se ha complementado con las notificaciones individualizadas de la red de médicos centinela que atiende a una población de 22.339 habitantes. Se estudió la cobertura y efectividad de la vacuna. Resultados. La cobertura vacunal en Ž65 años alcanzó el 62%. La incidencia de gripe fue de 42,6 casos por 1.000 habitantes. Alcanzó el máximo a mediados de enero, superando 750 casos semanales por 100.000 habitantes y 1.900 casos por 100.000 niños. La mayor tasa de gripe se observó en menores de 15 años (49,4 casos por 1.000 habitantes) y la menor en Ž65 años no institucionalizados (2,6 por 1.000 habitantes), aunque fue mayor en residencias geriátricas (62,1 por 1.000; p<0,0001). El 79% de los casos de 5 a 64 años causó absentismo escolar o laboral. Se identificó el virus de la gripe en 42/65 (65%) frotis nasofaríngeos, siendo el 90% virus gripal A(H3). La incidencia de gripe fue del 3,08% en los no vacunados y del 0,45% en vacunados (p<0,001). La efectividad global de la vacuna antigripal fue del 65%, y en Ž65 años del 73%.Conclusión. Aunque su efectividad no es total, la vacuna es la principal medida para la prevención de la gripe. La red de médicos centinela aporta información útil para la coordinación de actividades asistenciales y de salud pública frente a la gripe

Background. To quantify the incidence of flu in different groups of the population of Navarra in the 2004-2005 season, and to evaluate the effectiveness of anti-flu vaccination. Methods. The analysis of influenza cases in the system of compulsory notificable diseases was complemented by the individualised notifications in the network of sentinel doctors that covers a population of 22,339 inhabitants. The coverage and effectiveness of the vaccine was studied. Results. Vaccine coverage in Ž65 year olds reached 62%. The incidence of influenza was 42.6 cases per 1,000 inhabitants. It reached a maximum in mid-January, exceeding 750 weekly cases per 100,000 inhabitants and 1,900 cases per 100,000 children. The highest rate of influenza was observed in under-15 year olds (49.4 cases per 1,000 inhabitants) and the lowest in non-institutionalised Ž65 year olds (2.6 per 1,000 inhabitants), although it was higher in geriatric residences (62.1 per 1,000; p<0.0001). Seventy-nine percent of the cases from 5 to 64 years resulted in absenteeism from school or work. The flu virus was identified in 42/65 (65%) nasopharyngeal smears, 90% being influenza virus A(H3). The incidence of influenza was 3.08% in the unvaccinated and 0.45% in the vaccinated (p<0.001). The global effectiveness of the anti-flu vaccine was 65%, and in Ž65 years old it was 73%. Conclusion. Although its effectiveness is not total, the vaccine is the main measure for preventing influenza. The network of sentinel doctors provide useful information for the coordination of care and public health activities against flu

Brotes de gripe en población vacunada de residencias geriátricas en la temporada 2004-2005 / Influenza outbreaks in highly-vaccinated older institutionalised people in the 2004-2005 season

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[Ondansetron in the prophylaxis of postoperative nausea and vomiting in ambulatory cataract surgery]. / Ondansetrón en la profilaxis de las náuseas y los vómitos postoperatorios en cirugía de cataratas ambulatoria.

INTRODUCTION AND OBJECTIVE: Postoperative nausea and vomiting (PONV) are potentially serious complications of ophthalmic surgery. We assess the efficacy of ondansetron for antiemetic prophylaxis in outpatient unilateral cataract surgery under retrobulbar blockade. PATIENTS AND METHODS: Cohort study of patients undergoing unilateral cataract surgery between January 1996 and March 1997. The main predictive variable was intravenous administration of 4 mg of ondansetron 30 min before surgery and the main effect variable was the presence of PONV during the first 24 h after surgery. The incidence of PONV was calculated and an analysis of statistical significance was performed using a Mantel-Haenszel chi 2 test, describing the magnitude of association between relative risk and the corresponding confidence interval (95% CI). RESULTS: One hundred sixty-two patients were enrolled. Eighty-two patients received ondansetron and 80 did not. The two groups were similar with respect to control variables. PONV occurred in 23 patients (14.2%): in 16 (20%) who did not receive ondansetron and in 7 (8.2%) who did (p < 0.05). The relative risk of patients who received ondansetron was 0.42 (95% CI: 0.19-0.98) in comparison with those who did not. CONCLUSION: We found a high incidence of PONV, although the administration of ondansetron reduced PONV significantly.

[Nutritional status of Guatemalan refugees below 6 years of age]. / Estado de nutrición de los refugiados guatemaltecos menores de seis años.

OBJECTIVE: To determine changes in the nutritional status of Guatemalan refugee children under six years of age, who lived in Mexico between 1982 and 1996, under various nutrition-related programs implemented during that period. MATERIAL AND METHODS: A comparative analysis of 4 cross-sectional anthropometric studies performed in Chiapas (1982, 1989), Quintana Roo (1989) and Campeche and Quintana Roo in 1996. Malnutrition prevalence by weight/age and height/age indicators was calculated. Odds ratio and 95% confidence intervals were estimated. The implemented programs to improve nutritional status and health conditions are described. RESULTS: In 1982, high rates of malnutrition and mortality prevailed among refugee children. In 1989 some had been transferred to Campeche and Quintana Roo and others stayed in Chiapas. Their situation had improved and remained so until 1996. CONCLUSIONS: The implemented programs were successful to control the emergency and prevent new crises. However they only managed to maintain similar conditions for the refugees as those which prevail among the Mexican indians.

[Morbidity characteristics among elderly Mexicans: an analysis of the 1988 National Health Survey]. / Características de la morbilidad en población mexicana de edad avanzada: un análisis de la Encuesta Nacional de Salud 1988.

OBJECTIVE: Based on the 1988 National Health Survey data base, a preliminary approach to an epidemiologic profile of the Mexican elderly is proposed. MATERIAL AND METHODS: This paper analyzes both reported prevalences of some of the principal health problems in Mexicans over 60 years of age and the relationship between selected morbidity, socio-demographic variables and impairment of daily living activities, stratified by age. RESULTS: Results show that: a) the panorama of reported morbidity among the Mexican elderly is a combination of multiple causes, b) socially defined groups present heterogeneous disease patterns, c) selected morbidity is strongly related to daily living activity impairments. CONCLUSIONS: This approach may be used to improve research on living and health conditions of the Mexican elderly.