[Nirsevimab effectiveness against hospital admission for respiratory syncytial virus bronchiolitis in infants]. / Efectividad de nirsevimab en la prevención de los ingresos por bronquiolitis por virus respiratorio sincitial en lactantes.

OBJECTIVE: Respiratory syncytial virus (RSV) bronchiolitis is the leading cause of hospitalization in infants. This season, a long half-life monoclonal antibody (Nirsevimab) is available to prevent this disease for all infants born from 1 April-30 September to 2023 and all those born during RSV season (October2023- March 2024). The aim of this study was to evaluate the impact of the implementation of this antibody on RSV admissions in a tertiary hospital. METHODS: Observational, retrospective and analytical study. All patients <6 months in October admitted for bronchiolitis at 2 time points were included: T1 or Pre-nirsevimab time: 1 September 2015-30 September 2023 and T2 or Nirsevimab time: 1 October-31 December 2023. Total admissions due to any cause of infants <6 months in the same period were used as the reference population. To assess the impact of the implementation of nirsevimab, we calculated the reduction in the percentage of admissions due to RSV with respect to total admissions in both periods, and also in the 2023-2024 season we calculated the double negative test to calculate the effectiveness of the intervention (1-Odds ratio) x 100. RESULTS: In infants under 6 months of age, we found significant differences in the number of admissions for RSV bronchiolitis between the last season and the previous 7 seasons [574/1195 (48%) vs 6/138 (4.3%); p<0.01, RPI: 91%). In the 2023/2024 season, the effectiveness of nirsevimab in preventing admission for RSV bronchiolitis in children under 6 months of age was 85% (CI 95%: 32-97%). CONCLUSIONS: The implementation of nirsevimab has had an important impact on the number of hospital admissions for RSV bronchiolitis. There were no differences in the severity of bronchiolitis.

Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU): Trial Satisfaction and Attitudes towards Future Clinical Trials.

BACKGROUND: Clinical trial satisfaction is increasingly important for future trial designs and is associated with treatment adherence and willingness to enroll in future research studies or to recommend trial participation. In this post-trial survey, we examined participant satisfaction and attitudes toward future clinical trials in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU). METHODS: We developed an anonymous, participant satisfaction survey tailored to participants enrolled in the DIAN-TU-001 double-blind clinical trial of solanezumab or gantenerumab and requested that all study sites share the survey with their trial participants. A total of 194 participants enrolled in the trial at 24 study sites. We utilized regression analysis to explore the link between participants' clinical trial experiences, their satisfaction, and their willingness to participate in upcoming trials. RESULTS: Survey responses were received over a sixteen-month window during 2020-2021 from 58 participants representing 15 study sites. Notably, 96.5% of the survey respondents expressed high levels of satisfaction with the trial, 91.4% would recommend trial participation, and 96.5% were willing to enroll again. Age, gender, and education did not influence satisfaction levels. Participants reported enhanced medical care (70.7%) and pride in contributing to the DIAN-TU trial (84.5%). Satisfaction with personnel and procedures was high (98.3%). Respondents had a mean age of 48.7 years, with most being from North America and Western Europe, matching the trial's demographic distribution. Participants' decisions to learn their genetic status increased during the trial, and most participants endorsed considering future trial participation regardless of the DIAN-TU-001 trial outcome. CONCLUSION: Results suggest that DIAN-TU-001 participants who responded to the survey exhibited high motivation to participate in research, overall satisfaction with the clinical trial, and willingness to participate in research in the future, despite a long trial duration of 4-7 years with detailed annual clinical, cognitive, PET, MRI, and lumbar puncture assessments. Implementation of features that alleviate barriers and challenges to trial participation is like to have a high impact on trial satisfaction and reduce participant burden.

Transcriptional Profiles Reveal Deregulation of Lipid Metabolism and Inflammatory Pathways in Neurons Exposed to Palmitic Acid.

The effects of the consumption of high-fat diets (HFD) have been studied to unravel the molecular pathways they are altering in order to understand the link between increased caloric intake, metabolic diseases, and the risk of cognitive dysfunction. The saturated fatty acid, palmitic acid (PA), is the main component of HFD and it has been found increased in the circulation of obese and diabetic people. In the central nervous system, PA has been associated with inflammatory responses in astrocytes, but the effects on neurons exposed to it have not been largely investigated. Given that PA affects a variety of metabolic pathways, we aimed to analyze the transcriptomic profile activated by this fatty acid to shed light on the mechanisms of neuronal dysfunction. In the current study, we profiled the transcriptome response after PA exposition at non-toxic doses in primary hippocampal neurons. Gene ontology and Reactome pathway analysis revealed a pattern of gene expression which is associated with inflammatory pathways, and importantly, with the activation of lipid metabolism that is considered not very active in neurons. Validation by quantitative RT-PCR (qRT-PCR) of Hmgcs2, Angptl4, Ugt8, and Rnf145 support the results obtained by RNAseq. Overall, these findings suggest that neurons are able to respond to saturated fatty acids changing the expression pattern of genes associated with inflammatory response and lipid utilization that may be involved in the neuronal damage associated with metabolic diseases.

Comparación del tiempo de cicatrización entre N-butil cianoacrilato y ácido poliglicólico en caninos sometidos a esterilización / Comparison of healing times between N-butyl cyanoacrylate and polyglycolic acid in canines subjected to sterilization

RESUMEN El objetivo de este estudio fue comparar el tiempo de cicatrización entre N-butil cianocrilato (NBC) y ácido poliglicólico (AC) sobre el cierre tisular en caninos sometidos a operaciones de esterilización. Se realizó un estudio observacional, comparativo y descriptivo sobre una población de 80 perros (Canis familiaris) vivos. Los animales se dividieron en cuatro grupos de 20 perros cada uno según sexo y material de sutura, así: primero grupo, hembras que recibieron NBC; segundo grupo, machos y NBC; tercero grupo, hembras y AC como medio de sutura en piel y cuarto grupo, machos y AC. La técnica quirúrgica en hembras fue oforosalpingohisterectomia y en machos orquiectomia. El tiempo de cierre fue estadísticamente (p < 0,05) menor en los grupos de machos y hembras con el adhesivo NBC comparado con los dos grupos tratados con AC. Se concluye que el NBC es un material seguro y eficaz como medio de fijación tisular en ambas técnicas quirúrgicas que disminuye los días de cierre y recuperación.

ABSTRACT The aim of this study was to compare N-butyl cyanoacrylate (NBC) and polyglycolic acid (AC) in tissue closure in canines subjected to sterilization operations. An observational, comparative and descriptive study was conducted in a population of 80 living dogs (Canis familiaris). The animals were divided into 4 groups of 20 dogs each, according to gender and suture material: the first group consisted of females that received NBC; the second group consisted of males that received NBC; the third group consisted of females that received AC as skin suture; and the fourth group was formed by males that received AC. The surgical technique in females was salpingo-oophorectomy, and in males it was orchiectomy. The closure time was statistically (p < 0.05) lower in the male and female groups with the NBC adhesive in comparison to the two groups treated with AC. It was concluded that NBC is a safe and effective material for tissue fixation in both surgical techniques, decreasing times of closure and recovery.

A comparative cross-cultural study of the prevalence of late life depression in low and middle income countries.

BACKGROUND: Current estimates of the prevalence of depression in later life mostly arise from studies carried out in Europe, North America and Asia. In this study we aimed to measure the prevalence of depression using a standardised method in a number of low and middle income countries (LMIC). METHODS: A one-phase cross-sectional survey involving over 17,000 participants aged 65 years and over living in urban and rural catchment areas in 13 sites from 9 countries (Cuba, Dominican Republic, Puerto Rico, Mexico, Venezuela, Peru, China, India and Nigeria). Depression was assessed and compared using ICD-10 and EURO-D criteria. RESULTS: Depression prevalence varied across sites according to diagnostic criteria. The lowest prevalence was observed for ICD-10 depressive episode (0.3 to 13.8%). When using the EURO-D depression scale, the prevalence was higher and ranged from 1.0% to 38.6%. The crude prevalence was particularly high in the Dominican Republic and in rural India. ICD-10 depression was also associated with increased age and being female. LIMITATIONS: Generalisability of findings outside of catchment areas is difficult to assess. CONCLUSIONS: Late life depression is burdensome, and common in LMIC. However its prevalence varies from culture to culture; its diagnosis poses a significant challenge and requires proper recognition of its expression.

Importance of the lung perfusion scintigraphy in single lung transplantation.

Lung perfusion scintigraphy (LPS) with (99m)Tc-MAA gives valuable information about patients who will undergo a single lung transplantation. This technique makes it possible to evaluate and quantify the relative function of both lungs to select the organ to be transplanted. Once the surgery has been performed, the LPS represents a diagnostic method to study the status of the transplanted organ. Two patients who underwent single lung transplantation were studied in our hospital. In both cases, a pre-operative LPS was performed before surgery for selection of the organ to be transplanted and the scintigraphy study was performed a few months after transplantation to establish the perfusion function of the transplanted lung.

Antidepressant-like effects of an alkaloid extract of the aerial parts of Annona cherimolia in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Several species of Annona (Annonaceae) are used in traditional Mexican medicine by their anti-anxiety, anticonvulsant and tranquilizing properties. It has been reported that the alkaloids isolated from some species of the Annona have affinity to serotonergic 5-HT(1A) receptors and modulate dopaminergic transmission, which is involved in depressive disorders. AIM OF THE STUDY: To investigate the antidepressant-like effect of an alkaloid extract from the aerial parts of Annona cherimola (TA) in mice. MATERIALS AND METHODS: The antidepressant-like effect was evaluated in the forced swimming test. To elucidate a possible mechanism of action, experiments of synergism with antidepressant drugs, such as imipramine (IMI), clomipramine (CLIMI), and fluoxetine (FLX), were carried out. The neurotransmitter content (DA: dopamine, 5HT: serotonin and its metabolites, HVA: homovanillic acid and 5HIAA: 5-hydroxyindoleacetic) in the whole brain of mice were also determined by HPLC method. TA chemical composition was determined using high performance liquid chromatography-electrospray mass spectrometry. RESULTS: The results showed that repeated treatment with TA produced antidepressant-like effects in mice. This effect was not related to an increase in locomotor activity. Administration of TA facilitated the antidepressant effect of IMI and CLIMI as well as increased the turnover of DA and 5-HT. The alkaloids: 1,2-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzoquinoline-3,8,9,10-tetraol, anonaine, liriodenine, and nornuciferine were the main constituents of TA. CONCLUSIONS: Results showed that TA produces an antidepressant-like action from a generalized increase in monominergic turnover, supporting the use in tradicional medicine of Annona cherimolia, and strongly suggest its therapeutic potency as an antidepressant agent.

Functional properties of the Ustilago maydis alternative oxidase under oxidative stress conditions.

The mitochondrial respiratory chain of Ustilago maydis contains two terminal oxidases, the cytochrome c oxidase (COX) and the alternative oxidase (AOX). To understand the biochemical events that control AOX activity, we studied the regulation and function of AOX under oxidative stress. The activity of this enzyme was increased by both pyruvate (K(05)=2.6 mM) and purine nucleotides (AMP, K(05)=600 microM) in mitochondria using succinate as respiratory substrate. When U.maydis cells were grown in the presence of antimycin A, the amount of AOX in mitochondria was markedly increased and its selectivity towards AMP and pyruvate changed, suggesting that post-translational events may play a role in the regulation of AOX activity under stress conditions. Addition of antimycin A to isolated mitochondria induced the inactivation of AOX, the formation of lipid peroxides and the loss of glutathione from mitochondria. The two last processes are probably related with the time dependent inactivation of AOX, in agreement with the inhibition of the enzyme by tert-butyl hydroperoxide. Our results suggest that the in vivo operation of AOX in U. maydis depends on the mitochondrial antioxidant machinery, including the glutathione linked systems.

Induction of morphological changes in Ustilago maydis cells by octyl gallate.

The effects of octyl gallate on Ustilago maydis yeast cells were analysed in relation to its capacity to oxidize compounds (pro-oxidant actions). All phenolic compounds tested inhibited the alternative oxidase (AOX). However, only octyl gallate induced a morphological change in yeast cells and collapsed the mitochondrial membrane potential. In contrast to octyl gallate, propyl gallate and nordihydroguaiaretic acid caused only a negligible cell change and the membrane potential was not affected. Our findings show that structurally related phenolic compounds do not necessarily exert similar actions on target cells. Preincubation of U. maydis cells with trolox inhibited the change to pseudohyphal growth produced by octyl gallate. These results suggest that in addition to the inhibitory action of octyl gallate on the AOX, this compound induces a switch from yeast to a mycelium, probably through the formation of lipid peroxides.

Vascular anatomy of the foramen of Vicq d'Azyr: a microsurgical perspective.

INTRODUCTION: The foramen of Vicq d'Azyr, is a triangular-shaped area located rostral to the ventral median fissure of the medulla oblongata. Its importance relies on the fact that it is penetrated by small vessels from the vertebrobasilar axis that nourish vital pontine nuclei and tracts. We described the microvascular anatomy of the perforating vessels of the foramen of Vicq d'Azyr (FVA). MATERIALS AND METHODS: The vertebrobasilar junction arteries and the perforating arteries of the foramen of Vicq d'Azyr were examined using a surgical microscope in 21 formalin-fixed brain stems. RESULTS: The total number of perforating branches found was 286 in the 21 brains, an average of 13.6 perforators per brain, range 7 to 22. They arose as distal branches of 73 main trunks, average of 3.5 per brain, range 2 to 5, originating mainly from the basilar artery in 41 (56.1 %); the left ventral spinal artery in 12 (16.4 %), and the left vertebral artery in 8 (11 %). The average outer diameters of the left and right vertebral arteries were 3.2 mm and 2.9 mm, 4.1 mm for the basilar artery, and 0.6 mm for the right and left ventral spinal arteries. The branching pattern and interesting anatomic variations of the main vessels of the vertebro-basilar junction are also described. DISCUSSION: The vascular anatomy of the infratentorial compartment is highly variable. These variations should be kept in mind to avoid pitfalls during vascular or tumor surgery. In contrast, the entering locations of perforating vessels remain constant, referring to these zones as key areas when planning or doing surgical procedures in this region.

Searching for antibodies against Trichinella spiralis in the sera of patients with fever of unknown cause.

Human cases of trichinellosis are often difficult to identify because the signs and symptoms of the disease, if the infection produces any at all, are non-specific, being similar to those observed in several other infectious diseases. In an investigation of Mexican patients with fever of unknown aetiology, attempts were made to develop a serodiagnostic test for the detection of antibodies specific for Trichinella spiralis. The excretory and secretory products of T. spiralis larvae (from the muscle tissue of experimentally infected rats) were used as the antigens in an enzyme-linked immuno-electrotransfer blot assay. The sera tested came from patients with fever of unknown cause (N=250), patients confirmed to have infectious or parasitic diseases other than trichinellosis (N=134) and 168 apparently healthy subjects. Overall, 4% of the samples from the febrile group, 1.8% of those from the healthy subjects but none of the sera from those with 'other diseases' reacted with the antigens of interest (of 45, 49 and 55 kDa). The results not only confirm that human infection with T. spiralis may be asymptomatic but also indicate that such infection may be mis-diagnosed.

Effectiveness of terbinafine in the eradication of Microsporum canis from laboratory cats.

In this study, the coats of 20 cats with no dermatophytosis lesions were sampled for colonization by Microsporum canis, which was isolated in 45% of cases. All cats were treated with oral terbinafine for 3 weeks. The drug was administered orally at a daily dosage 8.25 mg kg-1. Mycologic status was assessed at the end of the treatment; and after follow-up at 2 days, and 4 and 9 weeks. The final evaluation revealed a complete mycologic cure of all cats by obtaining negative cultures, thereby demonstrating that terbinafine is an effective method of eradication of dermatophyte colonization.

Kinetic characterization of the rotenone-insensitive internal NADH: ubiquinone oxidoreductase of mitochondria from Saccharomyces cerevisiae.

Saccharomyces cerevisiae mitochondria contain an NADH:Q6 oxidoreductase (internal NADH dehydrogenase) encoded by NDI1 gene in chromosome XIII. This enzyme catalyzes the transfer of electrons from NADH to ubiquinone without the translocation of protons across the membrane. From a structural point of view, the mature enzyme has a single subunit of 53 kDa with FAD as the only prosthetic group. Due to the fact that S. cerevisiae cells lack complex I, the expression of this protein is essential for cell growth under respiratory conditions. The results reported in this work show that the internal NADH dehydrogenase follows a ping-pong mechanism, with a Km for NADH of 9.4 microM and a Km for oxidized 2,6-dichorophenolindophenol (DCPIP) of 6.2 microM. NAD+, one of the products of the reaction, did not inhibit the enzyme while the other product, reduced DCPIP, inhibited the enzyme with a Ki of 11.5 microM. Two dead-end inhibitors, AMP and flavone, were used to further characterize the kinetic mechanism of the enzyme. AMP was a linear competitive inhibitor of NADH (Ki = 5.5 mM) and a linear uncompetitive inhibitor of oxidized DCPIP (Ki = 11.5 mM), in agreement with the ping-pong mechanism. On the other hand, flavone was a partial inhibitor displaying a hyperbolic uncompetitive inhibition regarding NADH, and a hyperbolic noncompetitive inhibition with respect to oxidized DCPIP. The apparent intercept inhibition constant (Kii = 5.4 microM) and the slope inhibition constant (Kis = 7.1 microM) were obtained by non linear regression analysis. The results indicate that the ternary complex F-DCPIPox-flavone catalyzes the reduction of DCPIP, although with lower efficiency. The effect of pH on Vmax was studied. The Vmax profile shows two groups with pKa values of 5.3 and 7.2 involved in the catalytic process.

An alternative model for the transmembrane segments of the yeast H+-ATPase.

An alternative topological model for the yeast plasma membrane H(+)-ATPase from K. lactis was deduced by joint prediction, using 11 algorithms for the prediction of transmembrane segments complemented with hydrophobic moment analysis. Similarly to the model currently used in the literature, this alternative model contains 10 transmembrane segments, four in the N-half and six in the C-half of the protein. However, the distribution of the membrane-associated segments on the C-half of the enzyme differs in both models. Nine of the 10 transmembrane segments are highly hydrophobic with low hydrophobic moments, and are probably involved in structural roles. The fifth transmembrane segment is, on the other hand, less hydrophobic, with the highest hydrophobic moment, suggesting that this segment might have a dynamic role in the coupling of the hydrolysis of ATP with the translocation of protons across the membrane. The alignment of the Ca(2+)-ATPase, the Na(+)/K(+)-ATPase and the H(+)-ATPase sequences showed that these proteins have the same topology in the N-half, but important differences were found at the C-half of the enzymes. In contrast with the mammalian ATPases, the fifth transmembrane segment in the H(+)-ATPase appears early in the sequence, giving rise to a shorter cytoplasmic central loop. This alternative model will be useful in the designing of site-directed mutagenesis experiments and contains information for the fitting of the amino acid sequence into the transmembrane region of the three-dimensional model of the ATPase.

Proteins in vacuo: a molecular dynamics study of the unfolding behavior of highly charged disulfide-bond-intact lysozyme subjected to a temperature pulse.

Molecular dynamics simulations were used to interpret a variety of experimental data on highly charged disulfide-bond-intact lysozyme in vacuo. The simulation approach involved submitting a model of the protein [Reimann, Velázquez, and Tapia, J. Phys. Chem. B 102, 9344 (1998)] in a given charge state to a 3-ns-long heat pulse (usually at 500 K) followed by cooling or relaxation for 1 ns back to room temperature (293 K). This treatment yielded a charge threshold around Q(0)=8+ for obtaining significant unfolding, as indicated by an enhancement in collision cross section and conformer length. The collision cross sections and lengths theoretically obtained, along with the threshold charge state for initiating unfolding, were compatible with experimental results on lysozyme in vacuo. The unfolded, highly elongated conformations obtained for Q> or = 9+ displayed a significant level of non-native beta-sheet content which appeared to be additionally stabilized by charge self-solvation.

Unfolded in vacuo lysozyme folds into native, quasinative, and compact structures.

We show that the relaxation dynamics of unfolded in vacuo lysozyme is not random. Analyses of molecular dynamics trajectories in a convenient space of molecular shape descriptors reveal a "favored" pattern of transitions leading to stable conformations. The relaxation paths exhibit a balanced change in shape features: globular spheroids are formed slowly enough to allow the proper entanglement of secondary-structural elements. The present study shows that a protein in vacuo can actually (re)fold into native and quasinative structures. The driving force for these transformations is intrinsic to the polypeptide chain.

DNA structure and fluctuations sensed from a 1.1ns molecular dynamics trajectory of a fully charged Zif268-DNA complex in water.

Molecular dynamics simulations of the zinc finger domain of protein Zif268, in a complex with a high affinity DNA sequence, yields a globally stable system with small yet significant readjustments with persistence time of the order of 1.1ns. The results confirm the quality of the standard GROMOS87 force field with a corrected solvent-to-solute interaction that does not affect the water-water SPC interactions nor the intra-molecular cohesive forces. Specificity determinants are discussed. The simulations of DNA alone, with the same force field, showed the important role played by the solvent and the symmetry of the counterion distribution. (Tapia & Velázquez, J. Am. Chem. Soc., 119, 5934, 1997) In the present work, this feature was retained when appropriate. The results for root mean square deviations and temperature B-factors illustrate the reliability of this approach. The structure of DNA is held by its interactions with the zinc finger protein. This behavior is not much affected by the slow whithering away of finger-1 from DNA. The factors contributing to the molecular stability found in GROMOS' potential energy function appear to be sufficient to yield stable fluctuation patterns when surrounding medium effects are properly included.

Inactivation of the Kluyveromyces lactis H+-ATPase by dicyclohexylcarbodiimide: binding stoichiometry and effect of nucleophiles.

Dicyclohexylcarbodiimide (DCCD) inactivated the plasma membrane H+-ATPase (EC 3.6.1.35) from Kluyveromyces lactis, with a second-order rate constant of 420 M(-1) min(-1). The inhibition kinetics was apparently complex, due to degradation of DCCD with time. Neither Mg2+ nor Mg-ADP affected the inactivation of the ATPase by DCCD. In contrast, vanadate, a transition state analog of phosphate, partially protected the enzyme with a Kd of 14 microM, indicating a coupling between the DCCD-reactive site and the vanadate-binding site. The incubation of H+-ATPase with 14C-DCCD showed that the incorporation of 1.2 mol of DCCD/mol ATPase leads to complete inactivation. The hydrophobic carbodiimide reacted with the protonated form of the carboxylic group, which displayed a pKa of 7.4, strongly suggesting that the residue is in the hydrophobic environment of the membrane. Benzylamine increased the rate of inactivation by DCCD. In this case, full inactivation of the enzyme was associated with the incorporation of 2.4 mol of DCCD/mol of enzyme, indicating the opening of new reactive sites, resulting from a conformational change induced by benzylamine.