IL-4 shapes microglia-dependent pruning of the cerebellum during postnatal development.

Interleukin-4 (IL-4) is a type 2 cytokine with pleiotropic functions in adaptive immunity, allergies, and cognitive processes. Here, we show that low levels of IL-4 in the early postnatal stage delineate a critical period in which microglia extensively prune cerebellar neurons. Elevating the levels of this cytokine via peripheral injection, or using a mouse model of allergic asthma, leads to defective pruning, permanent increase in cerebellar granule cells, and circuit alterations. These animals also show a hyperkinetic and impulsive-like phenotype, reminiscent of attention-deficit hyperactivity disorder (ADHD). These alterations are blocked in Il4rαfl/fl::Cx3cr1-CreER mice, which are deficient in IL-4 receptor signaling in microglia. These findings demonstrate a previously unknown role for IL-4 during a neuroimmune critical period of cerebellar maturation and provide a first putative mechanism for the comorbidity between allergic disease and ADHD observed in humans.

A Novel Genetic Variant in MBD5 Associated with Severe Epilepsy and Intellectual Disability: Potential Implications on Neural Primary Cilia.

Disruptions in the MBD5 gene have been linked with an array of clinical features such as global developmental delay, intellectual disability, autistic-like symptoms, and seizures, through unclear mechanisms. MBD5 haploinsufficiency has been associated with the disruption of primary cilium-related processes during early cortical development, and this has been reported in many neurodevelopmental disorders. In this study, we describe the clinical history of a 12-year-old child harboring a novel MBD5 rare variant and presenting psychomotor delay and seizures. To investigate the impact of MBD5 haploinsufficiency on neural primary cilia, we established a novel patient-derived cell line and used CRISPR-Cas9 technology to create an isogenic control. The patient-derived neural progenitor cells revealed a decrease in the length of primary cilia and in the total number of ciliated cells. This study paves the way to understanding the impact of MBD5 haploinsufficiency in brain development through its potential impact on neural primary cilia.

ZIKV Strains Elicit Different Inflammatory and Anti-Viral Responses in Microglia Cells.

In recent years, the Zika Virus (ZIKV) has caused pandemic outbreaks associated with a high rate of congenital ZIKV syndrome (CZS). Although all strains associated with worldwide outbreaks derive from the Asian lineage, the reasons for their enhanced spread and severity are not fully understood. In this study, we conducted a comparative analysis of miRNAs (miRNA-155/146a/124) and their cellular targets (SOCS1/3, SHP1, TRAF6, IRAK1), as well as pro- and anti-inflammatory and anti-viral cytokines (IL-6, TNF-α, IFN-γ, IL-10, and IFN-ß) and peroxisome proliferator-activated receptor γ (PPAR-γ) expression in BV2 microglia cells infected with ZIKV strains derived from African and Asian lineages (ZIKVMR766 and ZIKVPE243). BV2 cells were susceptible to both ZIKV strains, and showed discrete levels of viral replication, with delayed release of viral particles without inducing significant cytopathogenic effects. However, the ZIKVMR766 strain showed higher infectivity and replicative capacity, inducing a higher expression of microglial activation markers than the ZIKVPE243 strain. Moreover, infection with the ZIKVMR766 strain promoted both a higher inflammatory response and a lower expression of anti-viral factors compared to the ZIKVPE243 strain. Remarkably, the ZIKKPE243 strain induced significantly higher levels of the anti-inflammatory nuclear receptor-PPAR-γ. These findings improve our understanding of ZIKV-mediated modulation of inflammatory and anti-viral innate immune responses and open a new avenue to explore underlining mechanisms involved in the pathogenesis of ZIKV-associated diseases.

Peripheral inflammatory markers during an acute bacterial infection in older patients with and without cognitive dysfunction: A case control study.

Dementia is a known risk factor for acute bacterial infections which may also play a significant role in promoting or accelerating cognitive impairment. Pneumonia and urinary tract infections are the main cause of hospitalisation of dementia patients and infections are a major precipitant of delirium. It is well established that peripheral immune signals induce a neuroinflammatory response largely mediated by microglial cells which is amplified with advanced age, neurodegenerative disorders and genetic characteristics. Reversely, the innate immune response to acute bacterial infection is tightly regulated by the brain. It remains unclear whether dysfunctional neural circuits affected by dementia and/or delirium could alter systemic innate immune responses at the periphery. The current study aims to determine if dementia and/or delirium are associated with an altered systemic inflammatory response to an acute bacterial infection. We recruited 46 hospitalised older patients with acute bacterial infections. From these, 29 participants had cognitive dysfunction (6 with delirium, 12 with dementia and 11 with delirium superimposed on dementia) and 17 had normal cognition. We also included a control group of 11 patients with dementia but with no current infection matched for age and educational status. Baseline characteristics were tested between groups using Kruskal-Wallis test and pairwise comparisons were subsequently assessed with Bonferroni correction for multiple comparisons for continuous variables. Chi square test was used to assess differences between groups in categorical data and correlations between peripheral inflammatory parameters were assessed with Spearman's test. The 4 groups with infection and the control group with no infection had similar characteristics except for cognitive function and functionality which was higher for the group of infected cognitively healthy participants. Levels of C-reactive protein were similar between the infected groups and higher than the non-infected dementia group. Infected patients with cognitive dysfunction (delirium and/or dementia) had higher serum levels of IL-6, TNF-alpha and IL-1beta. These participants had reduced expression of miR-145 in circulating exosomes which correlated negatively with miR-155 levels (r = -0.411, p = 0.027). Expression of CR1 in circulating CD14+ monocytes was higher in infected participants with cognitive dysfunction and, in this group, PICALM correlated both with TNF-alpha and IL-6. In contrast to what was observed in participants with normal cognition, expression of CR1 did not correlate with DAP12 in infected participants with cognitive dysfunction. Taken together, our findings suggest that cognitive dysfunction is associated with an exaggerated proinflammatory response during acute bacterial infection with deregulation of several molecular signalling pathways in circulating exosomes and in monocytes.

In vivo molecular imaging of the neuroinflammatory response to peripheral acute bacterial infection in older patients with cognitive dysfunction: A cross-sectional controlled study.

Introduction: Chronic neuroinflammatory events have been implicated in the pathophysiology of neurodegenerative conditions but no studies have directly examined the neuroinflammatory response to acute systemic infection in older people with dementia. The objective of this study was to determine the magnitude of the neuroinflammatory response triggered by acute systemic infection in older subjects with dementia and/or delirium compared to cognitively healthy controls. Methods: We recruited 19 participants (4 with delirium, 4 with dementia, 4 with delirium superimposed on dementia, 7 cognitively healthy) hospitalized with acute systemic bacterial infection not involving the Central Nervous System. Participants underwent [11C]-PK11195 PET and a neuropsychological assessment during hospital stay. The distribution volume ratio was estimated in the regions-of-interest using the Hammers' brain atlas. Results: In the subcortical analysis, we found that the cognitively healthy group presented regions with significantly higher DVR intensity than the other groups in the choroid plexus. Mean choroid plexus DVR positively correlated with MoCA (r = 0.66, p = 0.036). Conclusion: This study suggests that dementia and/or delirium is associated with a reduced neuroinflammatory response to acute systemic bacterial infection which can be the result of an immunosuppressive brain environment.

Generation and Characterization of Novel iPSC Lines from a Portuguese Family Bearing Heterozygous and Homozygous GRN Mutations.

Mutations in granulin (GRN) have been associated with neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL). In Portugal, GRN mutations account for around half of all FTLD cases with known genetic origin. Here, we describe the generation and characterization of three human-induced pluripotent stem cell (hiPSC) lines from a Portuguese family harboring heterozygous and homozygous GRN mutation. hiPSCs were reprogrammed from human dermal fibroblasts by episomal nucleofection of the Yamanaka factors. The new generated lines were positive for pluripotency markers, could be further differentiated to cells expressing all trilineage markers, and presented a normal karyotype. They were also capable of differentiating into 3D brain organoids and presented a significant decrease in progranulin protein levels. Hence, these cell lines constitute suitable new tools to elucidate the pathophysiological mechanisms associated with the GRN mutations in the context of FTLD.

[Interinstitutional Command Mexico: organizational decision-making in the face of COVID-19]. / Comando interinstitucional México: toma de decisiones organizacionales ante COVID-19.

Background: The third wave of COVID-19 in Mexico produced a high demand for hospital care, which is why it was created a multidisciplinary group to optimize decision-making: the Interinstitutional Command for the Health Sector (COISS, according to its initials in Spanish). So far, there is no scientific evidence of the COISS processes or their effect on the behavior of epidemiological indicators and the hospital care needs of the population in the context of COVID-19 in the entities involved. Objectives: To analyze the trend on epidemic risk indicators throughout the COISS group's management in the third wave of COVID-19 in Mexico. Material and methods: Mixed study: 1) non-systematic review of information from technical documents issued by COISS, 2) secondary analysis of open-access institutional databases through the description of healthcare needs of cases notified with COVID-19 symptoms, and an ecological analysis by each Mexican state on the behavior of hospital occupancy, RT-PCR positivity, and COVID-19 mortality in two-time points. Results: The COISS activity in identifying states with epidemic risk generated actions aimed at a reduction in hospital occupancy of beds, positivity by RT-PCR, and mortality from COVID-19. Conclusions: The decisions of the COISS group reduced the indicators of epidemic risk. Continuing the work of the COISS group is an urgent need. Conclusions: The decisions of the COISS group reduced the indicators of epidemic risk. Continuing the work of the COISS group is an urgent need.

Introducción: la tercera ola por COVID-19 en México provocó una alta demanda de atención hospitalaria, por lo cual se conformó un grupo multidisciplinario para optimizar la toma de decisiones sanitarias: Comando Interinstitucional del Sector Salud (COISS). Hasta el momento, no hay evidencia científica de los procesos del COISS ni de su efecto sobre el comportamiento de indicadores epidemiológicos y las necesidades de atención hospitalaria de la población bajo el contexto de COVID-19 en entidades federativas involucradas. Objetivos: analizar la tendencia de indicadores de riesgo epidémico durante la gestión del grupo COISS en la tercera ola por COVID-19 en México. Material y métodos: estudio mixto: 1) revisión no sistemática de documentos técnicos del COISS, 2) análisis secundario de bases de datos de libre acceso, mediante la descripción de necesidades de atención hospitalaria de los casos notificados con síntomas de la COVID-19 y un análisis ecológico por entidades federativas sobre el comportamiento de la ocupación hospitalaria, positividad y mortalidad por COVID-19 en dos cortes temporales. Resultados: la actividad del COISS en la identificación de entidades federativas de riesgo epidémico generó acciones encaminadas a una reducción en la ocupación hospitalaria de camas generales, positividad por RT-PCR y mortalidad por COVID-19. Conclusiones: las decisiones del grupo COISS disminuyeron los indicadores de riesgo epidémico. Continuar el trabajo del grupo COISS es una necesidad apremiante.

Cognitive Trajectories Following Acute Infection in Older Patients With and Without Cognitive Impairment: An 1-Year Follow-Up Study.

Introduction: Dementia is a known risk factor for both delirium and acute systemic infections which may also play a significant role in promoting or accelerating neurodegenerative disease. Infections are both the main causes of hospitalization of dementia patients and can be a major precipitant of delirium but currently it is not possible to predict the risk of cognitive decline in older patients exposed to acute infection. Objectives: We aimed to determine the level of cognitive change at 1-year follow up in individuals with different patterns of cognitive function (dementia, delirium, delirium superimposed on dementia) at the time of their hospitalization due to a systemic infection and to correlate these cognitive patterns with clinical status variables. Methods: We recruited 53 hospitalized geriatric patients with a systemic infection, and we collected 12-months follow up data for 34 patients. These patients were classified in four groups: no cognitive impairment (controls-C), delirium only (D), dementia only (Dem), and delirium superimposed to dementia (DD). Cognitive performance was measured by change in score on the Montreal Cognitive Assessment (MoCA) and delirium was identified using Confusion Assessment Measure (CAM). We examined performance on the MoCA in the first year after hospitalization, controlling for demographic characteristics, coexisting medical conditions, and type of infection. Results: For the 34 patients to whom follow-up data was available, delirium presence in individuals with prior dementia (DD group) was associated with a negative mean change score of 3-point (p < 0.02) at 1 year follow up, whereas dementia patients without delirium had a mean change score of 1.5-point lower at 12-months (p = 0.04), when comparing follow-up and baseline MoCA scores. Cognitively healthy patients did not significantly decrease their MoCA score at follow-up (p = 0.15). MoCA and NPI scores during hospitalization were significantly correlated with the level of cognitive decline in the four groups (r = 0.658, p < 0.01 and r = 0.439, p = 0.02, respectively). Conclusions: Premorbid dementia and delirium superimposed on dementia during hospitalization in older patients with acute infections predict cognitive decline at 1 year following admission. Taken together, our findings suggest a pathophysiological interaction between neurodegenerative changes, acute infection, and delirium.

Estimates of Geriatric Delirium Frequency in Noncardiac Surgeries and Its Evaluation Across the Years: A Systematic Review and Meta-analysis.

OBJECTIVES: Delirium is an acute neuropsychiatric syndrome associated with poor outcomes. Older adults undergoing surgery have a higher risk of manifesting perioperative delirium, particularly those having associated comorbidities. It remains unclear whether delirium frequency varies across surgical settings and if it has remained stable across the years. We conducted a systematic review to (1) determine the overall frequency of delirium in older people undergoing noncardiac surgery; (2) explore factors explaining the variability of the estimates; and (3) determine the changing of the estimates over the past 2 decades. DESIGN: Systematic review and meta-analysis. Literature search was performed in MEDLINE, PubMed, ISI Web of Science, EBSCO, ISRCTN registry, ScienceDirect, and Embase in January 2020 for studies published from 1995 to 2020. SETTING: Noncardiac surgical settings. PARTICIPANTS: Forty-nine studies were included with a total of 26,865 patients screened for delirium. METHODS: We included observational and controlled trials reporting incidence, prevalence, or proportion of delirium in adults aged ≥60 years undergoing any noncardiac surgery requiring hospitalization. Data extracted included sample size, reported delirium frequencies, surgery type, anesthesia type, delirium diagnosis method, length of hospitalization, and year of assessment. (PROSPERO registration no.: CRD42020160045). RESULTS: We found an overall pooled frequency of preoperative delirium of 17.9% and postoperative delirium (POD) of 23.8%. The POD estimates increased between 1995 and 2020 at an average rate of 3% per year. Pooled estimates of POD were significantly higher in studies not excluding patients with lower cognitive performance before surgery (28% vs 16%) and when general anesthesia was used in comparison to local, spinal, or epidural anesthesia (28% vs 20%). CONCLUSIONS AND IMPLICATIONS: Type of anesthesia and preoperative cognitive status were significant moderators of delirium frequency. POD in noncardiac surgery has been increasing across the years, suggesting that more resources should be allocated to delirium prevention and management.

miRNA-31 Improves Cognition and Abolishes Amyloid-ß Pathology by Targeting APP and BACE1 in an Animal Model of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia worldwide, characterized by progressive memory impairment, behavioral changes, and, ultimately, loss of consciousness and death. Recently, microRNA (miRNA) dysfunction has been associated with increased production and impaired clearance of amyloid-ß (Aß) peptides, whose accumulation is one of the most well-known pathophysiological markers of this disease. In this study, we identified several miRNAs capable of targeting key proteins of the amyloidogenic pathway. The expression of one of these miRNAs, miR-31, previously found to be decreased in AD patients, was able to simultaneously reduce the levels of APP and Bace1 mRNA in the hippocampus of 17-month-old AD triple-transgenic (3xTg-AD) female mice, leading to a significant improvement of memory deficits and a reduction in anxiety and cognitive inflexibility. In addition, lentiviral-mediated miR-31 expression significantly ameliorated AD neuropathology in this model, drastically reducing Aß deposition in both the hippocampus and subiculum. Furthermore, the increase of miR-31 levels was enough to reduce the accumulation of glutamate vesicles in the hippocampus to levels found in non-transgenic age-matched animals. Overall, our results suggest that miR-31-mediated modulation of APP and BACE1 can become a therapeutic option in the treatment of AD.

Abnormal mGluR-mediated synaptic plasticity and autism-like behaviours in Gprasp2 mutant mice.

Autism spectrum disorder (ASD) is characterized by dysfunction in social interactions, stereotypical behaviours and high co-morbidity with intellectual disability. A variety of syndromic and non-syndromic neurodevelopmental disorders have been connected to alterations in metabotropic glutamate receptor (mGluR) signalling. These receptors contribute to synaptic plasticity, spine maturation and circuit development. Here, we investigate the physiological role of Gprasp2, a gene linked to neurodevelopmental disabilities and involved in the postendocytic sorting of G-protein-coupled receptors. We show that Gprasp2 deletion leads to ASD-like behaviour in mice and alterations in synaptic communication. Manipulating the levels of Gprasp2 bidirectionally modulates the surface availability of mGluR5 and produces alterations in dendritic complexity, spine density and synaptic maturation. Loss of Gprasp2 leads to enhanced hippocampal long-term depression, consistent with facilitated mGluR-dependent activation. These findings demonstrate a role for Gprasp2 in glutamatergic synapses and suggest a possible mechanism by which this gene is linked to neurodevelopmental diseases.

Effects of a New Bioceramic Material on Human Apical Papilla Cells.

BACKGROUND: The development of materials with bioregenerative properties is critically important for vital pulp therapies and regenerative endodontic procedures. The aim of this study was to evaluate the cytocompatibility and cytotoxicity of a new endodontic biomaterial, PulpGuard, in comparison with two other biomaterials widely used in endodontic procedures, ProRoot Mineral Trioxide Aggregate (MTA) and Biodentine. METHODS: Apical papilla cells (APCs) were isolated from third molars with incomplete rhizogenesis from patients with orthodontic indication for dental extraction. Cultured APCs were incubated for 24, 48, or 72 h with different dilutions of eluates prepared from the three materials. Cellular viability, mobility, and proliferation were assessed in vitro using the Alamar Blue assay and a wound-healing test. The cells were also cultured in direct contact with the surface of each material. These were then analyzed via Scanning Electron Microscopy (SEM), and the surface chemical composition was determined by Energy-Dispersive Spectroscopy (EDS). RESULTS: Cells incubated in the presence of eluates extracted from ProRoot MTA and PulpGuard presented rates of viability comparable to those of control cells; in contrast, undiluted Biodentine eluates induced a significant reduction of cellular viability. The wound-healing assay revealed that eluates from ProRoot MTA and PulpGuard allowed for unhindered cellular migration and proliferation. Cellular adhesion was observed on the surface of all materials tested. Consistent with their disclosed composition, EDS analysis found high relative abundance of calcium in Biodentine and ProRoot MTA and high abundance of silicon in PulpGuard. Significant amounts of zinc and calcium were also present in PulpGuard discs. Concerning solubility, Biodentine and ProRoot MTA presented mild weight loss after eluate extraction, while PulpGuard discs showed significant water uptake. CONCLUSIONS: PulpGuard displayed a good in vitro cytocompatibility profile and did not significantly affect the proliferation and migration rates of APCs. Cells cultured in the presence of PulpGuard eluates displayed a similar profile to those cultured with eluates from the widely used endodontic cement ProRoot MTA.

Towards frailty biomarkers: Candidates from genes and pathways regulated in aging and age-related diseases.

OBJECTIVE: Use of the frailty index to measure an accumulation of deficits has been proven a valuable method for identifying elderly people at risk for increased vulnerability, disease, injury, and mortality. However, complementary molecular frailty biomarkers or ideally biomarker panels have not yet been identified. We conducted a systematic search to identify biomarker candidates for a frailty biomarker panel. METHODS: Gene expression databases were searched (http://genomics.senescence.info/genes including GenAge, AnAge, LongevityMap, CellAge, DrugAge, Digital Aging Atlas) to identify genes regulated in aging, longevity, and age-related diseases with a focus on secreted factors or molecules detectable in body fluids as potential frailty biomarkers. Factors broadly expressed, related to several "hallmark of aging" pathways as well as used or predicted as biomarkers in other disease settings, particularly age-related pathologies, were identified. This set of biomarkers was further expanded according to the expertise and experience of the authors. In the next step, biomarkers were assigned to six "hallmark of aging" pathways, namely (1) inflammation, (2) mitochondria and apoptosis, (3) calcium homeostasis, (4) fibrosis, (5) NMJ (neuromuscular junction) and neurons, (6) cytoskeleton and hormones, or (7) other principles and an extensive literature search was performed for each candidate to explore their potential and priority as frailty biomarkers. RESULTS: A total of 44 markers were evaluated in the seven categories listed above, and 19 were awarded a high priority score, 22 identified as medium priority and three were low priority. In each category high and medium priority markers were identified. CONCLUSION: Biomarker panels for frailty would be of high value and better than single markers. Based on our search we would propose a core panel of frailty biomarkers consisting of (1) CXCL10 (C-X-C motif chemokine ligand 10), IL-6 (interleukin 6), CX3CL1 (C-X3-C motif chemokine ligand 1), (2) GDF15 (growth differentiation factor 15), FNDC5 (fibronectin type III domain containing 5), vimentin (VIM), (3) regucalcin (RGN/SMP30), calreticulin, (4) PLAU (plasminogen activator, urokinase), AGT (angiotensinogen), (5) BDNF (brain derived neurotrophic factor), progranulin (PGRN), (6) α-klotho (KL), FGF23 (fibroblast growth factor 23), FGF21, leptin (LEP), (7) miRNA (micro Ribonucleic acid) panel (to be further defined), AHCY (adenosylhomocysteinase) and KRT18 (keratin 18). An expanded panel would also include (1) pentraxin (PTX3), sVCAM/ICAM (soluble vascular cell adhesion molecule 1/Intercellular adhesion molecule 1), defensin α, (2) APP (amyloid beta precursor protein), LDH (lactate dehydrogenase), (3) S100B (S100 calcium binding protein B), (4) TGFß (transforming growth factor beta), PAI-1 (plasminogen activator inhibitor 1), TGM2 (transglutaminase 2), (5) sRAGE (soluble receptor for advanced glycosylation end products), HMGB1 (high mobility group box 1), C3/C1Q (complement factor 3/1Q), ST2 (Interleukin 1 receptor like 1), agrin (AGRN), (6) IGF-1 (insulin-like growth factor 1), resistin (RETN), adiponectin (ADIPOQ), ghrelin (GHRL), growth hormone (GH), (7) microparticle panel (to be further defined), GpnmB (glycoprotein nonmetastatic melanoma protein B) and lactoferrin (LTF). We believe that these predicted panels need to be experimentally explored in animal models and frail cohorts in order to ascertain their diagnostic, prognostic and therapeutic potential.

miRNAs: New Biomarkers and Therapeutic Targets in Dementia.

BACKGROUND: Dementia is a complex pathological state that affects millions of individuals worldwide and is responsible for a huge socioeconomic burden, making it a major health concern of current times. Given the impact of dementia in both patients and caregivers, it is crucial to fully clarify the molecular mechanisms underlying dementia-associated disorders, since without this knowledge our ability to correctly diagnose and treat these diseases is severely hampered. METHODS: Epigenetic mechanisms, such as miRNA-mediated post-transcriptional regulation, have been reported to play a role in dementia pathogenesis. Given their ability to bind complementary mRNA sequences, miRNAs are able to induce temporary or permanent translation repression of their mRNA targets. RESULTS: Consequently, changes in miRNA levels may contribute to alterations in the expression of dementiarelated proteins, impacting the course of the disease. Conversely, studies have also reported that some of these proteins are able to regulate the biogenesis and transport of miRNAs, hinting at novel disease-related mechanisms that are now beginning to be explored. These findings have made miRNAs both interesting tools and promising targets in the design of novel therapeutic strategies. Moreover, the discovery of circulating miRNAs, which are released by cells of various tissues, including the brain, and travel in membrane-bound vesicles found in most biofluids, opened new possibilities concerning the usefulness of miRNAs as biomarkers of disease. CONCLUSION: In this context, the major aim of this review is to discuss the relevance of these small non-coding RNAs in dementia, focusing on their role as gene expression regulators, their potential as biomarkers of dementia subtype and stage, and the hypothesis of using miRNA modulation as an innovative therapeutic approach to treat dementia-related disorders.

Frailty in mouse ageing: A conceptual approach.

Human life expectancy has increased dramatically in the last century and as a result also the prevalence of a variety of age-related diseases and syndromes. One such syndrome is frailty, which is defined as a combination of organ dysfunctions leading to increased vulnerability to adverse health outcomes. In humans, frailty is associated with various biomarkers of ageing and predicts relevant outcomes such as responses to therapies and progression of health status and mortality. Moreover, it is relatively easy to assess. To foster translation of mechanistic understanding of the ageing process and, importantly, of interventions that may extend healthy lifespan, frailty scales have been reverse translated into mice in recent years. We will review these approaches with a view to identify what is known and what is not known at present about their validity, reproducibility and reliability with a focus on the potential for further improvement.

Cardiac arrest due to baclofen withdrawal syndrome.

A 41-year-old man presented with postcervical traumatic complete quadriparesis under intrathecal baclofen therapy (ITB) for refractory spasticity. Less than 24 h after having his baclofen pump substituted, he develops hyperthermia, seizures, cognitive depression, acute hypoxaemic respiratory failure and cardiovascular instability leading to mechanical ventilation and vasopressor support. He was transferred to an intensive care unit with diagnosis of community-acquired pneumonia leading to septic shock. He evolved with progressive clinical worsening and multisystem organ failure and cardiac arrest in non-shockable rhythm (pulseless electrical activity)--4 min resuscitation with return of spontaneous circulation. Considering the possible diagnosis of baclofen withdrawal syndrome and, in suspicion of ITB delivery disruption, the catheter system was surgically explored and a leaking tubule attachment was found. Despite aggressive cardiovascular, respiratory and renal support therapy, clinical improvement occurred only after restoration of intrathecal drug delivery. He was discharged from the hospital after 56 days, having returned to baseline status.

[Analysis of maternal deaths in Mexico occurred during 2009]. / Análisis de las muertes maternas en México ocurridas durante 2009.

BACKGROUND: Mexico reported 955 maternal deaths in 2011, with a ratio of 49 deaths per 100,000 live births. For 2015, the WHO commitment is to reduce the ratio to 22, equivalent to 415 maternal deaths. METHODS: it is a descriptive and retrospective study. In 1257 maternal deaths in 2009, we reviewed a sample of 173 records. Simple frequencies and percentages were calculated. RESULTS: direct causes of maternal death were preeclampsia-eclampsia, infection and obstetrical hemorrhage secondary to uterine atony, placental accreta and placenta previa. Fifteen patients died from abortion complications. Four patients died from extra-uterine pregnancy, because of delayed diagnosis and treatment. Indirect causes of maternal death were neoplasms, abdominal sepsis, vascular events, metabolic problems and heart disease; twenty-five patients died of atypical pneumonia and 11 more of influenza A H1N1. CONCLUSIONS: it is feasible to reduce maternal mortality by means of an adequate prenatal care, in quantity and quality of consultations, and avoiding high risk pregnancies caused by a history of obstetric factors and associated severe diseases. Influenza A H1N1 interrupted the downward trend in maternal mortality.

Introducción: en 2011 ocurrieron 955 defunciones maternas en México, 49.9 por 100 000 nacidos vivos. La meta de la Organización Mundial de la Salud para 2015 es reducir la tasa a 22.5: 560 defunciones anuales. Métodos: estudio descriptivo y retrospectivo de 1257 muertes maternas ocurridas en México durante 2009, con una muestra representativa de 173 expedientes. Se calcularon frecuencias simples y porcentajes. Resultados: las muertes maternas ocurrieron por causas directas como preeclampsia-eclampsia, infección y hemorragia obstétrica secundaria a atonía uterina, acretismo placentario y placenta previa. Quince mujeres tuvieron complicaciones por abortos. Cuatro murieron por embarazo extrauterino debido a diagnóstico y tratamiento tardíos. Las causas indirectas de la muerte materna fueron neoplasias, sepsis abdominal, eventos vasculares, problemas metabólicos y cardiopatías. Veinticinco pacientes fallecieron por neumonía atípica y 11 por influenza A H1N1. Conclusiones: es factible disminuir la mortalidad materna mediante suficientes consultas prenatales de calidad y evitar embarazos con riesgo alto por los antecedentes obstétricos y los padecimientos asociados. La influenza A H1N1 interrumpió la tendencia descendente de la mortalidad materna.

Temperature-responsive cationic block copolymers as nanocarriers for gene delivery.

Cationic block copolymers have been regarded as promising alternatives to the use of viral vectors for gene delivery. In this work, poly(N-isopropylacrylamide)n-block-poly((3-acrylamidopropyl)trimethylammonium chloride)m (PNIPAAMn-b-PAMPTMA(+)m) block copolymers with n=48 or 65 and m=6, 10 or 20 were synthesized and evaluated in terms of their potential for in vitro transfection of HeLa cells. These block copolymers collapse above a phase transition temperature, allowing the entrapment of the DNA molecules they are adsorbed to. The transfection efficiency increased with polymer concentration and was higher in the presence of a long PNIPAAM block and for a short charged block. In general, increasing the length of the charged block decreased the transfection efficiency. Additionally, polymer-DNA complexes (polyplexes) formed at lower polymer/DNA charge ratios caused lower cell toxicity levels. All polymers were shown to efficiently protect the DNA, even when they were present at low concentrations. At 37°C, the polyplexes mostly formed structures with size ranging from 100 to 500nm. The results also showed that the thermoresponsive contraction of PNIPAAM causes the charged block segments to be pressed out to the surface. The formation of compact structures seems to be a key factor in achieving high transfection efficiency.

[Analysis of dengue fever deaths in Mexico: 2009]. / Defunciones por dengue en México. Análisis del año 2009.

OBJECTIVE: to describe the dengue fever mortality. METHODS: a descriptive and retrospective study including 104 files reported deaths caused by dengue fever during 2009 to march 2010, was done. RESULTS: sixty (58 %) were women and 44 (42 %) men. An increased mortality between the ages of 11 and 40 years old (47 %) was observed. Colima was a state with high incidence of cases and Jalisco had the highest mortality. Thrombocytopenia was the rule (90.4 %) and in one third of the cases platelets were below 50,000/mm(3). A quarter of cases were associated with comorbility. The initial clinical manifestations included: bleeding, hypovolemia by depletion or hemorrhage, tachycardia, paleness, depressed level of consciousness and circulatory failure. The main cause of death was hypovolemic shock or sepsis. In 42 cases, severe dengue was considered. CONCLUSIONS: an association between the severity of dengue fever and mortality was observed. The main cause of mortality was a shock state.

Cell-Penetrating Peptides-Mechanisms of Cellular Uptake and Generation of Delivery Systems.

The successful clinical application of nucleic acid-based therapeutic strategies has been limited by the poor delivery efficiency achieved by existing vectors. The development of alternative delivery systems for improved biological activity is, therefore, mandatory. Since the seminal observations two decades ago that the Tat protein, and derived peptides, can translocate across biological membranes, cell-penetrating peptides (CPPs) have been considered one of the most promising tools to improve non-invasive cellular delivery of therapeutic molecules. Despite extensive research on the use of CPPs for this purpose, the exact mechanisms underlying their cellular uptake and that of peptide conjugates remain controversial. Over the last years, our research group has been focused on the S413-PV cell-penetrating peptide, a prototype of this class of peptides that results from the combination of 13-amino-acid cell penetrating sequence derived from the Dermaseptin S4 peptide with the SV40 large T antigen nuclear localization signal. By performing an extensive biophysical and biochemical characterization of this peptide and its analogs, we have gained important insights into the mechanisms governing the interaction of CPPs with cells and their translocation across biological membranes. More recently, we have started to explore this peptide for the intracellular delivery of nucleic acids (plasmid DNA, siRNA and oligonucleotides). In this review we discuss the current knowledge of the mechanisms responsible for the cellular uptake of cell-penetrating peptides, including the S413-PV peptide, and the potential of peptide-based formulations to mediate nucleic acid delivery.