Characterization of monoamine oxidase-B (MAO-B) as a biomarker of reactive astrogliosis in Alzheimer's disease and related dementias.

Reactive astrogliosis accompanies the two neuropathological hallmarks of Alzheimer's disease (AD)-Aß plaques and neurofibrillary tangles-and parallels neurodegeneration in AD and AD-related dementias (ADRD). Thus, there is growing interest in developing imaging and fluid biomarkers of reactive astrogliosis for AD/ADRD diagnosis and prognostication. Monoamine oxidase-B (MAO-B) is emerging as a target for PET imaging radiotracers of reactive astrogliosis. However, a thorough characterization of MAO-B expression in postmortem control and AD/ADRD brains is lacking. We sought to: (1) identify the primary cell type(s) expressing MAO-B in control and AD brains; (2) quantify MAO-B immunoreactivity in multiple brain regions of control and AD donors as a proxy for PET radiotracer uptake; (3) correlate MAO-B level with local AD neuropathological changes, reactive glia, and cortical atrophy; (4) determine whether the MAOB rs1799836 SNP genotype impacts MAO-B expression level; (5) compare MAO-B immunoreactivity across AD/ADRD, including Lewy body diseases (LBD) and frontotemporal lobar degenerations with tau (FTLD-Tau) and TDP-43 (FTLD-TDP). We found that MAO-B is mainly expressed by subpial and perivascular cortical astrocytes as well as by fibrous white matter astrocytes in control brains, whereas in AD brains, MAO-B is significantly upregulated by both cortical reactive astrocytes and white matter astrocytes across temporal, frontal, and occipital lobes. By contrast, MAO-B expression level was unchanged and lowest in cerebellum. Cortical MAO-B expression was independently associated with cortical atrophy and local measures of reactive astrocytes and microglia, and significantly increased in reactive astrocytes surrounding Thioflavin-S+ dense-core Aß plaques. MAO-B expression was not affected by the MAOB rs1799836 SNP genotype. MAO-B expression was also significantly increased in the frontal cortex and white matter of donors with corticobasal degeneration, Pick's disease, and FTLD-TDP, but not in LBD or progressive supranuclear palsy. These findings support ongoing efforts to develop MAO-B-based PET radiotracers to image reactive astrogliosis in AD/ADRD.

Assessment of the mechanical and physical characteristics of PET bricks with different aggregates.

Construction and demolition waste, along with discarded PET plastic bottles, have evolved into a widespread global resource. However, their current disposal in landfills poses a significant environmental pollution challenge. This research is centered on evaluating the performance of cement mortar composed by larger PET particles in conjunction with sand, construction and demolition waste, and lightweight expanded polystyrene aggregates. The primary objective of this study is to formulate a blend suitable for non-structural elements that can be easily manufactured for social housing construction. This modified blend extends upon the original certified mixture employed at CEVE for brick production, which encompasses cement and 3 mm-long PET particles. The experimental analysis revealed that blend containing 8 mm-long PET particles, in combination with fine aggregates of construction and demolition waste, attained a required mechanical strength of 2 MPa, while preserving the bulk density and hydric properties of the initial PET bricks developed at CEVE in Argentina.

An Insertion Within SIRPß1 Shows a Dual Effect Over Alzheimer's Disease Cognitive Decline Altering the Microglial Response.

Background: Microglial dysfunction plays a causative role in Alzheimer's disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPß1, a surface receptor that triggers amyloid-ß(Aß) phagocytosis via TYROBP. Objective: To analyze the impact of this copy-number variant in SIRPß1 expression and how it affects AD molecular etiology. Methods: Copy-number variant proxy rs2209313 was evaluated in GERALD and GR@ACE longitudinal series. Hippocampal specimens of genotyped AD patients were also examined. SIRPß1 isoform-specific phagocytosis assays were performed in HEK393T cells. Results: The insertion alters the SIRPß1 protein isoform landscape compromising its ability to bind oligomeric Aß and its affinity for TYROBP. SIRPß1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aß ratio (p = 0.018) and a higher risk to develop AD (OR = 1.678, p = 0.018). MRIs showed that Dup/Dup patients exhibited a worse initial response to AD. At the moment of diagnosis, all patients showed equivalent Mini-Mental State Examination scores. However, AD patients with the duplication had less hippocampal degeneration (p < 0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline (p = 0.013). Transcriptional analysis also shows that the SIRPß1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. Conclusions: The SIRPß1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aß. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPß1 structural variant might be considered as a potential modulator of this causative pathway.

Update on modifiable risk factors for Alzheimer's disease and related dementias.

PURPOSE OF REVIEW: All human beings undergo a lifelong cumulative exposure to potentially preventable adverse factors such as toxins, infections, traumatisms, and cardiovascular risk factors, collectively termed exposome. The interplay between the individual's genetics and exposome is thought to have a large impact in health outcomes such as cancer and cardiovascular disease. Likewise, a growing body of evidence is supporting the idea that preventable factors explain a sizable proportion of Alzheimer's disease and related dementia (ADRD) cases. RECENT FINDINGS: Here, we will review the most recent epidemiological, experimental preclinical, and interventional clinical studies examining some of these potentially modifiable risk factors for ADRD. We will focus on new evidence regarding cardiovascular risk factors, air pollution, viral and other infectious agents, traumatic brain injury, and hearing loss. SUMMARY: While greater and higher quality epidemiological and experimental evidence is needed to unequivocally confirm their causal link with ADRD and/or unravel the underlying mechanisms, these modifiable risk factors may represent a window of opportunity to reduce ADRD incidence and prevalence at the population level via health screenings, and education and health policies.

Outcomes with atezolizumab in metastatic urothelial cancer: real-world data from a single institution.

PURPOSE: Immune checkpoint inhibitors (ICIs) have been incorporated in the treatment of metastatic urothelial carcinoma (mUC) upon platinum-based chemotherapy according to the positive results of large clinical trials. Nevertheless, results from unselected populations reflecting real-world data (RWD) are highly informative to the clinician. We reviewed daily clinical practice outcomes in patients with mUC who received atezolizumab in our institution. METHODS: Here we evaluated the clinical activity and safety of atezolizumab in an unselected population of mUC patients who received atezolizumab between 2018 and 2022 reflecting RWD. Efficacy and safety information were retrospectively collected. RESULTS: A total of 63 patients were included. The mean age was 68 years and the objective response rate was 14.3%. The median progression-free survival was 3 months and the median overall survival 6 months. At 1 year, 42% of the patients were alive. ECOG (0 vs 1) and neutrophil-lymphocytes ratio < 2 at the start of ICI were positive prognostic factors that discriminated between long vs short survivors. Overall tolerance was good with no new safety signals. Five patients (17%) had treatment-related adverse events grade ≥ 2 that required corticosteroids. CONCLUSION: In this retrospective study, atezolizumab was an effective and tolerable treatment option for patients with mUC after progression to platinum-based chemotherapy. Yet, patient selection remains critical to improve outcomes.

Compatibility study of Duddingtonia flagrans conidia and its crude proteolytic extract.

This study aimed to evaluate the concomitant use of the nematophagous fungus Duddingtonia flagrans (AC001) and its protease-rich crude extract for the in vitro control of Panagrellus sp., Haemonchus spp., and Trichostrongylus spp. The nematicidal tests were carried out on larvae of the free-living nematode Panagrellus sp. and infective larvae of the gastrointestinal parasitic nematodes of domestic ruminants (Haemonchus spp. and Trichostrongylus spp). Five experimental groups were set: (1) one control group (G1) and (4) four treated groups -G2 - active crude extract; G3 - denatured crude extract; G4 - fungus, and G5 - fungus + active extract. Plates were incubated at 28 ºC for 24 h followed by the recovery of the larvae using the Baermann technique. The results showed a lower recovery of Panagrellus sp. larvae in the experimental groups compared to the control group, as follows: 52 % (G2), 16 % (G3), 46 % (G4), and 77 % (G5). An even greater reduction (77 ± 5 %) occurred in the group (G5). In addition, the authors observed lower averages of L3 of Haemonchus spp. and Trichostrongylus spp. in the experimental groups compared to the control group, as follows: 59 % (G2), 0 % (G3), 86 % (G4), and 76 % (G5). In turn, there was a difference (p < 0.01) between (G5) and (G2). The results this study indicate a positive effect from the compatible use of the D. flagrans fungus and its enzymatic crude extract (protease), which has been demonstrated here for the first time and with potential field applications for further designs.

Phase 4 Multinational Multicenter Retrospective and Prospective Real-World Study of Nivolumab in Recurrent and Metastatic Squamous Cell Carcinoma of the Head and Neck.

This study examined the real-world use of nivolumab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). This was a multinational retrospective study (VOLUME) assessing treatment effectiveness and safety outcomes and a prospective study (VOLUME-PRO) assessing HRQoL and patient-reported symptoms. There were 447 and 51 patients in VOLUME and VOLUME-PRO, respectively. Across both studies, the median age was 64.0 years, 80.9% were male, and 52.6% were former smokers. Clinical outcomes of interest included real-world overall survival (rwOS) and real-world progression-free survival (rwPFS). The median rwOS was 9.2 months. Among patients with at least one assessment, 21.7% reported their best response as 'partial response', with 3.9% reporting 'complete response'. The median duration of response (DoR) and median rwPFS were 11.0 months and 3.9 months, respectively. At baseline, VOLUME-PRO patients reported difficulties relating to fatigue, physical and sexual functioning, dyspnea, nausea, sticky saliva, dry mouth, pain/discomfort, mobility, and financial difficulties. There were improvements in social functioning and financial difficulties throughout the study; however, no other clinically meaningful changes were noted. No new safety concerns were identified. This real-world, multinational, multicenter, retrospective and prospective study supports the effectiveness and safety of nivolumab for R/M SCCHN patients.

Monocyte-derived cells invade brain parenchyma and amyloid plaques in human Alzheimer's disease hippocampus.

Microglia are brain-resident myeloid cells and play a major role in the innate immune responses of the CNS and the pathogenesis of Alzheimer's disease (AD). However, the contribution of nonparenchymal or brain-infiltrated myeloid cells to disease progression remains to be demonstrated. Here, we show that monocyte-derived cells (MDC) invade brain parenchyma in advanced stages of AD continuum using transcriptional analysis and immunohistochemical characterization in post-mortem human hippocampus. Our findings demonstrated that a high proportion (60%) of demented Braak V-VI individuals was associated with up-regulation of genes rarely expressed by microglial cells and abundant in monocytes, among which stands the membrane-bound scavenger receptor for haptoglobin/hemoglobin complexes or Cd163. These Cd163-positive MDC invaded the hippocampal parenchyma, acquired a microglial-like morphology, and were located in close proximity to blood vessels. Moreover, and most interesting, these invading monocytes infiltrated the nearby amyloid plaques contributing to plaque-associated myeloid cell heterogeneity. However, in aged-matched control individuals with hippocampal amyloid pathology, no signs of MDC brain infiltration or plaque invasion were found. The previously reported microglial degeneration/dysfunction in AD hippocampus could be a key pathological factor inducing MDC recruitment. Our data suggest a clear association between MDC infiltration and endothelial activation which in turn may contribute to damage of the blood brain barrier integrity. The recruitment of monocytes could be a consequence rather than the cause of the severity of the disease. Whether monocyte infiltration is beneficial or detrimental to AD pathology remains to be fully elucidated. These findings open the opportunity to design targeted therapies, not only for microglia but also for the peripheral immune cell population to modulate amyloid pathology and provide a better understanding of the immunological mechanisms underlying the progression of AD.

Cyclic Multiplex Fluorescent Immunohistochemistry Protocol to Phenotype Glial Cells in Formalin-Fixed Paraffin-Embedded Human Brain Sections.

There is a growing interest in expanding the multiplexing capability of immunohistochemistry to achieve a deeper phenotyping of various cell types in health and disease. Here, we describe a protocol of cyclic multiplex fluorescent immunohistochemistry that enables the labeling of up to 16 antigens on the same formalin-fixed paraffin-embedded section using "off-the-shelf," commercially available, primary antibodies as well as fluorescently conjugated secondary antibodies. Key steps include the denaturing/stripping of the antibodies by microwaving and the quenching of any remaining fluorescent signal between the cycles of otherwise traditional multiplexed fluorescent immunohistochemistry. We have successfully applied this protocol to characterize astrocytic and microglial responses to Aß plaques and neurofibrillary tangles in Alzheimer's disease brains, but it could be easily adapted to other user's needs regarding cell types, disease, and organ.

Cytotoxicity and Effects on the Synapsis Induced by Pure Cylindrospermopsin in an E17 Embryonic Murine Primary Neuronal Culture in a Concentration- and Time-Dependent Manner.

Cylindrospermopsin (CYN) is a cyanotoxin whose incidence has been increasing in the last decades. Due to its capacity to exert damage at different levels of the organism, it is considered a cytotoxin. Although the main target organ is the liver, recent studies indicate that CYN has potential toxic effects on the nervous system, both in vitro and in vivo. Thus, the aim of the present work was to study the effects of this cyanotoxin on neuronal viability and synaptic integrity in murine primary cultures of neurons exposed to environmentally relevant concentrations (0-1 µg/mL CYN) for 12, 24, and 48 h. The results demonstrate a concentration- and time-dependent decrease in cell viability; no cytotoxicity was detected after exposure to the cyanotoxin for 12 h, while all of the concentrations assayed decreased this parameter after 48 h. Furthermore, CYN was also demonstrated to exert damage at the synaptic level in a murine primary neuronal culture in a concentration- and time-dependent manner. These data highlight the importance of studying the neurotoxic properties of this cyanotoxin in different experimental models.

Cyclic multiplex fluorescent immunohistochemistry and machine learning reveal distinct states of astrocytes and microglia in normal aging and Alzheimer's disease.

BACKGROUND: Astrocytes and microglia react to Aß plaques, neurofibrillary tangles, and neurodegeneration in the Alzheimer's disease (AD) brain. Single-nuclei and single-cell RNA-seq have revealed multiple states or subpopulations of these glial cells but lack spatial information. We have developed a methodology of cyclic multiplex fluorescent immunohistochemistry on human postmortem brains and image analysis that enables a comprehensive morphological quantitative characterization of astrocytes and microglia in the context of their spatial relationships with plaques and tangles. METHODS: Single FFPE sections from the temporal association cortex of control and AD subjects were subjected to 8 cycles of multiplex fluorescent immunohistochemistry, including 7 astroglial, 6 microglial, 1 neuronal, Aß, and phospho-tau markers. Our analysis pipeline consisted of: (1) image alignment across cycles; (2) background subtraction; (3) manual annotation of 5172 ALDH1L1+ astrocytic and 6226 IBA1+ microglial profiles; (4) local thresholding and segmentation of profiles; (5) machine learning on marker intensity data; and (6) deep learning on image features. RESULTS: Spectral clustering identified three phenotypes of astrocytes and microglia, which we termed "homeostatic," "intermediate," and "reactive." Reactive and, to a lesser extent, intermediate astrocytes and microglia were closely associated with AD pathology (≤ 50 µm). Compared to homeostatic, reactive astrocytes contained substantially higher GFAP and YKL-40, modestly elevated vimentin and TSPO as well as EAAT1, and reduced GS. Intermediate astrocytes had markedly increased EAAT2, moderately increased GS, and intermediate GFAP and YKL-40 levels. Relative to homeostatic, reactive microglia showed increased expression of all markers (CD68, ferritin, MHC2, TMEM119, TSPO), whereas intermediate microglia exhibited increased ferritin and TMEM119 as well as intermediate CD68 levels. Machine learning models applied on either high-plex signal intensity data (gradient boosting machines) or directly on image features (convolutional neural networks) accurately discriminated control vs. AD diagnoses at the single-cell level. CONCLUSIONS: Cyclic multiplex fluorescent immunohistochemistry combined with machine learning models holds promise to advance our understanding of the complexity and heterogeneity of glial responses as well as inform transcriptomics studies. Three distinct phenotypes emerged with our combination of markers, thus expanding the classic binary "homeostatic vs. reactive" classification to a third state, which could represent "transitional" or "resilient" glia.

Dyspnea and COVID-19: A Review of Confounding Diagnoses during the Postpartum Period.

The puerperium is a complex period that begins with placental delivery and lasts for 6 weeks, during which readaptation of the female organism and redistribution of blood volume occur. This period is conducive to the occurrence of thromboembolic events. In the context of the SARS-CoV-2 pandemic, the virus responsible for COVID-19, the attention of the scientific community and health professionals has been focused on obtaining insights on different aspects of this disease, including etiology, transmission, diagnosis, and treatment. Regarding the pregnancy-postpartum cycle, it is opportune to review the clinical conditions that can occur during this period and to investigate dyspnea as a postpartum symptom in order to avoid its immediate association with COVID-19 without further investigation, which can lead to overlooking the diagnosis of other important and occasionally fatal conditions.

O puerpério é um período complexo que se inicia com a dequitação placentária e dura por 6 semanas, no qual a readaptação do organismo materno e a redistribuição do volume sanguíneo ocorrem, além de ser também um cenário propício para eventos pró-trombóticos. No contexto da pandemia de SARS-CoV-2, vírus responsável pela COVID-19, a atenção da comunidade científica e dos profissionais da saúde está voltada a elucidar os aspectos da doença, como a etiologia, a transmissão, o diagnóstico e o tratamento. Considerando o ciclo gravídico-puerperal, é oportuna a revisão de condições clínicas que ocorrem durante este período e que apresentam a dispneia como sintoma, a fim de evitar que ela seja automaticamente associada à COVID-19 sem investigações aprofundadas, o que pode levar à negligência do diagnóstico de outras condições importantes e que podem ser, por vezes, fatais.

Dyspnea and COVID-19: A Review of Confounding Diagnoses during the Postpartum Period / Dispneia e COVID-19: uma revisão de diagnósticos confundidores no período pós-parto

Abstract The puerperium is a complex period that begins with placental delivery and lasts for 6 weeks, during which readaptation of the female organism and redistribution of blood volume occur. This period is conducive to the occurrence of thromboembolic events. In the context of the SARS-CoV-2 pandemic, the virus responsible for COVID-19, the attention of the scientific community and health professionals has been focused on obtaining insights on different aspects of this disease, including etiology, transmission, diagnosis, and treatment. Regarding the pregnancy-postpartum cycle, it is opportune to review the clinical conditions that can occur during this period and to investigate dyspnea as a postpartum symptom in order to avoid its immediate association with COVID-19 without further investigation, which can lead to overlooking the diagnosis of other important and occasionally fatal conditions.

Resumo O puerpério é um período complexo que se inicia com a dequitação placentária e dura por 6 semanas, no qual a readaptação do organismo materno e a redistribuição do volume sanguíneo ocorrem, além de ser também um cenário propício para eventos pró-trombóticos. No contexto da pandemia de SARS-CoV-2, vírus responsável pela COVID-19, a atenção da comunidade científica e dos profissionais da saúde está voltada a elucidar os aspectos da doença, como a etiologia, a transmissão, o diagnóstico e o tratamento. Considerando o ciclo gravídico-puerperal, é oportuna a revisão de condições clínicas que ocorrem durante este período e que apresentam a dispneia como sintoma, a fimde evitar que ela seja automaticamente associada à COVID-19 sem investigações aprofundadas, o que pode levar à negligência do diagnóstico de outras condições importantes e que podem ser, por vezes, fatais.

Should We Open Fire on Microglia? Depletion Models as Tools to Elucidate Microglial Role in Health and Alzheimer's Disease.

Microglia play a critical role in both homeostasis and disease, displaying a wide variety in terms of density, functional markers and transcriptomic profiles along the different brain regions as well as under injury or pathological conditions, such as Alzheimer's disease (AD). The generation of reliable models to study into a dysfunctional microglia context could provide new knowledge towards the contribution of these cells in AD. In this work, we included an overview of different microglial depletion approaches. We also reported unpublished data from our genetic microglial depletion model, Cx3cr1CreER/Csf1rflx/flx, in which we temporally controlled microglia depletion by either intraperitoneal (acute model) or oral (chronic model) tamoxifen administration. Our results reported a clear microglial repopulation, then pointing out that our model would mimic a context of microglial replacement instead of microglial dysfunction. Next, we evaluated the origin and pattern of microglial repopulation. Additionally, we also reviewed previous works assessing the effects of microglial depletion in the progression of Aß and Tau pathologies, where controversial data are found, probably due to the heterogeneous and time-varying microglial phenotypes observed in AD. Despite that, microglial depletion represents a promising tool to assess microglial role in AD and design therapeutic strategies.

Amyloid-ß impairs the phagocytosis of dystrophic synapses by astrocytes in Alzheimer's disease.

Reactive astrocytes and dystrophic neurites, most aberrant presynaptic elements, are found surrounding amyloid-ß plaques in Alzheimer's disease (AD). We have previously shown that reactive astrocytes enwrap, phagocytose, and degrade dystrophic synapses in the hippocampus of APP mice and AD patients, but affecting less than 7% of dystrophic neurites, suggesting reduced phagocytic capacity of astrocytes in AD. Here, we aimed to gain insight into the underlying mechanisms by analyzing the capacity of primary astrocyte cultures to phagocytose and degrade isolated synapses (synaptoneurosomes, SNs) from APP (containing dystrophic synapses and amyloid-ß peptides), Tau (containing AT8- and AT100-positive phosphorylated Tau) and WT (controls) mice. We found highly reduced phagocytic and degradative capacity of SNs-APP, but not AT8/AT100-positive SNs-Tau, as compared with SNs-WT. The reduced astrocyte phagocytic capacity was verified in hippocampus from 12-month-old APP mice, since only 1.60 ± 3.81% of peri-plaque astrocytes presented phagocytic structures. This low phagocytic capacity did not depend on microglia-mediated astrocyte reactivity, because removal of microglia from the primary astrocyte cultures abrogated the expression of microglia-dependent genes in astrocytes, but did not affect the phagocytic impairment induced by oligomeric amyloid-ß alone. Taken together, our data suggest that amyloid-ß, but not hyperphosphorylated Tau, directly impairs the capacity of astrocytes to clear the pathological accumulation of oligomeric amyloid-ß, as well as of peri-plaque dystrophic synapses containing amyloid-ß, perhaps by reducing the expression of phagocytosis receptors such as Mertk and Megf10, thus increasing neuronal damage in AD. Therefore, the potentiation or recovery of astrocytic phagocytosis may be a novel therapeutic avenue in AD.

Regional differences in tobacco smoking and lung cancer in Portugal in 2018: a population-based analysis using nationwide incidence and mortality data.

OBJECTIVES: This study aims to estimate the proportion of lung cancer cases and deaths attributable to tobacco smoking in Portugal in 2018, complemented by trends in incidence and mortality, by sex and region. DESIGN: Cancer cases for 1998-2011 and cancer deaths for 1991-2018 were obtained from population-based registries and Statistics Portugal, respectively. We projected cases for 2018 and used reported deaths for the same year to estimate, using Peto's method, the number and proportion of lung cancer cases and deaths caused by tobacco smoking in 2018. We calculated the age-adjusted incidence and mortality rates in each year of diagnosis and death. We fitted a joinpoint regression to the observed data to estimate the annual percentage change (APC) in the rates. SETTING: Portugal. RESULTS: In 2018, an estimated 3859 cases and 3192 deaths from lung cancer were attributable to tobacco smoking in Portugal, with men presenting a population attributable fraction (PAF) of 82.6% (n=3064) for incidence and 84.1% (n=2749) for mortality, while in women those values were 51.0% (n=795) and 42.7% (n=443), respectively. In both sexes and metrics, the Azores were the region with the highest PAF and the Centre with the lowest. During 1998-2011, the APC for incidence ranged from 0.6% to 3.0% in men and 3.6% to 7.9% in women, depending on region, with mortality presenting a similar pattern between sexes. CONCLUSION: Exposure to tobacco smoking has accounted for most of the lung cancer cases and deaths estimated in Portugal in 2018. Differential patterns of tobacco consumption across the country, varying implementation of primary prevention programmes and differences in personal cancer awareness may have contributed to the disparities observed. Primary prevention of lung cancer remains a public health priority, particularly among women.

Enhancing microtubule stabilization rescues cognitive deficits and ameliorates pathological phenotype in an amyloidogenic Alzheimer's disease model.

In Alzheimer's disease (AD), and other tauopathies, microtubule destabilization compromises axonal and synaptic integrity contributing to neurodegeneration. These diseases are characterized by the intracellular accumulation of hyperphosphorylated tau leading to neurofibrillary pathology. AD brains also accumulate amyloid-beta (Aß) deposits. However, the effect of microtubule stabilizing agents on Aß pathology has not been assessed so far. Here we have evaluated the impact of the brain-penetrant microtubule-stabilizing agent Epothilone D (EpoD) in an amyloidogenic model of AD. Three-month-old APP/PS1 mice, before the pathology onset, were weekly injected with EpoD for 3 months. Treated mice showed significant decrease in the phospho-tau levels and, more interesting, in the intracellular and extracellular hippocampal Aß accumulation, including the soluble oligomeric forms. Moreover, a significant cognitive improvement and amelioration of the synaptic and neuritic pathology was found. Remarkably, EpoD exerted a neuroprotective effect on SOM-interneurons, a highly AD-vulnerable GABAergic subpopulation. Therefore, our results suggested that EpoD improved microtubule dynamics and axonal transport in an AD-like context, reducing tau and Aß levels and promoting neuronal and cognitive protection. These results underline the existence of a crosstalk between cytoskeleton pathology and the two major AD protein lesions. Therefore, microtubule stabilizers could be considered therapeutic agents to slow the progression of both tau and Aß pathology.

Comorbidities, timing of treatments, and chemotherapy use influence outcomes in stage III colon cancer: A population-based European study.

INTRODUCTION: For stage III colon cancer (CC), surgery followed by chemotherapy is the main curative approach, although optimum times between diagnosis and surgery, and surgery and chemotherapy, have not been established. MATERIALS AND METHODS: We analysed a population-based sample of 1912 stage III CC cases diagnosed in eight European countries in 2009-2013 aiming to estimate: (i) odds of receiving postoperative chemotherapy, overall and within eight weeks of surgery; (ii) risks of death/relapse, according to treatment, Charlson Comorbidity Index, time from diagnosis to surgery for emergency and elective cases, and time from surgery to chemotherapy; and (iii) time-trends in chemotherapy use. RESULTS: Overall, 97% of cases received surgery and 65% postoperative chemotherapy, with 71% of these receiving chemotherapy within eight weeks of surgery. Risks of death and relapse were higher for cases starting chemotherapy with delay, but better than for cases not given chemotherapy. Fewer patients with high comorbidities received chemotherapy than those with low (P < 0.001). Chemotherapy timing did not vary (P = 0.250) between high and low comorbidity cases. Electively-operated cases with low comorbidities received surgery more promptly than high comorbidity cases. Risks of death and relapse were lower for elective cases given surgery after four weeks than cases given surgery within a week. High comorbidities were always independently associated with poorer outcomes. Chemotherapy use increased over time. CONCLUSIONS: Our data indicate that promptly-administered postoperative chemotherapy maximizes its benefit, and that careful assessment of comorbidities is important before treatment. The survival benefit associated with slightly delayed elective surgery deserves further investigation.

Root causes and outcomes of postoperative pulmonary complications after abdominal surgery: a retrospective observational cohort study.

BACKGROUND: Postoperative pulmonary complications (PPCs) contribute significantly to overall postoperative morbidity and mortality. In abdominal surgery, PPCs remain frequent. The study aimed to analyze the profile and outcomes of PPCs in patients submitted to abdominal surgery and admitted in a Portuguese polyvalent intensive care unit. METHODS: From January to December 2017 in the polyvalent intensive care unit of Hospital Garcia de Orta, Almada, Portugal, we conducted a retrospective, observational study of inpatients submitted to urgent or elective abdominal surgery who had severe PPCs. We evaluated the perioperative risk factors and associated mortality. Logistic regression was performed to find which perioperative risk factors were most important in the occurrence of PPCs. RESULTS: Sixty patients (75% male) with a median age of 64.5 [47-81] years who were submitted to urgent or elective abdominal surgery were included in the analysis. Thirty-six patients (60%) developed PPCs within 48 h and twenty-four developed PPCs after 48 h. Pneumonia was the most frequent PPC in this sample. In this cohort, 48 patients developed acute respiratory failure and needed mechanical ventilation. In the emergency setting, peritonitis had the highest rate of PPCs. Electively operated patients who developed PPCs were mostly carriers of digestive malignancies. Thirty-day mortality was 21.7%. The risk of PPCs development in the first 48 h was related to the need for neuromuscular blocking drugs several times during surgery and preoperative abnormal arterial blood gases. Median abdominal surgical incision, long surgery duration, and high body mass index were associated with PPCs that occurred more than 48 h after surgery. The American Society of Anesthesiologists physical status score 4 and COPD/Asthma determined less mechanical ventilation needs since they were preoperatively optimized. Malnutrition (low albumin) before surgery was associated with 30-day mortality. CONCLUSION: PPCs after abdominal surgery are still a major problem since they have profound effects on outcomes. Our results suggest that programs before surgery, involve preoperative lifestyle changes, such as nutritional supplementation, exercise, stress reduction, and smoking cessation, were an effective strategy in mitigating postoperative complications by decreasing mortality.

A Natureza em Sade / Nature in Sade

A proposta deste artigo é analisar a ideia de natureza na obra clandestina de Sade, mais especificamente, nas histórias de "Justine" (1787/1999) e de "Juliette" (1801). O exame recairá sobre a fala de dois narradores (dos "Infortúnios da virtude" e da "Nova Justine") e de cinco personagens (Dubois, Noirceuil, Rodin, Braschi e Juliette). Pretende-se estudar quatro noções diferentes de natureza (a compensadora, a criadora, a estúpida e a inexistente) a fim de demonstrar que tais noções formam, na verdade, um único raciocínio, desenvolvido em uma gradação regressiva. Tudo começa em uma natureza onipotente e amoral. Esta se transforma em noção imoral, menos poderosa e que necessita do libertino para desorganizar a matéria, mas passa a se mostrar impotente e inconsequente, até revelar-se uma força tão misteriosa e incompreensível quanto a divindade.

The purpose of this article is to analyze the idea of nature in Sade's clandestine work, more specifically, in the stories of "Justine" (1787/1999) and "Juliette" (1801). The discussion will be based on the speech of two storytellers (from "The Misfortunes of Virtue" and "The New Justine") and five characters (Dubois, Noirceuil, Rodin, Braschi and Juliette). It is intended to study four different notions of nature (the compensator, the creator, the stupid and the nonexistent) in order to show that these notions actually form a single reasoning, developed in a regressive gradation. Everything begins in an omnipotent and amoral nature, which develops in an immoral, less powerful one that requires the libertine to disorganize matter, but it becomes impotent and inconsequential until it reveals itself to be as mysterious and incomprehensible as divinity.