Low-grade systemic inflammation stimulates microglial turnover and accelerates the onset of Alzheimer's-like pathology.

Several in vivo studies have shown that systemic inflammation, mimicked by LPS, triggers an inflammatory response in the CNS, driven by microglia, characterized by an increase in inflammatory cytokines and associated sickness behavior. However, most studies induce relatively high systemic inflammation, not directly compared with the more common low-grade inflammatory events experienced in humans during the life course. Using mice, we investigated the effects of low-grade systemic inflammation during an otherwise healthy early life, and how this may precondition the onset and severity of Alzheimer's disease (AD)-like pathology. Our results indicate that low-grade systemic inflammation induces sub-threshold brain inflammation and promotes microglial proliferation driven by the CSF1R pathway, contrary to the effects caused by high systemic inflammation. In addition, repeated systemic challenges with low-grade LPS induce disease-associated microglia. Finally, using an inducible model of AD-like pathology (Line 102 mice), we observed that preconditioning with repeated doses of low-grade systemic inflammation, prior to APP induction, promotes a detrimental effect later in life, leading to an increase in Aß accumulation and disease-associated microglia. These results support the notion that episodic low-grade systemic inflammation has the potential to influence the onset and severity of age-related neurological disorders, such as AD.

Clinical Importance of Differentiating Epstein-Barr Virus (EBV)-Positive Plasmacytoma From Plasmablastic Lymphoma: Another Unique Case of EBV-Positive Plasmacytoma in an Immunocompetent Patient.

Epstein-Barr virus (EBV)-positive plasmacytoma is a rare and unique plasma cell neoplasm that could arise in immunocompetent individuals. Given the molecular and immunohistochemical similarity of EBV-positive plasmacytomas to their significantly more aggressive counterpart, plasmablastic lymphoma (PBL), providers must distinguish between the two neoplasms. This case elucidates a presentation of EBV-positive plasmacytomas in a healthy, immunocompetent individual originating in the C4/C5 cervical neck region. The patient's clinical presentation, in combination with the surgical pathology from the mass biopsy, pointed toward EBV-positive plasmacytoma. Factors such as cellular proliferation rate, cellular atypia, and immunohistochemical staining help differentiate the two diseases. This case will further help providers in the oncologic world to identify these masses.

Cutaneous Necrosis of the Skin Secondary to Methicillin-Resistant Staphylococcus aureus (MRSA) and Bacteroides With Superimposed Herpes Simplex Virus Type II (HSV-II) in the Setting of Infective Endocarditis.

Herpes simplex virus type II (HSV-II) with superimposed bacterial skin infection is an uncommon presentation of cutaneous necrosis in the setting of infective endocarditis. This case reflects a unique presentation of an immunosuppressed patient with infective endocarditis complicated by septic emboli and cutaneous skin lesions attributable to HSV-II and superimposed bacterial skin infection. The patient presented from an outside hospital with symptoms consistent with acute onset heart failure and skin lesions. Transthoracic and transesophageal echocardiography performed there demonstrated focal thickening of the anterior mitral valve leaflet with severe mitral regurgitation. The patient then underwent extensive infectious work-up and was put on broad-spectrum antibiotics. Further work-up demonstrated greater than three DUKE minor criteria and reiterated the focal thickening of the anterior leaflet of the mitral valve, making infective endocarditis the most likely etiology. Biopsies of the skin lesions were performed which stained positive for HSV-II and grew methicillin-resistant Staphylococcus aureus and Bacteroides fragilis. The cardiothoracic surgery service ultimately decided not to perform any surgical intervention to the mitral valve during her hospitalization as she was deemed to be too high of a risk due to her thrombocytopenia and significant comorbidities. She was later discharged in hemodynamically stable condition on long-term intravenous antibiotics with repeat echocardiography demonstrating significant reduction in the mitral regurgitation and the focal thickening of the anterior leaflet of the mitral valve.

Does Gender Influence the Indication of Treatment and Long-Term Prognosis in Severe Aortic Stenosis?

INTRODUCTION: It is a matter of controversy whether the therapeutic strategy for severe aortic stenosis (AS) differs according to gender. METHODS: Retrospective study of patients diagnosed with severe AS (transvalvular mean gradient ≥ 40 mmHg and/or aortic valvular area < 1 cm2) between 2009 and 2019. Our aim was to assess the association of sex on AVR or medical management and outcomes in patients with severe AS. RESULTS: 452 patients were included. Women (51.1%) were older than men (80 ± 8.4 vs. 75.8 ± 9.9 years; p < 0.001). Aortic valve replacement (AVR) was performed less frequently in women (43.4% vs. 53.2%; p = 0.03), but multivariate analyses showed that sex was not an independent predictor factor for AVR. Age, Charlson index and symptoms were predictive factors (OR 0.81 [0.82-0.89], OR 0.81 [0.71-0.93], OR 22.02 [6.77-71.64]). Survival analysis revealed no significant association of sex within all-cause and cardiovascular mortalities (log-rank p = 0.63 and p = 0.07). Cox proportional hazards analyses showed AVR (HR: 0.1 [0.06-0.15]), Charlson index (HR: 1.13 [1.06-1.21]) and reduced LVEF (HR: 1.9 [1.32-2.73]) to be independent cardiovascular mortality predictors. CONCLUSIONS: Gender is not associated with AVR or long-term prognosis. Cardiovascular mortality was associated with older age, more comorbidity and worse LVEF.

Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aß pathology.

The sustained proliferation of microglia is a key hallmark of Alzheimer's disease (AD), accelerating its progression. Here, we aim to understand the long-term impact of the early and prolonged microglial proliferation observed in AD, hypothesizing that extensive and repeated cycling would engender a distinct transcriptional and phenotypic trajectory. We show that the early and sustained microglial proliferation seen in an AD-like model promotes replicative senescence, characterized by increased ßgal activity, a senescence-associated transcriptional signature, and telomere shortening, correlating with the appearance of disease-associated microglia (DAM) and senescent microglial profiles in human post-mortem AD cases. The prevention of early microglial proliferation hinders the development of senescence and DAM, impairing the accumulation of Aß, as well as associated neuritic and synaptic damage. Overall, our results indicate that excessive microglial proliferation leads to the generation of senescent DAM, which contributes to early Aß pathology in AD.

What is the radiation before 5G? A correlation study between measurements in situ and in real time and epidemiological indicators in Vallecas, Madrid.

BACKGROUND: Exposure of the general population to electromagnetic radiation emitted by mobile phone base stations is one of the greater concerns of residents affected by the proximity of these structures due to the possible relationship between radiated levels and health indicators. OBJECTIVES: This study aimed to find a possible relationship between some health indicators and electromagnetic radiation measurements. METHODS: A total of 268 surveys, own design, were completed by residents of a Madrid neighborhood surrounded by nine telephone antennas, and 105 measurements of electromagnetic radiation were taken with a spectrum analyzer and an isotropic antenna, in situ and in real - time, both outside and inside the houses. RESULTS: It was shown statistically significant p - values in headaches presence (p = 0.010), nightmares (p = 0.001), headache intensity (p < 0.001), dizziness frequency (p = 0.011), instability episodes frequency (p = 0.026), number of hours that one person sleeps per day (p < 0.001) and three of nine parameters studied from tiredness. Concerning cancer, there are 5.6% of cancer cases in the study population, a percentage 10 times higher than that of the total Spanish population. DISCUSSION: People who are exposed to higher radiation values present more severe headaches, dizziness and nightmares. Moreover, they sleep fewer hours.

Novel presenilin 1 mutation (p.Thr-Pro116-117Ser-Thr) in a Spanish family with early-onset Alzheimer's disease.

Presenilin 1 (PSEN1) is a γ-secretase component, which is in charge of the amyloid precursor protein (APP) cleavage. APP is believed to play a central role in the pathogenesis of Alzheimer's disease (AD). PSEN1 mutations are the most important causes of familial AD, being related to the earlier onset and rapid progression of the disease. Presenilins and APP mutations represent an extraordinary opportunity to study the pathophysiology of AD. We describe the clinical and genetic study of a 37-year-old male patient with a novel mutation in PSEN1 (p.Thr-Pro116-117Ser-Thr). We have studied the pedigree of his family with a further 9 members affected, all of them with onset in their 30s. We have also described the clinical data and results of brain biopsies in 2 of them. DNA sequencing of a tissue sample from an uncle of the patient, who died of AD in the 80s, showed the same mutation as in the patient. These data and predictive analysis indicate the pathogenicity of the mutation.

Coupled Proliferation and Apoptosis Maintain the Rapid Turnover of Microglia in the Adult Brain.

Microglia play key roles in brain development, homeostasis, and function, and it is widely assumed that the adult population is long lived and maintained by self-renewal. However, the precise temporal and spatial dynamics of the microglial population are unknown. We show in mice and humans that the turnover of microglia is remarkably fast, allowing the whole population to be renewed several times during a lifetime. The number of microglial cells remains steady from late postnatal stages until aging and is maintained by the spatial and temporal coupling of proliferation and apoptosis, as shown by pulse-chase studies, chronic in vivo imaging of microglia, and the use of mouse models of dysregulated apoptosis. Our results reveal that the microglial population is constantly and rapidly remodeled, expanding our understanding of its role in the maintenance of brain homeostasis.

CSF1R blockade slows the progression of amyotrophic lateral sclerosis by reducing microgliosis and invasion of macrophages into peripheral nerves.

Inflammation is a common neuropathological feature in several neurological disorders, including amyotrophic lateral sclerosis (ALS). We have studied the contribution of CSF1R signalling to inflammation in ALS, as a pathway previously reported to control the expansion and activation of microglial cells. We found that microglial cell proliferation in the spinal cord of SOD1(G93A) transgenic mice correlates with the expression of CSF1R and its ligand CSF1. Administration of GW2580, a selective CSF1R inhibitor, reduced microglial cell proliferation in SOD1(G93A) mice, indicating the importance of CSF1-CSF1R signalling in microgliosis in ALS. Moreover, GW2580 treatment slowed disease progression, attenuated motoneuron cell death and extended survival of SOD1(G93A) mice. Electrophysiological assessment revealed that GW2580 treatment protected skeletal muscle from denervation prior to its effects on microglial cells. We found that macrophages invaded the peripheral nerve of ALS mice before CSF1R-induced microgliosis occurred. Interestingly, treatment with GW2580 attenuated the influx of macrophages into the nerve, which was partly caused by the monocytopenia induced by CSF1R inhibition. Overall, our findings provide evidence that CSF1R signalling regulates inflammation in the central and peripheral nervous system in ALS, supporting therapeutic targeting of CSF1R in this disease.

Dark microglia: A new phenotype predominantly associated with pathological states.

The past decade has witnessed a revolution in our understanding of microglia. These immune cells were shown to actively remodel neuronal circuits, leading to propose new pathogenic mechanisms. To study microglial implication in the loss of synapses, the best pathological correlate of cognitive decline across chronic stress, aging, and diseases, we recently conducted ultrastructural analyses. Our work uncovered the existence of a new microglial phenotype that is rarely present under steady state conditions, in hippocampus, cerebral cortex, amygdala, and hypothalamus, but becomes abundant during chronic stress, aging, fractalkine signaling deficiency (CX3 CR1 knockout mice), and Alzheimer's disease pathology (APP-PS1 mice). Even though these cells display ultrastructural features of microglia, they are strikingly distinct from the other phenotypes described so far at the ultrastructural level. They exhibit several signs of oxidative stress, including a condensed, electron-dense cytoplasm and nucleoplasm making them as "dark" as mitochondria, accompanied by a pronounced remodeling of their nuclear chromatin. Dark microglia appear to be much more active than the normal microglia, reaching for synaptic clefts, while extensively encircling axon terminals and dendritic spines with their highly ramified and thin processes. They stain for the myeloid cell markers IBA1 and GFP (in CX3 CR1-GFP mice), and strongly express CD11b and microglia-specific 4D4 in their processes encircling synaptic elements, and TREM2 when they associate with amyloid plaques. Overall, these findings suggest that dark microglia, a new phenotype that we identified based on their unique properties, could play a significant role in the pathological remodeling of neuronal circuits, especially at synapses.

Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology.

The proliferation and activation of microglial cells is a hallmark of several neurodegenerative conditions. This mechanism is regulated by the activation of the colony-stimulating factor 1 receptor (CSF1R), thus providing a target that may prevent the progression of conditions such as Alzheimer's disease. However, the study of microglial proliferation in Alzheimer's disease and validation of the efficacy of CSF1R-inhibiting strategies have not yet been reported. In this study we found increased proliferation of microglial cells in human Alzheimer's disease, in line with an increased upregulation of the CSF1R-dependent pro-mitogenic cascade, correlating with disease severity. Using a transgenic model of Alzheimer's-like pathology (APPswe, PSEN1dE9; APP/PS1 mice) we define a CSF1R-dependent progressive increase in microglial proliferation, in the proximity of amyloid-ß plaques. Prolonged inhibition of CSF1R in APP/PS1 mice by an orally available tyrosine kinase inhibitor (GW2580) resulted in the blockade of microglial proliferation and the shifting of the microglial inflammatory profile to an anti-inflammatory phenotype. Pharmacological targeting of CSF1R in APP/PS1 mice resulted in an improved performance in memory and behavioural tasks and a prevention of synaptic degeneration, although these changes were not correlated with a change in the number of amyloid-ß plaques. Our results provide the first proof of the efficacy of CSF1R inhibition in models of Alzheimer's disease, and validate the application of a therapeutic strategy aimed at modifying CSF1R activation as a promising approach to tackle microglial activation and the progression of Alzheimer's disease.

Microglia regulate hippocampal neurogenesis during chronic neurodegeneration.

Neurogenesis is altered in neurodegenerative disorders, partly regulated by inflammatory factors. We have investigated whether microglia, the innate immune brain cells, regulate hippocampal neurogenesis in neurodegeneration. Using the ME7 model of prion disease we applied gain- or loss-of CSF1R function, as means to stimulate or inhibit microglial proliferation, respectively, to dissect the contribution of these cells to neurogenesis. We found that increased hippocampal neurogenesis correlates with the expansion of the microglia population. The selective inhibition of microglial proliferation caused a reduction in neurogenesis and a restoration of normal neuronal differentiation, supporting a pro-neurogenic role for microglia. Using a gene screening strategy, we identified TGFß as a molecule controlling the microglial pro-neurogenic response in chronic neurodegeneration, supported by loss-of-function mechanistic experiments. By the selective targeting of microglial proliferation we have been able to uncover a pro-neurogenic role for microglia in chronic neurodegeneration, suggesting promising therapeutic targets to normalise the neurogenic niche during neurodegeneration.

Evidencias experimentales con respecto al papel de distintos tipos de grasas insaturadas de la dieta en el envejecimiento / Experimental evidence on the role of different types unsaturated fats in the diet on ageing

La nutrición ha sido relacionada ampliamente con el proceso fisiológico del envejecimiento. Varios nutrientes, como ciertos tipos de grasa de la dieta y diversos antioxidantes, han demostrado poseer efectos positivos en enfermedades relacionadas con la edad. El tipo de grasa de la dieta afecta a la estructura y función mitocondrial, así como a su susceptibilidad al estrés oxidativo, todos, factores implicados en el envejecimiento. La presente revisión trata de resumir los estudios realizados por nuestro grupo de investigación en los últimos 10 años empleando aceite de oliva virgen, aceite de girasol o aceite de pescado como fuente de grasa insaturada de la dieta en relación con un modelo de envejecimiento en rata (AU9

Nutrition has been largely related to the physiological ageing process. Several nutrients, such as certain types of dietary fat and various antioxidants have been shown to have positive effects on age-related diseases. The type of dietary fat affects mitochondrial structure and function, as well as its susceptibility to oxidative stress, all factors involved in ageing. The present review aims to summarise the studies conducted by our research group in the past 10 years, using virgin olive oil, sunflower oil, or fish oil as a source of unsaturated fat diet relative to a rat model of ageing (AU)

Sunflower Oil but Not Fish Oil Resembles Positive Effects of Virgin Olive Oil on Aged Pancreas after Life-Long Coenzyme Q Addition.

An adequate pancreatic structure is necessary for optimal organ function. Structural changes are critical in the development of age-related pancreatic disorders. In this context, it has been reported that different pancreatic compartments from rats were affected according to the fat composition consumed. Since there is a close relationship between mitochondria, oxidative stress and aging, an experimental approach has been developed to gain more insight into this process in the pancreas. A low dosage of coenzyme Q was administered life-long in rats in order to try to prevent pancreatic aging-related alterations associated to some dietary fat sources. According to that, three groups of rats were fed normocaloric diets containing Coenzyme Q (CoQ) for two years, where virgin olive, sunflower, or fish oil was included as unique fat source. Pancreatic samples for microscopy and blood samples were collected at the moment of euthanasia. The main finding is that CoQ supplementation gives different results according to fat used in diet. When sunflower oil was the main fat in the diet, CoQ supplementation seems to improve endocrine pancreas structure and in particular ß-cell mass resembling positive effects of virgin olive oil. Conversely, CoQ intake does not seem to improve the structural alterations of exocrine compartment previously observed in fish oil fed rats. Therefore CoQ may improve pancreatic alterations associated to the chronic intake of some dietary fat sources.

[Experimental evidence on the role of different types unsaturated fats in the diet on ageing]. / Evidencias experimentales con respecto al papel de distintos tipos de grasas insaturadas de la dieta en el envejecimiento.

Nutrition has been largely related to the physiological ageing process. Several nutrients, such as certain types of dietary fat and various antioxidants have been shown to have positive effects on age-related diseases. The type of dietary fat affects mitochondrial structure and function, as well as its susceptibility to oxidative stress, all factors involved in ageing. The present review aims to summarise the studies conducted by our research group in the past 10 years, using virgin olive oil, sunflower oil, or fish oil as a source of unsaturated fat diet relative to a rat model of ageing.

[Greenlight-XPS laser vaporization, the new standard of treatment in men with myasthenia gravis and benign prostatic obstruction]? / La fotovaporización prostática con laser (PVPL) podría constituir una alternativa eficaz y segura a la resección transurethral (RTUP) en pacientes con miastenia gravis.

UNLABELLED: Patients with Benign Prostatic Obstruction (BPO) and Myasthenia Gravis (MG) treated with Transurethral Resection of the prostate (TURP) show a high incidence of urinary incontinence due to unnoticed damage to muscle fibres of the external sphincter. Photoselective laser vaporization could be an alternative treatment based on the hypothesis that using Laser as energy source in the treatment of BPH prevents sphincter damage because the energy is not transmitted outside the fiber tip. METHODS: We report the case of a man diagnosed of MG and symptomatic BPO treated satisfactorily with photoselective laser vaporization (GreenLight-XPS). RESULTS: Patient did not experienced postoperative secondary incontinence. CONCLUSIONS: Laser photoselective vaporization (GreenLight-XPS) could be the standard treatment for men with MG and BPO, whose prostate volume is less than 60 cc who are candidates for surgical treatment. Despite the extremely low incidence of these cases, further investigations are needed to confirm this affirmation.

Is there a role for systemic targeted therapy after surgical treatment for metastases of renal cell carcinoma?

Metastatic renal cell carcinoma (mRCC) is a challenging disease. Despite the new targeted therapies, complete remissions occur only in 1%-3% of the cases, and the most effective first-line treatment drugs have reached a ceiling in overall survival (ranging from 9 to 49 mo). Metastasectomy remains to be the only curative option in most patients with mRCC. Prognostic nomograms have been recently published, so we have tools to classify patients in risk groups, allowing us to detect the cases with the higher risk of recurrence after metastasectomy. Although sparse, there is some evidence of effectiveness of neoadjuvant targeted therapy before metastasectomy; but with an increase in surgical complications due to the effects of these new drugs in tissue healing. We have aimed to answer the question: Is there a role for systemic targeted therapy after surgical treatment for metastases of renal cell carcinoma? We have made a search in Pubmed database. As far as we know, evidence is low and it's based in case reports and small series of patients treated with adjuvant drugs after neoadjuvant therapy plus metastasectomy in cases of partial response to initial systemic treatment. Despite the limitations and high risk of bias, promising results and cases with long-term survival with this approach have been described. Two ongoing clinical trials may answer the question that concerns us.

La fotovaporización prostática con láser (PVPL) podría constituir una alternativa eficaz y segura a la resección transuretral (RTUP) en pacientes / Greenlight-XPS laser vaporization, the new standard of treatment in men with myasthenia gravis and benign prostatic obstruction?

OBJETIVOS: Los pacientes con miastenia gravis (MG) diagnosticados de sintomatología del tracto urinario inferior (STUI) secundaria a hiperplasia benigna de próstata (HBP), presentan una elevada incidencia de incontinencia urinaria al ser sometidos a resección transuretral de próstata (RTUp), secundaria a la lesión inadvertida de las fibras musculares del esfínter externo. La fotovaporización prostática con Láser podría ser una alternativa de tratamiento, ya que podría evitar el daño inadvertido del esfínter debido a que la energía no se transmite más allá de la punta de la fibra. MÉTODOS: Presentamos el caso de un varón con antecedente de MG y HBP sintomática tratado de forma satisfactoria mediante fotovaporiazación selectiva con Láser verde (GreenLight-XPS). RESULTADOS: El paciente no presentó incontinencia urinaria tras la cirugía. CONCLUSIONES: La fotovaporización prostática con Láser verde (GreenLight-XPS) podría ser el tratamiento estándar de aquellos varones con MG y HBP candidatos a tratamiento quirúrgico, con volumen prostático menor de 60 cc. A pesar de la baja incidencia de estos pacientes, futuros casos son necesarios para corroborar esta afirmación

Patients with Benign Prostatic Obstruction (BPO) and Myasthenia Gravis (MG) treated with Transurethral Resection of the prostate (TURP) show a high incidence of urinary incontinence due to unnoticed damage to muscle fibres of the external sphincter. Photoselective laser vaporization could be an alternative treatment based on the hypothesis that using Laser as energy source in the treatment of BPH prevents sphincter damage because the energy is not transmitted outside the fiber tip. METHODS: We report the case of a man diagnosed of MG and symptomatic BPO treated satisfactorily with photoselective laser vaporization (GreenLight-XPS). Results Patient did not experienced postoperative secondary incontinence. CONCLUSION: Laser photoselective vaporization (GreenLight-XPS) could be the standard treatment for men with MG and BPO, whose prostate volume is less than 60 cc who are candidates for surgical treatment. Despite the extremely low incidence of these cases, further investigations are needed to confirm this affirmation