Histamine and Immune Biomarkers in CNS Disorders

Neuroimmune dysregulation is a common phenomenon in different forms of central nervous system (CNS) disorders. Cross-links between central and peripheral immune mechanisms appear to be disrupted as reflected by a series of immune markers (CD3, CD4, CD7, HLA-DR, CD25, CD28, and CD56) which show variability in brain disorders such as anxiety, depression, psychosis, stroke, Alzheimer’s disease, Parkinson’s disease, attention-deficit hyperactivity disorder, migraine, epilepsy, vascular dementia, mental retardation, cerebrovascular encephalopathy, multiple sclerosis, brain tumors, cranial nerve neuropathies, mental retardation, and posttraumatic brain injury. Histamine (HA) is a pleiotropic monoamine involved in several neurophysiological functions, neuroimmune regulation, and CNS pathogenesis. Changes in brain HA show an age- and sex-related pattern, and alterations in brain HA levels are present in different CNS regions of patients with Alzheimer’s disease (AD). Brain HA in neuronal and nonneuronal compartments plays a dual role (neurotrophic versus neurotoxic) in a tissue-specific manner. Pathogenic mechanisms associated with neuroimmune dysregulation in AD involve HA, interleukin-1β, and TNF-α, whose aberrant expression contributes to neuroinflammation as an aggravating factor for neurodegeneration and premature neuronal death

Histamine and immune biomarkers in CNS disorders

La desregulación neuroinmune es un fenómeno común en diferentes formas de trastornos del sistema nervioso central (SNC). Los enlaces cruzados entre los mecanismos inmunitarios centrales y periféricos parecen estar interrumpidos, como se refleja en una serie de marcadores inmunitarios (CD3, CD4, CD7, HLA-DR, CD25, CD28 y CD56) que muestran variabilidad en trastornos cerebrales como ansiedad, depresión , psicosis, accidente cerebrovascular, enfermedad de Alzheimer, enfermedad de Parkinson, trastorno por déficit de atención con hiperactividad, migraña, epilepsia, demencia vascular, retraso mental, encefalopatía cerebrovascular, esclerosis múltiple, tumores cerebrales, neuropatías del nervio craneal, retraso mental y lesión cerebral postraumática. La histamina (HA) es una monoamina pleiotrópica involucrada en varias funciones neurofisiológicas, regulación neuroinmune y patogénesis del SNC. Los cambios en la HA cerebral muestran un patrón relacionado con la edad y el sexo, y las alteraciones en los niveles de HA cerebral están presentes en diferentes regiones del SNC de pacientes con enfermedad de Alzheimer (EA). La HA cerebral en los compartimentos neuronales y no neuronales desempeña una doble función (neurotrófica versus neurotóxica) de una manera específica del tejido. Los mecanismos patógenos asociados con la desregulación neuroinmune en la AD involucran HA, interleucina-1β , y TNF- α , cuya expresión aberrante contribuye a la neuroinflamación como factor agravante para la neurodegeneración y la muerte neuronal prematura

Real world data on the demographic and clinicopathological profile and management of patients with early-stage HER2-positive breast cancer and residual disease treated with adjuvant trastuzumab emtansine (KARMA study)

Adjuvant treatment; Early breast cancer; Human epidermal growth factor receptor-2Tratamiento adyuvante; Cáncer de mama temprano; Receptor 2 del factor de crecimiento epidérmico humanoTractament adjuvant; Càncer de mama precoç; Receptor 2 del factor de creixement epidèrmic humàIntroduction Trastuzumab emtansine (T-DM1) significantly improves invasive disease-free survival and reduces the risk of recurrence in patients with HER2-positive early breast cancer (EBC) with residual disease (RD). The KARMA study aimed to describe the characteristics and management of these patients in clinical practice in Spain. Material and methods We conducted a multicentre retrospective study in patients with HER2-positive EBC with RD following neoadjuvant treatment (NeoT) and who had received ≥1 dose of T-DM1 as adjuvant treatment. The primary endpoint was the evaluation of sociodemographic and clinicopathological characteristics of these patients. Results A total of 114 patients were included (March–July 2020). At diagnosis, most tumours were infiltrating ductal carcinoma (IDC) (93.9 %), grade 2 (56.1 %), and hormone receptor (HR)-positive (79.8 %). Over 75 % of patients had disease in operable clinical stages (T1–3 N0–1). In the neoadjuvant setting, 86.8 % of patients received trastuzumab plus pertuzumab, and 23.6 % achieved radiological complete response. Breast-conserving surgery was performed in 55.8 % of patients. Surgical specimens showed that 89.5 % of patients had IDC, 49.1 % grade 2, 84.1 % HR-positive, and 8.3 % HER2-negative disease. Most patients had RD classified as RCB-II and Miller/Payne grade 3/4. Grade 3 treatment-related adverse events (trAEs) occurred in 5.3 % of patients. No grade 4/5 AEs occurred. Over 95 % of patients were free of invasive-disease during T-DM1 adjuvant treatment. Conclusion The KARMA study describes the characteristics of patients with HER2-positive EBC with RD after NeoT and the real-life management of a T-DM1 adjuvant regimen, which showed a manageable safety profile in line with the KATHERINE trial data.This work was funded by Roche Farma SA (Spain). The sponsor was involved in the study design, collection, analysis, and interpretation of data, writing of the report, and in the decision to submit the article for publication

Genomics of Dementia: APOE- and CYP2D6-Related Pharmacogenetics

Dementia is a major problem of health in developed societies. Alzheimer's disease (AD), vascular dementia, and mixed dementia account for over 90% of the most prevalent forms of dementia. Both genetic and environmental factors are determinant for the phenotypic expression of dementia. AD is a complex disorder in which many different gene clusters may be involved. Most genes screened to date belong to different proteomic and metabolomic pathways potentially affecting AD pathogenesis. The ε4 variant of the APOE gene seems to be a major risk factor for both degenerative and vascular dementia. Metabolic factors, cerebrovascular disorders, and epigenetic phenomena also contribute to neurodegeneration. Five categories of genes are mainly involved in pharmacogenomics: genes associated with disease pathogenesis, genes associated with the mechanism of action of a particular drug, genes associated with phase I and phase II metabolic reactions, genes associated with transporters, and pleiotropic genes and/or genes associated with concomitant pathologies. The APOE and CYP2D6 genes have been extensively studied in AD. The therapeutic response to conventional drugs in patients with AD is genotype specific, with CYP2D6-PMs, CYP2D6-UMs, and APOE-4/4 carriers acting as the worst responders. APOE and CYP2D6 may cooperate, as pleiotropic genes, in the metabolism of drugs and hepatic function. The introduction of pharmacogenetic procedures into AD pharmacological treatment may help to optimize therapeutics

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Vaccine Development to Treat Alzheimer’s Disease Neuropathology in APP/PS1 Transgenic Mice

A novel vaccine addressing the major hallmarks of Alzheimer’s disease (AD), senile plaque-like deposits of amyloid beta-protein (Aβ), neurofibrillary tangle-like structures, and glial proinflammatory cytokines, has been developed. The present vaccine takes a new approach to circumvent failures of previous ones tested in mice and humans, including the Elan-Wyeth vaccine (AN1792), which caused massive T-cell activation, resulting in a meningoencephalitis-like reaction. The EB101 vaccine consists of A1-42 delivered in a novel immunogen-adjuvant composed of liposomes-containing sphingosine-1-phosphate (S1P). EB101 was administered to APPswe/PS1dE9 transgenic mice before and after AD-like pathological symptoms were detectable. Treatment with EB101 results in a marked reduction of Aβ plaque burden, decrease of neurofibrillary tangle-like structure density, and attenuation of astrocytosis. In this transgenic mouse model, EB101 reduces the basal immunological interaction between the T cells and immune activation markers in the affected hippocampal/cortical areas, consistent with decreased amyloidosis-induced inflammation. Therefore, immunization with EB101 prevents and reverses AD-like neuropathology in a significant manner by halting disease progression without developing behavioral spatial deficits in transgenic mice

DNA Methylation in Neurodegenerative and Cerebrovascular Disorders

DNA methylation is an epigenetic mechanism by which methyl groups are added to DNA, playing a crucial role in gene expression regulation. The aim of the present study is to compare methylation status of healthy subjects with that of patients with Alzheimer’s, Parkinson’s or Cerebrovascular diseases. We also analyze methylation status of a transgenic Alzheimer’s disease mouse model (3xTg-AD). Our results show that both global methylation (n = 141) and hydroxymethylation (n = 131) levels are reduced in DNA samples from buffy coats of patients with neurodegenerative disorders and age-related cerebrovascular disease. The importance of methylation and hydroxymethylation reduction is stressed by the finding that DNMT3a mRNA levels are also downregulated in buffy coats of patients with Dementia (n = 25). Global methylation is also reduced in brain, liver and serum samples of 3xTg-AD vs. wild type mice, such as DNMT3a mRNA levels that are also decreased in the brain of 3xTg-AD (n = 10). These results suggest that the use of global methylation and hydroxymethylation levels, together with the study of DNMT3a expression, could be useful as a new diagnostic biomarker for these prevalent disorders

Our lives in boxes : Perceived community mediators between housing insecurity and health using a PHOTOVOICE approach

While the negative effects of housing insecurity on health are well known, the mechanisms and mediators of these effects have been less well studied. The aim of this study is to identify perceived mediators involved in the relationship between housing insecurity and health. We used a participatory action research approach, the Photovoice methodology. It promotes a reflective process where participants critically discuss housing insecurity and human health and make recommendations to find solutions for the issues identified. This study was conducted with 18 members of the Platform for People Affected by Mortgages who were living in a situation of housing insecurity in Barcelona during the first half of 2017. Participants took 990 photographs, of which 147 were printed for analysis in discussion sessions. 109 of these photographs were then selected for categorization by the participants. 11 major categories emerged, representing various factors related to housing insecurity and health. Most categories were acknowledged as possible mediators of the housing/health problem, including: psychological changes; housing-related material aspects; health-related behaviors; eviction; harassment by financial institutions; and family, neighbors and social network. Others were considered as modifiers that could alter the effects of housing insecurity on health. Co-existing determinants may interact with housing insecurity, thereby increasing negative effects on health. Through this participatory approach, the Photovoice project gives insight into the mechanisms underlying the relationship between housing insecurity and human health, and provides valuable recommendations to combat this serious public health issue

Evaluación del comportamiento del fruto de arazá (Eugenia stipitata Mc Vaugh) en las operaciones de acondicionamiento húmedo poscosecha

Arazá fruits are coming from the departments of Caquetá and Putumayo in Colombia. They were selected and classified according to maturity index. Then, half of them were conditioned, and washed by immersion with tap water for 5 min, right after, they were sanitized with 100 ppm of sodium hypochlorite, and rinsed later to remove any residuals. Finally, residual humidity was removed by natural convection at room temperature. Fruits were stored for seven days at 13±1ºC and 95% HR±1. The conditioned fruits presented less decay than the controlled ones.Los frutos de arazá, proveniente de los departamentos de Caquetá y Putumayo, se seleccionaron y clasificaron; posteriormente se acondicionó la mitad de ellos realizando primero un lavado por inmersión con agua durante cinco min, luego se desinfectaron con 100 ppm de hipoclorito de sodio, y se enjuagaron después para retirar los residuos del desinfectante. Finalmente se retiró la humedad residual por medio de convección natural. La totalidad de los frutos fue almacenada durante siete días a 13±1ºC y 95% HR±1. Los frutos acondicionados presentaron un mejor comportamiento que los frutos sin acondicionar frente al ataque de hongos y enfermedades

A Comparative Evaluation of a Novel Vaccine in APP/PS1 Mouse Models of Alzheimer’s Disease

Immunization against amyloid-beta-peptide (Aβ) has been widely investigated as a potential immunotherapeutic approach for Alzheimer’s disease (AD). With the aim of developing an active immunogenic vaccine without need of coadjuvant modification for human trials and therefore avoiding such side effects, we designed the Aβ1–42 vaccine (EB101), delivered in a liposomal matrix, that based on our previous studies significantly prevents and reverses the AD neuropathology, clearing Aβ plaques while markedly reducing neuronal degeneration, behavioral deficits, and minimizing neuroinflammation in APP/PS1 transgenic mice. Here, the efficacy of our immunogenic vaccine EB101 was compared with the original immunization vaccine cocktail Aβ42 + CFA/IFA (Freund’s adjuvant), in order to characterize the effect of sphingosine-1-phosphate (S1P) in the immunotherapeutic response. Quantitative analysis of amyloid burden showed a notable decrease in the neuroinflammation reaction against Aβ plaques when S1P was compared with other treatments, suggesting that S1P plays a key role as a neuroprotective agent. Moreover, EB101 immunized mice presented a protective immunogenic reaction resulting in the increase of Aβ-specific antibody response and decrease of reactive glia in the affected brain areas, leading to a Th2 immunological reaction