A method to comprehensively identify germline SNVs, INDELs and CNVs from whole exome sequencing data of BRCA1/2 negative breast cancer patients.

In the rapidly evolving field of genomics, understanding the genetic basis of complex diseases like breast cancer, particularly its familial/hereditary forms, is crucial. Current methods often examine genomic variants-such as Single Nucleotide Variants (SNVs), insertions/deletions (Indels), and Copy Number Variations (CNVs)-separately, lacking an integrated approach. Here, we introduced a robust, flexible methodology for a comprehensive variants' analysis using Whole Exome Sequencing (WES) data. Our approach uniquely combines meticulous validation with an effective variant filtering strategy. By reanalyzing two germline WES datasets from BRCA1/2 negative breast cancer patients, we demonstrated our tool's efficiency and adaptability, uncovering both known and novel variants. This contributed new insights for potential diagnostic, preventive, and therapeutic strategies. Our method stands out for its comprehensive inclusion of key genomic variants in a unified analysis, and its practical resolution of technical challenges, offering a pioneering solution in genomic research. This tool presents a breakthrough in providing detailed insights into the genetic alterations in genomes, with significant implications for understanding and managing hereditary breast cancer.

Soluble factors influencing the neural stem cell niche in brain physiology, inflammation, and aging.

Within the adult central nervous system (CNS) of most mammals resides a resident stem cell population, known as neural stem cells (NSCs). NSCs are located within specific niches of the CNS and maintain a self-renewal and proliferative capacity to generate new neurons, astrocytes, and oligodendrocytes throughout adulthood. The NSC niches are dynamic and active environments that are within proximity to the systemic circulation and the cerebrospinal fluid (CSF). Therefore, NSCs respond not only to factors present in the local microenvironment of the niche but also to factors present in the systemic macroenvironment. The factors can be soluble forms such as cytokines and chemokines located in the circulation or directly from local cells, such as microglia and astrocytes. Additionally, recent evidence points towards physiological aging and its association with a progressive loss of function and a decline in the self-renewal and regenerative capacities of CNS NSCs, which can be further exacerbated by changes in the local and systemic milieu. This review will highlight the main intrinsic and extrinsic regulators of neural stem cell function under homeostatic and inflammatory conditions including those trafficked within extracellular membrane vesicles. Further, discussion will center around how intrinsic and extrinsic factors impact normal homeostatic functions within the adult brain and in aging.

Short-term treatment of iron deficiency anemia after cardiac surgery.

Iron deficiency anemia (IDA) is frequent after cardiac surgery and is associated with increased morbidity and mortality. In a retrospective study, we analyzed 106 patients with IDA (hemoglobin [Hb] ≤ 12 g/dl in women and ≤ 13 g/dl in men, transferrin saturation [TSAT] ≤ 20%) on admission to a Cardiac Rehabilitation Unit after cardiac surgery. The patients were divided into two groups, one was treated with oral sucrosomial iron (SI) and the other with intravenous ferric carboxymaltose (FCM). Patients received a single 1000 mg dose of FCM from the day after admission to rehabilitation (T1), or a 120 mg/day dose of SI from T1 until discharge (T2); after discharge, SI was reduced to 30 mg/day until the end of follow-up (T3). Hb was evaluated at T1, T2 and T3; the other hematological parameters at T1 and T3; natriuretic peptides at T1, T2 and T3; 6-minute walk test (6MWT) at T1 and T2. Folate, vitamin B12 and reticulocytes were sampled on admission. Folate deficiency was documented in 60.4% of patients. Hb increased in both groups with no significant differences between the two treatments (p = 0.397). The other iron metabolism parameters (sideremia, transferrin, TSAT) displayed similar behavior, showing a significant increase at T3 (p < 0.001) with both therapies, although the increase was faster with FCM. Ferritin - high on admission - decreased at T3 in the SI group and rose significantly in the FCM group (SI 219.5 vs. FCM 689 ng/ml p < 0.0001). The 6MWT increased significantly at T2, with an overlap between SI and FCM. In conclusion, the results of this study show that SI and FCM exhibit the same effectiveness on IDA; the response time to therapy of both treatments is also equally fast. SI and FCM induce a similar increase in functional capacity. The study shows that SI can be a viable alternative to FCM after cardiac surgery in terms of effectiveness and tolerability.

The role of neural stem cells in regulating glial scar formation and repair.

Glial scars are a common pathological occurrence in a variety of central nervous system (CNS) diseases and injuries. They are caused after severe damage and consist of reactive glia that form a barrier around the damaged tissue that leads to a non-permissive microenvironment which prevents proper endogenous regeneration. While there are a number of therapies that are able to address some components of disease, there are none that provide regenerative properties. Within the past decade, neural stem cells (NSCs) have been heavily studied due to their potent anti-inflammatory and reparative capabilities in disease and injury. Exogenously applied NSCs have been found to aid in glial scar healing by reducing inflammation and providing cell replacement. However, endogenous NSCs have also been found to contribute to the reactive environment by different means. Further understanding how NSCs can be leveraged to aid in the resolution of the glial scar is imperative in the use of these cells as regenerative therapies. To do so, humanised 3D model systems have been developed to study the development and maintenance of the glial scar. Herein, we explore the current work on endogenous and exogenous NSCs in the glial scar as well as the novel 3D stem cell-based technologies being used to model this pathology in a dish.

Exercise Training: The Holistic Approach in Cardiovascular Prevention.

Nowadays, there are robust clinical and pathophysiological evidence supporting the beneficial effects of physical activity on cardiovascular (CV) system. Thus, the physical activity is considered a key strategy for CV prevention. In fact, exercise training exerts favourable effects on all risk factors for CV diseases (i.e. essential hypertension, type 2 diabetes mellitus, hypercholesterolemia, obesity, metabolic syndrome, etc…). In addition, all training modalities such as the aerobic (continuous walking, jogging, cycling, etc.) or resistance exercise (weights), as well as the leisure-time physical activity (recreational walking, gardening, etc) prevent the development of the major CV risk factors, or delay the progression of target organ damage improving cardio-metabolic risk. Exercise training is also the core component of all cardiac rehabilitation programs that have demonstrated to improve the quality of life and to reduce morbidity in patients with CV diseases, mostly in patients with coronary artery diseases. Finally, it is still debated whether or not exercise training can influence the occurrence of atrial and ventricular arrhythmias. In this regard, there is some evidence that exercise training is protective predominantly for atrial arrhythmias, reducing the incidence of atrial fibrillation. In conclusion, the salutary effects evoked by physical acitvity are useful in primary and secondary CV prevention.

Discrepancy in pathology reports upon second review of radical orchiectomy specimens for testicular germ cell tumors.

INTRODUCTION: We sought to evaluate the discrepancies between primary pathology report and second pathology review of radical orchiectomy (RO) specimens. METHODS: A retrospective review was performed of RO specimens from the Ontario Cancer Registry. All cases required both a primary pathology report and a second pathology review from another institution. Histopathological variables assessed included histological subtype and components of mixed germ cell tumor (GCT), pathological tumor (pT) stage, lymphovascular invasion (LVI), spermatic cord invasion, and surgical margin. RESULTS: Between 1994 and 2015, 5048 ROs were performed with 2719 (53.9%) seminoma and 2029 (40.2%) non-seminoma. Of these, 519 (10.3%) received a second pathology review. There was concordance between primary pathology report and second pathology review in 326 (62.8%) cases. The most common discrepancies involved a change in pT stage (n=148, 28.5%), with upstaging in 83 (16%) and downstaging in 65 (12.5%) cases relative to the original pT stage. The second most common discrepancy regarded the reporting of LVI (n=121, 23.3%), with 62 (11.9%) reporting presence of LVI when the primary pathology report did not. Other discrepancies included a change in the histological subtype in 28 (5.4%) cases and spermatic cord margin status in five (9.6%) cases. CONCLUSIONS: Only 10% of orchiectomy specimens underwent a second pathology review, with nearly 40% of reviews leading to a meaningful change in parameters. Such variation could lead to incorrect tumor staging, estimate of relapse risk, and inappropriate treatment decisions. Expert pathology review of RO specimens should be considered, as it has significant implications for decision-making.

1,2,3-Triazole-Mediated Synthesis of 1-Methyleneisoquinolines: A Three-Step Synthesis of Papaverine and Analogues.

A metal-free three-step synthesis toward functionalized 1-methyleneisoquinolines from readily available substrates is reported. First, acetal-containing 1,2,3-triazoles were prepared via a high-yielding triazolization reaction and quantitatively converted into triazolo[5,1-a]isoquinolines. Next, the acid-promoted ring opening of these fused triazoles was studied in order to obtain coupling to a diverse scope of nucleophiles, including carbon nucleophiles such as veratrole. By means of non-nucleophilic strong acids under anhydrous conditions, a series of unprecedented isoquinolines and imidazo[5,1-a]isoquinolines was synthesized.

Automatic Setting Procedure for Exoskeleton-Assisted Overground Gait: Proof of Concept on Stroke Population.

Stroke-related locomotor impairments are often associated with abnormal timing and intensity of recruitment of the affected and non-affected lower limb muscles. Restoring the proper lower limbs muscles activation is a key factor to facilitate recovery of gait capacity and performance, and to reduce maladaptive plasticity. Ekso is a wearable powered exoskeleton robot able to support over-ground gait training. The user controls the exoskeleton by triggering each single step during the gait cycle. The fine-tuning of the exoskeleton control system is crucial-it is set according to the residual functional abilities of the patient, and it needs to ensure lower limbs powered gait to be the most physiological as possible. This work focuses on the definition of an automatic calibration procedure able to detect the best Ekso setting for each patient. EMG activity has been recorded from Tibialis Anterior, Soleus, Rectus Femoris, and Semitendinosus muscles in a group of 7 healthy controls and 13 neurological patients. EMG signals have been processed so to obtain muscles activation patterns. The mean muscular activation pattern derived from the controls cohort has been set as reference. The developed automatic calibration procedure requires the patient to perform overground walking trials supported by the exoskeleton while changing parameters setting. The Gait Metric index is calculated for each trial, where the closer the performance is to the normative muscular activation pattern, in terms of both relative amplitude and timing, the higher the Gait Metric index is. The trial with the best Gait Metric index corresponds to the best parameters set. It has to be noted that the automatic computational calibration procedure is based on the same number of overground walking trials, and the same experimental set-up as in the current manual calibration procedure. The proposed approach allows supporting the rehabilitation team in the setting procedure. It has been demonstrated to be robust, and to be in agreement with the current gold standard (i.e., manual calibration performed by an expert engineer). The use of a graphical user interface is a promising tool for the effective use of an automatic procedure in a clinical context.

Rastreamento ecográfico de primeiro trimestre para anomalias cromossômicas / Echographic Screening of first trimester for chromosome anomalies

As anomalias cromossômicas ou aneuploidias são causas importantes de mortalidade perinatal e deficiência mental na infância. o diagnóstico pré-natal dessas anomalias é um dos grandes objetivos envolvidos no atendimento à gestante em seu primeiro trimestre de gestação. a busca de técnicas não-invasivas para este fim tem norteado o estudo de inúmeros pesquisadores. este artigo traz um enfoque exclusivo para a ultra-sonografia.

Adenomiose / Adenomyosis

Neste artigo os autores fazem uma revisão bibliográfica da adenomiose; abordam o assunto enfatizando os aspectos de diagnóstico.

Ressonância nuclear magnética do sistema nervoso central fetal / Nuclear magnetc resonance of central nervous system

O presente artigo tem por objetivo apresentar a aplicabilidade da ressonância nuclear magnética no diagnóstico de malformações fetais do sistema nervoso central. para isso, demonstrar-se-á, com base em publicações atuais, suas indicações, vantagens e limitações em relação à ultra-sonografia.

Perfil de auto-anticorpos detectados em substrato rim-estômago de rato no Hospital São Lucas da PUCRS / Autoantibody profile in rat kidney-stomach substrate in the São Lucas Hospital of PUCRS

Objetivo:O trabalho descreve o perfil de autoanticorpos utilizando-se o substrato rim-estômago de rato em um centro de saúde terciário no período de um ano. Material e métodos: O estudo foi de série de casos, com dados obtidos do banco de dados do Setor de Imunologia do Laboratório de Patologia Clínica do Hospital São Lucas da PUCRS. Resultados: Em 262 pacientes (68% do sexo feminino) previamente selecionados por triagem clínica, avaliou-se o perfil de auto-anticorpos em substrato rim-estômago de rato através de imunofluorescência indireta. Anticorpos antimúsculo liso prevaleceram (31%), seguidos por anticorpos anti-reticulina (27%), anticorpos antimitocondriais (24%), anticélulas parietais gástricas (21%), anticorpos anti-"brush border" (4%) e antiLKM (liver-kidney microsome) (0,4%). A maioria dos pacientes com teste positivo para anticorpos antimúsculo liso cursou com titulações inferiores a 1/80 (ponto de corte para hepatite auto-imune). Anticorpos anti-ribossomais não foram detectados em quaisquer pacientes. À exceção do anticorpo antiLKM (presente apenas em um caso, sexo masculino), observou-se predominância do sexo feminino nos auto-anticorpos analisados; tal predomínio, entretanto, só alcançou significância estatística para anticorpos antimitocondriais (P = 0,04). Conclusão: O achado corrobora a possível relação entre fatores genéticos e hormonais na auto-imunidade.

Objective: This article describes the autoantibody profile using rat kidney-stomach substrate in a tertiary center in a year period. Material and methods: The design was a case series, being results obtained from the data bank of the Immunology Section of the Clinical Pathology Laboratory of Saint Lucas Hospital of PUCRS. Results: In 262 patients (68% females) previosly selected by clinical trial, we evaluated the antibody profile in rat kidney-stomach substrate by indirect immunofluorescence. Anti-smooth muscle antibodies predominated (31%), followed by anti-reticulin antibodies (27%), antimitochondrial antibodies (24%), anti-gastric parietal cells antibodies (21%), anti-"brush border" antibodies (4%) and liver-kidney microsome antibodies (0.4%). The majority of patients with a positive test for anti-smooth muscle antibodies had titers below 1/80 (cutoff for autoimmune hepatitis). Anti-ribosome antibodies were not detected in any patient. Apart from the liverkidney microsome antibody (seen in one male), a female predominance was observed for the other autoantibodies described; this predominance, nevertheless, was statistically significant only for antimitochondrial antibodies (P = 0.04). Conclusion: This finding corroborates a possible relationship of genetic and hormonal factors in autoimmunity.