In silico investigation of the role of miRNAs in a possible developmental origin of prostate cancer in F1 and F2 offspring of mothers exposed to a phthalate mixture.

A previous study using miRNA sequencing revealed that exposure to a mixture of phthalates during pregnancy and lactation dysregulated rno-miR-184 and rno-miR-141-3p in the ventral prostate (VP) of offspring. Here, rno-miR-184 and rno-miR-141-3 expressions were obtained by RT-qPCR in the VP of F1 males as well as in F2 offspring, aiming to establish a relationship with possible oncogenic targets through in silico analyses with multigenerational approach. Additionally, some targets were measured by western blots to highlight a possible relationship between the deregulated miRNAs and some of their targets. VP samples from rats exposed to a mixture of phthalates maternally during pregnancy and lactation (GD10 to PND21-F1) and VP from offspring (F2) were examined. The phthalate mixture at both concentrations (20 µg and 200 mg/kg/day) increased the expression of both miRNAs in the F1 (PND22 and 120) and F2 (descendants of F1-treated males) prostate. Target prediction analysis revealed that both microRNAs are responsible for modulating the expression and synthesis of 40 common targets. A phthalate target association analysis and the HPA database showed an interesting relationship among these possible miRNAs modulated targets with prostate adenocarcinoma and other oncogenic processes. Western blots showed alteration in P63, P53, WNT5, and STAT3 expression, which are targeted by the miRNAs, in the VP of F1/F2 males. The data draw attention to the epigenetic modulation in the prostate of descendants exposed to phthalates and adds to one of the few currently found in the literature to point to microRNAs signature as biomarkers of exposure to plasticizers.

Molecular identification of sharks from the genus Sphyrna (Elasmobranchii: Chondrichthyes) in Maranhão Coast (Brazil).

Sharks of the genus Sphyrna are under intense exploitation globally. In Brazil's northern coast, this genus represents a high proportion of fisheries landings and comprises four species. However, due to difficulty of specific identification when specimens are landed, most of the records are limited to the genus level. Here we analyzed the effectiveness of ITS2 (Internal Transcribed Spacer 2 of rDNA) fragment length protocol (Abercrombie et al., 2005) for identifying hammerhead shark species, comparing with the analysis of COI (Cytochrome oxidase subunit I) and ITS2 sequences. We evaluated samples of muscle tissue acquired in the main fishing ports of Maranhão: Carutapera, Raposa e Tutóia. Sampling was conducted between March 2017 to March 2018 and complemented with material deposited in collection (2015). COI results indicated the occurrence of endangered species which are prohibited to be landed. These include Sphyrna mokarran (67%), S. lewini (15%), S. tudes (3%), and S. tiburo (15%). For the ITS2 marker, we investigated the optimization of the protocol developed by Abercrombie (2005) for to improve the use in this geographical area througout design of a new primers.

Wunderlich syndrome as a rare complication of polyarteritis nodosa: a case report.

Spontaneous subcapsular and perirenal hemorrhage, known as Wunderlich syndrome (WS), is a rare clinical manifestation of polyarteritis nodosa (PAN). We report a case of a 48-year-old male with a history of recurrent episodes of leg muscle tenderness and dysesthesia, bilateral flank pain, painful nodular skin lesions in the lower limbs, weight loss, and difficult-to-control arterial hypertension. The abdominopelvic computed tomography angiography showed a large left perirenal hematoma, leading to the patient's admission to the intensive care unit. After the exclusion of infectious or neoplastic foci, the patient was diagnosed with PAN and started intravenous methylprednisolone pulses with a good response. Since WS is a rare initial clinical manifestation of PAN, an early diagnosis and aggressive treatment will significantly improve clinical outcomes.

Diamond-Blackfan anemia, the archetype of ribosomopathy: How distinct is it from the other constitutional ribosomopathies?

Diamond-Blackfan anemia (DBA) was the first ribosomopathy described in humans. DBA is a congenital hypoplastic anemia, characterized by macrocytic aregenerative anemia, manifesting by differentiation blockage between the BFU-e/CFU-e developmental erythroid progenitor stages. In 50 % of the DBA cases, various malformations are noted. Strikingly, for a hematological disease with a relative erythroid tropism, DBA is due to ribosomal haploinsufficiency in 24 different ribosomal protein (RP) genes. A few other genes have been described in DBA-like disorders, but they do not fit into the classical DBA phenotype (Sankaran et al., 2012; van Dooijeweert et al., 2022; Toki et al., 2018; Kim et al., 2017 [1-4]). Haploinsufficiency in a RP gene leads to defective ribosomal RNA (rRNA) maturation, which is a hallmark of DBA. However, the mechanistic understandings of the erythroid tropism defect in DBA are still to be fully defined. Erythroid defect in DBA has been recently been linked in a non-exclusive manner to a number of mechanisms that include: 1) a defect in translation, in particular for the GATA1 erythroid gene; 2) a deficit of HSP70, the GATA1 chaperone, and 3) free heme toxicity. In addition, p53 activation in response to ribosomal stress is involved in DBA pathophysiology. The DBA phenotype may thus result from the combined contributions of various actors, which may explain the heterogenous phenotypes observed in DBA patients, even within the same family.

Nueva era de la medicina basada en las células madre mesenquimales: bases, retos y perspectivas / New era of mesenchymal stem cell-based medicine: Basis, challenges and prospects

Las células madre de origen mesenquimal (CMM) suscitan un interés especial debido a sus propiedades regenerativas, antiinflamatorias, antiapoptóticas, contra el estrés oxidativo, antitumorales o antimicrobianas. Sin embargo, su implementación en clínica se topa con inconvenientes de la terapia celular como la incompatibilidad inmunológica, la formación de tumores, la posible transmisión de infecciones, la entrada en senescencia celular y la difícil evaluación de seguridad, dosis y potencia; así como complejas condiciones de almacenamiento, elevado coste económico o uso clínico poco práctico. Considerando que los efectos positivos de las CMM se deben, en gran medida, a los efectos paracrinos mediados por el conjunto de sustancias que segregan (factores de crecimiento, citoquinas, quimiocinas o microvesículas), la obtención in vitro de esos productos biológicos posibilita una medicina regenerativa libre de células sin los inconvenientes de la terapia celular. No obstante, esa nueva innovación terapéutica implica retos, como el reconocimiento de la heterogeneidad biológica de las CMM y la optimización y estandarización de su secretoma (AU)

Stem cells of mesenchymal origin (MSC) arouse special interest due to their regenerative, anti-inflammatory, anti-apoptotic, anti-oxidative stress, antitumor or antimicrobial properties. However, its implementation in the clinic runs into drawbacks of cell therapy (immunological incompatibility, tumor formation, possible transmission of infections, entry into cellular senescence, difficult evaluation of safety, dose and potency; complex storage conditions, high economic cost or impractical clinical use). Considering that the positive effects of MSC are due, to a large extent, to the paracrine effects mediated by the set of substances they secrete (growth factors, cytokines, chemokines or microvesicles), the in vitro obtaining of these biological products makes possible a medicine cell-free regenerative therapy without the drawbacks of cell therapy. However, this new therapeutic innovation implies challenges, such as the recognition of the biological heterogeneity of MSC and the optimization and standardization of their secretome (AU)

Multi-Domain Interventions for Dementia Prevention - A Systematic Review.

OBJECTIVES: There is a growing incidence of cognitive decline and dementia associated with the ageing population. Lifestyle factors such as diet, physical activity, and cognitive activities may individually or collectively be undertaken to increase one's odds of preventing cognitive decline and future dementia. This study will examine whether clinical trials using multidomain lifestyle intervention can significantly decrease the risk of cognitive decline and therefore dementia. DESIGN, SETTING AND PARTICIPANTS: This systematic literature review of multidomain lifestyle interventions for the prevention of cognitive decline and dementia followed the PRISMA guidelines. Clinical trials involving multidomain intervention (i.e., diet and physical activity, or without cognitive training) in older adults (≥ 49 years old) at higher risk of dementia were identified through 5 electronic databases (EMBASE, MEDLINE, CINAHL, Cochrane, and Scopus). A comprehensive search was performed to identify and retrieve publications until 15 November 2022. Trials were published in English. RESULTS: The included studies (n=15) assessed change in cognition in response to a multidomain lifestyle intervention. However, the cognitive outcome measures used in these studies were heterogeneous. Despite this heterogeneity, two thirds of the studies showed improvement in cognition following a multidomain intervention (n=10 with a total of 9,439 participants). However, five studies reported no improvement in cognition following the multidomain intervention. The most common form of dietary intervention included higher amount of fruit and vegetable intake; whole-grain cereal products instead of refined; low fat options in milk and meat products; and limiting sucrose intake to less than 50 g/day. Most clinical trial studies were powered to examining the effects of multidomain interventions in cognition but were not designed to test the contribution of individual domains (i.e., dietary changes, increased physical activity, or increased cognitive stimulation alone). CONCLUSION: This systematic review aimed to determine the effect of multimodal lifestyle interventions on cognitive outcomes in older adults at risk of dementia. We found that participants with conditions that may increase the risk of dementia, (e.g., hypertension, cardiovascular fragility) do benefit from multi-modal lifestyle changes including diet, physical activity, and cognitive training. Two thirds of studies using multidomain lifestyle interventions showed improvements in cognitive function. Trials with a focus on cognitive training, dietary improvement, and physical activity may prevent or delay cognitive decline in older adults including those at risk of developing dementia. Future studies should consider longer follow-up periods and adequate power to be able to examine the effects of each lifestyle component in the context of multimodal interventions.

New era of mesenchymal stem cell-based medicine: basis, challenges and prospects.

Stem cells of mesenchymal origin (MSC) arouse special interest due to their regenerative, anti-inflammatory, anti-apoptotic, anti-oxidative stress, antitumor or antimicrobial properties. However, its implementation in the clinic runs into drawbacks of cell therapy (immunological incompatibility, tumor formation, possible transmission of infections, entry into cellular senescence, difficult evaluation of safety, dose and potency; complex storage conditions, high economic cost or impractical clinical use). Considering that the positive effects of MSC are due, to a large extent, to the paracrine effects mediated by the set of substances they secrete (growth factors, cytokines, chemokines or microvesicles), the in vitro obtaining of these biological products makes possible a medicine cell-free regenerative therapy without the drawbacks of cell therapy. However, this new therapeutic innovation implies challenges, such as the recognition of the biological heterogeneity of MSC and the optimization and standardization of their secretome.

Mechanical osteoarthritis of the hip in a one medicine concept: a narrative review.

Human and veterinary medicine have historically presented many medical areas of potential synergy and convergence. Mechanical osteoarthritis (MOA) is characterized by a gradual complex imbalance between cartilage production, loss, and derangement. Any joint instability that results in an abnormal overload of the joint surface can trigger MOA. As MOA has a prevailing mechanical aetiology, treatment effectiveness can only be accomplished if altered joint mechanics and mechanosensitive pathways are normalized and restored. Otherwise, the inflammatory cascade of osteoarthritis will be initiated, and the changes may become irreversible. The management of the disease using non-steroidal anti-inflammatory drugs, analgesics, physical therapy, diet changes, or nutraceuticals is conservative and less effective. MOA is a determinant factor for the development of hip dysplasia in both humans and dogs. Hip dysplasia is a hereditary disease with a high incidence and, therefore, of great clinical importance due to the associated discomfort and significant functional limitations. Furthermore, on account of analogous human and canine hip dysplasia disease and under the One Medicine concept, unifying veterinary and human research could improve the well-being and health of both species, increasing the acknowledgement of shared diseases. Great success has been accomplished in humans regarding preventive conservative management of hip dysplasia and following One Medicine concept, similar measures would benefit dogs. Moreover, animal models have long been used to better understand the different diseases' mechanisms. Current research in animal models was addressed and the role of rabbit models in pathophysiologic studies and of the dog as a spontaneous animal model were highlighted, denoting the inexistence of rabbit functional models to investigate therapeutic approaches in hip MOA.

Integrated transcriptome and proteome analysis indicates potential biomarkers of prostate cancer in offspring of pregnant rats exposed to a phthalate mixture during gestation and lactation.

As the second leading cause of death for cancer among men worldwide, prostate cancer (PCa) prevention and detection remain a critical challenge. One aspect of PCa research is the identification of common environmental agents that may increase the risk of initiation and progression of PCa. Endocrine disrupting chemicals (EDCs) are strong candidates for risk factors, partially because they alter essential pathways for prostate gland development and oncogenesis. Phthalates correspond to a set of commercially used plasticizers that humans are exposed to ubiquitously. Here, we show that maternal exposure to a phthalate mixture interferes with the expression profile of mRNA and proteins in the ventral prostate of offspring and increases the susceptibility to prostate adenocarcinomas in aged animals. The data highlight Ubxn11, Aldoc, Kif5c, Tubb4a, Tubb3, Tubb2, Rab6b and Rab3b as differentially expressed targets in young and adult offspring descendants (PND22 and PND120). These phthalate-induced targets were enriched for pathways such as: dysregulation in post-translational protein modification (PTPM), cell homeostasis, HSP90 chaperone activity, gap junctions, and kinases. In addition, the Kif5c, Tubb3, Tubb2b and Tubb4a targets were enriched for impairment in cell cycle and GTPase activity. Furthermore, these targets showed strong relationships with 12 transcriptional factors (TF), which regulate the phosphorylation of eight protein kinases. The correlation of TF-kinases is associated with alterations in immune system, RAS/ErbB/VEGF/estrogen/HIF-1 signaling pathways, cellular senescence, cell cycle, autophagy, and apoptosis. Downregulation of KIF5C, TUBB3 and RAB6B targets is associated with poor prognosis in patients diagnosed with adenocarcinoma. Collectively, this integrative investigation establishes the post-transcriptional mechanisms in the prostate that are modulated by maternal exposure to phthalate mixture during gestation and lactation.

Physical and chemical characterization of drill cuttings: A review.

Drill cuttings comprise a mixture of rocks generated during drilling activities of exploration and production of oil and gas. These residues' properties are variable, depending on several drilling parameters and drilled rock composition. Many scientific studies have been published regarding the characterization of these residues. Articles summarizing these residues' characteristics and toxicity data are poorly explored in the literature. This work reviews the principal methods used to characterize drill cuttings and data about these residues' properties. Some authors have reported the large content of Zn in drill cuttings. These cuttings can be associated with base fluids (as olefins, varying from C11 to C18), and some time crude oil (high range of TPH, unresolved complex mixtures, and PAH compounds). Acute and chronic toxicity tests have shown negative impacts of different types of fluids, the components of these fluids, and cuttings on other marine organisms.

The REWRITE Study - REal-WoRld effectIveness of TrifluridinE/tipiracil in Patients with Previously Treated Metastatic Colorectal Cancer.

AIMS: In the pivotal RECOURSE trial, trifluridine/tipiracil improved survival outcomes in refractory metastatic colorectal cancer (mCRC), while demonstrating an acceptable toxicity profile. Routine clinical practice evidence is important to support the ongoing value of recently approved medicines. Our objective was to assess the utilisation patterns and real-world effectiveness of trifluridine/tipiracil in previously treated mCRC patients. MATERIALS AND METHODS: This was a retrospective observational study including consecutive patients who started trifluridine/tipiracil between 1 April 2018 and 30 September 2019 in the medical oncology departments of three major public hospitals in Portugal. The primary outcome measure was overall survival. Associations between overall survival and patient and tumour characteristics were assessed using multivariate Cox regression analyses. RESULTS: In total, 111 patients were included in the study, with a mean age of 64 years. From these, 45.9% received two prior lines of treatment, 47.8% had three or more previous lines of treatment and 83.6% had Eastern Cooperative Oncology Group (ECOG) performance status 0-1 at baseline. The median duration of trifluridine/tipiracil treatment was 3.7 cycles (95% confidence interval 3.4-4.1). Most patients (80.4%) remained on their planned dose throughout the trifluridine/tipiracil treatment period, fulfilling 100% relative dose intensity. The median overall survival in the total study cohort was 7.9 months (95% confidence interval 6.4-9.8) and the median progression-free survival was 3.4 months (95% confidence interval 3.2-3.9). The median overall survival was significantly higher in patients with a normal serum lactate dehydrogenase (LDH) level (median overall survival 11.2 months for [135, 205] IU/l LDH [95% confidence interval 8.2-NR] and 13.6 months for [205, 251] IU/l LDH [95% confidence interval 8.2-NR]) and in better fitted (ECOG = 0-1) patients (median overall survival 8.0 months; 95% confidence interval 6.7-10.0). The median time to worsening performance status was 6.2 months (95% confidence interval 5.0-8.0). Treatment discontinuation due to adverse events was low (3.1%). CONCLUSION: Our study confirms the effectiveness of trifluridine/tipiracil in real-life mCRC patients. Overall survival and progression-free survival outcomes are consistent with the efficacy profile reported in the earlier randomised RECOURSE clinical trial. Like other real-world studies, we found no additional safety concerns in the use of trifluridine/tipiracil.

Pathergy-like reaction induced by laser hair removal in a patient with Behçet disease.

Behçet disease (BD) is a rare systemic vasculitis of unknown etiology, primarily characterized by recurrent oral aphthous ulcers, genital ulcers, uveitis, and skin lesions. Pathergy test positivity is a nonspecific inflammatory response of the skin to trauma and supports the diagnosis. Recently, new inducers of pathergy reactions have been identified, for example, the placement of dental braces and laser hair removal. Our clinical case highlights the importance of thinking about this potential pathergy inducer in BD patients, to improve their quality of life and avoid complications.

Effect of plasma and heat treatments on orange juice quality.

Heat treatment is used in the orange juice industry to neutralize the action of pathogenic microorganisms. However, it can reduce the nutritional value of the juice. Thus, our study assessed the cold plasma treatment as an alternative method against Escherichia coli and Candida albicans in 'Lima' orange juice. Both, plasma and heat treatments, reduced the amount of E. coli in the juice, inactivating 16.72 and 100%, respectively. Plasma did not inactivate C. albicans, but heat treatment inactivated 100%. Plasma and heat treatment increased Hue angle and luminosity (more yellowish juice). Plasma reduced vitamin C, carotenoids, and polyphenols content, while increased flavonoids. Heat treatment reduced the carotenoid content. However, neither heat nor plasma treatment altered the antioxidant activity. The plasma treatment reduced the intensity of color (chroma), the soluble solids content and the acidity ratio, total sugars, and the vitamin C content of juice compared to the heat-treated and control juices. Plasma-treated juice showed increased levels of yellow flavonoids, total phenolics and antioxidant activity until the 12th day of storage.

Prevalence of negative behaviour in the dental setting and association with sociodemographic, oral health-related and psychosocial factors amongst Brazilian preschool children.

PURPOSE: To investigate the prevalence of negative behaviour in preschool children attending dental clinics and its association with sociodemographic, oral health-related and parental psychosocial factors. METHODS: A cross-sectional study was carried out with 145 parents/guardians and their children aged 4-6 years attending paediatric dentistry training programmes in a capital city of Midwest Brazil. Data were obtained from children's dental records, interviews, and questionnaires for parents/guardians. The outcome was negative child behaviour, based on the dentists' use or indication of behavioural control measures during the dental appointments, as registered in the children's dental records. Covariates were sociodemographic, clinical and parent/guardian psychosocial factors religiosity (DUREL index) and Sense of Coherence (SOC-13 scale). Bivariate analyses and Poisson regression with robust variance were performed. RESULTS: The prevalence of negative behaviour was 24.1% (95% CI = 17.9-31.7). In the bivariate analyses, the variables initially selected for the regression models (p < 0.25) were the parent/guardians' number of children and religiosity, and the children's dental pain and caries status in deciduous teeth. After adjustment, the prevalence of negative behaviour was 2.12 higher in children with teeth extracted due to caries. CONCLUSION: The prevalence of negative behaviour was high and associated with the presence of missing teeth due to caries, regardless of sociodemographic, psychosocial, and other oral health factors.

The data project: a shared approach between stakeholders of the healthcare system in definition of a therapeutic algorithm for inflammatory arthritis.

Rheumatic musculoskeletal diseases or RMD [rheumatoid arthritis (RA) and spondyloarthritis (SpA)] are systemic inflammatory diseases for which there are no biomarkers capable of predicting treatments with a higher likelihood of response in naive patients. In addition, the expiration of the anti-TNF blocking drugs' patents has resulted in the availability of anti-TNF biosimilar drugs with the same efficacy and safety than originators but at significantly reduced prices. To guarantee a personalized therapeutic approach to RMD treatment, a board of rheumatologists and stakeholders from the Campania region, Italy, developed a clinically applicable arthritis therapeutic algorithm to guide rheumatologists (DATA project). The general methodology relied on a Delphi technique forecast to produce a set of statements that summarized the experts' consensus. Selected clinical scenarios were discussed in light of the available evidence, and there were two rounds of voting on the therapeutic approaches. Separate discussions were held regarding rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. The decision-making factors for each disease were clinical presentation, demographics, and comorbidities. In this paper, we describe a virtuous process between rheumatologists and healthcare system stakeholders that resulted in the development of a shared therapeutic algorithm for RMD patients naive to bDMARDs.

Differences in mitochondrial function between brain and heart of senile rats exposed to acute hypobaric hypoxia. Role of nitric oxide.

Rat brain and heart display different endogenous protective responses against hypobaric hypoxia in an age-dependent way. The aim of the present work was to evaluate the effects of acute hypobaric hypoxia (HH, 48 h) on brain and heart mitochondrial function as well as the participation of nitric oxide (NO) in old rats (22-month old). Cortical mitochondria from rats exposed to HH decreased respiratory rates (37 %, state 3) and membrane potential (20 %), but NO and H2O2 production increased by 48 %, and 23 %, respectively. Hippocampal mitochondria preserved O2 consumption and H2O2 production, decreased membrane potential (18 %) and increased NO production (46 %). By contrast, HH decreased NO production (53 %) in mitochondria from left heart ventricles associated with increased cytochrome oxidase activity (39 %) and decreased NADPH oxidase activity (31 %). Also, a tendency to increase complex I-III (24 %) and complex II-III (65 %) activity was observed. In conclusion, after HH hippocampal and cortical mitochondria showed mild uncoupling and increased NO production. However, only the hippocampus preserved O2 consumption and H2O2 levels. Interestingly, heart mitochondria showed a decreased ROS production through increased cytochrome oxidase activity associated with a decrease in NO production. This may be interpreted as a self-protective mechanism against hypoxia.

Nociception associated with pain/distress in young children sedated for dental treatment: a clinical study with objective and subjective measures.

PURPOSE: To evaluate the association between children's pain/distress levels and patient characteristics (age, sex, history of dental pain), sedation type (level of sedation, sedative regimen), nociception and pain intensity reported by the parents in sedated children undergoing minimally invasive dental treatment. METHODS: This clinical study evaluated secondary outcomes of an RCT that evaluated the efficacy of dexmedetomidine sedation with or without ketamine. Only children who had nociception levels recorded using the Analgesia Nociception Index (ANI) were included (0-100; 0 = highest nociception). FLACC scale (Face, Legs, Activity, Cry and Consolability) was used to assess children's pain/distress (0-10; 0 = no pain/distress). Parental proxy report of the child's pain intensity during the treatment was performed using the Visual Analogue Scale (VAS; 0-100; 0 = no pain). The association between ANI, children's age and sex, dental pain history, sedation level, sedative regimen, and VAS with the FLACC was verified using the generalised estimation equation analysis (alpha 0.05). RESULTS: Participants were 31 children (51.6% boys) and their parents (90.3% mothers). Median FLACC was 3.3 (25th-75th percentiles 1.7-8.2), ANI 80.9 (74.7-85.8), and VAS 10 (1-23). FLACC associated with ANI (OR 0.96; 95% CI 0.93-0.99; p = 0.02), moderate sedation (0.13; 0.03-0.50; p = 0.003), and VAS (1.05; 1.01-1.10; p = 0.01). CONCLUSION: Pain/distress was generally low and more prominent with minimal (versus moderate) sedation and higher nociception.