Transthyretin binding heterogeneity and antiamyloidogenic activity of natural polyphenols and their metabolites

Transthyretin (TTR) is an amyloidogenic protein, the amyloidogenic potential of which is enhanced by a number of specific point mutations. The ability to inhibit TTR fibrillogenesis is known for several classes of compounds, including natural polyphenols, which protect the native state of TTR by specifically interacting with its thyroxine binding sites. Comparative analyses of the interaction and of the ability to protect the TTR native state for polyphenols, both stilbenoids and flavonoids, and some of their main metabolites have been carried out. A main finding of this investigation was the highly preferential binding of resveratrol and thyroxine, both characterized by negative binding cooperativity, to distinct sites in TTR, consistent with the data of x-ray analysis of TTR in complex with both ligands. Although revealing the ability of the two thyroxine binding sites of TTR to discriminate between different ligands, this feature has allowed us to evaluate the interactions of polyphenols with both resveratrol and thyroxine preferential binding sites, by using resveratrol and radiolabeled T4 as probes. Among flavonoids, genistein and apigenin were able to effectively displace resveratrol from its preferential binding site, whereas genistein also showed the ability to interact, albeit weakly, with the preferential thyroxine binding site. Several glucuronidated polyphenol metabolites did not exhibit significant competition for resveratrol and thyroxine preferential binding sites and lacked the ability to stabilize TTR. However, resveratrol-3-O-sulfate was able to significantly protect the protein native state. A rationale for the in vitro properties found for polyphenol metabolites was provided by x-ray analysis of their complexes with TTR

Mechanisms of endothelial cell dysfunction in cystic fibrosis

Although cystic fibrosis (CF) patients exhibit signs of endothelial perturbation, the functions of the cystic fibrosis conductance regulator (CFTR) in vascular endothelial cells (EC) are poorly defined. We sought to uncover biological activities of endothelial CFTR, relevant for vascular homeostasis and inflammation. We examined cells from human umbilical cords (HUVEC) and pulmonary artery isolated from non-cystic fibrosis (PAEC) and CF human lungs (CF-PAEC), under static conditions or physiological shear. CFTR activity, clearly detected in HUVEC and PAEC, was markedly reduced in CF-PAEC. CFTR blockade increased endothelial permeability to macromolecules and reduced trans‑endothelial electrical resistance (TEER). Consistent with this, CF-PAEC displayed lower TEER compared to PAEC. Under shear, CFTR blockade reduced VE-cadherin and p120 catenin membrane expression and triggered the formation of paxillin- and vinculin-enriched membrane blebs that evolved in shrinking of the cell body and disruption of cell-cell contacts. These changes were accompanied by enhanced release of microvesicles, which displayed reduced capability to stimulate proliferation in recipient EC. CFTR blockade also suppressed insulin-induced NO generation by EC, likely by inhibiting eNOS and AKT phosphorylation, whereas it enhanced IL-8 release. Remarkably, phosphodiesterase inhibitors in combination with a β2 adrenergic receptor agonist corrected functional and morphological changes triggered by CFTR dysfunction in EC. Our results uncover regulatory functions of CFTR in EC, suggesting a physiological role of CFTR in the maintenance EC homeostasis and its involvement in pathogenetic aspects of CF. Moreover, our findings open avenues for novel pharmacology to control endothelial dysfunction and its consequences in CF

La disabilità al tempo del Covid-19

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La imagen y la narrativa como herramientas para el abordaje psicosocial en escenarios de violencia. Departamentos de Boyacá, Cundinamarca, Valledupar.

El Diplomado De Profundización Acompañamiento Psicosocial en Escenarios de Violencia nos brinda herramientas de aprendizaje y conceptuales para ofrecer un acompañamiento psicosocial en los diferentes escenarios de violencia, comprendiendo la subjetividad como fuentes de acciones transformadoras y afrontamiento. La realización de este trabajo colaborativo se abordaron diferentes casos de violencia, siendo este contexto el que más afecta el país. Se destaca el acompañamiento de las poblaciones afectadas, quienes han tenido consecuencias económicas, política, social etc., dejando secuelas en la población afectada y la vulneración de sus derechos, En esta actividad se hace el reconocimiento de las historias narradas por las víctimas de violencia psicosocial. La narrativa ha permitido analizar y reflexionar acerca de propuestas para hacer un abordaje psicosocial, en el relato de Ana Ligia quien fue víctima del desplazamiento forzado, la población de Peñas Coloradas y la foto voz en donde se muestra los diferentes tipos de violencia que viven las comunidades, logrando la transformación de estos hechos violentos. Las victimas durante el proceso de afrontamiento, han apoyado en la reconstrucción de su memoria histórica, la aceptación y afrontamiento de las situaciones traumáticas que han marcado su vida. Como profesionales es importante implementar una herramienta que nos acerque a la víctima y ganar la confianza, pudiendo recolectar información que permita realizar un trabajo eficaz para la solucione de sus problemas. Durante el proceso de acompañamiento psicológico se busca la conservación de la salud mental, haciendo un análisis de los relatos, generando espacios de acompañamiento e implementando la narrativa como una herramienta que permita comprender la memoria colectiva. Finalmente, a partir de los análisis que se realizan de los relatos expuestos se elige el caso de Ana Ligia y se crean las preguntas estratégicas, de análisis y reflexivas orientadoras, identificando el impacto que el conflicto ha dejado en el ser humano, y reconocer los emergentes psicosociales.The Diploma Deepening Psychosocial Accompaniment in Violence Scenarios provides us with learning and conceptual tools to offer psychosocial support in the different scenarios of violence, understanding subjectivity as sources of transformative actions and coping. Carrying out this collaborative work will be addressed in different cases of violence, this context being the one that most affects the country. The accompaniment of the affected populations stands out, who have had economic, political, social consequences, etc., leaving consequences in the affected population and the violation of their rights, this activity recognizes the stories told by the victims of psychosocial violence. The narrative has allowed us to analyze and reflect on proposals to make a psychosocial approach, in the story of Ana Ligia who was a victim of forced displacement, the population of Peñas Coloradas and the photo voice where the different types of violence experienced by women are shown. communities, achieving the transformation of these violent events. During the coping process, the victims have supported the reconstruction of their historical memory, acceptance and coping with the traumatic situations that have marked their lives. As professionals, it is important to implement a tool that brings us closer to the victim and gain trust, being able to collect information that allows effective work to be done to solve their problems. During the process of psychological accompaniment, the preservation of mental health is sought, making an analysis of the stories, generating accompaniment spaces and implementing the narrative as a tool that allows understanding the collective memory. Finally, from the analyzes carried out of the exposed stories, the case of Ana Ligia is chosen and the strategic, analytical and reflective guiding questions are created, identifying the impact that the conflict has left on the human being, and recognizing the psychosocial emergencies

Children with special health care needs attending emergency department in Italy: analysis of 3479 cases

Background: Although children with special health care needs (CSHCN) represent a minority of the population, they go through more hospitalizations, more admissions to the Emergency Department (ED), and receive a major number of medical prescriptions, in comparison to general pediatric population. Objectives of the study were to determine the reasons for admission to the ED in Italian CSHCN, and to describe the association between patient's demographic data, clinical history, and health services requirements. Methods: Ad hoc web site was created to collect retrospective data of 3479 visits of CSHCN to the ED in 58 Italian Hospitals. Results: Seventy-two percent of patients admitted to ED were affected by a previously defined medical condition. Most of the ED admissions were children with syndromic conditions (54%). 44.2% of the ED admissions were registered during the night-time and/or at the weekends. The hospitalization rate was of 45.6% among patients admitted to the ED. The most common reason for admission to the ED was the presence of respiratory symptoms (26.6%), followed by gastrointestinal problems (21.3%) and neurological disorders (18.2%). 51.4% of the access were classified as 'urgent', with a red/yellow triage code. Considering the type of ED, 61.9% of the visits were conducted at the Pediatric EDs (PedEDs), 33.5% at the Functional EDs (FunEDs) and 4.6% at the Dedicated EDs (DedEDs). Patients with more complex clinical presentation were more likely to be evaluated at the PedEDs. CSHCN underwent to a higher number of medical procedures at the PedEDs, more in comparison to other EDs. Children with medical devices were directed to a PedED quite exclusively when in need for medical attention. Subjects under multiple anti-epileptic drug therapy attended to PedEDs or FunEDs generally. Patients affected by metabolic diseases were more likely to look for medical attention at FunEDs. Syndromic patients mostly required medical attention at the DedEDs. Conclusions: Access of CSHCN to an ED is not infrequent. For this reason, it is fundamental for pediatricians working in any kind of ED to increase their general knowledge about CHSCN and to gain expertise in the management of such patients and their related medical complexity

Polycystic Ovary Syndrome: Implication for Drug Metabolism on Assisted Reproductive Techniques—A Literature Review

Polycystic ovary syndrome (PCOS) affects 6–10% of women and could be considered one of the most common endocrine alterations in women of reproductive age. The syndrome is characterized by several hormonal and metabolic alterations, including insulin resistance and hyperandrogenism, which play a severe detrimental role in the patient’s fertility. We aimed to offer an overview about drug metabolism in the PCOS population. Nevertheless, we did not find any study that directly compared drug metabolism between PCOS and healthy women. We therefore decided to summarize briefly how hormonal and insulin sensitizer drugs act differently in healthy and PCOS women, who show altered steroidogenesis by theca cells and metabolic imbalance, focusing especially on assisted reproductive techniques. To date, data about drug metabolism in the PCOS population appears to be extremely limited. This important gap could have significant implications for therapeutic approaches and future perspectives: the dosage of drugs commonly used for the treatment of PCOS women should be tailored according to each patient’s characteristics; we should implement new clinical trials in order to identify the best pharmacologic strategy for PCOS patients undergoing in vitro fertilization (IVF); it would be advisable to create an international expert panel to investigate the drug metabolism in the PCOS population

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

Appendectomy during the COVID-19 pandemic in Italy: a multicenter ambispective cohort study by the Italian Society of Endoscopic Surgery and new technologies (the CRAC study)

Major surgical societies advised using non-operative management of appendicitis and suggested against laparoscopy during the COVID-19 pandemic. The hypothesis is that a significant reduction in the number of emergent appendectomies was observed during the pandemic, restricted to complex cases. The study aimed to analyse emergent surgical appendectomies during pandemic on a national basis and compare it to the same period of the previous year. This is a multicentre, retrospective, observational study investigating the outcomes of patients undergoing emergent appendectomy in March-April 2019 vs March-April 2020. The primary outcome was the number of appendectomies performed, classified according to the American Association for the Surgery of Trauma (AAST) score. Secondary outcomes were the type of surgical technique employed (laparoscopic vs open) and the complication rates. One thousand five hundred forty one patients with acute appendicitis underwent surgery during the two study periods. 1337 (86.8%) patients met the inclusion criteria: 546 (40.8%) patients underwent surgery for acute appendicitis in 2020 and 791 (59.2%) in 2019. According to AAST, patients with complicated appendicitis operated in 2019 were 30.3% vs 39.9% in 2020 (p = 0.001). We observed an increase in the number of post-operative complications in 2020 (15.9%) compared to 2019 (9.6%) (p < 0.001). The following determinants increased the likelihood of complication occurrence: undergoing surgery during 2020 (+ 67%), the increase of a unit in the AAST score (+ 26%), surgery performed > 24 h after admission (+ 58%), open surgery (+ 112%) and conversion to open surgery (+ 166%). In Italian hospitals, in March and April 2020, the number of appendectomies has drastically dropped. During the first pandemic wave, patients undergoing surgery were more frequently affected by more severe appendicitis than the previous year's timeframe and experienced a higher number of complications. Trial registration number and date: Research Registry ID 5789, May 7th, 202

How future surgery will benefit from SARS-COV-2-related measures: a SPIGC survey conveying the perspective of Italian surgeons

COVID-19 negatively affected surgical activity, but the potential benefits resulting from adopted measures remain unclear. The aim of this study was to evaluate the change in surgical activity and potential benefit from COVID-19 measures in perspective of Italian surgeons on behalf of SPIGC. A nationwide online survey on surgical practice before, during, and after COVID-19 pandemic was conducted in March-April 2022 (NCT:05323851). Effects of COVID-19 hospital-related measures on surgical patients' management and personal professional development across surgical specialties were explored. Data on demographics, pre-operative/peri-operative/post-operative management, and professional development were collected. Outcomes were matched with the corresponding volume. Four hundred and seventy-three respondents were included in final analysis across 14 surgical specialties. Since SARS-CoV-2 pandemic, application of telematic consultations (4.1% vs. 21.6%; p < 0.0001) and diagnostic evaluations (16.4% vs. 42.2%; p < 0.0001) increased. Elective surgical activities significantly reduced and surgeons opted more frequently for conservative management with a possible indication for elective (26.3% vs. 35.7%; p < 0.0001) or urgent (20.4% vs. 38.5%; p < 0.0001) surgery. All new COVID-related measures are perceived to be maintained in the future. Surgeons' personal education online increased from 12.6% (pre-COVID) to 86.6% (post-COVID; p < 0.0001). Online educational activities are considered a beneficial effect from COVID pandemic (56.4%). COVID-19 had a great impact on surgical specialties, with significant reduction of operation volume. However, some forced changes turned out to be benefits. Isolation measures pushed the use of telemedicine and telemetric devices for outpatient practice and favored communication for educational purposes and surgeon-patient/family communication. From the Italian surgeons' perspective, COVID-related measures will continue to influence future surgical clinical practice