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1.
Immunity ; 50(2): 446-461.e9, 2019 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-30709742

RESUMEN

Production of interleukin-17 (IL-17) and IL-22 by T helper 17 (Th17) cells and group 3 innate lymphoid cells (ILC3s) in response to the gut microbiota ensures maintenance of intestinal barrier function. Here, we examined the mechanisms whereby the immune system detects microbiota in the steady state. A Syk-kinase-coupled signaling pathway in dendritic cells (DCs) was critical for commensal-dependent production of IL-17 and IL-22 by CD4+ T cells. The Syk-coupled C-type lectin receptor Mincle detected mucosal-resident commensals in the Peyer's patches (PPs), triggered IL-6 and IL-23p19 expression, and thereby regulated function of intestinal Th17- and IL-17-secreting ILCs. Mice deficient in Mincle or with selective depletion of Syk in CD11c+ cells had impaired production of intestinal RegIIIγ and IgA and increased systemic translocation of gut microbiota. Consequently, Mincle deficiency led to liver inflammation and deregulated lipid metabolism. Thus, sensing of commensals by Mincle and Syk signaling in CD11c+ cells reinforces intestinal immune barrier and promotes host-microbiota mutualism, preventing systemic inflammation.


Asunto(s)
Células Dendríticas/inmunología , Microbioma Gastrointestinal/inmunología , Interleucina-17/inmunología , Interleucinas/inmunología , Lectinas Tipo C/inmunología , Proteínas de la Membrana/inmunología , Quinasa Syk/inmunología , Animales , Células Dendríticas/metabolismo , Microbioma Gastrointestinal/fisiología , Humanos , Interleucina-17/metabolismo , Interleucinas/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ganglios Linfáticos Agregados/inmunología , Ganglios Linfáticos Agregados/metabolismo , Ganglios Linfáticos Agregados/microbiología , Transducción de Señal/inmunología , Quinasa Syk/genética , Quinasa Syk/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Interleucina-22
2.
Br J Haematol ; 204(5): 1838-1843, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38471524

RESUMEN

Real-world data have revealed that a substantial portion of patients with myelodysplastic syndromes (MDS) does not respond to epigenetic therapy with hypomethylating agents (HMAs). The cellular and molecular reasons for this resistance to the demethylating agent and biomarkers that would be able to predict the treatment refractoriness are largely unknown. In this study, we shed light on this enigma by characterizing the epigenomic profiles of patients with MDS treated with azacitidine. Our approach provides a comprehensive view of the evolving DNA methylation architecture of the disease and holds great potential for advancing our understanding of MDS treatment responses to HMAs.


Asunto(s)
Azacitidina , Metilación de ADN , Síndromes Mielodisplásicos , Humanos , Azacitidina/uso terapéutico , Azacitidina/farmacología , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Estudios Retrospectivos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Antimetabolitos Antineoplásicos/uso terapéutico , Antimetabolitos Antineoplásicos/farmacología , Anciano de 80 o más Años , Epigénesis Genética/efectos de los fármacos , Resultado del Tratamiento
3.
PLoS Pathog ; 18(12): e1010800, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36574441

RESUMEN

Genome-wide genetic screens are powerful tools to identify genes that act as host factors of viruses. We have applied this technique to analyze the infection of HeLa cells by Vaccinia virus, in an attempt to find genes necessary for infection. Infection of cell populations harboring single gene inactivations resulted in no surviving cells, suggesting that no single gene knock-out was able to provide complete resistance to Vaccinia virus and thus allow cells to survive infection. In the absence of an absolute infection blockage, we explored if some gene inactivations could provide partial protection leading to a reduced probability of infection. Multiple experiments using modified screening procedures involving replication restricted viruses led to the identification of multiple genes whose inactivation potentially increase resistance to infection and therefore cell survival. As expected, significant gene hits were related to proteins known to act in virus entry, such as ITGB1 and AXL as well as genes belonging to their downstream related pathways. Additionally, we consistently found ß2-microglobulin, encoded by the B2M gene, among the screening top hits, a novel finding that was further explored. Inactivation of B2M resulted in 54% and 91% reduced VV infection efficiency in HeLa and HAP1 cell lines respectively. In the absence of B2M, while virus binding to the cells was unaffected, virus internalization and early gene expression were significantly diminished. These results point to ß2-microglobulin as a relevant factor in the Vaccinia virus entry process.


Asunto(s)
Virus Vaccinia , Vaccinia , Humanos , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Pruebas Genéticas , Células HeLa , Vaccinia/genética , Virus Vaccinia/genética , Replicación Viral/genética , Microglobulina beta-2
4.
Curr Opin Clin Nutr Metab Care ; 27(3): 252-255, 2024 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-38547323

RESUMEN

PURPOSE OF REVIEW: Sarcopenic obesity is a newly identified pathological entity defined by an increase in body fat mass with an associated sarcopenia, characterized by loss of muscle mass, strength, and function. Recently, the concomitant presence of skeletal alteration with sarcopenic obesity has been described leading to a new clinical entity defined osteosarcopenic obesity (OSO). Many studies have tried to unravel the metabolic complex mechanism leading to this clinical entity in order to understand the pathophysiology of this complex condition with the aim of posing an early diagnosis to improve the therapeutic approaches. The purpose of this narrative review is to highlight and revise recent studies on this issue. RECENT FINDINGS: Recent research in the field of OSO has highlighted the role of nutrition and physical activity in the development and management of these conditions. While molecular and cellular pathways remain partially understood, there is a growing focus on lifestyle interventions as key factors in reducing the impact of OSO. These studies emphasize the need for early diagnosis and appropriate therapeutic strategies to improve quality of life and decrease morbidity and mortality associated with OSO. SUMMARY: Although the pathophysiological pathways underlying OSO are not fully understood, the clinical implications underscore the need for expanded research in this field. This research is crucial for enabling early diagnosis and implementing effective therapeutic interventions, with the goal of reducing morbidity and mortality and enhancing quality of life.


Asunto(s)
Sarcopenia , Humanos , Sarcopenia/complicaciones , Sarcopenia/diagnóstico , Sarcopenia/terapia , Densidad Ósea , Calidad de Vida , Obesidad/terapia , Ejercicio Físico , Músculo Esquelético/patología
5.
Artículo en Inglés | MEDLINE | ID: mdl-39022899

RESUMEN

PURPOSE OF REVIEW: Sarcopenic obesity is a likely common, but certainly underestimated obesity phenotype, with an important negative clinical impact. Its definition and diagnosis have however remained elusive until recently. RECENT FINDINGS: Substantial progress has been recently made in sarcopenic obesity diagnostic tools, with the first international consensus proposed by the European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity (EASO). Very encouraging results emerge from initial implementation of the ESPEN-EASO algorithm. In addition, even more recent progress in global consensus on sarcopenia conceptual definition is likely to further enhance consistency in sarcopenic obesity identification. The latter Global Leadership Initiative on Sarcopenia (GLIS) initiative also adopted a new definition of muscle specific strength. Its inclusion in sarcopenia diagnostic constructs opens the possibility of its potential evaluation in sarcopenic obesity, also considering the emerging positive impact of obesity treatment and fat loss on muscle functional parameters. SUMMARY: New consensus tools for sarcopenic obesity diagnosis are likely to improve awareness, understanding, identification and treatment of this under-recognized obesity phenotype.

6.
Pharmacoepidemiol Drug Saf ; 33(7): e5857, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38988208

RESUMEN

PURPOSE: In the early stages of the COVID-19 pandemic, preliminary results that later proved to be incorrect suggested the possible efficacy of anti-infective drugs such as azithromycin for the treatment of SARS-CoV-2 infection. These preliminary data may have influenced the prescription of azithromycin. However, no individual-level data linking the use of this antibiotic to acute SARS-CoV-2 infection are available. The present analysis aims to fill this gap. METHODS: A retrospective population-based cohort design was used including patients diagnosed with SARS-CoV-2 infection in the period ranging from February 2020 to February 2022. The data source for antibiotic consumption was the drug database of outpatient prescriptions of Emilia-Romagna Region (Italy). Antibiotics were classified according to the Anatomical Therapeutic Chemical (ATC) classification system. Consumption rates and percentages of azithromycin DDDs (defined daily doses) during the acute phase of the infection were compared with a previous control period and with the post-acute phase. Analyses were stratified by four groups according to the prevalent virus variant at time of diagnosis. RESULTS: Comparing the previous control period with the acute phase of infections, the rates of azithromycin consumption (DDD per 1000 individuals per day) increased from 1.17 to 23.11, from 0.80 to 33.03, from 0.81 to 21.01, and from 1.02 to 9.76, in the pre-Alpha, Alpha, Delta, and Omicron periods, respectively. Similarly, the percentages of individuals receiving azithromycin, and the azithromycin DDDs percentages over total systemic antibiotics DDDs increased in acute phases of infection compared with control periods. The consumption rates and percentages returned to preinfection levels in the post-acute phase. In the study period, 12.9% of the use of azithromycin in the entire adult population of Emilia-Romagna was attributable to acute SARS-CoV-2 infection. CONCLUSIONS: Considering the low likelihood of bacterial coinfections, the increased azithromycin consumption in the acute phase of SARS-CoV-2 infection suggests inappropriate prescribing of this antibiotic.


Asunto(s)
Antibacterianos , Azitromicina , Tratamiento Farmacológico de COVID-19 , COVID-19 , Azitromicina/uso terapéutico , Humanos , Estudios Retrospectivos , Femenino , Masculino , Persona de Mediana Edad , Antibacterianos/uso terapéutico , Italia/epidemiología , Anciano , Adulto , COVID-19/epidemiología , SARS-CoV-2 , Adulto Joven , Anciano de 80 o más Años , Adolescente , Enfermedad Aguda , Pautas de la Práctica en Medicina/estadística & datos numéricos , Estudios de Cohortes
7.
Appetite ; 193: 107164, 2024 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-38103790

RESUMEN

BACKGROUND: Orthorexia Nervosa (ON) is a condition characterized by an obsessive focus on healthy eating, inflexible dietary rules, and persistent preoccupations with food. Despite it has been recently the subject of increasingly relevant studies, little is known about the mechanisms that might foster ON symptoms. OBJECTIVE: This study used a structural equation modeling approach to test the mediating effect of thoughts, worries, and preoccupations about food on the relationship that eating disorders (EDs) attitudes (e.g., dieting) and obsessive-compulsive thoughts and symptoms have with ON in a large community sample. It was hypothesized that the effect of dieting and obsessive-compulsive thoughts and symptoms on ON would be partially mediated by the presence of thoughts, worries, and preoccupations about food. METHODS: Data from a cross-sectional sample of 1328 participants (females = 976) recruited from the general population were asked to fill in an online survey comprising the Eating Attitude Test-26 (EAT-26), the Obsessive-compulsive subscale of the Symptom Checklist-90 Revised (SCL-90R-OC) and the Orthorexia Scale-15 (ORTO-15). RESULTS: Structural equation models indicated that both obsessive-compulsive thoughts and symptoms and dieting had a direct effect on ON and that food preoccupation partially mediated these relationships. CONCLUSION: These findings provide novel insight into the nature of ON that could aid its conceptualization and treatment.


Asunto(s)
Trastornos de Alimentación y de la Ingestión de Alimentos , Trastorno Obsesivo Compulsivo , Femenino , Humanos , Ortorexia Nerviosa , Estudios Transversales , Conducta Alimentaria , Ansiedad , Encuestas y Cuestionarios , Conductas Relacionadas con la Salud
8.
Eat Weight Disord ; 29(1): 25, 2024 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-38587606

RESUMEN

PURPOSE: The aim of the present review is to analyze dynamic interactions between nutrigenomics, environmental cues, and parental influence, which can all lead to children's neophobic reactions and its persistence in time. METHODS: We reviewed studies available on electronic databases, conducted on children aged from birth to 18 years. We also considered official websites of Italian Institutions, providing advice on healthy eating during infancy. RESULTS: Modern day societies are faced with an eating paradox, which has severe and ever-growing implications for health. In face of a wider availability of healthy foods, individuals instead often choose processed foods high in fat, salt and sugar content. Economic reasons surely influence consumers' access to foods. However, there is mounting evidence that food choices depend on the interplay between social learning and genetic predispositions (e.g., individual eating traits and food schemata). Neophobia, the behavioral avoidance of new foods, represents an interesting trait, which can significantly influence children's food refusal. Early sensory experiences and negative cognitive schemata, in the context of primary caregiver-child interactions, importantly contribute to the priming of children's food rejection. CONCLUSIONS: As neophobia strongly affects consumption of healthy foods, it will be relevant to rule definitively out its role in the genesis of maladaptive food choices and weight status in longitudinal studies tracking to adulthood and, in meanwhile, implement early in life effective social learning strategies, to reduce long-term effects of neophobia on dietary patterns and weight status. LEVEL OF EVIDENCE: Level II, controlled trials without randomization.


Asunto(s)
Señales (Psicología) , Alimentos , Humanos , Bases de Datos Factuales , Dieta Saludable , Patrones Dietéticos , Recién Nacido , Lactante , Preescolar , Niño , Adolescente
9.
World J Urol ; 41(2): 521-527, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36527471

RESUMEN

PURPOSE: To confirm the correlation between post-void residual urine ratio (PVR-R) and BOO diagnosed by pressure-flow studies (PFS) in males with lower urinary tract symptoms (LUTS) and to develop a clinical nomogram. METHODS: A consecutive series of patients aged 45 years or older with non-neurogenic LUTS were prospectively enrolled. Patients underwent standard diagnostic assessment for BOO including International Prostatic Symptoms Score, uroflowmetry, urodynamic studies, suprapubic ultrasound of the prostate, and ultrasound measurements of the bladder wall thickness (BTW). PVR-R was defined as follows: PVR-R = (PVR/total Bladder Volume [BV]) × 100). Logistic regression analysis was used to investigate predictors of pathological bladder emptying (BOO) defined as Schafer > II. A nomogram to predict BOO based on the multivariable logistic regression model was then developed. RESULTS: Overall 335 patients were enrolled. Overall, 131/335 (40%) presented BOO on PFS. In a multivariable logistic age-adjusted regression model BWT (odds ratio [OR]: 2.21 per mm; 95% confidence interval [CI], 1.57-3.09; p = 0.001), PVR-R (OR: 1.02 per %; 95% CI, 1.01-1.03; p = 0.034) and prostate volume (OR: 0.97 per mL; 95% CI, 0.95-0.98; p = 0.001) were significant predictors for BOO. The model presented an accuracy of 0.82 and a clinical net benefit in the range of 10-90%. CONCLUSIONS: The present study confirms the important role of PVR-ratio in the prediction of BOO. For the first time, we present a clinical nomogram including PVR-ratio for the prediction of BOO.


Asunto(s)
Síntomas del Sistema Urinario Inferior , Hiperplasia Prostática , Obstrucción del Cuello de la Vejiga Urinaria , Retención Urinaria , Masculino , Humanos , Nomogramas , Hiperplasia Prostática/diagnóstico , Obstrucción del Cuello de la Vejiga Urinaria/diagnóstico , Urodinámica , Síntomas del Sistema Urinario Inferior/diagnóstico
10.
Reprod Fertil Dev ; 35(5): 363-374, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36780707

RESUMEN

CONTEXT: One of the main problems of porcine in vitro maturation (IVM) is incomplete cytoplasmatic maturation. Nuclear and cytoplasmic maturation will determine the future success of fertilisation and embryo development. Insulin-transferrin-selenium (ITS) has insulin-like and antioxidant effects, and metformin (M) is an insulin-sensitiser and antioxidant drug. AIMS: To assess the effects of adding ITS and/or M in porcine IVM media on cytoplasmic maturation and early embryo development. METHODS: Cumulus -oocyte complexes (COC) were IVM with M (10-4 M), ITS (0.1% v/v), M+ITS or no adding (Control). KEY RESULTS: ITS increased glucose consumption compared to Control and M (P <0.01), and M+ITS did not differ from ITS or Control. Redox balance: M, ITS and M+ITS increased glutathione (P <0.01) and decreased lipid peroxidation (P <0.005). The viability of cumulus cells by flow cytometry increased with M (P <0.005) and decreased with ITS (P <0.001); M+ITS did not differ from Control. After IVF, M increased penetration and decreased male pronucleus (P <0.05). Embryo development: cleavage increased with M (P <0.05), and blastocysts increased with ITS and M+ITS (P <0.05). The number of blastocyst cells increased with ITS (P <0.05). CONCLUSIONS: Adding ITS and M+ITS to porcine IVM media benefits embryo development to blastocysts, but ITS alone has better effects than M+ITS. IMPLICATIONS: ITS is an excellent tool to improve IVM and embryo development after IVF in pigs.


Asunto(s)
Metformina , Selenio , Masculino , Animales , Porcinos , Selenio/farmacología , Insulina/farmacología , Transferrina/farmacología , Metformina/farmacología , Fertilización In Vitro/veterinaria , Oocitos , Desarrollo Embrionario , Blastocisto , Técnicas de Maduración In Vitro de los Oocitos/veterinaria
11.
Aging Clin Exp Res ; 35(6): 1393-1399, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37103663

RESUMEN

BACKGROUND: Widespread vaccination and emergence of less aggressive SARS-CoV2 variants may have blunted the unfavourable outcomes of COVID-19 in nursing home (NH) residents. We analysed the course of COVID-19 epidemic in NHs of Florence, Italy, during the "Omicron era" and investigated the independent effect of SARS-CoV2 infection on death and hospitalization risk. METHODS: Weekly SARS-CoV2 infection rates between November 2021 and March 2022 were calculated. Detailed clinical data were collected in a sample of NHs. RESULTS: Among 2044 residents, 667 SARS-CoV2 cases were confirmed. SARS-CoV2 incidence sharply increased during the Omicron era. Mortality rates did not differ between SARS-CoV2-positive (6.9%) and SARS-CoV2-negative residents (7.3%, p = 0.71). Chronic obstructive pulmonary disease and poor functional status, but not SARS-CoV2 infection independently predicted death and hospitalization. CONCLUSIONS: Despite that SARS-CoV2 incidence increased during the Omicron era, SARS-CoV2 infection was not a significant predictor of hospitalization and death in the NH setting.


Asunto(s)
COVID-19 , Humanos , SARS-CoV-2 , Hospitalización , Casas de Salud
12.
Pediatr Radiol ; 53(4): 727-738, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36121496

RESUMEN

Cirrhosis is a complex diffuse process whereby the architecture of the liver is replaced by abnormal nodules because of the presence of fibrosis. Several pediatric diseases such as extrahepatic portal vein obstruction, biliary atresia, alpha-1-antitrypsin deficit and autoimmune hepatitis can lead to cirrhosis and portal hypertension in children. In this article the authors describe interventional radiology procedures that can facilitate the diagnosis and treatment of diseases associated with liver cirrhosis and portal hypertension in the pediatric population. These procedures include image-guided liver biopsy, mesenteric-intrahepatic left portal vein shunts, balloon-occluded retrograde transvenous obliteration, transjugular intrahepatic portosystemic shunts and splenic embolization.


Asunto(s)
Hipertensión Portal , Derivación Portosistémica Intrahepática Transyugular , Niño , Humanos , Derivación Portosistémica Intrahepática Transyugular/métodos , Vena Porta , Hipertensión Portal/diagnóstico por imagen , Hipertensión Portal/cirugía , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico por imagen , Biopsia Guiada por Imagen , Resultado del Tratamiento
13.
Ophthalmic Plast Reconstr Surg ; 39(6): e192-e194, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37405766

RESUMEN

Isolated orbital mucocele without connection between the mass and paranasal sinuses is extremely rare and poorly understood. Literature review of these cases are very few and present more anteriorly in the orbit. Here, the authors present a 33-year-old female with an isolated left orbital apex mucocele without direct communication with the adjacent paranasal sinuses and other vital orbital structures. Endoscopic sinus surgery with marsupialization was performed, and an orbital mucocele was confirmed on histopathology. Although uncommon, previously reported cases, including our patient have remained disease free of recurrence for at least 1 year post-operatively.


Asunto(s)
Mucocele , Enfermedades de los Senos Paranasales , Senos Paranasales , Femenino , Humanos , Adulto , Enfermedades de los Senos Paranasales/diagnóstico , Enfermedades de los Senos Paranasales/cirugía , Mucocele/diagnóstico , Mucocele/cirugía , Órbita/patología , Endoscopía
14.
Molecules ; 28(3)2023 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-36770887

RESUMEN

Composites made of linear low-density polyethylene (LLDPE) and ß-cyclodextrin/d-limonene inclusion complex (CD-lim) were prepared by melt extrusion to develop a novel food packaging material. Scanning electron microscopy evidenced a fairly good dispersion of the filler within the polymeric matrix. Infrared spectroscopy coupled with thermogravimetric analysis confirmed the presence of CD-lim in the composites, proving that the applied technology of including the essential oil within ß-CD cages allows for preventing a sizable loss of d-limonene despite a high temperature and shear applied upon extrusion processing. Moreover, the influence of the filler on the thermal properties of PE was assessed. It was found that the cyclodextrin-based inclusion complex significantly fastens the crystallization path of the polyethylene matrix with an improved crystallization rate of the PE/CD-lim composites compared to the neat polymer.

15.
Eat Weight Disord ; 28(1): 73, 2023 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-37688675

RESUMEN

PURPOSE: The aim of the study was to examine the effects of meal supervision, provided by health professionals, volunteers or family members, on anthropometric, nutritional, psychological, and behavioural outcomes in patients with eating disorders (EDs). METHODS: The present systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The last search was conducted in three databases (PubMed, Scopus, and the Cochrane library). Inclusion criteria considered paediatric and adult patients suffering from EDs, regardless of ethnicity, and treated in different therapeutic settings. The quality of the studies was evaluated using the Newcastle Ottawa Scale (NOS) adapted for cross-sectional studies and Version 2 of the Cochrane risk-of-bias assessment tool for randomised trials. RESULTS: 3282 articles were retrieved, out of which only 6 met the eligibility criteria. A marked heterogeneity in definitions and approaches to supervised mealtime was observed. This variability emerged in the methodologies used in the supervised meal, and in the reference values for the outcome measures that were used, such as the analysis of different parameters. Based on these observations, mealtime assistance provided to patients with EDs shows an overall positive effect on eating behaviour and dysfunctional attitudes. Future research should be prompted to provide a thorough definition of a structured procedure for meal assistance to be potentially and systematically included in the nutritional rehabilitation protocols for patients with EDs. LEVEL OF EVIDENCE: Level IV systematic reviews of uncontrolled trials.


Asunto(s)
Ansiedad , Trastornos de Alimentación y de la Ingestión de Alimentos , Adulto , Humanos , Niño , Estudios Transversales , Antropometría , Comidas
16.
Carcinogenesis ; 43(8): 728-735, 2022 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-35675759

RESUMEN

Intraductal papillary mucinous neoplasms (IPMNs) are nonobligatory precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The identification of molecular biomarkers able to predict the risk of progression of IPMNs toward malignancy is largely lacking and sorely needed. Telomere length (TL) is associated with the susceptibility of developing cancers, including PDAC. Moreover, several PDAC risk factors have been shown to be associated with IPMN transition to malignancy. TL is genetically determined, and the aim of this study was to use 11 SNPs, alone or combined in a score (teloscore), to estimate the causal relation between genetically determined TL and IPMNs progression. For this purpose, 173 IPMN patients under surveillance were investigated. The teloscore did not show any correlation, however, we observed an association between PXK-rs6772228-A and an increased risk of IPMN transition to malignancy (HR = 3.17; 95%CI 1.47-6.84; P = 3.24 × 10-3). This effect was also observed in a validation cohort of 142 IPMNs even though the association was not statistically significant. The combined analysis was consistent showing an association between PXK-rs6772228-A and increased risk of progression. The A allele of this SNP is strongly associated with shorter LTL that in turn have been reported to be associated with increased risk of developing PDAC. These results clearly highlight the importance of looking for genetic variants as potential biomarkers in this setting in order to further our understanding the etiopathogenesis of PDAC and suggest that genetically determined TL might be an additional marker of IPMN prognosis.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Intraductales Pancreáticas , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Estudios Retrospectivos , Telómero/genética , Neoplasias Pancreáticas
17.
Eur J Clin Invest ; 52(12): e13863, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36039486

RESUMEN

BACKGROUND: Monoclonal antibodies that inhibit the proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein cholesterol (LDLc) by 55%, regardless of baseline treatments. Nonetheless, the effect of other lipid parameters, such as cholesterol remnants or, the so-called lipid residual risk, is unknown. METHODS: Multicenter and retrospective registry of patients treated with PCSK9 inhibitors from 14 different hospitals in Spain. Before and on-treatment lipid parameters were recorded. Residual lipid risk was estimated by (1) cholesterol remnants, (2) triglycerides/HDLc ratio (TG/HDL), (3) total cholesterol/HDLc (TC/HDL) and (4) the triglycerides-to-glucose index (TGGi). RESULTS: Six hundred fifty-two patients were analysed, mean age of 60.2 (9.63) years, 24.69% women and mean LDLc before treatment 149.24 (49.86) mg/dl. Median time to second blood determination was 187.5 days. On-treatment LDLc was 67.46 (45.78) mg/dl, which represented a 55% reduction. Significant reductions were observed for TG/HDL ratio, cholesterol remnants, TC/HDL ratio and TGGi. As consequence, 34.61% patients had LDLc <55 mg/dl and cholesterol remnants <30 mg/dl; additionally, 31.95% had cholesterol remnants <30 mg/dl but LDLc >55 mg/dl. Patients who had levels of cholesterol remnants >30 mg/dl before initiating the treatment with PCSK9 had higher reductions in cholesterol remnants, TG/HDL ratio, TC/HDL and TGGi. By contrast, no reduction differences were observed according to baseline LDLc (< or > the mean), age, gender or obesity. CONCLUSIONS: This multicenter and retrospective registry of real-world patients treated with PCSK9 inhibitors demonstrates a positive effect on cholesterol remnants and lipid residual risk beyond LDLc reductions.


Asunto(s)
Inhibidores de PCSK9 , Proproteína Convertasa 9 , Humanos , Femenino , Persona de Mediana Edad , Masculino , Estudios Retrospectivos , Colesterol , Triglicéridos , Sistema de Registros , HDL-Colesterol
18.
FASEB J ; 35(9): e21816, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34396583

RESUMEN

Proper physiological function of mammalian airways requires the differentiation of basal stem cells into secretory or multiciliated cells, among others. In addition, the self-renewal ability of these basal stem cells is crucial for developing a quick response to toxic agents in order to re-establish the epithelial barrier function of the airways. Although these epithelial missions are vital, little is known about those mechanism controlling airway epithelial regeneration in health and disease. p53 has been recently proposed as the guardian of homeostasis, promoting differentiation programs, and antagonizing a de-differentiation program. Here, we exploit mouse and human tracheal epithelial cell culture models to study the role of MDM2-p53 signaling in self-renewal and differentiation in the airway epithelium. We show that p53 protein regulation by MDM2 is crucial for basal stem cell differentiation and to keep proper cell proliferation. Therefore, we suggest that MDM2/p53 interaction modulation is a potential target to control regeneration of the mammalian airway epithelia without massively affecting the epithelium integrity and differentiation potential.


Asunto(s)
Diferenciación Celular/fisiología , Epitelio/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Mucosa Respiratoria/metabolismo , Células Madre/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Proliferación Celular/fisiología , Células Epiteliales/metabolismo , Femenino , Homeostasis/fisiología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Regeneración/fisiología , Transducción de Señal/fisiología , Tráquea/metabolismo
19.
J Cardiovasc Pharmacol ; 79(4): 523-529, 2022 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-34983910

RESUMEN

BACKGROUND: Previous evidence supports that monoclonal antibodies that inhibit the proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein cholesterol (LDLc) by 50%-65%, regardless of baseline treatments. We tested possible sex differences in a multicentre registry of real-world patients treated with PCSK9 inhibitors. METHODS: This is a multicentre and retrospective study of 652 patients initiating treatment with any PCSK9 inhibitor in 18 different hospitals. Before-treatment and on-treatment LDLc and medical treatments, clinical indication, and clinical features were recorded. RESULTS: Women represented 24.69% of the cohort. The use of statins was similar in both sexes, but women were receiving most frequently ezetimibe. Before-treatment median LDLc was 135 (interquartile range 115-166) mg, and it was higher in women. The median on-treatment LDLc was 57 (interquartile range 38-84) mg/dL, which represented a mean 54.5% reduction. On-treatment LDLc was higher in women, and the mean LDLc reduction was lower in women (47.4% vs. 56.9%; P = 0.0002) receiving evolocumab or alirocumab. The percentage of patients who achieved ≥50% LDLc reduction was higher in men (71.36% vs. 57.62%; P = 0.002). According to LDLc before-treatment quartiles, LDLc reduction was statistically lower in women in the 2 highest and a significant interaction of women and baseline LDLc >135 mg/dL was observed. Women were negatively associated with lower rates of LDLc treatment target achievement (odds ratio: 0.31). Differences were also observed in women with body mas index >25 kg/m2. Only 14 patients (2.14%) presented side effects. CONCLUSIONS: This multicentre and retrospective registry of real-world patients treated with PCSK9 inhibitors highlights significant gender differences in LDLc reduction.


Asunto(s)
Anticolesterolemiantes , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Anticolesterolemiantes/efectos adversos , LDL-Colesterol , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Masculino , Inhibidores de PCSK9 , Proproteína Convertasa 9 , Sistema de Registros , Estudios Retrospectivos , Caracteres Sexuales , Factores Sexuales
20.
Surg Endosc ; 36(9): 6473-6479, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35020053

RESUMEN

BACKGROUND: Artificial intelligence (AI) has the potential to enhance patient safety in surgery, and all its aspects, including education and training, will derive considerable benefit from AI. In the present study, deep-learning models were used to predict the rates of proficiency acquisition in robot-assisted surgery (RAS), thereby providing surgical programs directors information on the levels of the innate ability of trainees to facilitate the implementation of flexible personalized training. METHODS: 176 medical students, without prior experience with surgical simulators, were trained to reach proficiency in five tasks on a virtual simulator for RAS. Ensemble deep neural networks (DNN) models were developed and compared with other ensemble AI algorithms, i.e., random forests and gradient boosted regression trees (GBRT). RESULTS: DNN models achieved a higher accuracy than random forests and GBRT in predicting time to proficiency, 0.84 vs. 0.70 and 0.77, respectively (Peg board 2), 0.83 vs. 0.79 and 0.78 (Ring walk 2), 0.81 vs 0.81 and 0.80 (Match board 1), 0.79 vs. 0.75 and 0.71 (Ring and rail 2), and 0.87 vs. 0.86 and 0.84 (Thread the rings 2). Ensemble DNN models outperformed random forests and GBRT in predicting number of attempts to proficiency, with an accuracy of 0.87 vs. 0.86 and 0.83, respectively (Peg board 2), 0.89 vs. 0.88 and 0.89 (Ring walk 2), 0.91 vs. 0.89 and 0.89 (Match board 1), 0.89 vs. 0.87 and 0.83 (Ring and rail 2), and 0.96 vs. 0.94 and 0.94 (Thread the rings 2). CONCLUSIONS: Ensemble DNN models can identify at an early stage the acquisition rates of surgical technical proficiency of trainees and identify those struggling to reach the required expected proficiency level.


Asunto(s)
Aprendizaje Profundo , Procedimientos Quirúrgicos Robotizados , Inteligencia Artificial , Competencia Clínica , Simulación por Computador , Humanos , Procedimientos Quirúrgicos Robotizados/educación
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