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BACKGROUND AND AIMS: Comprehensive assessment of pharmacotherapy effects on atherogenic parameters (AP) that influence the risk of cardiovascular disease (CVD) is challenging due to interactions among a large number of parameters that modulate CVD risk. METHODS: We developed an illustrative tool, athero-contour (AC), which incorporates weighted key lipid, lipo- and glycoprotein parameters, to readily illustrate their overall changes following pharmacotherapy. We demonstrate the applicability of AC to assess changes in AP in response to saroglitazar treatment in patients with metabolic associated fatty liver disease (MAFLD) in the EVIDENCES IV study. RESULTS: The baseline AC of saroglitazar and placebo groups was worse than the mean of the general population. After 16-week treatment, AC improved significantly in the saroglitazar group due to alterations in very low-density lipoprotein, triglyceride, and glycoproteins. CONCLUSION: Using AC, we could readily and globally evaluate and visualize changes in AP. AC improved in patients with MAFLD following saroglitazar therapy.
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The objective of this study was to evaluate the effects of increasing levels of the M-E complex (xylanase, glucanase, cellulase, and invertase) Optimax E® on the performance of growing lambs, their digestibility, and their rumen microbiota, and to estimate NEm, NEg, and ruminal methane levels. Forty lambs (Katahdin x Dorset; 22.91 ± 4.16 kg) were randomly assigned to dietary concentrations of ME (0, 0.2, 0.4, and 0.8% DM) and fed individually for 77 days. Increasing M-E improved feed conversion (p < 0.05) as well as NEm and NEg (p < 0.05), which were associated with increased in vivo DM and NDF digestion (linear and quadratic p < 0.01). Few microbial families showed abundancy changes (Erysipelotrichaceae, Christensenellaceae, Lentisphaerae, and Clostridial Family XIII); however, the dominant phylum Bacteroidetes was linearly reduced, while Firmicutes increased (p < 0.01), resulting in a greater Firmicutes-to-Bacteroidetes ratio. Total Entodinium showed a quadratic response (p < 0.10), increasing its abundancy as the enzyme dose was augmented. The daily emission intensity of methane (per kg of DMI or AGD) was reduced linearly (p < 0.01). In conclusion, adding the M-E complex Optimax E® to growing lambs' diets improves their productive performance by acting synergistically with the rumen microbiota, modifying the Firmicutes-to-Bacteroidetes ratio toward more efficient fermentation, and shows the potential to reduce the intensity of greenhouse gas emissions from lambs.
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BACKGROUND: Every year, thousands of patients with hypertension reduce salt consumption in an effort to control their blood pressure. However, hypertension has a self-sustaining character in a significant part of the population. We hypothesized that chronic hypertension leads to irreversible renal damage that remains after removing the trigger, causing an elevation of the initial blood pressure. METHODS: Dahl salt-sensitive rat model was used for chronic, continuous observation of blood pressure. Rats were fed a high salt diet to induce hypertension, and then the diet was switched back to normal sodium content. RESULTS: We found that developed hypertension was irreversible by salt cessation: after a short period of reduction, blood pressure grew even higher than in the high-salt phase. Notably, the self-sustaining phase of hypertension was sensitive to benzamil treatment due to sustaining epithelial sodium channel hyperactivity, as shown with patch-clamp analysis. Glomerular damage and proteinuria were also irreversible. In contrast, some mechanisms, contributing to the development of salt-sensitive hypertension, normalized after salt restriction. Thus, flow cytometry demonstrated that dietary salt reduction in hypertensive animals decreased the number of total CD45+, CD3+CD4+, and CD3+CD8+ cells in renal tissues. Also, we found tubular recovery and improvement of glomerular filtration rate in the postsalt period versus a high-salt diet. CONCLUSIONS: Based on earlier publications and current data, poor response to salt restriction is due to the differential contribution of the factors recognized in the developmental phase of hypertension. We suggest that proteinuria or electrolyte transport can be prioritized over therapeutic targets of inflammatory response.
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Presión Sanguínea , Modelos Animales de Enfermedad , Hipertensión , Ratas Endogámicas Dahl , Cloruro de Sodio Dietético , Animales , Hipertensión/fisiopatología , Hipertensión/etiología , Ratas , Cloruro de Sodio Dietético/efectos adversos , Presión Sanguínea/fisiología , Presión Sanguínea/efectos de los fármacos , Masculino , Riñón/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Canales Epiteliales de Sodio/metabolismo , Dieta HiposódicaRESUMEN
BACKGROUND: Mycosis fungoides (MF) and Sézary syndrome (SS) are chronic malignant diseases that typically necessitate diverse strategies to achieve remission. Systemic interferon (IFN)-α (subtypes 2a and 2b) has been used to treat MF/SS since 1984; however, its production was recently stopped. The recombinant pegylated (PEG) form of IFN-α-2a remains the only alternative IFN treatment, although it has not been approved for use in MF/SS. OBJECTIVES: To assess the effectiveness and safety of PEG-IFN-α-2a in monotherapy and in combination with other treatments using time to next treatment (TTNT) as a measure of clinical therapeutic benefit in a real-world setting. METHODS: We conducted an international, multicentre retrospective study of patients with MF and SS (of any stage) treated with PEG-IFN-α-2a from July 2012 to February 2022. Patients were included across 11 centres in 10 countries. The primary endpoints were to determine the TTNT of PEG-IFN-α-2a and adverse events (AEs) in MF/SS. RESULTS: In total, 105 patients were included [mean (SD) age 61 (13.1) years]; 42 (40.0%) had stage IA-IIA and 63 (60.0%) had stage IIB-IVB disease. PEG-IFN-α-2a was combined with other therapies in 67 (63.8%) patients, most commonly with extracorporeal photopheresis (36%) and bexarotene (22%). Patients with stage I-IIA disease achieved an overall response rate (ORR) of 57%; the ORR in those with stage IIB-IVB disease was 51%. Combination treatment resulted in a median TTNT of 10.4â months (range 0.6-50.7) vs. 7.0â months (range 0.7-52.4) for those who received monotherapy (P < 0.01). Overall, the mean (SD) TTNT was 9.2 (10.6) months and the ORR was 53.3% (n = 56). A complete response was seen in 13% of patients and a partial response in 40%. AEs were described in 68.6% (n = 72) of patients. Flu-like symptoms (n = 28; 26.7%), lymphopenia (n = 24; 22.9%) and elevated liver function (n = 10; 9.5%) were the most frequently reported. Grade 3-4 AEs were reported in 23 (21.9%) patients, mostly related to myelosuppression. CONCLUSIONS: PEG-IFN-α-2a for MF/SS resulted in an ORR of 53.3% and a mean (SD) TTNT of 9.2 (10.6) months. Combination regimens were superior to monotherapy and doses of 180â µg PEG-IFN-α-2a weekly were related to a higher ORR.
Mycosis fungoides (MF) and Sézary syndrome (SS) are rare types of cancers of the lymphatic system (lymphomas). They result in patches, plaques and/or tumours on the skin that usually need a combination of treatments to be controlled. A drug called interferon alpha (IFN-α) has been used to treat cutaneous lymphomas since 1984, but its production was recently stopped, so another form of it called 'recombinant pegylated IFN α-2a' (PEG-IFN-α-2a) is the only alternative IFN treatment, even though it has not been formally approved for MF/SS. The lack of studies on PEG-IFN-α-2a for MF/SS treatment has meant that its use can vary between institutions. This study aimed to investigate the effectiveness, the safety and how well PEG-IFN-α-2a is tolerated as single treatment or in combination with other MF/SS treatments. We carried out a study of patients with MF/SS treated with PEG-IFN-α-2a between July 2012 and February 2022. In total, 105 patients were included from 10 countries. We found that 53% of the patients responded to PEG-IFN-α-2a treatment. We also found that doses of 180â µg weekly, as well as combining PEG-IFN-α-2a with other treatments, resulted in higher response rates and a longer time until a new treatment needed to be added. However, at least one adverse event occurred in 69% of patients. The most common were flu-like symptoms, a reduction in the number of white blood cells and increased liver function. Severe adverse events occurred in 21% of the patients, mostly related to a reduction in the number of blood cells. Overall, our study findings suggest that PEG-IFN-α-2a is an effective and generally well-tolerated option among the treatments for MF/SS, with patients experiencing a better response when it was used as part of a combination therapy and on doses of 180â µg weekly.
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Interferón-alfa , Micosis Fungoide , Polietilenglicoles , Proteínas Recombinantes , Síndrome de Sézary , Neoplasias Cutáneas , Humanos , Micosis Fungoide/tratamiento farmacológico , Micosis Fungoide/patología , Persona de Mediana Edad , Femenino , Masculino , Interferón-alfa/administración & dosificación , Interferón-alfa/efectos adversos , Interferón-alfa/uso terapéutico , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Estudios Retrospectivos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Anciano , Síndrome de Sézary/tratamiento farmacológico , Síndrome de Sézary/patología , Resultado del Tratamiento , Adulto , Factores de Tiempo , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Mogamulizumab (MOG) is an antibody targeting the CCR4 receptor, authorized for relapsed or refractory peripheral T-cell (PTCL) and cutaneous T-cell lymphomas (CTCL). Its adoption in guidelines and endorsement by FDA and EMA established it as a systemic treatment, especially for advanced disease stages due to its comparatively lower toxicity. Clinical trials and real-world evidence have underscored its efficacy in advanced CTCLs, including mycosis fungoides and Sézary syndrome; PTCLs; and adult T-cell leukemia/lymphoma (ATLL), showcasing positive outcomes. Notably, the drug has demonstrated significant response rates, disease stability, and extended periods of progression-free survival, suggesting its applicability in cases with multiple treatment lines. Its safety profile is generally manageable, with adverse events (AEs) primarily related to the skin, infusion-related reactions, drug eruptions, autoimmune diseases, and skin disorders. The latter seem to appear as CCR4 can promote the skin-specific homing of lymphocytes, and MOG is directed against this receptor. While combination with immunostimulatory agents like interferon alpha and interleukin 12 has shown promising results, caution is urged when combining with PD1 inhibitors due to the heightened risk of immune-mediated AEs. The introduction of MOG as a systemic treatment implies a significant advancement in managing these diseases, supported by its favorable safety profile and complementary mechanisms.
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Anticuerpos Monoclonales Humanizados , Leucemia-Linfoma de Células T del Adulto , Linfoma Cutáneo de Células T , Micosis Fungoide , Síndrome de Sézary , Neoplasias Cutáneas , Adulto , Humanos , Linfoma Cutáneo de Células T/tratamiento farmacológico , Micosis Fungoide/patología , Síndrome de Sézary/patología , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/patología , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: Early identification of those with NAFLD activity score ≥ 4 and significant fibrosis (≥F2) or at-risk metabolic dysfunction-associated steatohepatitis (MASH) is a priority as these patients are at increased risk for disease progression and may benefit from therapies. We developed and validated a highly specific metabolomics-driven score to identify at-risk MASH. METHODS: We included derivation (n = 790) and validation (n = 565) cohorts from international tertiary centers. Patients underwent laboratory assessment and liver biopsy for metabolic dysfunction-associated steatotic liver disease. Based on 12 lipids, body mass index, aspartate aminotransferase, and alanine aminotransferase, the MASEF score was developed to identify at-risk MASH and compared to the FibroScan-AST (FAST) score. We further compared the performance of a FIB-4 + MASEF algorithm to that of FIB-4 + liver stiffness measurements (LSM) by vibration-controlled transient elastography (VCTE). RESULTS: The diagnostic performance of the MASEF score showed an area under the receiver-operating characteristic curve, sensitivity, specificity, and positive and negative predictive values of 0.76 (95% CI 0.72-0.79), 0.69, 0.74, 0.53, and 0.85 in the derivation cohort, and 0.79 (95% CI 0.75-0.83), 0.78, 0.65, 0.48, and 0.88 in the validation cohort, while FibroScan-AST performance in the validation cohort was 0.74 (95% CI 0.68-0.79; p = 0.064), 0.58, 0.79, 0.67, and 0.73, respectively. FIB-4+MASEF showed similar overall performance compared with FIB-4 + LSM by VCTE ( p = 0.69) to identify at-risk MASH. CONCLUSION: MASEF is a promising diagnostic tool for the assessment of at-risk MASH. It could be used alternatively to LSM by VCTE in the algorithm that is currently recommended by several guidance publications.
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Diagnóstico por Imagen de Elasticidad , Enfermedad del Hígado Graso no Alcohólico , Humanos , Hígado/diagnóstico por imagen , Hígado/patología , Cirrosis Hepática/patología , Enfermedad del Hígado Graso no Alcohólico/patología , Fibrosis , Valor Predictivo de las Pruebas , Biopsia/efectos adversosRESUMEN
INTRODUCTION: Nonoperative management (NOM) along with supportive care has been the adopted approach for traumatic rib fractures; however, surgical approaches have emerged recently to treat this common pathology. Despite this, there are no guidelines for surgical rib fixation in patients with traumatic rib fractures. METHODS: An institutional review board-approved retrospective cohort study was performed at the Puerto Rico Trauma Hospital aiming to compare the outcomes and complications between patients with traumatic rib fractures who undergo surgical fixation and their counterparts with NOM. The study period comprised from January 2016 through July 2020. Outcomes were evaluated with negative binomial and logistic regressions. RESULTS: Fifty patients were identified for the surgical rib fixation group, who were matched to 150 patients who received NOM. The majority of patients were male (91.5%), with a median (interquartile range) age of 53 (29) years. Concomitant chest injuries were significantly more prevalent in the operative group, such as flail segment (P < 0.001), number of fractures (P < 0.001), and displaced rib fractures (P < 0.001). Although hospital length of stay was 25% (95% confidence interval: 1.02-1.54) longer in the surgical group, this intervention was associated with an 85% (95% confidence interval: 0.03-0.70) lower mortality rate when compared to conservative management. CONCLUSIONS: Rib fixation may offer some benefits in selected patients with traumatic rib fractures, such as those with bilateral rib fractures, multiple displaced rib fractures, flail segment, and concomitant thoracic injuries. This study may serve as a guide for treatment strategy and patient selection regarding the surgical management of traumatic rib fractures.
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Tórax Paradójico , Fracturas de las Costillas , Traumatismos Torácicos , Humanos , Masculino , Femenino , Persona de Mediana Edad , Fracturas de las Costillas/complicaciones , Fracturas de las Costillas/cirugía , Estudios Retrospectivos , Tórax Paradójico/etiología , Traumatismos Torácicos/complicaciones , Tiempo de Internación , Costillas , Fijación Interna de Fracturas/efectos adversosRESUMEN
Ionenes are poly(ionic liquids) (PILs) comprising a polymer backbone with ionic groups along the structure. Ionenes as solid-solid phase change materials are a recent research field, and some studies have demonstrated their potential in thermal dissipation into electronic devices. Eight ionenes obtained through Menshutkin reactions were synthesized and characterized. The analysis of the thermal tests allowed understanding of how the thermal properties of the polymers depend on the aliphatic nature of the dihalogenated monomer and the carbon chain length. The TGA studies concluded that the ionenes were thermally stable with T10% above 420 °C. The DSC tests showed that the prepared ionenes presented solid-solid transitions, and no melting temperature was appreciated, which rules out the possibility of solid-liquid transitions. All ionenes were soluble in common polar aprotic solvents. The hydrophilicity of the synthesized ionenes was studied by the contact angle method, and their total surface energy was calculated. Self-healing behavior was preliminarily explored using a selected sample. Our studies show that the prepared ionenes exhibit properties that make them potential candidates for applications as solid-solid phase change materials.
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Inactivating mutations in the ALMS1 gene in humans cause Alström syndrome, characterized by the early onset of obesity, insulin resistance, and renal dysfunction. However, the role of ALMS1 in renal function and hemodynamics is unclear. We previously found that ALMS1 is expressed in thick ascending limbs, where it binds and decreases Na+-K+-2Cl- cotransporter activity. We hypothesized that ALMS1 is expressed in macula densa cells and that its deletion enhances tubuloglomerular feedback (TGF) and reduces glomerular filtration rate (GFR) in rats. To test this, homozygous ALMS1 knockout (KO) and littermate wild-type Dahl salt-sensitive rats were studied. TGF sensitivity was higher in ALMS1 KO rats as measured by in vivo renal micropuncture. Using confocal microscopy, we confirmed immunolabeling of ALMS1 in macula densa cells (nitric oxide synthase 1 positive), supporting a role for ALMS1 in TGF regulation. Baseline glomerular capillary pressure was higher in ALMS1 KO rats, as was mean arterial pressure. Renal interstitial hydrostatic pressure was lower in ALMS1 KO rats, which is linked to increased Na+ reabsorption and hypertension. GFR was reduced in ALMS1 KO rats. Seven-week-old ALMS1 KO rats were not proteinuric, but proteinuria was present in 18- to 22-wk-old ALMS1 KO rats. The glomerulosclerosis index was higher in 18-wk-old ALMS1 KO rats. In conclusion, ALMS1 is involved in the control of glomerular hemodynamics in part by enhancing TGF sensitivity, and this may contribute to decreased GFR. Increased TGF sensitivity, enhanced glomerular capillary pressure, and hypertension may lead to glomerular damage in ALMS1 KO rats. These are the first data supporting the role of ALMS1 in TGF and glomerular hemodynamics.NEW & NOTEWORTHY ALMS1 is a novel protein involved in regulating tubuloglomerular feedback (TGF) sensitivity, glomerular capillary pressure, and blood pressure, and its dysfunction may reduce renal function and cause glomerular damage.
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Síndrome de Alstrom , Hipertensión , Enfermedades Renales , Humanos , Ratas , Animales , Ratas Endogámicas Dahl , Tasa de Filtración Glomerular/fisiología , HemodinámicaRESUMEN
This cross-sectional study analyzes spectroscopy data for long-term, never-medicated patients with schizophrenia to examine their levels of γ-aminobutyric acid (GABA) compared with those of healthy controls.
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Esquizofrenia , Humanos , Esquizofrenia/diagnóstico , Espectroscopía de Resonancia Magnética , Ácido Glutámico , Ácido gamma-Aminobutírico , Corteza PrefrontalRESUMEN
Rapidly progressive/crescentic glomerulonephritis (RPGN/CGN) involves the formation of glomerular crescents by maladaptive differentiation of parietal epithelial cells that leads to rapid loss of renal function. The molecular mechanisms of crescent formation are poorly understood. Therefore, new insights into molecular mechanisms could identify alternative therapeutic targets for RPGN/CGN. Analysis of kidney biopsies from patients with RPGN revealed increased interstitial, glomerular, and tubular expression of STING1, an accessory protein of the c-GAS-dependent DNA-sensing pathway, which was also observed in murine nephrotoxic nephritis induced by an anti-GBM antibody. STING1 was expressed by key cell types involved in RPGN and crescent formation such as glomerular parietal epithelial cells, and tubular cells as well as by inflammation accessory cells. In functional in vivo studies, Sting1-/- mice with nephrotoxic nephritis had lower kidney cytokine expression, milder kidney infiltration by innate and adaptive immune cells, and decreased disease severity. Pharmacological STING1 inhibition mirrored these findings. Direct STING1 agonism in parietal and tubular cells activated the NF-κB-dependent cytokine response and the interferon-induced genes (ISGs) program. These responses were also triggered in a STING1-dependent manner by the pro-inflammatory cytokine TWEAK. These results identify STING1 activation as a pathological mechanism in RPGN/CGN and TWEAK as an activator of STING1. Pharmacological strategies targeting STING1, or upstream regulators may therefore be potential alternatives to treat RPGN. © 2023 The Pathological Society of Great Britain and Ireland.
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Glomerulonefritis , Nefritis , Humanos , Ratones , Animales , Glomerulonefritis/genética , Riñón/patología , Glomérulos Renales/patología , Enfermedad Aguda , Citocinas/metabolismoRESUMEN
In this research, novel, organic, solid-liquid phase-change materials (PCMs) derived from methoxy polyethylene glycol (MPEG) and aromatic acyl chlorides (ACs) were prepared through a condensation reaction. The MPEGs were used as phase-change functional chains with different molecular weights (350, 550, 750, 2000, and 5000 g/mol). The aromatic ACs, terephthaloyl chloride (TPC) and isophthaloyl chloride (IPC), were employed as bulky linker cores. Solubility tests demonstrated that this family of PCMs is soluble in protic polar solvents such as H2O and MeOH, and insoluble in nonpolar solvents such as n-hexane. Fourier-ransform infrared spectroscopy (FT-IR UATR) and nuclear magnetic resonance (1H, 13C, DEPT 135°, COSY, HMQC, and HMBC NMR) were used to confirm the bonding of MPEG chains to ACs. The crystalline morphology of the synthesized materials was examined using polarized optical microscopy (POM), revealing the formation of spherulites with Maltese-cross-extinction patterns. Furthermore, it was confirmed that PCMs with higher molecular weights were crystalline at room temperature and exhibited an increased average spherulite size compared to their precursors. Thermal stability tests conducted through thermogravimetric analysis (TGA) indicated decomposition temperatures close to 400 °C for all PCMs. The phase-change properties were characterized by differential scanning calorimetry (DSC), revealing that the novel PCMs melted and crystallized between -23.7 and 60.2 °C and -39.9 and 45.9 °C, respectively. Moreover, the heat absorbed and released by the PCMs ranged from 57.9 to 198.8 J/g and 48.6 to 195.6 J/g, respectively. Additionally, the PCMs exhibited thermal stability after undergoing thermal cycles of melting-crystallization, indicating that energy absorption and release occurred at nearly constant temperatures. This study presents a new family of high-performance organic PCMs and demonstrates that the orientation of substituent groups in the phenylene ring influences supercooling, transition temperatures, and thermal energy storage capacity depending on the MPEG molecular weight.
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BACKGROUND: OSA has been associated with increased incidence and aggressiveness of melanoma. However, the long-term impact of OSA and CPAP treatment on the prognosis of melanoma remains unexplored. RESEARCH QUESTION: Are OSA and CPAP treatment associated independently with a poor prognosis for cutaneous melanoma? STUDY DESIGN AND METHODS: Four hundred forty-three patients with a diagnosis of cutaneous melanoma (2012-2015) underwent a sleep study within 6 months of diagnosis. The main 5-year outcome of the study was a composite of melanoma recurrence, metastasis, or mortality. Patients were divided into four groups: baseline apnea-hypopnea index (AHI) of fewer than 10 events/h (no OSA; control group), OSA treated with CPAP and good adherence, untreated or poor CPAP adherence in moderate (AHI, 10-29 events/h), and severe OSA (AHI, ≥ 30 events/h). Survival analysis was used to determine the independent role of OSA and CPAP treatment on melanoma composite outcome. RESULTS: Three hundred ninety-one patients (88.2%) were available for analysis at 5-year follow-up (mean age, 65.1 ± 15.2 years; 49% male; Breslow index, 1.7 ± 2.5 mm). One hundred thirty-nine patients had AHI of fewer than 10 events/h (control group); 78 patients with OSA were adherent to CPAP; and 124 and 50 patients had moderate and severe OSA, respectively, without CPAP treatment. Median follow-up was 60 months (interquartile range, 51-74 months). During follow-up, 32 relapses, 53 metastases, and 52 deaths occurred (116 patients showed at least one of the main composite outcomes). After adjusting for age, sex, sentinel lymph nodes affected at diagnosis, BMI, diabetes, nighttime with an oxygen saturation below 90%, Breslow index, Epworth sleepiness scale scores, and melanoma treatment, moderate (hazard ratio [HR], 2.45; 95% CI, 1.09-5.49) and severe OSA (HR, 2.96; 95% CI, 1.36-6.42) were associated with poorer prognosis of melanoma compared with the control group. However, good adherence to CPAP avoided this excess risk (HR, 1.66; 95% CI, 0.71-3.90). INTERPRETATION: Moderate to severe untreated OSA is an independent risk factor for poor prognosis of melanoma. Treatment with CPAP is associated with improved melanoma outcomes compared with untreated moderate to severe OSA.
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Melanoma , Neoplasias Cutáneas , Síndromes de la Apnea del Sueño , Apnea Obstructiva del Sueño , Humanos , Masculino , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Femenino , Apnea Obstructiva del Sueño/complicaciones , Melanoma/terapia , Melanoma/complicaciones , Estudios Prospectivos , Neoplasias Cutáneas/complicaciones , Recurrencia Local de Neoplasia/epidemiología , Síndromes de la Apnea del Sueño/complicaciones , Pronóstico , Presión de las Vías Aéreas Positiva ContínuaRESUMEN
Gender inequality across the world has been associated with a higher risk to mental health problems and lower academic achievement in women compared to men. We also know that the brain is shaped by nurturing and adverse socio-environmental experiences. Therefore, unequal exposure to harsher conditions for women compared to men in gender-unequal countries might be reflected in differences in their brain structure, and this could be the neural mechanism partly explaining women's worse outcomes in gender-unequal countries. We examined this through a random-effects meta-analysis on cortical thickness and surface area differences between adult healthy men and women, including a meta-regression in which country-level gender inequality acted as an explanatory variable for the observed differences. A total of 139 samples from 29 different countries, totaling 7,876 MRI scans, were included. Thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, presented no differences or even thicker regional cortices in women compared to men in gender-equal countries, reversing to thinner cortices in countries with greater gender inequality. These results point to the potentially hazardous effect of gender inequality on women's brains and provide initial evidence for neuroscience-informed policies for gender equality.
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Encéfalo , Equidad de Género , Masculino , Adulto , Humanos , Femenino , Encéfalo/diagnóstico por imagen , Factores SexualesRESUMEN
Studies of cellular and cytokine profiles have contributed to the inflammation hypothesis of schizophrenia; however, precise markers of inflammatory dysfunction remain elusive. A number of proton magnetic resonance spectroscopy (1H-MRS) studies in patients with first-episode psychosis (FEP) have shown higher brain levels of metabolites such as glutamate, myo-inositol (mI) and choline-containing compounds (tCho), suggesting neuroinflammation. Here, we present peripheral inflammatory profiles in antipsychotic-naive FEP patients and age-and-sex matched healthy controls, as well as cortical glutamate, mI and tCho levels using 1H-MRS. Inflammatory profiles were analyzed using cytokine production by peripheral blood mononuclear cells, that were either spontaneous or stimulated, in 48 FEP patients and 23 controls. 1H-MRS of the medial prefrontal cortex was obtained in 29 FEP patients and 18 controls. Finally, 16 FEP patients were rescanned after 4 weeks of treatment (open-label) with Risperidone. FEP patients showed a higher proportion of proinflammatory Th1/Th17 subset, and an increased spontaneous production of Interleukin (IL)-6, IL-2 and IL-4 compared with the control group. Results obtained from 1H-MRS showed no significant difference in either glutamate, mI or tCho between FEP and control groups. At baseline, CD8% showed a negative correlation with glutamate in FEP patients; after 4 weeks of risperidone treatment, the FEP group exhibited a decrease in glutamate levels which positively correlated with CD4 + T cells. Nevertheless, these correlations did not survive correction for multiple comparisons. FEP patients show evidence of immune dysregulation, affecting both the innate and adaptive immune response, with a predominantly Th2 signature. These findings, along with the changes produced by antipsychotic treatment, could be associated with both systemic and central inflammatory processes in schizophrenia.
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Antipsicóticos , Neuroquímica , Trastornos Psicóticos , Humanos , Risperidona/uso terapéutico , Antipsicóticos/uso terapéutico , Leucocitos Mononucleares/metabolismo , Ácido Glutámico/metabolismo , Interleucina-6 , Inflamación/complicacionesRESUMEN
Due to the number of polyphenols with multiple biological activities, propolis has high potential to be used as an active agent in food protective films. Therefore, this study aimed to develop and characterize a sodium alginate film with ethanolic extract of propolis (EEP) for its potential use as protective active packaging against filamentous fungi in ripened cheese. Three different concentrations of EEP were analyzed: 0, 5 and 10% w/v. The films obtained were characterized, assessing thermal and physicochemical properties, as well as the concentration of polyphenols in the EEP and antifungal activity of the active films. The incorporation of EEP in the films generated thermal stability with respect to the loss of mass. Total color values (ΔE) of the films were affected by the incorporation of the different concentrations of EEP, showing a decrease in luminosity (L*) of the films, while the chromatic parameters a* and b* increased in direct proportion to the EEP concentration. Antifungal activity was observed with a fungistatic mode of action, stopping the growth of the fungus in cheeses without development of filamentous molds, thus increasing the shelf life of the ripened cheese under the analytical conditions, over 30 days at room temperature. Overall, EEP can be used to prevent growth and proliferation of spoilage microorganisms in cheese.
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Background The renal mechanisms involved in the maintenance of human hypertension and resistance to treatment are not well understood. Animal studies suggest that chronic renal inflammation contributes to hypertension. We studied cells shed in first-morning urine samples from individuals who were hypertensive who exhibited difficult-to-control blood pressure (BP). We performed bulk RNA sequencing of these shed cells to develop transcriptome-wide associations with BP. We also analyzed nephron-specific genes and used an unbiased bioinformatic approach to find signaling pathways activated in difficult-to-control hypertension. Methods and Results Participants who completed the SPRINT (Systolic Blood Pressure Intervention Trial) at a single trial site were recruited, and cells shed in first-morning urine samples collected. A total of 47 participants were divided into 2 groups based on hypertension control. The BP-difficult group (n=29) had systolic BP>140 mm Hg, >120 mm Hg after intensive treatment for hypertension, or required more than the median number of antihypertensive drugs used in SPRINT. The easy-to-control BP group (n=18) comprised the remainder of the participants. A total of 60 differentially expressed genes were identified with a >2-fold change in the BP-difficult group. In BP-difficult participants, 2 of the most upregulated genes were associated with inflammation: Tumor Necrosis Factor Alpha Induced Protien 6 (fold change, 7.76; P=0.006) and Serpin Family B Member 9 (fold change, 5.10; P=0.007). Biological pathway analysis revealed an overrepresentation of inflammatory networks, including interferon signaling, granulocyte adhesion and diapedesis, and Janus Kinase family kinases in the BP-difficult group (P<0.001). Conclusions We conclude that transcriptomes from cells shed in first-morning urine identify a gene expression profile in difficult-to-control hypertension that associates with renal inflammation.
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Hipertensión , Nefritis , Humanos , Transcriptoma , Hipertensión/tratamiento farmacológico , Presión Sanguínea/fisiología , Antihipertensivos/uso terapéutico , Antihipertensivos/farmacología , Nefritis/genética , Nefritis/complicaciones , Inflamación/complicacionesRESUMEN
Intracellular long-chain acyl-coenzyme As (LC-acyl-CoAs) are thought to be under tight spatial and temporal controls, yet the ability to image LC-acyl-CoAs in live cells is lacking. Here, we developed a fluorescence resonance energy transfer (FRET) sensor for LC-acyl-CoAs based on the allosterically regulated interaction between α/ß hydrolase domain-containing 5 (ABHD5) and Perilipin 5. The genetically encoded sensor rapidly detects intracellular LC-acyl-CoAs generated from exogenous and endogenous fatty acids (FAs), as well as synthetic ABHD5 ligands. Stimulation of lipolysis in brown adipocytes elevated intracellular LC-acyl-CoAs in a cyclic fashion, which was eliminated by inhibiting PNPLA2 (ATGL), the major triglyceride lipase. Interestingly, inhibition of LC-acyl-CoA transport into mitochondria elevated intracellular LC-acyl-CoAs and dampened their cycling. Together, these observations reveal an intimate feedback control between LC-acyl-CoA generation from lipolysis and utilization in mitochondria. We anticipate that this sensor will be an important tool to dissect intracellular LC-acyl-CoA dynamics as well to discover novel synthetic ABHD5 ligands.
Asunto(s)
Acilcoenzima A , Transferencia Resonante de Energía de Fluorescencia , Acilcoenzima A/metabolismo , Lipólisis/fisiología , Lipasa/genética , Ácidos GrasosRESUMEN
PURPOSE: Substance misuse has long been recognized as a major predisposing risk factor for traumatic injury. However, there still exists no clear scientific consensus regarding the impact of drug use on patient outcomes. Therefore, this study aims to evaluate the demographic profile, hospital-course factors, and outcomes of trauma patients based on their toxicology. METHODS: This is a non-concurrent cohort study of 3709 patients treated at the Puerto Rico Trauma Hospital during 2002-2018. The sample was divided into four groups according to their toxicology status. Statistical techniques used included Pearson's chi-square test, Spearman correlation, and negative binomial and logistic regressions. RESULTS: Admission rates for marijuana (rho = 0.87) and marijuana and cocaine positive (rho = 0.68) patients increased. Positive toxicology patients underwent surgery more often than negative testing patients (marijuana: 68.7%, cocaine: 65.6%, marijuana & cocaine: 69.8%, negative: 57.0%). Among patients with non-penetrating injuries, a positive toxicology for cocaine or marijuana was linked to a 48% and 42% increased adjusted risk of complications, 37% and 27% longer TICU LOS, and 32% and 18% longer hospital LOS, respectively. CONCLUSION: Our results show an association between positive toxicology for either marijuana, cocaine, or both with higher need for surgery. Additionally, our results show an increase in complications, TICU LOS, and hospital LOS among non-penetrating trauma patients testing positive for marijuana or cocaine. Therefore, this study provides valuable information on the clinical profile of patients with positive toxicology, suggesting they might benefit from more aggressive management.
Asunto(s)
Cannabis , Cocaína , Heridas y Lesiones , Humanos , Cannabis/efectos adversos , Cocaína/efectos adversos , Estudios de Cohortes , Factores de Riesgo , Trastornos Relacionados con Sustancias/complicaciones , Heridas y Lesiones/complicaciones , Heridas y Lesiones/fisiopatologíaRESUMEN
Angiotensin-converting enzyme (ACE) hydrolyzes N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) into inactive fragments through its N-terminal site (ACE-N). We previously showed that Ac-SDKP mediates ACE inhibitors' cardiac effects. Whether increased bioavailability of endogenous Ac-SDKP caused by knocking out ACE-N also improves cardiac function in myocardial infarction (MI)-induced heart failure (HF) is unknown. Wild-type (WT) and ACE-N knockout (ACE-NKO) mice were subjected to MI by ligating the left anterior descending artery and treated with vehicle or Ac-SDKP (1.6 mg/kg/day, s.c.) for 5 weeks, after which echocardiography was performed and left ventricles (LV) were harvested for histology and molecular biology studies. ACE-NKO mice showed increased plasma Ac-SDKP concentrations in both sham and MI group compared to WT. Exogenous Ac-SDKP further increased its circulating concentrations in WT and ACE-NKO. Shortening (SF) and ejection (EF) fractions were significantly decreased in both WT and ACE-NKO mice post-MI, but ACE-NKO mice exhibited significantly lesser decrease. Exogenous Ac-SDKP ameliorated cardiac function post-MI only in WT but failed to show any additive improvement in ACE-NKO mice. Sarcoendoplasmic reticulum calcium transport ATPase (SERCA2), a marker of cardiac function and calcium homeostasis, was significantly decreased in WT post-MI but rescued with Ac-SDKP, whereas ACE-NKO mice displayed less loss of SERCA2 expression. Our study demonstrates that gene deletion of ACE-N resulted in improved LV cardiac function in mice post-MI, which is likely mediated by increased circulating Ac-SDKP and minimally reduced expression of SERCA2. Thus, future development of specific and selective inhibitors for ACE-N could represent a novel approach to increase endogenous Ac-SDKP toward protecting the heart from post-MI remodeling.