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1.
Arq. bras. oftalmol ; 88(1): e2023, 2025. tab, graf
Artículo en Inglés | LILACS-Express | LILACS | ID: biblio-1568846

RESUMEN

ABSTRACT Purpose: This study aimed to determine whether early-stage intraocular pressure can be modulated using a thermal face mask. Methods: In this prospective clinical study, healthy participants were randomized on a 1:1:1 allocation ratio to three mask groups: hypothermic (G1), normothermic (G2), and hyperthermic (G3). After randomization, 108 eyes from 108 participants were submitted to clinical evaluations, including measurement of initial intraocular pressure (T1). The thermal mask was then applied for 10 minutes, followed by a second evaluation of intraocular pressure (T2) and assessment of any side effects. Results: The hypothermic group (G1) showed a significant reduction in mean intraocular pressure between T1 (16.97 ± 2.59 mmHg) and T2 (14.97 ± 2.44 mmHg) (p<0.001). G2 showed no significant pressure difference between T1 (16.50 ± 2.55 mmHg) and T2 (17.00 ± 2.29 mmHg) (p=0.054). G3 showed a significant increase in pressure from T1 (16.53 ± 2.69 mmHg) to T2 (18.58 ± 2.95 mmHg) (p<0.001). At T1, there was no difference between the three study groups (p=0.823), but at T2, the mean values of G3 were significantly higher than those of G1 and G2 (p<0.00). Conclusion: Temperature was shown to significantly modify intraocular pressure. Thermal masks allow the application of temperature in a controlled, reproducible manner. Further studies are needed to assess the duration of these effects and whether they are reproducible in patients with pathologies that affect intraocular pressure.

2.
Arq Bras Oftalmol ; 88(1): e20230083, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39109739

RESUMEN

PURPOSE: This study aimed to determine whether early-stage intraocular pressure can be modulated using a thermal face mask. METHODS: In this prospective clinical study, healthy participants were randomized on a 1:1:1 allocation ratio to three mask groups: hypothermic (G1), normothermic (G2), and hyperthermic (G3). After randomization, 108 eyes from 108 participants were submitted to clinical evaluations, including measurement of initial intraocular pressure (T1). The thermal mask was then applied for 10 minutes, followed by a second evaluation of intraocular pressure (T2) and assessment of any side effects. RESULTS: The hypothermic group (G1) showed a significant reduction in mean intraocular pressure between T1 (16.97 ± 2.59 mmHg) and T2 (14.97 ± 2.44 mmHg) (p<0.001). G2 showed no significant pressure difference between T1 (16.50 ± 2.55 mmHg) and T2 (17.00 ± 2.29 mmHg) (p=0.054). G3 showed a significant increase in pressure from T1 (16.53 ± 2.69 mmHg) to T2 (18.58 ± 2.95 mmHg) (p<0.001). At T1, there was no difference between the three study groups (p=0.823), but at T2, the mean values of G3 were significantly higher than those of G1 and G2 (p<0.00). CONCLUSION: Temperature was shown to significantly modify intraocular pressure. Thermal masks allow the application of temperature in a controlled, reproducible manner. Further studies are needed to assess the duration of these effects and whether they are reproducible in patients with pathologies that affect intraocular pressure.


Asunto(s)
Presión Intraocular , Humanos , Presión Intraocular/fisiología , Estudios Prospectivos , Masculino , Femenino , Adulto , Adulto Joven , Tonometría Ocular/métodos , Tonometría Ocular/instrumentación , Factores de Tiempo , Máscaras , Valores de Referencia , Hipotermia Inducida/métodos , Persona de Mediana Edad , Reproducibilidad de los Resultados , Hipertermia Inducida/métodos
3.
J Exp Med ; 221(9)2024 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-39141127

RESUMEN

HIV-1 antiretroviral therapy is highly effective but fails to eliminate a reservoir of latent proviruses, leading to a requirement for life-long treatment. How the site of integration of authentic intact latent proviruses might impact their own or neighboring gene expression or reservoir dynamics is poorly understood. Here, we report on proviral and neighboring gene transcription at sites of intact latent HIV-1 integration in cultured T cells obtained directly from people living with HIV, as well as engineered primary T cells and cell lines. Proviral gene expression was correlated to the level of endogenous gene expression under resting but not activated conditions. Notably, latent proviral promoters were 100-10,000× less active than in productively infected cells and had little or no measurable impact on neighboring gene expression under resting or activated conditions. Thus, the site of integration has a dominant effect on the transcriptional activity of intact HIV-1 proviruses in the latent reservoir, thereby influencing cytopathic effects and proviral immune evasion.


Asunto(s)
Infecciones por VIH , VIH-1 , Provirus , Transcripción Genética , Integración Viral , Latencia del Virus , VIH-1/genética , VIH-1/fisiología , Humanos , Provirus/genética , Latencia del Virus/genética , Integración Viral/genética , Infecciones por VIH/virología , Infecciones por VIH/genética , Regulación Viral de la Expresión Génica , Regiones Promotoras Genéticas/genética , Linfocitos T CD4-Positivos/virología , Linfocitos T/virología , Linfocitos T/inmunología , Línea Celular
4.
Ophthalmol Retina ; 2024 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-39089460

RESUMEN

OBJECTIVE: To refine retinal peripherin-2 (PRPH2)-associated retinal degeneration (PARD) phenotypes using multimodal imaging. DESIGN: Retrospective review of clinical records and multimodal imaging. SUBJECTS: Patients who visited the inherited retinal degeneration (IRD) clinic at 2 tertiary referral eye centers with molecularly confirmed IRD due to PRPH2 variants. METHODS: Retinal imaging was reviewed using ultrawidefield (UWF) pseudocolor, UWF fundus autofluorescence, and spectral-domain OCT. Phenotypes were identified in the macular or peripheral region. A combined phenotype was considered if any phenotypes were present in both macular and peripheral regions. Mixed phenotypes in the macula or peripheral retina were considered if there were 2 distinct phenotypes identified in the same eye. The presence or absence of atrophy in the macular or peripheral area was also noted. MAIN OUTCOME MEASURE: Grading of multimodal imaging by phenotype and atrophy. RESULTS: A total of 144 eyes of 72 patients were included in this study. The majority of the eyes had combined macular and peripheral phenotypes (89/144, 61.8%), whereas 44 (30.6%) eyes had isolated macular findings, and 11 (7.6%) had isolated peripheral findings. Twenty-five eyes were classified with mixed macular phenotypes, whereas fundus flavimaculatus dystrophy type was the most common combined macular and peripheral phenotype (54/144, 37.5%): n = 10 with macular dystrophy and macular flavimaculatus dystrophy (MFD), and n = 15 with butterfly pattern dystrophy and MFD. Nearly half of the eyes (71/144, 49.3%) were identified to have concomitant outer retinal atrophy. Fundus flavimaculatus type dystrophy was also associated with the highest proportion of concomitant atrophy (57/71, 80.3%). CONCLUSIONS: Peripherin-2-associated retinal degeneration demonstrates a wide array of phenotypes using multimodal imaging. We report that combinations of classically described phenotypes were often seen. Additionally, macular and peripheral atrophy were often associated with PARD phenotypes. Refinement of PARD phenotypes using newer multimodal imaging techniques will likely assist diagnosis and future clinical trials. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

5.
Clin Genitourin Cancer ; : 102185, 2024 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-39217072

RESUMEN

BACKGROUND: Managing metastatic castration-resistant prostate cancer (mCRPC) in men aged ≥ 75 is challenging due to limited data. Regardless of age, in real-world clinical practice, most mCRPC still derive from failure of androgen deprivation therapy (ADT) with or without docetaxel (D) for metastatic castration-sensitive prostate cancer (mCSPC). As abiraterone acetate plus prednisone (AA) and enzalutamide (Enza) are common first-line treatments for mCRPC. The impact of prior use of D for mCSPC on the efficacy and safety of AA or Enza in this older population remains unclear. METHODS: A cohort of patients aged ≥ 75 years starting AA or Enza as first-line therapy for mCRPC from January 2015 to April 2019 was identified from the registries of 10 institutions. Patients were categorized into 2 groups based on previous use of D for mCSPC. Primary endpoints were cancer-specific survival (CSS) from AA or Enza start, CSS from ADT onset, and safety. We used Kaplan-Meier method to estimate the endpoints distribution, including median values with 95% confidence intervals (95% CI). RESULTS: Of the 337 patients identified, 24 (7.1%) received ADT+D and 313 (92.9%) received ADT alone for mCSPC. Median follow-up from AA/Enza start was 18.8 months. Median CSS from ADT or AA/Enza was not significantly different between ADT+D and ADT alone cohorts (71.9 vs. 52.7 months, P = .97; 25.4 vs. 27.2 months, P = .89, respectively). No statistically significant difference in adverse events (AEs) of any grade rate (58.3% vs. 52.1%, respectively; P = .67) or grade ≥ 3 (12.5% vs. 15.7%, respectively; P = 1.0) was found between ADT+D and ADT alone cohorts. CONCLUSIONS: Despite the innate limitations of a retrospective design and relatively small size of the ADT+D cohort, this analysis suggests that elderly men receiving AA or Enza as first-line therapy for mCRPC have similar survival outcomes and tolerability, regardless of previous D for mCSPC.

6.
Phys Rev Lett ; 133(6): 060401, 2024 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-39178447

RESUMEN

With the control of increasingly complex quantum systems, the relevant degrees of freedom we are interested in may not be those traditionally addressed by statistical quantum mechanics. Here, we employ quantum channels to define generalized subsystems, capturing the pertinent degrees of freedom, and obtain their associated canonical state. We show that the generalized subsystem description from almost any microscopic pure state of the whole system will behave similarly to its corresponding canonical state. Such canonical typicality behavior depends on the entropy of the channel used to define the generalized subsystem.

7.
Clin Neuropharmacol ; 47(4): 113-119, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39008541

RESUMEN

BACKGROUND: Alpha-synucleinopathies are incurable neurodegenerative diseases. Abelson tyrosine kinase inhibitors (Abl TKIs) may be disease-modifying therapies. This systematic review, meta-analysis, and meta-regression evaluated the use of Abl TKIs in their treatment. METHODS: We searched PubMed, Embase, and Cochrane databases for trials using Abl TKIs in patients with Parkinson's disease and Lewy body dementia published until July 2023. The outcome was the change in the MDS-UPDRS-III (Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale III). DerSimonian-Laird random-effects model was used to calculate the pooled effect estimates. Leave-one-out forest plots were used for the sensitivity analysis, and meta-regression (restricted maximum likelihood) was performed. RESULTS: Five studies (197 patients) were included. Nilotinib 300 mg had an effect size of -1.154 (95% confidence interval [CI], -3.000 to 0.692). Nilotinib 150 mg and bosutinib 100 mg versus placebo yielded 0.82 (95% CI, -3.76 to 5.41). Sensitivity analysis showed that 1 trial changed the significance of the nilotinib 300 mg single-arm analysis (MD = -1.723; 95% CI, -2.178 to -1.268). Meta-regression revealed that lower age (EC = -0.9103, SE = 0.2286, P < 0.0001) and higher baseline MDS-UPDRS-III scores (EC = 0.1210, SE = 0.0168, P < 0.0001) could explain the inefficacy of nilotinib 300 mg. CONCLUSIONS: Nilotinib (300 mg) proved effective postsensitivity analysis, unlike lower doses and bosutinib in Parkinson's disease/Lewy body dementia. Abl TKIs showed reduced efficacy in younger, more impaired patients, indicating the need for further testing with higher-potency drugs in patients who have diseases that are in the early stage but with a later onset.


Asunto(s)
Enfermedad por Cuerpos de Lewy , Enfermedad de Parkinson , Inhibidores de Proteínas Quinasas , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad por Cuerpos de Lewy/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Compuestos de Anilina/uso terapéutico , Nitrilos/uso terapéutico , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Quinolinas/uso terapéutico
8.
BMC Public Health ; 24(1): 2057, 2024 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-39085807

RESUMEN

BACKGROUND: The COVID-19 pandemic has significantly impacted education systems worldwide, with Brazil being one of the countries with the longest school closures. Over a million children and teenagers have been affected, leading to increased hunger and nutritional deficiencies. This study aimed to implement long-term surveillance of SARS-CoV-2 infections in public and private schools in Campo Grande, Brazil, after returning to in-person classes. METHODS: The study involved testing and genomic surveillance at 23 public and private schools in Campo Grande, Mato Grosso do Sul, Brazil, from October 18, 2021 to November 21, 2022. The participants eligible for enrollment were students aged 6-17 years and staff members from school institutions. At the time of collection, participants were asked if they had symptoms in the last two weeks. Whole-genome sequencing of SARS-CoV-2 was conducted to identify circulating variants and to compare them with those detected in the municipality. The demographic data and clinical history of the participants were described, and a logistic regression model was used to understand how the RT-qPCR results could be related to different characteristics. RESULTS: The study included 999 participants, most of whom were women. A total of 85 tests were positive, with an overall positivity rate of 3.2%. The dynamics of case frequency were consistent with those observed in the municipality during the study period. The most common symptoms reported were cough, rhinorrhea, headache, and sore throat. Symptoms were significantly associated with SARS-CoV-2 infection. Eleven lineages were identified in school community samples, with a frequency of occurrence per period similar to that found in the sequences available for the municipality. The most prevalent lineages within the sampling period were BA.2 (59.3%) and BA.5 (29.6%). CONCLUSIONS: Our findings demonstrate that schools can play a crucial role in epidemiological surveillance, helping trigger rapid responses to pathogens such as SARS-CoV-2. Long-term surveillance can be used to track outbreaks and assess the role of children and adults in transmission. It can also contribute to pandemic preparedness, enabling a rapid response to emergencies, such as COVID-19.


Asunto(s)
COVID-19 , SARS-CoV-2 , Instituciones Académicas , Humanos , COVID-19/epidemiología , COVID-19/diagnóstico , Brasil/epidemiología , Adolescente , Niño , Masculino , Femenino , Secuenciación Completa del Genoma
9.
Phys Rev E ; 109(6-1): 064129, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-39021004

RESUMEN

We study the performance of a quantum Otto heat engine with two spins coupled by a Heisenberg interaction, taking into account not only the mean values of work and efficiency but also their fluctuations. We first show that, for this system, the output work and its fluctuations are directly related to the magnetization and magnetic susceptibility of the system at equilibrium with either heat bath. We analyze the regions where the work extraction can be done with low relative fluctuation for a given range of temperatures, while still achieving an efficiency higher than that of a single spin system heat engine. In particular, we find that, due to the presence of "idle" levels, an increase in the interspin coupling can either increase or decrease fluctuations, depending on the other parameters. In all cases, however, we find that the relative fluctuations in work or efficiency remain large, implying that this microscopic engine is not very reliable as a source of work.

10.
Mol Cell Endocrinol ; 592: 112327, 2024 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-38996834

RESUMEN

This study addresses the increasing prevalence of obesity, especially among postmenopausal. Estrogen plays a crucial role in regulating adipose tissue in women, with its absence after menopause associated with metabolic complications. The study aimed to determine the lipolytic activity in different adipose tissue depots of ovariectomized rats submitted to a high-fat diet. Also, to analyze the expression of estrogen receptors in adipose tissues and perform histological and morphometric analyzes of these deposits. Female rats were ovariectomized (O) or sham operated (S). The animals were divided into groups: ovariectomized with high-fat diet (OF), sham-operated with high-fat diet (SF), ovariectomized with control diet (OC) or sham-operated with control diet as the control group (SC). After 24 weeks of consuming the diets, rats were killed and adipose tissue deposits were removed. Polymerase chain reaction was performed to analyze the expression of estrogen receptors in adipose tissues, lipolysis assay and histological analysis. Both the high-fat diet and ovariectomy increased body weight and adiposity. There was hypertrophy of adipocytes. Estrogen replacement therapy modulate lipolytic activity in different adipose depots, with different responses in relation to estrogen receptors. Estrogen receptor expression varied between fat depots. Mesenteric adipose tissue showed greater sensitivity to estrogen compared with others. Estrogen increased lipolytic activity in some fat depots, reducing in others. Expression of ERs depends of hormonal status and adipose tissue location, which may explain distinct actions of estrogen on the metabolism of adipose tissue and on the production of adipokines by them.


Asunto(s)
Tejido Adiposo , Dieta Alta en Grasa , Lipólisis , Ovariectomía , Ratas Wistar , Receptores de Estrógenos , Animales , Femenino , Dieta Alta en Grasa/efectos adversos , Tejido Adiposo/metabolismo , Receptores de Estrógenos/metabolismo , Ratas , Peso Corporal , Adiposidad/efectos de los fármacos , Adipocitos/metabolismo , Estrógenos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos
11.
Oral Dis ; 2024 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-38938052

RESUMEN

OBJECTIVES: To assess the prevalence of cutaneous and oral immune-related adverse events (irAEs) in cancer patients, risk factors for its development, and overall survival (OS). MATERIALS AND METHODS: This retrospective observational study which included 748 medical records of cancer patients who received immune checkpoint inhibitors (ICIs). Demographic and clinicopathological characteristics were collected and analyzed. RESULTS: Most patients were male (59.4%), with stage IV cancer (65%) and received pembrolizumab (46.7%). Four hundred fourteen (55.34%) patients developed cutaneous lesions, 84 (11.2%) developed oral mucosal lesions, and 70 (9.3%) developed xerostomia. The median time for irAEs development was 11 weeks for cutaneous and oral mucosal lesions, and 21.5 weeks for xerostomia. Patients who received PD-1 + CTLA-4 had a higher risk for developing cutaneous irAEs (p = 0.001), while those who underwent ICI and concurrent chemotherapy had a higher risk (p = 0.008) for developing oral mucosal lesions. Patients who presented oral and cutaneous irAEs had better OS than those who did not present (p = 0.0001). CONCLUSION: Cutaneous effects affected more than half of the patients, while oral effects and xerostomia were found in around 11% and 9% of patients, respectively. Concurrent chemotherapy and PD-1 + CTLA-4 were more associated with oral and cutaneous irAEs, respectively. Patients who developed such irAEs had better overall survival.

12.
Nanomaterials (Basel) ; 14(11)2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38869524

RESUMEN

The chemical stability of azithromycin (AZM) may be compromised depending on the imposed thermo-oxidative conditions. This report addresses evidence of this process under varying conditions of temperature (20-80 °C), exposure time to UV radiation (1-3 h irradiation at 257 nm), and air saturation (1-3 h saturation with atmospheric air at 1.2 L min-1 and 15 kPa) through electrochemical measurements performed with a thermoactivated cerium molybdate (Ce2(MoO4)3)/multi-walled carbon nanotubes (MWCNT)-based composite electrode. Thermal treatment at 120 °C led to coordinated water elimination in Ce2(MoO4)3, improving its electrocatalytic effect on antibiotic oxidation, while MWCNT were essential to reduce the charge-transfer resistance and promote signal amplification. Theoretical-experimental data revealed remarkable reactivity for the irreversible oxidation of AZM on the working sensor using phosphate buffer (pH = 8) prepared in CH3OH/H2O (10:90%, v/v). Highly sensitive (230 nM detection limit) and precise (RSD < 4.0%) measurements were recorded under these conditions. The results also showed that AZM reduces its half-life as the temperature, exposure time to UV radiation, and air saturation increase. This fact reinforces the need for continuous quality control of AZM-based pharmaceuticals, using conditions closer to those observed during their transport and storage, reducing impacts on consumers' health.

13.
Cell ; 187(13): 3357-3372.e19, 2024 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-38866018

RESUMEN

Microbial hydrogen (H2) cycling underpins the diversity and functionality of diverse anoxic ecosystems. Among the three evolutionarily distinct hydrogenase superfamilies responsible, [FeFe] hydrogenases were thought to be restricted to bacteria and eukaryotes. Here, we show that anaerobic archaea encode diverse, active, and ancient lineages of [FeFe] hydrogenases through combining analysis of existing and new genomes with extensive biochemical experiments. [FeFe] hydrogenases are encoded by genomes of nine archaeal phyla and expressed by H2-producing Asgard archaeon cultures. We report an ultraminimal hydrogenase in DPANN archaea that binds the catalytic H-cluster and produces H2. Moreover, we identify and characterize remarkable hybrid complexes formed through the fusion of [FeFe] and [NiFe] hydrogenases in ten other archaeal orders. Phylogenetic analysis and structural modeling suggest a deep evolutionary history of hybrid hydrogenases. These findings reveal new metabolic adaptations of archaea, streamlined H2 catalysts for biotechnological development, and a surprisingly intertwined evolutionary history between the two major H2-metabolizing enzymes.


Asunto(s)
Archaea , Hidrógeno , Hidrogenasas , Filogenia , Archaea/genética , Archaea/enzimología , Proteínas Arqueales/metabolismo , Proteínas Arqueales/química , Proteínas Arqueales/genética , Genoma Arqueal , Hidrógeno/metabolismo , Hidrogenasas/metabolismo , Hidrogenasas/genética , Hidrogenasas/química , Proteínas Hierro-Azufre/metabolismo , Proteínas Hierro-Azufre/genética , Proteínas Hierro-Azufre/química , Modelos Moleculares , Estructura Terciaria de Proteína
14.
Cell Rep ; 43(6): 114296, 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38823019

RESUMEN

To explore the influence of genetics on homeostatic regulation of dendritic cell (DC) numbers, we present a screen of DCs and their progenitors in lymphoid and non-lymphoid tissues in Collaborative Cross (CC) and Diversity Outbred (DO) mice. We report 30 and 71 loci with logarithm of the odds (LOD) scores >8.18 and ranging from 6.67 to 8.19, respectively. The analysis reveals the highly polygenic and pleiotropic architecture of this complex trait, including many of the previously identified genetic regulators of DC development and maturation. Two SNPs in genes potentially underlying variation in DC homeostasis, a splice variant in Gramd4 (rs235532740) and a missense variant in Orai3 (rs216659754), are confirmed by gene editing using CRISPR-Cas9. Gramd4 is a central regulator of DC homeostasis that impacts the entire DC lineage, and Orai3 regulates cDC2 numbers in tissues. Overall, the data reveal a large number of candidate genes regulating DC homeostasis in vivo.


Asunto(s)
Células Dendríticas , Sitios de Carácter Cuantitativo , Animales , Células Dendríticas/metabolismo , Ratones , Sitios de Carácter Cuantitativo/genética , Polimorfismo de Nucleótido Simple , Ratones Endogámicos C57BL , Recuento de Células , Mapeo Cromosómico , Homeostasis
15.
Environ Toxicol ; 39(9): 4278-4297, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38712533

RESUMEN

Cadmium (Cd) is a heavy metal that acts as endocrine disrupting chemical (EDC). Few studies have investigated the effects of Cd exposure on metabolic dysfunctions, such as type 1 and 2 diabetes mellitus (T1DM and T2DM). Thus, we assessed whether subacute Cd exposure at occupational levels causes abnormalities in white adipose tissue (WAT), liver, pancreas, and skeletal muscle. We administered cadmium chloride (CdCl2) (100 ppm in drinking water for 30 days) to female rats and evaluated Cd levels in serum and metabolic organs, morphophysiology, inflammation, oxidative stress, fibrosis, and gene expression. High Cd levels were found in serum, WAT, liver, pancreas, and skeletal muscle. Cd-exposed rats showed low adiposity, dyslipidemia, insulin resistance, systemic inflammation, and oxidative stress compared to controls. Cd exposure reduced adipocyte size, hyperleptinemia, increased cholesterol levels, inflammation, apoptosis and fibrosis in WAT. Cd-exposed rats had increased liver cholesterol levels, insulin receptor beta (IRß) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1α) expression, karyomegaly, inflammation, and fibrosis. Cd exposure reduced insulin levels and pancreatic islet size and increased inflammation and fibrosis. Cd exposure reduced skeletal muscle fiber diameter and increased IR expression and inflammation. Finally, strong positive correlations were observed between serum, tissue Cd levels, abnormal morphology, tissue inflammation and fibrosis. Thus, these data suggest that subacute Cd exposure impairs WAT, liver, pancreas and skeletal muscle function, leading to T1DM and T2DM features and other complications in female rats.


Asunto(s)
Cadmio , Diabetes Mellitus Tipo 2 , Hígado , Animales , Femenino , Diabetes Mellitus Tipo 2/inducido químicamente , Ratas , Cadmio/toxicidad , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Estrés Oxidativo/efectos de los fármacos , Diabetes Mellitus Tipo 1/inducido químicamente , Ratas Wistar , Páncreas/efectos de los fármacos , Páncreas/patología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Disruptores Endocrinos/toxicidad
16.
bioRxiv ; 2024 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-38746186

RESUMEN

HIV-1 anti-retroviral therapy is highly effective but fails to eliminate a reservoir of latent proviruses leading to a requirement for life-long treatment. How the site of integration of authentic intact latent proviruses might impact their own or neighboring gene expression or reservoir dynamics is poorly understood. Here we report on proviral and neighboring gene transcription at sites of intact latent HIV-1 integration in cultured T cells obtained directly from people living with HIV, as well as engineered primary T cells and cell lines. Proviral gene expression was correlated to the level of endogenous gene expression under resting but not activated conditions. Notably, latent proviral promoters were 10010,000X less active than in productively infected cells and had little or no measurable impact on neighboring gene expression under resting or activated conditions. Thus, the site of integration has a dominant effect on the transcriptional activity of intact HIV-1 proviruses in the latent reservoir thereby influencing cytopathic effects and proviral immune evasion.

17.
Front Immunol ; 15: 1352123, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38562938

RESUMEN

Broadly neutralising antibodies (bNAbs) targeting HIV show promise for both prevention of infection and treatment. Among these, 10-1074 has shown potential in neutralising a wide range of HIV strains. However, resistant viruses may limit the clinical efficacy of 10-1074. The prevalence of both de novo and emergent 10-1074 resistance will determine its use at a population level both to protect against HIV transmission and as an option for treatment. To help understand this further, we report the prevalence of pre-existing mutations associated with 10-1074 resistance in a bNAb-naive population of 157 individuals presenting to UK HIV centres with primary HIV infection, predominantly B clade, receiving antiretroviral treatment. Single genome analysis of HIV proviral envelope sequences showed that 29% of participants' viruses tested had at least one sequence with 10-1074 resistance-associated mutations. Mutations interfering with the glycan binding site at HIV Env position 332 accounted for 95% of all observed mutations. Subsequent analysis of a larger historic dataset of 2425 B-clade envelope sequences sampled from 1983 to 2019 revealed an increase of these mutations within the population over time. Clinical studies have shown that the presence of pre-existing bNAb mutations may predict diminished therapeutic effectiveness of 10-1074. Therefore, we emphasise the importance of screening for these mutations before initiating 10-1074 therapy, and to consider the implications of pre-existing resistance when designing prevention strategies.


Asunto(s)
Infecciones por VIH , VIH-1 , Humanos , Anticuerpos ampliamente neutralizantes , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Anticuerpos Neutralizantes , Prevalencia , Epítopos , VIH-1/genética , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Anticuerpos Anti-VIH , Reino Unido/epidemiología
18.
Front Immunol ; 15: 1354786, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38596680

RESUMEN

Introduction: With the reopening of schools during the coronavirus disease 2019 (COVID-19) pandemic, it was imperative to understand the role of students and education professionals in the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this paper, we determined the seroprevalence of the SARS-CoV-2 anti-nucleocapsid antibodies in the school community in Campo Grande, the capital and most populous city of the state of Mato Grosso do Sul (Brazil) and evaluated its association with sex, school level, and school type. Materials and methods: The survey was carried out in 20 public and private schools in the urban region of Campo Grande using the TR DPP® COVID-19 immunoglobulin M/immunoglobulin G (IgM/IgG) kit from the Immunobiological Technology Institute (Bio-Manguinhos, Rio de Janeiro, Brazil). Testing was carried out in three periods: from October to December 2021; from March to July 2022; and from August to November 2022. The participants were students aged 6-17 years enrolled in primary or secondary schools and professionals of different ages and roles. Results: During the first testing period, 162 participants were seropositive for the IgM and/or IgG anti-nucleocapsid SARS-CoV-2 antibodies, with an estimated seroprevalence of 19.6% using Bayesian multilevel regression. In the second period, 251 participants were seropositive (estimated seroprevalence, 34.6%), while in the third period, 393 participants were seroconverted (estimated seroprevalence, 56.7%). In 2022, there was an increase in the seroconversion rate compared to that in 2021. The most frequently described acute manifestations in the three periods were fever, headache, sore throat, and runny nose. In terms of the demographic profile, there was no predominance of seropositivity between the sexes, although women represented approximately 70% of the study population. There were also no differences between students and school staff. Discussion: The results made it possible to evaluate the extent of SARS-CoV-2 transmission in the school community through immunity developed against the virus, in addition to providing information about COVID-19 symptoms in children, adolescents, and adults.


Asunto(s)
COVID-19 , SARS-CoV-2 , Adolescente , Adulto , Niño , Humanos , Femenino , Brasil/epidemiología , COVID-19/epidemiología , Teorema de Bayes , Estudios Seroepidemiológicos , Anticuerpos Antivirales , Inmunoglobulina G , Inmunoglobulina M
19.
Artículo en Inglés | MEDLINE | ID: mdl-38643455

RESUMEN

Estrone (E1) constitutes the primary component in oral conjugated equine estrogens (CEEs) and serves as the principal estrogen precursor in the female circulation in the post-menopause. E1 induces endothelium-dependent vasodilation and activate PI3K/NO/cGMP signaling. To assess whether E1 mitigates vascular dysfunction associated with postmenopause and explore the underlying mechanisms, we examined the vascular effects of E1 in ovariectomized (OVX) rats, a postmenopausal experimental model. Blood pressure was measured using tail-cuff plethysmography, and aortic rings were isolated to assess responses to phenylephrine, acetylcholine (ACh), and sodium nitroprusside. Responses to ACh in rings pre-incubated with superoxide dismutase (SOD), catalase (CAT), or apocynin were also evaluated. Protein expression of SOD, CAT, NOX1, NOX2, and NOX4 was determined by Western blotting. E1 treatment resulted in decreased body weight and retroperitoneal fat, increased uterine weight, and prevented elevated blood pressure in the OVX group. Furthermore, E1 improved endothelium-dependent ACh vasodilation, activated compensatory antioxidant mechanisms - i.e. increased SOD and CAT antioxidant enzymes activity, and decreased NOX4 expression. This, in turn, helped prevent oxidative stress and endothelial dysfunction in OVX rats. Additionally, E1 treatment reversed the increased total LDL cholesterol observed in the OVX group. The findings underscore protective effects of E1 on the cardiovascular system, counteracting OVX-related oxidative stress and endothelial dysfunction in Wistar rats. E1 exhibits promising therapeutic benefits for managing cardiovascular health, particularly in postmenopausal conditions.

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