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1.
Sci Total Environ ; : 174671, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-39004368

RESUMO

The widespread and excessive use of pesticides in modern agricultural practices has caused pesticide contamination of the environment, animals, and humans, with confirmed serious health consequences. This study aimed to identify the 20 most critical substances based on an analysis of detection frequency (DF) and median concentrations (MC) across environmental and biological matrices. A sampling campaign was conducted across 10 case study sites in Europe and 1 in Argentina, each encompassing conventional and organic farming systems. We analysed 209 active substances in a total of 4609 samples. All substances ranked among the 20 most critical were detected in silicon wristbands worn by humans and animals and indoor dust from both farming systems. Five of them were detected in all environmental matrices. Overall, higher values of DF and MC, including in the blood plasma of animals and humans, were recorded in samples of conventional compared to organic farms. The differences between farming systems were greater in the environmental samples and less in animal and human samples. Ten substances were detected in animal blood plasma from conventional farms and eight in animal blood plasma from organic farms. Two of those, detected in both farming systems, are classified as hazardous for mammals (acute). Five substances detected in animal blood plasma from organic farms and seven detected in animal blood plasma from conventional farms are classified as hazardous for mammals (dietary). Three substances detected in human blood plasma are classified as carcinogens. Seven of the substances detected in human blood plasma are classified as endocrine disruptors. Six substances, of which five were detected in human blood plasma, are hazardous for reproduction/development. Efforts are needed to elucidate the unknown effects of mixtures, and it is crucial that such research also considers biocides and banned substances, which constitute a baseline of contamination that adds to the effect of substances used in agriculture.

2.
PLoS One ; 19(7): e0288895, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38976697

RESUMO

To assess whether biomarkers of systemic inflammation are associated with HIV acquisition or with the timing of ART initiation ("immediate", at diagnosis, versus "deferred", at 24 weeks post-diagnosis) in men-who-have-sex-with-men (MSM) and transgender women, we conducted a retrospective study comparing inflammatory biomarkers in participants' specimens collected before infection and after ≥2 years of effective ART. We measured biomarkers in four longitudinally collected plasma, including two specimens collected from each participant before and two after HIV acquisition and confirmed ART-suppression. Biomarkers were quantified by enzyme-linked immuno-assay or Meso Scale Discovery. When evaluating systematic variation in these markers over time, we found that multiple biomarkers consistently varied across participants' two pre-infection or two post-ART-suppression specimens. Additionally, we compared changes in biomarkers after vs before HIV acquisition. Across 47 participants, the levels of C-reactive protein (CRP), monocyte chemo-attractant protein-1, tumor necrosis factor-α and interferon gamma-induced protein-10 significantly increased while leptin and lipopolysaccharide binding protein (LBP) significantly decreased following HIV infection. Randomization to deferred-ART initiation was associated with greater increases in CRP and no decrease in LBP. Acquisition of HIV appeared to induce systemic inflammation, with elevation of biomarkers previously associated with infections and cardiovascular disease. Initiation of ART during the early weeks of infection tempered the increase in pro-inflammatory biomarkers compared to delaying ART for ~24 weeks after HIV diagnosis. These findings provide insight into potential mediators by which immediate-ART initiation improves health outcomes, perhaps because immediate-ART limits the size of the HIV reservoir or limits immune dysregulation that in turn trigger systemic inflammation.


Assuntos
Biomarcadores , Infecções por HIV , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/sangue , Masculino , Biomarcadores/sangue , Feminino , Adulto , Estudos Retrospectivos , Inflamação/sangue , Pessoa de Meia-Idade , Proteínas de Fase Aguda/metabolismo , Proteína C-Reativa/metabolismo , Proteína C-Reativa/análise , Fármacos Anti-HIV/uso terapêutico , Pessoas Transgênero , Proteínas de Transporte , Glicoproteínas de Membrana
3.
OTO Open ; 8(3): e163, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38974175

RESUMO

Objective: Evaluate the quality of responses from Chat Generative Pre-Trained Transformer (ChatGPT) models compared to the answers for "Frequently Asked Questions" (FAQs) from the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) Clinical Practice Guidelines (CPG) for Ménière's disease (MD). Study Design: Comparative analysis. Setting: The AAO-HNS CPG for MD includes FAQs that clinicians can give to patients for MD-related questions. The ability of ChatGPT to properly educate patients regarding MD is unknown. Methods: ChatGPT-3.5 and 4.0 were each prompted with 16 questions from the MD FAQs. Each response was rated in terms of (1) comprehensiveness, (2) extensiveness, (3) presence of misleading information, and (4) quality of resources. Readability was assessed using Flesch-Kincaid Grade Level (FKGL) and Flesch Reading Ease Score (FRES). Results: ChatGPT-3.5 was comprehensive in 5 responses whereas ChatGPT-4.0 was comprehensive in 9 (31.3% vs 56.3%, P = .2852). ChatGPT-3.5 and 4.0 were extensive in all responses (P = 1.0000). ChatGPT-3.5 was misleading in 5 responses whereas ChatGPT-4.0 was misleading in 3 (31.3% vs 18.75%, P = .6851). ChatGPT-3.5 had quality resources in 10 responses whereas ChatGPT-4.0 had quality resources in 16 (62.5% vs 100%, P = .0177). AAO-HNS CPG FRES (62.4 ± 16.6) demonstrated an appropriate readability score of at least 60, while both ChatGPT-3.5 (39.1 ± 7.3) and 4.0 (42.8 ± 8.5) failed to meet this standard. All platforms had FKGL means that exceeded the recommended level of 6 or lower. Conclusion: While ChatGPT-4.0 had significantly better resource reporting, both models have room for improvement in being more comprehensive, more readable, and less misleading for patients.

4.
Ophthalmol Sci ; 4(5): 100513, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38840779

RESUMO

Purpose: To describe a pilot study on the use of single-session, high-dose-rate, Food and Drug Administration-cleared, yttrium-90 (Y90) plaque brachytherapy for iris and iridociliary melanoma. Design: A single-center, clinical case series. Participants: Six consecutive patients were included in this study. Each was diagnosed with an iris or iridociliary melanoma based on clinical examination with or without biopsy. Methods: Each tumor was staged according to the American Joint Committee on Cancer criteria and received Y90 eye plaque brachytherapy. The main variables were tumor size, patient age, sex, and method of diagnosis (clinical or biopsy). Surgical techniques, treatment durations, and ocular side effects were recorded. Local control was defined as a lack of tumor growth or regression determined by clinical examinations, including slit-lamp and gonio photography, as well as high-frequency ultrasound measurements. Toxicity parameters included acute and short-term corneal/scleral change, anterior segment inflammation, and cataract progression. Main Outcome Measures: Local and systemic cancer control, tumor regression, visual acuity, as well as radiation-related normal tissue toxicity. Results: High-dose-rate Y90 plaque brachytherapy was used to treat small (American Joint Committee on Cancer cT1) category melanomas. Single-surgery high-dose-rate irradiations were performed under anesthesia. Because of short treatment durations, high-dose-rate Y90 did not require the additional procedures used for low-dose-rate plaque (e.g., sutures, amniotic membrane epicorneal buffering, Gunderson flaps, and second surgeries for plaque removal). Only conjunctival recession was used to avoid normal tissue irradiation. High-dose-rate Y90 treatment durations averaged 8.8 minutes (median, 7.9; range, 5.8-12.9). High-dose-rate Y90 brachytherapy was associated with no periorbital, corneal (Descemet folds), or conjunctival edema. There was no acute or short-term anterior uveitis, secondary cataract, scleropathy, radiation retinopathy, maculopathy, or optic neuropathy. The follow-up was a mean of 16.0 (range 12-24) months. Evidence of local control included a lack of expansion of tumor borders (n = 6, 100%), darkening with or without atrophy of the tumor surface (n = 5/6, 83%), and a mean 24.5% reduction in ultrasonographically measured tumor thickness. There were no cases of metastatic disease. Conclusions: High-dose-rate Y90 brachytherapy allowed for single-surgery, minimally invasive, outpatient irradiation of iris and iridociliary melanomas. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

5.
Plast Reconstr Surg Glob Open ; 12(6): e5855, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38841527

RESUMO

Background: Prompt coverage of vascular repairs in the extremities is needed to protect from desiccation and trauma. In the absence of local soft tissues to provide early coverage pending demarcation of the tissues and the zone of injury, there is no clear data in the literature on the ideal coverage method. This article is the first to review the use of dermal substitutes for temporary coverage of extremity vascular repairs pending definitive coverage. Methods: We conducted a review of the literature to identify previous articles indexed in PubMed and Ovid using these search terms: [(skin) OR (artificial skin) OR (Integra) OR (dermal substitute) OR (dermal substitute matrix) OR (dermal regeneration) OR (dermal regeneration matrix) OR (dermal regeneration template)] AND [(bypass) OR (graft) OR (vascular surgery) OR (revascularization) OR (salvage) OR (limb salvage) OR (vascular repair) OR (artery repair) OR (arterial repair)] AND [(limb) OR (extremity) OR (leg) OR (arm) OR (vascular injury) OR (amputation)]. Results: Of the 32 articles retrieved for initial review, five case reports with six patients of dermal substitute use for direct coverage of extremity repairs were identified. In all cases, the dermal substitute was able to provide stable coverage pending definitive coverage or was allowed to heal secondarily. Conclusions: Dermal substitute matrices are a potential means of temporary coverage of exposed extremity vascular repairs when there is a paucity of local soft tissues pending more definitive coverage.

6.
Philos Trans A Math Phys Eng Sci ; 382(2274): 20230257, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38826050

RESUMO

The OpenFlexure Microscope is an accessible, three-dimensional-printed robotic microscope, with sufficient image quality to resolve diagnostic features including parasites and cancerous cells. As access to lab-grade microscopes is a major challenge in global healthcare, the OpenFlexure Microscope has been developed to be manufactured, maintained and used in remote environments, supporting point-of-care diagnosis. The steps taken in transforming the hardware and software from an academic prototype towards an accepted medical device include addressing technical and social challenges, and are key for any innovation targeting improved effectiveness in low-resource healthcare. This article is part of the Theo Murphy meeting issue 'Open, reproducible hardware for microscopy'.


Assuntos
Microscopia , Microscopia/instrumentação , Microscopia/métodos , Humanos , Robótica/instrumentação , Robótica/tendências , Robótica/estatística & dados numéricos , Desenho de Equipamento , Impressão Tridimensional/instrumentação , Atenção à Saúde , Software , Sistemas Automatizados de Assistência Junto ao Leito
8.
Biomolecules ; 14(6)2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38927029

RESUMO

Encapsulins are self-assembling nano-compartments that naturally occur in bacteria and archaea. These nano-compartments encapsulate cargo proteins that bind to the shell's interior through specific recognition sequences and perform various metabolic processes. Encapsulation enables organisms to perform chemical reactions without exposing the rest of the cell to potentially harmful substances while shielding cargo molecules from degradation and other adverse effects of the surrounding environment. One particular type of cargo protein, the ferritin-like protein (FLP), is the focus of this review. Encapsulated FLPs are members of the ferritin-like protein superfamily, and they play a crucial role in converting ferrous iron (Fe+2) to ferric iron (Fe+3), which is then stored inside the encapsulin in mineralized form. As such, FLPs regulate iron homeostasis and protect organisms against oxidative stress. Recent studies have demonstrated that FLPs have tremendous potential as biosensors and bioreactors because of their ability to catalyze the oxidation of ferrous iron with high specificity and efficiency. Moreover, they have been investigated as potential targets for therapeutic intervention in cancer drug development and bacterial pathogenesis. Further research will likely lead to new insights and applications for these remarkable proteins in biomedicine and biotechnology.


Assuntos
Ferritinas , Ferritinas/química , Ferritinas/metabolismo , Humanos , Ferro/metabolismo , Ferro/química , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Bactérias/metabolismo
9.
Biomolecules ; 14(6)2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38927098

RESUMO

Cytochrome c (Cytc) is important for both mitochondrial respiration and apoptosis, both of which are altered in cancer cells that switch to Warburg metabolism and manage to evade apoptosis. We earlier reported that lysine 53 (K53) of Cytc is acetylated in prostate cancer. K53 is conserved in mammals that is known to be essential for binding to cytochrome c oxidase and apoptosis protease activating factor-1 (Apaf-1). Here we report the effects of this acetylation on the main functions of cytochrome c by expressing acetylmimetic K53Q in cytochrome c double knockout cells. Other cytochrome c variants analyzed were wild-type, K53R as a control that maintains the positive charge, and K53I, which is present in some non-mammalian species. Intact cells expressing K53Q cytochrome c showed 49% decreased mitochondrial respiration and a concomitant increase in glycolytic activity (Warburg effect). Furthermore, mitochondrial membrane potential was decreased, correlating with notably reduced basal mitochondrial superoxide levels and decreased cell death upon challenge with H2O2 or staurosporine. To test for markers of cancer aggressiveness and invasiveness, cells were grown in 3D spheroid culture. K53Q cytochrome c-expressing cells showed profoundly increased protrusions compared to WT, suggesting increased invasiveness. We propose that K53 acetylation of cytochrome c is an adaptive response that mediates prostate cancer metabolic reprogramming and evasion of apoptosis, which are two hallmarks of cancer, to better promote tumor survival and metastasis.


Assuntos
Apoptose , Citocromos c , Lisina , Neoplasias da Próstata , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/genética , Humanos , Citocromos c/metabolismo , Masculino , Acetilação , Lisina/metabolismo , Linhagem Celular Tumoral , Mitocôndrias/metabolismo , Potencial da Membrana Mitocondrial , Reprogramação Metabólica
10.
Cancer Discov ; 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38943574

RESUMO

Tumors frequently display high chromosomal instability and contain multiple copies of genomic regions. Here, we describe GRITIC, a generic method for timing genomic gains leading to complex copy number states, using single-sample bulk whole-genome sequencing data. By applying GRITIC to 6,091 tumors, we found that non-parsimonious evolution is frequent in the formation of complex copy number states in genome-doubled tumors. We measured chromosomal instability before and after genome duplication in human tumors and found that late genome doubling was followed by an increase in the rate of copy number gain. Copy number gains often accumulate as punctuated bursts, commonly after genome doubling. We infer that genome duplications typically affect the landscape of copy number losses, while only minimally impacting copy number gains. In summary, GRITIC is a novel copy number gain timing framework that permits the analysis of copy number evolution in chromosomally unstable tumors.

11.
Pflugers Arch ; 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38833170

RESUMO

Osteoclasts are multinucleated cells of hematopoietic origin, with a pivotal role in bone development and remodeling. Failure in osteoclast differentiation and activation leads to various bone disorders; thus, attention has focused on a search of molecules involved in osteoclast regulatory pathways. Caspase-8 appears to be an interesting candidate for further exploration, due to its potential function in bone development and homeostasis. Mouse bone marrow cells were differentiated into osteoclasts by RANKL stimulation. Increased activation of caspase-8 and its downstream executioner caspases (caspase-3 and caspase-6) was found during osteoclastogenesis. Subsequent inhibition of caspase-8, caspase-3, or caspase-6, respectively, during osteoclast differentiation showed distinct changes in the formation of TRAP-positive multinucleated cells and reduced expression of osteoclast markers including Acp5, Ctsk, Dcstamp, and Mmp9. Analysis of bone matrix resorption confirmed significantly reduced osteoclast function after caspase inhibition. The results clearly showed the role of caspases in the proper development of osteoclasts and contributed new knowledge about non-apoptotic function of caspases.

12.
J Strength Cond Res ; 38(7): 1189-1199, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38900170

RESUMO

ABSTRACT: Arroum, T, Hish, GA, Burghardt, KJ, Ghamloush, M, Bazzi, B, Mrech, A, Morse, PT, Britton, SL, Koch, LG, McCully, JD, Hüttemann, M, and Malek, MH. Mitochondria transplantation: Rescuing innate muscle bioenergetic impairment in a model of aging and exercise intolerance. J Strength Cond Res 38(7): 1189-1199, 2024-Mitochondria, through oxidative phosphorylation, are crucial for energy production. Disease, genetic impairment, or deconditioning can harm muscle mitochondria, affecting energy production. Endurance training enhances mitochondrial function but assumes mobility. Individuals with limited mobility lack effective treatments for mitochondrial dysfunction because of disease or aging. Mitochondrial transplantation replaces native mitochondria that have been damaged with viable, respiration-competent mitochondria. Here, we used a rodent model selectively bred for low-capacity running (LCR), which exhibits innate mitochondrial dysfunction in the hind limb muscles. Hence, the purpose of this study was to use a distinct breed of rats (i.e., LCR) that display hereditary skeletal muscle mitochondrial dysfunction to evaluate the consequences of mitochondrial transplantation. We hypothesized that the transplantation of mitochondria would effectively alleviate mitochondrial dysfunction in the hind limb muscles of rats when compared with placebo injections. In addition, we hypothesized that rats receiving the mitochondrial transplantation would experience an improvement in their functional capacity, as evaluated through incremental treadmill testing. Twelve aged LCR male rats (18 months old) were randomized into 2 groups (placebo or mitochondrial transplantation). One LCR rat of the same age and sex was used as the donor to isolate mitochondria from the hindlimb muscles. Isolated mitochondria were injected into both hindlimb muscles (quadriceps femoris, tibialis anterior (TA), and gastrocnemius complex) of a subset LCR (n = 6; LCR-M) rats. The remaining LCR (n = 5; LCR-P) subset received a placebo injection containing only the vehicle without the isolated mitochondria. Four weeks after mitochondrial transplantation, rodents were euthanized and hindlimb muscles harvested. The results indicated a significant (p < 0.05) increase in mitochondrial markers for glycolytic (plantaris and TA) and mixed (quadricep femoris) muscles, but not oxidative muscle (soleus). Moreover, we found significant (p < 0.05) epigenetic changes (i.e., hypomethylation) at the global and site-specific levels for a key mitochondrial regulator (transcription factor A mitochondrial) between the placebo and mitochondrial transplantation groups. To our knowledge, this is the first study to examine the efficacy of mitochondrial transplantation in a rodent model of aging with congenital skeletal muscle dysfunction.


Assuntos
Envelhecimento , Metabolismo Energético , Tolerância ao Exercício , Mitocôndrias Musculares , Músculo Esquelético , Animais , Músculo Esquelético/metabolismo , Ratos , Masculino , Envelhecimento/fisiologia , Mitocôndrias Musculares/metabolismo , Tolerância ao Exercício/fisiologia , Metabolismo Energético/fisiologia , Condicionamento Físico Animal/fisiologia , Modelos Animais de Doenças , Membro Posterior , Fosforilação Oxidativa
13.
Orthop Clin North Am ; 55(3): 355-362, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38782507

RESUMO

Fragility fractures as a result of osteoporosis, osteopenia, or vitamin D deficiency are some of the most common injuries encountered in orthopedics and require careful consideration when determining the appropriate management and treatment options. A thorough perioperative evaluation can identify causes of low bone mineral density allowing for initiation of appropriate therapy. Surgical treatment of these fractures can be difficult, and techniques should be employed to ensure stable fixation. It is important to understand the potential pitfalls associated with treatment of fragility fractures to prevent avoidable complications. Postoperative management is key to preventing future injuries in this unique patient population.


Assuntos
Doenças Ósseas Metabólicas , Osteoporose , Deficiência de Vitamina D , Humanos , Deficiência de Vitamina D/complicações , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/prevenção & controle , Osteoporose/complicações , Extremidade Superior/cirurgia , Extremidade Superior/lesões , Fraturas por Osteoporose/cirurgia , Fraturas por Osteoporose/prevenção & controle , Fraturas por Osteoporose/etiologia , Densidade Óssea
14.
J Health Commun ; 29(6): 383-393, 2024 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-38775659

RESUMO

To inform policy and messaging, this study examined characteristics of adolescents' and young adults' (AYAs') exposure to and engagement with nicotine and tobacco product (NTP) social media (SM) content. In this cross-sectional survey study, AYAs aged 13-26 (N=1,163) reported current NTP use, SM use frequency, and exposure to and engagement with SM content promoting and opposing NTP use (i.e. frequency, source[s], format[s], platform[s]). Participants who used NTPs (vs. did not use) were more likely to report having seen NTP content (p-values<.001). Prevalent sources were companies/brands (46.6%) and influencers (44.4%); prevalent formats were video (65.4%) and image (50.7%). Exposure to content promoting NTP use was prevalent on several popular platforms (e.g. TikTok, Instagram, Snapchat); exposure to content opposing NTP use was most prevalent on YouTube (75.8%). Among those reporting content engagement (i.e. liking, commenting on, or sharing NTP content; 34.6%), 57.2% engaged with influencer content. Participants reported engaging with content promoting and opposing NTP use on popular platforms (e.g. TikTok, Instagram, YouTube). Participants with (versus without) current NTP use were significantly more likely to use most SM platforms and to report NTP content exposure and engagement (p-values<.05). Results suggest that NTP education messaging and enforcement of platforms' content restrictions are needed.


Assuntos
Mídias Sociais , Produtos do Tabaco , Humanos , Mídias Sociais/estatística & dados numéricos , Adolescente , Masculino , Feminino , Estudos Transversais , Adulto Jovem , Adulto , Produtos do Tabaco/estatística & dados numéricos , Nicotina
15.
Front Immunol ; 15: 1360412, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38745652

RESUMO

A robust immune response is required for resistance to pulmonary tuberculosis (TB), the primary disease caused by Mycobacterium tuberculosis (Mtb). However, pharmaceutical inhibition of T cell immune checkpoint molecules can result in the rapid development of active disease in latently infected individuals, indicating the importance of T cell immune regulation. In this study, we investigated the potential role of CD200R during Mtb infection, a key immune checkpoint for myeloid cells. Expression of CD200R was consistently downregulated on CD14+ monocytes in the blood of subjects with active TB compared to healthy controls, suggesting potential modulation of this important anti-inflammatory pathway. In homogenized TB-diseased lung tissue, CD200R expression was highly variable on monocytes and CD11b+HLA-DR+ macrophages but tended to be lowest in the most diseased lung tissue sections. This observation was confirmed by fluorescent microscopy, which showed the expression of CD200R on CD68+ macrophages surrounding TB lung granuloma and found expression levels tended to be lower in macrophages closest to the granuloma core and inversely correlated with lesion size. Antibody blockade of CD200R in a biomimetic 3D granuloma-like tissue culture system led to significantly increased Mtb growth. In addition, Mtb infection in this system reduced gene expression of CD200R. These findings indicate that regulation of myeloid cells via CD200R is likely to play an important part in the immune response to TB and may represent a potential target for novel therapeutic intervention.


Assuntos
Mycobacterium tuberculosis , Células Mieloides , Tuberculose Pulmonar , Humanos , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Células Mieloides/imunologia , Células Mieloides/metabolismo , Receptores de Orexina/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Adulto , Feminino , Masculino , Antígenos CD/metabolismo , Antígenos CD/genética , Pessoa de Meia-Idade , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Pulmão/metabolismo , Biomimética , Monócitos/imunologia , Monócitos/metabolismo
16.
J Clin Invest ; 134(13)2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38722697

RESUMO

Newborn mammalian cardiomyocytes quickly transition from a fetal to an adult phenotype that utilizes mitochondrial oxidative phosphorylation but loses mitotic capacity. We tested whether forced reversal of adult cardiomyocytes back to a fetal glycolytic phenotype would restore proliferative capacity. We deleted Uqcrfs1 (mitochondrial Rieske iron-sulfur protein, RISP) in hearts of adult mice. As RISP protein decreased, heart mitochondrial function declined, and glucose utilization increased. Simultaneously, the hearts underwent hyperplastic remodeling during which cardiomyocyte number doubled without cellular hypertrophy. Cellular energy supply was preserved, AMPK activation was absent, and mTOR activation was evident. In ischemic hearts with RISP deletion, new cardiomyocytes migrated into the infarcted region, suggesting the potential for therapeutic cardiac regeneration. RNA sequencing revealed upregulation of genes associated with cardiac development and proliferation. Metabolomic analysis revealed a decrease in α-ketoglutarate (required for TET-mediated demethylation) and an increase in S-adenosylmethionine (required for methyltransferase activity). Analysis revealed an increase in methylated CpGs near gene transcriptional start sites. Genes that were both differentially expressed and differentially methylated were linked to upregulated cardiac developmental pathways. We conclude that decreased mitochondrial function and increased glucose utilization can restore mitotic capacity in adult cardiomyocytes, resulting in the generation of new heart cells, potentially through the modification of substrates that regulate epigenetic modification of genes required for proliferation.


Assuntos
Proliferação de Células , Mitocôndrias Cardíacas , Miócitos Cardíacos , Animais , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Camundongos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/genética , Mitocôndrias Cardíacas/patologia , Camundongos Knockout , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Complexo III da Cadeia de Transporte de Elétrons/genética , Glucose/metabolismo
17.
J Exp Med ; 221(7)2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38722309

RESUMO

SYNTAXIN-11 (STX11) is a SNARE protein that mediates the fusion of cytotoxic granules with the plasma membrane at the immunological synapses of CD8 T or NK cells. Autosomal recessive inheritance of deleterious STX11 variants impairs cytotoxic granule exocytosis, causing familial hemophagocytic lymphohistiocytosis type 4 (FHL-4). In several FHL-4 patients, we also observed hypogammaglobulinemia, elevated frequencies of naive B cells, and increased double-negative DN2:DN1 B cell ratios, indicating a hitherto unrecognized role of STX11 in humoral immunity. Detailed analysis of Stx11-deficient mice revealed impaired CD4 T cell help for B cells, associated with disrupted germinal center formation, reduced isotype class switching, and low antibody avidity. Mechanistically, Stx11-/- CD4 T cells exhibit impaired membrane fusion leading to reduced CD107a and CD40L surface mobilization and diminished IL-2 and IL-10 secretion. Our findings highlight a critical role of STX11 in SNARE-mediated membrane trafficking and vesicle exocytosis in CD4 T cells, important for successful CD4 T cell-B cell interactions. Deficiency in STX11 impairs CD4 T cell-dependent B cell differentiation and humoral responses.


Assuntos
Linfócitos B , Linfócitos T CD4-Positivos , Proteínas Qa-SNARE , Animais , Proteínas Qa-SNARE/metabolismo , Proteínas Qa-SNARE/genética , Linfócitos B/imunologia , Linfócitos B/metabolismo , Camundongos , Humanos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/metabolismo , Camundongos Knockout , Camundongos Endogâmicos C57BL , Feminino , Masculino , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Imunidade Humoral , Exocitose
18.
Hypertension ; 81(7): 1561-1573, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38708607

RESUMO

BACKGROUND: PlGF (placental growth factor)-based testing reduces severe maternal adverse outcomes. Repeat PlGF-based testing is not associated with improved perinatal or maternal outcomes. This planned secondary analysis aimed to determine whether there is a subgroup of women who benefit from repeat testing. METHODS: Pregnant individuals with suspected preterm preeclampsia were randomized to repeat revealed PlGF-based testing, compared with usual care where testing was concealed. Perinatal and maternal outcomes were stratified by trial group, by initial PlGF-based test result, and by PlGF-based test type (PlGF or sFlt-1 [soluble fms-like tyrosine kinase-1]/PlGF ratio). RESULTS: A total of 1252 pregnant individuals were included. Abnormal initial PlGF-based test identified a more severe phenotype of preeclampsia, at increased risk of adverse maternal and perinatal outcomes. Repeat testing was not significantly associated with clinical benefit in women with abnormal initial results. Of women with a normal initial result, 20% developed preeclampsia, with the majority at least 3 to 4 weeks after initial presentation. Repeat test results were more likely to change from normal to abnormal in symptomatic women (112/415; 27%) compared with asymptomatic women (163/890; 18%). A higher proportion of symptomatic women who changed from normal to abnormal were diagnosed with preeclampsia, compared with asymptomatic women. CONCLUSIONS: Our results do not demonstrate evidence of the clinical benefit of repeating PlGF-based testing if the initial result is abnormal. Judicious use of repeat PlGF-based testing to stratify risk may be considered at least 2 weeks after a normal initial test result, particularly in women who have symptoms or signs of preeclampsia. REGISTRATION: URL: https://www.isrctn.com/ISRCTN85912420; Unique identifier: ISRCTN85912420.


Assuntos
Fator de Crescimento Placentário , Pré-Eclâmpsia , Humanos , Feminino , Gravidez , Fator de Crescimento Placentário/sangue , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/sangue , Adulto , Biomarcadores/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Resultado da Gravidez , Recém-Nascido
19.
Cureus ; 16(3): e57281, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38690451

RESUMO

Objective To explore how socioeconomic status and patient characteristics may be associated with initial self-reports of pain and determine if there was an increased association with undergoing spine surgery. Methods Patients at an academic center between 2015 and 2021 who completed the Patient-Reported Outcomes Measurement Information System-Pain Interference (PROMIS-PI) questionnaire were included. Multivariable linear regression models were used to determine the association between insurance type and patient factors with initial reports of pain. Multivariable logistic regression models were used to determine the association between PI and the likelihood of surgery in two time periods, three and 12 months. Results The study included 9,587 patients. The mean PROMIS-PI scores were 61.93 (SD 7.82) and 63.74 (SD 6.93) in the cervical and lumbar cohorts, respectively. Medicaid and Workers' Compensation insurance patients reported higher pain scores compared to those with private insurance: Medicaid (cervical: 2.77, CI (1.76-3.79), p<0.001; lumbar (2.05, CI (1.52-2.59), p<0.001); Workers' Compensation (cervical: 2.12, CI (0.96-3.27), p<0.001; lumbar: 1.51, CI (0.79-2.23), p<0.001). Black patients reported higher pain compared to White patients (cervical: 1.50, CI (0.44-2.55), p=0.01; lumbar: 1.51, CI (0.94-2.08), p<0.001). Higher PROMIS-PI scores were associated with a higher likelihood of surgery. There was no increased association of likelihood of surgery in Black, Medicaid, or Workers' Compensation patients when controlling for pain severity. Conclusion Black patients and patients with Medicaid and Workers' compensation insurance were likely to report higher pain scores. Higher initial pain scores were associated with an increased likelihood of surgery. However, despite increased pain scores, Black patients and those with Medicaid and Workers' Compensation insurance did not have a higher likelihood of undergoing surgery.

20.
J Neurol Surg B Skull Base ; 85(3): 241-246, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38721368

RESUMO

Objectives Iatrogenic injury to the internal carotid artery (ICA) is one of the most catastrophic complications of endoscopic sinus and skull base surgery. Previous research has shown that packing with a crushed muscle graft at the injury site can be an effective management technique to control bleeding and prevent the need for ICA sacrifice. Here, we describe a novel and readily available repair donor site-an autologous lateral tongue muscle patch. Design Three representative cases of a successful repair of ICA injuries using a lateral tongue muscle patch are included in this study. The graft measured approximately 2 × 3 cm and was taken from the lateral intrinsic tongue musculature. We describe the harvest of the graft, its advantages, and the details of operative repair. Results The lateral tongue provides a large and readily accessible source of muscle within the surgical field that can be quickly harvested during an endoscopic procedure. For the first case, an expanding parasellar ICA pseudoaneurysm was managed with a tongue muscle patch and nasal packing. In the second case, a cavernous ICA injury was sustained during craniopharyngioma resection. Case three involved an ICA injury during endonasal debridement of invasive fungal rhinosinusitis. None of the patients required embolization or neurovascular stenting. Postoperative angiograms and serial computed tomography angiograms showed complete resolution of the pseudoaneurysm, and the patients continued to do well at least 1 year after repair. Conclusion Lateral tongue muscle graft is an effective and efficient method to manage ICA injuries during endoscopic endonasal surgery. Advantages include the speed of harvest, donor site being readily accessible in the surgical field, and low donor site morbidity. It should be added to the repertoire of possible donor sites for addressing catastrophic sinonasal bleeding.

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