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1.
Drug Alcohol Rev ; 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39228169

RESUMO

ISSUES: Health policy makers worldwide have adopted evidence-based legislation, largely directed at consumers, to reduce tobacco-related harm. It is suggested that limiting supply by decreasing retail availability can also reduce cigarette smoking. To inform policy makers this systematic literature review assesses whether reducing availability is associated with smoking behaviours. APPROACH: Systematic literature searches of five databases were carried out up to January 2023. Included studies had at least one exposure (tobacco retail density, proximity or mixed measures thereof) and outcomes of smoking behaviour. Meta-analysis of effect estimates were undertaken if there were at least three studies with similar population, exposure and outcome measures. KEY FINDINGS: Sixty-two studies were included, and positive associations were found between tobacco outlet density and cigarette smoking in pregnancy, youth, adults and cessation. Meta-analyses were undertaken for retail density and ever smoking (odds ratio [OR] 1.20; 95% confidence interval [CI] 1.04, 1.37; I2 = 87.3%), and current youth smoking (OR 1.23; 95% CI 1.08, 1.40; I2 = 0.0%), adult smoking (OR 1.11; 95% CI 1.01, 1.22; I2 = 74.8%); and mixed measures of retail availability near schools and current youth smoking (OR 1.03; 95% CI 1.01, 1.05; I2 = 0.0%). IMPLICATIONS AND CONCLUSION: There is evidence higher tobacco retail density is consistently associated with cigarette smoking in pregnant women, young people and adults when ecological studies are included in meta-analysis. Meanwhile, evidence synthesis reveals restrictive tobacco retail laws based on proximity or mixed measures near home or very near school may not reduce smoking except in men who smoke heavily. Mechanisms to reduce retailer density should be thus considered part of tobacco control strategies.

2.
BMJ Open ; 14(8): e083617, 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39122389

RESUMO

INTRODUCTION: Radiotherapy improves local tumour control in patients with soft tissue sarcoma of the extremities (STSE) but it also increases the probability of long-term toxicities such as tissue fibrosis, joint stiffness and lymphoedema. The use of radiation dose and volume thresholds, called dose constraints, may potentially reduce the development of toxicities in STSE. The aim of this study is to determine predictors of radiotherapy-related side effects for STSE. METHODS AND ANALYSIS: Predicting radiotherapy response, Toxicities and quality-of-life related functional outcomes in soft tissue sarcoma of the extremities (PredicT) is a multicentre observational study comprising two cohorts (PredicT A and B). PredicT A, a retrospective analysis of the UK VorteX (NCT00423618) and IMRiS clinical trials (NCT02520128), is aimed at deriving a statistical model for development of dose-volume constraints. This model will use receiving operator characteristics and multivariate analysis to predict radiotherapy side effects and patient-reported outcomes. PredicT B, a prospective cohort study of 150 patients with STSE, is aimed at testing the validity of those dose-volume constraints. PredicT B is open and planned to complete recruitment by September 2024. ETHICS AND DISSEMINATION: PredicT B has received ethical approval from North West - Liverpool Central Research Ethics Committee (20/NW/0267). Participants gave informed consent to participate in the study before taking part. We will disseminate our findings via publications, presentations, national and international conference meetings and engage with local charities. TRIAL REGISTRATION NUMBER: NCT05978024.


Assuntos
Extremidades , Qualidade de Vida , Sarcoma , Humanos , Sarcoma/radioterapia , Dosagem Radioterapêutica , Estudos Retrospectivos , Estudos Prospectivos , Neoplasias de Tecidos Moles/radioterapia , Resultado do Tratamento , Estudos Observacionais como Assunto , Masculino
3.
Nanoscale Adv ; 6(16): 4047-4061, 2024 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-39114141

RESUMO

Flowers are often discarded after cultural and religious events, making it worthwhile to explore the utilization of this floral waste for material production. Floral extracts contain a diverse array of phytochemicals such as polyphenols, flavonoids, and reducing sugars, which play a significant role in the formation and influencing the properties of zinc oxide (ZnO) nanoparticles. In this review, we delve into the importance of floral extract, methodology, mechanism, and influencing factors in the production of ZnO nanoparticles. Additionally, the role of green ZnO nanoparticles as an adsorbent and photocatalyst for water treatment is discussed. These floral extract-mediated ZnO nanoparticles exhibit advantages in agricultural and biomedical applications, including promoting seed germination and demonstrating antibacterial, anticancer, and antifungal properties. Cost analysis reveals that while various expenses are associated with ZnO production, scaling up processes can help reduce these costs. This review underscores the potential of floral waste extract for the synthesis of green ZnO nanoparticles, thereby contributing to waste-to-wealth strategies and adhering to green chemistry principles.

4.
Clin Neurol Neurosurg ; 245: 108477, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39098248

RESUMO

OBJECTIVE: Neurosurgery residents in Germany face numerous challenges including receiving comprehensive surgical training with adequate learning opportunities, achieving balanced work life equilibrium, maintaining a positive work environment and navigating career prospects. The objectives of this study are to assess overall satisfaction with the training program, identify factors contributing to dissatisfaction, explore various dimensions of the training program, evaluate the psychological well-being of residents, and ascertain their preferences for future subspecialties. METHODS: A questionnaire-based survey was conducted anonymously among neurosurgery residents from various training hospitals, nationwide. The survey utilized a quantitative questionnaire as data collection tool. The data collection took place from June 2021 to January 2023. RESULTS: The survey encompassed 120 neurosurgery residents, with a gender distribution of 55 % male and 45 % female. The respondents were primarily from university hospitals (53 %), followed by community hospitals (38 %) and private hospitals (9 %). In terms of training program satisfaction, 37 % reported moderate satisfaction, 39 % indicated below-moderate satisfaction, and 28 % experienced above-moderate satisfaction. The predominant causes of dissatisfaction identified were insufficient surgical exposure (reported by 39 % of respondents), suboptimal educational content (38 %), and inadequate research opportunities (32 %). Additionally, 24 % of respondents highlighted psychological stress, and 36 % reported frequent experiences of burnout. A majority (63 %) indicated a workload of 60-80 h weekly. About half of the residents indicated a future specialization interest in neurosurgical oncology. CONCLUSION: The results of the survey findings provide valuable insights into the challenges and aspirations of neurosurgery trainees in Germany. These results serve as a basis for improving the training system, enhancing the working environment, and guiding future planning in this field. To optimize the training of residents, it is important to address issues such as limited surgical and research opportunities and psychological well-being. The expressed interest in subspecializing offers guidance for shaping the training program's future direction.


Assuntos
Internato e Residência , Satisfação no Emprego , Neurocirurgia , Humanos , Alemanha , Feminino , Masculino , Neurocirurgia/educação , Inquéritos e Questionários , Adulto , Escolha da Profissão
5.
Urology ; 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-39173930

RESUMO

OBJECTIVE: To assess how race, ethnicity, primary language, clinical and other sociodemographic factors predict surgical treatment for pelvic organ prolapse (POP) in a minority-majority Hispanic population. METHODS: We identified patients with POP ICD-10 codes from Oct 2019 to Dec 2022 at our Urogynecology academic practice. Data were collected by chart review. Covariates were obtained by manual abstraction. Continuous and categorical variables were analyzed using t-test and chi-square test, and Wilcoxon rank-sum test for non-parametric data. A logistic regression model was fitted to identify independent predictors of surgery. RESULTS: Of 943 patients over 38 months, 441 (46.8%) underwent surgery. On univariate analysis, younger age, Hispanic/Latino ethnicity, Spanish as primary language, private insurance, stage of prolapse and obesity correlated with higher rates of surgical treatment. On multivariate regression, only age and prolapse compartment remained significant predictors. Younger age and apical prolapse increased the likelihood of surgery (OR=.98 [.96-.99], P = <.001; R=2.31 [1.13-4.72], P = <.001, respectively). CONCLUSION: Controlling for confounders, age, and apical prolapse compartment predicted surgical treatment for POP in our Hispanic minority-majority population. Previously identified barriers to care including minority status and non-English primary language do not appear to exist in our population. This may be related to linguistic, ethnic, and racial concordance between healthcare staff and patients, alongside protective aspects of ethnic enclaves. Further research is warranted to understand the impact of cultural barriers, such as provider language, on patient-provider dynamics and surgical decision-making.

6.
Methods Mol Biol ; 2845: 177-189, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39115666

RESUMO

Ferritinophagy is a selective form of autophagy in which ferritin, the primary intracellular iron storage protein complex, is targeted by NCOA4 (Nuclear receptor coactivator 4) to the lysosome for degradation. NCOA4-mediated ferritinophagy plays a crucial role in cellular iron metabolism, influencing iron homeostasis, heme synthesis, mitochondrial respiratory function, and ferroptosis, an iron-dependent form of cell death. Targeting ferritinophagy has emerged as a potential anticancer therapeutic strategy. In this context, we provide a flowchart of the procedures and accompanying protocols for monitoring ferritinophagic flux.


Assuntos
Autofagia , Ferritinas , Coativadores de Receptor Nuclear , Coativadores de Receptor Nuclear/metabolismo , Coativadores de Receptor Nuclear/genética , Ferritinas/metabolismo , Humanos , Ferro/metabolismo , Lisossomos/metabolismo , Animais
7.
Chem Biodivers ; : e202401934, 2024 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-39187695

RESUMO

From the leaves of Tithonia diversifolia,  nine sesquiterpenoids (1-9), including two new ones (1, 2) were isolated and structurally determined. Their chemical structures were elucidated by extensive analyses of HRESIMS and NMR spectral data, as well as comparison with the literature. All of the isolated compounds (except compounds 7, 8, 9) significantly exhibited cytotoxic activity against four human cancer cell lines (KB, HepG2, A549 and MCF7), with IC50 values ranging from 0.29-17.0 µM,  which was in the same range as the positive control ellipticine or even lower. Further, the apoptosis induction of two new compounds 1 and 2 were also investigated and reported. While compound 2 did not induce cell apoptosis in KB cells at test concentrations, compound 1 was found to possess anti-proliferative activity through concentration-dependently inducing cell cycle arrest at S phase, morphological changes, activation of caspase 3, and an increase in the early-stage apoptosis of KB cells at a concentration of 7.26 µM.

8.
J Neuropathol Exp Neurol ; 83(9): 736-744, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38964366

RESUMO

The circadian clock (CC) has biological and clinical implications in gliomas. Most studies focused on CC effects on the tumor microenvironment and the application of chronotherapy. The present study focused on CC gene expression patterns and intracellular oncogenic activities. Glioma gene expression data were collected from The Human Cancer Genome Atlas (TCGA) project. After applying inclusion and exclusion criteria, we selected 666 patients from TCGA-GBM and TCGA-LGG projects and included important clinicopathological variables. The entire cohort was subjected to clustering analysis and divided into CC1 and CC2 subtypes based on statistical, biological, and clinical criteria. CC2 gliomas showed higher expression of BMAL1 and CRY1 and lower expression of CRY2 and PER2 (adjusted P < .001). CC2 gliomas had q higher activity of cell proliferation, metabolic reprogramming, angiogenesis, hypoxia, and many oncogenic signals (P < .001). The CC2 subtype contained a higher proportion of glioblastomas (P < .001) and had a worse prognosis (P < .001). Stratified Kaplan-Meier and multivariable Cox analyses illustrated that the CC subtype is an independent prognostic factor to clinicopathological characteristics (P < .001), genetic aberrations (P = .006), and biological processes (P < .001). Thus, this study shows statistical evidence of CC subtypes and their biological, and clinicopathological significance in adult gliomas.


Assuntos
Neoplasias Encefálicas , Relógios Circadianos , Epigênese Genética , Glioma , Humanos , Glioma/genética , Glioma/patologia , Glioma/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Relógios Circadianos/genética , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Regulação Neoplásica da Expressão Gênica/genética , Idoso , Estudos de Coortes
9.
Sci Rep ; 14(1): 14341, 2024 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-38906916

RESUMO

Glioblastoma (GBM) is a highly aggressive and deadly brain cancer. Temozolomide (TMZ) is the standard chemotherapeutic agent for GBM, but the majority of patients experience recurrence and invasion of tumor cells. We investigated whether TMZ treatment of GBM cells regulates matrix metalloproteinases (MMPs), which have the main function to promote tumor cell invasion. TMZ effectively killed GL261, U343, and U87MG cells at a concentration of 500 µM, and surviving cells upregulated MMP9 expression and its activity but not those of MMP2. TMZ also elevated levels of MMP9 mRNA and MMP9 promoter activity. Subcutaneous graft tumors survived from TMZ treatment also exhibited increased expression of MMP9 and enhanced gelatinolytic activity. TMZ-mediated MMP9 upregulation was specifically mediated through the phosphorylation of p38 and JNK. This then stimulates AP-1 activity through the upregulation of c-Fos and c-Jun. Inhibition of the p38, JNK, or both pathways counteracted the TMZ-induced upregulation of MMP9 and AP-1. This study proposes a potential adverse effect of TMZ treatment for GBM: upregulation of MMP9 expression potentially associated with increased invasion and poor prognosis. This study also provides valuable insights into the molecular mechanisms by which TMZ treatment leads to increased MMP9 expression in GBM cells.


Assuntos
Regulação Neoplásica da Expressão Gênica , Glioblastoma , Metaloproteinase 9 da Matriz , Temozolomida , Proteínas Quinases p38 Ativadas por Mitógeno , Temozolomida/farmacologia , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Glioblastoma/genética , Glioblastoma/patologia , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Humanos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Antineoplásicos Alquilantes/farmacologia , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Fator de Transcrição AP-1/metabolismo , Regulação para Cima/efeitos dos fármacos , Camundongos
11.
Tob Use Insights ; 17: 1179173X241257683, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38826851

RESUMO

Background: Secondhand smoke (SHS) has detrimental effects on community health, including coronary heart diseases, stroke, lung cancer etc. This manuscript exploited data from the Vietnam Population-based Provincial Global Adult Tobacco Survey (PGATS) in 2022 to update the prevalence of adult exposure to SHS and associated socio-demographic factors. Methods: With the sample size of 71,981 adults aged 15+ throughout 30 provinces and cities in Vietnam, data was collected using the Global Adult Tobacco Survey (GATS) questionnaire. Bivariate analysis and multivariate logistic regression modelling were performed. Results: In the past 30 days, 44.4% (95% CI: 44.0%-44.9%) adults aged 15+ exposed to SHS at home while 23.1% (95% CI: 22.6%-23.6%) exposed to SHS at work. Female exposure to SHS in the past 30 days was higher at homes but lower at indoor workplaces. Participants aged 15-24 were likely to have higher odds of SHS exposure in the past 30 days to other age groups. Those living in the urban areas had 1.15 times higher odds (95% CI: 1.08-1.22) of exposure to SHS than those in the rural areas. Current smokers tended to have 2.2 times higher odds of exposure to SHS at the indoor workplaces compared to non-smokers (95% CI: 2.05-2.37). Conclusions: The prevalence of exposure to SHS at home was still relatively high amongst the adult population. While there was a significant reduction of SHS exposure at indoor workplaces, there was a higher prevalence of women being exposed to SHS at home. The Government of Vietnam should continue to strictly implement the smoke-free environment resolution at indoor workplaces and appropriate communication campaigns to protect people, especially women from SHS exposure at homes.

12.
Nat Commun ; 15(1): 4758, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38902234

RESUMO

To uncover molecular changes underlying blood-brain-barrier dysfunction in Alzheimer's disease, we performed single nucleus RNA sequencing in 24 Alzheimer's disease and control brains and focused on vascular and astrocyte clusters as main cell types of blood-brain-barrier gliovascular-unit. The majority of the vascular transcriptional changes were in pericytes. Of the vascular molecular targets predicted to interact with astrocytic ligands, SMAD3, upregulated in Alzheimer's disease pericytes, has the highest number of ligands including VEGFA, downregulated in Alzheimer's disease astrocytes. We validated these findings with external datasets comprising 4,730 pericyte and 150,664 astrocyte nuclei. Blood SMAD3 levels are associated with Alzheimer's disease-related neuroimaging outcomes. We determined inverse relationships between pericytic SMAD3 and astrocytic VEGFA in human iPSC and zebrafish models. Here, we detect vast transcriptome changes in Alzheimer's disease at the gliovascular-unit, prioritize perturbed pericytic SMAD3-astrocytic VEGFA interactions, and validate these in cross-species models to provide a molecular mechanism of blood-brain-barrier disintegrity in Alzheimer's disease.


Assuntos
Doença de Alzheimer , Astrócitos , Barreira Hematoencefálica , Pericitos , Proteína Smad3 , Fator A de Crescimento do Endotélio Vascular , Peixe-Zebra , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Humanos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Proteína Smad3/metabolismo , Proteína Smad3/genética , Astrócitos/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Pericitos/metabolismo , Pericitos/patologia , Masculino , Células-Tronco Pluripotentes Induzidas/metabolismo , Feminino , Idoso , Transcriptoma , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/irrigação sanguínea , Idoso de 80 Anos ou mais , Modelos Animais de Doenças
13.
Gene ; 927: 148646, 2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-38851365

RESUMO

Telomerase reverse transcriptase (TERT) and ß-catenin (CTNNB1) mutations may occur following the hepatocellular carcinoma (HCC) pathway signal. We conducted a Hierarchical cluster analysis study on 408 patients diagnosed with HCC by pathological surgery, identifying TERT promoter and CTNNB1 exon 3 mutations by sequencing. The overall preclinical characteristics, cumulative cut-point values, and the factors associated with these somatic mutations were analyzed in uni/multidimensional scaling model. HBV(+) HCV(-) HCC male patients who were older than 62.74 years old and have TERT promoter mutation as well as AFP > 489.78 ng/ml got a higher risk of HCC grade more than two from 27 % to 200 % with p < 0.05 (RR are from 1.27 [1.09-1.47] to 3.06 [2.04-4.61]). This mutation was a good indicator of grade 2 risk (HR = 0.37 [2.72-0.16], ß = -1.00, p = 0.019). TERT promoter and CTNNB1 exon 3 mutations independently influenced tumor size and tumor site status in grade 3 and HBV(-) HCV (-) male HCC patients, where the hazard rates, respectively, were 0.28 [0.09-0.89], 0.023 [0.0023-0.23] and 0.06 [0.012-0.32] (ß < 0 and p < 0.01). These two mutations inversely impacted each other the tumor sites status, especially in male HCC patients with grade 2 without B, C hepatitis virus (RRCTNNB1 exon 3 mutate - TERT promoter wildtype = 1.12 [1.04-1.20], p < 0.05). Consequently, the mutations in TERT promoter and CTNNB1 exon 3 may synchronize with other factors or independently impact the hepatocarcinogenesis and are important indicators for HCC prognostic in male patients with very high AFP levels or with moderately as well as poorly differentiated in tumor. Our results serve as the basis for further studies to understand the impact of different factors on the outcome of HCC, especially in monitoring and assessing the cancer risk of patients infect HBV and carry mutations.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Mutação , Telomerase , beta Catenina , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , beta Catenina/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , Neoplasias Hepáticas/patologia , Telomerase/genética , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Análise por Conglomerados , Regiões Promotoras Genéticas/genética , Adulto , População do Sudeste Asiático
14.
Langmuir ; 40(25): 13292-13302, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38871669

RESUMO

In this study, surface-enhanced Raman scattering substrates were investigated by the electrodeposition method to detect low concentrations of pesticides via the electrodeposition method with different agents from silver and gold precursors on APTES-modified ITO glass. A dual-potential method supplied three electrodes and was performed with a nucleation potential of 0.7 V for 2 s and a growth potential of -0.2 V for 500 s. The Ag film produced by the electrodeposition approach has great surface uniformity and good SERS signal amplification for the thiram insecticide at low concentrations. Interestingly, the ITO/APTES/Ag substrate extensively increased the sensitivity than the other investigated ones, thanks to the adequate assistance of amino groups of APTES in the denser and hierarchical deposition of Ag NPs. These observations were additionally elucidated via finite-difference time-domain (FDTD) calculation. For thiram, the detection was set at 10-8 M with an enhancement factor of up to 3.6 × 107 times. Comparing the SERS spectra of thiram at concentrations of 10-3, 10-4, and 10-5 M with a relative standard deviation (RSD) of less than 7.0% demonstrates excellent reproducibility of the ITO/APTES/Ag substrate. In addition, the special selectivity of the ITO/APTES/Ag substrate for thiram demonstrates that these nanostructures can identify pesticides with extreme sensitivity.

15.
Cureus ; 16(4): e59087, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38803760

RESUMO

Squamous cell carcinoma (SCC) is the second most common type of skin cancer. As ultraviolet exposure represents an important risk factor, SCC commonly occurs on the face, lips, scalp, hands, and heels. The foot is an unusual location to manifest SCC. In this report, we present a case of a 44-year-old woman with severe local recurrence of SCC in the right heel, four years after an initial excision of a primary, small lesion. For various reasons, the patient did not visit the clinic for follow-up assessment during this period. Considering the extent of the lesion and infection risk, the affected leg was amputated at one-third of the lower leg. This case report underlines the importance of educating patients about the risk of SCC and assisting them in attending follow-up visits. In addition, adequate attention should be given to foot lesions with suspicious appearance. Early detection would minimize systemic risks, including metastasis and infection, and maximize preserved function after surgical intervention.

16.
Br J Surg ; 111(5)2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38743864

RESUMO

BACKGROUND: Postoperative ileus, driven by the cholinergic anti-inflammatory pathway, is the most common complication in patients undergoing colorectal surgery. By inhibiting acetylcholinesterase, pyridostigmine can potentially modulate the cholinergic anti-inflammatory pathway and accelerate gastrointestinal recovery. This study aimed to assess the efficacy of pyridostigmine in improving gastrointestinal recovery after colorectal surgery. METHODS: This double-blinded RCT enrolled adult patients undergoing elective colorectal surgery at two hospitals in South Australia. Patients were randomized to 60 mg oral pyridostigmine or placebo twice daily starting 6 h after surgery until the first passage of stool. The primary outcome was GI-2, a validated composite measure of time to first stool and tolerance of oral diet. Secondary outcomes included incidence of postoperative ileus (defined as GI-2 greater than 4 days), duration of hospital stay, and 30-day complications, evaluated by intention-to-treat univariate analysis. RESULTS: Of 130 patients recruited (mean(s.d.) age 58.4(16.4) years; 73 men, 56%), 65 were allocated to each arm. The median GI-2 was 1 day shorter with pyridostigmine compared with placebo (2 (i.q.r. 1-3) versus 3 (2-4) days; P = 0.015). However, there were no significant differences in postoperative ileus (17.2 versus 21.5%; P = 0.532) or duration of hospital stay (median 5 (i.q.r. 4-8.75) versus 5 (4-7.5) days; P = 0.921). Similarly, there were no significant differences in overall complications, anastomotic leak, cardiac complications, or patient-reported side effects. CONCLUSION: Pyridostigmine resulted in a quicker return of GI-2 and was well tolerated. Larger multicentre studies are required to determine the optimal dosing and evaluate the impact of pyridostigmine in different surgical settings. Registration number: ACTRN12621000530820 (https://anzctr.org.au).


Assuntos
Inibidores da Colinesterase , Íleus , Complicações Pós-Operatórias , Brometo de Piridostigmina , Humanos , Masculino , Íleus/prevenção & controle , Íleus/etiologia , Feminino , Método Duplo-Cego , Pessoa de Meia-Idade , Complicações Pós-Operatórias/prevenção & controle , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/efeitos adversos , Inibidores da Colinesterase/uso terapêutico , Brometo de Piridostigmina/administração & dosagem , Brometo de Piridostigmina/uso terapêutico , Idoso , Tempo de Internação , Adulto , Resultado do Tratamento
17.
Nat Commun ; 15(1): 3802, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38714719

RESUMO

The interaction between nuclear receptor coactivator 4 (NCOA4) and the iron storage protein ferritin is a crucial component of cellular iron homeostasis. The binding of NCOA4 to the FTH1 subunits of ferritin initiates ferritinophagy-a ferritin-specific autophagic pathway leading to the release of the iron stored inside ferritin. The dysregulation of NCOA4 is associated with several diseases, including neurodegenerative disorders and cancer, highlighting the NCOA4-ferritin interface as a prime target for drug development. Here, we present the cryo-EM structure of the NCOA4-FTH1 interface, resolving 16 amino acids of NCOA4 that are crucial for the interaction. The characterization of mutants, designed to modulate the NCOA4-FTH1 interaction, is used to validate the significance of the different features of the binding site. Our results explain the role of the large solvent-exposed hydrophobic patch found on the surface of FTH1 and pave the way for the rational development of ferritinophagy modulators.


Assuntos
Microscopia Crioeletrônica , Ferritinas , Coativadores de Receptor Nuclear , Ferritinas/metabolismo , Ferritinas/química , Ferritinas/genética , Humanos , Coativadores de Receptor Nuclear/metabolismo , Coativadores de Receptor Nuclear/química , Coativadores de Receptor Nuclear/genética , Ligação Proteica , Sítios de Ligação , Ferro/metabolismo , Autofagia , Modelos Moleculares , Células HEK293 , Oxirredutases/metabolismo , Oxirredutases/química , Oxirredutases/genética , Proteólise , Mutação
18.
Ann Surg ; 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38716667

RESUMO

OBJECTIVE: To evaluate changes in opioid prescribing and patient-reported outcomes after surgery following implementation of Michigan's prescription drug monitoring program (PDMP) use mandate in June 2018. BACKGROUND: Most states mandate clinicians to query prescription drug monitoring program (PDMP) databases before prescribing controlled substances. Whether these PDMP use mandates affect opioid prescribing and patient-reported outcomes after surgery is unclear, especially among patients with elevated "Narx" scores, a risk score for overdose death used in most PDMPs. METHODS: We conducted an interrupted time series analysis of a statewide surgical registry linked to Michigan's PDMP database. Analyses included adults undergoing general surgical procedures during January 2017-October 2019. Outcomes included monthly mean days supplied in dispensed opioid prescriptions (those filled within 3 days of discharge) and monthly mean scores for 3 patient-reported outcomes (pain in the week after surgery, care satisfaction, regret undergoing surgery). Segmented regression models were used to assess for level and slope changes in outcomes in June 2018. Analyses were repeated among patients with Narx scores ≥200, a threshold that defines the top quartile. RESULTS: Analyses included 21,897 patients. The mandate was associated with a -0.5 (95% CI: -0.8, -0.2) level decrease in mean days supplied in dispensed opioid prescriptions, but not with worsened patient-reported outcomes. Findings were similar among patients with Narx scores ≥200. CONCLUSIONS: Following implementation of Michigan's PDMP use mandate, the duration of opioid prescriptions decreased, but patient-reported outcomes did not worsen. Findings suggest PDMP use mandates may not be associated with worsened experience among general surgical patients.

19.
Arch Pharm Res ; 47(4): 325-340, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38561494

RESUMO

Sialyllactoses (SLs) primarily include sialylated human milk oligosaccharides (HMOs) and bovine milk oligosaccharides (BMOs). First, the safety assessment of 3'-sialyllactose (3'-SL) and 6'-sialyllactose (6'-SL) revealed low toxicity in various animal models and human participants. SLs constitute a unique milk component, highlighting the essential nutrients and bioactive components crucial for infant development, along with numerous associated health benefits for various diseases. This review explores the safety, biosynthesis, and potential biological effects of SLs, with a specific focus on their influence across various physiological systems, including the gastrointestinal system, immune disorders, rare genetic disorders (such as GNE myopathy), cancers, neurological disorders, cardiovascular diseases, diverse cancers, and viral infections, thus indicating their therapeutic potential.


Assuntos
Lactose/análogos & derivados , Leite Humano , Leite , Oligossacarídeos , Humanos , Oligossacarídeos/química , Oligossacarídeos/metabolismo , Animais , Leite/química , Leite Humano/química , Leite Humano/metabolismo , Bovinos
20.
ANZ J Surg ; 2024 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-38680012

RESUMO

AIM: With the rise of structured, remote follow-up of colorectal cancers, there is the potential risk of underdiagnosing and undermanaging low anterior resection syndrome (LARS). This cohort study aims to determine the rate of LARS and its patterns of care, with the aim of generating a risk-stratified management algorithm that can be employed for nurse-led follow-up. METHOD: Patients who underwent elective anterior resection for the management of colorectal cancer between 1 January 2017 and 31 December 2021 were sent quality-of-life questionnaires (EORTC-QLQ-CR29 and LARS score) and surveyed for LARS symptoms and management utilized. RESULTS: Out of 70 patients who completed questionnaires, 71.4% had LARS and 42.9% had major LARS. The international Delphi consensus definition identified more patients (n = 50) with LARS than the LARS score (n = 41). Tumours located <8 cm from the anal verge, ULAR, and temporary stoma were predictive of major LARS on univariate analysis. However, only temporary stoma was predictive for LARS (OR 7.89 (1.15-53.95), P = 0.035) and majors LARS (8.14 (1.79-37.01), P = 0.007) on multivariate analysis. Forty-four percent of patients with LARS did not have input from any health professional for this condition. Consultation with specialist allied health and/or colorectal surgeons ranged from 4% to 22%. CONCLUSIONS: Our study highlights that with the current remote follow-up system focused on cancer outcomes a significant proportion of patients with LARS are overlooked, resulting in the underutilization of relevant health professionals and management options. We propose a nurse-led management algorithm to address this issue while still minimizing surgical outpatient load.

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