RESUMO
OBJECTIVE: Primary hyperparathyroidism is a common endocrine disorder, with 80% of all cases usually caused by one single hyperfunctioning parathyroid adenoma. Conventional imaging modalities for the diagnostic work-up of primary hyperparathyroidism (PHPT) include ultrasound of the neck, 99mTc-sestamibi scintigraphy, and four-dimensional computed tomography (4D-CT). However, the role of other imaging modalities, such as 11C-methionine PET/CT, in the care pathway for PHPT is currently unclear. Here, we report our experience of the diagnostic utility of 11C-methionine PET/CT in a single-center patient cohort (n = 45). DESIGN: Retrospective single-center cohort study. PATIENTS AND MEASUREMENTS: The data of eligible patients that underwent 11C-methionine PET/CT between 2014 and 2022 at Addenbrooke's Hospital (Cambridge, UK) were collected and analyzed. The clinical utility of imaging modalities was determined by comparing the imaging result with histopathological and biochemical outcomes following surgery. RESULTS: In patients with persistent primary hyperparathyroidism following previous surgery, 11C-methionine PET/CT identified a candidate lesion in 6 of 10 patients (60.0%), and histologically confirmed in 5 (50.0%). 11C-methionine PET/CT also correctly identified a parathyroid adenoma in 9 out of 12 patients (75.0%) that failed to be localized on other imaging modalities. 11C-methionine PET/CT had a sensitivity of 70.0% (95% CI 55.8 - 84.2%) for the detection of parathyroid adenomas. CONCLUSIONS: This study highlights a diagnostic role for 11C-methionine PET/CT in patients that have undergone unsuccessful prior surgery or have equivocal or negative prior imaging results, aiding localization and a targeted surgical approach.
Assuntos
Adenoma , Hiperparatireoidismo Primário , Neoplasias das Paratireoides , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Hiperparatireoidismo Primário/diagnóstico por imagem , Hiperparatireoidismo Primário/etiologia , Neoplasias das Paratireoides/diagnóstico por imagem , Neoplasias das Paratireoides/complicações , Estudos Retrospectivos , Estudos de Coortes , Adenoma/diagnóstico , Adenoma/diagnóstico por imagem , Metionina , Tecnécio Tc 99m Sestamibi , Racemetionina , Reino Unido , Glândulas ParatireoidesRESUMO
Currently, there are no biomarkers to predict lethal lung injury by radiation. Since it is not ethical to irradiate humans, animal models must be used to identify biomarkers. Injury to the female WAG/RijCmcr rat has been well-characterized after exposure to eight doses of whole thorax irradiation: 0-, 5-, 10-, 11-, 12-, 13-, 14- and 15-Gy. End points such as SPECT imaging of the lung using molecular probes, measurement of circulating blood cells and specific miRNA have been shown to change after radiation. Our goal was to use these changes to predict lethal lung injury in the rat model, 2 weeks post-irradiation, before any symptoms manifest and after which a countermeasure can be given to enhance survival. SPECT imaging with 99mTc-MAA identified a decrease in perfusion in the lung after irradiation. A decrease in circulating white blood cells and an increase in five specific miRNAs in whole blood were also tested. Univariate analyses were then conducted on the combined dataset. The results indicated that a combination of percent change in lymphocytes and monocytes, as well as pulmonary perfusion volume could predict survival from radiation to the lungs with 88.5% accuracy (95% confidence intervals of 77.8, 95.3) with a p-value of < 0.0001 versus no information rate. This study is one of the first to report a set of minimally invasive endpoints to predict lethal radiation injury in female rats. Lung-specific injury can be visualized by 99mTc-MAA as early as 2 weeks after radiation.
Assuntos
Lesão Pulmonar , MicroRNAs , Lesões Experimentais por Radiação , Lesões por Radiação , Humanos , Feminino , Ratos , Animais , Lesão Pulmonar/diagnóstico por imagem , Lesão Pulmonar/etiologia , Pulmão/diagnóstico por imagem , Pulmão/efeitos da radiação , Tomografia Computadorizada de Emissão de Fóton Único/métodos , MicroRNAs/genética , Biomarcadores , Lesões Experimentais por Radiação/diagnóstico por imagemRESUMO
BACKGROUND: Urinary extracellular vesicles (EVs) are a source of biomarkers with broad potential applications across clinical research, including monitoring radiation exposure. A key limitation to their implementation is minimal standardization in EV isolation and analytical methods. Further, most urinary EV isolation protocols necessitate large volumes of sample. This study aimed to compare and optimize isolation and analytical methods for EVs from small volumes of urine. METHODS: 3 EV isolation methods were compared: ultracentrifugation, magnetic bead-based, and size-exclusion chromatography from 0.5 mL or 1 mL of rat and human urine. EV yield and mass spectrometry signals (Q-ToF and Triple Quad) were evaluated from each method. Metabolomic profiling was performed on EVs isolated from the urine of rats exposed to ionizing radiation 1-, 14-, 30- or 90-days post-exposure, and human urine from patients receiving thoracic radiotherapy for the treatment of lung cancer pre- and post-treatment. RESULTS: Size-exclusion chromatography is the preferred method for EV isolation from 0.5 mL of urine. Mass spectrometry-based metabolomic analyses of EV cargo identified biochemical changes induced by radiation, including altered nucleotide, folate, and lipid metabolism. We have provided standard operating procedures for implementation of these methods in other laboratories. CONCLUSIONS: We demonstrate that EVs can be isolated from small volumes of urine and analytically investigated for their biochemical contents to detect radiation induced metabolomic changes. These findings lay a groundwork for future development of methods to monitor response to radiotherapy and can be extended to an array of molecular phenotyping studies aimed at characterizing EV cargo.
Assuntos
Vesículas Extracelulares , Exposição à Radiação , Animais , Biomarcadores/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Espectrometria de Massas , Ratos , UltracentrifugaçãoRESUMO
To develop a dynamic in vivo near-infrared (NIR) fluorescence imaging assay to quantify sequential changes in lung vascular permeability-surface area product (PS) in rodents. Dynamic NIR imaging methods for determining lung vascular permeability-surface area product were developed and tested on non-irradiated and 13 Gy irradiated rats with/without treatment with lisinopril, a radiation mitigator. A physiologically-based pharmacokinetic (PBPK) model of indocyanine green (ICG) pulmonary disposition was applied to in vivo imaging data and PS was estimated. In vivo results were validated by five accepted assays: ex vivo perfused lung imaging, endothelial filtration coefficient (Kf) measurement, pulmonary vascular resistance measurement, Evan's blue dye uptake, and histopathology. A PBPK model-derived measure of lung vascular permeability-surface area product increased from 2.60 ± 0.40 [CL: 2.42-2.78] mL/min in the non-irradiated group to 6.94 ± 8.25 [CL: 3.56-10.31] mL/min in 13 Gy group after 42 days. Lisinopril treatment lowered PS in the 13 Gy group to 4.76 ± 6.17 [CL: 2.12-7.40] mL/min. A much higher up to 5× change in PS values was observed in rats exhibiting severe radiation injury. Ex vivo Kf (mL/min/cm H2O/g dry lung weight), a measure of pulmonary vascular permeability, showed similar trends in lungs of irradiated rats (0.164 ± 0.081 [CL: 0.11-0.22]) as compared to non-irradiated controls (0.022 ± 0.003 [CL: 0.019-0.025]), with reduction to 0.070 ± 0.035 [CL: 0.045-0.096] for irradiated rats treated with lisinopril. Similar trends were observed for ex vivo pulmonary vascular resistance, Evan's blue uptake, and histopathology. Our results suggest that whole body dynamic NIR fluorescence imaging can replace current assays, which are all terminal. The imaging accurately tracks changes in PS and changes in lung interstitial transport in vivo in response to radiation injury.
Assuntos
Lesão Pulmonar Aguda , Permeabilidade Capilar/efeitos da radiação , Pulmão , Imagem Óptica , Lesões Experimentais por Radiação , Lesão Pulmonar Aguda/diagnóstico por imagem , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/fisiopatologia , Animais , Feminino , Verde de Indocianina/farmacocinética , Verde de Indocianina/farmacologia , Pulmão/irrigação sanguínea , Pulmão/diagnóstico por imagem , Pulmão/metabolismo , Pulmão/fisiopatologia , Lesões Experimentais por Radiação/diagnóstico por imagem , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/fisiopatologia , RatosRESUMO
BACKGROUND: Primary hyperparathyroidism (PHPTH) is a common endocrine disorder and an estimated 10% of cases are hereditary, related to syndromes including; multiple endocrine neoplasia (MEN) type 1, MEN type 4, MEN2A and hereditary hyperparathyroidism-jaw tumour syndrome. Establishing the underlying genetic cause for PHPTH allows for personalized and cost-effective management. Familial hypocalicuric hypercalcaemia (FHH) is a benign disorder of hypercalcaemia associated with an inappropriately low urinary calcium excretion, which is quantified by the calcium creatinine clearance ratio (CCCR). Recent NHS England National Genomic Test Directory testing criteria for familial hyperparathyroidism state testing patients presenting with PHPTH and CCCR > 0.02 presenting (i) <35 years of age, or (ii) <45y with one of (a) multiglandular disease, or (b) hyperplasia on histology, or (c) ossifying fibroma(s) of the maxilla and/ or mandible, or (d) a family history of unexplained PHPTH. The testing criterion for FHH is a CCCR < 0.02. AIMS AND METHODS: A retrospective review of patients referred for genetic testing over a 4 year period for suspected hereditary HPTH was performed. Genetic analysis was performed by next-generation sequencing of the following genes; MEN1, CDC73, CASR, CDKN1A, CDKN1B, CDKN2B, CDKN2C, RET, GCM2, GNA11, and AP2S1 in NHS-accredited Regional Genetic laboratories. Aims of this study were to better define testing criteria for suspected hereditary PHPTH in a UK cohort. RESULTS: A total of 121 patients were included in this study (92 female) with a mean age of 41 years (SD 17). A pathogenic germline variant was identified in 16% (n = 19). A pathogenic variant was identified in the PHPTH genes CDC73 in a single patient and MEN1 in six patients (6% of total), in the FHH genes, CASR in 11 patients and AP2S1 in a single paediatric case (10% of total). A variant of uncertain significance (VUS) was identified in eight patients (6%) but over the course of this study familial segregation studies and computational analysis enabled re-classification of four of the variants, with two VUS's in the CASR gene being upgraded to likely pathogenic variants. Age at diagnosis and multiglandular disease as sole risk factors were not predictive of a pathogenic germline variant in this cohort but a positive family history was strongly predictive (P = .0002). A significant difference in the mean calcium creatinine clearance ratio (CCCR) in those patients with an identified CASR pathogenic variant versus those without (P = .0001) was demonstrated in this study. Thirty-three patients were aged over 50 years and the diagnostic rate of a pathogenic variant was 15.1% in those patients >50 years of age compared to 15.9% in those <50 years. Five patients >50 years and with a CCCR of <0.01, were diagnosed with a pathogenic variant in CASR. CONCLUSION: Family history was the strongest predictor of hereditary PHPTH in this cohort. This study has highlighted the importance of re-evaluating VUS's in order to inform patient management and enable appropriate genetic counselling. Finally, this study has demonstrated the need to consider genetic testing for PHPTH in patients of any age, particularly those with additional risk factors.
Assuntos
Hipercalcemia , Hiperparatireoidismo Primário , Idoso , Criança , Feminino , Testes Genéticos , Humanos , Hipercalcemia/congênito , Hipercalcemia/genética , Hiperparatireoidismo Primário/genética , Recém-Nascido , Estudos Retrospectivos , Reino UnidoRESUMO
The goal of this study is to understand and mitigate the effects of wounds on acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE), for preparedness against a radiological attack or accident. Combined injuries from concomitant trauma and radiation are likely in these scenarios. Either exacerbation or mitigation of radiation damage by wound trauma has been previously reported in preclinical studies. Female WAG/RijCmcr rats received 13 Gy X-rays, with partial-body shielding of one leg. Within 2 h, irradiated rats and non-irradiated controls were given full-thickness skin wounds with or without lisinopril, started orally 7 days after irradiation. Morbidity, skin wound area, breathing interval and blood urea nitrogen were measured up to 160 days post-irradiation to independently evaluate wound trauma and DEARE. Wounding exacerbated morbidity in irradiated rats between 5 and 14 days post-irradiation (during the ARS phase), and irradiation delayed wound healing. Wounding did not alter delayed morbidities from radiation pneumonitis or nephropathy after 30 days post-irradiation. Lisinopril did not mitigate wound healing, but markedly decreased morbidity during DEARE from 31 through 160 days. The results derived from this unique model of combined injuries suggest different molecular mechanisms of injury and healing of ARS and DEARE after radiation exposure.
Assuntos
Síndrome Aguda da Radiação/complicações , Lisinopril/farmacologia , Lesões Experimentais por Radiação , Pneumonite por Radiação/complicações , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões/complicações , Animais , Nitrogênio da Ureia Sanguínea , Feminino , Estimativa de Kaplan-Meier , Lesões por Radiação , Proteção Radiológica , Ratos , Irradiação Corporal Total , Raios XRESUMO
Radiation therapy is used in ~50% of cancer patients to reduce the risk of recurrence and in some cases improve survival. Despite these benefits, doses can be limited by toxicity in multiple organs, including the heart. The underlying causes and biomarkers of radiation-induced cardiotoxicity are currently unknown, prompting the need for experimental models with inherent differences in sensitivity and resistance to the development of radiation-induced cardiotoxicity. We have identified the parental SS (Dahl salt-sensitive/Mcwi) rat strain to be a highly-sensitized model of radiation-induced cardiotoxicity. In comparison, substitution of rat chromosome 3 from the resistant BN (Brown Norway) rat strain onto the SS background (SS-3BN consomic) significantly attenuated radiation-induced cardiotoxicity. SS-3BN rats had less radiation-induced cardiotoxicity than SS rats, as measured by survival, pleural and pericardial effusions, echocardiogram parameters, and histological damage. Mast cells, previously shown to have predominantly protective roles in radiation-induced cardiotoxicity, were increased in the more resistant SS-3BN hearts postradiation. RNA sequencing from SS and SS-3BN hearts at 1 wk postradiation revealed 5,098 differentially expressed candidate genes across the transcriptome and 350 differentially expressed genes on rat chromosome 3, which coincided with enrichment of multiple pathways, including mitochondrial dysfunction, sirtuin signaling, and ubiquitination. Upstream regulators of enriched pathways included the oxidative stress modulating transcription factor, Nrf2, which is located on rat chromosome 3. Nrf2 target genes were also differentially expressed in the SS vs. SS-3BN consomic hearts postradiation. Collectively, these data confirm the existence of heritable modifiers in radiation-induced cardiotoxicity and provide multiple biomarkers, pathways, and candidate genes for future analyses. NEW & NOTEWORTHY This novel study reveals that heritable genetic factors have the potential to modify normal tissue sensitivity to radiation. Gene variant(s) on rat chromosome 3 can contribute to enhanced cardiotoxicity displayed in the SS rats vs. the BN and SS-3BN consomic rats. Identifying genes that lead to understanding the mechanisms of radiation-induced cardiotoxicity represents a novel method to personalize radiation treatment, as well as predict the development of radiation-induced cardiotoxicity.
Assuntos
Mapeamento Cromossômico , Cromossomos de Mamíferos , Genes Modificadores , Variação Genética , Cardiopatias/genética , Lesões por Radiação/genética , Animais , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Cardiopatias/metabolismo , Cardiopatias/patologia , Masculino , Mastócitos/metabolismo , Mastócitos/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Lesões por Radiação/metabolismo , Lesões por Radiação/patologia , Ratos Endogâmicos BN , Ratos Endogâmicos Dahl , Transdução de SinaisRESUMO
OBJECTIVES: The purpose of this study was to compare the agreement between two heparin assays, Hepcon HMS plus/Kaolin-ACT and Anti-Xa, and their predictive power in detecting circulating heparin levels post-reperfusion of the liver graft when compared with thromboelastogram (TEG) r time ratio in patients undergoing orthotopic liver transplantation (OLT). DESIGN: Prospective, observational cohort study design. SETTING: Single center, university hospital. PARTICIPANTS: Thirty-eight consecutive adults who had undergone liver transplant. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Paired arterial blood samples were collected before surgical incision, 5 minutes after administration of an average dose of 2,054±771 units of intravenous unfractionated heparin before caval cross-clamping, 5 minutes after portal reperfusion, 5 minutes after hepatic artery reperfusion, and 1 hour after hepatic artery reperfusion. The observations that heparin assay measurements were within the predetermined limits of agreement, strongly suggested the two heparin assays (Hepcon HMS plus and Anti-Xa assay) are interchangeable during prophylactic heparin dose therapy during OLT. Post-reperfusion, receiver operating characteristic curve analysis revealed high accuracy in measuring circulating heparin levels with both Anti-Xa and Hepcon HMS assays when compared with the TEG r time ratio assay. CONCLUSIONS: The point-of-care Hepcon HMS plus/Kaolin-ACT (activated clotting time) assay appeared to be a reliable alternative to the more expensive and laboratory-required Anti-Xa assay in monitoring the response to intravenous heparin in patients undergoing OLT.
Assuntos
Anticoagulantes/administração & dosagem , Inibidores do Fator Xa/administração & dosagem , Heparina/administração & dosagem , Transplante de Fígado/métodos , Preparações de Plantas/administração & dosagem , Profilaxia Pré-Exposição/métodos , Adulto , Idoso , Anticoagulantes/sangue , Testes de Coagulação Sanguínea/métodos , Estudos de Coortes , Feminino , Heparina/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tromboelastografia/métodosRESUMO
Chronic kidney disease is a known complication of hematopoietic stem cell transplant (HSCT) and can be caused by irradiation at the time of the HSCT. In our rat model there is a 6- to 8-wk latent period after irradiation that leads to the development of proteinuria, azotemia, and hypertension. The current study tested the hypothesis that decreased endothelial-derived factors contribute to impaired afferent arteriolar function in rats exposed to total body irradiation (TBI). WAG/RijCmcr rats underwent 11 Gy TBI, and afferent arteriolar responses to acetylcholine were determined at 1, 3, and 6 wk. Blood pressure and blood urea nitrogen were not different between control and irradiated rats. Afferent arteriolar diameters were not altered in irradiated rats. Impaired endothelial-dependent responses to acetylcholine were evident at 3 and 6 wk following TBI. Nitric oxide synthase (NOS), cyclooxygenase (COX), and epoxygenase (EPOX) contribution to acetylcholine dilator responses were evaluated. NOS inhibition with N(G)-nitro-l-arginine methyl ester (l-NAME) reduced acetylcholine responses by 50% in controls and 90% in 3-wk TBI rats. COX inhibition with indomethacin did not significantly alter the acetylcholine response in the presence or absence of l-NAME. EPOX inhibition with N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide significantly decreased acetylcholine responses (35%) in controls but did not significantly alter acetylcholine responses (4%) in TBI rats. Biochemical analysis revealed decreased urinary EPOX metabolites but no change in COX, NOS, or reactive oxygen species at 3 wk TBI. Taken together, these results indicate that afferent arteriolar endothelial dysfunction involves a decrease in EPOX metabolites that precedes the development of proteinuria, azotemia, and hypertension in irradiated rats.
Assuntos
Arteríolas/efeitos da radiação , Pressão Sanguínea/efeitos da radiação , Endotélio Vascular/efeitos da radiação , Vasodilatação/efeitos da radiação , Acetilcolina/farmacologia , Animais , Arteríolas/efeitos dos fármacos , Arteríolas/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Indometacina/farmacologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Ratos , Vasodilatação/efeitos dos fármacos , Irradiação Corporal TotalRESUMO
Arachidonic acid is metabolized to epoxyeicosatrienoic acids (EETs) by CYP epoxygenases, and EETs are kidney protective in multiple pathologies. We determined the ability of an EET analogue, EET-A, to mitigate experimental radiation nephropathy. The kidney expression of the EET producing enzyme CYP2C11 was lower in rats that received total body irradiation (TBI rat) compared with non-irradiated control. At 12 weeks after TBI, the rats had higher systolic blood pressure and impaired renal afferent arteriolar function compared with control, and EET-A or captopril mitigated these abnormalities. The TBI rats had 3-fold higher blood urea nitrogen (BUN) compared with control, and EET-A or captopril decreased BUN by 40-60%. The urine albumin/creatinine ratio was increased 94-fold in TBI rats, and EET-A or captopril attenuated that increase by 60-90%. In TBI rats, nephrinuria was elevated 30-fold and EET-A or captopril decreased it by 50-90%. Renal interstitial fibrosis, tubular and glomerular injury were present in the TBI rats, and each was decreased by EET-A or captopril. We further demonstrated elevated renal parenchymal apoptosis in TBI rats, which was mitigated by EET-A or captopril. Additional studies revealed that captopril or EET-A mitigated renal apoptosis by acting on the p53/Fas/FasL (Fas ligand) apoptotic pathway. The present study demonstrates a novel EET analogue-based strategy for mitigation of experimental radiation nephropathy by improving renal afferent arteriolar function and by decreasing renal apoptosis.
Assuntos
Injúria Renal Aguda/prevenção & controle , Eicosanoides/farmacologia , Rim/efeitos dos fármacos , Rim/efeitos da radiação , Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação/farmacologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Injúria Renal Aguda/fisiopatologia , Albuminúria/metabolismo , Albuminúria/prevenção & controle , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Hidrocarboneto de Aril Hidroxilases/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Captopril/farmacologia , Família 2 do Citocromo P450 , Citoproteção , Proteína Ligante Fas/metabolismo , Fibrose , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Hipertensão/prevenção & controle , Rim/irrigação sanguínea , Rim/metabolismo , Rim/patologia , Masculino , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/fisiopatologia , Ratos , Circulação Renal/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Esteroide 16-alfa-Hidroxilase/metabolismo , Receptor fas/metabolismoRESUMO
OBJECTIVES: To examine the role of epsilon-aminocaproic acid (EACA) administered after reperfusion of the donor liver in the incidences of thromboembolic events and acute kidney injury within 30 days after orthotopic liver transplantation. One-year survival rates between the EACA-treated and EACA-nontreated groups also were examined. DESIGN: Retrospective, observational, cohort study design. SETTING: Single-center, university hospital. PARTICIPANTS: The study included 708 adult liver transplantations performed from 2008 to 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: EACA administration was not associated with incidences of intracardiac thrombosis/pulmonary embolism (1.3%) or intraoperative death (0.6%). Logistic regression (n = 708) revealed 2 independent risk factors associated with myocardial ischemia (age and pre-transplant vasopressor use) and 8 risk factors associated with the need for post-transplant dialysis (age, female sex, redo orthotopic liver transplantation, preoperative sodium level, pre-transplant acute kidney injury or dialysis, platelet transfusion, and re-exploration within the first week after transplant); EACA was not identified as a risk factor for either outcome. One-year survival rates were similar between groups: 92% in EACA-treated group versus 93% in the EACA-nontreated group. CONCLUSIONS: The antifibrinolytic, EACA, was not associated with an increased incidence of thromboembolic complications or postoperative acute kidney injury, and it did not alter 1-year survival after liver transplantation.
Assuntos
Injúria Renal Aguda/etiologia , Ácido Aminocaproico/efeitos adversos , Antifibrinolíticos/efeitos adversos , Transplante de Fígado/efeitos adversos , Tromboembolia/etiologia , Ácido Aminocaproico/administração & dosagem , Antifibrinolíticos/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Terapia de Substituição Renal , Estudos Retrospectivos , Fatores de Risco , Análise de SobrevidaRESUMO
BACKGROUND: Graves' disease is an autoimmune disease caused by the production of auto-antibodies against the thyroid-stimulating hormone receptor, which stimulates follicular cell production of thyroid hormone. It is the commonest cause of hyperthyroidism and may cause considerable morbidity with increased risk of cardiovascular and respiratory adverse events. Five per cent of people with Graves' disease develop moderate to severe Graves' ophthalmopathy. Thyroid surgery for Graves' disease commonly falls into one of three categories: 1) total thyroidectomy, which aims to achieve complete macroscopic removal of thyroid tissue; 2) bilateral subtotal thyroidectomy, in which bilateral thyroid remnants are left; and 3) unilateral total and contralateral subtotal thyroidectomy, or the Dunhill procedure. Recent American Thyroid Association guidelines on treatment of Graves' hyperthyroidism emphasised the role of surgery as one of the first-line treatments. Total thyroidectomy removes target tissue for the thyroid-stimulating hormone receptor antibody. It controls hyperthyroidism at the cost of lifelong thyroxine replacement. Subtotal thyroidectomy leaves a thyroid remnant and may be less likely to lead to complications, however a higher rate of recurrent hyperthyroidism is expected and revision surgery would be challenging. The choice of the thyroidectomy technique is currently largely a matter of surgeon preference, and a systematic review of the evidence base is required to determine which option offers the best outcomes for patients. OBJECTIVES: To assess the optimal surgical technique for Graves' disease and Graves' ophthalmopathy. SEARCH METHODS: We searched the Cochrane Library, MEDLINE and PubMed, EMBASE, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). The date of the last search was June 2015 for all databases. We did not apply any language restrictions. SELECTION CRITERIA: Only randomised controlled trials (RCTs) involving participants with a diagnosis of Graves' disease based on clinical features and biochemical findings of hyperthyroidism were eligible for inclusion. Trials had to directly compare at least two surgical techniques of thyroidectomy. There was no age limit to study inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted and cross-checked the data for analysis, evaluation of risk of bias and establishment of 'Summary of findings' tables using the GRADE instrument. The senior review authors reviewed the data and reconciled disagreements. MAIN RESULTS: We included five RCTs with a total of 886 participants; 172 were randomised to total thyroidectomy, 383 were randomised to bilateral subtotal thyroidectomy, 309 were randomised to the Dunhill procedure and 22 were randomised to either bilateral subtotal thyroidectomy or the Dunhill procedure. Follow-up ranged between six months and six years. One trial had three comparison arms. All five trials were conducted in university hospitals or tertiary referral centres for thyroid disease. All thyroidectomies were performed by experienced surgeons. The overall quality of the evidence ranged from low to moderate. In all trials, blinding procedures were insufficiently described. Outcome assessment for objective outcomes was blinded in one trial. Surgeons were not blinded in any of the trials. One trial blinded participants. Attrition bias was a substantial problem in one trial, with 35% losses to follow-up. In one trial the analysis was not carried out on an intention-to-treat basis.Total thyroidectomy was more effective than subtotal thyroidectomy techniques (both bilateral subtotal thyroidectomy and the Dunhill procedure) at preventing recurrent hyperthyroidism in 0/150 versus 11/200 participants (OR 0.14 (95% CI 0.04 to 0.46); P = 0.001; 2 trials; moderate quality evidence). Total thyroidectomy was also more effective than bilateral subtotal thyroidectomy at preventing recurrent hyperthyroidism in 0/150 versus 10/150 participants (odds ratio (OR) 0.13 (95% confidence interval (CI) 0.04 to 0.44); P = 0.001; 2 trials; moderate quality evidence). Compared to bilateral subtotal thyroidectomy, the Dunhill procedure was more likely to prevent recurrent hyperthyroidism in 20/283 versus 8/309 participants (OR 2.73 (95% CI 1.28 to 5.85); P = 0.01; 3 trials; low quality evidence). Total thyroidectomy compared with subtotal thyroidectomy conferred a greater risk of permanent hypocalcaemia/hypoparathyroidism in 8/172 versus 3/221 participants (OR 4.79 (95% CI 1.36 to 16.83); P = 0.01; 3 trials; low quality evidence). Effects of the various surgical techniques on permanent recurrent laryngeal nerve palsy and regression of Graves' ophthalmopathy were neutral. One death was reported in one study in year three of follow-up. No study investigated health-related quality of life or socioeconomic effects. AUTHORS' CONCLUSIONS: Total thyroidectomy is more effective than subtotal thyroidectomy (both bilateral subtotal thyroidectomy and the Dunhill procedure) at preventing recurrent hyperthyroidism in Graves' disease. The type of surgery performed does not affect regression of Graves' ophthalmopathy. There was some evidence that total thyroidectomy compared with subtotal thyroidectomy conferred a greater risk of permanent hypocalcaemia/hypoparathyroidism, which however, was not seen in comparison with bilateral subtotal thyroidectomy. Permanent recurrent laryngeal nerve palsy did not seem to be affected by type of thyroidectomy. Health-related quality of life as a patient-important outcome measure should form a core determinant of any future trial on the effects of thyroid surgery for Graves' disease.
Assuntos
Doença de Graves/cirurgia , Tireoidectomia/métodos , Oftalmopatia de Graves/cirurgia , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Indução de Remissão/métodos , Reoperação , Prevenção Secundária , Tireoidectomia/efeitos adversosRESUMO
A young male patient presented with an incidental finding of a large supraglottic vascular lesion. The lesion was initially noted during intubation 4 years ago. Although originally listed for elective excision, there was a significant delay and at the time of surgery, the lesion proved too large to remove and a significant threat to the patient's airway. An emergency tracheostomy was performed, followed by two consecutive treatments with sclerotherapy agents to reduce the size of the lesion. It was then successfully excised using a Thunderbeat ultrasound and bipolar dissection and cautery device.
Assuntos
Escleroterapia , Malformações Vasculares , Humanos , Masculino , Malformações Vasculares/diagnóstico por imagem , Malformações Vasculares/terapiaRESUMO
PURPOSE: Vascular endothelium plays a central role in the pathogenesis of acute and chronic radiation injuries, yet the mechanisms which promote sustained endothelial dysfunction and contribute to late responding organ failure are unclear. We employed 2nd window (> 1100 nm emission) Near-Infrared (NIR) imaging using indocyanine green (ICG) to track and define the role of the notch ligand Delta-like ligand 4 (Dll4) in mediating vascular injury in two late-responding radiosensitive organs: the lung and kidney. PROCEDURES: Consomic strains of female Salt Sensitive or SS (Dll4-high) and SS with 3rd chromosome inherited from Brown Norway, SS.BN3 (Dll4-low) rats at ages 11-12 weeks were used to demonstrate the impact of reduced Dll4 expression on long-term vascular integrity, renal function, and survival following high-dose 13 Gy partial body irradiation at 42- and 90 days post-radiation. 2nd window dynamic NIR fluorescence imaging with ICG was analyzed with physiology-based pharmacokinetic modeling and confirmed with assays of endothelial Dll4 expression to assess the role of endogenous Dll4 expression on radiation injury protection. RESULTS: We show that SS.BN3 (Dll4-low) rats are relatively protected from vascular permeability disruption compared to the SS (Dll4-high) strain. We further demonstrated that SS.BN3 (Dll4-low) rats have reduced radiation induced loss of CD31+ vascular endothelial cells, and increased Dll4 vascular expression is correlated with vascular dysfunction. CONCLUSIONS: Together, these data suggest Dll4 plays a key role in pathogenesis of radiation-induced vascular injury to the lung and kidney.
Assuntos
Proteínas de Membrana , Lesões por Radiação , Lesões do Sistema Vascular , Ratos , Feminino , Animais , Células Endoteliais/metabolismo , Lesões do Sistema Vascular/diagnóstico por imagem , Lesões do Sistema Vascular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismoRESUMO
OBJECTIVES: Surgery remains the most effective treatment for retrosternal goiters. These commonly present as asymptomatic lesions in elderly patients, but may also cause airway and esophageal compression and, less commonly, may also be malignant. Although the majority of these goiters are amenable to transcervical thyroidectomy, in a minority of patients sternotomy is required. The ability to predict the need for sternotomy before operation would allow for safer surgery and operative counseling, as well as improved logistical efficiency if coordination with thoracic surgeons is required. In this report, we assess the radiologic factors that might be predictive of the need for sternotomy. METHODS: We performed a retrospective review of 97 retrosternal goiters for which thyroidectomy was performed within the otolaryngology department at Addenbrooke's Hospital, Cambridge, between 2001 and 2011. There were a total of 80 cervical excisions and 17 cases in which sternotomy was required. A detailed computed tomographic analysis of these 17 cases was undertaken to assess the predictive factors for the requirement of sternotomy. The factors assessed included posterior mediastinal extension, presence of an ectopic nodule, extension below the carina, extension below the aortic arch, a "conical shape" of the goiter, and tracheal compression. These were compared to the same factors in the control group of 80 patients, and Fisher's exact test was used to determine statistical significance. RESULTS: The significant predictive factors for sternotomy, were posterior mediastinal extension, extension below the carina, and a "conical" goiter in which the thoracic inlet becomes a ring of constriction (all p < 0.05). CONCLUSIONS: Our results suggest that it is possible to predict on the basis of computed tomographic imaging the need for sternotomy in retrosternal goiters.
Assuntos
Bócio Subesternal/cirurgia , Esternotomia/métodos , Tireoidectomia/métodos , Tomografia Computadorizada por Raios X/métodos , Idoso , Feminino , Seguimentos , Bócio Subesternal/diagnóstico por imagem , Humanos , Masculino , Valor Preditivo dos Testes , Estudos RetrospectivosRESUMO
Objectives of this study were to assess the utility of intra-operative ultrasound to resolve discordant pre-operative imaging prior to a lateral approach mini-parathyroidectomy, by studying prospective case series in a head and neck endocrine unit. Patients with primary hyperparathyroidism due to a single adenoma with discordant pre-operative ultrasound and sestamibi were enrolled. They underwent a further intra-operative ultrasound by a head and neck radiologist with a view to proceed with a mini-parathyroidectomy. The main outcome measure was utility of intra-operative ultrasound compared to operative findings and pre-operative imaging. Secondary measures were complications of mini-parathyroidectomy, operative and ambulatory discharge time. Twenty-two patients underwent surgery with intra-operative ultrasound in the surgical position. The intra-operative ultrasound findings correlated with the operative findings in all cases (100 %). There were 16 inferior adenomas and 6 superior adenomas. Six inferior adenomas were in a retrosternal position, eight were obscured by benign thyroid lesions and a further two reported pre-operatively as superior. Three out of six superior adenomas were reported as inferior pre-operatively as the inferior thyroid artery was inadequately visualised, two were retro-carotid and one was retro-oesophageal. All patients were discharged within 23 h of surgery. There were no unsuccessful focused explorations. Histological analysis confirmed the adenomas. No morbidity (vocal cord palsy, haematoma, hungry bones) was noted. The results indicated that intra-operative ultrasound by a dedicated radiologist is a valuable tool in resolving discordance of pre-operative imaging. Appropriate patient positioning with neck extension and muscle relaxation allows placement of the probe in the obscure retro-carotid and retro-oesophageal locations and unmasks apparent "mediastinal" parathyroids facilitating focused dissection.
Assuntos
Adenoma/diagnóstico por imagem , Adenoma/cirurgia , Hiperparatireoidismo Primário/diagnóstico por imagem , Hiperparatireoidismo Primário/cirurgia , Neoplasias das Paratireoides/diagnóstico por imagem , Neoplasias das Paratireoides/cirurgia , Paratireoidectomia/métodos , Algoritmos , Feminino , Humanos , Período Intraoperatório , Masculino , Estudos Prospectivos , Cintilografia , Compostos Radiofarmacêuticos , Tecnécio Tc 99m Sestamibi , Resultado do Tratamento , UltrassonografiaRESUMO
This study aimed to assess outcomes of revision endoscopic stapling and external excision of pharyngeal pouch. A 5-year prospective study was performed on all patients requiring revision pouch surgery following primary endoscopic stapling. Data were collected retrospectively. Eighteen patients underwent revision pouch surgery. In seven patients, pouch size was down-graded from 3 to 2, and these were stapled endoscopically. Two leaks resulted. Eleven patients with grade 1 or 3 pouches underwent external excision of pouch, with no post-operative complications. As per results external excision of pouch is safe for grade 1 and 3 pouches. It avoids risking redundant mucosa and recurrence of symptoms which can complicate stapling and enables a myotomy to be performed to reduce cricopharyngeal hypertonicity. The highest predictable success is with grade 2 pouches, whose size is amenable to adequate endoscopic stapling. However, the "staple over staple" effect of revision stapling leads to unpredictable fibrosis, which can contribute to risk of perforation.
Assuntos
Transtornos de Deglutição/cirurgia , Grampeamento Cirúrgico , Divertículo de Zenker/cirurgia , Adulto , Idoso , Transtornos de Deglutição/etiologia , Endoscopia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Estudos Prospectivos , Recidiva , Reoperação/métodos , Divertículo de Zenker/complicaçõesRESUMO
Intrathyroidal parathyroid adenomas (IPAs) are a rare cause of primary hyperparathyroidism. They are often difficult to localize preoperatively and intraoperatively, making diagnosis and treatment challenging. Current data on IPAs are sparse and fragmented in the literature. This makes it difficult to compare the effectiveness of different imaging and surgical techniques. To address this issue, this scoping review maps the literature on IPAs, focusing on four domains: clinical presentation, current localization methods, different surgical techniques, and histopathological features. A search of MEDLINE, Embase, and the Cochrane Library was conducted, with 19 studies meeting the inclusion criteria. The characteristics of IPAs on ultrasound, fine-needle aspiration, CT, MRI, sestamibi-based techniques, and selective venous sampling are summarized. Emerging imaging modalities, including autofluorescence, are introduced. Surgical methods and intraoperative factors that correlate with high success rates for removal are highlighted. This review also identifies gaps in knowledge to guide further research into this area.
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Adenoma , Neoplasias das Paratireoides , Humanos , Neoplasias das Paratireoides/diagnóstico por imagem , Neoplasias das Paratireoides/cirurgia , Glândulas Paratireoides/patologia , Diagnóstico por Imagem , Compostos Radiofarmacêuticos , Ultrassonografia , Adenoma/diagnóstico por imagem , Adenoma/cirurgia , Adenoma/patologia , Tecnécio Tc 99m SestamibiRESUMO
Introduction: The COVID-19 pandemic has exacerbated mental health issues among adolescents. Exercise is well-regarded for boosting mental health. Riding for Focus (R4F) is a 6-8 week cycling education program designed to equip middle school adolescents with basic cycling skills and introduce students to lifetime physical activity. A secondary goal of the R4F program is to improve adolescent mental health and psychosocial well-being. This study aimed to quantify the change in adolescent psychosocial well-being associated with the R4F program during the COVID-19 pandemic. Program evaluation also examined associations between participating in the R4F and mental health outcomes in the context of established risk factors, including gender, race, socioeconomic status, involvement in IEP programs, participation in after-school clubs, screen time, hours of sleep, and physical activity levels. Methods: Anonymous surveys were collected before and after the program in 20 schools in North America, with psychosocial well-being quantified using WHO-5 and PSC-17-Y. 1,148 middle school students, aged 11-14, completed pre intervention surveys. 815 students also completed post intervention surveys. Results: There was a general increase in psychosocial well-being after the R4F program and positive psychosocial well-being changes in students that identified as female, non-white, physically active, part of an IEP program, meeting screentime recommendations, and engaged in school programs, though effect sizes were small. Despite mental health improvements among underrepresented groups, relative risk assessments still indicated that males, white students, those from high socioeconomic status families still had reduced relative risk of developing psychosocial disorders post intervention. Discussion: These analyses illustrate the feasibility of cycling as a viable PE elective and the need for further, more robust studies to better assess the positive impacts of the R4F scholastic cycling program on the psychological health and well-being of middle school age children.
RESUMO
PURPOSE: To test IPW-5371 for the mitigation of the delayed effects of acute radiation exposure (DEARE). Survivors of acute radiation exposure are at risk for developing delayed multi-organ toxicities; however, there are no FDA-approved medical countermeasures (MCM) to mitigate DEARE. METHODS: WAG/RijCmcr female rat model of partial-body irradiation (PBI), by shielding part of one hind leg, was used to test IPW-5371 (7 and 20 mg kg-1 d-1) for mitigation of lung and kidney DEARE when started 15 d after PBI. Rats were fed known amounts of IPW-5371 using a syringe, instead of delivery by daily oral gavage, sparing exacerbation of esophageal injury by radiation. The primary endpoint, all-cause morbidity was assessed over 215 d. Secondary endpoints: body weight, breathing rate and blood urea nitrogen were also assessed. RESULTS: IPW-5371 enhanced survival (primary endpoint) as well as attenuated secondary endpoints of lung and kidney injuries by radiation. CONCLUSION: To provide a window for dosimetry and triage, as well as avoid oral delivery during the acute radiation syndrome (ARS), the drug regimen was started at 15 d after 13.5 Gy PBI. The experimental design to test mitigation of DEARE was customized for translation in humans, using an animal model of radiation that was designed to simulate a radiologic attack or accident. The results support advanced development of IPW-5371 to mitigate lethal lung and kidney injuries after irradiation of multiple organs.