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1.
Gastrointest Endosc ; 99(3): 408-416.e2, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37793506

RESUMO

BACKGROUND AND AIMS: We aimed to compare the long-term outcomes of patients with high-risk T1 colorectal cancer (CRC) resected endoscopically who received either additional surgery or surveillance. METHODS: We used data from routine care to emulate a target trial aimed at comparing 2 strategies after endoscopic resection of high-risk T1 CRC: surgery with lymph node dissection (treatment group) versus surveillance alone (control group). All patients from 14 tertiary centers who underwent an endoscopic resection for high-risk T1 CRC between March 2012 and August 2019 were included. The primary outcome was a composite outcome of cancer recurrence or death at 48 months. RESULTS: Of 197 patients included in the analysis, 107 were categorized in the treatment group and 90 were categorized in the control group. From baseline to 48 months, 4 of 107 patients (3.7%) died in the treatment group and 6 of 90 patients (6.7%) died in the control group. Four of 107 patients (3.7%) in the treatment group experienced a cancer recurrence and 4 of 90 patients (4.4%) in the control group experienced a cancer recurrence. After balancing the baseline covariates by inverse probability of treatment weighting, we found no significant difference in the rate of death and cancer recurrence between patients in the 2 groups (weighted hazard ratio, .95; 95% confidence interval, .52-1.75). CONCLUSIONS: Our study suggests that patients with high-risk T1 CRC initially treated with endoscopic resection may not benefit from additional surgery.


Assuntos
Neoplasias Colorretais , Recidiva Local de Neoplasia , Humanos , Estudos Retrospectivos , Recidiva Local de Neoplasia/patologia , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/patologia , Endoscopia/métodos , Excisão de Linfonodo , Fatores de Risco , Resultado do Tratamento
2.
Curr Opin Gastroenterol ; 39(2): 67-74, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36821453

RESUMO

PURPOSE OF REVIEW: Cholangioscopy is a mini-invasive endoscopic procedure, which consists in a direct intraductal visualization of the biliary tract. The purpose of this review is to summarize the technique, the clinical applications, as well as future perspectives of cholangioscopy. RECENT FINDINGS: Numerous technologic advances during the last decades have allowed for an improved utility and functionality, leading to a broader use of this procedure, for diagnostic or therapeutic purposes, in the setting of biliary diseases. Novel tools and emerging indications have been developed and more are yet to come. SUMMARY: Cholangioscopy can be performed by peroral, percutaneous transhepatic or intra-operative transcystic or transcholedochal access. Clinical applications of cholangioscopy are multiple, ranging from visual impression and optical guided biopsies of indeterminate biliary strictures to the management of difficult stones , guidance before biliary stenting and retrieval of migrated ductal stents. Multiple devices such as lithotripsy probes, biopsy forceps, snares and baskets have been developed to help achieve these procedures successfully.Cholangioscopy has improved the way biliary diseases can be visualized and treated. New technology, accessories, and applications are expected in the future.


Assuntos
Endoscopia do Sistema Digestório , Laparoscopia , Humanos , Endoscopia do Sistema Digestório/métodos , Biópsia
3.
Pancreatology ; 23(1): 48-56, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36517351

RESUMO

BACKGROUND: PRSS1 and PRSS2 constitute the only functional copies of a tandemly-arranged five-trypsinogen-gene cluster (i.e., PRSS1, PRSS3P1, PRSS3P2, TRY7 and PRSS2) on chromosome 7q35. Variants in PRSS1 and PRSS2, including missense and copy number variants (CNVs), have been reported to predispose to or protect against chronic pancreatitis (CP). We wondered whether a common trypsinogen pseudogene deletion CNV (that removes two of the three trypsinogen pseudogenes, PRSS3P2 and TRY7) might be associated with CP causation/predisposition. METHODS: We analyzed the common PRSS3P2 and TRY7 deletion CNV in a total of 1536 CP patients and 3506 controls from France, Germany, India and Japan by means of quantitative fluorescent multiplex polymerase chain reaction. RESULTS: We demonstrated that the deletion CNV variant was associated with a protective effect against CP in the French, German and Japanese cohorts whilst a trend toward the same association was noted in the Indian cohort. Meta-analysis under a dominant model yielded a pooled odds ratio (OR) of 0.68 (95% confidence interval (CI) 0.52-0.89; p = 0.005) whereas an allele-based meta-analysis yielded a pooled OR of 0.84 (95% CI 0.77-0.92; p = 0.0001). This protective effect is explicable by reference to the recent finding that the still functional PRSS3P2/TRY7 pseudogene enhancers upregulate pancreatic PRSS2 expression. CONCLUSIONS: The common PRSS3P2 and TRY7 deletion CNV was associated with a reduced risk for CP. This finding provides additional support for the emerging view that dysregulated PRSS2 expression represents a discrete mechanism underlying CP predisposition or protection.


Assuntos
Pancreatite Crônica , Tripsinogênio , Humanos , Alelos , Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença , Genótipo , Mutação , Pancreatite Crônica/genética , Tripsina/genética , Tripsinogênio/genética
4.
Proc Natl Acad Sci U S A ; 117(38): 23527-23538, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32907943

RESUMO

Clathrin light chain (CLC) subunits in vertebrates are encoded by paralogous genes CLTA and CLTB, and both gene products are alternatively spliced in neurons. To understand how this CLC diversity influences neuronal clathrin function, we characterized the biophysical properties of clathrin comprising individual CLC variants for correlation with neuronal phenotypes of mice lacking either CLC-encoding gene. CLC splice variants differentially influenced clathrin knee conformation within assemblies, and clathrin with neuronal CLC mixtures was more effective in membrane deformation than clathrin with single neuronal isoforms nCLCa or nCLCb. Correspondingly, electrophysiological recordings revealed that neurons from mice lacking nCLCa or nCLCb were both defective in synaptic vesicle replenishment. Mice with only nCLCb had a reduced synaptic vesicle pool and impaired neurotransmission compared to WT mice, while nCLCa-only mice had increased synaptic vesicle numbers, restoring normal neurotransmission. These findings highlight differences between the CLC isoforms and show that isoform mixing influences tissue-specific clathrin activity in neurons, which requires their functional balance.


Assuntos
Cadeias Leves de Clatrina , Vesículas Sinápticas/química , Vesículas Sinápticas/metabolismo , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/metabolismo , Células Cultivadas , Cadeias Leves de Clatrina/química , Cadeias Leves de Clatrina/genética , Cadeias Leves de Clatrina/metabolismo , Camundongos , Camundongos Knockout , Neurônios/citologia , Neurônios/metabolismo , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo
5.
Ann Rheum Dis ; 81(7): 979-989, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35393271

RESUMO

OBJECTIVE: To develop a composite responder index in primary Sjögren's syndrome (pSS): the Sjögren's Tool for Assessing Response (STAR). METHODS: To develop STAR, the NECESSITY (New clinical endpoints in primary Sjögren's syndrome: an interventional trial based on stratifying patients) consortium used data-driven methods based on nine randomised controlled trials (RCTs) and consensus techniques involving 78 experts and 20 patients. Based on reanalysis of rituximab trials and the literature, the Delphi panel identified a core set of domains with their respective outcome measures. STAR options combining these domains were proposed to the panel for selection and improvement. For each STAR option, sensitivity to change was estimated by the C-index in nine RCTs. Delphi rounds were run for selecting STAR. For the options remaining before the final vote, a meta-analysis of the RCTs was performed. RESULTS: The Delphi panel identified five core domains (systemic activity, patient symptoms, lachrymal gland function, salivary gland function and biological parameters), and 227 STAR options combining these domains were selected to be tested for sensitivity to change. After two Delphi rounds, a meta-analysis of the 20 remaining options was performed. The candidate STAR was then selected by a final vote based on metrological properties and clinical relevance. CONCLUSION: The candidate STAR is a composite responder index that includes all main disease features in a single tool and is designed for use as a primary endpoint in pSS RCTs. The rigorous and consensual development process ensures its face and content validity. The candidate STAR showed good sensitivity to change and will be prospectively validated by the NECESSITY consortium in a dedicated RCT.


Assuntos
Síndrome de Sjogren , Consenso , Humanos , Avaliação de Resultados em Cuidados de Saúde , Rituximab/uso terapêutico , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/tratamento farmacológico
6.
Endoscopy ; 54(7): 700-705, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-34500487

RESUMO

BACKGROUND: Gastrointestinal (GI) fistula is a life-threatening condition and a therapeutic challenge. Endoscopic approaches include mucosal abrasion, clip closure, or stent diversion, with moderate success rates in the long term. We assessed whether fistula endoscopic submucosal dissection with clip closure (FESDC) could lead to complete resolution of fistulas even after failure of previous endoscopic therapy. METHODS: Patients with GI fistulas, including those with previous failed treatment, were retrospectively included. The primary outcome was long-term (> 3 months) success of fistula healing. Secondary outcomes included technical success, safety, and factors associated with FESDC success. RESULTS: 23 patients (13 refractory 57 %) were included. Tight immediate sealing was achieved in 19 patients (83 %; 95 % confidence interval [CI] 61 %-95 %). Long-term closure was achieved in 14 patients (61 %; 95 %CI 39 %-80 %), with median follow-up of 20 months. Complications occurred in two patients (9 %). Previous local malignancy (P = 0.08) and radiotherapy (P = 0.047) were associated with a higher risk of failure. CONCLUSION: This novel FESDC strategy was demonstrated to be safe and feasible for permanent endoscopic closure of GI fistulas. Further studies are warranted to determine the place of this technique in the management of chronic GI fistula.


Assuntos
Fístula do Sistema Digestório , Ressecção Endoscópica de Mucosa , Fístula , Fístula do Sistema Digestório/etiologia , Fístula do Sistema Digestório/cirurgia , Ressecção Endoscópica de Mucosa/efeitos adversos , Endoscopia Gastrointestinal/efeitos adversos , Endoscopia Gastrointestinal/métodos , Fístula/etiologia , Humanos , Estudos Retrospectivos , Instrumentos Cirúrgicos , Resultado do Tratamento
7.
Endoscopy ; 54(1): 71-74, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33506454

RESUMO

BACKGROUND: Endoscopic internal drainage (EID) with double-pigtail stents or low negative-pressure endoscopic vacuum therapy (EVT) are treatment options for leakage after upper gastrointestinal oncologic surgery. We aimed to compare the effectiveness of these techniques. METHODS: Between 2016 and 2019, patients treated with EID in five centers in France and with EVT in Göttingen, Germany were included and retrospectively analyzed using univariate analysis. Pigtail stents were changed every 4 weeks; EVT was repeated every 3-4 days until leak closure. RESULTS: 35 EID and 27 EVT patients were included, with a median (interquartile range [IQR]) leak size of 0.75 cm (0.5-1.5). Overall treatment success was 100 % (95 % confidence interval [CI] 90 %-100 %) for EID vs. 85.2 % (95 %CI 66.3 %-95.8 %) for EVT (P = 0.03). The median (IQR) number of endoscopic procedures was 2 (2-3) vs. 3 (2-6.5; P = 0.003) and the median (IQR) treatment duration was 42 days (28-60) vs. 17 days (7.5-28; P < 0.001), for EID vs. EVT, respectively. CONCLUSION: EID and EVT provide high closure rates for upper gastrointestinal anastomotic leaks. EVT provides a shorter treatment duration, at the cost of a higher number of procedures.


Assuntos
Fístula Anastomótica , Tratamento de Ferimentos com Pressão Negativa , Fístula Anastomótica/etiologia , Fístula Anastomótica/cirurgia , Drenagem , Esofagectomia , Humanos , Estudos Retrospectivos
8.
Dig Endosc ; 34(7): 1433-1439, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35429360

RESUMO

OBJECTIVES: Endoscopic ultrasound-guided digestive anastomosis (EUS-A) is a new alternative under evaluation in patients presenting with afferent limb syndrome (ALS) after Whipple surgery. The aim of the present study is to analyze the safety and effectiveness of EUS-A in ALS. METHODS: This is an observational multicenter study. All patients ≥18 years old with previous Whipple surgery presenting with ALS who underwent an EUS-A using a lumen-apposing metal stent (LAMS) between 2015 and 2021 were included. The primary outcome was clinical success, defined as resolution of the ALS or ALS-related cholangitis. Furthermore, technical success, adverse event rate, and mortality were evaluated. RESULTS: Forty-five patients (mean age: 65.5 ± 10.2 years; 44.4% male) were included. The most common underlying disease was pancreatic cancer (68.9%). EUS-A was performed at a median of 6 weeks after local tumor recurrence. The most common approach used was the direct/freehand technique (66.7%). Technical success was achieved in 95.6%, with no differences between large (≥15 mm) and small LAMS (97.4% vs. 100%, P = 0.664). Clinical success was retained in 91.1% of patients. A complementary treatment by dilation of the stent followed by endoscopic retrograde cholangiopancreatography through the LAMS was performed in three cases (6.7%). There were six recurrent episodes of cholangitis (14.6%) and two procedure-related adverse events (4.4%) after a median follow-up of 4 months. Twenty-six patients (57.8%) died during the follow-up due to disease progression. CONCLUSION: EUS-A is a safe and effective technique in the treatment of malignant ALS, achieving high clinical success with an acceptable recurrence rate.


Assuntos
Colangite , Adolescente , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Colangite/etiologia , Colangite/cirurgia , Drenagem/métodos , Endossonografia/métodos , Stents/efeitos adversos , Resultado do Tratamento , Ultrassonografia de Intervenção/métodos
9.
Curr Opin Anaesthesiol ; 35(4): 528-535, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35787532

RESUMO

PURPOSE OF REVIEW: Nonoperating room anesthesia for digestive tract endoscopy has its own specificities and requires practical training. Monitoring devices, anesthetic drugs, understanding of procedures and management of complications are critical aspects. RECENT FINDINGS: New data are available regarding risk factors for intra- and postoperative complications (based on anesthesia registries), airway management, new anesthetic drugs, techniques of administration and management of advances in interventional endoscopy procedures. SUMMARY: Digestive tract endoscopy is a common procedure that takes place outside the operating room most of the time and has become more and more complex due to advanced invasive procedures. Prior evaluation of the patient's comorbidities and a good understanding of the objectives and constraints of the endoscopic procedures are required. Assessing the risk of gastric content aspiration is critical for determining appropriate anesthetic protocols. The availability of adequate monitoring (capnographs adapted to spontaneous ventilation, bispectral index), devices for administration of anesthetic/sedative agents (target-controlled infusion) and oxygenation (high flow nasal oxygenation) guarantees the quality of sedation and patient' safety during endoscopic procedures. Knowledge of the specificities of each interventional endoscopic procedure (endoscopic retrograde cholangiopancreatography, submucosal dissection) allows preventing complications during anesthesia.


Assuntos
Anestesia , Anestesiologia , Anestésicos , Anestesia/efeitos adversos , Anestesia/métodos , Endoscopia , Endoscopia Gastrointestinal/efeitos adversos , Trato Gastrointestinal , Humanos
10.
Kidney Int ; 100(1): 90-106, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33675847

RESUMO

The strong predictive value of proteinuria in chronic glomerulopathies is firmly established as well as the pathogenic role of angiotensin II promoting progression of glomerular disease with an altered glomerular filtration barrier, podocyte injury and scarring of glomeruli. Here we found that chronic angiotensin II-induced hypertension inhibited autophagy flux in mouse glomeruli. Deletion of Atg5 (a gene encoding a protein involved autophagy) specifically in the podocyte resulted in accelerated angiotensin II-induced podocytopathy, accentuated albuminuria and glomerulosclerosis. This indicates that autophagy is a key protective mechanism in the podocyte in this condition. Angiotensin-II induced calpain activity in podocytes inhibits autophagy flux. Podocytes from mice with transgenic expression of the endogenous calpain inhibitor calpastatin displayed higher podocyte autophagy at baseline that was resistant to angiotensin II-dependent inhibition. Also, sustained autophagy with calpastatin limited podocyte damage and albuminuria. These findings suggest that hypertension has pathogenic effects on the glomerular structure and function, in part through activation of calpains leading to blockade of podocyte autophagy. These findings uncover an original mechanism whereby angiotensin II-mediated hypertension inhibits autophagy via calcium-induced recruitment of calpain with pathogenic consequences in case of imbalance by calpastatin activity. Thus, preventing a calpain-mediated decrease in autophagy may be a promising new therapeutic strategy for nephropathies associated with high renin-angiotensin system activity.


Assuntos
Podócitos , Angiotensina II/toxicidade , Animais , Autofagia , Proteínas de Ligação ao Cálcio , Glomérulos Renais , Camundongos
11.
Endoscopy ; 53(3): 300-332, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33567467

RESUMO

1: ESGE recommends in patients with acute upper gastrointestinal hemorrhage (UGIH) the use of the Glasgow-Blatchford Score (GBS) for pre-endoscopy risk stratification. Patients with GBS ≤ 1 are at very low risk of rebleeding, mortality within 30 days, or needing hospital-based intervention and can be safely managed as outpatients with outpatient endoscopy.Strong recommendation, moderate quality evidence. 2: ESGE recommends that in patients with acute UGIH who are taking low-dose aspirin as monotherapy for secondary cardiovascular prophylaxis, aspirin should not be interrupted. If for any reason it is interrupted, aspirin should be re-started as soon as possible, preferably within 3-5 days.Strong recommendation, moderate quality evidence. 3: ESGE recommends that following hemodynamic resuscitation, early (≤ 24 hours) upper gastrointestinal (GI) endoscopy should be performed. Strong recommendation, high quality evidence. 4: ESGE does not recommend urgent (≤ 12 hours) upper GI endoscopy since as compared to early endoscopy, patient outcomes are not improved. Strong recommendation, high quality evidence. 5: ESGE recommends for patients with actively bleeding ulcers (FIa, FIb), combination therapy using epinephrine injection plus a second hemostasis modality (contact thermal or mechanical therapy). Strong recommendation, high quality evidence. 6: ESGE recommends for patients with an ulcer with a nonbleeding visible vessel (FIIa), contact or noncontact thermal therapy, mechanical therapy, or injection of a sclerosing agent, each as monotherapy or in combination with epinephrine injection. Strong recommendation, high quality evidence. 7 : ESGE suggests that in patients with persistent bleeding refractory to standard hemostasis modalities, the use of a topical hemostatic spray/powder or cap-mounted clip should be considered. Weak recommendation, low quality evidence. 8: ESGE recommends that for patients with clinical evidence of recurrent peptic ulcer hemorrhage, use of a cap-mounted clip should be considered. In the case of failure of this second attempt at endoscopic hemostasis, transcatheter angiographic embolization (TAE) should be considered. Surgery is indicated when TAE is not locally available or after failed TAE. Strong recommendation, moderate quality evidence. 9: ESGE recommends high dose proton pump inhibitor (PPI) therapy for patients who receive endoscopic hemostasis and for patients with FIIb ulcer stigmata (adherent clot) not treated endoscopically. (A): PPI therapy should be administered as an intravenous bolus followed by continuous infusion (e. g., 80 mg then 8 mg/hour) for 72 hours post endoscopy. (B): High dose PPI therapies given as intravenous bolus dosing (twice-daily) or in oral formulation (twice-daily) can be considered as alternative regimens.Strong recommendation, high quality evidence. 10: ESGE recommends that in patients who require ongoing anticoagulation therapy following acute NVUGIH (e. g., peptic ulcer hemorrhage), anticoagulation should be resumed as soon as the bleeding has been controlled, preferably within or soon after 7 days of the bleeding event, based on thromboembolic risk. The rapid onset of action of direct oral anticoagulants (DOACS), as compared to vitamin K antagonists (VKAs), must be considered in this context.Strong recommendation, low quality evidence.


Assuntos
Endoscopia Gastrointestinal , Hemostase Endoscópica , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/terapia , Humanos
12.
Crit Care ; 25(1): 49, 2021 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-33549136

RESUMO

BACKGROUND: Little is known on the outcome and risk factors for mortality of patients admitted in Intensive Care units (ICUs) for Acute cholangitis (AC). METHODS: Retrospective multicenter study included adults admitted in eleven intensive care units for a proven AC from 2005 to 2018. Risk factors for in-hospital mortality were identified using multivariate analysis. RESULTS: Overall, 382 patients were included, in-hospital mortality was 29%. SOFA score at admission was 8 [5-11]. Biliary obstruction was mainly related to gallstone (53%) and cancer (22%). Median total bilirubin and PCT were respectively 83 µmol/L [50-147] and 19.1 µg/L [5.3-54.8]. Sixty-three percent of patients (n = 252) had positive blood culture, mainly Gram-negative bacilli (86%) and 14% produced extended spectrum beta lactamase bacteria. At ICU admission, persisting obstruction was frequent (79%) and biliary decompression was performed using therapeutic endoscopic retrograde cholangiopancreatography (76%) and percutaneous transhepatic biliary drainage (21%). Adjusted mortality significantly decreased overtime, adjusted OR for mortality per year was 0.72 [0.54-0.96] (p = 0.02). In a multivariate analysis, factors at admission associated with in-hospital mortality were: SOFA score (OR 1.14 [95% CI 1.05-1.24] by point, p = 0.001), lactate (OR 1.21 [95% CI 1.08-1.36], by 1 mmol/L, p < 0.001), total serum bilirubin (OR 1.26 [95% CI 1.12-1.41], by 50 µmol/L, p < 0.001), obstruction non-related to gallstones (p < 0.05) and AC complications (OR 2.74 [95% CI 1.45-5.17], p = 0.002). Time between ICU admission and biliary decompression > 48 h was associated with in-hospital mortality (adjusted OR 2.73 [95% CI 1.30-6.22], p = 0.02). CONCLUSIONS: In this large retrospective multicenter study, we found that AC-associated mortality significantly decreased overtime. Severity of organ failure, cause of obstruction and local complications of AC are risk factors for mortality, as well as delayed biliary drainage > 48 h.


Assuntos
Colangite/microbiologia , Colangite/fisiopatologia , Mortalidade/tendências , Idoso , Idoso de 80 Anos ou mais , Colangite/epidemiologia , Feminino , Humanos , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Escores de Disfunção Orgânica , Estudos Retrospectivos , Fatores de Risco
14.
Proc Natl Acad Sci U S A ; 113(35): 9816-21, 2016 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-27540116

RESUMO

Clathrin, a cytosolic protein composed of heavy and light chain subunits, assembles into a vesicle coat, controlling receptor-mediated endocytosis. To establish clathrin light chain (CLC) function in vivo, we engineered mice lacking CLCa, the major CLC isoform in B lymphocytes, generating animals with CLC-deficient B cells. In CLCa-null mice, the germinal centers have fewer B cells, and they are enriched for IgA-producing cells. This enhanced switch to IgA production in the absence of CLCa was attributable to increased transforming growth factor ß receptor 2 (TGFßR2) signaling resulting from defective endocytosis. Internalization of C-X-C chemokine receptor 4 (CXCR4), but not CXCR5, was affected in CLCa-null B cells, and CLC depletion from cell lines affected endocytosis of the δ-opioid receptor, but not the ß2-adrenergic receptor, defining a role for CLCs in the uptake of a subset of signaling receptors. This instance of clathrin subunit deletion in vertebrates demonstrates that CLCs contribute to clathrin's role in vivo by influencing cargo selectivity, a function previously assigned exclusively to adaptor molecules.


Assuntos
Linfócitos B/imunologia , Cadeias Leves de Clatrina/genética , Endocitose/imunologia , Deleção de Genes , Switching de Imunoglobulina , Animais , Linfócitos B/patologia , Córtex Cerebral/citologia , Córtex Cerebral/imunologia , Cadeias Leves de Clatrina/imunologia , Regulação da Expressão Gênica , Humanos , Imunoglobulina A/biossíntese , Imunoglobulina A/genética , Fígado/citologia , Fígado/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/citologia , Miocárdio/imunologia , Especificidade de Órgãos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/imunologia , Receptores CXCR4/genética , Receptores CXCR4/imunologia , Receptores Opioides delta/genética , Receptores Opioides delta/imunologia , Receptores de Fatores de Crescimento Transformadores beta/agonistas , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/imunologia , Baço/citologia , Baço/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia
15.
J Biol Chem ; 292(51): 20834-20844, 2017 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-29097553

RESUMO

Clathrins are cytoplasmic proteins that play essential roles in endocytosis and other membrane traffic pathways. Upon recruitment to intracellular membranes, the canonical clathrin triskelion assembles into a polyhedral protein coat that facilitates vesicle formation and captures cargo molecules for transport. The triskelion is formed by trimerization of three clathrin heavy-chain subunits. Most vertebrates have two isoforms of clathrin heavy chains, CHC17 and CHC22, generating two clathrins with distinct cellular functions. CHC17 forms vesicles at the plasma membrane for receptor-mediated endocytosis and at the trans-Golgi network for organelle biogenesis. CHC22 plays a key role in intracellular targeting of the insulin-regulated glucose transporter 4 (GLUT4), accumulates at the site of GLUT4 sequestration during insulin resistance, and has also been implicated in neuronal development. Here, we demonstrate that CHC22 and CHC17 share morphological features, in that CHC22 forms a triskelion and latticed vesicle coats. However, cellular CHC22-coated vesicles were distinct from those formed by CHC17. The CHC22 coat was more stable to pH change and was not removed by the enzyme complex that disassembles the CHC17 coat. Moreover, the two clathrins were differentially recruited to membranes by adaptors, and CHC22 did not support vesicle formation or transferrin endocytosis at the plasma membrane in the presence or absence of CHC17. Our findings provide biochemical evidence for separate regulation and distinct functional niches for CHC17 and CHC22 in human cells. Furthermore, the greater stability of the CHC22 coat relative to the CHC17 coat may be relevant to its excessive accumulation with GLUT4 during insulin resistance.


Assuntos
Cadeias Pesadas de Clatrina/química , Cadeias Pesadas de Clatrina/metabolismo , Sequência de Aminoácidos , Cadeias Pesadas de Clatrina/genética , Vesículas Revestidas por Clatrina/metabolismo , Vesículas Revestidas por Clatrina/ultraestrutura , Endocitose , Transportador de Glucose Tipo 4/metabolismo , Células HeLa , Humanos , Resistência à Insulina , RNA Interferente Pequeno/genética , Homologia de Sequência de Aminoácidos , Transferrina/metabolismo
16.
Gastrointest Endosc ; 88(3): 511-518, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29660322

RESUMO

BACKGROUND AND AIMS: Endobiliary dysplasia may persist after endoscopic papillectomy. Intraductal radiofrequency ablation (ID-RFA) is a potential alternative to complementary surgery. The aim of this study was to evaluate the efficacy and safety of ID-RFA for the treatment of adenomatous intraductal residue after endoscopic papillectomy. METHODS: A prospective open-label multicenter study included patients with histologically proven endobiliary adenoma remnant (ductal extent <20 mm) after endoscopic papillectomy for ampullary tumor. RFA (effect 8, power 10 W, 30 seconds) was performed during ERCP. Biliary ± pancreatic stent was placed at the end of the procedure. Endpoints were (1) the rate of residual neoplasia (ie, low-grade dysplasia [LGD], high-grade dysplasia [HGD], or invasive carcinoma) at 6 and 12 months, (2) rate of surgery, and (3) adverse events. RESULTS: Twenty patients (67 ± 11 years of age, 12 men) were included. The endobiliary adenoma was in LGD in 15 patients and HGD in 5 patients. All underwent 1 successful ID-RFA session with biliary stent placement and recovered uneventfully. Five (25%) received a pancreatic stent. The rates of residual neoplasia were 15% and 30% at 6 and 12 months, respectively. Only 2 patients (10%) were referred for surgery. Eight patients (40%) experienced at least 1 adverse event between ID-RFA and 12 months of follow-up. No major adverse event occurred. HGD at inclusion was associated with higher dysplasia recurrence at 12 months (P = .01). CONCLUSIONS: ID-RFA of residual endobiliary dysplasia after endoscopic papillectomy can be offered as an alternative to surgery, with a 70% chance of dysplasia eradication at 12 months after a single session and a good safety profile. Patient follow-up remains warranted after ID-RFA. (Clinical trial registration number: NCT02825524.).


Assuntos
Adenocarcinoma/cirurgia , Adenoma/cirurgia , Ampola Hepatopancreática/cirurgia , Neoplasias do Ducto Colédoco/cirurgia , Neoplasia Residual/cirurgia , Ablação por Radiofrequência , Adenocarcinoma/patologia , Adenoma/patologia , Idoso , Ampola Hepatopancreática/patologia , Neoplasias do Ducto Colédoco/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/patologia , Estudos Prospectivos , Resultado do Tratamento
18.
Eur Radiol ; 28(1): 206-213, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28710577

RESUMO

PURPOSE: The aim of this prospective study was to evaluate the feasibility, tolerance and performance of virtual enteroscopy (VE) using carbon dioxide for small-bowel distension in patients with suspected small-bowel tumours (SBTs). PATIENTS AND METHODS: After IRB approval, 17 patients with suspected SBTs were prospectively included. Radiation dose was compared to 34 matched patients (2 for 1) for age, gender and body weight, who had undergone CT-enteroclysis with neutral contrast (CTE). Performance of VE was evaluated through comparison with the current standard of reference, including surgery and/or enteroscopy and/or follow-up. RESULTS: Tolerance was excellent in 16/17 patients (94%). The radiation dose was lower for VE than for CTE (533 ± 282 vs. 974 ± 505 mGy.cm; p = 0.002). With VE, a total of 25 polyps >5 mm in size were depicted in 12/17 patients. On a per-lesion analysis, sensitivity and positive predictive value of VE were 92.0% and 92.0%, respectively. On a per-segment analysis VE had a sensitivity and specificity of 95.0% and 87.0%, respectively. CONCLUSION: Our preliminary study suggests that VE is a feasible and well-tolerated technique with high sensitivity and specificity for the diagnosis of SBT. KEY POINTS: • Virtual enteroscopy is feasible and well tolerated. • Virtual enteroscopy appears to be accurate for detection of small-bowel tumours. • Sensitivity and PPV of virtual enteroscopy is 92.0% and 92.0%. • Radiation dose is lower with virtual enteroscopy compared to MDCT-enteroclysis.


Assuntos
Dióxido de Carbono/administração & dosagem , Endoscopia Gastrointestinal/métodos , Neoplasias Intestinais/diagnóstico por imagem , Intestino Delgado/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adolescente , Adulto , Feminino , Humanos , Insuflação , Neoplasias Intestinais/patologia , Intestino Delgado/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto Jovem
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