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2.
Aesthetic Plast Surg ; 48(6): 1067-1075, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37816946

RESUMO

BACKGROUND: Although laser Doppler imaging (LDI) accurately delineates a hypoperfused area to help target hyaluronidase treatment, laser speckle contrast imaging (LSCI) is more appropriate for assessing microvascular hemodynamics and has greater reproducibility than LDI. This study investigated the use of LSCI in the evaluation and treatment of six patients who developed vascular complications after facial dermal filler injections. METHODS: The areas of vascular occlusion were accurately defined in real time by LSCI and were more precise than visual inspections or photographic evidence for guiding needling and hyaluronidase treatment. RESULTS: All patients had achieved satisfactory outcomes as early as Day 2 of treatment and no procedure-related complications were reported after a median follow-up of 9.5 (7-37) days. CONCLUSION: LSCI accurately and noninvasively delineated vascular occlusions in real time among patients experiencing complications of facial dermal filler injections. Moreover, LSCI was more accurate than visual and photographic evaluations. Clinicians can use LSCI to reliably follow-up therapeutic outcomes after salvage interventions for vascular occlusions. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


Assuntos
Técnicas Cosméticas , Preenchedores Dérmicos , Humanos , Preenchedores Dérmicos/efeitos adversos , Imagem de Contraste de Manchas a Laser , Hialuronoglucosaminidase , Reprodutibilidade dos Testes , Indução Percutânea de Colágeno , Técnicas Cosméticas/efeitos adversos , Ácido Hialurônico
3.
Plast Reconstr Surg ; 2023 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-37506358

RESUMO

Transumbilical breast augmentation with pre-filled silicone implants has been performed previously, but technical challenges remain to accommodate more implant options and dissection planes. We aimed to demonstrate the feasibility of transumbilical breast augmentation using various types of pre-filled silicone implants (TUSBA), and its applicability for subglandular, subfascial, dual-plane implantation. In the early stage, TUSBA was primarily performed using endoscope-assisted blunt dissection, and later converted to full endoscopy dissection to achieve better results. Endoscope was used to confirm the pocket and check bleeding for both groups. For endoscope-assisted group, surgical techniques were modified from conventional TUBA. In full endoscopy TUSBA, the entire dissection process was performed under endoscopic monitoring. Preliminary data of patients undergoing TUSBA from June 2016 to April 2021 were retrospectively reviewed. Breast implants with smooth, textured or nanotextured surface properties and round or anatomical shapes were used, with sizes up to 500 mL. Seventy-four patients with mean age 36.4 years (range: 21-55 years) were enrolled in this study. Follow-up ranged from 1 month to 4 years and 6 months (mean: 15.6 months). No excessive postoperative pain in breast or abdomen was reported. Surgery outcomes were aesthetically pleasing in both groups. In the endoscope-assisted group, 3 (4.6%) required major revisional procedures. No revision was required in the full endoscopy group. TUSBA with various types of silicone implants is feasible, and accommodable to all dissection planes. Full endoscopy technique is helpful in reducing the higher complication rate.

4.
Clin Cosmet Investig Dermatol ; 15: 2335-2343, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36339944

RESUMO

Purpose: Many patients with axillary osmidrosis (AO) cannot tolerate the local irritation of strong antiperspirants and discontinue AO use within a short time. This study evaluates the effect of long-term antiperspirant use on postoperative complications after osmidrosis surgery. Patients and Methods: A total of 116 females (66 antiperspirant and 50 non-antiperspirant cases) who underwent osmidrosis surgery were retrospectively reviewed. Postoperative complications were compared between the 2 groups. Results: Patients with long-term antiperspirant use had a lower risk of full-thickness skin necrosis compared with those who did not use antiperspirants (odds ratio [OR] = 0.048, 95% confidence Interval [CI]: 0.006-0.392, p = 0.005). Patients with antiperspirants use also had a lower risk of moderate-to-severe erythema compared to those without antiperspirants use (moderate vs mild erythema: OR = 0.351, 95% CI: 0.129-0.959, p = 0.041; severe vs mild erythema: OR = 0.161, 95% CI: 0.047-0.550, p = 0.004). Patients who used antiperspirants also had a lower risk of severe skin erosion compared to those who did not use antiperspirants (severe vs mild skin erosion: OR = 0.164, 95% CI: 0.037-0.725, p = 0.017). There was a trend of lower risk in moderate skin erosion in patients with antiperspirant use compared to those without antiperspirant use, but it was not statistically significant (moderate vs mild epidermal damage and peeling: OR = 0.406, 95% CI: 0.158-1.043, p = 0.061). Conclusion: Postoperative complications in patients with AO who undergo osmidrosis surgery are lower in those with a long-term antiperspirant use compared to patients who did not use antiperspirants.

5.
Mol Cell ; 82(19): 3661-3676.e8, 2022 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-36206740

RESUMO

Mitochondrial Ca2+ uptake, mediated by the mitochondrial Ca2+ uniporter, regulates oxidative phosphorylation, apoptosis, and intracellular Ca2+ signaling. Previous studies suggest that non-neuronal uniporters are exclusively regulated by a MICU1-MICU2 heterodimer. Here, we show that skeletal-muscle and kidney uniporters also complex with a MICU1-MICU1 homodimer and that human/mouse cardiac uniporters are largely devoid of MICUs. Cells employ protein-importation machineries to fine-tune the relative abundance of MICU1 homo- and heterodimers and utilize a conserved MICU intersubunit disulfide to protect properly assembled dimers from proteolysis by YME1L1. Using the MICU1 homodimer or removing MICU1 allows mitochondria to more readily take up Ca2+ so that cells can produce more ATP in response to intracellular Ca2+ transients. However, the trade-off is elevated ROS, impaired basal metabolism, and higher susceptibility to death. These results provide mechanistic insights into how tissues can manipulate mitochondrial Ca2+ uptake properties to support their unique physiological functions.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Cálcio , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Trifosfato de Adenosina , Animais , Cálcio/metabolismo , Canais de Cálcio , Proteínas de Ligação ao Cálcio/genética , Dissulfetos/metabolismo , Humanos , Camundongos , Proteínas de Transporte da Membrana Mitocondrial/genética , Espécies Reativas de Oxigênio/metabolismo
6.
Cancers (Basel) ; 14(6)2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35326662

RESUMO

This study aims to investigate the role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in early prediction of response and survival following epithelial growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy in patients with advanced lung adenocarcinomas and EGFR mutations. Thirty patients with stage IIIB/IV lung adenocarcinomas and EGFR mutations receiving first-line EGFR-TKIs were prospectively evaluated between November 2012 and May 2015. EGFR mutations were quantified by delta cycle threshold (dCt). 18F-FDG PET/CT was performed before and 2 weeks after treatment initiation. PET response was assessed based on PET Response Criteria in Solid Tumors (PERCIST). Baseline and percentage changes in the summed standardized uptake value, metabolic tumor volume (bsumMTV and ΔsumMTV, respectively), and total lesion glycolysis of ≤5 target lesions/patient were calculated. The association between parameters (clinical and PET) and non-progression disease after 3 months of treatment in CT based on the Response Evaluation Criteria in Solid Tumors Version 1.1 (nPD3mo), progression-free survival (PFS), and overall survival (OS) were tested. The median follow-up time was 19.6 months. The median PFS and OS were 12.0 and 25.3 months, respectively. The PERCIST criteria was an independent predictor of nPD3mo (p = 0.009), dCt (p = 0.014) and bsumMTV (p = 0.014) were independent predictors of PFS, and dCt (p = 0.014) and ΔsumMTV (p = 0.005) were independent predictors of OS. 18F-FDG PET/CT achieved early prediction of outcomes in patients with advanced lung adenocarcinomas and EGFR mutations receiving EGFR-TKIs.

7.
Int Wound J ; 19(7): 1829-1837, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35289489

RESUMO

Few studies have assessed the efficacy and safety of reconstruction of sternal infection using a pectoralis muscle flap combined with a rectus abdominis muscle (RAM) sheath fasciocutaneous flap. We report here our experience with this procedure to reconstruct the sternal defect in patients (n = 46) with a deep sternal wound infection (DSWI) after cardiac surgery. After wound reconstruction, the proportion of prolonged mechanical ventilation use and intensive care unit (ICU) stay were 17.4% (n = 8) and 21.7% (n = 10), respectively. The 30-day all-cause mortality was 15.2%; recurrence rate was 17.4%; postoperative complications were 15.2%; and median hospital stay was 31 (0-157) days. Multivariate logistic regression analysis revealed that hypertension (ß = 21.32, 95%CI 4.955-37.68, P = .014), drainage-tube use (ß = 0.944, 95%CI 0.273-1.614, P = .008), and prolonged intensive care unit stay (ß = 53.65, 95%CI 31.353-75.938, P < .001) were significantly correlated with hospital stay. In conclusion, a procedure including surgical debridement, sternal reconstruction with bilateral PM and RAM sheath flap, long-term antibiotics, and adequate drainage is a beneficial technique in the reconstruction of deep sternal wound infection after cardiac surgery. Duration of drainage tube use may be as an index for a hospital stay or wound healing.


Assuntos
Músculos Peitorais , Reto do Abdome , Humanos , Músculos Peitorais/cirurgia , Reto do Abdome/cirurgia , Infecção da Ferida Cirúrgica/etiologia , Infecção da Ferida Cirúrgica/cirurgia , Desbridamento/métodos , Estudos Retrospectivos , Esterno/cirurgia
8.
Ann Plast Surg ; 88(1s Suppl 1): S110-S113, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35225857

RESUMO

ABSTRACT: Kimura disease (KD) is a rare, chronic inflammatory disorder presenting with solitary or multiple masses. Treatment options include surgical excision, corticosteroids, and radiotherapy; however, optimal therapy remains to be established. Moreover, efficacy of a humanized monoclonal antibody, dupilumab (Dupixent), requires to be demonstrated. Here, we present a 36-year-old male patient with an enlarging mass in the left medial thigh and chronic eczema over the abdomen and lower legs. Kimura disease was diagnosed after surgical excision. Postoperative treatment with dupilumab was applied with an initial dose of 600 mg followed by 300 mg every 2 weeks for 8 months. No recurrence of KD was observed in the 1-year follow-up. The eczematous lesions improved greatly. To our knowledge, this is the first report of using dupilumab for treating KD.


Assuntos
Doença de Kimura , Coxa da Perna , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Humanos , Masculino , Coxa da Perna/cirurgia , Resultado do Tratamento
9.
Antioxidants (Basel) ; 10(11)2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34829701

RESUMO

Shikonin mitigated tumor cell proliferation by elevating reactive oxygen species (ROS) levels. Herein, we investigated the effects of shikonin on renal cancer cell (RCC) cell proliferation. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay indicated that shikonin dose-dependently reduced the proliferation of Caki-1 and ACHN cells. Shikonin remarkably triggered necrosis and apoptosis in Caki-1 and ACHN cells in proportion to its concentration. Moreover, necrostatin-1 recovered cell viability in the presence of shikonin. Elevated ROS levels and mitochondrial dysfunction were also found in shikonin treatment groups. Pretreatment with N-acetyl cysteine remarkably mitigated shikonin-induced cell death and ROS generation. Western blot analysis revealed that shikonin reduced pro-PARP, pro-caspase-3, and Bcl-2 expression and increased cleavage PARP expression. Enhanced autophagy was also found in the shikonin-treated group as evidenced by acridine orange staining. Moreover, light chain 3B (LC3B)-II accumulation and enhanced p62 expression indicated that autophagy occurred in the shikonin-treated group. LC3B knockdown considerably recovered cell viability in the presence of shikonin. Shikonin treatment elevated p38 activity in a dose-dependent manner. In conclusion, our results revealed that shikonin triggered programmed cell death via the elevation of ROS level and p38 activity in different types of RCC cells. These findings suggested that shikonin may be a potential anti-RCC agent.

10.
J Am Podiatr Med Assoc ; 111(4)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34478538

RESUMO

Subungual schwannoma is quite rare and often causes nail deformity and difficulty in wearing shoes. Complete tumor excision is the treatment of choice, and we advocate that restoring the nail appearance should be considered at the same time. We present the case of 43-year-old man with a big toe subungual schwannoma. We designed a zigzag incision method to excise the tumor and also corrected nail-bed deformity. The patient had a smooth recovery, and the nail plate regrew with a good appearance.


Assuntos
Hallux , Doenças da Unha , Neurilemoma , Adulto , Humanos , Masculino , Doenças da Unha/cirurgia , Unhas , Neurilemoma/complicações , Neurilemoma/cirurgia , Retalhos Cirúrgicos
11.
Ann Plast Surg ; 86(2S Suppl 1): S123-S126, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33438963

RESUMO

ABSTRACT: The Morel-Lavallée lesion (MLL) is a posttraumatic close degloving injury, which is often underdiagnosed at first. Patients with MLLs usually present with tender and enlarging soft tissue swelling with fluctuation, decreased skin sensation, ecchymosis, or even skin necrosis hours to days after the inciting injury. The lesion can lead to intractable morbidity if it remains untreated. There is no consensus regarding the treatment for MLL at present. Here, we report an MLL in the pretibial region of a 43-year-old woman who experienced a low-energy contusion in a motorbike accident. The pretibial lesion was diagnosed using sonography and fine-needle aspiration. We successfully treated the patient by performing percutaneous debridement via a small incision and injections of fibrin after conservative treatment failed. The method we herein propose achieved the goal of open surgical debridement, providing faster recovery and a high degree of patient comfort. We reviewed the available pertinent literature and propose our own treatment protocol with the aim to establish common therapies ofMLL.


Assuntos
Adesivo Tecidual de Fibrina , Lesões dos Tecidos Moles , Adulto , Desbridamento , Drenagem , Feminino , Humanos , Ultrassonografia
12.
Ann Plast Surg ; 84(1S Suppl 1): S123-S127, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31833899

RESUMO

Injection of fillers has gained popularity over the past decades in aesthetic treatments. Calcium hydroxylapatite (CaHA; Radiesse) was introduced in the year 2003 and received approval from the Food and Drug Administration in 2006 for the treatment of moderate-to-severe wrinkles. The properties of CaHA include biostimulation, neocollagenesis, and stability over a long period. However, similar to other fillers, CaHA is associated with the risk of complications such as ecchymosis, inflammation, local infection, skin necrosis, and vascular occlusion. Iatrogenic vision loss remains the most devastating complication related to vascular occlusion. Development of vision impairment is associated with a relatively high risk of permanent damage to vision acuity and poor prognosis. The current report presents a case of a patient who suffered from skin necrosis, vision impairment, and ophthalmoplegia after the injection of CaHA into the nasal dorsum. Significant improvement in visual acuity was observed during hospitalization after the treatment. The patient recovered to near-normal visual acuity and completely recovered from ophthalmoplegia. We aimed to discuss the current treatment employed and review the literature on CaHA-related vision loss.


Assuntos
Técnicas Cosméticas , Envelhecimento da Pele , Materiais Biocompatíveis , Cálcio , Técnicas Cosméticas/efeitos adversos , Durapatita/efeitos adversos , Humanos , Acuidade Visual
13.
J Gen Physiol ; 146(6): 495-508, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26621774

RESUMO

Members of the CLC family of Cl(-) channels and transporters are homodimeric integral membrane proteins. Two gating mechanisms control the opening and closing of Cl(-) channels in this family: fast gating, which regulates opening and closing of the individual pores in each subunit, and slow (or common) gating, which simultaneously controls gating of both subunits. Here, we found that intracellularly applied Cd(2+) reduces the current of CLC-0 because of its inhibition on the slow gating. We identified CLC-0 residues C229 and H231, located at the intracellular end of the transmembrane domain near the dimer interface, as the Cd(2+)-coordinating residues. The inhibition of the current of CLC-0 by Cd(2+) was greatly enhanced by mutation of I225W and V490W at the dimer interface. Biochemical experiments revealed that formation of a disulfide bond within this Cd(2+)-binding site is also affected by mutation of I225W and V490W, indicating that these two mutations alter the structure of the Cd(2+)-binding site. Kinetic studies showed that Cd(2+) inhibition appears to be state dependent, suggesting that structural rearrangements may occur in the CLC dimer interface during Cd(2+) modulation. Mutations of I290 and I556 of CLC-1, which correspond to I225 and V490 of CLC-0, respectively, have been shown previously to cause malfunction of CLC-1 Cl(-) channel by altering the common gating. Our experimental results suggest that mutations of the corresponding residues in CLC-0 change the subunit interaction and alter the slow gating of CLC-0. The effect of these mutations on modulations of slow gating of CLC channels by intracellular Cd(2+) likely depends on their alteration of subunit interactions.


Assuntos
Cádmio/farmacologia , Canais de Cloreto/metabolismo , Ativação do Canal Iônico/efeitos dos fármacos , Sequência de Aminoácidos , Sítios de Ligação , Canais de Cloreto/química , Canais de Cloreto/genética , Células HEK293 , Humanos , Dados de Sequência Molecular , Mutação , Ligação Proteica
14.
Ann Plast Surg ; 69(6): 622-6, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23154332

RESUMO

INTRODUCTION: Mallet fractures are avulsions of the terminal extensor tendon from the base of the distal phalangeal bone with a bony fragment. Surgical treatment, which provides accurate anatomical reduction and rigid fixation, is recommended for mallet fractures with involvement of more than one third of the base of the distal phalangeal bone. Various surgical methods have been reported, but there is still no standard treatment modality. The purpose of this investigation was to assess the results of our modified tenodesis method for mallet fractures. MATERIALS AND METHODS: Using our method, the dorsal fracture fragment was reduced and fixed to the main part of the distal phalangeal bone by 2 stitches of "figure-of-eight" 4-0 Prolene sutures. We reviewed 12 consecutive patients with 13 mallet fractures treated with our modified tenodesis method between January 2009 and March 2012. This retrospective study was composed of 7 male and 5 female patients, with a mean age of 35.7 years (range, 25-56 years). All patients underwent surgical treatment and sequent 3-week finger splinting. Patient follow-up lasted 3 to 6 months, with a mean period of 5.2 months. RESULTS: The modified tenodesis method allowed accurate anatomical reconstruction of the injured extensor mechanism. Grading by Crawford criteria showed that the outcome was "excellent" in 8 of 13 digits and "good" in 5 of 13 digits. The follow-up hand x-rays also revealed congruent joint surfaces of distal interphalangeal joints with no evidence of joint space narrowing. No wound complications were encountered, and all the patients returned to normal activities without any disability. CONCLUSIONS: The modified tenodesis method is simple and effective to provide accurate anatomical reduction and fixation for treatment of type I mallet fractures. No device penetration of the small bony fragment or pinning through the distal interphalangeal joint is required, and the surgical complication rate is low. We recommend this treatment modality for all but chronic cases.


Assuntos
Traumatismos dos Dedos/cirurgia , Falanges dos Dedos da Mão/lesões , Fraturas Ósseas/cirurgia , Tenodese/métodos , Adulto , Contusões/complicações , Contusões/diagnóstico por imagem , Contusões/cirurgia , Feminino , Traumatismos dos Dedos/diagnóstico por imagem , Falanges dos Dedos da Mão/diagnóstico por imagem , Falanges dos Dedos da Mão/fisiopatologia , Fraturas Ósseas/diagnóstico por imagem , Fraturas Ósseas/etiologia , Deformidades Adquiridas da Mão/diagnóstico por imagem , Deformidades Adquiridas da Mão/etiologia , Deformidades Adquiridas da Mão/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Radiografia , Amplitude de Movimento Articular , Estudos Retrospectivos , Contenções
16.
Pediatr Neonatol ; 53(2): 98-104, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22503256

RESUMO

BACKGROUND: The purpose of this article is to identify the pitfalls of sonography in the diagnosis of liver abscesses, hematomas, and hepatic tumors, which appear similar and therefore are difficult to differentiate from each other. METHODS: Cases were collected at the China Medical University Hospital between January 2008 and January 2010. Liver abscesses were initially diagnosed by sonograph in selected patients who were younger than 18 years. RESULTS: There were 15 patients in whom a liver mass was diagnosed by ultrasound, but 6 of them were excluded from further study because of failure to meet any of the screening criteria. Nine patients with a mean age of 11.3 years (range 5-17 years) were initially suspected to have liver abscesses by ultrasound and were enrolled in the study. These nine patients were identified as follows: five with liver abscess, one with liver hematoma, one with hepatic lymphoma, one with perihepatic abscess, and one with undifferentiated liver sarcoma. Ultrasonography alone was sufficient for diagnosis in five patients. Four patients required abdominal CT scanning to confirm final diagnosis. CONCLUSION: Different liver lesions may present sonographic images similar to those of liver abscesses. Therefore, it is suggested that patients in whom liver abscesses were diagnosed by ultrasound undergo further evaluation if the clinical condition is less likely.


Assuntos
Abscesso Hepático/diagnóstico por imagem , Adolescente , Proteína C-Reativa/análise , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Ultrassonografia
17.
Hu Li Za Zhi ; 58(3 Suppl): 90-6, 2011 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-21678273

RESUMO

This article describes the author's experience caring for a female with breast cancer who was reported dead by her family four years earlier due to a long-term disappearance. She had been transferred multiple times hospital to hospital due to inability to afford medical care. Data were collected via observations, interviews, and physical assessments. The author identified four primary problems, including impaired tissue integrity, pain, being compelled to abandon treatment due to financial status, desire for familial support, and sense of guilt toward her family. The author used Watson's Caring Theory to build trust with the patient and provided guidance on wound treatment, pain relief, and rebuilding family relationships in order to help restore the patient's identity and financial aid. As a result, the patient was able to transfer to a public hospital where she received free medical assistance and regained hope in her therapy. However, the palliative-care coordinator misinterpreted the referral and, as a result, experienced moral distress. After clarifying and explaining the meaning and importance of the patient referral, the coordinator accepted her and continued care. This case report can provide a reference for nurses caring for patients without personal identity or financial aid. Nurses should be aware of the presence of moral distress in other medical team members. Early recognition and timely management of team members' moral distress is fundamental to providing the best quality of care for patients and their families.


Assuntos
Neoplasias da Mama/enfermagem , Neoplasias da Mama/psicologia , Feminino , Humanos , Pessoa de Meia-Idade , Princípios Morais
18.
J Biol Chem ; 285(48): 37663-71, 2010 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-20861014

RESUMO

The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, an ATP binding cassette (ABC) protein whose defects cause the deadly genetic disease cystic fibrosis (CF), encompasses two nucleotide binding domains (NBD1 and NBD2). Recent studies indicate that in the presence of ATP, the two NBDs coalesce into a dimer, trapping an ATP molecule in each of the two interfacial composite ATP binding sites (site 1 and site 2). Experimental evidence also suggests that CFTR gating is mainly controlled by ATP binding and hydrolysis in site 2, whereas site 1, which harbors several non-canonical substitutions in ATP-interacting motifs, is considered degenerated. The CF-associated mutation G551D, by introducing a bulky and negatively charged side chain into site 2, completely abolishes ATP-induced openings of CFTR. Here, we report a strategy to optimize site 1 for ATP binding by converting two amino acid residues to ABC consensus (i.e. H1348G) or more commonly seen residues in other ABC proteins (i.e. W401Y,W401F). Introducing either one or both of these mutations into G551D-CFTR confers ATP responsiveness for this disease-associated mutant channel. We further showed that the same maneuver also improved the function of WT-CFTR and the most common CF-associated ΔF508 channels, both of which rely on site 2 for gating control. Thus, our results demonstrated that the degenerated site 1 can be rebuilt to complement or support site 2 for CFTR function. Possible approaches for developing CFTR potentiators targeting site 1 will be discussed.


Assuntos
Trifosfato de Adenosina/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Fibrose Cística/metabolismo , Mutação de Sentido Incorreto , Motivos de Aminoácidos , Substituição de Aminoácidos , Sítios de Ligação , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/química , Humanos , Ligação Proteica , Estrutura Terciária de Proteína
19.
Am J Med Sci ; 340(5): 350-5, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20724904

RESUMO

INTRODUCTION: Limited data are available on coronary lesion morphology for patients with false-negative radionuclide findings together with typical angina symptoms. METHODS: The study group consisted of 25 subjects with a negative pharmacological thallium (Tl)-201 single-photon emission computed tomography perfusion imaging study but typical angina symptoms and coronary artery disease (CAD) confirmed by coronary angiography. The control group included 690 subjects with a positive pharmacological Tl-201 single-photon emission computed tomography study and CAD. RESULTS: The study group showed a significantly older and higher female ratio than the control group. Significant differences were found between the 2 groups in the presence of current smoking status and hypertension. A noticeably higher percentage of positive metabolic syndrome ratio, number of metabolic syndrome components, high waist-to-hip ratio percentage and high waist circumference percentage in the study group. The study group was noticeably lower in mean numbers of culprit vessel involvement and mean lesion numbers than the control group. There were more individuals with type A classification and a lower proportion of complex stenoses--which contain type B2 and C lesions--in the study group than in the control group. The study group had significantly fewer calcified stenoses and complex morphology stenoses--the latter of which include lesion morphologies with chronic total occlusion, diffuse and calcification--than the control group. CONCLUSIONS: For the high probability of CAD lesions that requires interventional therapy, patients with negative myocardial scintigraphy but typical angina symptoms would be beneficial to intensive medical treatment and coronary study.


Assuntos
Angina Pectoris/diagnóstico por imagem , Doença da Artéria Coronariana/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Coração , Adulto , Idoso , Idoso de 80 Anos ou mais , Angina Pectoris/diagnóstico , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/patologia , Vasos Coronários/patologia , Feminino , Coração/anatomia & histologia , Coração/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Radioisótopos de Tálio , Tomografia Computadorizada de Emissão de Fóton Único
20.
J Gen Physiol ; 135(5): 399-414, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20421370

RESUMO

Cystic fibrosis transmembrane conductance regulator (CFTR), a member of the adenosine triphosphate (ATP) binding cassette (ABC) superfamily, is an ATP-gated chloride channel. Like other ABC proteins, CFTR encompasses two nucleotide binding domains (NBDs), NBD1 and NBD2, each accommodating an ATP binding site. It is generally accepted that CFTR's opening-closing cycles, each completed within 1 s, are driven by rapid ATP binding and hydrolysis events in NBD2. Here, by recording CFTR currents in real time with a ligand exchange protocol, we demonstrated that during many of these gating cycles, NBD1 is constantly occupied by a stably bound ATP or 8-N(3)-ATP molecule for tens of seconds. We provided evidence that this tightly bound ATP or 8-N(3)-ATP also interacts with residues in the signature sequence of NBD2, a telltale sign for an event occurring at the NBD1-NBD2 interface. The open state of CFTR has been shown to represent a two-ATP-bound NBD dimer. Our results indicate that upon ATP hydrolysis in NBD2, the channel closes into a "partial NBD dimer" state where the NBD interface remains partially closed, preventing ATP dissociation from NBD1 but allowing the release of hydrolytic products and binding of the next ATP to occur in NBD2. Opening and closing of CFTR can then be coupled to the formation and "partial" separation of the NBD dimer. The tightly bound ATP molecule in NBD1 can occasionally dissociate from the partial dimer state, resulting in a nucleotide-free monomeric state of NBDs. Our data, together with other structural/functional studies of CFTR's NBDs, suggest that this process is poorly reversible, implying that the channel in the partial dimer state or monomeric state enters the open state through different pathways. We therefore proposed a gating model for CFTR with two distinct cycles. The structural and functional significance of our results to other ABC proteins is discussed.


Assuntos
Transportadores de Cassetes de Ligação de ATP/fisiologia , Trifosfato de Adenosina/fisiologia , Regulador de Condutância Transmembrana em Fibrose Cística/fisiologia , Modelos Moleculares , Transportadores de Cassetes de Ligação de ATP/química , Trifosfato de Adenosina/química , Animais , Células CHO , Membrana Celular/fisiologia , Células Cultivadas , Cricetinae , Cricetulus , Regulador de Condutância Transmembrana em Fibrose Cística/química , Fenômenos Eletrofisiológicos , Feminino , Ativação do Canal Iônico/fisiologia , Nucleotídeos/fisiologia , Ovário/citologia , Técnicas de Patch-Clamp
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