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1.
Mol Cell ; 81(19): 3904-3918.e6, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34375581

RESUMO

Polyamines, small organic polycations, are essential for cell viability, and their physiological levels are homeostatically maintained by post-transcriptional regulation of key biosynthetic enzymes. In addition to de novo synthesis, cells can also take up polyamines; however, identifying cellular polyamine transporters has been challenging. Here we show that the S. cerevisiae HOL1 mRNA is under translational control by polyamines, and we reveal that the encoded membrane transporter Hol1 is a high-affinity polyamine transporter and is required for yeast growth under limiting polyamine conditions. Moreover, we show that polyamine inhibition of the translation factor eIF5A impairs translation termination at a Pro-Ser-stop motif in a conserved upstream open reading frame on the HOL1 mRNA to repress Hol1 synthesis under conditions of elevated polyamines. Our findings reveal that polyamine transport, like polyamine biosynthesis, is under translational autoregulation by polyamines in yeast, highlighting the extensive control cells impose on polyamine levels.


Assuntos
Proteínas de Transporte de Cátions/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Poliaminas/metabolismo , Biossíntese de Proteínas , Ribossomos/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Transporte Biológico , Proteínas de Transporte de Cátions/genética , Regulação Fúngica da Expressão Gênica , Proteínas de Membrana Transportadoras/genética , Fases de Leitura Aberta , Fatores de Iniciação de Peptídeos/genética , Fatores de Iniciação de Peptídeos/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Ribossomos/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Proteínas de Saccharomyces cerevisiae/genética , Fator de Iniciação de Tradução Eucariótico 5A
2.
Spinal Cord ; 60(8): 694-700, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35110695

RESUMO

STUDY DESIGN: Non-randomized crossover trial. OBJECTIVES: The objective of this study was to assess the oxygen uptake during exercise using the Adapted ROWing machine (AROW) compared to the more commonly used Arm Crank Ergometry (ACE) for people with spinal cord injury/disease (SCI/D) with or without trunk stability. SETTING: Canada, Vancouver. METHODS: Participants were from a convenience sample of 14 adults with SCI/D (age 21-63 y) which include those with lumbar to low cervical impairments currently exercising at least once per week using cardiovascular exercise equipment at our Physical Activity Research Centre. The interventions were non-randomized steady-state exercise bouts at self-selected low and moderate workloads on the AROW and ACE for 5 min each. Our primary outcomes were the rate of oxygen consumption (mL/kg/min) and the Borg 0-10 Rating Scale of Perceived Exertion (RPE). RESULTS: A repeated measures two-way ANOVA (p < 0.05) indicated that exercising on the AROW resulted significantly greater oxygen consumption and perceived exertion than ACE at similar sub-maximal workloads which may be explained by the differences in efficiency between the devices (Partial eta squared = 0.84, F stat = 48.25; Partial eta squared = 0.86, F stat = 53.54). CONCLUSIONS: We have demonstrated that this form of upper extremity exercise had a greater RPE and VO2 on the ACE at a given workload. Thus, the AROW could provide a functional upper extremity workout that can be used for daily exercise for those with varying levels of SCI.


Assuntos
Exercício Físico , Traumatismos da Medula Espinal , Adulto , Braço/fisiologia , Ergometria , Exercício Físico/fisiologia , Teste de Esforço/métodos , Humanos , Pessoa de Meia-Idade , Consumo de Oxigênio/fisiologia , Traumatismos da Medula Espinal/terapia , Esportes Aquáticos/fisiologia , Adulto Jovem
3.
Sensors (Basel) ; 22(4)2022 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-35214452

RESUMO

With the ever-increasing popularity of wearable devices, data on the time and location of popular walking, running, and bicycling routes is expansive and growing rapidly. These data are currently used primarily for route discovery and mobile context awareness, as it provides precise and updated information about urban dynamics. We leverage these data to build ad hoc transportation flows, and we present a novel model that creates delivery networks from these zero-emission transportation flows. We evaluate the model using data from two popular datasets, and our results indicate that such networks are indeed possible, and can help reduce traffic, emissions, and delivery times. Moreover, we demonstrate how our results can be consistently reproduced in different cities with different subsets of carriers. We then extend our work into predicting routes of vehicles, hence possible delivery flows, based on the traces history. We conclude this paper by laying the groundwork for a future real-world study.


Assuntos
Crowdsourcing , Ciclismo , Cidades , Meios de Transporte/métodos , Caminhada
5.
Am J Physiol Regul Integr Comp Physiol ; 310(6): R493-501, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26719305

RESUMO

This study examines how chronically hyperglycemic rainbow trout modulate glucose kinetics in response to graded exercise up to critical swimming speed (Ucrit), with or without exogenous glucose supply. Our goals were 1) to quantify the rates of hepatic glucose production (Ra glucose) and disposal (Rd glucose) during graded swimming, 2) to determine how exogenous glucose affects the changes in glucose fluxes caused by exercise, and 3) to establish whether exogenous glucose modifies Ucrit or the cost of transport. Results show that graded swimming causes no change in Ra and Rd glucose at speeds below 2.5 body lengths per second (BL/s), but that glucose fluxes may be stimulated at the highest speeds. Excellent glucoregulation is also achieved at all exercise intensities. When exogenous glucose is supplied during exercise, trout suppress hepatic production from 16.4 ± 1.6 to 4.1 ± 1.7 µmol·kg(-1)·min(-1) and boost glucose disposal to 40.1 ± 13 µmol·kg(-1)·min(-1). These responses limit the effects of exogenous glucose to a 2.5-fold increase in glycemia, whereas fish showing no modulation of fluxes would reach dangerous levels of 114 mM of blood glucose. Exogenous glucose reduces metabolic rate by 16% and, therefore, causes total cost of transport to decrease accordingly. High glucose availability does not improve Ucrit because the fish are unable to take advantage of this extra fuel during maximal exercise and rely on tissue glycogen instead. In conclusion, trout have a remarkable ability to adjust glucose fluxes that allows them to cope with the cumulative stresses of a glucose overload and graded exercise.


Assuntos
Glucose/farmacocinética , Glucose/toxicidade , Oncorhynchus mykiss , Esforço Físico , Natação , Animais , Glicemia/metabolismo , Metabolismo dos Carboidratos/efeitos dos fármacos , Feminino , Glucagon/sangue , Glucose/biossíntese , Glicogênio/metabolismo , Hiperglicemia/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Oxirredução , Consumo de Oxigênio/efeitos dos fármacos
6.
J Exp Biol ; 219(Pt 2): 250-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26792337

RESUMO

Muscle performance depends on the supply of metabolic fuels and disposal of end-products. Using circulating metabolite concentrations to infer changes in fluxes is highly unreliable because the relationship between these parameters varies greatly with physiological state. Quantifying fuel kinetics directly is therefore crucial to the understanding of muscle metabolism. This review focuses on how carbohydrates, lipids and amino acids are provided to fish muscles during hypoxia and swimming. Both stresses force white muscle to produce lactate at higher rates than it can be processed by aerobic tissues. However, lactate accumulation is minimized because disposal is also strongly stimulated. Exogenous supply shows that trout have a much higher capacity to metabolize lactate than observed during hypoxia or intense swimming. The low density of monocarboxylate transporters and their lack of upregulation with exercise explain the phenomenon of white muscle lactate retention. This tissue operates as a quasi-closed system, where glycogen stores act as an 'energy spring' that alternates between explosive power release during swimming and slow recoil from lactate in situ during recovery. To cope with exogenous glucose, trout can completely suppress hepatic production and boost glucose disposal. Without these responses, glycemia would increase four times faster and reach dangerous levels. The capacity of salmonids for glucoregulation is therefore much better than presently described in the literature. Instead of albumin-bound fatty acids, fish use lipoproteins to shuttle energy from adipose tissue to working muscles during prolonged exercise. Proteins may play an important role in fueling muscle work in fish, but their exact contribution is yet to be established. The membrane pacemaker theory of metabolism accurately predicts general properties of muscle membranes such as unsaturation, but it does not explain allometric patterns of specific fatty acids. Investigations of metabolic fuel kinetics carried out in fish to date have demonstrated that these ectotherms use several unique strategies to orchestrate energy supply to working muscles and to survive hypoxia.


Assuntos
Metabolismo Energético/fisiologia , Peixes/metabolismo , Hipóxia/fisiopatologia , Músculos/fisiopatologia , Natação/fisiologia , Animais , Cinética , Membranas
7.
J Exp Biol ; 218(Pt 18): 2873-80, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26232417

RESUMO

Rainbow trout are generally considered to be poor glucoregulators. To evaluate this, exogenous glucose was administered to chronically hyperglycemic fish at twice the endogenous rate of hepatic production, and their ability to modulate glucose fluxes was tested. Our goals were to determine: (1) whether hyperglycemic fish maintain higher glucose fluxes than normal; (2) whether they can lower hepatic production (Ra glucose) or stimulate disposal (Rd glucose) to cope with a carbohydrate overload; and (3) an estimate of the relative importance of glucose as an oxidative fuel. Results show that hyperglycemic trout sustain elevated baseline Ra and Rd glucose of 10.6 ± 0.1 µmol kg(-1) min(-1) (or 30% above normal). If 50% of Rd glucose was oxidized as in mammals, glucose could account for 36 to 100% of metabolic rate when exogenous glucose is supplied. In response to exogenous glucose, rainbow trout can completely suppress hepatic glucose production and increase disposal 2.6-fold, even with chronically elevated baseline fluxes. Such large changes in fluxes limit the increase in blood glucose to 2.5-fold and are probably mediated by the effects of insulin on glucose transporters 2 and 4 and on key enzymes of carbohydrate metabolism. Without this strong and rapid modulation of glucose kinetics, glycemia would rise four times faster to reach dangerous levels, exceeding 100 mmol l(-1). Such responses are typical of mammals, but rather unexpected for an ectotherm. The impressive plasticity of glucose kinetics demonstrated here suggests that trout have a much better glucoregulatory capacity than is usually portrayed in the literature.


Assuntos
Metabolismo dos Carboidratos , Glucose/metabolismo , Oncorhynchus mykiss/metabolismo , Animais , Glicemia/análise , Gorduras na Dieta , Glucose/administração & dosagem , Fígado/metabolismo
8.
Endosc Int Open ; 11(1): E24-E31, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36618873

RESUMO

Background and study aims The increase in hepaticojejunostomies has led to an increase in benign strictures of the anastomosis. Double balloon enteroscopy-assisted ERCP (DBE-ERCP) and percutaneous transhepatic biliary drainage (PTBD) are treatment options; however, there is lack of long-term outcomes, with no consensus on management. We performed a retrospective study assessing the outcomes of patients referred for endoscopic management of hepaticojejunostomy anastomotic strictures (HJAS). Patients and methods All consecutive patients at a tertiary institution underwent endoscopic intervention for suspected HJAS between 2009 and 2021 were enrolled. Results Eighty-two subjects underwent DBE-ERCP for suspected HJAS. The technical success rate was 77 % (63/82). HJAS was confirmed in 41 patients. The clinical success rate for DBE-ERCP ± PTBD was 71 % (29/41). DBE-ERCP alone achieved clinical success in 49 % of patients (20/41). PTBD was required in 49 % (20/41). Dual therapy was required in 22 % (9/41). Those with liver transplant had less technical success compared to other surgeries (72.1 % vs 82.1 % P  = 0.29), less clinical success with DBE-ERCP alone (40 % vs 62.5 % P  = 0.16) and required more PTBD (56 % vs 37.5 % P  = 0.25). All those with ischemic biliopathy (n = 9) required PTBD for clinical success, required more DBE-ERCP (4.4 vs 2.0, P = 0.004), more PTBD (4.7 vs 0.3, P  < 0.0001), longer treatment duration (181.6 vs 99.5 days P  = 0.12), and had higher rates of recurrence (55.6 % vs 30.3 % P  = 0.18) compared to those with HJAS alone. Liver transplant was the leading cause of ischemic biliopathy (89 %). The overall adverse event rate was 7 %. Conclusions DBE-ERCP is an effective diagnostic and therapeutic tool in those with altered gastrointestinal anatomy and is associated with low complication rates.

9.
J Biol Chem ; 286(11): 8819-28, 2011 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-21212272

RESUMO

Myosin VIIa is crucial in hearing and visual processes. We examined the kinetic and association properties of the baculovirus expressed, truncated mouse myosin VIIa construct containing the head, all 5IQ motifs and the putative coiled coil domain (myosin VIIa-5IQ). The construct appears to be monomeric as determined by analytical ultracentrifugation experiments, and only single headed molecules were detected by negative stain electron microscopy. The relatively high basal steady-state rate of 0.18 s(-1) is activated by actin only by ∼3.5-fold resulting in a V(max) of 0.7 s(-1) and a K(ATPase) of 11.5 µM. There is no single rate-limiting step of the ATP hydrolysis cycle. The ATP hydrolysis step (M·T M·D·P) is slow (12 s(-1)) and the equilibrium constant (K(H)) of 1 suggests significant reversal of hydrolysis. In the presence of actin ADP dissociates with a rate constant of 1.2 s(-1). Phosphate dissociation is relatively fast (>12 s(-1)), but the maximal rate could not be experimentally obtained at actin concentrations ≤ 50 µM because of the weak binding of the myosin VIIa-ADP-P(i) complex to actin. At higher actin concentrations the rate of attached hydrolysis (0.4 s(-1)) becomes significant and partially rate-limiting. Our findings suggest that the myosin VIIa is a "slow", monomeric molecular motor with a duty ratio of 0.6.


Assuntos
Trifosfato de Adenosina/química , Miosinas/química , Trifosfato de Adenosina/genética , Trifosfato de Adenosina/metabolismo , Motivos de Aminoácidos , Animais , Cinética , Camundongos , Miosina VIIa , Miosinas/genética , Miosinas/metabolismo , Estrutura Terciária de Proteína
10.
World J Gastrointest Oncol ; 14(3): 568-586, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35321279

RESUMO

Barrett's esophagus (BE) is the precursor to esophageal adenocarcinoma (EAC). Progression to cancer typically occurs in a stepwise fashion through worsening dysplasia and ultimately, invasive neoplasia. Established EAC with deep involvement of the esophageal wall and/or metastatic disease is invariably associated with poor long-term survival rates. This guides the rationale of surveillance of Barrett's in an attempt to treat lesions at an earlier, and potentially curative stage. The last two decades have seen a paradigm shift in management of Barrett's with rapid expansion in the role of endoscopic eradication therapy (EET) for management of dysplastic and early neoplastic BE, and there have been substantial changes to international consensus guidelines for management of early BE based on evolving evidence. This review aims to assist the physician in the therapeutic decision-making process with patients by comprehensive review and summary of literature surrounding natural history of Barrett's by histological stage, and the effectiveness of interventions in attenuating the risk posed by its natural history. Key findings were as follows. Non-dysplastic Barrett's is associated with extremely low risk of progression, and interventions cannot be justified. The annual risk of cancer progression in low grade dysplasia is between 1%-3%; EET can be offered though evidence for its benefit remains confined to highly select settings. High-grade dysplasia progresses to cancer in 5%-10% per year; EET is similarly effective to and less morbid than surgery and should be routinely performed for this indication. Risk of nodal metastases in intramucosal cancer is 2%-4%, which is comparable to operative mortality rate, so EET is usually preferred. Submucosal cancer is associated with nodal metastases in 14%-41% hence surgery remains standard of care, except for select situations.

11.
Ther Adv Gastrointest Endosc ; 15: 26317745221076705, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35252863

RESUMO

Acute gastrointestinal perforations occur either from spontaneous or iatrogenic causes. However, particular attention should be made in acute iatrogenic perforations as timely diagnosis and endoscopic closure prevent morbidity and mortality. With the increasing use of diagnostic endoscopy and advances in therapeutic endoscopy worldwide, the endoscopist must be able to recognize and manage perforations. Depending on the size and location of the defect, a variety of endoscopic clips, stents, and suturing devices are available. This review aims to prepare and guide the endoscopist to use the right tools and techniques for optimal patient outcomes.

12.
JGH Open ; 5(7): 834-836, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34263082

RESUMO

We describe an unusual endoscopic finding, caused by a dominant ovarian follicle compressing a low-lying ascending colon just inferior to a patulous retroverted cecum. Endoscopically detected extra-colonic lesions represent a diverse group of pathologies, and it is important the endoscopist has an appreciation of the varied number of benign and malignant causes-including those of gynecological origin.

13.
JMIR Rehabil Assist Technol ; 8(3): e19946, 2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34254945

RESUMO

BACKGROUND: A tele-rehabilitation platform was developed to improve access to ambulatory rehabilitation services in Hong Kong. The development was completed in October 2019 and rolled out for use to occupational therapists, physiotherapists, and speech therapists. During the COVID-19 pandemic, rehabilitation services were severely interrupted. Tele-rehabilitation was used extensively to meet the demand for rehabilitation service delivery. OBJECTIVE: The aims of this study were to (1) describe the design and development process of a tele-rehabilitation service, and (2) study how the tele-rehabilitation platform was used to overcome the disruption of rehabilitation service during the COVID-19 pandemic. METHODS: Tele-rehabilitation was developed utilizing 4 core determinants of Unified Theory of Acceptance and Use of Technology as guiding principles. A generic prescription platform, called the activity-based prescription system, and a mobile app, called the Rehabilitation App, were built. Five outcomes were used to examine the utilization of tele-rehabilitation both before and during the pandemic: throughput, patient demographic, patient conditions, workforce, and satisfaction from patients and staff. RESULTS: There was a tremendous increase in the use of tele-rehabilitation during pandemic. The total number of patients (up until July 2020) was 9101, and the main age range was between 51 to 70 years old. Tele-rehabilitation was used for a much wider scope of patient conditions than originally planned. More than 1112 therapists, which constituted 50.6% of the total workforce (1112/2196), prescribed tele-rehabilitation to their patients. Moreover, there was a high satisfaction rate from patients, with a mean rating of 4.2 out of 5, and a high adherence rate to prescribed rehabilitation activities (107840/131995, 81.7%). CONCLUSIONS: The findings of our study suggested that tele-rehabilitation in the form of a generic prescription platform and mobile app can be an effective means to provide rehabilitation to patient. During the COVID-19 pandemic, tele-rehabilitation has been used extensively and effectively to mitigate service disruption. Our findings also provide support that there is a high level of satisfaction with tele-rehabilitation; however, a longer duration study is required to demonstrate the sustained use of tele-rehabilitation, especially after the pandemic.

14.
PLoS One ; 16(6): e0237055, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34166368

RESUMO

A key aspect in defining cell state is the complex choreography of DNA binding events in a given cell type, which in turn establishes a cell-specific gene-expression program. Here we wanted to take a deep analysis of DNA binding events and transcriptional output of a single cell state (K562 cells). To this end we re-analyzed 195 DNA binding proteins contained in ENCODE data. We used standardized analysis pipelines, containerization, and literate programming with R Markdown for reproducibility and rigor. Our approach validated many findings from previous independent studies, underscoring the importance of ENCODE's goals in providing these reproducible data resources. We also had several new findings including: (i) 1,362 promoters, which we refer to as 'reservoirs,' that are defined by having up to 111 different DNA binding-proteins localized on one promoter, yet do not have any expression of steady-state RNA (ii) Reservoirs do not overlap super-enhancer annotations and distinct have distinct properties from super-enhancers. (iii) The human specific SVA repeat element may have been co-opted for enhancer regulation and is highly transcribed in PRO-seq and RNA-seq. Collectively, this study performed by the students of a CU Boulder computational biology class (BCHM 5631 -Spring 2020) demonstrates the value of reproducible findings and how resources like ENCODE that prioritize data standards can foster new findings with existing data in a didactic environment.


Assuntos
Biologia Computacional/métodos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Genoma Humano , Regiões Promotoras Genéticas , Sequências Repetitivas de Ácido Nucleico , Humanos , Células K562 , Reprodutibilidade dos Testes
15.
Artigo em Inglês | MEDLINE | ID: mdl-31465877

RESUMO

Hypoxia-tolerant animals use metabolic suppression as an essential strategy to survive low oxygen. Ectotherms can alter membrane lipid composition in response to changes in environmental temperature, but it is currently unknown whether chronic hypoxia can also elicit membrane restructuring. The goal of this study was to investigate a possible physiological link between membrane remodelling and metabolic suppression in goldfish exposed to prolonged hypoxia (4 weeks at 10% air saturation). We have tested the hypothesis that chronic hypoxia would modulate membrane lipid composition in ways that are consistent with known mechanisms of ion pump inhibition. Because homeoviscous membrane restructuring could interfere with the response to hypoxia, measurements were made at 2 temperatures. Results show that hypoxic goldfish suppress metabolic rate by 74% (at 13 °C) and 63% (at 20 °C). This study is the first to reveal that cold-acclimated animals undergo extensive, tissue-specific restructuring of membrane lipids as they reach minimal metabolic rates. However, hypoxia does not affect membrane composition in fish acclimated to 20 °C. The strong membrane response of cold-acclimated fish involves increases in cholesterol abundance (in white muscle and gills) and in fatty acid saturation, mainly caused by a reduction in %22:6 (docosahexaenoic acid in gills and liver). Major ion pumps like Na+/K+-ATPase are known to be inhibited by cholesterol and activated by 22:6. Because ion pumping by membrane-bound ATPases accounts for a large fraction of basal cellular energy use, we propose that the membrane responses reported here could be a novel mechanism to promote metabolic suppression in cold-acclimated animals.


Assuntos
Ácidos Graxos/metabolismo , Hipóxia/metabolismo , Animais , Colesterol/metabolismo , Carpa Dourada , Temperatura
16.
J Neurol Surg B Skull Base ; 80(5): 500-504, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31534892

RESUMO

Objective This study describes the safety and efficacy of mometasone furoate eluting stents in the management of petrous apex cholesterol granuloma approached through an endonasal endoscopic route and assesses the restenosis rate. Methods Consecutive patients undergoing endoscopic endonasal marsupialization of a petrous apex cholesterol granuloma at a tertiary referral center who had a mometasone furoate eluting stent placed intraoperatively were reviewed in a retrospective fashion. Postoperative endoscopy was used to determine success of surgery and stenting. Results Five patients were included in the study, three were primary cases and two patients had revision surgeries performed. The steroid eluting stent was placed successfully and safely in all patients with no dural or vascular injuries. The average follow-up duration was 10.6 months. There was no restenosis in three patients and one patient had an immediate restenosis that was debrided in clinic (revision case). This was patent at the 16 months follow-up. One patient also developed stenosis, 4 months after surgery due to sphenoid sinusitis. Conclusion Mometasone furoate eluting stents are safe and effective in the primary management of petrous apex cholesterol granuloma. Further studies are needed to assess their efficacy in revision cases and for long term results.

17.
J Neurol Surg B Skull Base ; 80(4): 416-423, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31316887

RESUMO

Introduction Endoscopic endonasal skull base surgery (EESBS) leads to significant alterations in sinonasal anatomy and physiology. However, there is limited data available on quality of life (QOL) outcomes following EESBS. Methods A retrospective review of patients undergoing EESBS from January 2014 to April 2017 was performed. Records were reviewed for clinical history, operative details, and 22-item Sinonasal Outcomes Test (SNOT-22) scores. Unadjusted and adjusted linear regression models were utilized to compare change in SNOT-22 scores from baseline in patients who underwent a simple sella approach (SA) or an extended beyond sella approach (BSA). Results A total of 108 patients were in the SA group, while 61 patients were in the BSA group. SNOT-22 scores were available at baseline and 3 months for 84 patients, while 6-month scores were available for 49 patients. SNOT-22 scores for all patients were not significantly different at 3 months ( p = 0.40) or at 6 months ( p = 0.58). Unadjusted linear regression model did not show an association between the type of approach and change in SNOT-22 score at 3 months ( p = 0.07) and 6 months ( p = 0.28). Adjusted regression model showed a significant decrease in SNOT-22 scores at 3 months ( p = 0.04) for the BSA group, but there was no significant change in SNOT-22 score at 6 months ( p = 0.22). Conclusion Patients undergoing EESBS had no significant change in outcomes at 3 and 6 months. A more extensive BSA was not associated with worse QOL outcomes as measured by SNOT-22.

18.
Pigment Cell Melanoma Res ; 32(2): 259-268, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30117292

RESUMO

Coinheritance of germline mutation in cyclin-dependent kinase inhibitor 2A (CDKN2A) and loss-of-function (LOF) melanocortin 1 receptor (MC1R) variants is clinically associated with exaggerated risk for melanoma. To understand the combined impact of these mutations, we established and tested primary human melanocyte cultures from different CDKN2A mutation carriers, expressing either wild-type MC1R or MC1RLOF variant(s). These cultures expressed the CDKN2A product p16 (INK4A) and functional MC1R. Except for 32ins24 mutant melanocytes, the remaining cultures showed no detectable aberrations in proliferation or capacity for replicative senescence. Additionally, the latter cultures responded normally to ultraviolet radiation (UV) by cell cycle arrest, JNK, p38, and p53 activation, hydrogen peroxide generation, and repair of DNA photoproducts. We propose that malignant transformation of melanocytes expressing CDKN2A mutation and MC1RLOF allele(s) requires acquisition of somatic mutations facilitated by MC1R genotype or aberrant microenvironment due to CDKN2A mutation in keratinocytes and fibroblasts.


Assuntos
Predisposição Genética para Doença , Melanócitos/metabolismo , Melanócitos/efeitos da radiação , Mutação/genética , Receptor Tipo 1 de Melanocortina/genética , Raios Ultravioleta , Adolescente , Adulto , Animais , Células Cultivadas , Senescência Celular/genética , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Dano ao DNA , Feminino , Heterozigoto , Humanos , Masculino , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Fosforilação/efeitos da radiação , Receptor Tipo 1 de Melanocortina/metabolismo , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Adulto Jovem , beta-Galactosidase/metabolismo
19.
Elife ; 72018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29697373

RESUMO

Cortical capillaries are prone to obstruction, which over time, could have a major impact on brain angioarchitecture and function. The mechanisms that govern the removal of these obstructions and what long-term fate awaits obstructed capillaries, remains a mystery. We estimate that ~0.12% of mouse cortical capillaries are obstructed each day (lasting >20 min), preferentially in superficial layers and lower order branches. Tracking natural or microsphere-induced obstructions revealed that 75-80% of capillaries recanalized within 24 hr. Remarkably, 30% of all obstructed capillaries were pruned by 21 days, including some that had regained flow. Pruning involved regression of endothelial cells, which was not compensated for by sprouting. Using this information, we predicted capillary loss with aging that closely matched experimental estimates. Genetic knockdown or inhibition of VEGF-R2 signaling was a critical factor in promoting capillary recanalization and minimizing subsequent pruning. Our studies reveal the incidence, mechanism and long-term outcome of capillary obstructions which can also explain age-related capillary rarefaction.


Assuntos
Capilares/fisiologia , Córtex Cerebral/fisiologia , Células Endoteliais/fisiologia , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Camundongos , Modelos Biológicos
20.
Ann Otol Rhinol Laryngol ; 127(4): 270-274, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29478327

RESUMO

OBJECTIVE: To assess the imaging findings of computed topography (CT) and magnetic resonance imaging (MRI) in adults with postlingual deafness and otherwise normal clinical history and physical exam. Additionally, determine the influence and implications of these findings with respect to surgical outcomes and cost. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral hospital. PATIENTS: Adults with postlingual deafness with no history of prior ear surgery, chronic ear disease, meningitis, otosclerosis, or head trauma. INTERVENTIONS: Cochlear implantation of 1 or both ears, with preoperative CT, MRI, or both. MAIN OUTCOME MEASURES: Imaging results were classified as normal, abnormal affecting surgery, incidental requiring follow-up, or incidental not requiring follow-up. Average cost of each imaging modality was determined. RESULTS: A total of 128 patients met the inclusion criteria. Of these, 82 (64.1%) had both CT and MRI performed, 33 (25.8%) had CT, and 13 (10.2%) had MRI prior to cochlear implant (CI). Scans were normal in 125 (97.7%) of cases. Of the remaining 3 (2.3%) patients, there were incidental findings requiring follow-up. All implants were placed successfully, and in no instance did the results of the scan influence the surgery. The average cost of imaging per patient was $4707. CONCLUSION: In adults with postlingual deafness with an otherwise benign clinical history, CT and MRI are unlikely to affect or preclude surgery. With new MRI safe cochlear implants, imaging can be performed safely postoperatively if needed.


Assuntos
Implante Coclear , Surdez/cirurgia , Adulto , Implante Coclear/efeitos adversos , Implante Coclear/métodos , Análise Custo-Benefício , Surdez/diagnóstico , Surdez/etiologia , Feminino , Humanos , Imageamento por Ressonância Magnética/economia , Imageamento por Ressonância Magnética/métodos , Masculino , Avaliação de Processos e Resultados em Cuidados de Saúde , Cuidados Pré-Operatórios/economia , Cuidados Pré-Operatórios/métodos , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/economia , Tomografia Computadorizada por Raios X/métodos , Estados Unidos
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