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1.
Clin Cancer Res ; 29(20): 4196-4208, 2023 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-37556118

RESUMO

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is an aggressive tumor with low response rates to frontline PD-1 blockade. Natural killer (NK) cells are a promising cellular therapy for T cell therapy-refractory cancers, but are frequently dysfunctional in patients with HNSCC. Strategies are needed to enhance NK cell responses against HNSCC. We hypothesized that memory-like (ML) NK cell differentiation, tumor targeting with cetuximab, and engineering with an anti-EphA2 (Erythropoietin-producing hepatocellular receptor A2) chimeric antigen receptor (CAR) enhance NK cell responses against HNSCC. EXPERIMENTAL DESIGN: We generated ML NK and conventional (c)NK cells from healthy donors, then evaluated their ability to produce IFNγ, TNF, degranulate, and kill HNSCC cell lines and primary HNSCC cells, alone or in combination with cetuximab, in vitro and in vivo using xenograft models. ML and cNK cells were engineered to express anti-EphA2 CAR-CD8A-41BB-CD3z, and functional responses were assessed in vitro against HNSCC cell lines and primary HNSCC tumor cells. RESULTS: Human ML NK cells displayed enhanced IFNγ and TNF production and both short- and long-term killing of HNSCC cell lines and primary targets, compared with cNK cells. These enhanced responses were further improved by cetuximab. Compared with controls, ML NK cells expressing anti-EphA2 CAR had increased IFNγ and cytotoxicity in response to EphA2+ cell lines and primary HNSCC targets. CONCLUSIONS: These preclinical findings demonstrate that ML differentiation alone or coupled with either cetuximab-directed targeting or EphA2 CAR engineering were effective against HNSCCs and provide the rationale for investigating these combination approaches in early phase clinical trials for patients with HNSCC.


Assuntos
Neoplasias de Cabeça e Pescoço , Receptores de Antígenos Quiméricos , Humanos , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Linhagem Celular Tumoral , Células Matadoras Naturais , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Anticorpos Monoclonais/metabolismo , Diferenciação Celular
2.
J Clin Invest ; 133(13)2023 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-37279078

RESUMO

Since the T-box transcription factors (TFs) T-BET and EOMES are necessary for initiation of NK cell development, their ongoing requirement for mature NK cell homeostasis, function, and molecular programming remains unclear. To address this, T-BET and EOMES were deleted in unexpanded primary human NK cells using CRISPR/Cas9. Deleting these TFs compromised in vivo antitumor response of human NK cells. Mechanistically, T-BET and EOMES were required for normal NK cell proliferation and persistence in vivo. NK cells lacking T-BET and EOMES also exhibited defective responses to cytokine stimulation. Single-cell RNA-Seq revealed a specific T-box transcriptional program in human NK cells, which was rapidly lost following T-BET and EOMES deletion. Further, T-BET- and EOMES-deleted CD56bright NK cells acquired an innate lymphoid cell precursor-like (ILCP-like) profile with increased expression of the ILC-3-associated TFs RORC and AHR, revealing a role for T-box TFs in maintaining mature NK cell phenotypes and an unexpected role of suppressing alternative ILC lineages. Our study reveals the critical importance of sustained EOMES and T-BET expression to orchestrate mature NK cell function and identity.


Assuntos
Imunidade Inata , Proteínas com Domínio T , Humanos , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Células Matadoras Naturais/metabolismo , Fatores de Transcrição/metabolismo , Citocinas/metabolismo
3.
J Robot Surg ; 17(5): 2331-2338, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37378796

RESUMO

There is increasing demand for colorectal robotic training for general surgery residents. We implemented a robotic colorectal surgery curriculum expecting that it would increase resident exposure to the robotic platform and would increase the number of graduating general surgery residents obtaining a robotic equivalency certificate. The aim of this study is to describe the components of the curriculum and characterize the immediate impact of the implementation or residents. Our curriculum started in 2019 and consists of didactics, simulation, and clinical performance. Objectives are specified for both junior residents (post-graduate years [PGY]1-2) and senior residents (PGY3-5). The robotic colorectal surgical experience was characterized by comparing robotic to non-robotic operations, differences in robotic operations across post-graduate year, and percentage of graduates achieving an equivalency certificate. Robotic operations are tracked using case log annotation. From 2017 to 2021, 25 residents logged 681 major operations on the colorectal service (PGY1 mean = 7.6 ± 4.6, PGY4 mean = 29.7 ± 14.4, PGY5 mean = 29.8 ± 14.8). Robotic colorectal operations made up 24% of PGY1 (49% laparoscopic, 27% open), 35% of PGY4 (35% laparoscopic, 29% open), and 41% of PGY5 (44% laparoscopic, 15% open) major colorectal operations. Robotic bedside experience is primarily during PGY1 (PGY1 mean 2.0 ± 2.0 bedside operations vs 1.4 ± 1.6 and 0.2 ± 0.4 for PGY4 and 5, respectively). Most PGY4 and 5 robotic experience is on the console (PGY4 mean 9.1 ± 7.7 console operations, PGY5 mean 12.0 ± 4.8 console operations). Rates of robotic certification for graduating chief residents increased from 0% for E-2013 to 100% for E-2018. Our robotic colorectal curriculum for general surgery residents has facilitated earlier and increased robotic exposure for residents and increased robotic certification for our graduates.


Assuntos
Neoplasias Colorretais , Cirurgia Geral , Internato e Residência , Procedimentos Cirúrgicos Robóticos , Robótica , Humanos , Procedimentos Cirúrgicos Robóticos/métodos , Robótica/educação , Educação de Pós-Graduação em Medicina , Currículo , Competência Clínica , Cirurgia Geral/educação
4.
Front Integr Neurosci ; 15: 665467, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33927598

RESUMO

The aging process and age-related diseases such as Alzheimer's disease (AD), are very heterogeneous and multifactorial, making it challenging to diagnose the disease based solely on genetic, behavioral tests, or clinical history. It is yet to be explained what ophthalmological tests relate specifically to aging and AD. To this end, we have selected the common degu (Octodon degus) as a model for aging which develops AD-like signs to conduct ophthalmological screening methods that could be clinical markers of aging and AD. We investigated ocular health using ophthalmoscopy, fundus photography, intraocular pressure (IOP), and pupillary light reflex (PLR). The results showed significant presence of cataracts in adult degus and IOP was also found to increase significantly with advancing age. Age had a significant effect on the maximum pupil constriction but other pupil parameters changed in an age-independent manner (PIPR retention index, resting pupil size, constriction velocity, redilation plateau). We concluded that degus have underlying factors at play that regulate PLR and may be connected to sympathetic, parasympathetic, and melanopsin retinal ganglion cell (ipRGC) deterioration. This study provides the basis for the use of ocular tests as screening methods for the aging process and monitoring of neurodegeneration in non-invasive ways.

6.
Surg Obes Relat Dis ; 16(8): 1030-1034, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32540149

RESUMO

BACKGROUND: Complications related to laparoscopic adjustable gastric banding (LAGB) have led to an increased number of removals. An uncommon but potentially devastating complication is gastric band erosion into the gastric lumen, which can be managed by open surgical, laparoscopic, and endoscopic approaches. OBJECTIVE: A wide array of management techniques has been reported for removal of LAGB that have eroded into the stomach. We describe the preferred method for successful endoscopic band removal at our institution. SETTING: Community tertiary-care referral hospital accredited by the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program. METHODS: A single-center, retrospective review of a prospectively maintained database was used to identify patients who underwent LAGB removal from 2009 to 2019. We identified the subset of patients with band erosion. We analyzed patient characteristics, presenting symptoms, diagnostic modalities, and method of band extraction. RESULTS: A total of 132 patients underwent LAGB removal, among whom 22 (16.7%) patients were diagnosed with erosion. Seven (32%) patients underwent laparoscopic removal, 14 (64%) patients underwent endoscopic removal, and 1 patient (4%) underwent combined laparoscopic and endoscopic approach. These latter patients had variable amounts of erosion and buckle visibility, but all underwent endoscopic retrieval. We found that using an endoscopic retrograde cholangiopancreatography guidewire with an endoscopic retrograde cholangiopancreatography mechanical lithotriptor for band transection and snare for retrieval have been effective. CONCLUSIONS: A standardized, multidisciplinary, and minimally invasive endoscopic approach for LAGB erosion has been found to be successful without the need for further surgical intervention and may be offered to patients upon discovery of erosion.


Assuntos
Cirurgia Bariátrica , Gastroplastia , Laparoscopia , Obesidade Mórbida , Cirurgia Bariátrica/efeitos adversos , Remoção de Dispositivo , Gastroplastia/efeitos adversos , Humanos , Obesidade Mórbida/cirurgia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Reoperação , Estudos Retrospectivos , Resultado do Tratamento
7.
Front Neurosci ; 14: 161, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32256305

RESUMO

Accumulation of amyloid-beta (Aß) peptides is regarded as the hallmark of neurodegenerative alterations in the brain of Alzheimer's disease (AD) patients. In the eye, accumulation of Aß peptides has also been suggested to be a trigger of retinal neurodegenerative mechanisms. Some pathological aspects associated with Aß levels in the brain are synaptic dysfunction, neurochemical remodeling and glial activation, but these changes have not been established in the retina of animals with Aß accumulation. We have employed the Octodon degus in which Aß peptides accumulated in the brain and retina as a function of age. This current study investigated microglial morphology, expression of PSD95, synaptophysin, Iba-1 and choline acetyltransferase (ChAT) in the retina of juvenile, young and adult degus using immunolabeling methods. Neurotransmitters glutamate and gamma-aminobutyric acid (GABA) were detected using immunogold labeling and glutamate receptor subunits were quantified using Western blotting. There was an age-related increase in presynaptic and a decrease in post-synaptic retinal proteins in the retinal plexiform layers. Immunolabeling showed changes in microglial morphology characteristic of intermediate stages of activation around the optic nerve head (ONH) and decreasing activation toward the peripheral retina. Neurotransmitter expression pattern changed at juvenile ages but was similar in adults. Collectively, the results suggest that microglial activation, synaptic remodeling and neurotransmitter changes may be consequent to, or parallel to Aß peptide and phosphorylated tau accumulation in the retina.

8.
J Am Coll Surg ; 231(1): 54-58, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32156654

RESUMO

BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) requires diversity in residency. The self-identified race/ethnicities of general surgery applicants, residents, and core teaching faculty were assessed to evaluate underrepresented minority (URM) representation in surgery residency programs and to determine the impact of URM faculty and residents on URM applicants' selection for interview or match. STUDY DESIGN: Data from the 2018 application cycle were collated for 10 general surgery programs. Applicants without a self-identified race/ethnicity were excluded. URMs were defined as those identifying as black/African American, Hispanic/Latino/of Spanish origin, and American Indian/Alaskan Native/Native Hawaiian/Pacific Islander-Samoan. Statistical analyses included chi-square tests and a multivariate model. RESULTS: Ten surgery residency programs received 9,143 applications from 3,067 unique applicants. Applications from white, Asian, Hispanic/Latino, black/African American, and American Indian applicants constituted 66%, 19%, 8%, 7% and 1%, respectively, of those applications selected to interview and 66%, 13%, 11%, 8%, and 2%, respectively, of applications resulting in a match. Among programs' 272 core faculty and 318 current residents, 10% and 21%, respectively, were identified as URMs. As faculty diversity increased, there was no difference in selection to interview for URM (odds ratio [OR] 0.83; 95% CI 0.54 to 1.28, per 10% increase in faculty diversity) or non-URM applicants (OR 0.68; 95% CI 0.57 to 0.81). Similarly, greater URM representation among current residents did not affect the likelihood of being selected for an interview for URM (OR 1.20; 95%CI 0.90 to 1.61) vs non-URM applicants (OR 1.28; 95% CI 1.13 to 1.45). Current resident and faculty URM representation was correlated (r = 0.8; p = 0.005). CONCLUSIONS: Programs with a greater proportion of URM core faculty or residents did not select a greater proportion of URM applicants for interview. However, core faculty and resident racial diversity were correlated. Recruitment of racially/ethnically diverse trainees and faculty will require ongoing analysis to develop effective recruitment strategies.


Assuntos
Educação de Pós-Graduação em Medicina/métodos , Etnicidade , Docentes de Medicina , Cirurgia Geral/educação , Internato e Residência/métodos , Grupos Minoritários , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estados Unidos
9.
J Surg Educ ; 76(6): e15-e23, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31175064

RESUMO

OBJECTIVE: Diversity is an ill-defined entity in general surgery training. The Accreditation Council for Graduate Medical Education recently proposed new common program requirements including verbiage requiring diversity in residency. "Recruiting" for diversity can be challenging within the constraints of geographic preference, type of program, and applicant qualifications. In addition, the Match process adds further uncertainty. We sought to study the self-identified racial/ethnic distribution of general surgery applicants to better ascertain the characteristics of underrepresented minorities (URM) within the general surgery applicant pool. DESIGN: Program-specific data from the Electronic Residency Application Service was collated for the 2018 medical student application cycle. Data were abstracted for all participating programs' applicants and those selected to interview. Applicants who did not enter a self-identified race/ethnicity were excluded from analysis. URM were defined as those identifying as Black/African American, Hispanic/Latino/of Spanish origin, American Indian/Alaskan Native, or Native Hawaiian/Pacific Islander-Samoan. Appropriate statistical analyses were accomplished. SETTING: Ten general surgery residency programs-5 independent programs and 5 university programs. PARTICIPANTS: Residency applicants to the participating general surgery residency programs. RESULTS: Ten surgery residency programs received 10,312 applications from 3192 unique applicants. Seven hundred and seventy-eight applications did not include a self-identified race/ethnicity and were excluded from analysis. The racial/ethnic makeup of applicants in this study cohort was similar to that from 2017 to 2018 Electronic Residency Application Service data of 4262 total applicants to categorical general surgery. Programs received a median of 1085 (range: 485-1264) applications each and altogether selected 617 unique applicants for interviews. Overall, 2148 applicants graduated from US medical schools, and of those, 595 (28%) were offered interviews. The mean age of applicants was 28.8 ± 3.8 years and 1316 (41%) were female. Hispanic/Latino/of Spanish origin, Black, and American Indian/Alaskan Native/Hawaiian/Pacific Islander-Samoan applicants constituted 12%, 8%, and 1% of total applicants, but only 8%, 6%, and 1% of those selected for interview. Overall, 29% of applicants had United States Medical Licensing Examination (USMLE) Step 1 scores ≤220; 37 (6%) of those selected for interviews had a USMLE Step 1 score of ≤220. A higher proportion of URM applicants had USMLE scores ≤220 compared to White and Asian applicants. Non-white self-identification was a significant independent predictor of a lower likelihood of interview selection. Female gender, USMLE Step 1 score >220, and graduating from a US medical school were associated with an increased likelihood of being selected to interview. CONCLUSIONS: URM applicants represented a disproportionately smaller percentage of applicants selected for interview. USMLE Step 1 scores were lower among the URM applicants. Training programs that use discreet USMLE cutoffs are likely excluding URM at a higher rate than their non-URM applicants. Attempts to recruit racially/ethnically diverse trainees should include program-level analysis to determine disparities and a focused strategy to interview applicants who might be overlooked by conventional screening tools.


Assuntos
Cirurgia Geral/educação , Internato e Residência , Grupos Minoritários/estatística & dados numéricos , Critérios de Admissão Escolar/estatística & dados numéricos , Adulto , Feminino , Humanos , Entrevistas como Assunto , Masculino , Estados Unidos
11.
J Surg Educ ; 75(1): 7-13, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28734949

RESUMO

OBJECTIVE: To evaluate the success of the annual program evaluation process and describe the experience of a Program Evaluation Committee for a General Surgery residency program. DESIGN: We conducted a retrospective review of the Program Evaluation Committee's meeting minutes, data inputs, and outcomes from 2014 to 2016. We identified top priorities by year, characterized supporting data, summarized the improvement plans and outcome measures, and evaluated whether the outcomes were achieved at 1 year. SETTING: Virginia Mason Medical Center General Surgery Residency Program. PARTICIPANTS: Program Evaluation Committee members including the Program Director, 2 Associate Program Directors, 2 Senior Faculty Members, and 1 Resident. RESULTS: All outcome measures were achieved or still in progress at 1 year. This included purchasing a GI mentor to improve endoscopic simulation training, establishing an outpatient surgery rotation to increase the volume of cases, and implementing a didactic course on adult learning principles for faculty development to improve intraoperative teaching. Primary reasons for slow progress were lack of follow-through by delegates or communication breakdown. CONCLUSIONS: The annual program evaluation process has been successful in identifying top priorities, developing action plans, and achieving outcome measures using our systematic evaluation process.


Assuntos
Competência Clínica , Educação de Pós-Graduação em Medicina/organização & administração , Cirurgia Geral/educação , Internato e Residência/organização & administração , Centros Médicos Acadêmicos , Comitês Consultivos , Feminino , Humanos , Masculino , Avaliação de Resultados em Cuidados de Saúde , Avaliação de Programas e Projetos de Saúde , Estudos Retrospectivos , Virginia
12.
J Surg Educ ; 74(6): e8-e14, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28666959

RESUMO

OBJECTIVE: The Accreditation Council for Graduate Medical Education requires accredited residency programs to implement competency-based assessments of medical trainees based upon nationally established Milestones. Clinical competency committees (CCC) are required to prepare biannual reports using the Milestones and ensure reporting to the Accreditation Council for Graduate Medical Education. Previous research demonstrated a strong correlation between CCC and resident scores on the Milestones at 1 institution. We sought to evaluate a national sampling of general surgery residency programs and hypothesized that CCC and resident assessments are similar. DESIGN: Details regarding the makeup and process of each CCC were obtained. Major disparities were defined as an absolute mean difference of ≥0.5 on the 4-point scale. A negative assessment disparity indicated that the residents evaluated themselves at a lower level than did the CCC. Statistical analysis included Wilcoxon rank sum and Sign tests. SETTING: CCCs and categorical general surgery residents from 15 residency programs completed the Milestones document independently during the spring of 2016. RESULTS: Overall, 334 residents were included; 44 (13%) and 43 (13%) residents scored themselves ≥0.5 points higher and lower than the CCC, respectively. Female residents scored themselves a mean of 0.08 points lower, and male residents scored themselves a mean of 0.03 points higher than the CCC. Median assessment differences for postgraduate year (PGY) 1-5 were 0.03 (range: -0.94 to 1.28), -0.11 (range: -1.22 to 1.22), -0.08 (range: -1.28 to 0.81), 0.02 (range: -0.91 to 1.00), and -0.19 (range: -1.16 to 0.50), respectively. Residents in university vs. independent programs had higher rates of negative assessment differences in medical knowledge (15% vs. 6%; P = 0.015), patient care (17% vs. 5%; P = 0.002), professionalism (23% vs. 14%; P = 0.013), and system-based practice (18% vs. 9%; P = 0.031) competencies. Major assessment disparities by sex or PGY were similar among individual competencies. CONCLUSIONS: Surgery residents in this national cohort demonstrated self-awareness when compared to assessments by their respective CCCs. This was independent of program type, sex, or level of training. PGY 5 residents, female residents, and those from university programs consistently rated themselves lower than the CCC, but these were not major disparities and the significance of this is unclear.


Assuntos
Acreditação , Competência Clínica , Educação de Pós-Graduação em Medicina/métodos , Cirurgia Geral/educação , Autoavaliação (Psicologia) , Comitês Consultivos , Estudos de Coortes , Educação Baseada em Competências , Feminino , Humanos , Internato e Residência/métodos , Masculino , Estudos Prospectivos , Estados Unidos
13.
Artigo em Inglês | MEDLINE | ID: mdl-28326023

RESUMO

Clinical assessment of pupil appearance and pupillary light reflex (PLR) may inform us the integrity of the autonomic nervous system (ANS). Current clinical pupil assessment is limited to qualitative examination, and relies on clinical judgment. Infrared (IR) video pupillography combined with image processing software offer the possibility of recording quantitative parameters. In this study we describe an IR video pupillography set-up intended for human and animal testing. As part of the validation, resting pupil diameter was measured in human subjects using the NeurOptics™ (Irvine, CA, USA) pupillometer, to compare against that measured by our IR video pupillography set-up, and PLR was assessed in guinea pigs. The set-up consisted of a smart phone with a light emitting diode (LED) strobe light (0.2 s light ON, 5 s light OFF cycles) as the stimulus and an IR camera to record pupil kinetics. The consensual response was recorded, and the video recording was processed using a custom MATLAB program. The parameters assessed were resting pupil diameter (D1), constriction velocity (CV), percentage constriction ratio, re-dilation velocity (DV) and percentage re-dilation ratio. We report that the IR video pupillography set-up provided comparable results as the NeurOptics™ pupillometer in human subjects, and was able to detect larger resting pupil size in juvenile male guinea pigs compared to juvenile female guinea pigs. At juvenile age, male guinea pigs also had stronger pupil kinetics for both pupil constriction and dilation. Furthermore, our IR video pupillography set-up was able to detect an age-specific increase in pupil diameter (female guinea pigs only) and reduction in CV (male and female guinea pigs) as animals developed from juvenile (3 months) to adult age (7 months). This technique demonstrated accurate and quantitative assessment of pupil parameters, and may provide the foundation for further development of an integrated system useful for clinical applications.

14.
N Z Med J ; 130(1450): 78-88, 2017 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-28207727

RESUMO

AIM: To describe the prevalence of diabetic retinopathy (DR) in patients at first presentation for diabetic retinal screening in the greater Wellington region with the intent of service evaluation. METHODS: This is a retrospective study using data collected from patients newly referred for diabetic retinal screening between 2006-2015 (prevalence analysis, n=12667). The prevalence of DR was calculated by gender, ethnicity, age, type of diabetes and glycaemic control (HbA1c). Chi-square test and multiple logistic regression was used for data analysis. RESULTS: The prevalence of any DR was 22.5% (n=2852) (non-sight-threatening (NST-DR) n=2562, 20.2%, sight-threatening (ST-DR) n=290, 2.3%). Type 1 diabetes and poor HbA1c control were strongly associated with any degree of DR. Old-age (>65 years), and Asian and Pacific Island (PI) ethnicity had moderately greater odds compared with European. Male gender had marginally increased odds for any DR. CONCLUSION: This study identified a large proportion (97.7%) of patients (no DR n=9815, 77.5%, NST-DR n=2562, 20.2%) who can be managed in the community by appropriately supported primary care providers, and do not require referral to secondary care ophthalmology. In addition to early detection of ST-DR (2.3%), retinal screening is an early opportunity for education of patients with no DR or NST-DR.


Assuntos
Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Retinopatia Diabética/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Idoso , Criança , Atenção à Saúde , Diabetes Mellitus Tipo 1/prevenção & controle , Diabetes Mellitus Tipo 2/prevenção & controle , Retinopatia Diabética/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Prevalência , Estudos Retrospectivos , Distribuição por Sexo , Seleção Visual , Adulto Jovem
15.
PLoS One ; 10(8): e0135499, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26267479

RESUMO

New studies show that the retina also undergoes pathological changes during the development of Alzheimer's disease (AD). While transgenic mouse models used in these previous studies have offered insight into this phenomenon, they do not model human sporadic AD, which is the most common form. Recently, the Octodon degus has been established as a sporadic model of AD. Degus display age-related cognitive impairment associated with Aß aggregates and phosphorylated tau in the brain. Our aim for this study was to examine the expression of AD-related proteins in young, adult and old degus retina using enzyme-linked or fluorescence immunohistochemistry and to quantify the expression using slot blot and western blot assays. Aß4G8 and Aß6E10 detected Aß peptides in some of the young animals but the expression was higher in the adults. Aß peptides were observed in the inner and outer segment of the photoreceptors, the nerve fiber layer (NFL) and ganglion cell layer (GCL). Expression was higher in the central retinal region than in the retinal periphery. Using an anti-oligomer antibody we detected Aß oligomer expression in the young, adult and old retina. Immunohistochemical labeling showed small discrete labeling of oligomers in the GCL that did not resemble plaques. Congo red staining did not result in green birefringence in any of the animals analyzed except for one old (84 months) animal. We also investigated expression of tau and phosphorylated tau. Expression was seen at all ages studied and in adults it was more consistently observed in the NFL-GCL. Hyperphosphorylated tau detected with AT8 antibody was significantly higher in the adult retina and it was localized to the GCL. We confirm for the first time that Aß peptides and phosphorylated tau are expressed in the retina of degus. This is consistent with the proposal that AD biomarkers are present in the eye.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/genética , Regulação da Expressão Gênica/fisiologia , Octodon/metabolismo , Retina/metabolismo , Proteínas tau/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Fosforilação , Proteínas tau/metabolismo
16.
J Surg Res ; 192(2): 656-63, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25091340

RESUMO

BACKGROUND: Diabetic (DM) patients frequently lack autologous vascular tissue required for revascularization procedures and dialysis access creation. We have developed a tissue-engineered graft that uses adipose-derived stem cells (ASC) as endothelial cell substitutes. Here, we compare DM versus nondiabetic (NDM) ASC in terms of isolation efficiency, proliferation, commitment toward endothelial lineage, and seeding onto the luminal surface of a graft. METHODS: ASC were isolated from liposuction specimens of vascular surgery patients. Proliferation was assessed by constructing growth curves over 14 d. ASC were differentiated in endothelial growth medium (EGM2). Endothelial commitment was assessed by measuring endothelial cell-specific gene expression (CD31, von Willebrand factor) and by cord formation on Matrigel. Finally, ASC were seeded onto a vascular scaffold, flow conditioned, and imaged with confocal microscopy. RESULTS: Diabetes did not alter ASC isolation efficiency (224,028 ± 20,231 cells/g adipose for DM (n = 53) versus 259,345 ± 15,441 cells/g adipose for NDM (n = 145; P = 0.21). Growth curves for DM (n = 6) and NDM (n = 6) also appeared similar. After culture in EGM2, upregulation of CD31 and von Willebrand factor message was observed in NDM; these markers were found within the primary cultures of DM but no upregulation was observed after culture in EGM2. Both groups exhibited similar cord formation on Matrigel and retention to vascular scaffolds. CONCLUSIONS: Isolation and proliferation studies suggest that adipose is a promising source of stem cells for tissue engineering in the DM population. The angiogenic potential of DM ASC appears intact; however, differences in acquisition of endothelial cell markers suggest that differentiation may be inhibited or delayed by diabetes.


Assuntos
Tecido Adiposo/citologia , Células-Tronco Adultas/citologia , Prótese Vascular , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/patologia , Células Endoteliais/citologia , Adulto , Biomarcadores , Cadáver , Diferenciação Celular , Linhagem da Célula , Proliferação de Células , Feminino , Humanos , Lipectomia , Masculino , Neovascularização Fisiológica
17.
Alzheimers Dement ; 10(2): 251-61, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24011928

RESUMO

Alzheimer's disease (AD) is the most common form of dementia with progressive deterioration of memory and cognition. Complaints related to vision are common among AD patients. Several changes in the retina, lens, and in the vasculature have been noted in the AD eye that may be the cause of visual symptoms experienced by the AD patient. Anatomical changes have been detected within the eye before signs of cognitive impairment and memory loss are apparent. Unlike the brain, the eye is a unique organ that can be visualized noninvasively at the cellular level because of its transparent nature, which allows for inexpensive testing of biomarkers in a clinical setting. In this review, we have searched for candidate biomarkers that could enable diagnosis of AD, covering ocular neurodegeneration associated with functional tests. We explore the evidence that suggests that inexpensive, noninvasive clinical tests could be used to detect AD ocular biomarkers.


Assuntos
Doença de Alzheimer/complicações , Oftalmopatias/etiologia , Vias Visuais/patologia , Doença de Alzheimer/genética , Oftalmopatias/genética , Oftalmopatias/patologia , Humanos
18.
J Neurol ; 260(1): 21-9, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22729387

RESUMO

Anterior cerebral artery (ACA) ischemia may be underdiagnosed following subarachnoid hemorrhage (SAH). The purpose of this study is to characterize the prevalence, timing, and risk factors for ACA infarction, following primary spontaneous SAH. This was a retrospective study of consecutive SAH patients. Final admission CT scans were reviewed for the presence of ACA infarction, and prior scans serially reviewed to determine timing of infarct. Infarctions were categorized as any, early (days 0-3), late (days 4-15), or perioperative (2 days after aneurysm treatment). Demographic and clinical variables were statistically interrogated to identify predictors of infarct types. Of the 474 study patients, ACA infarctions occurred in 8 % of patients, with 42 % occurring during the early period. Multivariate logistic regression identified H/H grade 4/5 (p < 0.001), ACA/ACom aneurysm location (p < 0.001), and surgical clipping (p = 0.011) as independent predictors of any ACA infarct. In Cox hazards analysis, H/H grade 4/5 (p < 0.001), CT score 3/4 (p = 0.042), ACA/ACom aneurysm location (p < 0.001), and surgical clipping (p = 0.012) independently predicted any ACA infarct. Bivariate logistic regression identified non-Caucasian race (p = 0.032), H/H grade 3/4 (p < 0.001), CT score 3/4 (p = 0.006), IVH (p = 0.027), and ACA/ACom aneurysm (p = 0.001) as predictors of early infarct (EI). Late infarct (LI) was predicted by H/H grade 4/5 (p = 0.040), ACA/ACom aneurysm (p < 0.001), and vasospasm (p = 0.027), while postoperative infarct (PI) was predicted by surgical clipping (p = 0.044). Log-rank analyses confirmed non-Caucasian race (p = 0.024), H/H grade 3/4 (p < 0.001), CT score 3/4 (p = 0.003), IVH (p = 0.010), and ACA/ACom aneurysm (p < 0.001) as predictors of EI. LI was predicted by ACA/ACom aneurysm (p < 0.001) while surgical clipping (p = 0.046) again predicted PI. Clinical severity/grade and ACA/ACom aneurysm location are the most consistent predictors of ACA infarctions. Vasospastic and non-vasospastic processes may concurrently contribute to ACA infarcts.


Assuntos
Infarto da Artéria Cerebral Anterior/epidemiologia , Infarto da Artéria Cerebral Anterior/etiologia , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/epidemiologia , Adulto , Idoso , Análise de Variância , Feminino , Humanos , Infarto da Artéria Cerebral Anterior/diagnóstico por imagem , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prevalência , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Hemorragia Subaracnóidea/diagnóstico por imagem , Tomografia Computadorizada por Raios X
19.
Gastrointest Endosc ; 75(4): 748-56, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22301340

RESUMO

BACKGROUND: Data on balloon enteroscopy-assisted ERCP (BEA-ERCP) versus laparoscopy-assisted ERCP (LA-ERCP) in post-Roux-en-Y gastric bypass (RYGB) patients are lacking. OBJECTIVES: To compare BEA-ERCP with LA-ERCP in post-RYGB patients and to identify factors that predict therapeutic success with BEA-ERCP. DESIGN: Retrospective chart review. SETTING: A single North American tertiary referral center. PATIENTS: The review included 56 bariatric post-RYGB patients who underwent ERCP. INTERVENTIONS: BEA-ERCP or LA-ERCP. MAIN OUTCOME MEASUREMENTS: Cannulation rate, therapeutic success, hospital stay, complications, procedure duration, endoscopist time, and cost. RESULTS: A total of 32 patients underwent BEA-ERCP, and 24 underwent LA-ERCP. LA-ERCP was superior to BEA-ERCP in papilla identification (100% vs 72%, P = .005), cannulation rate (100% vs 59%, P < .001), and therapeutic success (100% vs 59%, P < .001). The total procedure time was shorter (P < .001) and endoscopist time was longer (P = .006) for BEA-ERCP. There was no difference in postprocedure hospital stay (P = .127) or complication rate (P = .392) between the 2 groups. In the BEA-ERCP group, in patients having a Roux limb + biliopancreatic (from ligament of Treitz to jejunojejunal anastomosis), a limb length less than 150 cm was associated with therapeutic success. Starting with BEA-ERCP and continuing with LA-ERCP after a failed BEA-ERCP saved $1015 compared with starting with LA-ERCP. LIMITATIONS: Single center, retrospective study. CONCLUSIONS: In centers with expertise in deep enteroscopy and ERCP, post-RYGB patients with a Roux + ligament of Treitz to jejunojejunal anastomosis limb length less than 150 cm should first be offered deep enteroscopy-assisted ERCP. In patients with Roux + ligament of Treitz to jejunojejunal anastomosis (LTJJ) limb length 150 cm or longer, LA-ERCP should be the preferred approach because of the lack of need for a second procedure, equivalent morbidity and hospital stay, decreased endoscopist time, and decreased cost.


Assuntos
Adenocarcinoma/diagnóstico , Anastomose em-Y de Roux/efeitos adversos , Colangiopancreatografia Retrógrada Endoscópica/métodos , Enteroscopia de Duplo Balão , Laparoscopia , Neoplasias Pancreáticas/diagnóstico , Ampola Hepatopancreática , Cálculos/diagnóstico , Cálculos/terapia , Distribuição de Qui-Quadrado , Colangiopancreatografia Retrógrada Endoscópica/economia , Coledocolitíase/diagnóstico , Coledocolitíase/terapia , Doenças do Ducto Colédoco/diagnóstico , Doenças do Ducto Colédoco/terapia , Constrição Patológica/diagnóstico , Constrição Patológica/terapia , Custos e Análise de Custo , Enteroscopia de Duplo Balão/efeitos adversos , Enteroscopia de Duplo Balão/economia , Feminino , Derivação Gástrica/efeitos adversos , Humanos , Laparoscopia/efeitos adversos , Laparoscopia/economia , Masculino , Pessoa de Meia-Idade , Ductos Pancreáticos , Estudos Retrospectivos
20.
Indian J Surg ; 73(3): 230-2, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22654340

RESUMO

Surgeons are commonly asked to evaluate patients with subepithelial masses of the stomach. Glomus tumors are subepithelial mesenchymal tumors that are rarely included in the differential diagnosis when evaluating these patients. We present the case of 55-year old man with a gastric glomus tumor that was diagnosed preoperatively and removed by laparoscopic wedge resection. We review the preoperative evaluation and classic finding associated with this uncommon entity.

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