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1.
Brain Inj ; : 1-8, 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38328943

RESUMO

OBJECTIVE: The LIMBIC Military and Tactical Athletic Research Study (MATARS) framework was established to confirm and extend understanding of concussion with initial studies driven by clinical data collected between 2015 and 2020 in a collegiate sports setting. The LIMBIC MATARS framework will be leveraged to apply gold-standard and innovative research designs to advance the science of concussion. This manuscript provides the background, methodology, and initial demographic data associated with the LIMBIC MATARS. METHODS: Consensus-based common data elements were used to conduct a retrospective chart review, specific to collegiate athletes diagnosed with concussions between 2015 and 2020 at 11 universities. RESULTS: A final sample of 1,311 (47.8% female) concussions were diagnosed during the five-year study period from athletes participating in a variety of National Collegiate Athlete Association (NCAA) sports. The LIMBIC MATARS demographic data, align with the NCAA and other pioneering multi-site concussion-related studies in terms of biological sex, race and ethnicity, and sport participation. CONCLUSION: This pragmatic, methodological approach was used to address several a priori hypotheses related to concussion, align with other multi-site studies of concussion, and establish a consortium for future investigations.

2.
Brain Inj ; : 1-9, 2023 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-37691328

RESUMO

OBJECTIVE: To determine if there were concussion diagnosis and recovery disparities between collegiate athletes with Black and White racial identities. DESIGN: Retrospective cohort study. METHODS: Concussion information was extracted from NCAA athlete medical files at LIMBIC MATARS member institutions from the 2015-16' to 2019-20' academic years. A total of 410 concussions from 9 institutions were included that provided all independent (i.e. racial identity of Black or White) and dependent variable information (i.e. dates of injury, diagnosis, symptom resolution, and return to sport) that were analyzed using Mann-Whitney U tests. The sample consisted of 114 (27.8%) concussions sustained by Black athletes and 296 (72.1%) sustained by White athletes. RESULTS: The overall sample had a median of 0 days between injury occurrence to diagnosis, 7 days to symptom resolution, and 12 days to return to sport. No significant timing differences were observed for concussion diagnosis (p = .14), symptom resolution (p = .39), or return to sport (p = 0.58) between collegiate athletes with Black versus White racial identities. CONCLUSIONS: These findings may reflect equitable access to onsite sports medicine healthcare resources that facilitate concussion management in the collegiate sport setting. Future work should explore these associations with a larger and more diverse sample of collegiate athletes.

3.
Gynecol Oncol ; 170: 221-228, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36709663

RESUMO

BACKGROUND: IGF signaling has been implicated in the pathogenesis and progression of ovarian carcinoma (OC). Single agent activity and safety of ganitumab (AMG 479), a fully human monoclonal antibody against IGF1R that blocks binding of IGF1 and IGF2, were evaluated in patients with platinum-sensitive recurrent OC. METHODS: Patients with CA125 progression (GCIG criteria) or measurable disease per RECIST following primary platinum-based therapy received 18 mg/kg of ganitumab q3w. The primary endpoint was objective response rate (ORR) assessed per RECIST 1.1 by an independent radiology review committee (IRC) and/or GCIG CA125 criteria. Secondary endpoints included clinical benefit rate (CBR), progression free survival (PFS) and overall survival (OS). RESULTS: 61 pts. were accrued. Objective responses were seen in 5/61 patients (ORR 8.2%, 95% CI, 3.1-18.8) with 1 partial response (PR) by RECIST and 2 complete responses (CR) as well as 2 PR by CA125 criteria. CBR was 80.3% (95% CI, 67.8-89.0%). The median PFS according to RECIST by IRC was 2.1 months (95% CI, 2.0-3.1). The median PFS per RECIST IRC and/or CA125 was 2.0 months (95% CI, 1.8-2.2). The median OS was 21 months (95% CI, 19.5-NA). The most common overall adverse events were fatigue (36.1%) and hypertension (34.4%). Grade 1/2 hyperglycemia occurred in 30.4% of patients. Hypertension (11.5%) and hypersensitivity (8.2%) were the most frequent grade 3 adverse events. CONCLUSIONS: IGF1R inhibition with ganitumab was well-tolerated, however, our results do not support further study of ganitumab as a single agent in unselected OC patients.


Assuntos
Anticorpos Monoclonais Humanizados , Neoplasias Ovarianas , Humanos , Feminino , Anticorpos Monoclonais/efeitos adversos , Neoplasias Ovarianas/tratamento farmacológico
4.
AJNR Am J Neuroradiol ; 42(8): 1550-1556, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34117018

RESUMO

BACKGROUND AND PURPOSE: Artificial intelligence decision support systems are a rapidly growing class of tools to help manage ever-increasing imaging volumes. The aim of this study was to evaluate the performance of an artificial intelligence decision support system, Aidoc, for the detection of cervical spinal fractures on noncontrast cervical spine CT scans and to conduct a failure mode analysis to identify areas of poor performance. MATERIALS AND METHODS: This retrospective study included 1904 emergent noncontrast cervical spine CT scans of adult patients (60 [SD, 22] years, 50.3% men). The presence of cervical spinal fracture was determined by Aidoc and an attending neuroradiologist; discrepancies were independently adjudicated. Algorithm performance was assessed by calculation of the diagnostic accuracy, and a failure mode analysis was performed. RESULTS: Aidoc and the neuroradiologist's interpretation were concordant in 91.5% of cases. Aidoc correctly identified 67 of 122 fractures (54.9%) with 106 false-positive flagged studies. Diagnostic performance was calculated as the following: sensitivity, 54.9% (95% CI, 45.7%-63.9%); specificity, 94.1% (95% CI, 92.9%-95.1%); positive predictive value, 38.7% (95% CI, 33.1%-44.7%); and negative predictive value, 96.8% (95% CI, 96.2%-97.4%). Worsened performance was observed in the detection of chronic fractures; differences in diagnostic performance were not altered by study indication or patient characteristics. CONCLUSIONS: We observed poor diagnostic accuracy of an artificial intelligence decision support system for the detection of cervical spine fractures. Many similar algorithms have also received little or no external validation, and this study raises concerns about their generalizability, utility, and rapid pace of deployment. Further rigorous evaluations are needed to understand the weaknesses of these tools before widespread implementation.


Assuntos
Aprendizado Profundo , Fraturas da Coluna Vertebral , Adulto , Algoritmos , Inteligência Artificial , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/lesões , Feminino , Humanos , Masculino , Estudos Retrospectivos , Sensibilidade e Especificidade , Fraturas da Coluna Vertebral/diagnóstico por imagem
5.
Sci Rep ; 10(1): 20278, 2020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-33219267

RESUMO

Cognitive Multisensory Rehabilitation (CMR) is a promising therapy for upper limb recovery in stroke, but the brain mechanisms are unknown. We previously demonstrated that the parietal operculum (parts OP1/OP4) is activated with CMR exercises. In this exploratory study, we assessed the baseline difference between OP1/OP4 functional connectivity (FC) at rest in stroke versus healthy adults to then explore whether CMR affects OP1/OP4 connectivity and sensorimotor recovery after stroke. We recruited 8 adults with chronic stroke and left hemiplegia/paresis and 22 healthy adults. Resting-state FC with the OP1/OP4 region-of-interest in the affected hemisphere was analysed before and after 6 weeks of CMR. We evaluated sensorimotor function and activities of daily life pre- and post-CMR, and at 1-year post-CMR. At baseline, we found decreased FC between the right OP1/OP4 and 34 areas distributed across all lobes in stroke versus healthy adults. After CMR, only four areas had decreased FC compared to healthy adults. Compared to baseline (pre-CMR), participants improved on motor function (MESUPES arm p = 0.02; MESUPES hand p = 0.03; MESUPES total score p = 0.006); on stereognosis (p = 0.03); and on the Frenchay Activities Index (p = 0.03) at post-CMR and at 1-year follow-up. These results suggest enhanced sensorimotor recovery post-stroke after CMR. Our results justify larger-scale studies.


Assuntos
Terapia Cognitivo-Comportamental/métodos , Lobo Parietal/fisiologia , Reabilitação do Acidente Vascular Cerebral/métodos , Acidente Vascular Cerebral/fisiopatologia , Extremidade Superior/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Doença Crônica/reabilitação , Conectoma , Retroalimentação Sensorial/fisiologia , Feminino , Seguimentos , Voluntários Saudáveis , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Movimento/fisiologia , Lobo Parietal/diagnóstico por imagem , Projetos Piloto , Recuperação de Função Fisiológica/fisiologia , Descanso/fisiologia , Resultado do Tratamento
6.
Lab Chip ; 20(1): 168-174, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31796944

RESUMO

Quantifiably monitoring sweat rate and volume is important to assess the stress level of individuals and/or prevent dehydration, but despite intense research, a convenient, continuous, and low-cost method to monitor sweat rate and total sweat volume loss remains an un-met need. We present here an ultra-simple wearable sensor capable of measuring sweat rate and volume accurately. The device continuously monitors sweat rate by wicking the produced sweat into hydrogels that measurably swell in their physical geometry. The device has been designed as a simple to fabricate, low-cost, disposable patch. This patch exhibits stable and predictable operation over the maximum variable chemistry expected for sweat (pH 4-9 and salinity 0-100 mM NaCl). Preliminary in vivo testing of the patch has been achieved during aerobic exercise, and the sweat rates measured via the patch accurately follow actual sweat rates.


Assuntos
Hidrogéis/análise , Dispositivos Eletrônicos Vestíveis , Hidrogéis/economia , Tamanho da Partícula , Dispositivos Eletrônicos Vestíveis/economia
7.
Sci Total Environ ; 642: 553-566, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-29909322

RESUMO

The potential catastrophic event of a landslide bringing contaminants to surface waters has been highlighted in public media, but there are still few scientific studies analyzing the risk of landslides with contaminated soil. The aim of this study is to present a method to estimate the risk of potential long-term ecological effects on water bodies due to contaminated soil released into a river through a landslide. The study constitutes further development of previous work focusing on the instantaneous (short-term) release of contaminants and associated effects. Risk is here defined as the probability of surface water failing to comply with environmental quality standards (EQS). The transport model formulation is kept simple enough to allow for a probabilistic analysis as a first assessment of the impact on the river water quality from a landslide runout deposit containing contaminated soil. The model is applied at a contaminated site located adjacent to the Göta Älv River that discharges into the Gothenburg estuary, in southwest Sweden. The results from the case study show that a contaminated runout deposit will likely cause contamination levels above EQSs in the near area for a long time and that it will take several years for the deposit to erode, with the greatest erosion at the beginning when water velocities are their highest above the deposit. A contaminated landslide runout deposit will thus act as a source of contamination to the downstream water system until all the contaminated deposit has been eroded away and the contaminants have been transported from the deposit to the river, and further to the river mouth - diluted but not necessarily negligible. Therefore, it is important to prevent landslides of contaminated soil or waste, and if such events were to occur, to remove the contaminated runout deposit as soon as possible.

8.
Oncogenesis ; 6(5): e340, 2017 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-28530705

RESUMO

CCN5/WISP-2 is an anti-invasive molecule and prevents breast cancer (BC) progression. However, it is not well understood how CCN5 prevents invasive phenotypes of BC cells. CCN5 protein expression is detected in estrogen receptor-α (ER-α) -positive normal breast epithelial cells as well as BC cells, which are weakly invasive and rarely metastasize depending on the functional status of ER-α. A unique molecular relation between CCN5 and ER-α has been established as the components of the same signaling pathway that coordinate some essential signals associated with the proliferation as well as delaying the disease progression from a non-invasive to invasive phenotypes. Given the importance of this connection, we determined the role of CCN5 in regulation of ER-α in different cellular settings and their functional relationship. In a genetically engineered mouse model, induced expression of CCN5 in the mammary ductal epithelial cells by doxycycline promotes ER-α expression. Similarly, CCN5 regulates ER-α expression and activity in normal and neoplastic breast cells, as documented in various in vitro settings such as mouse mammary gland culture, human mammary epithelial cell and different BC cell cultures in the presence or absence of human recombinant CCN5 (hrCCN5) protein. Mechanistically, at least in the BC cells, CCN5 is sufficient to induce ER-α expression at the transcription level via interacting with integrins-α6ß1 and suppressing Akt followed by activation of FOXO3a. Moreover, in vitro and in vivo functional assays indicate that CCN5 treatment promotes response to tamoxifen in triple-negative BC (TNBC) cells possibly via restoring ER-α. Collectively, these studies implicates that the combination treatments of CCN5 (via activation of CCN5 or hrCCN5 treatment) and tamoxifen as potential therapies for TNBC.

9.
Transfus Med ; 27(2): 136-141, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28134466

RESUMO

BACKGROUND: It is well established that as a blood unit ages, fewer of the unit's red blood cells (RBCs) remain in circulation post-transfusion. The mechanism for clearance is not well defined. Phosphatidylethanolamine (PE) is a phospholipid that is primarily found on the inner leaflet of healthy cells, and is an important ligand for phagocytosis of dead cells when exposed. OBJECTIVES: The objective of the present study was to measure the change in PE exposure in donor RBCs over increasing storage ages using the novel PE-specific probe, duramycin. METHODS: Five adsol (AS-1) preserved RBC units were sampled weekly for 6 weeks and were labelled with duramycin. The percentage of PE exposed on red cells in each sample was determined using flow cytometry. Surface phosphatidylserine (PS) was evaluated for comparison. RESULTS: We found that RBCs in AS-preserved donor units increasingly exposed PE, from less than 1% in freshly processed RBCs, to nearly 20% at 42 days of storage and correlated with increased relative vesiculation or microparticle concentration and release of cell-free haemoglobin. By comparison, only 5% of cells exposed PS at 42 days. CONCLUSION: We conclude that exposure of PE in the RBC outer membrane was higher than that of PS during 42 days of storage and correlated significantly with increased vesiculation and release of haemoglobin.


Assuntos
Preservação de Sangue , Micropartículas Derivadas de Células/metabolismo , Senescência Celular , Membrana Eritrocítica/metabolismo , Fosfatidiletanolaminas/metabolismo , Feminino , Citometria de Fluxo/métodos , Humanos , Masculino , Fatores de Tempo
10.
Clin Obes ; 7(2): 59-69, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28112860

RESUMO

The purpose of this study was to explore the relation of physical activity (PA) and sedentary time (SED) to insulin sensitivity and adipokines. We assessed PA and SED using Actical accelerometers and insulin resistance (HOMA-IR) in 2109 participants (free of type 1 and 2 diabetes mellitus) from Framingham Generation 3 and Omni 2 cohorts (mean age 46 years, 54% women). Systemic inflammation (C-reactive protein [CRP]) and circulating adipokines were measured 6 years earlier. Steps per day, moderate-to-vigorous PA (MVPA) and SED per wear time (%SED) were predictor variables in multivariable regression analyses, with HOMA-IR, CRP and circulating adipokines as outcome measures. We reported that higher MVPA and more steps per day were associated with lower HOMA-IR, adjusting for %SED (ß = -0.036, P = 0.002; ß = -0.041, P = 0.005). Steps were inversely associated with CRP, but were directly associated with insulin-like growth factor (IGF)-1 levels (ß = -0.111, P = 0.002; ß = 3.293, P = 0.007). %SED was positively associated with HOMA-IR (ß = 0.033, P < 0.0001), but non-significant after adjusting for MVPA (P = 0.13). %SED was associated with higher ratio of leptin/leptin receptor (sOB-R) and higher adipocyte fatty acid-binding protein (FABP)4 (ß = 0.096, P < 0.0001; ß = 0.593, P = 0.002). Our findings suggest differential influences of PA vs. SED on metabolic pathways, with PA modulating insulin resistance and inflammation, whereas SED influences FABPs.


Assuntos
Adipocinas/sangue , Exercício Físico/fisiologia , Resistência à Insulina/fisiologia , Insulina/sangue , Comportamento Sedentário , Proteína C-Reativa/metabolismo , Proteínas de Ligação a Ácido Graxo/sangue , Feminino , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Leptina/sangue , Masculino , Pessoa de Meia-Idade , Receptores para Leptina/sangue , Análise de Regressão
11.
J Vet Intern Med ; 30(3): 771-8, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26992049

RESUMO

BACKGROUND: Biliary sludge is associated with gallbladder (GB) dysmotility and mucus hypersecretion suggesting a link between biliary sludge and the formation of GB mucoceles (GBM). If biliary sludge progresses to GBM, treatment to reduce the production and progression of sludge is warranted. HYPOTHESIS/OBJECTIVES: The objective of this study was to determine the course of biliary sludge in dogs. ANIMALS: Seventy-seven healthy, client-owned dogs ≥4 years of age screened for biliary sludge; 45 affected dogs identified. METHODS: Prospective, observational design. Serial ultrasound examinations were evaluated at 3, 6, 9, and 12 months to monitor degree of sludge based on proportion of GB filled with sludge (mild [0.01-24.4%], moderate [24.5-49.4%], moderate to severe [49.5-74.4%], severe [74.5-100%]), gravity dependency of sludge, and GB dimensions. RESULTS: After 1 year of follow-up, the degree of sludge was mild (34%), moderate (47%), moderate to severe (13%), severe (3%), or absent (3%). There was no significant difference in median degree of sludge over 1 year (P = .36). There were no significant changes in the gravity dependency of sludge over 1 year. A subset of dogs, 24%, with initial gravity-dependent sludge developed a combination of nondependent and dependent sludge. Dogs had resolved (2%), decreased (19%), static (40%), increased (29%), or recurrent (10%) sludge at the conclusion of the study. CONCLUSIONS AND CLINICAL IMPORTANCE: Biliary sludge was prevalent, affected dogs remained asymptomatic, and it rarely resolves in healthy dogs over a period of 1 year. Some dogs developed nongravity-dependent sludge within 1 year, which might indicate changes in consistency of sludge.


Assuntos
Bile/diagnóstico por imagem , Doenças do Cão/patologia , Doenças da Vesícula Biliar/veterinária , Animais , Bile/química , Bile/fisiologia , Doenças do Cão/diagnóstico por imagem , Cães , Feminino , Doenças da Vesícula Biliar/diagnóstico por imagem , Doenças da Vesícula Biliar/patologia , Masculino , Ultrassonografia/veterinária
12.
Nat Commun ; 6: 8653, 2015 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-26611117

RESUMO

Multiple studies have identified loci associated with the risk of developing prostate cancer but the associated genes are not well studied. Here we create a normal prostate tissue-specific eQTL data set and apply this data set to previously identified prostate cancer (PrCa)-risk SNPs in an effort to identify candidate target genes. The eQTL data set is constructed by the genotyping and RNA sequencing of 471 samples. We focus on 146 PrCa-risk SNPs, including all SNPs in linkage disequilibrium with each risk SNP, resulting in 100 unique risk intervals. We analyse cis-acting associations where the transcript is located within 2 Mb (±1 Mb) of the risk SNP interval. Of all SNP-gene combinations tested, 41.7% of SNPs demonstrate a significant eQTL signal after adjustment for sample histology and 14 expression principal component covariates. Of the 100 PrCa-risk intervals, 51 have a significant eQTL signal and these are associated with 88 genes. This study provides a rich resource to study biological mechanisms underlying genetic risk to PrCa.


Assuntos
Neoplasias da Próstata/genética , Bases de Dados Genéticas , Predisposição Genética para Doença , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Elementos Reguladores de Transcrição , Análise de Sequência de RNA
13.
Br J Cancer ; 113(5): 817-26, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26151456

RESUMO

BACKGROUND: Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer. METHODS: We used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype. RESULTS: Overall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: ⩾35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m(-2)) and endometrioid subtypes (pHR: 1.08 per 5 kg m(-2)), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m(-2)) subtype, but only the association with high-grade serous cancers was significant. CONCLUSIONS: Higher BMI is associated with adverse survival among the majority of women with ovarian cancer.


Assuntos
Neoplasias Epiteliais e Glandulares/patologia , Obesidade/patologia , Neoplasias Ovarianas/patologia , Índice de Massa Corporal , Carcinoma Epitelial do Ovário , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Epiteliais e Glandulares/mortalidade , Obesidade/mortalidade , Neoplasias Ovarianas/mortalidade
14.
Clin Exp Immunol ; 179(1): 108-18, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25142403

RESUMO

Multiple sclerosis (MS) is an immune-mediated chronic central nervous system (CNS) disease affecting more than 400 000 people in the United States. Myelin-reactive CD4 T cells play critical roles in the formation of acute inflammatory lesions and disease progression in MS and experimental autoimmune encephalomyelitis (EAE), a well-defined mouse model for MS. Current MS therapies are only partially effective, making it necessary to develop more effective therapies that specifically target pathogenic myelin-specific CD4 T cells for MS treatment. While suppressing T-bet, the key transcription factor in T helper type 1 (Th1) cells, has been demonstrated to be beneficial in prevention and treatment of EAE, the therapeutic potential of retinoic acid-related orphan receptor gamma t (ROR)γt, the key transcription factor for Th17 cells, has not been well-characterized. In this study, we characterized the correlation between RORγt expression and other factors affecting T cell encephalitogenicity and evaluated the therapeutic potential of targeting RORγt by siRNA inhibition of RORγt. Our data showed that RORγt expression correlates with interleukin (IL)-17 production, but not with the encephalitogenicity of myelin-specific CD4 T cells. IL-23, a cytokine that enhances encephalitogenicity, does not enhance RORγt expression significantly. Additionally, granulocyte-macrophage colony-stimulating factor (GM-CSF) levels, which correlate with the encephalitogenicity of different myelin-specific CD4 T cell populations, do not correlate with RORγt. More importantly, inhibiting RORγt expression in myelin-specific CD4 T cells with an siRNA does not reduce disease severity significantly in adoptively transferred EAE. Thus, RORγt is unlikely to be a more effective therapeutic target for ameliorating pathogenicity of encephalitogenic CD4 T cells.


Assuntos
Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Expressão Gênica , Regulação da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Interleucina-23/metabolismo , Interleucina-23/farmacologia , Camundongos , Camundongos Knockout , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Bainha de Mielina/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Interferência de RNA
15.
Artigo em Inglês | MEDLINE | ID: mdl-25500335

RESUMO

Most genome-wide association studies have explored relationships between genetic variants and plasma phospholipid fatty acid proportions, but few have examined apparent genetic influences on the membrane fatty acid profile of red blood cells (RBC). Using RBC fatty acid data from the Framingham Offspring Study, we analyzed over 2.5 million single nucleotide polymorphisms (SNPs) for association with 14 RBC fatty acids identifying 191 different SNPs associated with at least 1 fatty acid. Significant associations (p<1×10(-8)) were located within five distinct 1MB regions. Of particular interest were novel associations between (1) arachidonic acid and PCOLCE2 (regulates apoA-I maturation and modulates apoA-I levels), and (2) oleic and linoleic acid and LPCAT3 (mediates the transfer of fatty acids between glycerolipids). We also replicated previously identified strong associations between SNPs in the FADS (chromosome 11) and ELOVL (chromosome 6) regions. Multiple SNPs explained 8-14% of the variation in 3 high abundance (>11%) fatty acids, but only 1-3% in 4 low abundance (<3%) fatty acids, with the notable exception of dihomo-gamma linolenic acid with 53% of variance explained by SNPs. Further studies are needed to determine the extent to which variations in these genes influence tissue fatty acid content and pathways modulated by fatty acids.


Assuntos
Cromossomos Humanos/genética , Eritrócitos/metabolismo , Ácidos Graxos/sangue , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , 1-Acilglicerofosfocolina O-Aciltransferase/genética , Acetiltransferases/genética , Idoso , Proteínas da Matriz Extracelular/genética , Elongases de Ácidos Graxos , Genótipo , Glicoproteínas/genética , Humanos , Desequilíbrio de Ligação , Estudos Longitudinais , Masculino , Massachusetts , Pessoa de Meia-Idade
16.
Sci Rep ; 4: 4026, 2014 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-24504028

RESUMO

We evaluated homologous recombination deficient (HRD) phenotypes in epithelial ovarian cancer (EOC) considering BRCA1, BRCA2, and RAD51C in a large well-annotated patient set. We evaluated EOC patients for germline deleterious mutations (n = 899), somatic mutations (n = 279) and epigenetic alterations (n = 482) in these genes using NGS and genome-wide methylation arrays. Deleterious germline mutations were identified in 32 (3.6%) patients for BRCA1, in 28 (3.1%) for BRCA2 and in 26 (2.9%) for RAD51C. Ten somatically sequenced patients had deleterious alterations, six (2.1%) in BRCA1 and four (1.4%) in BRCA2. Fifty two patients (10.8%) had methylated BRCA1 or RAD51C. HRD patients with germline or somatic alterations in any gene were more likely to be high grade serous, have an earlier diagnosis age and have ovarian and/or breast cancer family history. The HRD phenotype was most common in high grade serous EOC. Identification of EOC patients with an HRD phenotype may help tailor specific therapies.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Proteínas de Ligação a DNA/genética , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , Sequência de Bases , Carcinoma Epitelial do Ovário , Metilação de DNA/genética , Feminino , Recombinação Homóloga/genética , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias Epiteliais e Glandulares/classificação , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Ovarianas/classificação , Neoplasias Ovarianas/mortalidade , Análise de Sequência de DNA
17.
J Vet Intern Med ; 27(4): 913-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23731243

RESUMO

BACKGROUND: Pancreatitis is a common disease in cats that is difficult to diagnose. HYPOTHESIS/OBJECTIVES: To determine the sensitivity and specificity of ultrasonographic changes of the pancreas with serum feline pancreatic lipase immunoreactivity (fPLI) as the standard for diagnosis of pancreatitis. ANIMALS: 35 cats with clinical signs consistent with pancreatitis with an abdominal ultrasound examination and serum fPLI concentration measured within 3 days of the ultrasound. METHODS: Retrospective study: Pancreatic thickness, pancreatic margination, pancreatic echogenicity, and peripancreatic fat echogenicity were evaluated. Sensitivity and specificity were calculated with an elevated serum fPLI concentration indicative of pancreatitis as the standard for diagnosis. RESULTS: Serum fPLI was elevated and diagnostic for pancreatitis in 19 of 35 cats. The single ultrasound characteristic with the highest sensitivity was hyperechoic peripancreatic fat at 68% (95% confidence interval = 44-87%), indicating a moderate probability that cats with pancreatitis will have this abnormality on ultrasonographic examination. Specificity was >90% for each of increased pancreatic thickness, abnormal pancreatic margin, and hyperechoic peripancreatic fat. The sensitivity and specificity of ultrasound were 84% (95% confidence interval = 60-97%) and 75% (95% confidence interval = 48-93%), respectively, in cats with elevated serum fPLI indicative of pancreatitis. CONCLUSIONS AND CLINICAL IMPORTANCE: The presence of a thick left limb of the pancreas, severely irregular pancreatic margins, and hyperechoic peripancreatic fat in cats with appropriate clinical signs and elevated serum fPLI are highly supportive of pancreatitis.


Assuntos
Doenças do Gato/diagnóstico por imagem , Lipase/sangue , Pâncreas/enzimologia , Pancreatite/veterinária , Animais , Gatos , Lipase/metabolismo , Pancreatite/sangue , Pancreatite/diagnóstico por imagem , Estudos Retrospectivos , Sensibilidade e Especificidade , Ultrassonografia
18.
J Vet Intern Med ; 27(4): 806-13, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23647265

RESUMO

BACKGROUND: Ultrasound examination is commonly used in the diagnostic evaluation of liver disease in dogs. HYPOTHESIS/OBJECTIVES: To determine if hepatic sonographic features were predictive of findings on liver histopathology. We hypothesized that there would be a relationship between sonographic features and the category of liver disease based on histologic assessment. ANIMALS: One hundred and thirty-eight dogs in which the liver was evaluated by both abdominal ultrasound examination and histopathologic examination. Twenty-five dogs were included in each of the following categories based on histopathology: normal, degenerative, vascular, inflammatory, and neoplasia. Thirteen dogs had nodular regeneration. METHODS: Retrospective study. Medical records of dogs from 2005 to 2010 were searched for cases in which the liver was evaluated by abdominal ultrasound examination as well as by histopathology. After independent evaluation of ultrasound images, the recorded sonographic features were analyzed to identify abnormalities associated with each histopathologic diagnosis or degree of fibrosis. RESULTS: Sixty-four percent of sonographically unremarkable livers had histologic abnormalities. Both microhepatia and the identification of abnormal vasculature were significantly associated with a histopathologic diagnosis of vascular disease. Hepatic masses were significantly associated with a diagnosis of neoplasia. Dilated common bile duct and thickened gall bladder wall were significantly associated with hepatitis. There were no sonographic findings consistently present with hepatic fibrosis. CONCLUSION AND CLINICAL IMPORTANCE: Although some ultrasonographic findings, including masses, microhepatia, anomalous veins, and biliary changes, are associated with specific histopathologic abnormalities, sonographic findings are inconsistently detected in many disorders. Overall, hepatic ultrasonographic abnormalities have substantial limitations in predicting the underlying disease.


Assuntos
Doenças do Cão/patologia , Hepatopatias/veterinária , Animais , Doenças do Cão/diagnóstico por imagem , Cães , Hepatopatias/diagnóstico por imagem , Hepatopatias/patologia , Estudos Retrospectivos , Ultrassonografia
19.
J Vet Intern Med ; 26(6): 1288-94, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23061570

RESUMO

BACKGROUND: Chronic diarrhea is common in dogs and has many causes. Ultrasonographic descriptions of many gastrointestinal diseases have been published, but the diagnostic utility of ultrasonography in dogs with chronic diarrhea has not been investigated. HYPOTHESIS: Diagnostic utility of abdominal ultrasound will be highest in dogs with GI neoplasia and lowest in those with inflammatory disorders. ANIMALS: 87 pet dogs with chronic diarrhea. METHODS: Prospective study in which medical records were reviewed and contribution of abdominal ultrasound toward making diagnosis was scored. RESULTS: In 57/87 (66%) of dogs, the same diagnosis would have been reached without ultrasonography. In 13/87 (15%) of dogs, the ultrasound examination was vital or beneficial to making the diagnosis. Univariable analysis identified that increased diagnostic utility was associated with weight loss (P = .0086), palpation of an abdominal or rectal mass (P = .0031), diseases that commonly have mass lesions visible on ultrasound examination (P < .0001), and a final diagnosis of GI neoplasia. Multivariable regression indicated that utility of abdominal ultrasonography would be 30 times more likely to be high in dogs in which an abdominal or rectal mass was palpated (odds ratio 30.5, 95% CI 5.5-169.6) (P < .0001) versus dogs without a palpable mass. In 15/87 (17%) of dogs, additional benefits of ultrasonography to case management, independent of the contribution to the diagnosis of diarrhea, were identified. CONCLUSIONS AND CLINICAL IMPORTANCE: Overall, the diagnostic utility of abdominal ultrasonography was low in dogs with chronic diarrhea. Identification of factors associated with high diagnostic utility is an indication to perform abdominal ultrasonography in dogs with chronic diarrhea.


Assuntos
Abdome/diagnóstico por imagem , Diarreia/veterinária , Doenças do Cão/diagnóstico por imagem , Enteropatias/veterinária , Abdome/patologia , Animais , Doença Crônica , Diarreia/diagnóstico por imagem , Diarreia/patologia , Doenças do Cão/patologia , Cães , Feminino , Enteropatias/diagnóstico por imagem , Enteropatias/patologia , Masculino , Ultrassonografia
20.
J Clin Microbiol ; 50(9): 3063-5, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22718933

RESUMO

We investigated the use of whole-genome mapping and pulsed-field gel electrophoresis (PFGE) with isolates from an outbreak of Salmonella enterica serotype Saintpaul. PFGE and whole-genome mapping were concordant with 22 of 23 isolates. Whole-genome mapping is a viable alternative tool for the epidemiological analysis of Salmonella food-borne disease investigations.


Assuntos
Mapeamento Cromossômico/métodos , Surtos de Doenças , Tipagem Molecular/métodos , Infecções por Salmonella/epidemiologia , Infecções por Salmonella/microbiologia , Salmonella enterica/classificação , Salmonella enterica/genética , Eletroforese em Gel de Campo Pulsado/métodos , Humanos , Epidemiologia Molecular/métodos , Salmonella enterica/isolamento & purificação
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