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1.
Mol Cell Proteomics ; 19(1): 114-127, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31243064

RESUMO

Hypertrophic cardiomyopathy (HCM) is defined by pathological left ventricular hypertrophy (LVH). It is the commonest inherited cardiac condition and a significant number of high risk cases still go undetected until a sudden cardiac death (SCD) event. Plasma biomarkers do not currently feature in the assessment of HCM disease progression, which is tracked by serial imaging, or in SCD risk stratification, which is based on imaging parameters and patient/family history. There is a need for new HCM plasma biomarkers to refine disease monitoring and improve patient risk stratification. To identify new plasma biomarkers for patients with HCM, we performed exploratory myocardial and plasma proteomics screens and subsequently developed a multiplexed targeted liquid chromatography-tandem/mass spectrometry-based assay to validate the 26 peptide biomarkers that were identified. The association of discovered biomarkers with clinical phenotypes was prospectively tested in plasma from 110 HCM patients with LVH (LVH+ HCM), 97 controls, and 16 HCM sarcomere gene mutation carriers before the development of LVH (subclinical HCM). Six peptides (aldolase fructose-bisphosphate A, complement C3, glutathione S-transferase omega 1, Ras suppressor protein 1, talin 1, and thrombospondin 1) were increased significantly in the plasma of LVH+ HCM compared with controls and correlated with imaging markers of phenotype severity: LV wall thickness, mass, and percentage myocardial scar on cardiovascular magnetic resonance imaging. Using supervised machine learning (ML), this six-biomarker panel differentiated between LVH+ HCM and controls, with an area under the curve of ≥ 0.87. Five of these peptides were also significantly increased in subclinical HCM compared with controls. In LVH+ HCM, the six-marker panel correlated with the presence of nonsustained ventricular tachycardia and the estimated five-year risk of sudden cardiac death. Using quantitative proteomic approaches, we have discovered six potentially useful circulating plasma biomarkers related to myocardial substrate changes in HCM, which correlate with the estimated sudden cardiac death risk.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31550371

RESUMO

OBJECTIVE: The aim of this study was to determine the risk of developing a systemic autoimmune rheumatic disease (ARD) after an initial diagnosis of interstitial pneumonia with autoimmune features (IPAF). METHODS: We performed a retrospective cohort study of patients with interstitial lung disease (ILD) who were evaluated at Columbia University Irving Medical Center from 2009 to 2017. We divided patients with idiopathic ILD into two groups: those who met IPAF criteria and those who did not meet IPAF criteria at initial ILD diagnosis. We examined the association between IPAF and diagnosis of ARD during the follow-up period using a multivariable-adjusted logistic regression model. RESULTS: Of the 697 patients with ILD who were screened, 174 met inclusion criteria (50 met IPAF criteria and 124 did not). During a median follow-up period of 5.2 years, 16% (8/50) of subjects with IPAF were diagnosed with an ARD compared with 1.6% (2/124) of subjects without IPAF (P = 0.001). Adjusting for age, sex, smoking status and use of immunosuppressive therapy, the odds of progressing to an ARD were 14 times higher in subjects with IPAF than in those without IPAF (odds ratio 14.18, 95% CI 1.44-138.95, P = 0.02). CONCLUSION: The presence of IPAF confers an increased risk of developing an ARD. Patients with IPAF should therefore be followed closely for the development of an ARD.

3.
J Inherit Metab Dis ; 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31452203

RESUMO

Extracellular matrix (ECM) disruption is known to be an early pathological feature of the Mucopolysaccharidoses (MPS). Collagen is the main component of the ECM and its metabolism could act as a useful indicator of ECM disruption. We have measured the specific collagen breakdown products; urinary free hydroxylated (Lys-OH) and glycosylated hydroxylysines (Lys-O-Gal and Lys-O-GalGlc) in MPS patients using a tandem liquid chromatography tandem mass spectrometry assay. A pilot study cohort analysis indicated that concentrations of lysine and Lys-OH were raised significantly in MPS I (Hurler) disease patients. Lys-O-GalGlc was raised in MPS II and MPS VI patients and demonstrated a significant difference between MPS I Hurler and an MPS I Hurler-Scheie group. Further analysis determined an age association for glycosylated hydroxylysine in control samples similar to that observed for the glycosaminoglycans. Using defined age ranges and treatment naïve patient samples we confirmed an increase in glycosylated hydroxylysines in MPS I and in adult MPS IVA. We also looked at the ratio of Lys-O-Gal to Lys-O-GalGlc, an indicator of the source of collagen degradation, and noticed a significant change in the ratio for all pediatric MPS I, II, and IV patients, and a small significant increase in adult MPS IV. This indicated that the collagen degradation products were coming from a source other than bone such as cartilage or connective tissue. To see how specific the changes in glycosylated hydroxylysine were to MPS patients we also looked at levels in patients with other inherited metabolic disorders. MPS patients showed a trend towards increased glycosylated hydroxylysines and an elevated ratio compared to other metabolic disorders that included Battens disease, Fabry disease, Pyridoxine-dependent epilepsy (due to mutations in ALDH7A1), and Niemann Pick C disease.

5.
Cell Rep ; 27(12): 3709-3723.e5, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216486

RESUMO

The pathogenesis of idiopathic pulmonary fibrosis (IPF), an intractable interstitial lung disease, is unclear. Recessive mutations in some genes implicated in Hermansky-Pudlak syndrome (HPS) cause HPS-associated interstitial pneumonia (HPSIP), a clinical entity that is similar to IPF. We previously reported that HPS1-/- embryonic stem cell-derived 3D lung organoids showed fibrotic changes. Here, we show that the introduction of all HPS mutations associated with HPSIP promotes fibrotic changes in lung organoids, while the deletion of HPS8, which is not associated with HPSIP, does not. Genome-wide expression analysis revealed the upregulation of interleukin-11 (IL-11) in epithelial cells from HPS mutant fibrotic organoids. IL-11 was detected predominantly in type 2 alveolar epithelial cells in end-stage IPF, but was expressed more broadly in HPSIP. Finally, IL-11 induced fibrosis in WT organoids, while its deletion prevented fibrosis in HPS4-/- organoids, suggesting IL-11 as a therapeutic target. hPSC-derived 3D lung organoids are, therefore, a valuable resource to model fibrotic lung disease.

6.
J Asthma ; 56(11): 1193-1197, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30395734

RESUMO

Introduction: Mepolizumab targets eosinophils in the treatment of asthma. The dose used for asthma is considerably lower than that used for treating eosinophilic granulomatosis with polyangiitis, a recently approved indication. While intravenous mepolizumab use has reported utility in non-asthma eosinophilic disorders, the efficacy of the subcutaneous asthma dosing of the drug for eosinophilic pneumonia is not known. Case study: A middle-aged female was diagnosed with eosinophilic pneumonia. The patient's clinical/radiologic/laboratory findings, response to treatment, and respiratory function studies are described. Results: A woman, born in 1962, had repeated pneumonia hospitalizations from 2007 through 2010. In October 2010, a lung biopsy showed findings consistent with chronic eosinophilic pneumonia and chronic asthma. The patient also had chronic sinusitis. Long term systemic corticosteroids were prescribed but the patient became oxygen dependent by 2014. Omalizumab was administered for 1 year starting in 2015 without improvement in symptoms. In 2016, mepolizumab 100 mg subcutaneously every 4 weeks was initiated. Symptomatic improvement with decreased oxygen and systemic corticosteroid requirements were noted. A chest CT performed in February 2018 showed marked improvement compared to a study in 2016. Interval spirometric improvements were noted. Peripheral blood eosinophils/mm3 prior to mepolizumab were 237, and while on mepolizumab were 10. Conclusion: Parenchymal eosinophilic lung disease may respond to asthma-dosed mepolizumab. Mepolizumab treatment in asthma where concomitant interstitial disease is suspected, may offer an advantage over omalizumab in the ability to reduce eosinophils not only in airways, but also in lung parenchyma.

7.
Eur Respir Rev ; 27(150)2018 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-30578332

RESUMO

Imaging techniques are an essential component of the diagnostic process for interstitial lung diseases (ILDs). Chest radiography is frequently the initial indicator of an ILD, and comparison of radiographs taken at different time points can show the rate of disease progression. However, radiography provides only limited specificity and sensitivity and is primarily used to rule out other diseases, such as left heart failure. High-resolution computed tomography (HRCT) is a more sensitive method and is considered central in the diagnosis of ILDs. Abnormalities observed on HRCT can help identify specific ILDs. HRCT also can be used to evaluate the patient's prognosis, while disease progression can be assessed through serial imaging. Other imaging techniques such as positron emission tomography-computed tomography and magnetic resonance imaging have been investigated, but they are not commonly used to assess patients with ILDs. Disease severity may potentially be estimated using quantitative methods, as well as visual analysis of images. For example, comprehensive assessment of disease staging and progression in patients with ILDs requires visual analysis of pulmonary features that can be performed in parallel with quantitative analysis of the extent of fibrosis. New approaches to image analysis, including the application of machine learning, are being developed.


Assuntos
Doenças Pulmonares Intersticiais/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Fibrose Pulmonar/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Diagnóstico Diferencial , Progressão da Doença , Humanos , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/fisiopatologia , Doenças Pulmonares Intersticiais/terapia , Aprendizado de Máquina , Imagem por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Valor Preditivo dos Testes , Prognóstico , Fibrose Pulmonar/fisiopatologia , Fibrose Pulmonar/terapia , Interpretação de Imagem Radiográfica Assistida por Computador , Reprodutibilidade dos Testes , Índice de Gravidade de Doença
8.
Chest ; 153(6): 1387-1395, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29353024

RESUMO

BACKGROUND: We aimed to examine short- and long-term mortality in a mixed population of patients with interstitial lung disease (ILD) with acute respiratory failure, and to identify those at lower vs higher risk of in-hospital death. METHODS: We conducted a single-center retrospective cohort study of 126 consecutive adults with ILD admitted to an ICU for respiratory failure at a tertiary care hospital between 2010 and 2014 and who did not undergo lung transplantation during their hospitalization. We examined associations of ICU-day 1 characteristics with in-hospital and 1-year mortality, using Poisson regression, and examined survival using Kaplan-Meier curves. We created a risk score for in-hospital mortality, using a model developed with penalized regression. RESULTS: In-hospital mortality was 66%, and 1-year mortality was 80%. Those with connective tissue disease-related ILD had better short-term and long-term mortality compared with unclassifiable ILD (adjusted relative risk, 0.6; 95% CI, 0.3-0.9; and relative risk, 0.6; 95% CI, 0.4-0.9, respectively). Our prediction model includes male sex, interstitial pulmonary fibrosis diagnosis, use of invasive mechanical ventilation and/or extracorporeal life support, no ambulation within 24 h of ICU admission, BMI, and Simplified Acute Physiology Score-II. The optimism-corrected C-statistic was 0.73, and model calibration was excellent (P = .99). In-hospital mortality rates for the low-, moderate-, and high-risk groups were 33%, 65%, and 96%, respectively. CONCLUSIONS: We created a risk score that classifies patients with ILD with acute respiratory failure from low to high risk for in-hospital mortality. The score could aid providers in counseling these patients and their families.


Assuntos
Estado Terminal/mortalidade , Unidades de Terapia Intensiva , Doenças Pulmonares Intersticiais/mortalidade , Síndrome do Desconforto Respiratório do Adulto/mortalidade , Idoso , Feminino , Seguimentos , Mortalidade Hospitalar/tendências , Hospitalização/tendências , Humanos , Doenças Pulmonares Intersticiais/complicações , Masculino , Pessoa de Meia-Idade , New York/epidemiologia , Síndrome do Desconforto Respiratório do Adulto/etiologia , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendências , Fatores de Tempo
9.
ERJ Open Res ; 3(3)2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28845429

RESUMO

In chronic hypersensitivity pneumonitis (CHP), lack of improvement or declining lung function may prompt use of immunosuppressive therapy. We hypothesised that use of azathioprine or mycophenolate mofetil with prednisone reduces adverse events and lung function decline, and improves transplant-free survival. Patients with CHP were identified. Demographic features, pulmonary function tests, incidence of treatment-emergent adverse events (TEAEs) and transplant-free survival were characterised, compared and analysed between patients stratified by immunosuppressive therapy. A multicentre comparison was performed across four independent tertiary medical centres. Among 131 CHP patients at the University of Chicago medical centre (Chicago, IL, USA), 93 (71%) received immunosuppressive therapy, and had worse baseline forced vital capacity (FVC) and diffusing capacity, and increased mortality compared with those who did not. Compared to patients treated with prednisone alone, TEAEs were 54% less frequent with azathioprine therapy (p=0.04) and 66% less frequent with mycophenolate mofetil (p=0.002). FVC decline and survival were similar between treatment groups. Analyses of datasets from four external tertiary medical centres confirmed these findings. CHP patients who did not receive immunosuppressive therapy had better survival than those who did. Use of mycophenolate mofetil or azathioprine was associated with a decreased incidence of TEAEs, and no difference in lung function decline or survival when compared with prednisone alone. Early transition to mycophenolate mofetil or azathioprine may be an appropriate therapeutic approach in CHP, but more studies are needed.

11.
Anal Chem ; 87(24): 12238-44, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26537538

RESUMO

The mucopolysaccharidoses (MPS) are lysosomal storage disorders that result from defects in the catabolism of glycosaminoglycans. Impaired muscle, bone, and connective tissue are typical clinical features of MPS due to disruption of the extracellular matrix. Markers of MPS disease pathology are needed to determine disease severity and monitor effects of existing and emerging new treatments on disease mechanisms. Urine samples from a small cohort of MPS-I, -II, and -VI patients (n = 12) were analyzed using label-free quantative proteomics. Fifty-three proteins including many associated with extracellular matrix organization were differently expressed. A targeted multiplexed peptide MRM LC-MS/MS assay was used on a larger validation cohort of patient samples (MPS-I n = 18, MPS-II n = 12, MPS-VI n = 6, control n = 20). MPS-I and -II groups were further subdivided according to disease severity. None of the markers assessed were altered significantly in the mild disease groups compared to controls. ß-galactosidase, a lysosomal protein, was elevated 3.6-5.7-fold significantly (p < 0.05) in all disease groups apart from mild MPS-I and -II. Collagen type Iα, fatty-acid-binding-protein 5, nidogen-1, cartilage oligomeric matrix protein, and insulin-like growth factor binding protein 7 concentrations were elevated in severe MPS I and II groups. Cartilage oligomeric matrix protein, insulin-like growth factor binding protein 7, and ß-galactosidase were able to distinguish the severe neurological form of MPS-II from the milder non-neurological form. Protein Heg1 was significantly raised only in MPS-VI. This work describes the discovery of new biomarkers of MPS that represent disease pathology and allows the stratification of MPS-II patients according to disease severity.


Assuntos
Biomarcadores/urina , Matriz Extracelular/metabolismo , Mucopolissacaridoses/metabolismo , Mucopolissacaridoses/urina , Proteômica/métodos , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida de Alta Pressão , Humanos , Nanotecnologia
12.
Malar J ; 12: 306, 2013 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-24127739

RESUMO

BACKGROUND: Severe malaria may be complicated by the acute respiratory distress syndrome (ARDS), which is associated with a high mortality. In the present report, a series of three cases of imported malaria complicated by refractory severe ARDS supported with extracorporeal membrane oxygenation (ECMO) is presented. METHODS: One female and two male adult patients (ages 39 to 53) were included. Two patients had Plasmodium falciparum infection and one patient had Plasmodium vivax and Plasmodium ovale co-infection. Anti-malarial therapy consisted in intravenous quinine (in two patients) and intravenous quinidine (in one patient), plus clindamycin or doxycycline. RESULTS: Despite lung protective ventilation, a conservative strategy of fluid management, corticosteroids (two patients), prone position (two patients) and inhaled nitric oxide (one patient), refractory severe ARDS supervened (PaO2 to FiO2 ratio 68) and venovenous ECMO was then initiated. In one patient, a bicaval dual-lumen cannula was inserted; in the two other patients, a two-site configuration was used. Two patients survived to hospital-discharge (duration of ECMO support: 8.5 days) and one patient died from nosocomial sepsis and multi-organ failure after 40 days of ECMO support. CONCLUSIONS: ECMO support allowed adequate oxygenation and correction of hypercapnia under lung protective ventilation, therefore reducing ventilator-induced lung injury. ECMO referral should be considered early in malaria complicated by severe ARDS refractory to conventional treatment.


Assuntos
Oxigenação por Membrana Extracorpórea , Malária/fisiopatologia , Síndrome do Desconforto Respiratório do Adulto/parasitologia , Síndrome do Desconforto Respiratório do Adulto/terapia , Adulto , Antimaláricos/uso terapêutico , Evolução Fatal , Feminino , Humanos , Malária/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Plasmodium/isolamento & purificação
13.
Eur Respir J ; 41(6): 1324-30, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23728404

RESUMO

A third of patients with idiopathic pulmonary fibrosis (IPF) develop pulmonary hypertension (PH-IPF), which is associated with increased mortality. Whether an altered gene expression profile in the pulmonary vasculature precedes the clinical onset of PH-IPF is unknown. We compared gene expression in the pulmonary vasculature of IPF patients with and without PH with controls. Pulmonary arterioles were isolated using laser capture microdissection from 16 IPF patients: eight with PH (PH-IPF) and eight with no PH (NPH-IPF), and seven controls. Probe was prepared from extracted RNA, and hybridised to Affymetrix Hu133 2.0 Plus genechips. Biometric Research Branch array tools and Ingenuity Pathway Analysis software were used for analysis of the microarray data. Univariate analysis revealed 255 genes that distinguished IPF arterioles from controls (p<0.001). Mediators of vascular smooth muscle and endothelial cell proliferation, Wnt signalling and apoptosis were differentially expressed in IPF arterioles. Unsupervised and supervised clustering analyses revealed similar gene expression in PH-IPF and NPH-IPF arterioles. The pulmonary arteriolar gene expression profile is similar in IPF patients with and without coexistent PH. Pathways involved in vascular proliferation and aberrant apoptosis, which may contribute to pulmonary vascular remodelling, are activated in IPF patients.


Assuntos
Arteríolas/metabolismo , Perfilação da Expressão Gênica , Hipertensão Pulmonar/metabolismo , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Proliferação de Células , Análise por Conglomerados , Feminino , Regulação da Expressão Gênica , Humanos , Imuno-Histoquímica , Microdissecção e Captura a Laser , Pulmão/patologia , Doenças Pulmonares Intersticiais/metabolismo , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Transcriptoma
14.
Semin Dial ; 26(3): 344-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23095044

RESUMO

Expenditures on dialysis vascular access now exceed $2.5 Billion annually in the US. Studies suggest that significant savings could be achieved by increasing arteriovenous fistula (AVF) prevalence to >65%. It is common but unsubstantiated opinion that AVF have lower maintenance costs than arteriovenous grafts (AVG). This manuscript tests this hypothesis by direct comparison. Equipment utilization time and supply utilization on 110 thrombectomy procedures on AVF and 258 on AVG were compared. Procedures techniques were standardized within one facility and procedures performed by a multiple but limited number of operators. There were no significant differences in demographic variables and comorbid factors between groups. Time to complete AVF thrombectomy was 1.7 times that for AVG. In addition, major supplies used such as wires and balloons were also significantly greater. Interventionists who took longer than average to thrombectomize AVF took longer than average to thrombectomize AVG. The prevalence of arterial inflow lesions was 1.5 greater in thrombosed AVF versus Thrombosed AVG. Procedure costs when analyzed in terms of procedure time, room utilization, staff, and equipment are significantly greater for thrombosed AVF than thrombosed AVG.


Assuntos
Derivação Arteriovenosa Cirúrgica/economia , Prótese Vascular/economia , Oclusão de Enxerto Vascular/terapia , Trombectomia/economia , Comorbidade , Feminino , Oclusão de Enxerto Vascular/economia , Humanos , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Diálise Renal
15.
Fertil Steril ; 95(5): 1560-7.e1-3, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21333981

RESUMO

OBJECTIVE: To investigate the mechanism underlying the appearance of a 20-kd HSP70 fragment and its consequences in the ectopic endometrium of endometriosis patients. DESIGN: Experimental study. SETTING: Research institute and obstetrics and gynecology clinic. PATIENT(S): Participants with (n = 18) and without (n = 20) endometriosis. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Reverse-transcription polymerase chain reaction, protease assays, and in silico tools were used to investigate the origin of the 20-kd HSP70 fragment. Immunocolocalization studies were carried out to determine whether subtilisin/kexin isozyme 1 (SKI-1) and HSP70 are colocalized. Expression and localization of surrogate markers of inflammation, such as nuclear factor NF-κB and interleukin IL-6 were examined by immunoblotting and in situ studies. RESULT(S): HSP70 is posttranslationally processed into a 20-kd fragment by SKI-1, a protease of the subtilisin family, in ectopic endometrium (ECE). Immunocolocalization studies revealed spatial proximity of SKI-1 and HSP70 in ECE. Furthermore, ECE demonstrated nuclear localization of the transcription factor, NF-κB and high expression of its target protein, IL-6. CONCLUSION(S): This study hints at the possible mechanisms underlying the trimming of HSP70 in ECE and also at the role of proteases in the pathogenesis of endometriosis. The possible repercussions of HSP70 fragmentation include dysregulation of key regulatory proteins, resulting in the escalation of inflammatory events in endometriotic lesions.


Assuntos
Endometriose/etiologia , Proteínas de Choque Térmico HSP70/metabolismo , Doenças Peritoneais/etiologia , Processamento de Proteína Pós-Traducional/fisiologia , Adulto , Sequência de Bases , Endometriose/genética , Endometriose/metabolismo , Endometriose/patologia , Feminino , Proteínas de Choque Térmico HSP70/genética , Humanos , Dados de Sequência Molecular , Doenças Peritoneais/genética , Doenças Peritoneais/metabolismo , Doenças Peritoneais/patologia , Pró-Proteína Convertases/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Serina Endopeptidases/metabolismo , Subtilisina/metabolismo , Distribuição Tecidual , Adulto Jovem
16.
Am J Respir Cell Mol Biol ; 45(3): 453-8, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21131446

RESUMO

We have previously shown that the transcription-promoting activity of serum response factor (SRF) is partially regulated by its extranuclear redistribution. In this study, we examined the cellular mechanisms that facilitate SRF nuclear entry in canine tracheal smooth muscle cells. We used in vitro pull-down assays to determine which karyopherin proteins bound SRF and found that SRF binds KPNA1 and KPNB1 through its nuclear localization sequence. Immunoprecipitation studies also demonstrated direct SRF-KPNA1 interaction in HEK293 cells. Import assays demonstrated that KPNA1 and KPNB1 together were sufficient to mediate rapid nuclear import of SRF-GFP. Our studies also suggest that SRF is able to gain nuclear entry through an auxiliary, nuclear localization sequence-independent mechanism.


Assuntos
Transporte Ativo do Núcleo Celular , Músculo Liso/citologia , Fator de Resposta Sérica/metabolismo , Linhagem Celular , Núcleo Celular/metabolismo , Dimerização , Proteínas de Fluorescência Verde/metabolismo , Humanos , Imunoprecipitação , Microscopia de Fluorescência/métodos , Modelos Biológicos , Mutação , Ligação Proteica , Proteínas Recombinantes de Fusão/química , alfa Carioferinas/metabolismo
17.
West J Emerg Med ; 11(2): 197-200, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20823972

RESUMO

BACKGROUND: Intussusception is a condition found primarily in the pediatric population. In the adult population, however, intussusception is usually due to a pathological process, with a higher risk of bowel obstruction, vascular compromise, inflammatory changes, ischemia, and necrosis. Radiographic and sonographic evidence can aid in the diagnosis. Surgical intervention involving resection of affected bowel is the standard of care in adult cases of intussusception. CASE REPORTS: We present the case of a 21-year-old female who presented to the Emergency Department with diffuse cramping abdominal pain and distention. Workup revealed ileocecal intussusception, with a prior appendectomy scar serving as the lead point discovered during exploratory laparotomy. We also present the case of a 66-year-old male, who presented with one week of intermittent lower abdominal pain associated with several episodes of nausea and vomiting. Workup revealed ileocolic intussusception secondary to adenocarcinoma of the right colon, confirmed upon exploratory laparotomy with subsequent right hemicolectomy. CONCLUSION: In the adult population, intussusception is usually caused by a lead point, with subsequent telescoping of one part of the bowel into an adjacent segment. While intussusception can occur in any part of the bowel, it usually occurs between a freely moving segment and either a retroperitoneal or an adhesion-fixed segment. The etiology may be associated with pathological processes such as carcinoma or iatrogenic causes, such as scars or adhesions from prior surgeries. The cases presented here demonstrate important etiologies of abdominal pain in adult patients. Along with gynecological etiologies of lower quadrant abdominal pain in female patients, it is important for the emergency physician to expand the differential diagnosis to include other causes, such as intussusceptions, especially given the symptoms that could be associated with bowel obstruction.

18.
Anal Bioanal Chem ; 398(4): 1801-8, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20730526

RESUMO

The isoprenoids farnesyl-(FPP) and geranylgeranylpyrophosphate (FPP and GGPP) are two major lipid intermediates in the mevalonate pathway. They participate in post-translational modification of members of the superfamily of small guanosine triphosphatases (GTPases; Ras, Rab, Rac, etc.) via prenylation reactions. Due to the important role of these proteins in a number of cell processes, in particular cell growth, division, and differentiation, investigation of the involvement of isoprenoids in these processes is of great interest. In a previously published report, we described a fully validated assay for the quantitation of the two isoprenoids using a high-performance liquid chromatography (HPLC)-fluorescence detection (FLD) method. The current work expands on the previous method and enhances it greatly by using a much faster state-of-the-art ultrahigh-performance liquid chromatography (UHPLC) technique coupled to tandem mass spectrometry (MS/MS). The method exhibited a linear concentration range of 5-250 ng/mL for FPP and GGPP in human brain tissue; it was shown to be unaffected by ion suppression and provided results almost six times faster than the HPLC-FLD assay. Comparison of UHPLC-MS/MS and HPLC-FLD yielded excellent comparability of the two assays for both isoprenoids. Based on the UHPLC-MS/MS assay, a novel in vitro test system was implemented to study enzyme specificity for distinct amino acid CAAX motifs, which is potentially useful for investigating target interactions of new therapeutics for diseases involving pathological regulation of isoprenoids and/or small GTPases.


Assuntos
Alquil e Aril Transferases/química , Química Encefálica , Cromatografia Líquida de Alta Pressão/métodos , Farnesil-Difosfato Farnesiltransferase/química , Fosfatos de Poli-Isoprenil/análise , Sesquiterpenos/análise , Espectrometria de Massas em Tandem/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Alquil e Aril Transferases/metabolismo , Encéfalo/enzimologia , Encéfalo/metabolismo , Farnesil-Difosfato Farnesiltransferase/metabolismo , Feminino , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Fosfatos de Poli-Isoprenil/metabolismo , Sesquiterpenos/metabolismo
19.
Fertil Steril ; 94(6): 1964-71, 1971.e1, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20236630

RESUMO

OBJECTIVE: To examine proteins aberrantly expressed in the ectopic endometrium compared with eutopic endometrium from the same patient. DESIGN: Experimental study. SETTING: Research institute and an obstetrics and gynecology clinic (National Institute for Research in Reproductive Health and Sanjeevani Diagnostic Center and Maternity Home, India). PATIENT(S): Twenty participants with (n=11) and without (n=9) endometriosis. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Protein identification by two-dimensional (2D) electrophoresis and mass spectrometry as well as validation of the identified proteins by studying protein expression via Western blot and protein localization via immunohistochemical analysis. RESULT(S): Computer-assisted image analysis detected the presence of 53 protein spots in ectopic 2D gels that were conspicuous by their absence in the 2D maps of eutopic and control endometrium, i.e., these spots were detected only in ectopic gels. Eleven spots were identified by mass spectrometry. The expression of four of these proteins-haptoglobin, Rho-GDIα, SM-22α, and Rab37-have been validated by immunohistochemical and Western blotting analysis. CONCLUSION(S): This study assumes significance, as there are no reports on the comparison of the global protein profiles of paired eutopic and ectopic endometrium. Furthermore, the study demonstrates a definitive difference in the protein repertoire of the ectopic endometrium compared with its uterine counterpart in the same patient. Such studies are relevant in deciphering the complex biology of the endometriotic lesion.


Assuntos
Endometriose/metabolismo , Endométrio/metabolismo , Proteoma/análise , Doenças Uterinas/metabolismo , Estudos de Casos e Controles , Coristoma/metabolismo , Coristoma/patologia , Eletroforese em Gel Bidimensional , Endometriose/patologia , Endométrio/patologia , Feminino , Humanos , Proteoma/metabolismo , Doenças Uterinas/patologia
20.
Hypertension ; 52(2): 249-55, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18606901

RESUMO

Vitamin D receptor activation is associated with improved survival in patients with chronic kidney disease, but the mechanism of this benefit is unclear. To better understand the effects of vitamin D on endothelial function, blood pressure, albuminuria, and inflammation in patients with chronic kidney disease (2 patients stage 2, remaining stage 3), we conducted a pilot trial in 24 patients who were randomly allocated equally to 3 groups to receive 0, 1, or 2 microg of paricalcitol, a vitamin D analog, orally for 1 month. Placebo-corrected change in flow mediated dilatation with a 1-microg dose was 0.5% and 0.4% with a 2-microg dose (P>0.2). At 1 month, the treatment:baseline ratio of high sensitivity C-reactive protein was 1.5 (95% CI: 1.1 to 2.1; P=0.02) with placebo, 0.8 (95% CI: 0.3 to 1.9; P=0.62) with a 1-microg dose, and 0.5 (95% CI: 0.3 to 0.9; P=0. 03) with a 2-microg dose of paricalcitol. At 1 month, the treatment:baseline ratio of 24-hour albumin excretion rate was 1.35 (95% CI: 1.08 to 1.69; P=0.01) with placebo, 0.52 (95% CI: 0.40 to 0.69; P<0.001) with a 1-microg dose, and 0.54 (95% CI: 0.35 to 0.83; P=0. 01) with a 2-microg dose (P<0.001 for between group changes). No differences were observed in iothalamate clearance, 24-hour ambulatory blood pressure, or parathyroid hormone with treatment or on washout. Thus, paricalcitol-induced reduction in albuminuria and inflammation may be mediated independent of its effects on hemodynamics or parathyroid hormone suppression. Long-term randomized, controlled trials are required to confirm these benefits of vitamin D analogs.


Assuntos
Albuminúria/prevenção & controle , Ergocalciferóis/administração & dosagem , Mediadores da Inflamação/metabolismo , Falência Renal Crônica/tratamento farmacológico , Falência Renal Crônica/mortalidade , Idoso , Idoso de 80 Anos ou mais , Albuminúria/diagnóstico , Albuminúria/epidemiologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Falência Renal Crônica/diagnóstico , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Probabilidade , Valores de Referência , Medição de Risco , Índice de Gravidade de Doença , Resultado do Tratamento
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