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1.
Artigo em Inglês | MEDLINE | ID: mdl-32799544

RESUMO

Significance: In humans, imbalances in the reduction-oxidation (redox) status of cells are associated with many pathological states. In addition, many therapeutics and prophylactics used as interventions for diverse pathologies either directly modulate oxidant levels or otherwise influence endogenous cellular redox systems. Recent Advances: The cellular machineries that maintain redox homeostasis or that function within antioxidant defense systems rely heavily on the regulated reactivities of sulfur atoms either within or derived from the amino acids cysteine and methionine. Recent advances have substantially advanced our understanding of the complex and essential chemistry of biological sulfur-containing molecules. Critical Issues: The redox machineries that maintain cellular homeostasis under diverse stresses can consume large amounts of energy to generate reducing power and/or large amounts of sulfur-containing nutrients to replenish or sustain intracellular stores. By understanding the metabolic pathways underlying these responses, one can better predict how to protect cells from specific stresses. Future Directions: Here, we summarize the current state of knowledge about the impacts of different stresses on cellular metabolism of sulfur-containing molecules. This analysis suggests that there remains more to be learned about how cells use sulfur chemistry to respond to stresses, which could in turn lead to advances in therapeutic interventions for some exposures or conditions.

2.
Proc Natl Acad Sci U S A ; 116(23): 11408-11417, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31097586

RESUMO

Thioredoxin reductase-1 (TrxR1)-, glutathione reductase (Gsr)-, and Nrf2 transcription factor-driven antioxidant systems form an integrated network that combats potentially carcinogenic oxidative damage yet also protects cancer cells from oxidative death. Here we show that although unchallenged wild-type (WT), TrxR1-null, or Gsr-null mouse livers exhibited similarly low DNA damage indices, these were 100-fold higher in unchallenged TrxR1/Gsr-double-null livers. Notwithstanding, spontaneous cancer rates remained surprisingly low in TrxR1/Gsr-null livers. All genotypes, including TrxR1/Gsr-null, were susceptible to N-diethylnitrosamine (DEN)-induced liver cancer, indicating that loss of these antioxidant systems did not prevent cancer cell survival. Interestingly, however, following DEN treatment, TrxR1-null livers developed threefold fewer tumors compared with WT livers. Disruption of TrxR1 in a marked subset of DEN-initiated cancer cells had no effect on their subsequent contributions to tumors, suggesting that TrxR1-disruption does not affect cancer progression under normal care, but does decrease the frequency of DEN-induced cancer initiation. Consistent with this idea, TrxR1-null livers showed altered basal and DEN-exposed metabolomic profiles compared with WT livers. To examine how oxidative stress influenced cancer progression, we compared DEN-induced cancer malignancy under chronically low oxidative stress (TrxR1-null, standard care) vs. elevated oxidative stress (TrxR1/Gsr-null livers, standard care or phenobarbital-exposed TrxR1-null livers). In both cases, elevated oxidative stress was correlated with significantly increased malignancy. Finally, although TrxR1-null and TrxR1/Gsr-null livers showed strong Nrf2 activity in noncancerous hepatocytes, there was no correlation between malignancy and Nrf2 expression within tumors across genotypes. We conclude that TrxR1, Gsr, Nrf2, and oxidative stress are major determinants of liver cancer but in a complex, context-dependent manner.


Assuntos
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Glutationa Redutase/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Estresse Oxidativo/fisiologia , Tiorredoxina Redutase 1/metabolismo , Animais , Antioxidantes/metabolismo , Dano ao DNA/fisiologia , Progressão da Doença , Regulação da Expressão Gênica/fisiologia , Glutationa/metabolismo , Hepatócitos/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Metaboloma/fisiologia , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Oxirredução
3.
Br J Pharmacol ; 176(4): 532-543, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30221761

RESUMO

Intermediary metabolism and detoxification place high demands on the disulfide reductase systems in most hepatocyte subcellular compartments. Biosynthetic, metabolic, cytoprotective and signalling activities in the cytosol; regulation of transcription in nuclei; respiration in mitochondria; and protein folding in endoplasmic reticulum all require resident disulfide reductase activities. In the cytosol, two NADPH-dependent enzymes, glutathione reductase and thioredoxin reductase, as well as a recently identified NADPH-independent system that uses catabolism of methionine to maintain pools of reduced glutathione, supply disulfide reducing power. However the necessary discontinuity between the cytosol and the interior of organelles restricts the ability of the cytosolic systems to support needs in other compartments. Maintenance of molecular- and charge-gradients across the inner-mitochondrial membrane, which is needed for oxidative phosphorylation, mandates that the matrix maintain an autonomous set of NADPH-dependent disulfide reductase systems. Elsewhere, complex mechanisms mediate the transfer of cytosolic reducing power into specific compartments. The redox needs in each compartment also differ, with the lumen of the endoplasmic reticulum, the mitochondrial inter-membrane space and some signalling proteins in the cytosol each requiring different levels of protein oxidation. Here, we present an overview of the current understanding of the disulfide reductase systems in major subcellular compartments of hepatocytes, integrating knowledge obtained from direct analyses on liver with inferences from other model systems. Additionally, we discuss relevant advances in the expanding field of redox signalling. LINKED ARTICLES: This article is part of a themed section on Chemical Biology of Reactive Sulfur Species. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.4/issuetoc.


Assuntos
Dissulfetos/metabolismo , Fígado/metabolismo , Oxirredutases/metabolismo , Animais , Humanos , NADP/metabolismo , Organelas/metabolismo , Oxirredução , Frações Subcelulares/metabolismo
4.
Free Radic Biol Med ; 127: 248-261, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29609022

RESUMO

Over the past seven decades, research on autotrophic and heterotrophic model organisms has defined how the flow of electrons ("reducing power") from high-energy inorganic sources, through biological systems, to low-energy inorganic products like water, powers all of Life's processes. Universally, an initial major biological recipient of these electrons is nicotinamide adenine dinucleotide-phosphate, which thereby transits from an oxidized state (NADP+) to a reduced state (NADPH). A portion of this reducing power is then distributed via the cellular NADPH-dependent disulfide reductase systems as sequential reductions of disulfide bonds. Along the disulfide reduction pathways, some enzymes have active sites that use the selenium-containing amino acid, selenocysteine, in place of the common but less reactive sulfur-containing cysteine. In particular, the mammalian/metazoan thioredoxin systems are usually selenium-dependent as, across metazoan phyla, most thioredoxin reductases are selenoproteins. Among the roles of the NADPH-dependent disulfide reductase systems, the most universal is that they provide the reducing power for the production of DNA precursors by ribonucleotide reductase (RNR). Some studies, however, have uncovered examples of NADPH-independent disulfide reductase systems that can also support RNR. These systems are summarized here and their implications are discussed.


Assuntos
NADH NADPH Oxirredutases/metabolismo , NADP/metabolismo , Ribonucleotídeo Redutases/metabolismo , Animais , Humanos , Oxirredução
5.
Cell Rep ; 19(13): 2771-2781, 2017 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-28658624

RESUMO

Energetic nutrients are oxidized to sustain high intracellular NADPH/NADP+ ratios. NADPH-dependent reduction of thioredoxin-1 (Trx1) disulfide and glutathione disulfide by thioredoxin reductase-1 (TrxR1) and glutathione reductase (Gsr), respectively, fuels antioxidant systems and deoxyribonucleotide synthesis. Mouse livers lacking both TrxR1 and Gsr sustain these essential activities using an NADPH-independent methionine-consuming pathway; however, it remains unclear how this reducing power is distributed. Here, we show that liver-specific co-disruption of the genes encoding Trx1, TrxR1, and Gsr (triple-null) causes dramatic hepatocyte hyperproliferation. Thus, even in the absence of Trx1, methionine-fueled glutathione production supports hepatocyte S phase deoxyribonucleotide production. Also, Trx1 in the absence of TrxR1 provides a survival advantage to cells under hyperglycemic stress, suggesting that glutathione, likely via glutaredoxins, can reduce Trx1 disulfide in vivo. In triple-null livers like in many cancers, deoxyribonucleotide synthesis places a critical yet relatively low-volume demand on these reductase systems, thereby favoring high hepatocyte turnover over sustained hepatocyte integrity.


Assuntos
Glutationa Redutase/metabolismo , Hepatócitos/citologia , Hepatócitos/metabolismo , Tiorredoxina Redutase 1/metabolismo , Tiorredoxinas/metabolismo , Animais , Proliferação de Células/fisiologia , Humanos , Masculino , Camundongos
6.
Semin Arthritis Rheum ; 47(3): 323-330, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28624172

RESUMO

OBJECTIVE: Nerve growth factor antibodies (NGF-ab) have shown promising analgesic efficacy. Aim was to describe reader training efforts and present reliability data focusing on radiographic eligibility in the tanezumab program. METHODS: A multi-step process was used for reader calibration and reliability testing. First, a reference standard set of cases was created and diagnostic performance was evaluated. A second exercise focused on agreement of ordinal assessment (Kellgren-Lawrence grading) of radiographic osteoarthritis. Subsequently, 11 readers were trained and read a test set of 100 cases focused on eligibility assessments. Additional reliability testing and calibration of five core readers assessing eligibility of 30 cases was performed 3 and 6 months after study start. RESULTS: Sensitivity for the reference standard readings ranged from 0.50 to 0.90 and specificity from 0.40 to 0.83. Overall agreement for Kellgren-Lawrence grading ranged from 71.4% to 82.9%. For the 11 reader exercise, in 76% of cases at least 8 of 11 readers agreed on eligibility status. For the reliability testing 3 months after study start, in 80.0% of cases at least 4 of 5 readers agreed on eligibility with a κ = 0.43 (95% CI: 0.32-0.54). For the reliability testing after 6 months, in 83.3% of cases at least 4 of 5 readers agreed on eligibility with a κ = 0.52 (95% CI: 0.41-0.63). CONCLUSIONS: After intense efforts spent in the development of an imaging program for an NGF-ab clinical program, the achieved reliability for eligibility assessment is substantial but not perfect. Ongoing efforts of calibration prior to including additional readers to the program and during study conduct between current readers will be needed to ensure agreement on potential adverse events and radiographic disease severity.


Assuntos
Ensaios Clínicos como Assunto , Osteoartrite/diagnóstico por imagem , Radiografia/normas , Analgésicos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Humanos , Variações Dependentes do Observador , Osteoartrite/tratamento farmacológico , Osteonecrose/diagnóstico por imagem , Seleção de Pacientes , Padrões de Referência , Reprodutibilidade dos Testes , Índice de Gravidade de Doença
7.
J Clin Densitom ; 19(4): 485-491, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27052635

RESUMO

Quantitative computed tomography (QCT) measurements have been used extensively to ascertain information about bone quality and density due to the 3-dimensional information provided and the ability to segment out trabecular and cortical bones. QCT imaging helps to improve our understanding of the role that each bone compartment plays in the pathogenesis and prognosis of fracture. This study was conducted to explore longitudinal changes in femoral neck (FN) cortical bone structure using both volumetric bone mineral density (vBMD) and cortical shell thickness assessments via QCT in a double-blind, randomized, multicenter clinical trial in postmenopausal women with type 2 diabetes mellitus. This study also examined whether treatment-associated changes in the cortical bone vBMD and thickness in femoral neck quadrants could be evaluated. Subjects were randomized to rosiglitazone (RSG) or metformin (MET) for 52 wk followed by 24 wk of open-label MET. A subset of 87 subjects underwent QCT scans of the hip at baseline, after 52 wk of double-blind treatment, and after 24 wk of treatment with MET using standard full-body computed tomography scanners. All scans were evaluated and analyzed centrally. Cortical vBMD at the FN was precisely segmented from trabecular bone and used to assess a possible therapeutic effect on this bone compartment. QCT analysis showed reductions in adjusted mean percentage change in vBMD and in absolute cortical thickness occurred with RSG treatment from baseline to week 52, whereas changes with MET were generally minimal. The reductions observed during RSG treatment for 1 yr appeared to partially reverse during the open-label MET phase from weeks 52 to 76. The femoral neck quadrant may provide utility as a potential endpoint in clinical trials for the understanding of the therapeutic effect of new entities on cortical bone vs trabecular bone; however, further clinical validation is needed. TRIAL REGISTRATION: The protocol (GSK study number AVD111179) was registered on ClinicalTrials.gov as NCT00679939.


Assuntos
Osso Cortical/diagnóstico por imagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Colo do Fêmur/diagnóstico por imagem , Hipoglicemiantes/uso terapêutico , Tiazolidinedionas/uso terapêutico , Tomografia Computadorizada por Raios X , Osso Cortical/efeitos dos fármacos , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Diabetes Mellitus Tipo 2/fisiopatologia , Método Duplo-Cego , Feminino , Colo do Fêmur/efeitos dos fármacos , Fraturas Ósseas/diagnóstico , Humanos , Estudos Longitudinais , Pós-Menopausa , Fatores de Risco , Rosiglitazona
8.
J Clin Densitom ; 19(2): 220-5, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26071169

RESUMO

New densitometer installation requires cross-calibration for accurate longitudinal assessment. When replacing a unit with the same model, the International Society for Clinical Densitometry recommends cross-calibrating by scanning phantoms 10 times on each instrument and states that spine bone mineral density (BMD) should be within 1%, whereas total body lean, fat, and %fat mass should be within 2% of the prior instrument. However, there is limited validation that these recommendations provide adequate total body cross-calibration. Here, we report a total body cross-calibration experience with phantoms and humans. Cross-calibration between an existing and new Lunar iDXA was performed using 3 encapsulated spine phantoms (GE [GE Lunar, Madison, WI], BioClinica [BioClinica Inc, Princeton, NJ], and Hologic [Hologic Inc, Bedford, MA]), 1 total body composition phantom (BioClinica), and 30 human volunteers. Thirty scans of each phantom and a total body scan of human volunteers were obtained on each instrument. All spine phantom BMD means were similar (within 1%; <-0.010 g/cm2 bias) between the existing and new dual-energy X-ray absorptiometry unit. The BioClinica body composition phantom (BBCP) BMD and bone mineral content (BMC) values were within 2% with biases of 0.005 g/cm2 and -3.4 g. However, lean and fat mass and %fat differed by 4.6%-7.7% with biases of +463 g, -496 g, and -2.8%, respectively. In vivo comparison supported BBCP data; BMD and BMC were within ∼2%, but lean and fat mass and %fat differed from 1.6% to 4.9% with biases of +833 g, -860 g, and -1.1%. As all body composition comparisons exceeded the recommended 2%, the new densitometer was recalibrated. After recalibration, in vivo bias was lower (<0.05%) for lean and fat; -23 and -5 g, respectively. Similarly, BBCP lean and fat agreement improved. In conclusion, the BBCP behaves similarly, but not identical, to human in vivo measurements for densitometer cross-calibration. Spine phantoms, despite good BMD and BMC agreement, did not detect substantial lean and fat differences observed using BBCP and in vivo assessments. Consequently, spine phantoms are inadequate for dual-energy X-ray absorptiometry whole body composition cross-calibration.


Assuntos
Composição Corporal , Densidade Óssea , Imagem Corporal Total , Absorciometria de Fóton/métodos , Absorciometria de Fóton/normas , Adulto , Calibragem , Feminino , Humanos , Masculino , Imagens de Fantasmas , Coluna Vertebral/diagnóstico por imagem , Imagem Corporal Total/instrumentação , Imagem Corporal Total/métodos
9.
Ann Rheum Dis ; 73(6): 1067-70, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23606704

RESUMO

OBJECTIVES: To evaluate if the mean smallest detectable change (SDC) of multiple time intervals using the Bland & Altman (B&A) levels of agreement (LoA) method is an appropriate surrogate for the generalisability analysis method for estimating the overall SDC of radiological progression in rheumatoid arthritis (RA) trials. Secondly, to compare the SDC based on 95% LoA with the SDC based on 80% LoA, and to investigate the association between SDC and baseline damage and progression. METHODS: Fifteen datasets from randomised controlled trials in RA were scored by 13 experienced readers as pairs according to the modified Sharp/van der Heijde method. The SDC using the 95% and 80% LoA and the generalisability methods was calculated. RESULTS: 21 295 radiographic time points from 7643 patients were included. The mean (range) SDC for the LoA and the generalisability methods was 3.1 (2.3-4.3) and 3.2 (2.3-4.6) units, respectively. The mean ± SD difference between the two methods was -0.13 ± 0.28. The mean SDC including all intervals (n=31) was 3.0 ± 0.7 for 95% LoA and 2.0 ± 0.4 for 80% LoA. No relationship was observed between baseline damage and the SDC, whereas the SDC increased with increasing radiological progression. CONCLUSIONS: The mean of the interval SDCs obtained by the simple LoA method is a valid surrogate for the SDC obtained by complex generalisability methods. The SDC depends on the level of radiographic progression rather than on the level of absolute damage. In addition, the use of an SDC based on 80% rather than on 95% LoA is proposed.


Assuntos
Artrite Reumatoide/diagnóstico por imagem , Limite de Detecção , Análise de Variância , Artrite Reumatoide/terapia , Bases de Dados Factuais , Progressão da Doença , Humanos , Radiografia , Ensaios Clínicos Controlados Aleatórios como Assunto , Reprodutibilidade dos Testes , Resultado do Tratamento
10.
J Clin Endocrinol Metab ; 98(4): 1519-28, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23450056

RESUMO

CONTEXT: Postmenopausal status and type 2 diabetes mellitus (T2DM) are independent risk factors for fractures. An increased fracture risk has been observed with rosiglitazone (RSG), a thiazolidinedione, in patients with T2DM. DESIGN AND SETTING: This was a randomized, double-blind study in postmenopausal women with T2DM. A 52-week double-blind phase (RSG or metformin [MET]) was followed by a 24-week open-label phase, during which time all patients received MET. MAIN OUTCOME MEASURES: The primary endpoint was to assess the mean percentage change in bone mineral density (BMD) at the femoral neck (FN) by dual-energy x-ray absorptiometry from baseline to week 52 in the RSG treatment group. Key secondary objectives included assessment of changes in BMD at the total hip, trochanter, and lumbar spine and to evaluate RSG effects on bone turnover markers. RESULTS: From baseline to week 52, RSG was associated with a reduction in FN BMD by dual-energy x-ray absorptiometry (-1.47%). During the open-label phase (weeks 52-76), no further loss in FN BMD was observed. A decrease in BMD occurred at the total hip during RSG or MET treatment at 52 weeks (-1.62 and -0.72%, respectively). Total hip BMD loss by RSG was attenuated after switching to MET and was similar between treatment groups at the end of the open-label phase. From baseline to week 52, bone turnover markers significantly increased with RSG compared with MET, but decreased significantly during the open-label phase. CONCLUSIONS: RSG for 52 weeks in postmenopausal women with T2DM was associated with small reductions in FN, total hip, and lumbar spine BMD and increased bone turnover markers. These effects are attenuated after cessation of RSG treatment.


Assuntos
Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Pós-Menopausa/efeitos dos fármacos , Tiazolidinedionas/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Regulação para Baixo/efeitos dos fármacos , Substituição de Medicamentos , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Metformina/efeitos adversos , Metformina/farmacologia , Metformina/uso terapêutico , Pessoa de Meia-Idade , Rosiglitazona , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico
11.
Semin Arthritis Rheum ; 43(1): 1-8, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23290692

RESUMO

OBJECTIVE: Using placebo data from a recently completed disease-modifying osteoarthritis (OA) drug trial, we seek to inform study design of future radiographic studies. METHODS: Eligible patients aged ≥40 years, with body mass index (BMI) 25-40kg/m(2) and symptomatic knee OA diagnosed by modified Kellgren and Lawrence grade (KLG) 2 or 3 and pain/stiffness and/or use of medication for knee pain in the past year, were assessed by radiography using a modified Lyon-schuss (mL/S) protocol for joint space narrowing (JSN) (primary outcome variable) at baseline and weeks 48 and 96. Multifaceted quality control was conducted throughout. Repeat images were requested when the medial tibial plateau (MTP) was not aligned (inter-margin distance [IMD] >1.5mm) or for other quality issues. Data are given mean ± standard deviation. RESULTS: Patients (74.9% female; 61.3 ± 9.1 years) had BMI 31.6 ± 4.1kg/m(2) at baseline; 222 (173 females) had KLG2, 264 (191 female) KLG3. A significant loss in joint space width (JSW) from baseline to week 48 (-0.13 ± 0.36mm) and to week 96 (-0.22 ± 0.45mm) was observed for all randomised placebo patients (p < 0.001 for both), and at both time points when stratified by KLG2 or KLG3. Standard deviations were small relative to mean changes, providing standardised response means for all placebo patients of 0.35 (week 48) and 0.48 (week 96). CONCLUSIONS: Using a tightly controlled radiographic technique, JSN is a viable outcome variable for determining disease progression in mild-to-moderate knee OA. The mL/S protocol is a sensitive and feasible method for OA studies aiming to assess rate of JSN in the knee.


Assuntos
Antirreumáticos/uso terapêutico , Articulação do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/tratamento farmacológico , Projetos de Pesquisa , Adulto , Idoso , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico por imagem , Radiografia , Índice de Gravidade de Doença
12.
Rheumatology (Oxford) ; 52(8): 1404-7, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23329683

RESUMO

OBJECTIVE: The aim of this study is to provide data on the adjudication rate for a predetermined threshold of difference in change score between two readers in randomized controlled trials (RCTs). METHODS: Fifteen datasets from RCTs in RA were scored by 13 experienced readers as pairs according to the modified Sharp-van der Heijde method. The theoretical adjudication rates for thresholds of between 3 and 20 units were calculated. We investigated the influence of the number of time points within the same session, the length of the interval and disease duration on the adjudication rates. RESULTS: A total of 21,295 time points from 7643 patients from 15 databases were included in the analysis. The adjudication rate was inversely related to the threshold. Higher adjudication rates were observed with a higher number of time points, longer time intervals and in early versus established RA. The adjudication rates ranged from 0% to 22% depending on the scenario. CONCLUSION: With trained and experienced readers, the adjudication rate in RA RCTs is low even with very conservative adjudication thresholds.


Assuntos
Artrite Reumatoide/diagnóstico por imagem , Progressão da Doença , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Adulto , Artrografia/métodos , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Reumatologia/legislação & jurisprudência , Índice de Gravidade de Doença
13.
Ann Rheum Dis ; 72(2): 187-95, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23144445

RESUMO

OBJECTIVE: To determine if inhibition of inducible nitric oxide synthase (iNOS) with cindunistat hydrochloride maleate slows progression of osteoarthritis (OA) METHODS: This 2-year, multinational, double-blind, placebo-controlled trial enrolled patients with symptomatic knee OA (Kellgren and Lawrence Grade (KLG) 2 or 3). Standard OA therapies were permitted throughout. Patients were randomly assigned to cindunistat (50 or 200 mg/day) or placebo. Randomisation was stratified by KLG. Radiographs to assess joint space narrowing (JSN) were acquired using the modified Lyon-schuss protocol at baseline, week 48 and 96. RESULTS: Of 1457 patients (50 mg/day, n=485; 200 mg/day, n=486; placebo, n=486), 1048 (71.9%) completed the study. Patients were predominantly women; 56% had KLG3. The primary analysis did not demonstrate superiority of cindunistat versus placebo for rate of change in JSN. In KLG2 patients, JSN after 48 weeks was lower with cindunistat 50 mg/day versus placebo (p=0.032). Least-squares mean±SE JSN with cindunistat 50 mg/day ( -0.048±0.028 mm) and 200 mg/day (-0.062±0.028 mm) were 59.9% (95% CI 6.8% to 106.9%) and 48.7% (95% CI -8.4% to 93.9%) of placebo, improvement was not maintained at 96 weeks. No improvement was observed for KLG3 patients at either time-point. Cindunistat did not improve joint pain or function, but was generally well tolerated. CONCLUSIONS: Cindunistat (50 or 200 mg/day) did not slow the rate of JSN versus placebo. After 48-weeks, KLG2 patients showed less JSN; however, the improvement was not sustained at 96-weeks. iNOS inhibition did not slow OA progression in KLG3 patients. CLINICAL TRIAL LISTING: NCT00565812.


Assuntos
Amidinas/uso terapêutico , Cisteína/análogos & derivados , Inibidores Enzimáticos/uso terapêutico , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Osteoartrite do Joelho/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Cisteína/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico por imagem , Placebos , Radiografia , Resultado do Tratamento
14.
J Drug Assess ; 1(1): 11-9, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-27536422

RESUMO

OBJECTIVES: Post-hoc analyses have shown an increase incidence of fractures among type 2 diabetes (T2DM) patients treated with thiazolidinediones (TZDs). The mechanisms by which TZDs may be associated with increased fracture risk is not well understood. This article describes the study design and baseline characteristics for a prospective, randomized, double-blind, active-controlled trial to evaluate the effects of rosiglitazone on changes in measures of skeletal structure, surrogates of bone strength and metabolism. METHODS: Postmenopausal women without osteoporosis and diagnosed with T2DM were randomized in a double-blind design to either rosiglitazone or metformin for 52 weeks, then all subjects received open-label metformin for 24 weeks. Study endpoints included changes in bone mineral density (BMD), quantitative computed tomography (QCT), digitized hip radiography (HXR) and high resolution magnetic resonance imaging (hrMRI). Serum markers of bone metabolism and indices of glycemic control were assessed within and between treatment groups. RESULTS: A total of 226 subjects were randomized. Baseline characteristics included: age 63.8 ± 6.5 years; years postmenopausal 16.9 ± 8.4; duration of diabetes 3.5 (1.8-7.8) years; body mass index (BMI) 31.4 ± 5.9 kg/m(2); and glycated hemoglobin (HbA1c) 6.4 ± 0.65%. At baseline, mean T-scores were -0.95 ± 0.91 at the femoral neck, -0.02 ± 0.97 at the total hip and -0.55 ± 1.25 at the total spine. Since there are no well recognized techniques to determine bone mass and structure at the distal limbs (cortical bone sites where fractures were reported in RSG subjects), using the femoral neck as a surrogate for these areas may be a potential limitation of the study. CONCLUSION: This is the first randomized trial utilizing multiple techniques to evaluate bone mass, structure, serum markers of bone remodeling, and potential reversibility of changes after discontinuation of rosiglitazone. This study will provide information about RSG bone effects in a population of postmenopausal women at risk for bone loss and subsequent fracture. CLINICALTRIALSGOV NUMBER: NCT00679939.

15.
Radiology ; 259(3): 875-84, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21325035

RESUMO

UNLABELLED: Quantitative imaging biomarkers could speed the development of new treatments for unmet medical needs and improve routine clinical care. However, it is not clear how the various regulatory and nonregulatory (eg, reimbursement) processes (often referred to as pathways) relate, nor is it clear which data need to be collected to support these different pathways most efficiently, given the time- and cost-intensive nature of doing so. The purpose of this article is to describe current thinking regarding these pathways emerging from diverse stakeholders interested and active in the definition, validation, and qualification of quantitative imaging biomarkers and to propose processes to facilitate the development and use of quantitative imaging biomarkers. A flexible framework is described that may be adapted for each imaging application, providing mechanisms that can be used to develop, assess, and evaluate relevant biomarkers. From this framework, processes can be mapped that would be applicable to both imaging product development and to quantitative imaging biomarker development aimed at increasing the effectiveness and availability of quantitative imaging. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100800/-/DC1.


Assuntos
Biomarcadores , Diagnóstico por Imagem , Difusão de Inovações , Avaliação da Tecnologia Biomédica/normas , Pesquisa Biomédica/organização & administração , Conflito de Interesses , Aprovação de Equipamentos , Europa (Continente) , Humanos , Valor Preditivo dos Testes , Estados Unidos , United States Food and Drug Administration
16.
Spine (Phila Pa 1976) ; 34(22): 2437-43, 2009 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-19829258

RESUMO

STUDY DESIGN: Image analysis model development. OBJECTIVE: The objective of this study was to develop a novel clinical workflow tool that uses model-based shape recognition technology to allow efficient, semiautomated detailed annotation of each vertebra between T4 and L4 on plain lateral radiographs. SUMMARY OF BACKGROUND DATA: Identification of prevalent vertebral fractures, especially when not symptomatic, has been problematic despite their importance. There is a recognized need to increase the opportunities to detect vertebral fractures so that clinically beneficial therapeutic interventions can be initiated. METHODS: Radiographs obtained from 165 subjects in the Canadian Multicenter Osteoporosis Study (CaMos) were used to construct a vertebral shape model of the vertebral column from T4 to L4 using a statistical learning technique, as well as to estimate the accuracy and precision of this automated software tool for vertebral shape analysis. Radiographs showing scoliosis greater than 15 degrees were excluded. RESULTS: Vertebral contours defined by 95 points per vertebra, represented by 79,895 points in total, were assessed on 841 individual vertebrae. The mean absolute accuracy error calculated over each vertebra in each test image was 1.06 +/- 1.2 mm. This value corresponded to an average 3.4% of vertebral height. The mean precision error, reflecting interobserver variability, per vertebra of the resulting annotations was 0.61 +/- 0.73 mm. This value corresponded to an average 2.3% of vertebral height. Accuracy and precision error estimates did not differ notably by vertebral level. CONCLUSION: The results of the current study indicate that statistical modeling can provide a robust tool for the accurate and precise semiautomated annotation of vertebral body shape from T4 to L4 in patients who do not have scoliosis greater than 15 degrees . This method may prove useful as a clinical workflow tool to aid the physician in vertebral fracture assessment and might contribute to decision-making about pharmacologic treatment of osteoporosis.


Assuntos
Processamento de Imagem Assistida por Computador/métodos , Modelos Estatísticos , Reconhecimento Automatizado de Padrão/métodos , Radiografia/métodos , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fluxo de Trabalho , Inteligência Artificial , Simulação por Computador , Técnicas de Apoio para a Decisão , Humanos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/patologia , Variações Dependentes do Observador , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Software , Fraturas da Coluna Vertebral/patologia , Vértebras Torácicas/diagnóstico por imagem , Vértebras Torácicas/patologia
17.
West Indian med. j ; 25(3): 133-7, Sept. 1976.
Artigo em Inglês | MedCarib | ID: med-11168

RESUMO

A case is described of a Jamaican Negro female infant with resistant cardiac failure due to an aorta-pulmonary window which was successfully closed using a cardio-pulmonary bypass operation (AU)


Assuntos
Feminino , Humanos , Lactente , Aorta/cirurgia , Ponte Cardiopulmonar , Circulação Extracorpórea , Cardiopatias Congênitas/cirurgia , Artéria Pulmonar/cirurgia , Jamaica
18.
Arch Dis Child ; 51(3): 214-8, Mar. 1976.
Artigo em Inglês | MedCarib | ID: med-13120

RESUMO

Vitamin-D deficiency is not as rare in Jamaica as previously believed. 9 children with vitamin-D deficiency rickets have been seen at the University Hospital of the West Indies during the past 5 years. All were over 3 years of age at time of presentation. Both dietary deficiency of vitamin-D and lack of exposure to sunlight seem to be important causes. Children living in rural Jamaica seem to be more susceptible to the disease than those living in a city, due perhaps to more prolonged breast feeding and lack of fortified milk feeds on weaning.(AU)


Assuntos
Humanos , Lactente , Pré-Escolar , Criança , Masculino , Feminino , Raquitismo , Fosfatase Alcalina/sangue , Afro-Americanos , Aleitamento Materno , Cálcio/sangue , Dieta , Ergocalciferóis/uso terapêutico , Crescimento , Jamaica , Fósforo/sangue , Raquitismo/diagnóstico , Raquitismo/etiologia , Raquitismo/genética , Raquitismo Hipofosfatêmico/tratamento farmacológico , Luz Solar
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