RESUMO
BACKGROUND AND AIMS: Gastric bypass is known to have larger effects on weight and metabolism than gastric banding. However, scarce data exist as to whether the differences are translated into differential risks of cardiovascular disease (CVD)-related morbidities. The objective was to examine whether adults with obesity and CVD who underwent gastric bypass have a lower rate of acute care use (emergency department [ED] visit or unplanned hospitalization) for CVD than those with gastric banding. METHODS AND RESULTS: We performed a comparative effectiveness study of gastric bypass versus banding among adults with obesity and CVD who underwent either surgery, using population-based [ED] and inpatient samples in California, Florida, and Nebraska from 2005 through 2011. The primary outcome was acute care use for CVD during a two-year postoperative period. We constructed negative binomial regression models to compare the event rate during sequential 6-month periods, using gastric banding group as the reference. We identified 11,229 adults with obesity and CVD who underwent gastric bypass and 3896 adults who had gastric banding. Patients with gastric bypass had significantly lower rate of the outcome compared to those with banding in the 7-12 months postoperative period (adjusted rate ratio [aRR] 0.77; 95% confidence interval [CI], 0.61-0.98; P = 0.03). The significant reduction in the rate persisted during 13-18 months (aRR 0.71; 95% CI, 0.57-0.90; P = 0.005) and 19-24 months (aRR 0.66; 95% CI, 0.52-0.82; P < 0.001) after bariatric surgery. CONCLUSION: In this population-based comparative effectiveness study of adults with obesity and CVD, the rate of acute care use for CVD was lower after gastric bypass compared to gastric banding.
Assuntos
Doenças Cardiovasculares/terapia , Derivação Gástrica , Gastroplastia , Obesidade/cirurgia , Adulto , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Pesquisa Comparativa da Efetividade , Feminino , Derivação Gástrica/efeitos adversos , Gastroplastia/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/diagnóstico , Obesidade/epidemiologia , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
SUMMARY: Patients with type 2 diabetes mellitus (DM2) have increased fracture risk. We found that African-American women with DM2 have increased cortical porosity and lower cortical bone density at the radius than non-diabetic controls. These cortical deficits are associated with hyperglycemia and may contribute to skeletal fragility associated with DM2. INTRODUCTION: Fracture risk is increased in patients with type 2 diabetes mellitus (DM2) despite normal areal bone mineral density (aBMD). DM2 is more common in African-Americans than in Caucasians. It is not known whether African-American women with DM2 have deficits in bone microstructure. METHODS: We measured aBMD at the spine and hip by DXA, and volumetric BMD (vBMD) and microarchitecture at the distal radius and tibia by HR-pQCT in 22 DM2 and 78 non-diabetic African-American women participating in the Study of Women Across the Nation (SWAN). We also measured fasting glucose and HOMA-IR. RESULTS: Age, weight, and aBMD at all sites were similar in both groups. At the radius, cortical porosity was 26% greater, while cortical vBMD and tissue mineral density were lower in women with DM2 than in controls. There were no differences in radius total vBMD or trabecular vBMD between groups. Despite inferior cortical bone properties at the radius, FEA-estimated failure load was similar between groups. Tibia vBMD and microarchitecture were also similar between groups. There were no significant associations between cortical parameters and duration of DM2 or HOMA-IR. However, among women with DM2, higher fasting glucose levels were associated with lower cortical vBMD (r=-0.54, p=0.018). CONCLUSIONS: DM2 and higher fasting glucose are associated with unfavorable cortical bone microarchitecture at the distal radius in African-American women. These structural deficits may contribute to the increased fracture risk among women with DM2. Further, our results suggest that hyperglycemia may be involved in mechanisms of skeletal fragility associated with DM2.
Assuntos
Diabetes Mellitus Tipo 2/patologia , Rádio (Anatomia)/patologia , Absorciometria de Fóton/métodos , Negro ou Afro-Americano/estatística & dados numéricos , Glicemia/metabolismo , Densidade Óssea/fisiologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/fisiopatologia , Jejum/sangue , Feminino , Articulação do Quadril/fisiopatologia , Humanos , Resistência à Insulina/fisiologia , Vértebras Lombares/fisiopatologia , Pessoa de Meia-Idade , Porosidade , Rádio (Anatomia)/diagnóstico por imagem , Rádio (Anatomia)/fisiopatologia , Tíbia/diagnóstico por imagem , Tíbia/patologia , Tíbia/fisiopatologia , Tomografia Computadorizada por Raios X/métodos , Estados Unidos/epidemiologiaRESUMO
The Escherichia coli AcrB multidrug transporter recognizes a wide range of toxic chemicals and actively extrudes them from cells. The molecular basis of multidrug transport in AcrB remains unknown. Herein, we describe normal mode analyses to study important regions for drug recognition and extrusion in this transporter. Based on the X-ray structure of AcrB, an elastic network model has been able to correct errors arising from crystal imperfection in the experimental B-factors. The results allow us to understand the functional dynamics of this membrane protein. It is expected that this technique can be applied to other membrane proteins with known structures.
Assuntos
Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/química , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Cristalografia , Cristalografia por Raios X , Substâncias Macromoleculares/química , Proteínas de Membrana/química , Modelos Moleculares , Conformação ProteicaRESUMO
BACKGROUND AND PURPOSE: We analyzed the impact on survival outcomes of treatment interruptions due to toxicity arising during the concurrent phase of chemotherapy/radiotherapy (ChT/RT) for our limited-stage small-cell cancer (LSCLC) population over the past 10 years. MATERIALS AND METHODS: From 1989 to 1999, 215 patients received treatment for LSCLC, consisting of six cycles of alternating cyclophosphamide/doxorubicin or epirubicin/vincristine (CAV; CEV) and etoposide/cisplatin (EP). Thoracic RT was started with EP at either the second or third cycle (85% of patients). RT dose was either 40 Gy in 15 fractions over 3 weeks or 50 Gy in 25 fractions over 5 weeks, delivered to a target volume encompassing gross disease and suspected microscopic disease with a 2 cm margin. Treatment breaks arising during concurrent ChT+RT were used to manage severe symptomatic or hematologic toxicities. We used the interruptions in thoracic RT as the 'marker' for any concurrent break and measured 'break duration' by the total length of time (in days) RT was interrupted, since that also signaled that ChT could be re-initiated. Patient results were analyzed for the impact of interruptions/treatment prolongation on overall and disease-free survival. RESULTS: For all patients, 2-year and 5-year overall and disease-specific survivals were 22.7 and 7.2, 27.6 and 9.3%, respectively; overall and disease-specific median survivals were 14.7 months each. A total of 56 patients (26%) had treatment breaks due to toxicity. Hematologic depression caused the majority of breaks (88%). The median duration of breaks was 5 days (range 1-18). Patients with and without interruptions were compared for a range of prognostic factors and were not found to have any significant differences. Comparing interrupted/uninterrupted courses, median survivals were 13.8 versus 15.6 months, respectively, and 5-year overall survivals were 4.2 versus 8.3%, respectively. There was a statistical difference between overall survival curves which favored the uninterrupted group (P=0.01). When comparing a series of prognostic variables, multivariable analysis found that the most significant factor influencing survival in the present study was the presence of treatment breaks (P=0.006). There was a trend for development of any recurrence in the patients with breaks (P=0.08). When controlling for the use of prophylactic cranial irradiation (PCI) in the two groups, the rate of failure in the chest was higher in the patients with RT breaks (58 vs. 33%). The rate of failure in the brain was dependent on the use of PCI only. CONCLUSIONS: Interruptions in treatment to palliate the toxicity from concurrent chemoradiation result in poorer local control and decreased survival.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Pequenas/tratamento farmacológico , Carcinoma de Células Pequenas/radioterapia , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Epirubicina/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Vincristina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Pequenas/mortalidade , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Indução de Remissão , Taxa de Sobrevida , Falha de TratamentoRESUMO
PURPOSE: To describe the clinical features and outcomes in patients who had a flap buttonhole during laser in situ keratomileusis (LASIK) and propose an etiopathogenic mechanism for this complication. SETTING: University Eye Center, Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China. METHODS: Retrospective review of case records of 6 patients (6 eyes) who had a flap buttonhole during LASIK. RESULTS: The mean patient age was 38.2 years +/- 4.1 (SD) and the mean preoperative spherical equivalent (SE) refraction, -8.13 +/- 4.04 diopters (D). Mean keratometry was 44.20 +/- 1.30 D. Retreatment was performed after a mean interval of 9.2 +/- 3.2 months. Final postoperative SE refraction was -0.44 +/- 0.58 D after a mean follow-up of 59.0 +/- 5.3 weeks. No patient experienced loss of best spectacle-corrected visual acuity. CONCLUSIONS: Retreatment of eyes that have a flap buttonhole during LASIK is associated with good visual outcomes. Flap buttonholes can produce alterations in refraction, so retreatment is best performed after the refractive error has stabilized. Microkeratome malfunction may be responsible for the occurrence of a flap buttonhole during LASIK in eyes that do not have significant corneal steepening.
Assuntos
Doenças da Córnea/etiologia , Complicações Intraoperatórias , Ceratomileuse Assistida por Excimer Laser In Situ/efeitos adversos , Retalhos Cirúrgicos/patologia , Adulto , Doenças da Córnea/patologia , Doenças da Córnea/cirurgia , Feminino , Humanos , Masculino , Miopia/cirurgia , Refração Ocular , Reoperação , Estudos Retrospectivos , Ruptura Espontânea , Resultado do Tratamento , Acuidade VisualRESUMO
CONTEXT: Animal models and human studies suggest that osteocytes regulate the skeleton's response to mechanical unloading in part by an increase in sclerostin. However, few studies have reported changes in serum sclerostin in humans exposed to reduced mechanical loading. OBJECTIVE: We determined changes in serum sclerostin and bone turnover markers in healthy adult men undergoing controlled bed rest. DESIGN, SETTING, AND PARTICIPANTS: Seven healthy adult men (31 ± 3 yr old) underwent 90 d of 6° head down tilt bed rest at the University of Texas Medical Branch Institute for Translational Sciences-Clinical Research Center. OUTCOMES: Serum sclerostin, PTH, vitamin D, bone resorption and formation markers, urinary calcium and phosphorus excretion, and 24-h pooled urinary markers of bone resorption were evaluated before bed rest [baseline (BL)] and at bed rest d 28 (BR-28), d 60 (BR-60), and d 90 (BR-90). Bone mineral density was measured at BL, BR-60, and 5 d after the end of the study (BR+5). Data are reported as mean ± SD. RESULTS: Consistent with prior reports, bone mineral density declined significantly (1-2% per month) at weight-bearing skeletal sites. Serum sclerostin was elevated above BL at BR-28 (+29 ± 20%; P = 0.003) and BR-60 (+42 ± 31%; P < 0.001), with a lesser increase at BR-90 (+22 ± 21%; P = 0.07). Serum PTH levels were reduced at BR-28 (-17 ± 16%; P = 0.02) and BR-60 (-24 ± 14%; P = 0.03) and remained lower than BL at BR-90 (-21 ± 21%; P = 0.14), but did not reach statistical significance. Serum bone turnover markers were unchanged; however, urinary bone resorption markers and calcium were significantly elevated at all time points after bed rest (P < 0.01). CONCLUSIONS: In healthy men subjected to controlled bed rest for 90 d, serum sclerostin increased, with a peak at 60, whereas serum PTH declined, and urinary calcium and bone resorption markers increased.
Assuntos
Repouso em Cama , Proteínas Morfogenéticas Ósseas/sangue , Absorciometria de Fóton , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Biomarcadores/urina , Densidade Óssea , Reabsorção Óssea/metabolismo , Reabsorção Óssea/urina , Osso e Ossos/metabolismo , Cálcio/urina , Marcadores Genéticos , Decúbito Inclinado com Rebaixamento da Cabeça , Humanos , Estudos Longitudinais , Masculino , Hormônio Paratireóideo/sangue , Fósforo/urina , Aptidão Física , Vitamina D/sangueRESUMO
The problem of the propagation of conformational changes over long distances or through a closely packed protein is shown to fit a model of a ligand-induced conformational change between two protein states selected by evolution. Moreover, the kinetics of the pathway between these states is also selected so that the energy of ligand binding and the speed of the transition between conformational states are physiologically appropriate. The crystallographic data of a wild-type aspartate receptor that has negative cooperativity and a mutant that has no cooperativity but has native transmembrane signaling are shown to support this model.
Assuntos
Conformação Proteica , Apoproteínas/química , Proteínas de Bactérias/química , Cristalografia por Raios X , Escherichia coli/química , Cinética , Modelos Moleculares , Receptores de Aminoácido/químicaRESUMO
Rat pancreas acinar cells contain 5-hydroxytryptamine (5-HT; 10.86 +/- 2.52 ng/i.u. amylase), all of which can be accounted for by the 5-HT recovered from the zymogen granule fraction of these cells (10.70 +/- 3.06 ng/i.u. amylase). When incubated with [14C]5-HT dispersed acinar cells take up the amine and concentrate it in zymogen granules. These cells will also take up [14C]5-HTP (5-hydroxytryptophan), decarboxylate it and store the [14C]5-HT so produced in zymogen granules. 5-HTP itself is not taken up by the granules. 5-HT is incorporated into zymogen granules early in their formation; no amine is accumulated by mature zymogen granules and the amine within the mature granule is not exchangeable with extragranular amine. When dispersed acinar cells pre-labelled with [14C]5-HT and [3H]leucine are stimulated with caerulein, there is a synchronous increase in amylase activity and secretion of [14C]5-HT and [3H]protein; the ratios of [3H]protein/[14C]5-HT in zymogen granules and in the secretory products are identical. Pancreas acinar cells take up L-DOPA, decarboxylate it and store the dopamine produced in zymogen granules but the dopamine is not retained by the granules (t1/2 approximately equal to 90 min) and dopamine secretion from cells exposed to caerulein could not be demonstrated. It is concluded that 5-HT is a normal component of rat pancreas acinar cell zymogen granule. The granular amine has a turnover rate similar to that of granular protein and is released when the cells are stimulated to secrete protein. All the 5-HT released from the cell originates in zymogen granules.
Assuntos
5-Hidroxitriptofano/metabolismo , Pâncreas/metabolismo , Serotonina/metabolismo , Amilases/metabolismo , Animais , Ceruletídeo/farmacologia , Grânulos Citoplasmáticos/metabolismo , Dopamina/metabolismo , Precursores Enzimáticos/metabolismo , Técnicas In Vitro , Pâncreas/citologia , Proteínas/metabolismo , Ratos , Ratos Endogâmicos , Frações Subcelulares/metabolismo , Fatores de TempoRESUMO
Amino acid decarboxylation activity in dispersed rat pancreas acinar cells and fractions derived by differential centrifugation of homogenate of these cells was studied. The rate of decarboxylation was measured by determining the rate of production of the [3H]-amine from [3H]-amino acid or the rate of production of 14CO2 from the [14C]-carboxy-labelled amino acid. Only the hydroxylated amino acids L-dopa and 5-hydroxytryptophan are decarboxylated by intact dispersed pancreas acinar cells or cell homogenates at all pH values and amino acid concentrations tested. The decarboxylase activity is located exclusively in the cell cytosol. Each substrate competitively inhibits the decarboxylation of the other and the decarboxylation of each is inhibited by NSD-1055. The estimated Km and Vmax are, for L-dopa, 4.8 X 10(-5) M and 2.5 nmol/mg protein/min and for 5-hydroxytryptophan, 2.9 X 10(-5) M and 0.3 nmol/mg protein/min. The pH optimum for 5-hydroxytryptophan decarboxylation is from 7.0-8.5 while that for L-dopa is 7.0. It is concluded that pancreas acinar cells possess a single aromatic amino acid decarboxylase specific for the hydroxylated amino acids L-dopa and 5-hydroxytryptophan, and which is similar in all properties studied to the aromatic amino acid decarboxylase found in several other mammalian tissues.
Assuntos
Descarboxilases de Aminoácido-L-Aromático/metabolismo , Levodopa/metabolismo , Pâncreas/metabolismo , Serotonina/metabolismo , Animais , Ligação Competitiva , Descarboxilação , Feminino , Histidina/metabolismo , Técnicas In Vitro , Pâncreas/enzimologia , Ratos , Ratos Endogâmicos , Triptofano/metabolismo , Tirosina/metabolismoRESUMO
Activin A is a cytokine whose multiple functions have yet to be fully determined. In this study, the role of proinflammatory cytokines in regulatory control of activin A production was shown in synoviocytes and chondrocytes. Additional facets of functional inflammation-related activities of activin A were also determined. Results showed that activin A concentrations in the synovial fluid of patients with rheumatoid arthritis and gout were elevated relative to those in patients with osteoarthritis. Further studies showed that production of activin A by synoviocytes and chondrocytes in culture was stimulated by cytokines such as IL-1, transforming growth factor-beta (TGF-beta), interferon-gamma (IFN-gamma), and IL-8, consistent with previous studies in regard to the control of activin A production in marrow stromal cells and monocytes by cytokines, glucocorticoids and retinoic acid. In addition, the relationship of activin A to IL-6-induced biological activities was investigated. Three major IL-6 activities involved in inflammatory responses were found to be suppressed by activin A. In a dose-dependent manner, activin A efficiently suppressed IL-6-induced proliferation of 7TD1 B lymphoid cells, phagocytic activity of monocytic M1 cells, and fibrinogen production in HepG2. Therefore, it is likely that activin A serves as a suppressor for IL-6, dampening inflammatory responses, and has the potential to perform some previously unrecognized roles in inflammation.