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21.
Carlos R Ferreira Dillon Kavanagh Ralf Oheim Kristin Zimmerman Julian Stürznickel Xiaofeng Li Paul Stabach R Luke Rettig Logan Calderone Colin MacKichan Aaron Wang Hunter A Hutchinson Tracy Nelson Steven M Tommasini Simon von Kroge Imke AK Fiedler Ethan R Lester Gilbert W Moeckel Björn Busse Thorsten Schinke Thomas O Carpenter Michael A Levine Mark C Horowitz Demetrios T Braddock 《Journal of bone and mineral research》2021,36(5):942-955
Inactivating mutations in human ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) may result in early-onset osteoporosis (EOOP) in haploinsufficiency and autosomal recessive hypophosphatemic rickets (ARHR2) in homozygous deficiency. ARHR2 patients are frequently treated with phosphate supplementation to ameliorate the rachitic phenotype, but elevating plasma phosphorus concentrations in ARHR2 patients may increase the risk of ectopic calcification without increasing bone mass. To assess the risks and efficacy of conventional ARHR2 therapy, we performed comprehensive evaluations of ARHR2 patients at two academic medical centers and compared their skeletal and renal phenotypes with ENPP1-deficient Enpp1asj/asj mice on an acceleration diet containing high phosphate treated with recombinant murine Enpp1-Fc. ARHR2 patients treated with conventional therapy demonstrated improvements in rickets, but all adults and one adolescent analyzed continued to exhibit low bone mineral density (BMD). In addition, conventional therapy was associated with the development of medullary nephrocalcinosis in half of the treated patients. Similar to Enpp1asj/asj mice on normal chow and to patients with mono- and biallelic ENPP1 mutations, 5-week-old Enpp1asj/asj mice on the high-phosphate diet exhibited lower trabecular bone mass, reduced cortical bone mass, and greater bone fragility. Treating the Enpp1asj/asj mice with recombinant Enpp1-Fc protein between weeks 2 and 5 normalized trabecular bone mass, normalized or improved bone biomechanical properties, and prevented the development of nephrocalcinosis and renal failure. The data suggest that conventional ARHR2 therapy does not address low BMD inherent in ENPP1 deficiency, and that ENPP1 enzyme replacement may be effective for correcting low bone mass in ARHR2 patients without increasing the risk of nephrocalcinosis. © 2021 American Society for Bone and Mineral Research (ASBMR). 相似文献
22.
23.
Mark Friedlander Alan Sandler Brian Kavanagh Timothy Winton Jonathan Benumof 《Journal canadien d'anesthésie》1994,41(1):26-30
Hypoxic pulmonary vasoconstriction (HPV) has not been demonstrated in human single lung anaesthesia in the lateral decubitus position (LDP). The purpose of this study was to determine whether (1) HPV occurs in the non-dependent, nonventilated lung, and (2) if the infusion of sodium nitroprusside (SNP) inhibits HPV During intravenous anaesthesia the tracheas of seven patients were intubated with double lumen endotracheal tubes. Standard monitors plus radial and pulmonary arterial catheters were placed. Patients were positioned in the LDP and haemodynamic and gas exchange data were recorded for each of three stages; I: two-lung ventilation, II: single, dependent lung ventilation (1LV) and III: 1LV with infusion of SNP. In stage II the PaO2 decreased from 531 ± 42 mmHg to 285 ± 42 mmHg (P < 0.05) and Qs/Qt increased from 12.3 ± 2.7 to 29.0 ± 6.3% (P < 0.05). With SNP infusion there was a 30% increase in cardiac index (CI) (P < 0.05). The SNP infusion was not associated with changes in Qs/ Qt or PaO2. This model demonstrates changes in Qs/ Qt and PaO2 associated with single-lung ventilation in ASA I and II patients in the LDP but we were unable to demonstrate inhibition of HPV by SNP. 相似文献
24.
Effect of dietary inducer dimethylfumarate on glutathione in cultured human retinal pigment epithelial cells. 总被引:5,自引:0,他引:5
K C Nelson J L Carlson M L Newman P Sternberg D P Jones T J Kavanagh D Diaz J Cai M Wu 《Investigative ophthalmology & visual science》1999,40(9):1927-1935
PURPOSE: To determine the effect of dimethylfumarate (DMF), an inducer of glutathione (GSH)-dependent detoxification, on intracellular GSH levels in cultured human retinal pigment epithelium (hRPE) cells, its mechanism of action, and its effect on hRPE cells subjected to oxidative injury. METHODS: Established hRPE cell lines were treated with DMF and assayed by high-pressure liquid chromatography for intracellular and extracellular GSH levels. Quantification of gamma-glutamylcysteine synthetase (GLCL) was determined through northern and western blot analyses, and activity was measured. Effects of pretreatment with DMF on GSH redox status of hRPE cells was determined. Sensitivity of hRPE cells to oxidative stress was determined using tert-butylhydroperoxide as the oxidative agent. RESULTS: Dimethylfumarate caused a transient decrease followed by a significant increase in intracellular GSH. Glutathione increased maximally at 24 hours with 100 to 200 microM DMF. The initial decrease could be accounted for by the formation of a DMF-GSH conjugate. Dimethylfumarate treatment increased the steady state mRNA expression of the regulatory subunit of GLCL, but no increase was seen for the catalytic subunit. However, protein levels were increased for both, and the catalytic activity of GLCL was also increased. Whereas the initial decrease in GSH made hRPE cells more susceptible to oxidative damage, pretreatment with DMF under conditions that increased intracellular GSH protected hRPE cells against oxidative damage. CONCLUSIONS: These results suggest a means by which the antioxidant capability of hRPE may be augmented without direct antioxidant supplementation. Specifically, a dietary compound that conjugates with GSH can induce GSH synthesis, increase GSH concentration, and improve protection by GSH-dependent detoxification pathways in hRPE. However, the early depletion of GSH before stimulated synthesis necessitates caution in prevention strategies using dietary inducers. 相似文献
25.
Background
Gated myocardial perfusion single-photon emission computed tomographic (SPECT) imaging is currently performed by step-and-shoot detector rotation, resulting in acquisition dead time and lengthened study duration compared with nongated SPECT imaging with continuous or pseudocontinuous rotation. Dead time is particularly undesirable in new fast-gated SPECT imaging protocols with inotropic pharmacologic stress.Methods and Results
This article evaluated the influence of projections’ angular spacing on quantitative measurements of left ventricular ejection fraction (LVEF) and perfusion from postexercise 99mTc-labeled sestamibi images. Gated 60-projection data sets from 30 patients were compacted into 30- and 15-projection sets. The three sets (corresponding to 3-, 6-, and 12-degree spacing over 180 degrees) were reconstructed into gated and ungated short-axis image sets. LVEFs were measured from the gated images according to a previously described automatic algorithm, whereas perfusion was assessed from the ungated images by a 20-segment division of their maximal pixel polar maps. LVEF values were essentially unchanged between 60- and 30-projection images (y=0.37+0.996x; r=0.999; standard error of the estimate=0.56) and 60- and 15-projection images (y=1.35+0.987x; r=0.999; standard error of the estimate=0.77) in the 30 patients. Overall, 30- and 15-projection polar maps differed by 1.87%±1.24% and 4.38%±2.25% from the 60-projection polar maps, respectively. Segmental perfusion score agreement between 60- and 30-projection images and between 60- and 15-projection images was 93% (κ=0.92; p<0.001) and 83% (κ=0.81; p<0.001), respectively. Sixty- and 30-projection images were visually undistinguishable, whereas loss of image resolution was noticed in many 15-projection gated and ungated images.Conclusions
Thirty-projection gated SPECT imaging is a practical, accurate, and time-saving approach in standard gated protocols and, potentially, fast-gated protocols. Fifteen-projection gated SPECT imaging is not generally recommended and should be considered only for LVEF assessment in conjunction with fast-gated protocols. 相似文献26.
27.
Diane C Bodurka Charles Levenback Judith K Wolf Jacalyn Gano J Taylor Wharton John J Kavanagh David M Gershenson 《Journal of clinical oncology》2003,21(2):291-297
PURPOSE: To evaluate the efficacy and toxicity of irinotecan in patients with metastatic platinum-resistant or platinum-refractory epithelial ovarian cancer or primary peritoneal cancer. PATIENTS AND METHODS: Thirty-one patients with measurable disease were enrolled in our study at The University of Texas M.D. Anderson Cancer Center. Twenty-five of these patients were treated with irinotecan at a dose of 300 mg/m2 intravenously for 90 minutes every 3 weeks; the remaining six patients were treated with 250 mg/m2 because their age was greater than 65 years. Median age was 57 years (range, 38 to 74 years). The majority (84%) had a Zubrod performance status of 0. All patients were evaluated for irinotecan toxicity, and 29 (94%) were evaluable for response. RESULTS: The overall response rate was 17.2%. One patient (3%) had a complete response, four (14%) had partial responses, 14 (48%) had stable disease, and 10 had (35%) disease progression. Median progression-free survival was 2.8 months (range, 1.1 to 16 months), median duration of response was 1.4 months (range, 0.7 to 10.1 months); median survival from primary diagnosis was 24.3 months (range, 6.5 to 85.7 months); and median survival from initiation of irinotecan was 10.1 months (range, 2.3 to 34 months). Major toxicities included fatigue (16 patients), neutropenia (11 patients), diarrhea (nine patients), nausea (10 patients), and anorexia (seven patients). Eleven patients required dose reductions because of these toxicities. No treatment-related deaths occurred. CONCLUSION: Irinotecan has moderate efficacy and substantial toxicity in patients with metastatic platinum-resistant or platinum-refractory epithelial ovarian or primary peritoneal cancer. 相似文献
28.
Although the relationship between streptococcal tonsillitis and acute guttate psoriasis is well recognized, its relationship to chronic forms of psoriasis is less established. In order to explore this further, the authors questioned 35 patients with severe psoriasis and 35 age-matched eczema controls about their history of significant sore throats (i.e. requiring a GP visit) and any resultant worsening of the skin condition. A third of the psoriasis patients reported recurrent sore throats which worsened their skin condition. This was true of only one (3%) of the 35 eczema controls. The authors discuss these findings in the context of recent laboratory work on the association between streptococcal infection and psoriasis. 相似文献
29.
30.
BD White A Kong E Khoo AM Southcott 《Journal of Medical Imaging and Radiation Oncology》2005,49(4):319-321
Tracheobronchopathia osteochondroplastica (TO) is a rare benign disease characterized by the presence of osseous and cartilaginous submucosal nodules projecting into the tracheobronchial tree. Most cases are asymptomatic and discovered incidentally at post‐mortem. We identified a case of TO on thoracic spiral CT and confirmed the diagnosis on bronchoscopy. This article reviews the imaging characteristics of TO, and shows the 3‐D virtual bronchoscopic and multiplanar reconstruction appearances of TO. 相似文献