The involvement of platelets and the c-mpl receptor in the regulation of thrombopoietin (TPO) plasma concentrations and tissue mRNA levels was investigated in both normal mice and mice defective in ...c-mpl (c-mpl-/-). Although c-mpl-/- mice have fewer platelets and higher plasma TPO activity than normal mice, there was no increase in TPO mRNA levels as measured by an S1 nuclease protection assay. After the intravenous injection of 125l-TPO, specific uptake of radioactivity by the spleen and blood cells was present in the normal mice, but absent in the c-mpl-/- mice. Platelet-rich plasma (PRP) from normal mice was able to bind and internalize 125I-TPO, whereas PRP from c-mpl-/-mice lacked this ability. Analysis of 125l-TPO binding to normal PRP indicated that binding was specific and saturable, with an approximate affinity of 560 pmol/L and 220 receptors per platelet. PRP from normal mice was also able to degrade 125l-TPO into lower molecular weight fragments. After the intravenous injections, c-mpl-/- mice cleared a dose of 125l-TPO at a much slower rate than did normal mice. Injection of washed platelets from normal mice into c-mpl-/- mice resulted in a dramatic, but transient, decrease in plasma TPO levels. These data provide evidence that platelets regulate plasma TPO levels via binding to the c-mpl receptor on circulating platelets.
We have shown in a series of studies that irradiation of YBa
2Cu
3O
7−
δ
(YBCO) with ions of energy in the range of 30–350 keV through a suitable mask can be used to create highly localized damage ...regions in the films. This technique has been successfully employed to create high quality Josephson junctions in YBCO with an ion beam implanter capable of in situ low temperature electrical measurement during implantation and focussed ion beam nanolithography. The fabricated devices show a clear dc and ac Josephson effects. This technique is very promising in terms of simplicity and flexibility of fabrication and has potential for high density integration.
Abstract Background Educating medical students in surgical subspecialty fields can be challenging, and the optimal timing and curriculum remain unknown. Despite advocacy for earlier exposure, ...competing core clerkship rotations often leave little time for subspecialty fields. We report our experience with a novel, short, and focused curriculum in surgical oncology for the third-year medical students. Methods A 2-wk (2009–2010) and a 4-wk (2010–2011) curriculum in surgical oncology were developed for the third-year students at a tertiary-referral cancer center, including formal didactics, rotation in clinical service of students' choosing (breast, gastrointestinal, endocrine, or melanoma), and case-based learning and presentation. Paired pre- and postrotation questionnaires were prospectively completed, including 20 items assessing knowledge and four items assessing experience. Grading was anonymous, and change in score was assessed by Wilcoxon signed-rank test. Results Paired questionnaires from 47 students (2-wk rotation, n = 26; 4-wk rotation, n = 21) showed a median improvement of three points (21.4%) from pre- to posttests ( P < 0.001). The improvement did not differ by the length of rotation or by the specific clinical service. Nearly all (93%) reported a positive and inspiring experience. The most valuable avenue of learning was reported as the time spent with resident or fellow or attending (92%), followed by self-directed reading (62%) and didactic lectures (28%). Conclusions A short and focused curriculum in surgical oncology, including structured didactics and clinical rotation, had positive impact for the third-year students. Given the increasing work-hour limits, it is important to note that the time spent in the clinical setting continues to be ranked as the most educationally valuable by medical students.
Objective: To assess the long-term systemic and neurologic responses to enzyme replacement therapy (ERT) with macrophage-targeted glucocerebrosidase in patients with type 3 Gaucher’s disease. Study ...design: Patients with type 3 Gaucher’s disease (n = 21), aged 8 months to 35 years, were enrolled in a prospective study. Enzyme dose was adjusted to control systemic manifestations. Clinical and laboratory evaluations were performed at baseline and every 6 to 12 months thereafter. Patients were followed up for 2 to 8 years. Results: Significant improvement in hemoglobin levels, platelet count, and acid phosphatase values occurred. Liver and spleen volume markedly decreased, and bone structure improved. Nineteen patients had asymptomatic interstitial lung disease unresponsive to ERT. Supranuclear gaze palsy remained stable in 19 patients, worsened in one patient, and improved in one. Cognitive function remained unchanged or improved over time in 13 patients but decreased in 8 patients, 3 of whom developed progressive myoclonic encephalopathy accompanied by cranial magnetic resonance imaging and electroencephalographic deterioration. Conclusions: At relatively high doses, ERT reverses almost all the systemic manifestations in patients with type 3 Gaucher’s disease. Most treated patients do not deteriorate neurologically. Novel therapeutic strategies are required to reverse the pulmonary and neuronopathic aspects of the disease. (J Pediatr 2001;138:539-47)
cDNA from the C4b-binding site of the human C3b/C4b receptor (CR1) was used to find homologous sequences in the guinea pig. This cDNA identified an 18S mRNA species in guinea pig spleen, but not ...liver. Probing of a guinea pig spleen cDNA library identified clones with identical 1.5-kb inserts, which also hybridized to mRNA in spleen, but not liver. Sequence analysis of the insert revealed a single long open-reading frame coding for a 20,000 Mr protein consisting of two short consensus repeat motifs homologous to human CR1, and unique sequence at the amino- and carboxy-terminals of the short consensus repeats. This sequence did not encode peptides with features of transmembrane domains or signal peptides. Antibody to this complement receptor-related protein-beta galactosidase fusion protein recognized a 20,000 Mr protein in SDS lysates of guinea pig spleen, lymph node, lymphocytes, neutrophils, and peritoneal macrophages. Immunoprecipitation of human serum by this antibody revealed an 180,000 Mr protein reacting both with the anti-guinea pig protein antibody and with anti-human CR1 antibody. Immunoprecipitation of guinea pig serum revealed no protein reacting with the anti-guinea pig protein antibody. Tissue staining of cultured peritoneal macrophages with this antibody showed intracellular staining, as opposed to membrane staining obtained with anti-guinea pig Ig antibody. The lack of membrane expression was confirmed by surface protein radiolabeling experiments and by fluorescent staining of surface proteins. Thus, we have identified a guinea pig protein with homology to human CR1, which may have an unusual property for this class of proteins in that it appears to be intracellular.
A Mercury orbiter mission is challenging from thermal and mass perspectives. The Mercury Surface, Space Environment, Geochemistry, and Ranging (MESSENGER) mission overcomes these challenges while ...avoiding esoteric technologies by using an innovative approach with commonly available materials, minimal moving parts, and maximum heritage. This approach yields a spacecraft with good margins in all categories and low technical risk. The key concepts are a ceramic-cloth sunshade, an integrated lightweight structure and high- performance propulsion system, and a solar array incorporating optical solar reflectors (OSRs). The sunshade maintains the spacecraft at room temperature. The integrated structure and propulsion system provides ample mass margin. The solar array with OSRs, which has already undergone significant testing, provides thermal margin even if the panels are inadvertently pointed directly at the Sun at 0.3 AU.
0.3
AU
.
Background The methotrexate analogue 10-ethyl-10-deazaaminopterin (10-EdAM, or edatrexate) has shown antitumor activity in preclinical testing and clinical studies of patients with breast, lung and ...head and neck carcinomas. A phase II study was conducted in patients with advanced pancreatic adenocarcinoma. Patients and methods Forty patients were enrolled on the clinical trial. Edatrexate was administered intravenously at a dose of 80 mg/m2 weekly for 5 weeks. The treatment course was repeated every 6 weeks. Results Two partial responses were observed. Both of these patients had partial responses which lasted 2 and 3.5 months. The median survival for all patients was 3.5 months. Serious (grade 3 or 4) toxic effects were primarily mucosal, hematologic, and dermatologic. Two patients experienced severe pulmonary toxic reactions. Conclusion At the dose and schedule used, edatrexate was poorly tolerated and did not demonstrate significant antitumor activity.
ON two previous occasions we presented the number and population ratios of board-certified physicians and surgeons in practice in the United States, comparing them over time with the total number of ...physicians in active practice beyond residency according to their declared fields of specialization. These data included information on residents in training and the age and sex of practitioners. Our purpose here is to update this information for the period from 1980 to 1986, adding a more detailed treatment of the number of women in the various specialties and age groups of medicine. Following on our reports of 1975
1
and . . .
A Phase I study was conducted to determine whether the addition of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to a combined 5-fluorouracil (5-FU) and folinic acid ...(FA) regimen would allow an escalated starting dose of 5-FU. FA (500 mg/m2) was administered as a 2-hour infusion on days 1 through 5, with 5-FU administered as a bolus injection 1 hour after the initiation of FA. Fifteen patients were enrolled in the trial; six were entered at a dose level of 375 mg/m2 of 5-FU, six at 450 mg/m2, and three at 540 mg/m2. rhGM-CSF was administered subcutaneously on days 6 through 15. A course of therapy was repeated every 28 days. Serious toxicity was observed at 450 mg/m2, with two patients developing grade 3 mucositis and one, grade 4 mucositis. Dose-limiting toxicity occurred at 540 mg/m2, at which point three patients developed grade 4 mucositis. One patient with metastatic colon cancer who received 5-FU at 540 mg/m2 achieved a partial response. Because of this persistent mucositis, the addition of rhGM-CSF used in this schedule would not allow an increased starting dose of 5-FU.
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