Citations

AbstractAlthough hyperhomocysteinemia is an independent risk factor for cardiovascular disease, a direct role for homocysteine (Hcy) in this disease remains to be shown. Whereas diet-induced hyperhomocysteinemia promotes atherosclerosis in animal models, the effects of Hcy on atherogenesis in the absence of dietary perturbations is not known. We have generated double knock-out mice with targeted deletions of the genes for apolipoprotein E (apoE) and cystathionine β-synthase (CBS), which converts Hcy to cystathionine. ApoE−/−/CBS−/− mice developed aortic lesions even in the absence of dietary manipulation; lesion area and lesion cholesteryl ester (CE) and triglyceride (TG) contents increased with animal age and plasma Hcy levels. Plasma total cholesterol was significantly increased, whereas high density lipoprotein (HDL) cholesterol and TG concentrations of apoE−/−/CBS−/− mice were decreased. Cholesterol esterification and activities of enzymes catalyzing CE or TG formation in the vessel wall and in peritoneal macrophages were not changed by hyperhomocysteinemia. However, uptake of human acetyl-LDL, but not native low density lipoprotein (LDL), by mouse peritoneal macrophages was higher in the presence of hyperhomocysteinemia. These results suggest that isolated hyperhomocysteinemia is atherogenic and alters hepatic and macrophage lipoprotein metabolism, in part, by enhancing uptake of modified LDL.

The objective of this study was to define the workforce needs for the specialty of endocrinology, diabetes, and metabolism in the United States between 1999 and 2020. An interactive model of factors likely to influence the balance between the supply and demand of endocrinologists during the next 20 yr was constructed. The model used data from a wide range of sources and was developed under the guidance of a panel of experts derived from sponsoring organizations of endocrinologists. We determined current and projected numbers and demographics of endocrinologists in the United States workforce and the anticipated balance between supply and demand from 1999 to 2020. There were 3,623 adult endocrinologists in the workforce in 1999, of which 2,389 (66%) were in office-based practice. Their median age was 49 yr. Both total office visits and services performed by endocrinologists (particularly for diabetes) increased substantially during the 1990s. Waiting time for an initial appointment is presently longer for endocrinologists than for other physicians. Compared with a balanced, largely closed-staff health maintenance organization, the current national supply of endocrinologists is estimated to be 12% lower than demand. The number of endocrinologists entering the market has continuously fallen over the previous 5 yr, from 200 in 1995 to 171 in 1999. Even if this downward trend were abruptly stopped, the model predicts that demand will exceed supply from now until 2020. Whereas this gap narrows from 2000 to 2008 due to projected growth of managed care, it widens thereafter due to the aging of both the population and the endocrine workforce. Inclusion of other factors such as projected real income growth and increased prevalence of age-related endocrine disorders (e.g. diabetes and osteoporosis) further accentuates the deficit. If the number of endocrinologists entering the workforce remains at 1999 levels, demand will continue to exceed supply from now through 2020 for adult endocrinologists, and the gap will widen progressively from 2010 onward. The present analysis indicates that the number of endocrinologists entering the workforce will not be sufficient to meet future demand. These data suggest that steps should be taken to stop the ongoing decline in the number of endocrinologists in training and consideration should be given to actions designed to increase the number of endocrinologists in practice in the years ahead.

Purpose: To investigate the effect of granulocyte colony-stimulating factor (G-CSF) on hematopoietic toxicities, supportive care requirements, time to complete intensive therapy, and event-free survival (EFS) and overall survival (OS) in children with high-risk acute lymphoblastic leukemia (HR-ALL). Patients and Methods: A total of 287 children with HR-ALL were randomly assigned to intensive chemotherapy regimens (New York I [NY I] or NY II) as part of the Children’s Cancer Group (CCG)-1901 protocol. The induction phases consisted of five drugs (vincristine, prednisone, l-asparaginase, daunorubicin, and cyclophosphamide). Initial consolidation comprised six-agent chemotherapy combined with 18 Gy of total-brain irradiation. Patients were randomly assigned to receive G-CSF (5 μg/kg/day) during either induction or initial consolidation. A crossover study analysis was done on the 259 patients who completed both phases of therapy. Results: The mean time to neutrophil recovery (≥ 0.5 × 109/L) was reduced with G-CSF (16.7 v 19.1 days, P = .0003); however, patients who received G-CSF did not have significantly reduced episodes of febrile neutropenia (149 v 164, P = .41), positive blood cultures (57 v 61, P = .66), or serious infections (75 v 79, P = .62). Hospitalization (14.0 v 13.9 days, P = .87) and induction therapy completion times (NY I, 30.3 v 31.3 days, P = .11; NY II, 33.4 v 32.3 days, P = .40) were not significantly altered. There were no differences in 6-year EFS (P = .24) or OS (P = .54) between patients receiving or not receiving G-CSF on CCG-1901, NY I and NY II. Conclusion: Children with high-risk ALL do not appear to benefit from prophylactic G-CSF.

Atherosclerosis is the major cause of adult mortality in the developed world, and a significant contributor to atherosclerotic plaque progression involves smooth muscle cell recruitment to the intima of the vessel wall. Controversy currently exists on the exact origin of these recruited cells. Here we use sex-mismatched bone marrow transplant subjects to show that smooth muscle cells throughout the atherosclerotic vessel wall can derive from donor bone marrow. We demonstrate extensive recruitment of these cells in diseased compared with undiseased segments and exclude cell–cell fusion events as a cause for this enrichment. These data have broad implications for our understanding of the cellular components of human atherosclerotic plaque and provide a potentially novel target for future diagnostic and therapeutic strategies.

Thumb motion and stability were examined after sequential division of support ligaments of the trapeziometacarpal (TMC) to simulate the pathologic condition of ligament laxity. The motion obtained with passive circumduction was measured with a magnetic tracking system. The lengths of the TMC joint ligaments were approximated by measuring the distance between origin and insertion of each ligament. The change in this apparent interorigin distance of the ligaments was measured before and after ligament sectioning. The anterior oblique ligament (AOL) and the ulnar collateral ligament (UCL) had the greatest effect on TMC joint stability during circumduction of the thumb. Division of the first intermetacarpal ligament (IML) did not produce a change in apparent length of other ligaments. We conclude that small changes in ligament length affect thumb stability and alter the path of circumduction. Neither the IML or posterior oblique ligaments were major stabilizers of the TMC joint during circumduction, prehensile grasp, or tip pinch. Reconstruction of the AOL and UCL ligaments should be considered for treatment of the initial stages of TMC instability.

Purpose: Between February 1993 and September 1995, 739 patients with metastatic breast cancer were entered on an Intergroup trial (E1193) comparing doxorubicin (60 mg/m2), paclitaxel (175 mg/m2/24 h), and the combination of doxorubicin and paclitaxel (AT, 50 mg/m2 and 150 mg/m2/24 h, plus granulocyte colony-stimulating factor 5 mg/kg) as first-line therapy. Patients receiving single-agent doxorubicin or paclitaxel were crossed over to the other agent at time of progression. Patients and Methods: Patients were well balanced for on-study characteristics. Results: Responses (complete response and partial response) were seen in 36% of doxorubicin, 34% of paclitaxel, and 47% of AT patients (P = .84 for doxorubicin v paclitaxel, P = .007 for v AT, P = .004 for paclitaxel v AT). Median time to treatment failure (TTF) is 5.8, 6.0, and 8.0 months for doxorubicin, paclitaxel, and AT, respectively (P = .68 for doxorubicin v paclitaxel, P = .003 for doxorubicin v AT, P = .009 for paclitaxel v AT). Median survivals are 18.9 months for patients taking doxorubicin, 22.2 months for patients taking paclitaxel, and 22.0 months for patients taking AT (P = not significant). Responses were seen in 20% of patients crossing from doxorubicin → paclitaxel and 22% of patients crossing from paclitaxel → doxorubicin (P = not significant). Changes in global quality-of-life measurements from on-study to week 16 were similar in all three groups. Conclusion: (1) doxorubicin and paclitaxel, in the doses used here, have equivalent activity; (2) the combination of AT results in superior overall response rates and time to TTF; and (3) despite these results, combination therapy with AT did not improve either survival or quality of life compared to sequential single-agent therapy.