Calculation of the estimated creatinine clearance in avoiding drug dosing errors in the older patient.

BACKGROUND: The population of hospitalized older patients is increasing. We investigated whether clinicians accurately detected renal insufficiency in older patients and chose correct doses of commonly prescribed antibiotics. METHODS: We conducted a retrospective chart review of 1044 patients > 80 years admitted to the University of California Davis Medical Center between January and December 1997 with a diagnosis of infection. Inclusion criteria included data necessary to calculate creatinine clearance using the Cockroft-Gault equation and administration of any of the study antibiotics. Patients with unstable renal function, defined as an increase in creatinine of > or = 1.0 mg/dL/day were excluded. Administered dosages of each study drug were compared with the appropriate adjusted doses. We examined the variables of age, weight, serum creatinine, and sex to determine whether any were individually predictive of dosing errors. RESULTS: Dosing errors were identified in all of the antibiotics studied, and the overall dosing error rate was 34%. The factors that were predictive of dosage errors were advanced age and low body weight. Serum creatinine and sex were not statistically significant factors. CONCLUSIONS: Widespread errors in medication dosing are made in elderly hospitalized patients. The Cockroft-Gault equation reveals significant renal insufficiency requiring dose adjustments in most elderly patients studied, especially those > 85 years of age and with low body weight. Estimation of glomerular filtration rate should be performed routinely on all admitted patients older than 80 and in any patient with low lean body mass.

Structural injury of osteosarcoma mitochondria by a novel antitumour agent, 2-methylfuranonaphthoquinone.

The effect of the novel anticancer 2-methylnaphtho[2,3-b]furan-4,9-dione (FNQ3) on human osteosarcoma cell lines (HuO9 and HuO9N2) was investigated. The IC50 values of FNQ3 were 5.95 microM for HuO9 and 3.86 microM for HuO9N2, while that for normal fibroblasts (WI-38 cell line) was 35.8 microM. The selectivity in antitumour activity which was estimated from the IC50 ratio of normal fibroblasts to tumour cells was 6.0 and 9.3 fold for HuO9 and HuO9N2, respectively. FNQ3 at 23.6 microM selectively injured mitochondria of HuO9 cells starting at 36 h and HuO9N2 cells at 24 h, whereas WI-38 cells were unaffected even after 72 h. These results demonstrated that FNQ3 was selectively toxic to the mitochondria of osteosarcoma cells similar to carcinoma cells (Pan et al. (1997) J. Electron Microsc. 46: 181), in comparison to normal cells.

Multiple coronary aneurysms in a case of systemic lupus erythematosus.

A 29-year-old woman with active systemic lupus erythematosus (SLE) sustained an anterior myocardial infarction and demonstrated angiographic evidence of multiple, diffuse coronary aneurysms. Coronary artery aneurysms have been reported in 11 prior cases of patients with SLE. A Medline search of the literature revealed no prior reports of extensive aneurysmal dilatations involving all three main coronary arteries (left anterior descending, left circumflex, and right coronary arteries).

Estrogen deficiency increases the ability of stromal cells to support murine osteoclastogenesis via an interleukin-1and tumor necrosis factor-mediated stimulation of macrophage colony-stimulating factor production.

To analyze how estrogen blocks osteoclastogenesis, we investigated the effects of ovariectomy on osteoclast (OC) formation in co-cultures of purified OC precursors and purified stromal cells (SC). OC formation was higher in co-cultures containing SC from ovariectomized mice than in those containing SC from sham-operated mice, thus suggesting that estrogen regulates osteoclastogenesis by targeting SC. Ovariectomy also increased the mononuclear cell secretion of interleukin (IL)-1) and tumor necrosis factor (TNF) and the SC production of macrophage colony-stimulating factor (MCSF). Osteoclastogenesis and SC production of M-CSF were not blocked by in vitro estrogen treatment but were decreased by in vivo treatment of donor mice with either estrogen or a combination of the IL-1 inhibitor, IL-1 receptor antagonist, and the TNF inhibitor, TNF binding protein. IL-1 and TNF production were also blocked by in vivo estrogen treatment, demonstrating that the increased bone marrow levels of IL-1 and TNF characteristic of ovariectomized mice induce the formation of a SC population characterized by a high production of M-CSF and increased pro-osteoclastogenic activity. Since in co-cultures of SC and OC precursors M-CSF levels correlated with OC production (r = 0.7, p < 0.0001), the data also indicate that the pro-osteoclastogenic activity of SC is proportional to their secretion of M-CSF. The ability of estrogen to decrease SC production of M-CSF and the pro-osteoclastogenic activity of these cells by regulating IL-1 and TNF production is a previously undescribed mechanism by which estrogen down-regulates osteoclastogenesis.

Human blood-mobilized hematopoietic precursors differentiate into osteoclasts in the absence of stromal cells.

Osteoclastogenesis is a complex process that is facilitated by bone marrow stromal cells (SCs). To determine if SCs are an absolute requirement for the differentiation of human hematopoietic precursors into fully mature, osteoclasts (OCs), CD34+ cells were mobilized into the peripheral circulation with granulocyte colony-stimulating factor, harvested by leukapheresis, and purified by magnetic-activated cell sorting. This procedure yields a population of CD34+ cells that does not contain SC precursors, as assessed by the lack of expression of the SC antigen Stro-1, and that differentiates only into hematopoietic cells. We found that CD34+, Stro-1- cells cultured with a combination of granulocyte/macrophage colony-stimulating factor, interleukin 1, and interleukin 3 generated cells that fulfill current criteria for the characterization of OCs, including multinucleation, presence of tartrate-resistant acid phosphatase, and expression of the calcitonin and vitronectin receptors and of pp60c-src tyrosine kinase. These OCs also expressed mRNA for the noninserted isoform of the calcitonin receptor and excavated characteristic resorption pits in devitalized bone slices. These data demonstrate that accessory SCs are not essential for human osteoclastogenesis and that granulocyte colony-stimulating factor treatment mobilizes OC precursors into the peripheral circulation.

Bone quality factor analysis: a new noninvasive technique for the measurement of bone density and bone strength.

The sensitivity of bone mineral density (BMD) as a predictor of fracture risk is limited by the fact that this index does not take into account the geometrical and material characteristics of bone. In contrast, both BMD and bone architecture influence the quality factor (QF), the fraction of the inverse of the energy lost in one cycle of deformation. In this study we have compared the sensitivity of a QF analyzer and dual-energy X-ray absorptiometry (DXA) in detecting the changes induced by ovariectomy (OVX) on the QF, impact strength, and BMD of the femur of mature rats. QF and BMD were measured noninvasively before and 4 weeks after OVX or sham operation using a QF analyzer developed in our laboratory and a Hologic QDR 2000 bone densitometry, respectively. Impact strength was measured in excised femurs at the end of the study. The in vivo short-term precision (coefficient of variation) of the QF analyzer was 1.9%. BMD and QF measurements were highly correlated (r = 0.80,p <0.0001). At baseline, QF and BMD were similar in OVX and sham-operated rats. At 4 weeks, BMD was 14.7 + or - 0.9% lower than at baseline (p < 0.001) in OVX rats and 5.3 + or - 1.3% lower in sham-operated rats (p <0.05). QF decreased 36.0 + or - 2.8% (p <0.0001) in OVX and 10.6 + or - 3.6% in sham rats (p <0.01). As a result, at 4 weeks the difference between sham-operated and OVX rats was larger (p < 0.05) by QF than by BMD. Moreover, QF correlated better than BMD with impact strength and the difference in impact strength between sham and OVX mice was closer to that in QF than that in BMD. These data demonstrate that QF analysis is a precise technique that is more sensitive than DXA in detecting the changes in bone density and strength induced by OVX. QF analysis may represent a new, simple, and economic technique for predicting fracture risk.

Simultaneous block of interleukin-1 and tumor necrosis factor is required to completely prevent bone loss in the early postovariectomy period.

Considerable evidence supports the hypothesis that estrogen prevents bone loss by blocking the production of cytokines in bone or bone marrow. However, controversy remains on the role of candidate factors, such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF). As IL-1 and TNF have many additive and/or synergistic effects in bone, we tested the hypothesis that the simultaneous block of IL-1 and TNF is required to prevent the initial phase of rapid bone loss that follows ovariectomy (ovx). To this aim, rats were ovariectomized and treated for 2 weeks with either IL-1 receptor antagonist (IL-1ra), an inhibitor of IL-1, or TNF-binding protein (TNFbp), an inhibitor of TNF. Ovx increased bone marrow cell secretion of IL-1 and TNF and decreased the bone density of the distal femur, as measured by dual energy x-ray absorptiometry. Ovx-induced bone loss was decreased by both IL-1ra and TNFbp and completely prevented by simultaneous treatment with IL-1ra and TNFbp. Combined treatment with IL-1ra and TNFbp decreased urinary pyridinoline cross-links, a marker of bone resorption that reflects osteoclast number and osteoclast activity, whereas treatment with either inhibitor alone was less effective. Both IL-1ra and TNFbp decreased the number of osteoclasts on the endocortical surfaces and stimulated bone formation, but the two inhibitors had no additive effects on these indexes, suggesting that inhibition of osteoclastogenesis and stimulation of bone formation do not account for the additive bone-sparing effects of IL-1ra and TNFbp. These inhibitors had no effect in sham-operated rats, indicating that they specifically blocked estrogen-dependent events. In conclusion, these data indicate that in the early post-ovx period, IL-1 and TNF play a critical causal role in inducing bone loss and do so by stimulating bone resorption and inhibiting bone formation.

Interleukin 4 enhances osteoblast macrophage colony-stimulating factor, but not interleukin 6, production.

To determine if interleukin 4's (IL-4) recently discovered skeletal effects could be explained by its effects on osteoblasts, we have examined IL-4's impact on macrophage colony stimulating factor (M-CSF) and interleukin 6 (IL-6) secretion by the murine osteoblastic cell line MC3T3-E1. Interleukin-4 increased colony-forming activity in MC3T3 supernatants two-threefold with colony cytomorphology, cytohistochemistry, and blockade of the effect by anti-M-CSF antibody, indicating that the IL-4-induced activity was M-CSF. MC3T3 M-CSF supernatant activity increased in a time-dependent manner with positive IL-4 effects seen after a 24-hour exposure. The maximal IL-4 effective dose was 100 U/ml where conditioned media from IL-4-treated cells contained twofold more M-CSF than control cells (400 U/ml versus 200 U/ml M-CSF) as detected by a sandwich M-CSF ELISA. Northern blots showed that IL-4 (200 U/ml) rapidly increased steady-state M-CSF mRNA levels with maximal induction observed by 2 hours followed by a decline to near basal levels by 24 hours. IL-4 also dose dependently increased M-CSF mRNA levels with maximal induction (fourfold) seen at 100 U/ml IL-4. In contrast to its impact on MC3T3 M-CSF production, IL-4 (200 U/ml) did not stimulate MC3T3 IL-6 secretion whereas IL-1 (1 pM) stimulated a 500-fold increase in MC3T3 IL-6 release.(ABSTRACT TRUNCATED AT 250 WORDS)