Effects of tumor promoters and cocarcinogens on growth and differentiation of cultured human esophageal epithelial cells

The acute effects of 12-O-tetradecanoylphorbol-13-acetate [(TPA) CAS: 56937-68-9], T-2 toxin (CAS: 21259-20-1), capsaicin (CAS: 404-86-4), cigarette smoke condensate (CSC), and ethanol (CAS: 3807-77-0) were examined in secondary cultured human esophageal epithelial cells in serum-free LHC-8 medium. Effects were evaluated by morphology and measurement of clonal growth rate (population doublings per day), cross-linked envelope (CLE) formation, and the enzymatic activities of ornithine decarboxylase (ODC) and plasminogen activator (PA). All compounds tested were inhibitory to clonal growth; concentrations causing 50% growth inhibition were estimated as 10 nM TPA, 6 nM T-2 toxin, 40 microM capsaicin, 8 micrograms CSC/ml, 540 mM ethanol, and 0.8 microgram CSC/ml with 220 mM ethanol. None of the compounds tested induced CLE formation, although calcium ionophore (A23187) could induce CLE in at least 60% of the cells. TPA (10 and 100 nM) decreased the ODC activity of cells, and capsaicin (100 microM) induced ODC by 220%. TPA (1-100 nM) and capsaicin (100 microM) also induced PA activity. Slight increases in ODC activity by CSC (10 micrograms/ml), CSC (1 microgram/ml) with ethanol, and T-2 toxin (1 nM) were observed, but PA activity was not affected by these compounds. The results indicated that the response of human esophageal epithelial cells to TPA is both similar to and different from that reported for human epidermal and bronchial cells in vitro. Enhancement of PA activity and decrease in ODC by TPA are found in all three human epithelial cell types. However, these changes are not associated in esophageal cells with increased CLE formation as reported in studies with the use of bronchial and epidermal epithelial cells. The results from these acute studies provide the basis for designing in vitro carcinogenesis investigations using these agents.     

Postamputation neuromas and other symptomatic stump abnormalities: detection with CT

One of the potentially troublesome sequelae of limb amputations is the development of stump neuromas at the severed ends of major nerves. The ability to define them and to distinguish them from other causes of stump pain is of considerable clinical significance. Computed tomography was performed on ten lower limb amputees with stump pain. Five patients had neuromas that were manifest as focal or generalized alteration in the caliber, size, or contour of the nerve trunk in the affected stump. The remaining five patients each had an abnormality detected; these abnormalities included heterotopic bone formation, popliteal artery aneurysm, lipoma, scar tissue, and abscess in the contralateral limb.     

Pain intensity assessment by bedside nurses and palliative care consultants: a retrospective study

Objective To evaluate the specificity, sensitivity, and accuracy of pain intensity assessments (0–10) conducted by registered nurses (RN) and clinical nurse assistants (CAN) as compared to those conducted by the palliative care consultant (PCC).Patients and methods We performed a retrospective review of charts of patients who had received palliative care consult between April 2002 and August 2002. Data on patient demographic, date of palliative care consult, and date and intensity of pain assessment were collected. A numerical rating scale from 0 (no pain) to 10 (worst pain) was used to assess pain intensity. The data were included for analysis if the pain intensity assessment was performed during the same shift by all three care providers (RN, CNA, and PCC).Results Forty-one charts were found to include a complete pain assessment performed by the RN, CNA, and PCC. The agreement of pain intensity between the PCC and both the RN and CNA was poor. For a diagnosis of moderate-to-severe pain, the RNs intensity assessment had a specificity of 90% but a sensitivity of 45%, and the CNAs intensity assessment had a specificity of 100% but a sensitivity of only 30%. The Spearman correlation coefficient between the intensity assessments performed by the PCC and the RN was 0.56 (p=0.00) and between those by the PCC and the CNA 0.22 (p=0.15).Conclusion Lack of agreement between pain intensity assessments performed by the PCC and bedside nurse suggests possible inconsistencies in the way the assessments were performed. Better education on how to perform standard pain intensity assessment is needed.     

Cocaine and pregnancy: clinical and toxicological implications for the neonate

Recent studies show that the rate of cocaine use by pregnant women in the United States is much higher than realized hitherto, and an increasing number of infants are being born to cocaine-using mothers. In an ongoing research project to study the effects of cocaine on pregnancy outcome, we studied 70 infants born to cocaine-using women. These infants were matched to a drug-free comparison group selected from the population of the same hospital: children of pregnant women of a similar racial and socioeconomic distribution, but with no history or evidence of licit or illicit drug use during pregnancy. Cocaine-exposed infants had lower birth weight, shorter gestation, and a smaller head circumference than control infants. Cocaine-exposed infants also had neurobehavioral abnormalities at initial evaluation and a higher rate of perinatal complications. Toxicological evaluation of urines of neonates born to cocaine-using women showed that benzoylecgonine, a primary metabolite of cocaine, persisted in the urines for as long as 120 h after delivery. We discuss the role of the immature fetal and neonatal system in the clinical and toxicological outcome of the infant, and emphasize that further long-term studies of this will be needed.     

The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo

Dasatinib is a potent tyrosine kinase inhibitor that is used to treat chronic myeloid leukemia in patients resistant or intolerant to imatinib mesylate. While designed to inhibit Abl and Src kinases, dasatinib shows multitarget effects, including inhibition of the macrophage colony‐stimulating factor (M‐CSF) receptor c‐fms. We have shown previously that dasatinib abrogates osteoclast formation and activity in vitro owing, in part, to its specificity for c‐fms. In this study we examined whether dasatinib could significantly alter bone volume in a model of physiologic bone turnover. Sprague‐Dawley rats were administered dasatinib (5 mg/kg/day) or vehicle by gavage or zoledronic acid (ZOL; 100 µg/kg/6 weeks) subcutaneously. Following 4, 8, and 12 weeks of treatment, serum biochemical, bone morphometric, and histologic analyses were performed. Whole‐body bone mineral density and tibial cortical thickness where unchanged in the dasatinib‐ or ZOL‐treated animals relative to controls. However, micro–computed tomographic (µCT) analysis of cancellous bone at the proximal tibias showed that trabecular volume (BV/TV) and thickness (Tb.Th) were increased in dasatinib‐treated animals at levels comparable with those of the ZOL‐treated group. These changes were associated with a decrease in osteoclast numbers (N.Oc/B.Pm) and surface (Oc.S/BS) and decreased serum levels of the osteoclast marker c‐terminal collagen crosslinks (CTX‐1). Mineral apposition rate (MAR), bone‐formation rate (BFR), and levels of the serum osteoblast markers osteocalcin and N‐terminal propeptide of type I procollagen (P1NP) were not altered significantly in the dasatinib‐treated animals relative to controls. These studies show that dasatinib increases trabecular bone volume at least in part by inhibiting osteoclast activity, suggesting that dasatinib therapy may result in dysregulated bone remodeling. © 2010 American Society for Bone and Mineral Research     

Targeted Disruption of the CXCL12/CXCR4 Axis Inhibits Osteolysis in a Murine Model of Myeloma‐Associated Bone Loss

The plasma cell (PC) malignancy, multiple myeloma (MM), is unique among hematological malignancies in its capacity to cause osteoclast (OC)‐mediated skeletal destruction. We have previously shown that elevated plasma levels of PC‐derived CXCL12 are associated with presence of X‐ray detectable osteolytic lesions in MM patients. To further investigate this relationship, plasma levels of CXCL12 and βCrossLaps, a marker of bone loss, were measured. A strong correlation between levels of CXCL12 and OC‐mediated bone resorption was identified. To confirm the OC‐activating potential of MM PC‐derived CXCL12 in vivo, we established a model of MM‐mediated focal osteolysis, wherein MM PC lines, such as RPMI‐8226, were injected into the tibias of nude mice. Implanting RPMI‐8226 gave rise to osteolytic lesions proximal to the tumor, resulting in a 5% decrease in bone volume (BV) compared with vehicle control. Importantly, bone loss was significantly inhibited with systemic administration of the CXCL12/CXCR4 antagonist T140. Furthermore, implanting CXCL12‐overexpressing RPMI‐8226 cells resulted in a 13% decrease in BV and was associated with increased OC recruitment proximal to the tumor, increased serum matrix metalloproteinase activity, and increased levels of collagen I degradation products. These findings confirm our hypothesis that MM PC‐derived CXCL12 stimulates the recruitment and activity of OC, thereby contributing to the formation of MM osteolytic lesions.     

Convulsive status epilepticus after ischemic stroke and intracerebral hemorrhage: frequency,predictors, and impact on outcome in a large administrative dataset

Objective  

Relatively little is known about the epidemiology of generalized convulsive status epilepticus (GCSE) in acute ischemic and hemorrhagic stroke. We examined the occurrence of GCSE in acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) using a large discharge database.