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Objective: To describe the patterns of prescription drug use among child and adolescent survivors of cancer in the early post-therapy period compared with matched peers without a cancer history.Study Design: Using the MarketScan commercial insurance claims database, we performed a retrospective cohort study identifying survivors of pediatric (0-21 years of age at diagnosis) leukemia, lymphoma, central nervous system, bone, or gonadal cancers who completed therapy from 2000 to 2011 and remained insured for 3 years post-therapy. Prescription fills during the first 3 years post-therapy were examined, categorized by drug class, and compared with age-, sex-, and region-matched individuals without cancer.Results: We identified 1414 survivors and 14 007 comparators. Compared with those without cancer, survivors had 1.5-4.5 times greater risk for filling opioids. Survivors of leukemia, lymphoma, central nervous system, and bone cancers had 2-5 times the risk for antidepressant and 3-7 times the risk for anxiolytic use. Survivors of leukemia, lymphoma, and bone tumors had 3-13 times the risk for angiotensin-converting enzyme inhibitors by the third year post-therapy.Conclusion: Compared with peers without cancer, survivors of childhood cancer have greater rates of prescription use across many drug classes, suggesting greater medical morbidity. Survivors were more likely to use opioid, psychoactive, hormone, and cardiovascular medications. All general pediatricians and subspecialists should be aware of potentially emerging morbidities during the early post-therapy period to guide risk-based surveillance and survivorship care. [ABSTRACT FROM AUTHOR]

An introduction to the journal is presented in which the author discusses book reviews, including the book "Systems Theory for Pragmatic Schooling: Toward Principles of Democratic Education," by Craig Cunningham.

Background: Prior trials suggest it is safe to defer transfusion at hemoglobin levels above 7 to 8 g/dL in most patients. Patients with acute coronary syndrome may benefit from higher hemoglobin levels. Methods: We performed a pilot trial in 110 patients with acute coronary syndrome or stable angina undergoing cardiac catheterization and a hemoglobin <10 g/dL. Patients in the liberal transfusion strategy received one or more units of blood to raise the hemoglobin level ≥10 g/dL. Patients in the restrictive transfusion strategy were permitted to receive blood for symptoms from anemia or for a hemoglobin <8 g/dL. The predefined primary outcome was the composite of death, myocardial infarction, or unscheduled revascularization 30 days post randomization. Results: Baseline characteristics were similar between groups except age (liberal, 67.3; restrictive, 74.3). The mean number of units transfused was 1.6 in the liberal group and 0.6 in the restrictive group. The primary outcome occurred in 6 patients (10.9%) in the liberal group and 14 (25.5%) in the restrictive group (risk difference = 15.0%; 95% confidence interval of difference 0.7% to 29.3%; P = .054 and adjusted for age P = .076). Death at 30 days was less frequent in liberal group (n = 1, 1.8%) compared to restrictive group (n = 7, 13.0%; P = .032). Conclusions: The liberal transfusion strategy was associated with a trend for fewer major cardiac events and deaths than a more restrictive strategy. These results support the feasibility of and the need for a definitive trial. [Copyright &y& Elsevier]

In greater Augusta of central Maine, 53 out of 1093 (4.8%) private bedrock well water samples from 1534 km(2) contained [U] >30 μg/L, the U.S. Environmental Protection Agency's (EPA) Maximum Contaminant Level (MCL) for drinking water; and 226 out of 786 (29%) samples from 1135 km(2) showed [Rn] >4,000 pCi/L (148 Bq/L), the U.S. EPA's Alternative MCL. Groundwater pH, calcite dissolution and redox condition are factors controlling the distribution of groundwater U but not Rn due to their divergent chemical and hydrological properties. Groundwater U is associated with incompatible elements (S, As, Mo, F, and Cs) in water samples within granitic intrusions. Elevated [U] and [Rn] are located within 5-10 km distance of granitic intrusions but do not show correlations with metamorphism at intermediate scales (10(0)-10(1) km). This spatial association is confirmed by a high-density sampling (n = 331, 5-40 samples per km(2)) at local scales (≤10(-1) km) and the statewide sampling (n = 5857, 1 sample per 16 km(2)) at regional scales (10(2)-10(3) km). Wells located within 5 km of granitic intrusions are at risk of containing high levels of [U] and [Rn]. Approximately 48 800-63 900 and 324 000 people in Maine are estimated at risk of exposure to U (>30 μg/L) and Rn (>4000 pCi/L) in well water, respectively.

We examined the role of multidrug resistance protein (MRP) 1 (ABCC1) in the emergence of mitoxantrone (MX) cross-resistance in a MCF7 breast cancer cell line selected for resistance to etoposide. The resistant cell line, MCF7/VP, expresses high levels of MRP1, whereas the parental cell line, MCF7/WT, does not. MCF7/VP cells are 6-10-fold cross-resistant to MX when compared with MCF7/WT cells. Drug transport studies in intact MCF7/VP cells revealed that MX resistance is associated with reduced MX accumulation due to enhanced MX efflux. MX efflux is ATP dependent and inhibited by sulfinpyrazone and cyclosporin A. Inhibition of MX efflux with these agents sensitizes cells to MX cytotoxicity and partially reverses MX resistance in MCF7/VP cells. Whereas resistance is partially attributable to increased MX efflux in MRP1-expressing MCF7/VP cells, we found no evidence for glutathione or other conjugates of MX in these cells. Moreover, glutathione depletion with buthionine sulfoximine had no effect on MX transport or sensitivity in MCF7/VP cells. MRP1 substrates are generally amphiphilic anions such as glutathione conjugates or require the presence of physiological levels of glutathione for MRP1-mediated transport. Therefore we conclude that MRP1 overexpression is unlikely to be responsible for increased MX efflux and resistance in MCF7/VP cells. In considering the potential involvement of other MRP family isoforms, a 3-fold increase in the expression of MRP5 was observed in MCF7/VP cells. However, stable expression of a transduced MRP5 expression vector in MCF7/WT cells failed to confer MX resistance. Because other transporters known to be associated with MX resistance, including P-glycoprotein and BCRP/MXR (ABCG2), are not expressed in MCF7/VP cells, we conclude that increased MX efflux and resistance in MCF7/VP cells is attributable to a novel transport mechanism or that MX represents a novel class of cationic, glutathione-independent MRP1 substrates.

Previous studies in our laboratory have shown that the phase III efflux transporter multidrug-resistance protein (MRP)1 can act synergistically with the phase II conjugating glutathione S-transferases (GST) to confer resistance to the toxicities of some electrophilic drugs and carcinogens. To determine whether the distinct efflux transporter MRP2 could also potentiate GST-mediated protection from electrophilic toxins, we examined the effect of regulatable GSTP1-1 expression in MRP2-rich HepG2 cells on 4-nitroquinoline 1-oxide (4NQO)-induced cytotoxicity and genotoxicity (nucleic-acid adduct formation). Expression of GSTP1-1 was associated with a fourfold to tenfold protection from 4NQO-induced cytotoxicity. Inhibition of MRP2-mediated efflux activity by sulfinpyrazone or cyclosporin A completely reversed GSTP1-1-associated resistance-a result indicating that GSTP1-1-mediated cytoprotection is absolutely dependent on MRP2 efflux activity. Moreover, MRP2 efflux activity also augmented GSTP1-1-mediated protection from 4NQO-induced nucleic-acid adduct formation. We conclude that MRP2-mediated efflux of the glutathione conjugate of 4NQO and/or another toxic derivative of 4NQO is required to support GSTP1-1-associated protection from 4NQO toxicities in HepG2 cells.

In human neutrophils, the choline-containing phosphoglycerides contain almost equal amounts of alkylacyl- and diacyl-linked subclasses. In contrast to phosphatidylinositol hydrolysis which yields diacylglycerol, hydrolysis of choline-containing phosphoglycerides by phospholipase D coupled with phosphohydrolase yields both alkylacyl- and diacylglycerol. While diacylglycerol activates protein kinase C, alkylacylglycerol does not, and its role is unclear. Yet previous studies have shown that exogenous alkylacyl- and diacylglycerols can prime for the release of radiolabeled arachidonic acid (AA) in intact neutrophils stimulated by formyl-methionyl-leucyl-phenylalanine. We have now examined the effects of both diacylglycerol (1-oleoyl-2-acetylglycerol; OAG) and alkylacylglycerol (1-O-hexadecyl-2-acetylglycerol; EAG) on the activation of mitogen-activated protein (MAP) kinase and the 85-kDa cytosolic phospholipase A2 (cPLA2) in human neutrophils. We observed that while OAG could effectively activate p42 and p44 MAP kinases along with cPLA2 in a time- and concentration-dependent manner, EAG could not. A novel p40 MAP kinase isoform is also present and activated in response to OAG treatment; the behavior of this MAP kinase isoform is discussed. The activation of cPLA2 and MAP kinase by 20 microM OAG could be inhibited by pretreatment with 1 microM GF-109203X, a selective inhibitor of protein kinase C. Although only OAG activated cPLA2, both OAG and EAG primed for the release of AA mass as determined by gas chromatography/mass spectrometry. The priming of AA release by OAG may be explained by the phosphorylation of cPLA2 through the activation of protein kinase C linked to MAP kinase. However, priming by EAG appears to involve a separate mechanism that is dependent on a different PLA2. Our results support a role for phospholipase D-derived products modulating the activation of cPLA2, further supporting the idea of cross-talk among various phospholipases.

Thirty dogs with chronic superficial keratitis (CSK) were randomly assigned to treatment with 0.2 per cent cyclosporin ointment or 0.1 per cent dexamethasone drops. They were treated for six weeks and examined before and after three and six weeks of treatment, and then every three weeks without treatment until the lesions recurred. The regression of the disease during the treatment and the time to a recurrence after the cessation of treatment were determined. Changes in the size of the corneal lesions were measured by image analysis of photographs taken at each examination, and the severity of adnexal changes such as conjunctival hyperaemia was assessed by means of a scoring system. Clinical evaluations suggested that both drugs were equally effective as treatments for CSK and a statistical analysis showed that they had reduced the size of the lesions to the same extent at each examination. There was a significant increase in tear production, measured by the Schirmer tear test, during the treatment with cyclosporin.

1-O-Octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3) is a synthetic diether phospholipid that is competitive with phosphatidylserine binding to the regulatory domain of protein kinase C (PKC). Our previous studies indicate that the selective inhibition of tumor cell growth by ET-18-OCH3 may be due to altered signal transduction mechanisms, including the inhibition of PKC. To further define the mechanism of action of ET-18-OCH3, we have used it to study the role of PKC in regulation of the transcription factor NF-kappa B, which is activated by diverse stimuli. In the 293.27.2 human kidney cell line, as in hematopoietic cells of all lineages, NF-kappa B is stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 alpha (IL-1 alpha). The response to either TNF-alpha or IL-1 alpha is synergistically enhanced by TPA. However, the regulatory mechanisms and signal transduction systems responsible for NF-kappa B activation in response to these different stimuli have not been determined in detail. We have used ET-18-OCH3 and auranofin, which inhibit PKC by different mechanisms, to assess the role of PKC in NF-kappa B activation. ET-18-OCH3 markedly inhibits TPA-induced NF-kappa B activation, as measured by HIV long terminal repeat-directed expression of beta-galactosidase. The IC50 for inhibition by ET-18-OCH3 is approximately 2 microM, a noncytotoxic concentration. Inhibition of TPA-induced NF-kappa B activation was dependent upon preincubation with ET-18-OCH3, and the drug was active at approximately 2 mol% of total cellular phospholipid. ET-18-OCH3 did not inhibit NF-kappa B activation by either TNF-alpha or IL-1 alpha, indicating that there are multiple distinct signal transduction pathways leading to activation of NF-kappa B. We have confirmed these results using auranofin, an antirheumatic drug that is a specific PKC inhibitor interacting with the catalytic domain. Like ET-18-OCH3, auranofin blocked NF-kappa B activation by TPA but not by TNF-alpha or IL-1 alpha. Also like the ether lipid, auranofin only partially blocked the synergy exhibited by TPA and TNF-alpha. To confirm the role of NF-kappa B in this response, we measured NF-kappa B by electrophoretic mobility shift assay. Both ET-18-OCH3 and auranofin inhibited cellular induction of the active NF-kappa B complex in response to TPA but not in response to TNF-alpha.(ABSTRACT TRUNCATED AT 400 WORDS)

Madin-Darby canine kidney (MDCK) cells were used to study the synthesis of diglycerides from choline phospholipids (PC) in response to 12-O-tetradecanoylphorbol-13-acetate (TPA). In this system, diglyceride formation was blocked in the presence of ethanol (0.5%), and a corresponding amount of phosphatidylethanol (PEt) was formed, indicating that phospholipase D is responsible for the diglyceride production. Analysis of the subclasses of phosphatidylethanol revealed 1-O-alkyl-(alkyl), 1-O-alk-1'-enyl-(alkenyl), and 1-acyl species of PEt (38.0, 8.3, and 53.7%, respectively). The molecular species of the alkyl-PEt most closely matched the alkyl-PC. No change in the relative amounts of alkyl- versus acyl-PEt was observed with time after stimulation. Comparison of the alkyl content of PEt (38.0%) and the parent PC (15.2%) indicated a marked selectivity for the alkyl subclass of PC. A cell-free assay (Huang, C., Wykle, R. L., Daniel, L. W., and Cabot, M. C. (1992) J. Biol. Chem. 267, 16859-16865) for phospholipase D was also used to confirm the selectivity of the enzyme for alkyl-PC versus acyl-PC. The predominant molecular species of PEt contained saturated acyl or alkyl chains in position-1 and monounsaturated residues in position-2 accounting for approximately 50% of the total PEt. 1-O-Octadecyl-2-oleoyl-sn-glycerol, a representative alkyl molecular species, was synthesized and tested for its effect upon protein kinase C derived from MDCK cells. This alkyl-diglyceride (DG) neither stimulated protein kinase C nor inhibited its activation by diacylglycerol. In summary, TPA-stimulated phospholipase D is selective for the alkyl-PC subclass in MDCK cells. The alkyl-DG subsequently formed does not appear to function as a second-messenger in activating protein kinase C.