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Context: Anthropogenic and natural disturbances may interact synergistically, magnifying their individual effects on biodiversity. However, few studies have measured responses of ecological communities to multiple stressors at landscape scales. Objectives: We use a long-term dataset to test for synergistic effects of anthropogenic and natural disturbance on plant community diversity and composition in a large protected area. Methods: We quantified changes in plant communities over two decades in 98 plots in Waterton Lakes National Park, Canada. Fifty-three plots burned in a wildfire in the interim. We modeled the effects of wildfire, proximity to trails or roads, and their interaction on changes in species richness, community composition, relative abundance of disturbance-associated species, and colonization by exotic species. Results: Interactions between wildfire and proximity to roads and trails affected all metrics except species richness. Only one interaction was synergistic: the relative abundance of disturbance-associated species following wildfire was magnified closer to recreational corridors. The other community metrics showed unexpected patterns. For example, plots with no exotic species in the baseline survey that burned in the wildfire were more likely to gain exotic species than unburned plots only when they were distant from recreational corridors. Conclusions: Our study demonstrates interactive effects of natural and anthropogenic disturbance at landscape scales within a protected area. Plant community response to wildfire was influenced by proximity to recreational corridors, sometimes in surprising ways. As the frequency and severity of anthropogenic and natural disturbances both continue to rise, documenting the prevalence and magnitude of interactions between them is key to predicting long-term effects and designing mitigation strategies. [ABSTRACT FROM AUTHOR]

Context: Protected areas are a cornerstone of the global strategy for conserving biodiversity, and yet their efficacy in comparison to unprotected areas is rarely tested. In the highly fragmented forests of temperate regions, landscape context and forest history may be more important than protection status for plant species diversity. Objectives: To determine whether there are differences in plant diversity between protected areas and private lands while controlling for landscape context, forest age, and other important factors. Methods: We used a database of 156 one-hectare forest plots distributed over 120,000 km in the fragmented forests of southern Ontario to test whether protected areas and private forests differed in native species richness, relative abundance of exotic species, and the probability of finding species of conservation concern. Results: Plots with more forest on the surrounding landscape had higher native species richness, lower abundance of exotic species, and greater probability of supporting at least one species of conservation concern. Young forests tended to have higher abundance of exotics, and were less likely to support species of conservation concern. Surprisingly, privately owned forests had greater native species richness and were more likely to support species of conservation concern once these other factors were accounted for. In addition, there were significant interactions between ownership type, forest history, and landscape context. Conclusions: Our results highlight the importance of privately owned forests in this region, and the need to consider forest history and landscape context when comparing the efficacy of protected areas versus private land for sustaining biodiversity. [ABSTRACT FROM AUTHOR]

Given age-related differences in drug metabolism and indications for hematopoietic SCT (HSCT), personalized drug dosing of the conditioning regimen and post-transplant immunosuppression may reduce graft rejection, relapse rates and toxicity in pediatric HSCT recipients. This manuscript summarizes the pharmacokinetic/dynamic data of HSCT conditioning and post-grafting immunosuppression, presented at the First Annual Pediatric Bone Marrow Transplant Consortium (PBMTC) meeting in April 2013. Personalized dosing of BU to a target plasma exposure reduces graft rejection in children and improves relapse/toxicity rates in adults. Current weight-based dosing achieves the target BU exposure in only a minority (24.3%) of children. The initial BU dose should be based on the European Medicines Agency nomogram or population pharmacokinetic models to improve the numbers of children achieving the target exposure. There are limited pharmacokinetic data for treosulfan, CY, fludarabine and alemtuzumab as HSCT conditioning in children. For post-grafting immunosuppression, mycophenolic acid (MPA) clearance may be increased in younger children (<12 years). The preferred MPA pharmacokinetic monitoring parameters and target range are still evolving in HSCT recipients. Multi-institutional trials incorporating properly powered pharmacokinetic/dynamic studies are needed to assess the effect of variability in the plasma exposure of drugs/metabolites on clinical outcomes in pediatric HSCT recipients. [ABSTRACT FROM AUTHOR]

We investigated sirolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis in patients with advanced hematological malignancies receiving myeloablative hematopoietic cell transplantation (HCT) from HLA-identical sibling donors. On the basis of pre-study stopping rules, the trial was closed to accrual after enrollment of 11 adult patients. In all, 7 of the 11 patients received BU-containing preparative regimens. Sirolimus was discontinued in three patients because of the toxicity-related events of severe sinusoidal obstructive syndrome, portal vein thrombosis, altered mental status and in one patient because of the risk of poor wound healing. In all, 6 of the 11 patients developed grade II-IV acute GVHD (AGVHD) a median of 15.5 days post HCT. Two of three patients with grade IV AGVHD had sirolimus discontinued by 9 days post HCT. All patients responded to AGVHD therapy without GVHD-related deaths. There were two non-relapse- and two relapse-related deaths. At a median follow-up of 38 months (2-47 months), 7 of 11 patients were alive without disease. MMF and sirolimus GVHD prophylaxis did not reduce the risk of AGVHD, however, there were no GVHD-related deaths. The severe toxicities in the patients receiving the BU-containing preparative regimens limited the continued use of sirolimus and MMF for the prevention of AGVHD. [ABSTRACT FROM AUTHOR]

Heme oxygenase-1 (HO-1) is an anti-inflammatory enzyme that maintains homeostasis during cellular stress. Given previous findings that shorter length variants of a HO-1 promoter region GTn microsatellite polymorphism are associated with increased HO-1 expression in cell lines, we hypothesized that shorter variants would also be associated with increased levels of HO-1 expression, less inflammation and lower levels of inflammation-associated viral replication in human immunodeficiency virus (HIV)-infected subjects. Healthy donors (n=20) with shorter GTn repeats had higher HO-1 mRNA transcript in peripheral blood mononuclear cells stimulated with lipopolysaccharide (r=−0.38, P=0.05). The presence of fewer GTn repeats in subjects with untreated HIV disease was associated with higher HO-1 mRNA levels in peripheral blood (r=−0.41, P=0.02); similar observations were made in CD14+ monocytes from antiretroviral-treated subjects (r=−0.36, P=0.04). In African-Americans, but not Caucasians, greater GTn repeats were correlated with higher soluble CD14 levels during highly active antiretroviral therapy (r=0.38, P=0.007) as well as higher mean viral load off-therapy (r=0.24, P=0.04). These data demonstrate that the HO-1 GTn microsatellite polymorphism is associated with higher levels of HO-1 expression and that this pathway may have important effects on the association between inflammation and HIV replication. [ABSTRACT FROM AUTHOR]

Renal disease is a major complication in patients following myeloablative allogeneic hematopoietic cell transplantation (HCT). Post-HCT patients receive immunosuppressive regimens containing calcineurin inhibitor (CNIs), cyclosporine or tacrolimus, for graft-versus-host disease prophylaxis. In this retrospective trial, we investigated pharmacogenomic associations in the multidrug resistance (ABCB1) and cytochrome P450 3A5 (CYP3A5) genes and acute kidney injury (AKI) and chronic kidney disease (CKD) in a cohort of 121 patients. ABCB1 and CYP3A5 are responsible for the renal disposition of CNIs, which are known to be nephrotoxic. AKI was defined as doubling of baseline serum creatinine during the first 100 days post-HCT, and CKD as at least one glomerular filtration rate <60 ml/min/m2 between 6 and 18 months post-HCT. Patients were genotyped for CYP3A5*1>*3 and ABCB1 single nucleotide polymorphisms (SNPs) (1199G>A, 1236C>T, 2677G>T/A and 3435C>T). Odds ratios were calculated using logistic regression. Haplotype estimation and univariate association analyses were performed because of strong ABCB1 linkage disequilibrium (LD). AKI occurred in 48 of 121 patients (39.7%) and CKD in 16 of 66 patients (24.2%). No pharmacogenomic associations were found between ABCB1 and CYP3A5 SNPs and the incidences of AKI or CKD. The degree of LD(r2) between ABCB1 SNPs was estimated as follows: 2677G>T/3435C>T (0.44), 1236C>T/3435C>T (0.42) and 1236C>T/2677G>T (0.72). ABCB1 1199G>A showed no LD to other SNPs (<0.05). No associations were found between the most common ABCB1 haplotypes and AKI or CKD. Since no significant pharmacogenomic associations were observed, tailoring CNIs dosing based on these genotypes is unlikely to lower significantly the risk of renal injury following myeloablative HCT.The Pharmacogenomics Journal (2008) 8, 248–255; doi:10.1038/sj.tpj.6500472; published online 14 August 2007 [ABSTRACT FROM AUTHOR]

Abstract Our objective was to review the frequency and pattern of signal abnormalities seen on conventional MRI in patients with suspected neuropsychiatric systemic lupus erythematosus (NP-SLE). We reviewed 116 MRI examinations of the brain performed on 85 patients with SLE, (81 women, four men, aged 21–78 years, mean 40.6 years) presenting with neurological disturbances. MRI was normal or nearly normal in 34%. In 60% high-signal lesions were observed on T2-weighted images, frequently in the frontal and parietal subcortical white matter. Infarct-like lesions involving gray and white matter were demonstrated in 21 of cases. Areas of restricted diffusion were seen in 12 of the 67 patients who underwent diffusion-weighted imaging. Other abnormalities included loss of brain volume, hemorrhage, meningeal enhancement, and bilateral high signal in occipital white-matter. The MRI findings alone did not allow us to distinguish between thromboembolic and inflammatory events in many patients. Some patients with normal MRI improved clinically while on immunosuppressive therapy. More sensitive and/or specific imaging methods, such as spectroscopy and perfusion-weighted imaging, should be investigated in these subgroups of patients with suspected NP-SLE. [ABSTRACT FROM AUTHOR]

Purpose: Carboplatin is frequently dosed to achieve a desired area under the plasma concentration-time curve (AUC) by using the Calvert or Chatelut equations to estimate carboplatin clearance. Accurate determination of glomerular filtration rate (GFR) is necessary to correctly calculate carboplatin clearance using the Calvert equation. In clinical practice, the Cockcroft-Gault formula is frequently used to estimate GFR, but this practice has been reported to under- and overestimate carboplatin clearance. The purpose of this trial was to compare determinations of carboplatin clearance using the Chatelut equation and four separate GFR determinations, including 99mTc-DTPA, the Cockcroft-Gault formula, a 24-h urine collection and a 2-h urine collection. Methods: Carboplatin clearance was estimated in 21 previously untreated extensive-stage small-cell lung cancer patients. GFR was determined using 99mTc-DTPA, the Cockcroft-Gault formula, 24-h urine collection and 2-h urine collection. Serum and urine creatinine concentrations were measured using enzymatic assays. The carboplatin clearance was then calculated by individually adding 25 to the four GFR determinations based on the Calvert equation, which states that carboplatin clearance equals GFR+25 (nonrenal clearance). The carboplatin clearance was also estimated using the Chatelut equation. The five determinations of carboplatin clearance were compared using Friedman's test and post-hoc Wilcoxon signed rank tests. Precision and bias for each carboplatin clearance determination were calculated assuming that 99mTc-DTPA provided the most accurate measure of GFR. Results: A statistically significant difference was found between the five methods of estimating carboplatin clearance (P<0.001). No difference was found between carboplatin clearance calculated using 99mTc-DTPA and the Chatelut equation, the Cockcroft-Gault formula or the 2-h urine collection. The Chatelut equation provided more precision and less bias than the 2-h urine collection (median precision 20% and 30%, median bias –1% and –18%, respectively). Conclusion: Compared to 99mTc-DTPA, the Chatelut equation more accurately estimates carboplatin clearance than the Cockcroft-Gault formula, the 2-h urine collection and the 24-h urine collection. The greater negative bias found for the latter three estimates of carboplatin clearance could result in underdosing of carboplatin. [ABSTRACT FROM AUTHOR]