Douglas H. Deutschman

Predicting obstructive coronary artery disease with serum sphingosine-1-phosphate

BACKGROUND Sphingolipids are emerging as important signaling molecules that may be produced by cardiac tissue during ischemic stress or as a consequence of inflammation. Because both inflammation and myocardial ischemia are associated with coronary artery disease (CAD), a study was designed to test the ability of serum sphingolipids to predict obstructive CAD. METHODS The study consisted of 308 consecutive patients undergoing coronary angiography for all indications. The primary data points were the assessment of coronary artery stenosis with angiography and the measurements of serum sphingolipids. RESULTS In this diverse population, serum sphingosine-1-phosphate (S1P) was a significant predictor of CAD (P <.001). Multivariate analysis with logistic regression demonstrated that serum S1P was more predictive of obstructive CAD (odds ratio = 7.61) than the traditional risk factors (age, sex, family history of CAD, diabetes mellitus, lipid profile, hypertension, etc.). A 3-variable S1PC composite score was derived by combining the power of the S1P marker with the 2 most important risk factors, age and sex. The relationship between the S1PC and CAD scores was continuous and progressive, such that patients with elevated S1PC scores had higher occurrences of obstructive CAD. S1PC was also predictive of disease severity; 53.2% of patients in the fourth S1PC quartile had 2 to 3 vessel CAD, whereas only 5.2% of patients in the first S1PC quartile had 2 to 3 vessel disease (RR = 10.2 for severity). CONCLUSIONS Serum S1P is a remarkably strong and robust predictor of both the occurrence and severity of coronary stenosis. An S1P-based composite score may be useful as a novel, non-invasive indicator of obstructive CAD.

Quantitative Analysis of the Timing of the Origin and Diversification of Extant Placental Orders

Fossil evidence is consistent with origination and diversification of extant placental orders in the early Tertiary (Explosive Model), and with the possibility of some orders having stem taxa extending into the Cretaceous (Long Fuse Model). Fossil evidence that 15 of 18 extant placental orders appeared and began diversification in the first 16 m.y. of the Cenozoic is, however, at odds with molecular studies arguing some orders diversified up to 40 m.y. earlier in the Early Cretaceous (Short Fuse Model). The quality of the fossil record was assessed by tabulating localities of all mammals in the last 105 m.y. Global locality data (except Africa) for 105 m.y. of eutherian evolution indicate discernible biogeographic patterns by the last 15 m.y. of the Cretaceous. Eutherian genera increase from 11 in latest Cretaceous to 139 in earliest Tertiary, although both are represented by about 50 localities. Yet even in the Late Cretaceous of North America and Asia where eutherians are abundant, none of the 18 extant orders are definitely known. A series of Monte Carlo simulations test whether the rapid appearance of most mammalian orders is statistically significant, and if so, whether it is a radiation event or an artifact of a limited fossil record. Monte Carlo tests affirm that the clustering of appearances in the early Cenozoic is statistically significant. Quantitative analysis of the locality data suggests that the number of genera described is a function of the number of localities sampled. In contrast, the number of orders is not a simple function of localities and thus does not appear to be limited by localities. A second set of Monte Carlo simulations confirms that the increase in orders cannot be explained by the limited number of localities sampled. Even for best-fit simulations, the observed pattern of ordinal appearances is steeper than expected under a variety of null models. These quantitative analyses of the fossil record demonstrate that the rapid ordinal appearances cannot be ascribed to limited Late Cretaceous sample sizes; thus, early Tertiary ordinal diversification is real. Although the fossil record is incomplete, it appears adequate to reject the hypothesis that orders of placentals began to diversify before the K/T boundary.

Simulating the effects of different fire regimes on plant functional groups in Southern California

A spatially explicit landscape model of disturbance and vegetation succession, LANDIS, was used to examine the effect of fire regime on landscape patterns of functional group dominance in the shrublands and forests of the southern California foothills and mountains. Three model treatments, frequent (35 year), moderate (70 year), and infrequent (1050 year) fire cycles, were applied to the landscape for 500 year. The model was calibrated and tested using a dataset representing an initial random distribution of six plant functional groups on an even-aged landscape. Calibration of the three fire regime treatments resulted in simulation of fire cycles within 7% of these intended values when fire cycles were averaged across ten replicated model runs per treatment. Within individual 500-year model runs, the error in the simulated fire cycle (average area burned per decade) reached 11% for the moderate and frequent fire cycle treatments and 53% for infrequent. The infrequent fire regime resulted in an old landscape dominated by the three most shade tolerant and long-lived functional groups, while shorter-lived and less shade tolerant seeders and resprouters disappeared from the landscape. The moderate fire regime, similar to what is considered the current fire regime in the southern California foothills, resulted in a younger landscape where the facultative resprouter persisted along with the long-lived shade tolerant functional groups, but the obligate seeder with low fire tolerance disappeared, despite its moderate shade tolerance. The frequent fire regime resulted in the persistence of all functional groups on the landscape with more even cover, but the same rank order as under the moderate regime. The model, originally developed for northern temperate forests, appears to be useful for simulating the disturbance regime in this fire-prone Mediterranean-type ecosystem.

Relationships between human disturbance and wildlife land use in urban habitat fragments

Habitat remnants in urbanized areas typically conserve biodiversity and serve the recreation and urban open-space needs of human populations. Nevertheless, these goals can be in conflict if human activity negatively affects wildlife. Hence, when considering habitat remnants as conservation refuges it is crucial to understand how human activities and land uses affect wildlife use of those and adjacent areas. We used tracking data (animal tracks and den or bed sites) on 10 animal species and information on human activity and environmental factors associated with anthropogenic disturbance in 12 habitat fragments across San Diego County, California, to examine the relationships among habitat fragment characteristics, human activity, and wildlife presence. There were no significant correlations of species presence and abundance with percent plant cover for all species or with different land-use intensities for all species, except the opossum (Didelphis virginiana), which preferred areas with intensive development. Woodrats (Neotoma spp.) and cougars (Puma concolor) were associated significantly and positively and significantly and negatively, respectively, with the presence and prominence of utilities. Woodrats were also negatively associated with the presence of horses. Raccoons (Procyon lotor) and coyotes (Canis latrans) were associated significantly and negatively and significantly and positively, respectively, with plant bulk and permanence. Cougars and gray foxes (Urocyon cinereoargenteus) were negatively associated with the presence of roads. Roadrunners (Geococcyx californianus) were positively associated with litter. The only species that had no significant correlations with any of the environmental variables were black-tailed jackrabbits (Lepus californicus) and mule deer (Odocoileus hemionus). Bobcat tracks were observed more often than gray foxes in the study area and bobcats correlated significantly only with water availability, contrasting with results from other studies. Our results appear to indicate that maintenance of habitat fragments in urban areas is of conservation benefit to some animal species, despite human activity and disturbance, as long as the fragments are large.

Species prioritization for monitoring and management in regional multiple species conservation plans

ABSTRACT Successful conservation plans are not solely achieved by acquiring optimally designed reserves. Ongoing monitoring and management of the biodiversity in those reserves is an equally important, but often neglected or poorly executed, part of the conservation process. In this paper we address one of the first and most important steps in designing a monitoring program – deciding what to monitor. We present a strategy for prioritizing species for monitoring and management in multispecies conservation plans. We use existing assessments of threatened status, and the degree and spatial and temporal extent of known threats to link the prioritization of species to the overarching goals and objectives of the conservation plan. We consider both broad and localized spatial scales to capture the regional conservation context and the practicalities of local management and monitoring constraints. Spatial scales that are commensurate with available data are selected. We demonstrate the utility of this strategy through application to a set of 85 plants and animals in an established multispecies conservation plan in San Diego County, California, USA. We use the prioritization to identify the most prominent risk factors and the habitats associated with the most threats to species. The protocol highlighted priorities that had not previously been identified and were not necessarily intuitive without systematic application of the criteria; many high‐priority species have received no monitoring attention to date, and lower‐priority species have. We recommend that in the absence of clear focal species, monitoring threats in highly impacted habitats may be a way to circumvent the need to monitor all the targeted species.

Spatial and Temporal Variation in Estuarine Fish and Invertebrate Assemblages: Analysis of an 11 -year Data Set

Protocols for monitoring wetland mitigation and restoration projects call for routine counts of animals, yet long-term spatial and temporal patterns are rarely examined. An analysis of monitoring data from three southern California estuaries spanning 11 years, four seasons, and multiple stations within the estuaries revealed differences in spatio-temporal patterns between fish and invertebrates. Ordination analysis showed that fish assemblages were more predictable from environmental variables than were invertebrate assemblages. Variation in the fish assemblage was, primarily due to seasonal differences that were driven by changes in temperature. Invertebrates showed little seasonal variation, but a much higher degree of interannual variation than fish. Streamflow and dissolved oxygen were significant predictors of the invertebrate assemblage, indicating that irregular disturbances such as flooding events had a more important effect on the invertebrate assemblage than predictable seasonal cues such as temperature. Variation in fish and invertebrates was high both between and within the three estuaries, indicating that differences exist on multiple spatial scales. The influence of spatial and temporal factors on estuarine invertebrate and fish communities should be considered in planning monitoring programs for wetland mitigation or restoration sites.

Landscape restoration in southern California forblands: Response of abandoned farmland to invasive annual grass control

A large-scale experiment using 1-ha plots was done to control invasive Mediterranean annual grasses, primarily Bromus spp., in farmlands abandoned for 20 years in southern California. Treatments were a grass-specific herbicide, and herbicide plus dethatching. Dethatching was done to improve the contact of herbicide with newly growing grass seedlings, and to remove litter that may potentially affect germination of native annuals. Native annuals had increased richness in response to grass control, but had low cover in all but two of six years when precipitation was adequate. Dethatching did not improve forb response. Two exotic species of Erodium were the greatest beneficiaries of exotic grass control, but the positive response of native forbs in spite of Erodium dominance suggests a competitive hierarchy of less intense interaction between the native forbs and Erodium than between native forbs and exotic grasses. After five years, grasses began to recover from the herbicide treatments, indicating the need for periodic management of exotic grasses to maintain richness and cover of native forbs. Shrubs that occur on adjacent hills did not recolonize during these six years, suggesting that the valley bottoms may have always been forblands rather than shrublands. The study shows that restoration can be used to rediscover the former vegetation of long-disturbed landscapes.

Determining nest predators of the Least Bell's Vireo through point counts, tracking stations, and video photography

Abstract We compared three methods to determine nest predators of the Least Bells Vireo (Vireo bellii pusillus) in San Diego County, California, during spring and summer 2000. Point counts and tracking stations were used to identify potential predators and video photography to document actual nest predators. Parental behavior at depredated nests was compared to that at successful nests to determine whether activity (frequency of trips to and from the nest) and singing vs. non-singing on the nest affected nest predation. Yellow-breasted Chats (Icteria virens) were the most abundant potential avian predator, followed by Western Scrub-Jays (Aphelocoma californica). Coyotes (Canis latrans) were abundant, with smaller mammalian predators occurring in low abundance. Cameras documented a 48% predation rate with scrub-jays as the major nest predators (67%), but Virginia opossums (Didelphis virginiana, 17%), gopher snakes (Pituophis melanoleucus, 8%) and Argentine ants (Linepithema humile, 8%) were also confirmed predators. Identification of potential predators from tracking stations and point counts demonstrated only moderate correspondence with actual nest predators. Parental behavior at the nest prior to depredation was not related to nest outcome.

Anti-S1P Antibody as a Novel Therapeutic Strategy for VEGFR TKI-Resistant Renal Cancer

Purpose: VEGFR2 tyrosine kinase inhibition (TKI) is a valuable treatment approach for patients with metastatic renal cell carcinoma (RCC). However, resistance to treatment is inevitable. Identification of novel targets could lead to better treatment for patients with TKI-naïve or -resistant RCC. Experimental Design: In this study, we performed transcriptome analysis of VEGFR TKI-resistant tumors in a murine model and discovered that the SPHK–S1P pathway is upregulated at the time of resistance. We tested sphingosine-1-phosphate (S1P) pathway inhibition using an anti-S1P mAb (sphingomab), in two mouse xenograft models of RCC, and assessed tumor SPHK expression and S1P plasma levels in patients with metastatic RCC. Results: Resistant tumors expressed several hypoxia-regulated genes. The SPHK1 pathway was among the most highly upregulated pathways that accompanied resistance to VEGFR TKI therapy. SPHK1 was expressed in human RCC, and the product of SPHK1 activity, S1P, was elevated in patients with metastatic RCC, suggesting that human RCC behavior could, in part, be due to overproduction of S1P. Sphingomab neutralization of extracellular S1P slowed tumor growth in both mouse models. Mice bearing tumors that had developed resistance to sunitinib treatment also exhibited tumor growth suppression with sphingomab. Sphingomab treatment led to a reduction in tumor blood flow as measured by MRI. Conclusions: Our findings suggest that S1P inhibition may be a novel therapeutic strategy in patients with treatment-naïve RCC and also in the setting of resistance to VEGFR TKI therapy. Clin Cancer Res; 21(8); 1925–34. ©2015 AACR.

Assessing and Prioritizing Ecological Communities for Monitoring in a Regional Habitat Conservation Plan

In nature reserves and habitat conservation areas, monitoring is required to determine if reserves are meeting their goals for preserving species, ecological communities, and ecosystems. Increasingly, reserves are established to protect multiple species and communities, each with their own conservation goals and objectives. As resources are always inadequate to monitor all components, criteria must be applied to prioritize both species and communities for monitoring and management. While methods for prioritizing species based on endangerment or risk have been established, approaches to prioritizing ecological communities for monitoring are not well developed, despite a long-standing emphasis on communities as target elements in reserve design. We established guidelines based on four criteria derived from basic principles of conservation and landscape ecology—extent, representativeness, fragmentation, and endangerment—to prioritize communities in the San Diego Multiple Species Conservation Plan (MSCP). The MSCP was one of the first multiple-species habitat conservation areas established in California, USA, and it has a complex spatial configuration because of the patterns of surrounding land use, which are largely urbanized. In this case study, high priority communities for monitoring include coastal sage scrub (high endangerment, underrepresented within the reserve relative to the region, and moderately fragmented), freshwater wetlands, and coastal habitats (both have high fragmentation, moderate endangerment and representativeness, and low areal extent). This framework may be useful to other conservation planners and land managers for prioritizing the most significant and at-risk communities for monitoring.