Long-term Variation in Agricultural Edge-of-Field Phosphorus Transport during Snowmelt, Rain, and Mixed Runoff Events.

Runoff of nutrients and erosion of soil from agricultural lands affect soil fertility and are important nonpoint contributors of P and N to surface and ground waters, yet studies of edge-of-field nutrient transport from snowmelt or rainfall runoff on frozen ground are limited. The objective of this study was to quantify the temporal and spatial variation in edge-of-field snowmelt, rain, and mixed (rain on snow) runoff events for sediment and P loadings in five agricultural subwatersheds over a 12-yr period. Edge-of-field runoff events from five subwatersheds at Pioneer Farm near Platteville, WI, ranging in size from approximately 4 to 30 ha were sampled using automated samplers from 2002 through 2014 to determine sediment and P yields (mass loads). Mean dissolved reactive P (DRP) runoff concentrations for each event type (rain = 1.24 mg L, snow = 1.90 mg L, mix = 2.23 mg L) were above total P (TP) water quality guidelines for surface waters. The percentages of TP that was DRP for snow, mixed, and rain events were 74, 84, and 39%, respectively. Although variation in total annual P yield in edge-of-field runoff was noted between years and among sites within a given year, when aggregated over the study period, the subwatersheds showed similar transport characteristics with respect to DRP and TP yield. This study highlights the importance of examining long-term datasets in quantifying annual yields and understanding the timing of DRP and TP transport for developing best management practices and improving model accuracy in cold weather agricultural systems.

A conceptual framework for predicting and addressing the consequences of disease-related microvascular dysfunction.

OBJECTIVE: A growing body of evidence indicates that impaired microvascular perfusion plays a pathological role in a number of diseases. This manuscript aims to better define which aspects of microvascular perfusion are important, what mass transport processes (eg, insulin action, tissue oxygenation) may be impacted, and what therapies might reverse these pathologies. METHODS: We derive a theory of microvascular perfusion and solute flux drawing from established relationships in mass transport and anatomy. We then apply this theory to predict relationships between microvascular perfusion parameters and microvascular solute flux. RESULTS: For convection-limited exchange processes (eg, pulmonary oxygen uptake), our model predicts that bulk blood flow is of primary importance. For diffusion-limited exchange processes (eg, insulin action), our model predicts that perfused capillary density is of primary importance. For convection/diffusion co-limited exchange processes (eg, tissue oxygenation), our model predicts that various microvascular perfusion parameters interact in a complex, context-specific manner. We further show that our model can predict established mass transport defects in disease (eg, insulin resistance in diabetes). CONCLUSIONS: The contributions of microvascular perfusion parameters to tissue-level solute flux can be described using a minimal mathematical model. Our results hold promise for informing therapeutic interventions targeting microvascular perfusion.

The economic impact of implementing a multiple inflammatory biomarker-based approach to identify, treat, and reduce cardiovascular risk.

OBJECTIVES: To develop an economic model to estimate the change in the number of events and costs of non-fatal myocardial infarction (MI) and non-fatal ischemic stroke (IS) as a result of implementing routine risk-stratification with a multiple inflammatory biomarker approach. METHODS: Reductions in the numbers of non-fatal MI and non-fatal IS events and in related per-member-per-month (PMPM) and 5-year costs (excluding test costs) due to biomarker testing were modeled for a US health plan with one million beneficiaries. Inputs for the model included literature-based MI and IS incidence rates, healthcare costs associated with MI and IS, laboratory results of biomarker testing, MI and IS hazard ratios related to biomarker levels, patient monitoring and intervention costs and use/costs of preventative pharmacotherapy. Preventative pharmacotherapy inputs were based on an analysis of pharmacy claims data. Costs savings (2013 USD) were assessed for patients undergoing biomarker testing compared to the standard of care. Data from MDVIP and Cleveland Heart Lab supported two critical inputs: (1) treatment success rates and (2) the population distribution of biomarker testing. Incidence rates, hazard ratios, and other healthcare costs were obtained from the literature. RESULTS: For a health plan with one million members, an estimated 21,104 MI and 22,589 IS events occurred in a 5-year period. Routine biomarker testing among a sub-group of beneficiaries ≥35 years old reduced non-fatal MI and IS events by 2039 and 1869, respectively, yielding cost savings of over $187 million over 5 years ($3.13 PMPM), excluding test costs. Results were sensitive to changes in treatment response rates. Nonetheless, cost savings were observed for all input values. CONCLUSIONS: This study suggests that health plans can realize substantial cost savings by preventing non-fatal MI and IS events after implementation of routine biomarker testing. Five-year cost savings before test costs could exceed $3.13 PMPM.

Strategy for cardiovascular repair: role of stem cells in 2012 and beyond.

Stem cell based repair of the heart has captured the mind and imagination of cardiovascular specialists and the lay public. Significant progress has been made at the bench defining the mechanisms of action. This work has gone on further to demonstrate that there is an endogenous stem cell based repair process that attempts to repair the myocardium in response to acute ischemic injury. At the same time investigators at both the bench and in clinical populations have investigated the effects of distinct adult stem cell populations in the peri-infarct period as well as patients with chronic heart failure. In this review we attempt to lay a framework to review how cardiovascular regenerative medicine has progressed to date, summarize what we have learned to date, and discuss how the field may evolve in the future.

SDF-1 in myocardial repair.

Stem cell therapy for the prevention and treatment of cardiac dysfunction holds significant promise for patients with ischemic heart disease. Excitingly early clinical studies have demonstrated safety and some clinical feasibility, while at the same time studies in the laboratory have investigated mechanisms of action and strategies to optimize the effects of regenerative cardiac therapies. One of the key pathways that has been demonstrated critical in stem cell-based cardiac repair is (stromal cell-derived factor-1) SDF-1:CXCR4. SDF-1:CXCR4 has been shown to affect stem cell homing, cardiac myocyte survival and ventricular remodeling in animal studies of acute myocardial infarction and chronic heart failure. Recently released clinical data suggest that SDF-1 alone is sufficient to induce cardiac repair. Most importantly, studies like those on the SDF-1:CXCR4 axis have suggested mechanisms critical for cardiac regenerative therapies that if clinical investigators continue to ignore will result in poorly designed studies that will continue to yield negative results.

Stem cells for myocardial regeneration.

The field of cardiovascular regenerative medicine has made significant strides over the past decade. Clinical trials have demonstrated benefit in acute myocardial infarction (AMI) and chronic heart failure (CHF). As the field has matured, it has defined novel biology and invented an array of therapeutic strategies that are currently under development. In this brief review, we attempt to conceptualize the knowledge to date as well as examine how this knowledge has been translated to various therapeutic strategies.

Plasmid-based transient human stromal cell-derived factor-1 gene transfer improves cardiac function in chronic heart failure.

We previously demonstrated that transient stromal cell-derived factor-1 alpha (SDF-1) improved cardiac function when delivered via cell therapy in ischemic cardiomyopathy at a time remote from acute myocardial infarction (MI) rats. We hypothesized that non-viral gene transfer of naked plasmid DNA-expressing hSDF-1 could similarly improve cardiac function. To optimize plasmid delivery, we tested SDF-1 and luciferase plasmids driven by the cytomegalovirus (CMV) promoter with (pCMVe) or without (pCMV) translational enhancers or α myosin heavy chain (pMHC) promoter in a rodent model of heart failure. In vivo expression of pCMVe was 10-fold greater than pCMV and pMHC expression and continued over 30 days. We directly injected rat hearts with SDF-1 plasmid 1 month after MI and assessed heart function. At 4 weeks after plasmid injection, we observed a 35.97 and 32.65% decline in fractional shortening (FS) in control (saline) animals and pMHC-hSDF1 animals, respectively, which was sustained to 8 weeks. In contrast, we observed a significant 24.97% increase in animals injected with the pCMVe-hSDF1 vector. Immunohistochemistry of cardiac tissue revealed a significant increase in vessel density in the hSDF-1-treated animals compared with control animals. Increasing SDF-1 expression promoted angiogenesis and improved cardiac function in rats with ischemic heart failure along with evidence of scar remodeling with a trend toward decreased myocardial fibrosis. These data demonstrate that stand-alone non-viral hSDF-1 gene transfer is a strategy for improving cardiac function in ischemic cardiomyopathy.

[Isolated oligodontia: a case presentation and review of the literature].

Tooth agenesis is a common developmental anomaly that appears in 2.2-10% of the general population (excluding agenesis of third molars). Congenital tooth agenesis can be either Hypodontia (agenesis of fewer than six teeth excluding third molars) or Oligodontia (agenesis of more than six teeth excluding third molars). Oligodontia can occur either as an isolated condition (non-syndromic oligodontia) or be associated with cleft lip\palate and other genetic syndromes (syndromatic oligodontia). The purpose of this article is to present an unusual case of non-syndromic oligodontia and describe the dental treatment for this condition. The patient was a 25 years old healthy male with a chief complaint of multiple teeth agenesis and TMJ dysfunction. The family history revealed that the mother, grandmother and siblings have also multiple teeth agenesis. Clinical examination revealed missing of nine teeth in the maxilla (12,13, 15,15, 17, 23, 24, 25, 27) and 10 teeth in the mandible (32, 33, 34, 35, 37, 42, 43, 44, 45, 47). The patient's dental treatment plan included preparing provisional over-dentures, orthodontic treatment and dental implants (after extractions of the deciduous teeth). In the discussion of the article the pathology and the genetics of oligodontia are reviewed.

Diversity patterns amongst herbivorous dinosaurs and plants during the Cretaceous: implications for hypotheses of dinosaur/angiosperm co-evolution.

Palaeobiologists frequently attempt to identify examples of co-evolutionary interactions over extended geological timescales. These hypotheses are often intuitively appealing, as co-evolution is so prevalent in extant ecosystems, and are easy to formulate; however, they are much more difficult to test than their modern analogues. Among the more intriguing deep time co-evolutionary scenarios are those that relate changes in Cretaceous dinosaur faunas to the primary radiation of flowering plants. Demonstration of temporal congruence between the diversifications of co-evolving groups is necessary to establish whether co-evolution could have occurred in such cases, but is insufficient to prove whether it actually did take place. Diversity patterns do, however, provide a means for falsifying such hypotheses. We have compiled a new database of Cretaceous dinosaur and plant distributions from information in the primary literature. This is used as the basis for plotting taxonomic diversity and occurrence curves for herbivorous dinosaurs (Sauropodomorpha, Stegosauria, Ankylosauria, Ornithopoda, Ceratopsia, Pachycephalosauria and herbivorous theropods) and major groups of plants (angiosperms, Bennettitales, cycads, cycadophytes, conifers, Filicales and Ginkgoales) that co-occur in dinosaur-bearing formations. Pairwise statistical comparisons were made between various floral and faunal groups to test for any significant similarities in the shapes of their diversity curves through time. We show that, with one possible exception, diversity patterns for major groups of herbivorous dinosaurs are not positively correlated with angiosperm diversity. In other words, at the level of major clades, there is no support for any diffuse co-evolutionary relationship between herbivorous dinosaurs and flowering plants. The diversification of Late Cretaceous pachycephalosaurs (excluding the problematic taxon Stenopelix) shows a positive correlation, but this might be spuriously related to poor sampling in the Turonian-Santonian interval. Stegosauria shows a significant negative correlation with flowering plants and a significant positive correlation with the nonflowering cycadophytes (cycads, Bennettitales). This interesting pattern is worthy of further investigation, and it reflects the decline of both stegosaurs and cycadophytes during the Early Cretaceous.

Association between myeloperoxidase levels and risk of coronary artery disease.

CONTEXT: Myeloperoxidase (MPO), a leukocyte enzyme that promotes oxidation of lipoproteins in atheroma, has been proposed as a possible mediator of atherosclerosis. OBJECTIVE: To determine the association between MPO levels and prevalence of coronary artery disease (CAD). DESIGN, SETTING, AND PATIENTS: Case-control study conducted from July to September 2000 in a US tertiary care referral center, including 158 patients with established CAD (cases) and 175 patients without angiographically significant CAD (controls). MAIN OUTCOME MEASURES: Association of MPO levels per milligram of neutrophil protein (leukocyte-MPO) and MPO levels per milliliter of blood (blood-MPO) with CAD risk. RESULTS: Leukocyte- and blood-MPO levels were both significantly greater in patients with CAD than in controls (P<.001). In multivariable models adjusting for traditional cardiovascular risk factors, Framingham risk score, and white blood cell counts, MPO levels were significantly associated with presence of CAD, with an OR of 11.9 (95% CI, 5.5-25.5) for the highest vs lowest quartiles of leukocyte-MPO and an OR of 20.4 (95% CI, 8.9-47.2) for the highest vs lowest quartiles of blood-MPO. CONCLUSIONS: Elevated levels of leukocyte- and blood-MPO are associated with the presence of CAD. These findings support a potential role for MPO as an inflammatory marker in CAD and may have implications for atherosclerosis diagnosis and risk assessment.

HIV-1 Vpr enhances viral burden by facilitating infection of tissue macrophages but not nondividing CD4+ T cells.

Prior experiments in explants of human lymphoid tissue have demonstrated that human immunodeficiency virus type 1 (HIV-1) productively infects diverse cellular targets including T cells and tissue macrophages. We sought to determine the specific contribution of macrophages and T cells to the overall viral burden within lymphoid tissue. To block infection of macrophages selectively while preserving infection of T cells, we used viruses deficient for viral protein R (Vpr) that exhibit profound replication defects in nondividing cells in vitro. We inoculated tonsil histocultures with matched pairs of congenic viruses that differed only by the presence of a wild-type or truncated vpr gene. Although these viruses exhibited no reduction in the infection or depletion of T cells, the ability of the Vpr-deficient R5 virus to infect tissue macrophages was severely impaired compared with matched wild-type R5 virus. Interestingly, the Vpr-deficient R5 virus also exhibited a 50% reduction in overall virus replication compared with its wild-type counterpart despite the fact that macrophages represent a small fraction of the potential targets of HIV-1 infection in these tissues. Collectively, these data highlight the importance of tissue macrophages in local viral burden and further implicate roles for CC chemokine receptor 5, macrophages, and Vpr in the life cycle and pathogenesis of HIV-1.

HIV-1 actively replicates in naive CD4(+) T cells residing within human lymphoid tissues.

Although HIV-1 gene expression is detected in naive, resting T cells in vivo, such cells are resistant to productive infection in vitro. However, we found that the endogenous microenvironment of human lymphoid tissues supports de novo infection and depletion of this population. Cell cycle analysis and DNA labeling experiments established that these cells were definitively quiescent and thus infected de novo. Quantitation of the "burst size" within naive cells further demonstrated that these cells were productively infected and contributed to the local viral burden. These findings demonstrate that lymphoid tissues support active HIV-1 replication in resting, naive T cells. Moreover, these cells are not solely reservoirs of latent virus but are permissive hosts for viral replication that likely targets them for elimination.

Incremental prognostic value of elevated baseline C-reactive protein among established markers of risk in percutaneous coronary intervention.

BACKGROUND: Established methods of risk assessment in percutaneous coronary intervention have focused on clinical and anatomical lesion characteristics. Emerging evidence indicates the substantial contribution of inflammatory processes to short-term and long-term outcomes in coronary artery disease. METHODS AND RESULTS: Within a single-center registry of contemporary percutaneous coronary revascularization strategies with postprocedural creatine kinase and clinical events routinely recorded, we assessed the association of baseline C-reactive protein with death or myocardial infarction within the first 30 days. Predictive usefulness of baseline C-reactive protein within the context of established clinical and angiographic predictors of risk was also examined. Among 727 consecutive patients, elevated baseline C-reactive protein before percutaneous coronary intervention was associated with progressive increase in death or myocardial infarction at 30 days (lowest quartile, 3.9%, versus highest quartile, 14.2%; P=0.002). Among clinical and procedural characteristics, baseline C-reactive protein remained independently predictive of adverse events, with the highest quartile of C-reactive protein associated with an odds ratio for excess 30-day death or myocardial infarction of 3.68 (95% CI, 1.51 to 8.99; P=0.004). A predictive model that included baseline C-reactive protein quartiles, American College of Cardiology/American Heart Association lesion score, acute coronary syndrome presentation, and coronary stenting appears strongly predictive of 30-day death or myocardial infarction within this population (C-statistic, 0.735) and among individual patients (Brier score, 0.006). CONCLUSIONS: Elevated baseline C-reactive protein portends heightened risk of 30-day death or myocardial infarction after coronary intervention. Coupled anatomic, clinical, and inflammatory risk stratification demonstrates strong predictive utility among patients undergoing percutaneous coronary intervention and may be useful for guiding future strategies.

Inhibition of choroidal neovascularization by intravenous injection of adenoviral vectors expressing secretable endostatin.

Endostatin is a cleavage product of collagen XVIII that inhibits tumor angiogenesis and growth. Interferon alpha2a blocks tumor angiogenesis and causes regression of hemangiomas, but has no effect on choroidal neovascularization (CNV). Therefore, inhibitors of tumor angiogenesis do not necessarily inhibit ocular neovascularization. In this study, we used an intravenous injection of adenoviral vectors containing a sig-mEndo transgene consisting of murine immunoglobulin kappa-chain leader sequence coupled to sequence coding for murine endostatin to investigate the effect of high serum levels of endostatin on CNV in mice. Mice injected with a construct in which sig-mEndo expression was driven by the Rous sarcoma virus promoter had moderately high serum levels of endostatin and significantly smaller CNV lesions at sites of laser-induced rupture of Bruch's membrane than mice injected with null vector. Mice injected with a construct in which sig-mEndo was driven by the simian cytomegalovirus promoter had approximately 10-fold higher endostatin serum levels and had nearly complete prevention of CNV. There was a strong inverse correlation between endostatin serum level and area of CNV. This study provides proof of principle that gene therapy to increase levels of endostatin can prevent the development of CNV and may provide a new treatment for the leading cause of severe loss of vision in patients with age-related macular degeneration.

Simulium cuasiexiguum, a new blackfly species (Diptera: Simuliidae) from the Minaçu area in the State of Goiás, Central Brazil.

During studies of Simuliidae at a suspected new focus of human onchocerciasis in central Brazil a new species of Simulium was found. Full descriptions of the adults and pupae of this species, S. cuasiexiguum, are described here, its affinities to closely related species in the subgenus Notolepria are discussed and its distribution in Brazil recorded.

Primary and recombinant HIV type 1 strains resistant to protease inhibitors are pathogenic in mature human lymphoid tissues.

Preserved peripheral CD4+ T cell counts despite virologic failure in patients undergoing protease inhibitor (PI)-containing antiviral regimens are a frequent occurrence in human immunodeficiency virus (HIV) disease. One hypothesis to explain the relative sparing of CD4+ T cells is that HIV strains exhibiting PI resistance concomitantly are attenuated in terms of cytopathicity for mature T cells. To test this hypothesis, we used a three-dimensional human tonsil histoculture microenvironment to assess the pathogenic potential of a panel of primary and recombinant HIV-1 strains derived from patients experiencing PI failure. All the viruses tested replicated efficiently in these cultures and, in some cases, better than comparable wild-type viral isolates. Furthermore, the PI-resistant strains depleted CD4+ T cells potently and comparably with wild-type isolates in these ex vivo lymphoid tissues. These results demonstrate that PI-resistant viruses are not inherently less pathogenic for mature T cells. Therefore, the sustained peripheral lymphocyte counts in patients with selective virologic failure may be due to specific defects in viral replication in other cell compartments or to an undefined host adaptation to viral infection during PI therapy.

Simulium cuasiexiguum, a new blackfly species (Diptera: Simuliidae) from the Minaçu area in the State of Goiás, Central Brazil

During studies of Simuliidae at a suspected new focus of human onchocerciasis in central Brazil a new species of Simulium was found. Full descriptions of the adults and pupae of this species, S. cuasiexiguum, are described here, its affinities to closely related species in the subgenus Notolepria are discussed and its distribution in Brazil recorded

Smooth muscle cell surface tissue factor pathway activation by oxidized low-density lipoprotein requires cellular lipid peroxidation.

Tissue factor, which is expressed in vascular lesions, increases thrombin production, blood coagulation, and smooth muscle cell proliferation. We demonstrate that oxidized low-density lipoprotein (LDL) induces surface tissue factor pathway activity (ie, activity of the tissue factor:factor VIIa complex) on human and rat smooth muscle cells. Tissue factor messenger RNA (mRNA) was induced by oxidized LDL or native LDL; however, native LDL did not markedly increase tissue factor activity. We hypothesized that oxidized LDL mediated the activation of the tissue factor pathway via an oxidant-dependent mechanism, because antioxidants blocked the enhanced tissue factor pathway activity by oxidized LDL, but not the increased mRNA or protein induction. We separated total lipid extracts of oxidized LDL using high-performance liquid chromatography (HPLC). This yielded 2 major peaks that induced tissue factor activity. Of the known oxysterols contained in the first peak, 7alpha- or 7beta-hydroxy or 7-ketocholesterol had no effect on tissue factor pathway activity; however, 7beta-hydroperoxycholesterol increased tissue factor pathway activity without induction of tissue factor mRNA. Tertiary butyl hydroperoxide also increased tissue factor pathway activity, suggesting that lipid hydroperoxides, some of which exist in atherosclerotic lesions, activate the tissue factor pathway. We speculate that thrombin production could be elevated via a mechanism involving peroxidation of cellular lipids, contributing to arterial thrombosis after plaque rupture. Our data suggest a mechanism by which antioxidants may offer a clinical benefit in acute coronary syndrome and restenosis.

Exclusion limits on the WIMP-nucleon cross section from the cryogenic dark matter search.

The Cryogenic Dark Matter Search (CDMS) employs Ge and Si detectors to search for weakly interacting massive particles (WIMPs) via their elastic-scattering interactions with nuclei while discriminating against interactions of background particles. CDMS data, accounting for the neutron background, give limits on the spin-independent WIMP-nucleon elastic-scattering cross section that exclude unexplored parameter space above 10 GeV/c2 WIMP mass and, at >75% C.L., the entire 3sigma allowed region for the WIMP signal reported by the DAMA experiment.