Participatory landscape analysis to guide restoration of ponderosa pine ecosystems in the American Southwest

Over the past 5 decades, stand-replacing crown fires have increased in size and frequency throughout the long-needled pine forests of the American Southwest. Suppression of frequent, low-intensity ground fires has resulted in dense stands of fire-prone trees over large areas. Efforts to restore forest structure to conditions that would permit a return to historical fire regimes, characterized by frequent ground fire, are hindered by the inability of managers and the public to compare the effects of alternative forest management practices on fire behavior and a host of other issues. Currently, forest management is mired in controversy, endangering ecosystem function, biodiversity, public safety, and municipal watersheds. Our research program, motivated by the need to examine cumulative effects of many independent management decisions over large planning areas, focuses on the development of spatial data and modeling tools that enable diverse stakeholders to work together to guide landscape-scale planning efforts. Data layers describing forest composition and structure facilitate modeling of fire threat and wildlife habitat over areas of several hundred thousand hectares. Modeling alternative forest management scenarios via a collaborative, public process fosters informed discourse and helps conflicting parties forge appropriate policy and identify management responses that meet restoration objectives.     

Cytolysis and piecemeal degranulation as distinct modes of activation of airway mucosal eosinophils

In contrast to the protective effect of chronic caloric restriction on tumor development, we have shown that fasting sustained tumor initiation in rat liver by a noninitiating dose of diethylnitrosamine. Here we investigated whether fasting had a similar favorable effect on initiation in the colorectal mucosa in 80 male F344 rats. Animals fasted for 4 days were given a single s.c. dose of azoxymethane (AOM) (20 mg/kg) on the first day of re-feeding, and rates of kinetic proliferative parameters, and development of the pre-neoplastic lesions such as aberrant crypt foci (ACF), were evaluated. Starvation before AOM treatment enhanced the growth of ACF, as shown by the significantly higher crypt multiplicity of fasted/re-fed rats as compared with fully fed rats (3.97 +/- 0.50 vs. 2.64 +/- 0.20, p < or = 0.025). This difference was associated with perturbations in cell death and cell proliferation. Fasting induced apoptosis and depressed cell division, while re-feeding had opposite effects, resulting in a higher percentage of S-phase cells at the time of AOM injection and 2 days thereafter. Starvation-induced apoptosis may represent the mitogenic stimulus to an increase in the number of cells susceptible to AOM damage, and may favor its fixation, leading to enhanced growth of ACF. Our data therefore suggest that fasting/re-feeding enhances colon cancer.     

Menin, the product of the MEN1 gene, is a nuclear protein

The MEN1 gene, mutations in which are responsible for multiple endocrine neoplasia type 1 (MEN1), encodes a 610-amino acid protein, denoted menin. The amino acid sequence of this putative tumor suppressor offers no clue to the function or subcellular location of the protein. We report herein, based on immunofluorescence, Western blotting of subcellular fractions, and epitope tagging with enhanced green fluorescent protein, that menin is located primarily in the nucleus. Enhanced green fluorescent protein-tagged menin deletion constructs identify at least two independent nuclear localization signals (NLS), both located in the C-terminal fourth of the protein. Among the 68 known independent disease-associated mutations, none of the 22 missense and 3 in-frame deletions affect either of the putative NLS sequences. However, if expressed, none of the truncated menin proteins resulting from the 43 known frameshift/nonsense mutations would retain both the NLSs. The precise role(s) of menin in the nucleus remain to be understood.     

Molecular cloning and functional characterization of murine sphingosine kinase

Sphingosine-1-phosphate (SPP) is a novel lipid messenger that has dual function. Intracellularly it regulates proliferation and survival, and extracellularly, it is a ligand for the G protein-coupled receptor Edg-1. Based on peptide sequences obtained from purified rat kidney sphingosine kinase, the enzyme that regulates SPP levels, we report here the cloning, identification, and characterization of the first mammalian sphingosine kinases (murine SPHK1a and SPHK1b). Sequence analysis indicates that these are novel kinases, which are not similar to other known kinases, and that they are evolutionarily conserved. Comparison with Saccharomyces cerevisiae and Caenorhabditis elegans sphingosine kinase sequences shows that several blocks are highly conserved in all of these sequences. One of these blocks contains an invariant, positively charged motif, GGKGK, which may be part of the ATP binding site. From Northern blot analysis of multiple mouse tissues, we observed that expression was highest in adult lung and spleen, with barely detectable levels in skeletal muscle and liver. Human embryonic kidney cells and NIH 3T3 fibroblasts transiently transfected with either sphingosine kinase expression vectors had marked increases (more than 100-fold) in sphingosine kinase activity. The enzyme specifically phosphorylated D-erythro-sphingosine and did not catalyze the phosphorylation of phosphatidylinositol, diacylglycerol, ceramide, D,L-threo-dihydrosphingosine or N, N-dimethylsphingosine. The latter two sphingolipids were competitive inhibitors of sphingosine kinase in the transfected cells as was previously found with the purified rat kidney enzyme. Transfected cells also had a marked increase in mass levels of SPP with a concomitant decrease in levels of sphingosine and, to a lesser extent, in ceramide levels. Our data suggest that sphingosine kinase is a prototypical member of a new class of lipid kinases. Cloning of sphingosine kinase is an important step in corroborating the intracellular role of SPP as a second messenger.     

Specific binding of L-triiodothyronine modulates Na(+)-K(+)-ATPase activity in adult rat cerebrocortical synaptosomes

Interactions of L-triiodothyronine (T3) in adult rat cerebrocortical synaptosomes were studied in vitro. Scatchard plot analysis revealed two sets of T3 binding sites. The degree of saturation of T3 binding sites (putative receptor) correlated well with the dose-dependent inhibition of Na(+)-K(+)-ATPase activity in synaptosomes. The relative binding affinities and relative inhibition of enzyme activities for different TH analogues were L-T3 > T3-amine > TRIAC = L-T4 > r-T3 > T2 and L-T3 > T3-amine > TRIAC > L-T4 > r-T3 > T2, respectively. The present study demonstrates the nature of inhibition of synaptosomal Na(+)-K(+)-ATPase activity may be as a function of T3 occupancy of synaptosomal receptor sites in adult mammalian brain.     

Autonomous cell death of mouse male germ cells during fetal and postnatal period

OBJECTIVE: To determine the utility of CT-determined main pulmonary artery diameter (MPAD) for predicting pulmonary hypertension (PH) in patients with parenchymal lung disease. DESIGN: Retrospective review of right-heart hemodynamic data and chest CT scans in 45 patients. SETTING: Tertiary-referral teaching hospital and VA hospital. PATIENTS: Between October 1990 and December 1995, 36 patients referred for evaluation of parenchymal lung disease or possible pulmonary vascular disease were found to have PH, as defined by mean pulmonary artery pressure (mPAP) > or =20 mm Hg. Nine control patients (mPAP <20 mm Hg) were also identified (4 from hospital records search, 5 after evaluation for possible PH). RESULTS: CT-determined MPAD was 35+/-6 mm in patients with PH and 27+/-2 mm in control subjects. In our group of patients, MPAD > or =29 mm had a sensitivity of 87%, specificity of 89%, positive predictive value (PPV) of 0.97, and positive likelihood ratio (LR) of 7.91 for predicting PH; in the subgroup of patients with parenchymal lung disease (n=28, PH and control subjects), MPAD > or =29 mm had a sensitivity of 84%, specificity of 75%, PPV of 0.95, and positive LR of 3.36 for predicting PH. The most specific findings for the presence of PH were both MPAD > or =29 mm and segmental artery-to-bronchus ratio > 1:1 in three or four lobes (specificity, 100%). There was no linear correlation between the degree of PH and MPAD (r=0.124). CONCLUSIONS: CT-determined MPAD has excellent diagnostic value for detection of PH in patients with advanced lung disease. Therefore, standard chest CT scans can be used to screen for PH as a cause of exertional limitation in patients with parenchymal lung disease. Because CT is commonly used to evaluate parenchymal lung disease, this information is readily available.     

Effect of recombinant erythropoietin on hospital admissions, readmissions, length of stay, and costs of dialysis patients

To examine the effects of recombinant human erythropoietin (rHuEPO) on hospital utilization, hospital costs, and Medicare reimbursements for hospital care, a longitudinal, matched cohort study was conducted using Medicare claims data of 23,806 Medicare-eligible, dialysis patients who received rHuEPO, did not have a transplant, and were alive for 18 mo or longer and 22,720 controls matched on age, sex, race, cause of ESRD, and dialysis modality. The relative odds (rHuEPO versus control) of admission for all causes and for specific causes over 9 mo, adjusted for admission in the prior 9 mo and the per patient change in total admissions, inpatient days, hospital costs, and Medicare hospital payments between the prior 9-mo period and the subsequent 9-mo period was examined. The adjusted relative odds (95% confidence interval) of admission (rHuEPO versus control) was: higher and statistically significant for all causes, 1.08 (1.03 to 1.14); seizure, 1.52 (1.28 to 1.75); vascular access revision, 1.11 (1.06 to 1.17), and heart failure, 1.17 (1.09 to 1.26); higher but not statistically significant for angina, 1.09 (0.99 to 1.20) and stroke, 1.08 (0.86 to 1.31); and lower but not statistically significant for myocardial infarction, 0.91 (0.72 to 1.10); peripheral vascular disease, 0.81 (0.60 to 1.02); anemia, 0.86 (0.56 to 1.17); and depression, 0.89 (0.37 to 1.40). The mean change per 1,000 patients in admissions was less by 38 (P = 0.03) because of fewer readmissions, and in days was 1,309 less (P < 0.001), for patients treated with rHuEPO versus controls. The mean change per patient in hospital costs was $371 less and was statistically significant (P = 0.03) and in Medicare hospital payments was $132 less but was not statistically significant (P = 0.43) for patients treated with rHuEPO versus controls. rHuEPO was associated with an increase in the probability of hospital admission (particularly admissions potentially related to adverse effects) but a decrease in readmissions, overall admissions, hospital days, and cost to hospitals in this cohort of patients surviving for 18 mo. Although not realized short term, Medicare savings from potential rHuEPO-related reductions in hospital care may be long term through future adjustments in diagnosis-related group-based hospital payment.     

Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis

Uric acid, the naturally occurring product of purine metabolism, is a strong peroxynitrite scavenger, as demonstrated by the capacity to bind peroxynitrite but not nitric oxide (NO) produced by lipopolysaccharide-stimulated cells of a mouse monocyte line. In this study, we used uric acid to treat experimental allergic encephalomyelitis (EAE) in the PLSJL strain of mice, which develop a chronic form of the disease with remissions and exacerbations. Uric acid administration was found to have strong therapeutic effects in a dose-dependent fashion. A regimen of four daily doses of 500 mg/kg uric acid was required to promote long-term survival regardless of whether treatment was initiated before or after the clinical symptoms of EAE had appeared. The requirement for multiple doses is likely to be caused by the rapid clearance of uric acid in mice which, unlike humans, metabolize uric acid a step further to allantoin. Uric acid treatment also was found to diminish clinical signs of a disease resembling EAE in interferon-gamma receptor knockout mice. A possible association between multiple sclerosis (MS), the disease on which EAE is modeled, and uric acid is supported by the finding that patients with MS have significantly lower levels of serum uric acid than controls. In addition, statistical evaluation of more than 20 million patient records for the incidence of MS and gout (hyperuricemic) revealed that the two diseases are almost mutually exclusive, raising the possibility that hyperuricemia may protect against MS.