Showing papers by "Saint Louis University published in 1998"

The Efficacy of Live Attenuated, Cold-Adapted, Trivalent, Intranasal Influenzavirus Vaccine in Children

Abstract: Background Influenzavirus vaccine is used infrequently in healthy children, even though the rates of influenza in this group are high. We conducted a multicenter, double-blind, placebo-controlled trial of a live attenuated, cold-adapted, trivalent influenzavirus vaccine in children 15 to 71 months old. Methods Two hundred eighty-eight children were assigned to receive one dose of vaccine or placebo given by intranasal spray, and 1314 were assigned to receive two doses approximately 60 days apart. The strains included in the vaccine were antigenically equivalent to those in the inactivated influenzavirus vaccine in use at the time. The subjects were monitored with viral cultures for influenza during the subsequent influenza season. A case of influenza was defined as an illness associated with the isolation of wild-type influenzavirus from respiratory secretions. Results The intranasal vaccine was accepted and well tolerated. Among children who were initially seronegative, antibody titers increased by a fac...

Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group.

Abstract: Objectives To evaluate the safety and physiologic response of inhaled nitric oxide (NO) in patients with acute respiratory distress syndrome (ARDS). In addition, the effect of various doses of inhaled NO on clinical outcome parameters was assessed. Design Prospective, multicenter, randomized, double-blind, placebo-controlled study. Setting Intensive care units of 30 academic, teaching, and community hospitals in the United States. Patients Patients with ARDS, as defined by the American-European Consensus Conference, were enrolled into the study if the onset of disease was within 72 hrs of randomization. Interventions Patients were randomized to receive placebo (nitrogen gas) or inhaled NO at concentrations of 1.25, 5, 20, 40, or 80 ppm. Measurements and main results Acute increases in PaO2, decreases in mean pulmonary arterial pressure, intensity of mechanical ventilation, and oxygenation index were examined. Clinical outcomes examined were the dose effects of inhaled NO on mortality, the number of days alive and off mechanical ventilation, and the number of days alive after meeting oxygenation criteria for extubation. A total of 177 patients were enrolled over a 14-month period. An acute response to treatment gas, defined as a PaO2 increase > or =20%, was seen in 60% of the patients receiving inhaled NO with no significant differences between dose groups. Twenty-four percent of placebo patients also had an acute response to treatment gas during the first 4 hrs. The initial increase in oxygenation translated into a reduction in the FIO2 over the first day and in the intensity of mechanical ventilation over the first 4 days of treatment, as measured by the oxygenation index. There were no differences among the pooled inhaled NO groups and placebo with respect to mortality rate, the number of days alive and off mechanical ventilation, or the number of days alive after meeting oxygenation criteria for extubation. However, patients receiving 5 ppm inhaled NO showed an improvement in these parameters. In this dose group, the percentage of patients alive and off mechanical ventilation at day 28 (a post hoc analysis) was higher (62% vs. 44%) than the placebo group. There was no apparent difference in the number or type of adverse events reported among those patients receiving inhaled NO compared with placebo. Four patients had methemoglobin concentrations >5%. The mean inspired nitrogen dioxide concentration in inhaled NO patients was 1.5 ppm. Conclusions From this placebo-controlled study, inhaled NO appears to be well tolerated in the population of ARDS patients studied. With mechanical ventilation held constant, inhaled NO is associated with a significant improvement in oxygenation compared with placebo over the first 4 hrs of treatment. An improvement in oxygenation index was observed over the first 4 days. Larger phase III studies are needed to ascertain if these acute physiologic improvements can lead to altered clinical outcome.

Co-occurrence of Abuse of Different Drugs in Men The Role of Drug-Specific and Shared Vulnerabilities

Abstract: Background Previous research has demonstrated genetic and environmental influences on abuse of individual substances, but there is less known about how these factors may influence the co-occurrence of abuse of different illicit drugs. Methods We studied 3372 male twin pairs from the Vietnam Era Twin Registry. They were interviewed using the Diagnostic Interview Schedule, Version III, Revised to investigate the extent to which the abuse of different categories of drugs occurs together within an individual, as well as the possibility that genetic and environmental factors are responsible for observed co-occurrence. Co-occurrence was quantified using odds ratios and conditional probabilities. Multivariate biometrical modeling analyses were used to assess genetic and environmental influences on co-occurrence. Results Abusing any category of drug was associated with a marked increase in the probability of abusing every other category of drugs. We found evidence for a shared or common vulnerability factor that underlies the abuse of marijuana, sedatives, stimulants, heroin or opiates, and psychedelics. This shared vulnerability is influenced by genetic, family environmental, and nonfamily environmental factors, but not every drug is influenced to the same extent by the shared vulnerability factor. Marijuana, more than other drugs, was influenced by family environmental factors. Each category of drug, except psychedelics, had genetic influences unique to itself (ie, not shared with other drug categories). Heroin had larger genetic influences unique to itself than did any other drug. Conclusion There are genetically and environmentally determined characteristics that comprise a shared or common vulnerability to abuse a range of illicit drugs.

Diagnosis and Management of Rhinitis: Complete Guidelines of the Joint Task Force on Practice Parameters in Allergy, Asthma and Immunology

Abstract: This document contains complete guidelines for diagnosis and management of rhinitis developed by the Joint Task Force on Practice Parameters in Allergy, Asthma and Immunology, representing the American Academy of Allergy, Asthma and Immunology, the American College of Allergy, Asthma and Immunology and the Joint Council on Allergy, Asthma and Immunology. The guidelines are comprehensive and begin with statements on clinical characteristics and diagnosis of different forms of rhinitis (allergic, non-allergic, occupational rhinitis, hormonal rhinitis [pregnancy and hypothyroidism], drug-induced rhinitis, rhinitis from food ingestion), and other conditions that may be confused with rhinitis. Recommendations on patient evaluation discuss appropriate use of history, physical examination, and diagnostic testing, as well as unproven or inappropriate techniques that should not be used. Parameters on management include use of environmental control measures, pharmacologic therapy including recently introduced therapies and allergen immunotherapy. Because of the risks to patients and society from sedation and performance impairment caused by first generation antihistamines, second generation antihistamines that reduce or eliminate these side effects should usually be considered before first generation antihistamines for the treatment of allergic rhi-nitis. The document emphasizes the importance of rhinitis management for co-morbid conditions (asthma, sinusitis, otitis media). Guidelines are also presented on special considerations in patients subsets (children, the elderly, pregnancy, athletes and patients with rhinitis medicamentosa); and when consultation with an allergist-immunologist should be considered.

Endorsers in Advertising: The Case of Negative Celebrity Information

Abstract: The use of celebrity endorsers is a popular executional device, but it is not without risk. The authors report three studies examining how negative information about a celebrity can affect the brand the celebrity endorses. Using an associative network model of memory as a theoretical framework, they considered four moderating variables: the size of the association set for the brand, the size of the association set for the celebrity, the timing of the negative celebrity information, and the strength of the associative link between the brand and the celebrity. In the first two studies, they used a fictitious but realistic celebrity endorser and in the third they used an actual celebrity. Negative information about a celebrity resulted in a decline in attitude toward the endorsed brand only for the fictitious celebrity. That general relationship was moderated in varying degrees by association set size, timing of the negative information, and the strength of the link between brand and celebrity.

Survey Article: The Coming of Age of Deliberative Democracy

Abstract: roposed as a reformist and sometimes even as a radical political ideal,deliberative democracy begins with the critique of the standard practices ofliberal democracy. Although the idea can be traced to Dewey and Arendt andthen further back to Rousseau and even Aristotle, in its recent incarnation theterm stems from Joseph Bessette, who explicitly coined it to oppose the elitist or‘‘aristocratic’’ interpretation of the American Constitution.

A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Mycophenolate Mofetil Investigators.

Abstract: BACKGROUND After heart transplantation, 1-year and 5-year survival rates are 79% and 63%, respectively, with rejection, infection, and allograft coronary artery disease accounting for the majority of deaths. Mycophenolate mofetil (MMF), an inhibitor of the de novo pathway for purine biosynthesis, decreases rejection in animals and in human renal transplantation. METHODS In a double-blind, active-controlled trial, 28 centers randomized 650 patients undergoing their first heart transplant to receive MMF (3000 mg/day) or azathioprine (1.5-3 mg/kg/day), in addition to cyclosporine and corticosteroids. Rejection and survival data were obtained for 6 and 12 months, respectively. Because 11% of the patients withdrew before receiving study drug, data were analyzed on all randomized patients (enrolled patients) and on patients who received study medications (treated patients). RESULTS Survival and rejection were similar in enrolled patients (MMF, n=327; azathioprine, n=323). In treated patients (MMF, n=289; azathioprine, n=289), the MMF group compared with the azathioprine group was associated with significant reduction in mortality at 1 year (18 [6.2%] versus 33 deaths [11.4%]; P=0.031) and a significant reduction in the requirement for rejection treatment (65.7% versus 73.7%; P=0.026). There was a trend for fewer MMF patients to have > or = grade 3A rejection (45.0% versus 52.9%; P=0.055) or require the murine monoclonal anti-CD3 antibody or antithymocyte globulin (15.2% versus 21.1%; P=0.061). Opportunistic infections, mostly herpes simplex, were more common in the MMF group (53.3% versus 43.6%; P=0.025). CONCLUSIONS Substitution of MMF for azathioprine may reduce mortality and rejection in the first year after cardiac transplantation.

Prospective investigation of positron emission tomography in lung nodules.

Abstract: PURPOSESolitary pulmonary nodules (SPNs) are commonly identified by chest radiographs and computed tomography (CT). Biopsies are often performed to evaluate the nodules further. An accurate, noninvasive diagnostic test could avoid the morbidity and costs of invasive tissue sampling. We evaluated the ability of fluorine-18 deoxyglucose positron emission tomography (FDG-PET) to discriminate between benign and malignant pulmonary nodules in a prospective, multicenter trial.METHODSEighty-nine patients who had newly identified indeterminate SPNs on chest radiographs and CT were evaluated with FDG-PET. PET data were analyzed semiquantitatively by calculating standardized uptake values (SUVs) as an index of FDG accumulation and also by a visual scoring method. PET results were compared with pathology results.RESULTSSixty SPNs were malignant and 29 were benign. Using SUV data, PET had an overall sensitivity and specificity for detection of malignant nodules of 92% and 90%. Visual analysis provided a slightly high...

HFE gene knockout produces mouse model of hereditary hemochromatosis

Abstract: Hereditary hemochromatosis (HH) is a common autosomal recessive disease characterized by increased iron absorption and progressive iron storage that results in damage to major organs in the body. Recently, a candidate gene for HH called HFE encoding a major histocompatibility complex class I-like protein was identified by positional cloning. Nearly 90% of Caucasian HH patients have been found to be homozygous for the same mutation (C282Y) in the HFE gene. To test the hypothesis that the HFE gene is involved in regulation of iron homeostasis, we studied the effects of a targeted disruption of the murine homologue of the HFE gene. The HFE-deficient mice showed profound differences in parameters of iron homeostasis. Even on a standard diet, by 10 weeks of age, fasting transferrin saturation was significantly elevated compared with normal littermates (96 ± 5% vs. 77 ± 3%, P < 0.007), and hepatic iron concentration was 8-fold higher than that of wild-type littermates (2,071 ± 450 vs. 255 ± 23 μg/g dry wt, P < 0.002). Stainable hepatic iron in the HFE mutant mice was predominantly in hepatocytes in a periportal distribution. Iron concentrations in spleen, heart, and kidney were not significantly different. Erythroid parameters were normal, indicating that the anemia did not contribute to the increased iron storage. This study shows that the HFE protein is involved in the regulation of iron homeostasis and that mutations in this gene are responsible for HH. The knockout mouse model of HH will facilitate investigation into the pathogenesis of increased iron accumulation in HH and provide opportunities to evaluate therapeutic strategies for prevention or correction of iron overload.

Modal Choice in a World of Alliances: Analyzing Organizational Forms in the International Hotel Sector

Abstract: In the new management landscape, where interfirm collaborations are common, international companies today have fully owned operations and equity joint ventures, as well as non-equity alliances, which in the service sector include franchising and management service agreements. What determines the optimum choice of organizational mode? The new syncretic theory developed in this paper combines concepts from transaction costs theory, agency theory, corporate knowledge and organizational capability theories to answer this question. The paper then tests these concepts to explain the incidence of these modes in the international hotel business, using canonical discriminant analysis, as well as logistical regression using a generalized LOGIT model. The choice of “entry mode” is shown to be determined by both country or environmental variables, as well as firm-specific variables.

Systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), multiple organ failure (MOF): are we winning the battle?

Abstract: The problems of inflammation and infection leading to organ dysfunction and failure continue to be the major problems after injury and operations and with intensive care for many diseases and problems. When SIRS goes to MODS and MOF, the mortality becomes high, ranging from 30-80% depending on the number of failed organs. In spite of this, there have been recent exciting discoveries and contributions to patient care. A reasonable question then is, are we making progress and if so, can we document it? Are the incidence and mortality of MOF decreasing? The literature comparing care over some years suggests a decrease in ICU mortality in patients with severe organ failure, a decrease in elective surgical mortality, and improvement in the results of care and outcome for trauma patients. Review of problems occurring in sick and injured patients indicates that certain problems are decreasing in frequency, such as renal failure and ARDS after trauma, stress gastrointestinal bleeding, and abdominal abscesses, and these should improve outcome. There are a number of exciting therapies that help certain patients but not everyone. These controversies challenge us to focus on where and when there are positive benefits. Risk factors for MOF are addressed to focus on early intervention. The possibilities of multiple therapeutic agents are described. Finally, we describe and emphasize our recommendation to strive to prevent MODS and SIRS.

Cognitive function following acute sleep restriction in children ages 10-14.

Abstract: STUDY OBJECTIVES: Various aspects of human performance were assessed in children after sleep loss PARTICIPANTS: Sixteen children (7 males, 9 females) between the ages of 10 and 14 years DESIGN AND INTERVENTIONS: Children were randomly assigned to either a control (CTRL) group, with 11 hours in bed, or an experimental sleep restriction (SR) group, with 5 hours in bed, on a single night in the sleep laboratory MEASUREMENTS: Both groups were evaluated the following day with a battery of performance and sleepiness measures Psychomotor and cognitive performance tests were given during four 1-hour testing sessions at 2-hour intervals RESULTS: A multiple sleep latency test (MSLT) documented shorter latencies for SR children than controls Significant treatment differences were discovered in three of four variables of verbal creativity, including fluency, flexibility, and average indices There were also group differences found on the Wisconsin Card Sorting Test (WCST), which may be indicative of difficulty learning new abstract concepts Measures of rote performance and less-complex cognitive functions, including measures of memory and learning and figural creativity, did not show differences between groups, perhaps because motivation could overcome sleepiness-related impairment for these tasks CONCLUSIONS: Higher cognitive functions in children, such as verbal creativity and abstract thinking, are impaired after a single night of restricted sleep, even when routine performance is relatively maintained Language: en

Matching products with endorsers: attractiveness versus expertise

Abstract: The importance of fit between the endorser and the endorsed product has been described as the “match‐up hypothesis”. Much “match‐up hypothesis” research has focused on physical attraction. We present two studies which collectively suggest that, while attractive endorsers do positively affect attitude toward the endorsed brand, expertise is a more important dimension for driving the fit between an endorser and a brand. Study One examines physical attractiveness as a match‐up factor. Results indicate a general “attractiveness effect”, but not a match‐up effect based on attractiveness. Study Two considers expertise as the match‐up dimension. A match‐up effect was found based on expertise.

CHARGE Association: An Update and Review for the Primary Pediatrician

Abstract: CHARGE association is a nonrandom pattern of congenital anomalies that occurs together more frequently than one would expect on the basis of chance. This common multiple anomaly condition has an estimated prevalence of 1:10,000. The number of children diagnosed with CHARGE association is increasing, owing presumably to greater awareness of this condition and advances in the care of complex, chronically ill children, resulting in improved survival and outcome. This review of CHARGE association presents diagnostic criteria that may define a concise, recognizable syndrome with a single pathogenetic basis. This review also summarizes our current understanding of the management for this complex and chronic multiple congenital anomaly condition and discusses the pathogenetic basis for this condition.

Physical Activity and Minority Women: A Qualitative Study

Abstract: Few physical activity research studies have been conducted with minority women. The purpose of this study was to explore patterns of physical activity among minority women. Focus groups were conducted with volunteers older than age 40. Each group was led by a trained moderator familiar with the ethnic community targeted. The sessions were audiotaped and professionally transcribed. Constructs were researched and codes were developed. Data were analyzed using NUD*IST qualitative analysis program. While participants did not identify themselves as "exercisers," they indicated they got enough physical activity from caregiving, housekeeping, and workday activities. The most common environmental barriers to becoming more physically active included safety, availability, and cost. Personal barriers included lack of time, health concerns, and lack of motivation. Results indicate the importance of terminology and assessment when conducting physical activity research in these populations. Also, results suggest many barriers are changeable with policies and interventions.

Assessing the current validity of the Bem Sex-Role Inventory.

Abstract: The Bem Sex-Role Inventory (BSRI) is a widelyused instrument in measuring gender role perceptions.Recent concerns regarding the validity of the adjectiveshave arisen as changes in the roles of men and women have occurred in American society sincethe 1970's. A partial replication of the method that Bem(1974) used to validate the masculine and feminineadjectives comprising the instrument was conducted. All but two of the adjectives were validatedusing Bem's criteria. These findings suggest that theBSRI may still be a valid instrument for assessing genderroles. However, evidence was revealed that traditional masculine and feminine gender role perceptionsmay be weakening. Future validation of the BSRI iswarranted in light of these patterns.

19-Nor-1-alpha-25-dihydroxyvitamin D2 (Paricalcitol) safely and effectively reduces the levels of intact parathyroid hormone in patients on hemodialysis.

Abstract: Paricalcitol (19-nor-1alpha-25-dihydroxyvitamin D2), a new vitamin D analog developed for the treatment of secondary hyperparathyroidism, was evaluated in three double-blind, placebo-controlled, dose-escalating, randomized multicenter trials. A total of 78 patients (40 Paricalcitol injection, 38 placebo) achieved treatment phase eligibility, which included intact parathyroid hormone (iPTH) > or = 400 pg/ml, normalized serum calcium levels between 8.0 and 10.0 mg/dl, and calcium x phosphorus product values less than 75. Study end points included a decrease in iPTH of at least 30% or a maximum of five dose escalations. After a 4-wk washout, paricalcitol or placebo was administered intravenously three times per week after dialysis for 12 wk. Study drug was started at a dose of 0.04 microg/kg and was increased by 0.04 microg/kg every 2 wk to a maximal allowable dose of 0.24 microg/kg or until at least a 30% decrease in serum iPTH was achieved. The dose of paricalcitol that decreased iPTH by at least 30% became the maintenance dose. Of 40 patients receiving paricalcitol, 27 (68%) had at least a 30% decrease in serum iPTH for 4 consecutive weeks, compared with three of 38 patients (8%) receiving placebo (P < 0.001). For patients who received 12 wk of treatment with paricalcitol, the levels of iPTH decreased significantly from 795+/-86 to 406+/-106 pg/ml (P < 0.001), whereas the values for PTH were 679+/-41 pg/ml before and 592+/-41 pg/ml after 12 wk of therapy in patients receiving placebo (P=NS). Also, there was a significant difference between treatment groups for the change from baseline PTH levels (P < 0.001). Paricalcitol treatment resulted in a significant reduction in serum alkaline phosphatase from 148+/-23 U/L to 101+/-14 U/L (P < 0.001) in patients treated for 12 wk compared with 120+/-9 U/L to 130+/-11 U/L (P=NS) in patients receiving placebo for 12 wk. Importantly, hypercalcemia did not occur before achieving target serum iPTH levels in any of the paricalcitol-treated patients. There was no significant difference for the change from baseline in serum phosphorus within or between treatment groups. There was no significant difference in adverse events between the paricalcitol and placebo-treated groups. These studies demonstrate that paricalcitol safely and effectively suppresses iPTH levels in hemodialysis patients. This second generation vitamin D analog may have a wider therapeutic window than current vitamin D preparations, and thus may allow reduction in PTH with less hypercalcemia.

Relationship of indoor allergen exposure to skin test sensitivity in inner-city children with asthma☆☆☆★★★♢

Abstract: Background: It is important to understand the relationship between environmental allergen exposure dose and the risk of atopic individuals becoming sensitized to that allergen if we are to change the risk of sensitization and morbidity from allergic disease Objective: The objective of these studies was to determine whether there was a dose response between current exposure to mite, cockroach, and cat allergen in inner-city children and to determine the prevalence of sensitization to these allergens Methods: A sample of 500 children was selected from the 1528 children enrolled in the National Cooperative Inner City Asthma Study Children were selected who had a sample of home dust and valid skin test responses performed with a MultiTest skin test device The samples of home dust were collected from the floor and furniture in the kitchen, bedroom, and television/living room and were assayed for Der p 1, Der f 1, Bla g 1, and Fel d 1 allergens Results: Each allergen level correlated significantly between rooms in individual homes Mite (Der p 1 and Der f 1) and cat (Fel d 1) allergen levels were frequently below the detection limit of the assay Cockroach allergen (Bla g 1) concentrations in the child's bedroom were related to the prevalence of positive skin test responses to cockroach allergen extract among the children, with an odds ratio for sensitization of 145 (111-192) Positive skin test responses to cockroach allergen were seen in 15% of children exposed to bedroom dust with a Bla g 1 concentration below the level of detection compared with a rate of 32% in bedrooms with Bla g 1 levels of 1 to 2 U/g and 40% to 44% among those in rooms with 4 U/g or greater The relationship between exposure and positive skin test responses was clearly stronger among atopic children with a greater number of positive skin test responses Conclusions: Despite widespread exposure to household allergens, the strongest relationship between exposure and sensitization was seen in the bedroom The dose response between exposure to cockroach allergen and sensitization suggested that exposure to low doses of allergen, 2 U/g or less, was a risk factor and that the risk plateaus above 4 U/g Atopy modified the relationship of exposure to sensitization (J Allergy Clin Immunol 1998;102:563-70)

Metformin decreases food consumption and induces weight loss in subjects with obesity with type II non-insulin-dependent diabetes.

Abstract: Metformin often promotes weight loss in patients with obesity with non-insulin-dependent diabetes mellitus (NIDDM). The mechanism may be attributed to decreased food intake. This study has tested the effect of metformin on satiety and its efficacy in inducing weight loss. Twelve diet-treated NIDDM women with obesity were randomly given two dose levels (850 mg or 1700 mg) of metformin or placebo at 0800 for three consecutive days followed by a meal test on the third day on three occasions using a 3x3 Latin square design. The number of sandwich canapes eaten in three consecutive 10-minute periods beginning at 1400 hours was used to quantitate food intake, and the level of subjective hunger was rated just before the sandwich meal with a linear analogue hunger rating scale at 1400 after a 6-hour fast. The prior administration of metformin produced a reduction in calorie intake after each of the two doses of metformin treatment. The 1700-mg metformin dose had the most marked appetite suppressant action. Similarly, hunger ratings were significantly lowered after metformin, and the effect was most pronounced after the administration of 1700 mg of metformin. To assess the efficacy of metformin in reducing bodyweight, 48 diet-treated NIDDM women with obesity who had failed to lose weight by diet therapy were first placed on a 1200-kcal ADA (American Diabetes Association) diet before being randomized to receive either metformin (850 mg) or placebo twice daily in a double-blind fashion for 24 weeks. A 4-week single-blind placebo lead-in period preceded and a 6-week single-blind placebo period followed the 24-week double-blind treatment period. Subjects treated with metformin continued to lose weight throughout 24 weeks of treatment; their mean maximum weight loss was 8 kg greater than that of the placebo group, with corresponding lower HbA1C and fasting blood glucose levels at the end of the active treatment period. These results indicate that metformin decreases calorie intake in a dose-dependent manner and leads to a reduction in bodyweight in NIDDM patients with obesity.

Deformation-induced ATP release from red blood cells requires CFTR activity

Abstract: Recently, it was reported that rabbit and human red blood cells (RBCs) release ATP in response to mechanical deformation. Here we investigate the hypothesis that the activity of the cystic fibrosis...

Dating topography of the Sierra Nevada, California, using apatite (U–Th)/He ages

Abstract: The upward motion of rock masses relative to the Earth's surface has been documented for most of the main mountain belts using thermochronological and petrological techniques. More fundamental to the physical processes of mountain building, however, is the motion of the Earth's surface itself, which remains elusive. Here we describe a technique for estimating the age of topographic relief by mapping the low-temperature thermal structure imparted by river incision using the ages of apatites determined from their uranium, thorium and helium contents. The technique exploits horizontal variations in temperature in the shallow crust that result from range-normal river drainages, because cooling beneath ancient river valleys occurs earlier than beneath intervening ridges. Our results from the Sierra Nevada, California, indicate that two of the modern transverse drainages, the Kings and the San Joaquin, had developed deep canyons by the Late Cretaceous period, suggesting that the high topography of the range is ~50–60 million years older than generally thought.

Molecular recognition of angiogenesis inhibitors fumagillin and ovalicin by methionine aminopeptidase 2

Abstract: Angiogenesis inhibitors are a novel class of promising therapeutic agents for treating cancer and other human diseases. Fumagillin and ovalicin compose a class of structurally related natural products that potently inhibit angiogenesis by blocking endothelial cell proliferation. A synthetic analog of fumagillin, TNP-470, is currently undergoing clinical trials for treatment of a variety of cancers. A common target for fumagillin and ovalicin recently was identified as the type 2 methionine aminopeptidase (MetAP2). These natural products bind MetAP2 covalently, inhibiting its enzymatic activity. The specificity of this binding is underscored by the lack of inhibition of the closely related type 1 enzyme, MetAP1. The molecular basis of the high affinity and specificity of these inhibitors for MetAP2 has remained undiscovered. To determine the structural elements of these inhibitors and MetAP2 that are involved in this interaction, we synthesized fumagillin analogs in which each of the potentially reactive epoxide groups was removed either individually or in combination. We found that the ring epoxide in fumagillin is involved in the covalent modification of MetAP2, whereas the side chain epoxide group is dispensable. By using a fumagillin analog tagged with fluorescein, His-231 in MetAP2 was identified as the residue that is covalently modified by fumagillin. Site-directed mutagenesis of His-231 demonstrated its importance for the catalytic activity of MetAP2 and confirmed that the same residue is covalently modified by fumagillin. These results, in agreement with a recent structural study, suggest that fumagillin and ovalicin inhibit MetAP2 by irreversible blockage of the active site.

IL-1 produced and released endogenously within human islets inhibits beta cell function.

Abstract: Resident macrophages have been suggested to participate in the initiation of beta cell damage during the development of autoimmune diabetes. The purpose of this study was to determine if the endogenous production and release of interleukin 1 (IL-1) in human islets of Langerhans by resident macrophages results in the inhibition of beta cell function. Treatment of human islets with a combination of tumor necrosis factor (TNF) + lipopolysaccharide (LPS) + interferon-gamma (IFN-gamma) stimulates inducible nitric oxide synthase (iNOS) expression, nitric oxide production, and inhibits glucose-stimulated insulin secretion. The IL-1 receptor antagonist protein (IRAP) prevents TNF + LPS + IFN-gamma-induced iNOS expression and nitrite production, and attenuates the inhibitory effects on glucose-stimulated insulin secretion by human islets. Inhibition of iNOS activity by aminoguanidine also attenuates TNF + LPS + IFN-gamma-induced inhibition of insulin secretion by human islets. These results indicate that the inhibitory effects of TNF + LPS + IFN-gamma are mediated by nitric oxide, produced by the actions of IL-1 released endogenously within human islets. Reverse transcriptase polymerase chain reaction was used to confirm that TNF + LPS + IFN-gamma stimulates the expression of both IL-1alpha and IL-1beta in human islets. Two forms of evidence indicate that resident macrophages are the human islet cellular source of IL-1: culture conditions that deplete islet lymphoid cells prevent TNF + LPS + IFN-gamma-induced iNOS expression, nitric oxide production, and IL-1 mRNA expression by human islets; and IL-1 and the macrophage surface marker CD69 colocalize in human islets treated with TNF + LPS + IFN-gamma as determined by immunohistochemical analysis. Lastly, nitric oxide production is not required for TNF + LPS + IFN-gamma-induced IL-1 release in human islets. However, cellular damage stimulates IL-1 release by islet macrophages. These findings support the hypothesis that activated islet macrophages may mediate beta cell damage during the development of insulin-dependent diabetes by releasing IL-1 in human islets followed by cytokine-induced iNOS expression by beta cells.

Executive Summary of Joint Task Force Practice Parameters on Diagnosis and Management of Rhinitis

Abstract: Rhinitis is a significant cause of widespread morbidity, medical treatment costs, reduced work productivity and lost school days. Although sometimes mistakenly viewed as a trivial disease, symptoms of allergic and non-allergic rhinitis may significantly impact a patient's quality of life, by causing fatigue, headache, cognitive impairment and other systemic symptoms. In addition, many antihistamines commonly used for treatment can themselves cause performance impairment that may contribute to fatal automobile accidents, work place accidents, decreased work productivity and in children, impaired school performance. Appropriate management of rhinitis may be an important component in effective management of coexisting or complicating respiratory conditions, such as asthma, sinusitis, or chronic otitis media. Rhinitis may be caused by allergic, non-allergic, infectious, hormonal, occupational, and other factors. Defining the causes of rhinitis in an individual is important because different rhinitis syndromes may require different therapeutic approaches for optimal management, an important consideration as more treatment options become available. This Executive Summary reviews key points about diagnosis and management of rhinitis contained in the comprehensive document, Diagnosis and Management of Rhinitis: Complete Guidelines of Joint Task Force on Practice Parameters in Allergy, Asthma and Immunology, and Joint Task Force Algorithm and Annotations for Diagnosis and Management of Rhinitis. These documents represent a consensus opinion of the Joint Task Force on Practice Parameters in Allergy, Asthma and Immunology, a national panel co-sponsored by the American Academy of Allergy, Asthma and Immunology, the American College of Allergy, Asthma and Immunology, and the Joint Council on Allergy, Asthma and Immunology.

Using celebrity endorsers effectively: lessons from associative learning

Abstract: The use of celebrity endorsers in advertising is wide‐spread – as much as 20 percent of all advertising use some type of celebrity endorser. Marketers invest significant dollars in securing the promotional support of well‐known individuals. Associative learning principles are presented as a useful framework for understanding how celebrity endorsers can be used more effectively. Principles such as repetition, overshadowing, blocking, belongingness, CS pre‐exposure, association set size, and extinction are introduced and linked to specific managerial suggestions for improving the use of celebrity endorsers.