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Solid organ transplant (SOT) recipients are at increased risk of influenza disease and associated complications. The mainstay of prevention is the annual standard-dose influenza vaccine, as studies showed decreased influenza-related morbidity and mortality in vaccinated SOT recipients compared to those unvaccinated. Nonetheless, the immune response in this high-risk population is suboptimal compared to healthy individuals. Over the past two decades, several vaccination strategies have been investigated to overcome this inadequate immune response in SOT recipients. Howbeit, the best vaccination strategy and optimal timing of influenza vaccination remain unclear. This review will provide a detailed summary of studies of various influenza vaccination strategies in adult SOT recipients, discussing immunogenicity results, and addressing their limitations and knowledge gaps.

Since 1978, in the first decades of in vitro fertilization (IVF), the use of ovarian hyperstimulation allowed for the development and transfer of multiple embryos. As IVF technology improved, the number of multiple pregnancies increased, which led to gradual reduction in the number of embryos that were transferred. Embryo freezing (vitrification) was recommended to allow subsequent transfer if the fresh cycle was unsuccessful. However, experimentation has continued to improve pregnancy outcomes. We discuss here the significance of frozen embryo transfer cycle and the impact of uterine and peripheral immunity dominated by NK cells and regulatory T cells and human chorionic gonadotropin on pregnancy outcome in this innovative mode of IVF therapy.

Summary Short sleep duration is associated with excess body mass among adolescents and young adults. The mechanisms theorized to drive that association suggest that persistent exposure to short sleep should be associated with greater accumulations of body mass. We use prospective cohort data from four waves of the National Longitudinal Study of Adolescent to Adult Health (1994–2009; n = 14 800) to examine associations between cumulative exposure to short sleep throughout adolescence and early adulthood and obesity and elevated waist circumference outcomes. We compare several clinical and distribution-based standards of short sleep to assess which measures are associated most strongly with body mass. Cumulative exposure to short sleep exhibits dose–response associations with obesity and elevated waist circumference. Relative to respondents with no instances of short sleep, those who slept −0.50 standard deviations or less than the age and sex-specific average sleep hours in all four waves had 1.45 [95% confidence interval (CI): 1.03, 2.04] times the odds of being obese and 1.45 (95% CI: 1.02, 2.06) times the odds of having an elevated waist circumference. Our findings suggest that cumulative exposure to short sleep during adolescence and young adulthood may play an important role in the etiology of obesity and elevated waist circumference during this important developmental period.

Objective The average BMI is rising even as the U.S. population grows increasingly diverse. Prior research by examining BMI trends in diverse groups including whites, blacks, Chinese, Filipinos, Asian Indians, Mexicans, Puerto Ricans, and Cubans who are U.S. born, recent immigrants, or long-term immigrants was extended. Methods Cross-sectional data from the 1989 to 2011 waves of the National Health Interview Survey (N = 989,273) have been pooled and linear regression models to examine trends in BMI among U.S. adults have been used. Results Annual increases in BMI are greatest among U.S.-born Puerto Ricans and Mexicans and slowest among foreign born Chinese. Among the U.S. born in 2011, Chinese adults have an average BMI below the threshold for overweight, whereas blacks, Mexicans, and Puerto Ricans have average BMIs in the obese range. Foreign-born adults average lower BMIs than U.S. born adults in most race/ethnic groups, and nativity disparities generally widen over time. BMI increases across calendar periods rather than birth cohorts. Conclusion Our results suggest that calendar period interventions may be particularly useful in reversing rising BMIs in the United States. However, interventions must be tailored to different race/ethnic and nativity groups in order to reduce disparities in body mass.

Predation events during ontogeny may have long-term consequences for fish population abundance and variability. We used a stage-based matrix model to evaluate Walleye Sander vitreus and Brown Trout Salmo trutta predation on Chinook Salmon Oncorhynchus tshawytscha parr of the Muskegon River stock and the relative influence of parr predation on the long-term population dynamics and recruitment of Chinook Salmon in Lake Michigan. The model predicted the number of Chinook Salmon individuals in each stage (fry, smolts, and lake age 0 [recruits] through lake age 4) and forecasted population trajectories based on demographic data (e.g., survival, growth, and fecundity). The relative influence of parr predation was compared with influences of environmental stochasticity in the egg stage and Alewife Alosa pseudoharengus abundance (prey for lake-stage salmon) on Chinook Salmon fecundity, recruitment, and population growth. To simulate environmental stochasticity and the influence of Alewife abundance, we v...

This article explores the tensions between Jesus's command to “turn the other cheek” and the historical reality that many Christians have participated in acts of violence and have sometimes justified their actions as the will of God. Many considerations of the relationship between Christianity and violence have focused on historical instances such as the Crusades of Middle Ages and the violent persecution of heretics during the Inquisition. However, it is evident that Christian-inspired holy wars and persecutions continue in various forms up to the present. This article offers a brief historical survey of the debates over just war theory and pacifism, but it primarily illuminates the cultural sources of violence in the Christian tradition that lead to actual violence in society. Finally, consideration is given to Christian thinkers who articulate a nonviolent theology of Christianity.

Terrestrial mud volcanoes (TMVs) represent geochemically diverse habitats with varying sulfur sources and yet sulfur cycling in these environments remains largely unexplored. Here we characterized the sulfur-metabolizing microorganisms and activity in four TMVs in Azerbaijan. A combination of geochemical analyses, biological rate measurements and molecular diversity surveys (targeting metabolic genes aprA and dsrA and SSU ribosomal RNA) supported the presence of active sulfur-oxidizing and sulfate-reducing guilds in all four TMVs across a range of physiochemical conditions, with diversity of these guilds being unique to each TMV. The TMVs varied in potential sulfate reduction rates (SRR) by up to four orders of magnitude with highest SRR observed in sediments where in situ sulfate concentrations were highest. Maximum temperatures at which SRR were measured was 60°C in two TMVs. Corresponding with these trends in SRR, members of the potentially thermophilic, spore-forming, Desulfotomaculum were detected in these TMVs by targeted 16S rRNA analysis. Additional sulfate-reducing bacterial lineages included members of the Desulfobacteraceae and Desulfobulbaceae detected by aprA and dsrA analyses and likely contributing to the mesophilic SRR measured. Phylotypes affiliated with sulfide-oxidizing Gamma- and Betaproteobacteria were abundant in aprA libraries from low sulfate TMVs, while the highest sulfate TMV harboured 16S rRNA phylotypes associated with sulfur-oxidizing Epsilonproteobacteria. Altogether, the biogeochemical and microbiological data indicate these unique terrestrial habitats support diverse active sulfur-cycling microorganisms reflecting the in situ geochemical environment.

Adenosine and extracellular adenosine triphosphate (ATP) have multiple physiological central nervous system actions including regulation of cerebral blood flow, inflammation and sleep. However, their exact sleep regulatory mechanisms remain unknown. Extracellular ATP and adenosine diphosphate are converted to adenosine monophosphate (AMP) by the enzyme ectonucleoside triphosphate diphosphohydrolase 1, also known as CD39, and extracellular AMP is in turn converted to adenosine by the 5'-ectonuleotidase enzyme CD73. We investigated the role of CD73 in sleep regulation. Duration of spontaneous non-rapid eye movement sleep (NREMS) was greater in CD73-knockout (KO) mice than in C57BL/6 controls whether determined in our laboratory or by others. After sleep deprivation (SD), NREMS was enhanced in controls but not CD73-KO mice. Interleukin-1 beta (IL1β) enhanced NREMS in both strains, indicating that the CD73-KO mice were capable of sleep responses. Electroencephalographic power spectra during NREMS in the 1.0-2.5 Hz frequency range was significantly enhanced after SD in both CD73-KO and WT mice; the increases were significantly greater in the WT mice than in the CD73-KO mice. Rapid eye movement sleep did not differ between strains in any of the experimental conditions. With the exception of CD73 mRNA, the effects of SD on various adenosine-related mRNAs were small and similar in the two strains. These data suggest that sleep is regulated, in part, by extracellular adenosine derived from the actions of CD73.

Predation mortality among Chinook salmon Oncorhynchus tshawytscha parr can act at small spatiotemporal scales and cause variability in parr survival and potential recruitment. We analyzed predator diets and multiplied per capita consumption rates by predator population estimates to evaluate the relative effect of predation by stocked sport fishes on the variability in survival of Chinook salmon parr in the Muskegon River, Michigan, from 2004 to 2007. Brown trout Salmo trutta were a major predator of Chinook salmon parr, consuming from 15% to 34% of the total number available, while walleyes Sander vitreus consumed from 0.2% to 15%. Walleyes also consumed large quantities of brown trout and rainbow trout O. mykiss. Brown trout predation on Chinook salmon parr was largely dependent on parr size, while walleye predation was buffered by the availability of rainbow trout and brown trout. Predation mortality appeared to be responsible for a more than three-fold difference in the survival of Chinook sal...

There is an ongoing and contentious debate about the degree of similarity between the U.S. and Canada. Academic and popular literature is often characterized by opinion, folklore, misinformation, and stereotypes (Rosenau 2006). Some scholars posit that the differences between Canada and the U.S. are large and that the two countries are as unlike as “Fire and Ice” (Adams 2003), although such research often lacks analytical rigor, relies extensively on quotes from Updike or De Tocqueville, and focuses on a narrow set of opinions or consumption patterns (Smith 2005). We contribute to this debate by using a broad set of health lifestyle indicators for U.S. States (and Washington D.C.) and Canadian Provinces and Territories to empirically examine intra- and inter-national differences. Health lifestyles are important because they reflect the underlying social, cultural, economic, and policy environments of each area; exhibit marked variation across States, Provinces, and Territories; are important indicators of population health; and might be effectively modified by social policies.

OBJECTIVE: This paper addresses the relationship between suicide mortality and family structure and socioeconomic status for U.S. adult men and women. METHODS: We use Cox proportional hazard models and individual level, prospective data from the National Health Interview Survey Linked Mortality File (1986-2002) to examine adult suicide mortality. RESULTS: Larger families and employment are associated with lower risks of suicide for both men and women. Low levels of education or being divorced or separated, widowed, or never married are associated with increased risks of suicide among men, but not among women. CONCLUSIONS: We find important sex differences in the relationship between suicide mortality and marital status and education. Future suicide research should use both aggregate and individual level data and recognize important sex differences in the relationship between risk factors and suicide mortality-a central cause of preventable death in the United States. Language: en

Substantial evidence suggests that brain regions that have been disproportionately used during waking will require a greater intensity and/or duration of subsequent sleep. For example, rats use their whiskers in the dark and their eyes during the light, and this is manifested as a greater magnitude of electroencephalogram (EEG) slow-wave activity in the somatosensory and visual cortex during sleep in the corresponding light and dark periods respectively. The parsimonious interpretation of such findings is that sleep is distributed across local brain regions and is use-dependent. The fundamental properties of sleep can also be experimentally defined locally at the level of small neural assemblies such as cortical columns. In this view, sleep is orchestrated, but not fundamentally driven, by central mechanisms. We explore two physiological markers of local, use-dependent sleep, namely, an electrical marker apparent as a change in the size and shape of an electrical evoked response, and a metabolic marker evident as an evoked change in blood volume and oxygenation delivered to activated tissue. Both markers, applied to cortical columns, provide a means to investigate physiological mechanisms for the distributed homeostatic regulation of sleep, and may yield new insights into the consequences of sleep loss and sleep pathologies on waking brain function.

We present major league baseball (MLB) player life expectancies with attention to age, period, and cohort trends, and anthropometric and performance measures. We employ more than 100 years of data on a select population to produce some of the most accurate life expectancy estimates for U.S. adult males extant. Baseball players are a valuable population to study because they provide a wealth of longitudinal population data encompassing a multitude of cohorts and periods; there is detailed and accurate information about their births, deaths, and careers; their performance is recorded, evaluated, and highly scrutinized in a public forum; and they represent a subset of the U.S. male population that is marked by high levels of physical fitness and social and economic success, which may provide insights into potential longevity gains for the general population. MLB players typically have longer life expectancies than the general male population because of their high physical activity and overall health (Schnor, Parner, and Lange, 2000); selection for talent and fitness (Abel and Kruger, 2006); favorable heights and weights; low smoking rates (Severson et al., 2005); access to high-quality healthcare during their careers (Metropolitan Life Insurance Company, 1975); and high prestige and incomes, which allow access to high-quality healthcare during and after their baseball careers (Haupert, 2003; Kotarba, 2001; Nakao and Treas, 1990). Waterbor et al. (1988) found that MLB players who debuted between 1911 and 1925 had a 6 percent lower age standardized mortality rate than white men in the United States. Abel and Kruger (2006) determined that players who debuted between 1900 and 1939 lived 4.8 years longer than the age-adjusted male population. And the Metropolitan Life Insurance Company (1975) revealed that those who played between 1876 and 1973 had 28 percent lower mortality than white males in the general population. The mortality advantage for MLB players was small for those who debuted between 1876 and 1900, and larger for those who debuted between 1901 and 1973. We extend prior research by examining MLB players who debuted between 1902 and 2004, and estimating life expectancies that adjust for period and cohort trends in survival.

We compared small-mesh (4-mm) fyke netting and boat electrofishing for sampling a littoral fish assemblage in Muskegon Lake, Michigan. We hypothesized that fyke netting selects for small-bodied fishes and electrofishing selects for large-bodied fishes. Three sites were sampled during May (2004 and 2005), July (2005 only), and September (2004 and 2005). We found that the species composition of captured fish differed considerably between fyke netting and electrofishing based on nonmetric multidimensional scaling (NMDS). Species strongly associated with fyke netting (based on NMDS and relative abundance) included the brook silverside Labidesthes sicculus, banded killifish Fundulus diaphanus, round goby Neogobius melanostomus, mimic shiner Notropis volucellus, and bluntnose minnow Pimephales notatus, whereas species associated with electrofishing included the Chinook salmon Oncorhynchus tshawytscha, catostomids (Moxostoma spp. and Catostomus spp.), freshwater drum Aplodinotus grunniens, walleye Sande...

What represents the tipping point for a predominantly brick & mortar industry like rail/transit to finally adopt an SE approach? Some argue the industry's recent struggles to successfully implement software-intensive, technology-driven projects are a clear wake-up call to address requirements management in a systematic, disciplined way. Attempts to manage requirements have yielded mixed results. Are business enterprise needs truly linked to project delivery goals? How will technical staff be convinced to shift their focus to user needs rather than pre-defining the solution? Can program managers see requirements management as their means to achieve schedule and budget goals? Case studies highlight attempts to transform an industry: lessons learned from mismanaged requirements – analyzing where the process breaks down; applying requirements management methods to support automating rail operations; novel techniques for triaging & tagging requirements engaging the whole project team.

SUMMARY 1. We sampled along a nearshore transect (10-m bathymetric contour) in Lake Michigan to determine diet, 24-h feeding periodicity, daily ration and food requirements of an invasive fish, the alewife, Alosa pseudoharengus, relative to zooplankton abundance and production. Our objective was to determine whether the alewife controls the abundance of two invasive, predatory cladocerans, Bythotrephes longimanus and Cercopagis pengoi. 2. Bosminidae was the most abundant prey taxon and Chydoridae, Leptodora, Chironomidae and Bythotrephes were the least abundant. Neither Bythotrephes nor Cercopagis were important prey for small alewives (£100 mm). Bythotrephes was eaten by over 50% of large alewives (>100 mm) and accounted for 10–27% of the diet weight. Cercopagis was eaten by about 30% of the large alewives but only accounted 1% of the diet weight. 3. Food weight in stomachs was highest early in the night for small alewives and lowest at night for large alewives. Chironomidae and large Chydoridae were the preferred prey of small alewives. Bythotrephes and large Chydoridae were the preferred prey for large alewives. 4. Food requirements of alewife were much less than production for most prey taxa, although the consumption of Bythotrephes greatly exceeded production on both dates. Alewives consumed only 3% of Cercopagis production. High selectivity and food requirements of alewife for Bythotrephes, and low selectivity and food requirements for Cercopagis, probably explain the difference in abundance between these two invasive cladocerans at our nearshore site in Lake Michigan.

A-349821 is a selective histamine H3 receptor antagonist/inverse agonist. Herein, binding of the novel non-imidazole H3 receptor radioligand [3H]A-349821 to membranes expressing native or recombinant H3 receptors from rat or human sources was characterized and compared with the binding of the agonist [3H]N-α-methylhistamine ([3H]NαMH). [3H]A-349821 bound with high affinity and specificity to an apparent single class of saturable sites and recognized human H3 receptors with 10-fold higher affinity compared to rat H3 receptors. [3H]A-349821 detected larger populations of receptors compared to [3H]NαMH. Displacement of [3H]A-349821 binding by H3 receptor antagonists/inverse agonists was monophasic, suggesting recognition of a single binding site, while that of H3 receptor agonists was biphasic, suggesting recognition of both high- and low-affinity H3 receptor sites. pKi values of high-affinity binding sites for H3 receptor competitors utilizing [3H]A-349821 were highly correlated with pKi values obtained with [3H]NαMH, consistent with labelling of H3 receptors by [3H]A-349821. Unlike assays utilizing [3H]NαMH, addition of GDP had no effect on saturation parameters measured with [3H]A-349821, while displacement of [3H]A-349821 binding by the H3 receptor agonist histamine was sensitive to GDP. In conclusion, [3H]A-349821 labels interconvertible high- and low-affinity states of the H3 receptor, and displays improved selectivity over imidazole-containing H3 receptor antagonist radioligands. [3H]A-349821 competition studies showed significant differences in the proportions and potencies of high- and low-affinity sites across species, providing new information about the fundamental pharmacological nature of H3 receptors. Keywords: Histamine, radioligand binding, H3-receptor binding, radiolabelled H3-receptor antagonist, radiolabelled H3-receptor inverse agonist, [3H]A-349821, guanine nucleotide shift, G-protein, G-protein-coupled receptor Introduction To date, a majority of histamine H3 receptor-binding studies have relied on the H3 receptor-selective agonists [3H]RαMH and [3H]NαMH as radiolabels (van der Goot & Timmerman, 2000). While having high selectivity and specific binding along with favorable signal to noise ratios, binding of these agonist radioligands to H3 receptors is sensitive to guanine nucleotides, suggesting that H3 receptor agonist radioligands recognize both high- and low-affinity receptor sites (Arrang et al., 1990; West et al., 1990a; Kilpatrick & Michel, 1991; Clark et al., 1993). This makes characterization of H3 receptors difficult because of assay-dependent variables, such as membrane preparation procedures (Childers & Lariviere, 1984; Kim & Neubig, 1987) and ionic composition of assay buffers that can alter receptor–G-protein interactions and affect the apparent affinity state of the receptor (Hamblin & Creese, 1982; Kilpatrick & Michel, 1991; Parkinson & Fredholm, 1992). Several radiolabelled H3-antagonists have been described previously, such as [3H]S-methylthioperamide, [125I]iodophenpropit, [125I]iodoproxyfan, [3H]thioperamide, [3H]{"type":"entrez-nucleotide","attrs":{"text":"GR168320","term_id":"238436299","term_text":"GR168320"}}GR168320 and [3H]clobenpropit (Jansen et al., 1992; Ligneau et al., 1994; Yanai et al., 1994; Alves-Rodrigues et al., 1996; Brown et al., 1996; Harper et al., 1999), but they have not been widely used. This is attributable to a variety of limiting factors, such as low specific activity, poor H3 receptor specificity, equivocal functional properties or lack of commercial availability. Moreover, all of the previously referenced H3 receptor antagonist radiolabels contain an imidazole moiety, which may be responsible for off-target binding to 5-HT3 receptors, H4 receptors and cytochrome P450 isoenzymes (Labella et al., 1992; Leurs et al., 1995; Schlicker et al., 1995; Alves-Rodrigues et al., 1996; Harper et al., 1999; Yang et al., 2002; Esbenshade et al., 2005a; Kitbunnadaj et al., 2005). More recently, we described the first non-imidazole, H3 receptor antagonist, [3H]A-317920 (Esbenshade et al., 2005b; Yao et al., 2005). [3H]A-317920 is a highly selective and potent radiolabel useful for detection and characterization of recombinant rat H3 receptors expressed in C6 cells, a rat glioma cell line, or native H3 receptors expressed in rat cortical tissue. However, this radioligand does not recognize human H3 receptors with high affinity, and as such has limited utility. Subsequent medicinal chemistry efforts revealed a novel non-imidazole H3 receptor ligand, A-349821, having high potency and selectivity for both rat and human H3 receptors in competition-binding assays and potent antagonist activity in a variety of in vitro functional assays as well as H3 receptor-mediated in vivo models (Esbenshade et al., 2004). A-349821 also displayed highly efficacious and potent inverse agonist properties in [35S]GTPγS-binding assays across species (Esbenshade et al., 2004). Competition-binding studies carried out with ∼75 G-protein coupled receptors (GPCRs) and ligand-gated ion channels showed minimal crossreactivity (IC50>1 μM), with weak affinity (IC50=250 nM) observed for α2c adrenergic receptors (Esbenshade et al., 2004). With these promising binding and pharmacological properties, [3H]A-349821 was prepared and evaluated as a radiolabel for the detection of H3 receptors in membranes expressing recombinant or native rat or human H3 receptors. Like the agonist radioligand [3H]NαMH, [3H]A-349821 exhibited specific and saturable binding to tissues or cell lines expressing either rat or human H3 receptors. Detailed competition-binding studies using a large panel of H3 receptor ligands were performed to compare the pharmacology of [3H]A-349821 with that of [3H]NαMH. The effects of guanosine 5′-diphosphate (GDP) on binding were determined to investigate the contribution of low- and high-affinity binding states to the observed pharmacology. Herein, we describe the use of [3H]A-349821 as the first non-imidazole radioligand for the highly specific detection and characterization of both rat and human H3 receptors.

Hexokinase (HK) II content is elevated in fatigue resistant muscle fibres and exercise trained muscle. The aim of this study was to determine if exercise capacity is dependent on muscle HK protein content. C57Bl/6 mice with a 50% HK knockout (HK+/−), no genetic manipulation (wild-type, WT) and an ∼3-fold HK overexpression (HKTg) were tested. Mice (n = 12/group) completed both a maximal oxygen consumption test and an endurance capacity test (run at ∼75% ) on an enclosed treadmill equipped to measure gas exchange. Arterial and venous catheters were surgically implanted into separate groups of mice (n = 9–11/group) in order to measure an index of muscle glucose uptake (Rg) during 30 min of treadmill exercise. Maximum work rate (0.95 ± 0.05, 1.00 ± 0.04 and 1.06 ± 0.07 kg m min−1), (137 ± 3, 141 ± 4 and 141 ± 5 ml kg−1 min−1) and maximal respiratory exchange ratio (1.04 ± 0.02, 1.00 ± 0.03 and 1.04 ± 0.04) were similar in HK+/−, WT and HKTg, respectively. Exercise endurance capacity (measured as time to exhaustion) increased as HK content increased (55 ± 11, 77 ± 5 and 98 ± 9 min) and this was related to Rg measured in mice during 30 min of exercise (13 ± 2, 24 ± 5 and 42 ± 5 μmol (100 g)−1 min−1). Muscle glycogen in sedentary HK+/− mice and HK+/− mice following 30 min of exercise were significantly lower than in HKTg and WT mice. However, the net exercise-induced muscle glycogen breakdown was equal in the three genotypes. In summary, HK protein content within the range studied (a) was not associated with a difference in the capacity to perform maximal intensity exercise, (b) was a powerful determinant of the ability to sustain moderate intensity exercise, as reducing HK content impaired endurance and increasing HK content enhanced endurance, and (c) although directly related to exercise endurance, was not a determinant of net muscle glycogen usage during exercise. In conclusion, adaptations that increase HK protein content and/or functional activity such as regular exercise contribute to increased muscular endurance.

Cigarette smoking is a particularly pernicious behavior because of its high prevalence and mortality risk. We use the powerful methodology of life tables with covariates and employ the National Health Interview Survey-Multiple Cause of Death file to illuminate the interrelations of smoking with other risk factors, and with the combined influences of smoking prevalence and population size on smoking-attributable mortality. We find that the smoking-mortality gap is only modestly affected by other risk factors and excess deaths due to smoking among U.S. adults in the year 2000 were as great as 340,000. Better knowledge of the prevalence and mortality risk associated with cigarette smoking statuses enhances the future health and longevity prospects of the U.S. population.

A-331440 {4′-[3-(3(R)-(dimethylamino)-pyrrolidin-1-yl)-propoxy]-biphenyl-4-carbonitrile}, a potent and selective antagonist of histamine H3 receptors, yielded positive results in an in vitro micronucleus assay, predictive of genotoxicity in vivo. Because this compound has highly favourable properties and potential as an antiobesity agent, new compounds of this general chemical class were sought that would retain or improve upon the high potency and selectivity of A-331440 for H3 receptors, but would lack the potential for genotoxicity obtained with that compound. Our working hypothesis was that the biphenyl rings in A-331440 might contribute to interactions with DNA and thereby predispose toward genotoxicity. Toward this end, several analogues were prepared, with substituents introduced onto the biaryl ring to alter the orientation, electronegativity, and polarity of this moiety, and were tested for their radioligand binding potency and selectivity and their propensity to induce genotoxicity in the in vitro micronucleus assay. Using this strategy, novel compounds were discovered that retained or improved upon the potency and selectivity of A-331440 for H3 receptors and were devoid of genotoxicity in vitro. Of these, the simple mono- and di-fluorinated analogues (A-417022 [4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3′-fluoro-1,1′-biphenyl-4-carbonitrile] and A-423579 [4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]-propoxy}-3′,5′-difluoro-1,1′-biphenyl-4-carbonitrile], respectively) were found to bind to H3 receptors at least as potently as A-331440, while lacking genotoxicity in the micronucleus assay. The reason of the lack of genotoxicity of the fluorinated analogues is unclear, but is especially noteworthy in light of the general principle that fluorine and hydrogen are very similar in size. Therefore, these fluorinated analogues of A-331440 represented the most potent and potentially safest compounds for further evaluation as antiobesity leads. Preliminary findings with one of these examples, A-417022, in a mouse model of obesity are presented.

Structure-activity relationships of homopiperazine-containing alkoxybiaryl nitriles employing various D-amino acid moieties and their N-furanoyl analogues were undertaken. This led to A-320436, a potent and selective non-imidazole H(3)-receptor antagonist possessing balanced affinity for both rat and human H(3)-receptors. This compound was shown to demonstrate in vitro and in vivo functional antagonism and is non-neurotoxic at doses (i.p.) up to 163 mg/kg in a general observation test.

Objective. We explore, first, whether wealth relates to mortality risk independent of income and education, and second, whether wealth closes the black-white gap in U.S. adult mortality while controlling for other socioeconomic and sociodemographic factors. Methods. We employ the Cox proportional hazards models on data from the 1992 wave of the Health and Retirement Study linked to deaths through 1998, to analyze pre-retirement adult mortality in the United States. Results. The findings suggest that broader measures of SES, including wealth, are significant for understanding adult mortality. Further, vastly lower asset holdings among blacks, compared to whites, not only affects their financial wellbeing but also their survival prospects. Conclusions. Research and social policies that aim to understand and close health disparities in the United States may be poorly conceived if they ignore the impact of wealth on premature adult mortality. Material disadvantage remains a pressing social and political issue in the United States, not only because it shapes the daily life chances and experiences of individuals, but also because it leads directly to premature mortality (Kitagawa and Hauser, 1973; Rogers, Hummer, and Nam, 2000). Prior research on the links between socioeconomic status (SES) and mortality have found, first, that broader dimensions of socioeconomic wellbeing link to health and mortality independent of employment, income, and education, and second, that alternate indicators are quite important when understanding mortality as individuals age (Krueger et al., 2000; Robert and House, 1996). We expand on these two bodies of literature to clarify the relationship between wealth and mortality within a recent, nationally representative prospective sample of individuals aged 51 to 61.

In the last twenty years we have realized that the immune system synthesizes a class of peptides, termed cytokines, that play a central role in alerting the brain to ongoing inflammation in peripheral tissues. Among the brain's responses to proinflammatory cytokines, or agents that induce these cytokines, are certain alterations in sleep profiles. Characteristically there is an increase in non-rapid eye movement sleep (NREMS), and NREMS intensity is often accompanied by a decrease in rapid eye movement sleep (REMS). Cytokines appear to play a role in normal sleep regulation; during pathology, higher levels of cytokines amplify the physiological cytokine sleep mechanisms. In this review we summarize the extensive literature on the roles of interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) in sleep regulation, and their interactions with the neuropeptides growth hormone-releasing hormone (GHRH) and corticotropin-releasing hormone (CRH). We reach the tentative conclusion that the sleep-promoting actions of IL-1 and GHRH are mediated via anterior hypothalamic neurons that are receptive to these substances. It also seems likely that TNF-alpha and CRH also influence these neurons. In addition, we discuss an array of research issues raised by these studies that remain to be resolved.

Background Disturbances in sleep patterns are a complicating factor in recovery from alcoholism. The effects of acute and chronic alcohol treatments on sleep in rats were determined. Methods Adult male Sprague-Dawley rats were acclimated to a temperature-controlled chamber, and electromyograms and electroencephalograms (EEGs) were obtained during 23-hr recording sessions. Time spent in rapid eye movement sleep (REMS) and non-REM sleep (NREMS), EEG slow-wave activity (SWA) during NREMS, a spectral analysis of the EEG by fast Fourier transform, and brain temperatures were determined. Results Acute exposure to alcohol (2.3 and 3.0 g/kg) by gastric intubation at the beginning of dark onset produced an increase in NREMS and a suppression of SWA. Spectral analysis revealed that during the first 4 hr there was a small increase in very-low-frequency bands (0.5–2 Hz), with a suppression of higher-frequency bands. This was followed by a suppression of low-frequency bands. A dose of 3.0 g/kg at light onset caused an increase in NREMS and a suppression of SWA. Spectral analysis revealed a suppression of low-frequency bands throughout the first 12 hr of recording but no change on high-frequency bands with light-onset alcohol. Chronic treatment with alcohol (6% alcohol in a liquid diet with pair-fed isocaloric controls) for 3 weeks produced an increase in NREMS and a decrease in EEG power density in frequency bands above 2 Hz. Chronic alcohol also reduced the circadian variation of REMS, an effect that showed a rebound 1 week after the alcohol treatment was terminated. Two weeks after the alcohol treatment was stopped, NREMS and REMS values returned to baseline. Conclusions These results demonstrate differences in the effect of acute alcohol on sleep depending on the time of administration and demonstrate that distinct alterations in sleep patterns are induced by chronic treatments in as little as 3 weeks.

A one-step purification of [His1-mono-125I-Tyr10,Nle27]-hGHRH(1-32)-NH2, prepared using chloramine-T, by HPLC with isocratic elution is described. The labeled GHRH analog was suitable for GHRH receptor binding assays. Copyright © 2002 John Wiley & Sons, Ltd.

The sections in this article are: 1 Sleep-Related Hormone Changes 2 Rhythms of Hormones 2.1 The Somatotropic Axis 2.2 Corticotropin-Glucocorticoid Axis 2.3 Thyroid-Stimulating Hormone-Thyroid Axis 2.4 The Gonadotropins-gonad Axis 2.5 Prolactin 2.6 Melatonin 2.7 Renin (Angiotensin)-Aldosterone System 2.8 Other Hormones 3 Effects of Hormones on Sleep 3.1 Somatotropic Axis 3.2 Corticotropin-Releasing Hormone-Corticotropin Axis 3.3 Thyroid Hormones 3.4 Gonadotropins 3.5 Prolactin and Vasoactive Intestinal Peptide 3.6 Vasopressin 3.7 Steroid Hormones 3.8 Melatonin 3.9 Gastrointestinal Hormones 4 Cytokines 5 Infection and Sleep 6 Effects of Cytokines on Sleep 6.1 Interleukin-1 6.2 Tumor Necrosis Factor 6.3 Interferons 6.4 Fibroblast Growth Factor 6.5 IL-10, IL-2, and IL-6 7 Links Between the Effects of Cytokines and Hormones on Sleep 8 Conclusion

Objective. This article examines individual level black-white differences in adult homicide mortality. Homicide is a major social problem and a central cause of preventable death in the United States. A homicide not only claims one life prematurely but can also devastate a family, friends, and a neighboring community. Methods. We link eight consecutive years of the National Health Interview Survey (1987–94) to the Multiple Cause of Death file through the National Death Index (1987–97), and use Cox proportional hazard models to examine the role of social factors in black-white homicide mortality in the United States. Results. We find that individual level sociodemographic characteristics—age, sex, marital status, education, employment status, and geographic factors—explain almost 35 percent of the racial differences in homicide mortality. Conclusions. These results demonstrate the contributions that National Center for Health Statistics data can make to criminological literature and reveal the mechanisms through which blacks experience higher homicide mortality than whites. Such illumination may lead to a reduction in the fourth leading preventable cause of death in the United States.

Experiment 1 examined whether the use of the DSM-III-R decision trees increased the accuracy of DSM-III-R diagnoses. Results indicated that the use of the decision trees interacted with the level of DSM-III-R experience to affect diagnostic accuracy. The use of the decision trees resulted in a modest increase in diagnostic accuracy for participants with less DSM-III-R experience; for participants with more DSM-III-R experience, the use of the decision trees had no significant effect on diagnostic accuracy. Experiment 2 examined whether the use of the DSM-III-R decision trees increased the accuracy and confidence and decreased the time of DSM-III-R diagnosis across participants with varying levels of DSM-III-R experience. The primary analyses consisted of a 3 × 2 × 2-multivariate analysis of variance (MANOVA) to determine whether the use of the decision trees increased diagnostic accuracy and diagnostic confidence and decreased diagnostic time. Results indicated (1) the experienced participants made more accurate diagnoses than the less-experienced and no-experience participants; (2) the decision trees, combined with practice, increased class diagnostic accuracy and decreased diagnostic time; and (3) participants were more confident in their diagnosis when they used the decision trees than when they did not use the decision trees. Supplementary analyses consisted of two one-way analysis of variance (ANOVA) procedures and indicated that participants' preference for and knowledge of how to use the decision trees did not significantly affect their diagnostic accuracy. © 2000 John Wiley & Sons, Inc J Clin Psychol 56: 73–88, 2000.

Interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) are involved in physiologic sleep regulation. Administration of exogenous IL-1 beta or TNF-alpha induces increased non-rapid eye movement sleep (NREMS). Inhibition of IL-1 or TNF reduces spontaneous sleep. There is a diurnal rhythm of TNF-alpha mRNA and IL-1 beta mRNA in brain with highest levels occurring during peak sleep periods. Mice lacking either the TNF 55-kD receptor or the IL-1 type I receptor sleep less than do strain controls. IL-1 beta and TNF-alpha are part of a larger biochemical cascade involved in sleep regulation; other somnogenic substances in this cascade include growth hormone-releasing hormone and nitric oxide. Several additional substances are involved in inhibitory feedback mechanisms, some of which inhibit IL-1 and TNF. A major challenge to sleep research is to define how and where these molecular steps produce sleep.

Few prediction schemes have been more accurate, and at the same time more perplexing, than the Super Bowl Stock Market Predictor, which asserts that the league affiliation of the Super Bowl winner predicts stock market direction. In this study, the authors examine the record and statistical significance of this anomaly and demonstrate that an investor would have clearly outperformed the market by reacting to Super Bowl game outcomes. Copyright 1990 by American Finance Association.