Evaluation of adrenal suppression of a lipid enhanced, topical emollient cream formulation of hydrocortisone butyrate 0.1% in treating children with atopic dermatitis

Corticosteroids are currently the first line of treatment for patients with atopic dermatitis. In the pediatric population however, the potential impact of adrenal suppression is always an important safety concern. Twenty boys and girls, 5-12 years of age, with normal adrenal function and a history of atopic dermatitis were maximally treated three times daily with a lipid-rich, moisturizing formulation of hydrocortisone butyrate 0.1% for up to 4 weeks. At the conclusion of the 4-week treatment period, cosyntropin injection stimulation testing showed no evidence of adrenal suppression. In addition, the therapy was noted to be highly efficacious, with a clinical success rate of 80% (Physician Global Score of (0) clear or (1) almost clear). No local side effects associated with prolonged use of topical corticosteroids were reported. In summary, this study supports the contention that this lipid-rich, moisturizing formulation of hydrocortisone butyrate 0.1% was a well-tolerated and beneficial treatment for atopic dermatitis, demonstrating no adrenal suppression in the pediatric population aged 5-12 years. The relevance of these findings for children below 5 years of age, because of difference in body mass/surface area ratios, remains to be determined.     

West Nile virus—induced acute flaccid paralysis is prevented by monoclonal antibody treatment when administered after infection of spinal cord neurons

Acute flaccid polio-like paralysis occurs during natural West Nile virus (WNV) infection in a subset of cases in animals and humans. To evaluate the pathology and the possibility for therapeutic intervention, the authors developed a model of acute flaccid paralysis by injecting WNV directly into the sciatic nerve or spinal cord of hamsters. By directly injecting selected sites of the nervous system with WNV, the authors mapped the lesions responsible for hind limb paralysis to the lumbar spinal cord. Immunohistochemical analysis of spinal cord sections from paralyzed hamsters revealed that WNV-infected neurons localized primarily to the ventral motor horn of the gray matter, consistent with the polio-like clinical presentation. Neuronal apoptosis and diminished cell function were identified by TUNEL (terminal deoxynucleotidyl transferase—mediated BrdUTP nick end labeling) and choline acetyltransferase staining, respectively. Administration of hE16, a potently neutralizing humanized anti-WNV monoclonal antibody, 2 to 3 days after direct WNV infection of the spinal cord, significantly reduced paralysis and mortality. Additionally, a single injection of hE16 as late as 5 days after WNV inoculation of the sciatic nerve also prevented paralysis. Overall, these experiments establish that WNV-induced acute flaccid paralysis in hamsters is due to neuronal infection and injury in the lumbar spinal cord and that treatment with a therapeutic antibody prevents paralysis when administered after WNV infection of spinal cord neurons.     

Quantification of baboon cortical S2 serotonin receptors in vivo with 3-N-(2'-F18)fluoroethylspiperone and positron emission tomography

We used the ligand 3-N-(2'-F18)fluoroethylspiperone (FESP) and positron emission tomography (PET) to quantify in vivo serotonin S2 neuroreceptor density and affinity in the baboon frontal cortex. In the cortex, FESP binds specifically and exclusively to S2 receptors, and an equilibrium is reached when the rate of ligand-receptor association and dissociation become equal. Using multiple studies in the same baboon, an equilibrium (saturation) analysis approach provided a linear Hill plot with a slope of 1.02 (r2 = 0.988, P less than 0.0001), indicative of ligand binding to a single receptor class. Using serial PET scans, a dynamic approach was also used to quantify S2 receptors in the frontal cortex of the baboon, which provided an estimate of receptor density Bmax = 35.6 +/- 10.9 pmol/g. The rate constants corresponding to transport into and out of tissue were K1* = 0.2720 +/- 0.0299 mol/min.g and k2* = 0.0786 +/- 0.0315 min-1, respectively. The ligand-receptor dissociation constant was k4* = 0.0154 +/- 0.0109 min-1.     

Peripheral keratitis associated with erythema elevatum diutinum

PURPOSE: To describe a case of peripheral keratitis associated with erythema elevatum diutinum (EED), an unusual immune-complex-mediated cutaneous vasculitis. DESIGN: Observational case report. METHODS: A 25-year-old man who was diagnosed 15 months previously with erythema elevatum diutinum presented with an inflammatory peripheral keratitis of the left eye. RESULTS: Serologic investigations for systemic disorders associated with vasculitic peripheral ulcerative keratitis were unremarkable. As the sclerokeratitis was thought to represent an ocular extension of the patient's cutaneous vasculitis, dapsone therapy was initiated and resulted in a rapid response of both the cutaneous and the ocular inflammation. CONCLUSIONS: Erythema elevatum diutinum should be included in the differential diagnosis of vasculitic peripheral keratitis.     

Recent and future declines of a historically widespread pollinator linked to climate,land cover,and pesticides

The acute decline in global biodiversity includes not only the loss of rare species, but also the rapid collapse of common species across many different taxa. The loss of pollinating insects is of particular concern because of the ecological and economic values these species provide. The western bumble bee (Bombus occidentalis) was once common in western North America, but this species has become increasingly rare through much of its range. To understand potential mechanisms driving these declines, we used Bayesian occupancy models to investigate the effects of climate and land cover from 1998 to 2020, pesticide use from 2008 to 2014, and projected expected occupancy under three future scenarios. Using 14,457 surveys across 2.8 million km² in the western United States, we found strong negative relationships between increasing temperature and drought on occupancy and identified neonicotinoids as the pesticides of greatest negative influence across our study region. The mean predicted occupancy declined by 57% from 1998 to 2020, ranging from 15 to 83% declines across 16 ecoregions. Even under the most optimistic scenario, we found continued declines in nearly half of the ecoregions by the 2050s and mean declines of 93% under the most severe scenario across all ecoregions. This assessment underscores the tenuous future of B. occidentalis and demonstrates the scale of stressors likely contributing to rapid loss of related pollinator species throughout the globe. Scaled-up, international species-monitoring schemes and improved integration of data from formal surveys and community science will substantively improve the understanding of stressors and bumble bee population trends.

There are many examples of the loss of an iconic species where the culprit was unmistakable and the outcome was clear, but the reasons why common species decline is often not obvious and likely due to multiple causes. During the 19th century, shotgun blasts across central North America signaled the demise of the passenger pigeon (Ectopistes migratorius), once estimated to be 40% of the total bird population in the continent with up to 2 billion individuals (1). Over a century later, we have libraries of laws, policies, and best practices guiding conservation efforts, yet we find ourselves amid a new period of mass extinction (2, 3). Today, species’ declines often stem from indirect effects of human activities such as climate change or environmental degradation via gradual land conversion. Increasingly, common but understudied species are quietly disappearing over short time periods. The global decline of insect pollinators is an example of such a pattern (3–5).By facilitating reproduction in over 85% of flowering plants (6), pollinators provide a critical ecosystem function, create the foundation of terrestrial food webs, and serve as a linchpin to cascading effects across species (7). Many forbs have coevolved mutualistic relationships with pollinators, with forbs providing nectar or pollen and pollinators increasing forb fecundity (seed set) by orders of magnitude (8). Forbs in turn provide a food resource for other taxa, including species of conservation need and economic interest. For example, greater sage-grouse (Centrocercus urophasianus) depends on early spring forbs during brooding (9) and brown bear’s (Ursus arctos) seasonal diets can consist largely of flower roots such as sweet vetch (Hedysarum spp.) (10). Pollinators also support food webs by serving as food for insectivorous birds and lizards and other arthropods such as dragonflies, ants, and spiders (11). Losing even a single common pollinator species can disrupt the entire pollinator networks (7, 12), with abrupt consequences for the species that directly or indirectly rely on them for food, including humans which benefit from crop pollination services of $1.5 billion annually in the United States alone (13). Because of the integral role of pollinators across ecosystems, especially related to species of concern and human benefit, it is imperative to evaluate the drivers of pollinator declines.Drastic declines in pollinators are well represented by the story of the western bumble bee (Bombus occidentalis) which was once broadly distributed and locally abundant throughout western North America (14). The historical distribution of B. occidentalis extended from alpine regions of Arizona and New Mexico to central British Columbia and from the Pacific coastline east to the Black Hills of South Dakota (14, 15). As demand for greenhouse pollination grew in the 1990s, industrial scale rearing and commercialization of B. occidentalis grew as well due to the species’ biological and economic attributes (16). Starting in 1996, captive reared B. occidentalis populations distributed across North America to greenhouses and open field settings for pollination services experienced increased disease, particularly the fungus Vairimorpha (previously Nosema) bombi (17), providing a likely source of disease to wild colonies. Captive rearing became unsustainable due to disease impacts on managed colonies and was abandoned by the commercial bumble bee industry in the early 2000s (18). The demise of commercial B. occidentalis populations coincided with declines observed in wild B. occidentalis starting in 1998 in southern Oregon (19), urban San Francisco (20), and British Columbia (21). An independent assessment of V. bombi in museum specimens demonstrated increased prevalence of the pathogen in wild B. occidentalis starting in 1994 (22), supporting the hypothesis that the continental spread of V. bombi via the commercial pollination industry contributed to the wild B. occidentalis decline into the early 2000s (5).In 2015, the U.S. Fish and Wildlife Service (FWS) was petitioned to list B. occidentalis as threatened or endangered under the Endangered Species Act (23). Studies attributed declines of B. occidentalis populations to V. bombi, but also to additional factors including other diseases, habitat destruction, lethal and sublethal effects of pesticides, climate change, competition with nonnative honey bees (Apis mellifera), and high vulnerability of the species to negative genetic factors arising from reductions in population size due to haplodiploid reproduction (24, 25). Most information regarding the impacts of these threats has been drawn from localized studies and studies of surrogate bumble bee species. No studies have quantitatively investigated the cumulative effects of changing climate, land cover, and pesticide use. Therefore, the effect of each of these stressors, independently or concurrently, on B. occidentalis at range-wide scales remains unclear, subsequently leaving best management directions equally uncertain.Disentangling the relative contribution of potential drivers to range-wide trends necessitates an extensive investigation using methods that can integrate diverse data sources across the multidecadal time span of declines. Prior research has investigated the relationships between bumble bee species declines and a variety of stressors (24, 25). However, studies of Bombus species rarely evaluate multiple types of stressors simultaneously to allow for a more direct comparison of mechanisms of decline while also employing analytical methods that account for the imperfect detection of species during surveys. Failure to account for imperfect detection results in the confounding of the occupancy and detection processes and the degree of bias introduced is unknowable (26). Hierarchical models provide a less biased approach by separating the observation process involving sampling error from the biological processes of interest.Here, we build on previous research and apply robust quantitative methods that account for imperfect detection to test competing mechanisms associated with the decline of this once-widespread North American pollinator. We use hierarchical Bayesian occupancy models to investigate the contributions of climate, land cover, and pesticide use to trends in B. occidentalis occupancy across the western conterminous United States. We investigate the effects of climate and land cover on B. occidentalis occupancy from 1998 to 2020 and incorporate the effects of pesticides in a subset analysis from 2008 to 2014. We evaluate trends in occupancy across the range of B. occidentalis and among ecoregions representing unique geographic areas where populations experience varying intensities of stressors (Fig. 1A). In addition to estimating contemporary, spatially explicit trends using preexisting and newly collected bumble bee survey data, we also use a scenario approach to project future occupancy to the mid-century (2050 to 2059). Our unique approach to project future declines blends multiple climate models, emission levels, land cover change forecasts, and potential effects from other continued stressors to generate three future scenarios encompassing a range of plausible outcomes.Open in a separate windowFig. 1.Maps of ecoregions used to assess changes in the occupancy of B. occidentalis (A), mean predicted occupancy in 1998 and 2020 (B, C), and projected mean occupancy under three future scenarios (D, E, F) in the western conterminous United States.     

Do beta-adrenergic blockade and sleep state affect cardiorespiratory control in neonatal lambs? Multivariate autoregressive modeling approach

Beta-Blockers are used in pregnancy-associated hypertension and in postnatal cardiac arrhythmias, and the neonate may get them in breast milk. We therefore studied the effects of beta-adrenergic medication on interrelations between heart rate (HR), respiration, and arterial blood pressure (aBP) in newborn lambs. The influence of sleep state on these cardiorespiratory interrelations was also examined. HR, aBP, and respiration (based on transthoracic electrical impedance) were recorded and the sleep state was visually documented in five healthy chronically instrumented newborn lambs before the age of 30 d. Propranolol was given (1 mg/kg). Two-min stationary segments of the three signals were analyzed using a multivariate autoregressive model, which yields oscillations of the signals and intersignal relationships as source contributions. The variabilities of aBP and HR were greatest at the low frequencies (less than 0.25 Hz) and so were their intersignal relationships (including baroreflex). The respiratory variability was greatest at the frequencies corresponding to the respiratory rate. During quiet sleep, the variabilities in HR, aBP, and respiration were lowest. The impact of respiratory oscillations on other signals increased but the impact of aBP variability decreased during quiet sleep. beta-Blockade and sleep state affected separately the cardiovascular and respiratory variables and their interrelations. beta-Blockade reduced HR and increased pulse pressure. The overall heart rate variability and the respiratory low-frequency contribution to heart rate variability decreased due to the beta-blockade. We postulate that the beta-adrenergic system is an important regulator of HR and HR variability in neonatal lambs and also of the low-frequency components of the respiratory sinus arrhythmia.(ABSTRACT TRUNCATED AT 250 WORDS)