Role of EP3 and EP4 prostaglandin receptors in reorganization of the cytoskeleton in mature human osteoclasts

OBJECTIVE: Osteoclasts are central to the pathophysiology of several bone diseases. Prostaglandin E2 (PGE2) is well known to influence osteoclasts indirectly, but its direct action on osteoclasts is still controversial and the relevant receptors are unknown. We investigated the distribution and function of EP receptors in human mature osteoclasts. METHODS: Osteoclasts were extracted from femurs and tibias of human fetuses obtained from legal abortions. In situ hybridization and immunohistochemistry were used to detect the presence of EP1, EP2, EP3, and EP4 receptors on these cells. Actin staining and fluorescent microscopy were used to detect the effects of receptor activation on the cytoskeleton. RESULTS: Only EP3 and EP4 receptors were detected at the RNA and protein level in osteoclasts. These receptors were functional: PGE2 decreased the number of osteoclasts presenting an actin ring; 11-deoxy-PGE1, an EP2 and EP4 agonist, also decreased the number of tartrate-resistant acid phosphatase-positive cells with an actin ring; sulprostone, an EP3-specific agonist, had no effect on this variable but increased the number of cells with lamellipodia. CONCLUSION: Mature human osteoclasts present 2 subtypes of EP receptors, namely EP3 and EP4, that mediate different actions of PGE2 on these cells: activation of the EP4 receptors inhibits actin ring formation and activation of the EP3 receptors increases the number of lamellipodia. Activation or inhibition of these receptors by specific agents could be used to study and influence osteoclast function.     

Budesonide Versus Acetazolamide for Prevention of Acute Mountain Sickness

Background

Inhaled budesonide has been suggested as a novel prevention for acute mountain sickness. However, efficacy has not been compared with the standard acute mountain sickness prevention medication acetazolamide.

Antibiotic-impregnated catheters associated with significant decrease in nosocomial and multidrug-resistant bacteremias in critically ill patients

OBJECTIVE: To evaluate the impact of using central venous catheters (CVCs) impregnated with the combination of minocycline and rifampin on nosocomial bloodstream infections (BSIs), morbidity, and mortality in cancer patients in the ICU. DESIGN: Prospective surveillance study consisting of the following two time periods: September 1997 through August 1998 (ie, fiscal year [FY] 1998); and from September 1998 through August 1999 (ie, FY 1999). SETTING: ICUs of a tertiary care hospital in Houston, TX. PATIENTS: Cancer patients in the medical ICU (MICU) and surgical ICU (SICU). INTERVENTIONS: ICUs started using CVCs impregnated with the minocycline-rifampin combination at the beginning of FY 1999. Measurements and main results:The rates of nosocomial BSIs and other patients' characteristics were compared for the two study periods to determine the impact of using the impregnated catheters in the ICU. Patients' characteristics, including antibiotic use, were comparable for the two study periods in both the MICU and the SICU. The rate of nosocomial BSIs in the MICU unit decreased from 8.3 to 3.5 per 1,000 patient-days (p < 0.01), and decreased in the SICU from 4.8 to 1.3 per 1,000 patient-days (p < 0.01) in FY 1999. Nosocomial vancomycin-resistant enterococcus (VRE) bacteremia also decreased significantly (p = 0.004). Length of stay in the MICU and SICU significantly decreased in FY 1999 (p < 0.01 and p = 0.03, respectively). The duration of hospitalization decreased for MICU and SICU patients (p = 0.06 and p < 0.01, respectively). The rate of catheter-related infections decreased from 3.1 to 0.7 per 1,000 patient-days in FY 1999 (p = 0.02). The decrease in infections resulted in net savings of at least $1,450,000 for FY 1999. CONCLUSIONS: The use of antibiotic-impregnated CVCs in the MICU and SICU was associated with a significant decrease in nosocomial BSIs, including VRE bacteremia, catheter-related infections, and lengths of hospital and ICU stays.     

The effectiveness of interventions to reduce the household economic burden of illness and injury: a systematic review

Objective

To determine the nature, scope and effectiveness of interventions to reduce the household economic burden of illness or injury.

Methods

We systematically reviewed reports published on or before 31 January 2014 that we found in the CENTRAL, CINAHL, Econlit, Embase, MEDLINE, PreMEDLINE and PsycINFO databases. We extracted data from prospective controlled trials and assessed the risk of bias. We narratively synthesized evidence.

Findings

Nine of the 4330 studies checked met our inclusion criteria – seven had evaluated changes to existing health-insurance programmes and two had evaluated different modes of delivering information. The only interventions found to reduce out-of-pocket expenditure significantly were those that eliminated or substantially reduced co-payments for a given patient population. However, the reductions only represented marginal changes in the total expenditures of patients. We found no studies that had been effective in addressing broader household economic impacts – such as catastrophic health expenditure – in the disease populations investigated.

Conclusion

In general, interventions designed to reduce the complex household economic burden of illness and injury appear to have had little impact on household economies. We only found a few relevant studies using rigorous study designs that were conducted in defined patient populations. The studies were limited in the range of interventions tested and they evaluated only a narrow range of household economic outcomes. There is a need for method development to advance the measurement of the household economic consequences of illness and injury and facilitate the development of innovative interventions to supplement the strategies based on health insurance.     

Headache with Aura: A case report of ocular melanoma

Background

Headaches and visual complaints are common conditions encountered in the emergency department. While a patient's age, risk factors, and comorbidities often aid in risk stratification and guide emergency department evaluation, atypical presentations of serious disease may still occur in young otherwise healthy patients

Metabolism of dehydroepiandrosterone sulfate (DS) in normal women and women with high DS concentrations.

In order to determine the contribution of serum dehydroepiandrosterone sulfate (DS) to estrone (E1) production in normal women and the effect of chronic elevation of the serum DS concentration on DS metabolism, four normal women and four women with high endogenous serum DS were infused with [3H]DS and [14C]E1 or [14C]testosterone for 6 h. Blood samples were analyzed for radioactivity as DS, dehydroepiandrosterone (D), androstenedione, testosterone, and dihydrotestosterone. Urine was collected for analysis of creatinine, 17-ketosteroids (17-KS), and radioactivity as estrone (E1). The serum DS of 12.4 +/- 1.44 mumol/L (mean +/- SE) in the group with high DS was higher than that of 3.96 +/- 1.0 mumol/L (1.46 +/- 0.37 micrograms/mL) in the normals (P less than 0.005). Those with high DS also had increased 17-KS (13.2 +/- 2.0 vs. 5.68 +/- 0.68 mg/day, P less than 0.025) and a higher blood production rate of DS (PBDS) (126 +/- 21 (n = 3) vs. 54.3 +/- 13.8 mmol/day, P less than 0.05) but a lower MCRDS (10.94 +/- 0.61 (n = 3) vs. 13.8 +/- 0.27 L/day, P less than 0.01) than that in normals. In the four normal women the fraction of infused DS converted to estrone ( [rho]BMDS E1) was 0.00078 +/- 0.00018, the amount of E1 produced from serum DS was 41.3 +/- 15 nmol/day, the basal plasma E1 was 102 +/- 18 pmol/L, the MCRE1 was 1340 +/- 181 L/day, the value for blood production of E1 (PBE1) was 129 +/- 12 nmol/day, and the portion of E1 derived from DS was 30.4 +/- 9.4%. Correlation analysis of the data from these eight subjects showed that 17-KS, PBDS, and the serum DS were all correlated with body surface area, body weight, and ponderal index and that 17-KS excretion, PBDS, and serum DS were all correlated with one another. The most important predictors of 17-KS excretion were serum DS (P less than 0.001) and the ponderal index (P less than 0.05).     

Age-determined expression of priming protease TMPRSS2 and localization of SARS-CoV-2 in lung epithelium

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) novel coronavirus 2019 (COVID-19) global pandemic has led to millions of cases and hundreds of thousands of deaths. While older adults appear at high risk for severe disease, hospitalizations and deaths due to SARS-CoV-2 among children have been relatively rare. Integrating single-cell RNA sequencing (scRNA-seq) of developing mouse lung with temporally resolved immunofluorescence in mouse and human lung tissue, we found that expression of SARS-CoV-2 Spike protein primer TMPRSS2 was highest in ciliated cells and type I alveolar epithelial cells (AT1), and TMPRSS2 expression increased with aging in mice and humans. Analysis of autopsy tissue from fatal COVID-19 cases detected SARS-CoV-2 RNA most frequently in ciliated and secretory cells in airway epithelium and AT1 cells in peripheral lung. SARS-CoV-2 RNA was highly colocalized in cells expressing TMPRSS2. Together, these data demonstrate the cellular spectrum infected by SARS-CoV-2 in lung epithelium and suggest that developmental regulation of TMPRSS2 may underlie the relative protection of infants and children from severe respiratory illness.     

From the Cover: Contrasting drivers of diversity in hosts and parasites across the tropical Andes

Geographic turnover in community composition is created and maintained by eco-evolutionary forces that limit the ranges of species. One such force may be antagonistic interactions among hosts and parasites, but its general importance is unknown. Understanding the processes that underpin turnover requires distinguishing the contributions of key abiotic and biotic drivers over a range of spatial and temporal scales. Here, we address these challenges using flexible, nonlinear models to identify the factors that underlie richness (alpha diversity) and turnover (beta diversity) patterns of interacting host and parasite communities in a global biodiversity hot spot. We sampled 18 communities in the Peruvian Andes, encompassing ∼1,350 bird species and ∼400 hemosporidian parasite lineages, and spanning broad ranges of elevation, climate, primary productivity, and species richness. Turnover in both parasite and host communities was most strongly predicted by variation in precipitation, but secondary predictors differed between parasites and hosts, and between contemporary and phylogenetic timescales. Host communities shaped parasite diversity patterns, but there was little evidence for reciprocal effects. The results for parasite communities contradicted the prevailing view that biotic interactions filter communities at local scales while environmental filtering and dispersal barriers shape regional communities. Rather, subtle differences in precipitation had strong, fine-scale effects on parasite turnover while host–community effects only manifested at broad scales. We used these models to map bird and parasite turnover onto the ecological gradients of the Andean landscape, illustrating beta-diversity hot spots and their mechanistic underpinnings.

Turnover in community composition across space, or “beta diversity,” reflects eco-evolutionary processes that determine range limits of species (1–3). These processes include adaptive specialization on particular habitats, barriers to dispersal, and interactions among species (4–6). Antagonistic interactions between hosts and parasites may have an underappreciated effect on turnover (7), as evidenced by the sensitivity of host populations to novel parasites. For example, introductions of avian malaria (Plasmodium relictum) and avian pox (Avipoxvirus) led to extinctions or range contractions for dozens of endemic Hawaiian honeycreeper species (8). Introduced parasites have also driven shifts in community composition when competing hosts differ in susceptibility to infection (9). While these cases highlight extreme impacts of parasites on host communities, it remains unclear whether host–parasite interactions generally drive turnover in continental faunas, whether such effects are reciprocal or unidirectional, and whether these interactions also impact diversity patterns at regional scales or over evolutionary time.A persistent challenge in studying the factors that underlie community assembly is that turnover is dynamic and exhibits nonlinear variation over space and time (10). As a result, different processes may underlie turnover, depending on the scale at which the community is defined (11–13). For instance, numerous studies have asserted that adaptive specialization on abiotic conditions and barriers to dispersal drive regional turnover patterns while biotic interactions filter communities locally (2, 14). Still, the spatial scales of these various processes are uncertain (11, 15, 16), and empirical tests are complicated by the fact that potential drivers of turnover tend to be spatially autocorrelated (17).To determine the drivers and scale of community turnover in complex systems, we need appropriate, nonlinear analytical tools. Generalized dissimilarity models (GDMs) are an extension of matrix regression that provides two notable innovations: 1) GDMs can incorporate various biotic and abiotic predictors into a single model, and 2) GDMs explicitly model the curvilinear relationship between community dissimilarity and ecological or geographic distance (4, 10, 18). This modeling framework is better suited than linear matrix regression to identifying key factors underlying turnover in complex environments (19–21). In addition, by incorporating phylogenetic measures of community diversity and similarity, we can use GDMs to test how drivers of turnover have varied over evolutionary time (22). Comparing “phylogenetic turnover” to species turnover allows us to distinguish deep-time processes that may restrict the ranges of clades from contemporary processes that may constrain the range limits of individual species (2). For example, evolutionary conservation of traits may exclude entire clades from certain habitats, leading to strong phylogenetic turnover over ecological gradients (3). Alternatively, if traits that underpin environmental associations are evolutionarily labile, species turnover will be higher than phylogenetic turnover and better predicted by ecological variation.The tropical Andes provide an ideal natural laboratory for investigating community turnover in response to biotic and abiotic changes in the environment. Habitable elevational gradients spanning more than 5,000 vertical meters encompass rapid changes in vegetation structure, temperature, atmospheric pressure, ultraviolet (UV) exposure, and precipitation (23, 24). The Andean cordillera generates broad orographic precipitation, but its complex topography also creates a patchwork of rain shadows. Rain-shadowed slopes and valleys fragment the ranges of humid and dry-adapted species, particularly those occurring at higher elevations (25–29). Environmental change across elevational gradients of the Andes is exceptionally rapid compared to change along axes parallel to the cordillera. As a result, spatial distance and environmental difference are decoupled. Pairs of communities separated by the same geographic distance may have similar or contrasting environments. In this way, this landscape provides the opportunity to pinpoint environmental effects on community turnover and distinguish them from the effects of dispersal limitation.The Andes are a global hot spot for species richness and turnover, evolutionary distinctness, and small-ranged species (30–33). Species interactions are thought to be particularly important in shaping Andean community turnover: For example, Andean birds are often highly specialized on particular habitats and resources (13, 34), and competitive exclusion is thought to further limit and reinforce range boundaries (7, 35–37). However, parasitism has received less attention as a driver of turnover compared to competition (35, 37) and bird–plant mutualisms (36, 38, 39). One important group that could affect bird turnover is the hemosporidians (Apicomplexa: Haemosporida), a diverse clade of vector-borne parasites in the genera Haemoproteus, Parahaemoproteus, Plasmodium, and Leucocytozoon (40, 41). These parasites can reduce the fitness of their hosts, even in low-level chronic infections (42), and are thought to have the potential to shape avian biogeographic patterns (40, 43). Hemosporidian communities in turn are thought to be influenced to varying degrees by host community, climate, and barriers to dispersal (44–51), but improved modeling frameworks with new data are needed to reciprocally test the causes of host and parasite turnover across biodiverse, tropical landscapes.In this study, we identified and compared the drivers of diversity in interacting bird and hemosporidian communities of the Peruvian Andes. First, we tested whether similar or different drivers affect host and parasite turnover; second, we tested how drivers of turnover vary with spatial scale; and third, we tested how drivers of turnover have changed over evolutionary time. Then, we used a complementary modeling approach to identify sources of variation in species richness among host and parasite communities, respectively. We used these models to map host and parasite turnover and richness to identify hot spots for faunal overlap and transition, critical zones for biodiversity study and protection.