The power to detect regional declines in common bird populations using continental monitoring data.

Anthropogenic environmental change is driving the rapid loss of biodiversity. Large declines in the abundance of historically common species are now emerging as a major concern. Identifying declining populations through long-term biodiversity monitoring is vital for implementing timely conservation measures. It is, therefore, critical to evaluate the likelihood that persistent long-term population trends of a given size could be detected using existing monitoring data and methods. Here, we test the power to detect declines in Australia's common landbirds using long-term citizen science monitoring. We use spatially explicit simulations of occupancy dynamics and virtual sampling, designed to mimic bird monitoring in better-sampled regions of Australia, to assess likely power in these data to detect trends relevant for conservation. We predict the statistical power for 326 common species that meet minimum requirements for monitoring data across 10 regions of Australia, estimating the number of species for which we would have a high (≥80%) chance of detecting declines of different sizes. The power to detect declines of ≥30% per decade was predicted to be high for at least one-third of the common species in 7 of 10 regions, with a total of 103 (32% of 326) unique species sufficiently monitored in at least one region. These species spanned 12 taxonomic orders, four orders of magnitude in body mass, and a broad diversity of dietary guilds, suggesting the current species pool will likely serve as robust indicators for a broad range of environmental states and pressures. Power was strongly affected by species' detectability, and power to detect even large declines was negligible when species are detected on ≤50% of visits to an occupied site. Predicted power for many species fell just short of the 80% threshold in one or more regions, which suggests an increase in effort targeting these species could greatly enhance the species and regional representation of these data. Against the backdrop of unprecedented biodiversity losses, this study shows how critical evaluation of existing monitoring schemes is valuable both for assessing the contribution of citizen science schemes to biodiversity monitoring and for designing strategic monitoring to significantly improve the knowledge these schemes provide.

Age-associated changes in the blood-brain barrier: comparative studies in human and mouse.

AIMS: While vascular pathology is a common feature of a range of neurodegenerative diseases, we hypothesized that vascular changes occur in association with normal ageing. Therefore, we aimed to characterize age-associated changes in the blood-brain barrier (BBB) in human and mouse cohorts. METHODS: Immunohistochemistry and Evans blue assays were used to characterize BBB dysfunction (tight junction protein expression and serum plasma protein accumulation), vascular pathology (pericyte loss and vascular density) and glial pathology (astrocyte and microglial density) in ageing neurological control human prefrontal cortex (a total of 23 cases from 5 age groups representing the spectrum of young adult to old age: 20-30 years, 31-45 years, 46-60 years, 61-75 years and 75+) and C57BL/6 mice (3 months, 12 months, 18 months and 24 months, n = 5/6 per group). RESULTS: Quantification of the tight junction protein ZO-1 within the cortex and cerebellum of the mouse cohort showed a significant trend to both increased number (cortex P < 0.001, cerebellum P < 0.001) and length (cortex P < 0.001, cerebellum P < 0.001) of junctional breaks associated with increasing age. GFAP expression significantly correlated with ageing in the mice (P = 0.037). In the human cohort, assessment of human protein accumulation (albumin, fibrinogen and human IgG) demonstrated cells morphologically resembling clasmatodendritic astrocytes, indicative of BBB dysfunction. Semiquantitative assessment of astrogliosis in the cortex expression revealed an association with age (P = 0.003), while no age-associated changes in microglial pathology, microvascular density or pericyte coverage were detected. CONCLUSIONS: This study demonstrates BBB dysfunction in normal brain ageing, both in human and mouse cohorts.

Characterization of the heterozygous glucokinase knockout mouse as a translational disease model for glucose control in type 2 diabetes.

BACKGROUND AND PURPOSE: The global heterozygous glucokinase (GK) knockout (gk(wt/del)) male mouse, fed on a high-fat (60% by energy) diet, has provided a robust and reproducible model of hyperglycaemia. This model could be highly relevant to some facets of human type 2 diabetes (T2D). We aimed to investigate the ability of standard therapeutic agents to lower blood glucose at translational doses, and to explore the glucose-lowering potential of novel glucokinase activators (GKAs) in this model. EXPERIMENTAL APPROACH: We measured the ability of insulin, metformin, glipizide, exendin-4 and sitagliptin, after acute or repeat dose administration, to lower free-feeding glucose levels in gk(wt/del) mice. Further, we measured the ability of novel GKAs, GKA23, GKA71 and AZD6370 to control glucose either alone or in combination with some standard agents. KEY RESULTS: A single dose of insulin (1 unit·kg(-1)), metformin (150, 300 mg·kg(-1)), glipizide (0.1, 0.3 mg·kg(-1)), exendin-4 (2, 20 µg·kg(-1)) and GKAs reduced free-feeding glucose levels. Sitagliptin (10 mg·kg(-1)), metformin (300 mg·kg(-1)) and AZD6370 (30, 400 mg·kg(-1)) reduced glucose excursions on repeat dosing. At a supra-therapeutic dose (400 mg·kg(-1)), AZD6370 also lowered basal levels of glucose without inducing hypoglycaemia. CONCLUSION AND IMPLICATIONS: Standard glucose-lowering therapeutic agents demonstrated significant acute glucose lowering in male gk(wt/del) mice at doses corresponding to therapeutic free drug levels in man, suggesting the potential of these mice as a translatable model of human T2D. Novel GKAs also lowered glucose in this mouse model.

Chronic glucokinase activator treatment at clinically translatable exposures gives durable glucose lowering in two animal models of type 2 diabetes.

BACKGROUND AND PURPOSE: Pharmacological activation of glucokinase (GK) lowers blood glucose in animal models and humans, confirming proof of concept for this mechanism. However, recent clinical evidence from chronic studies suggests that the glucose-lowering effects mediated by glucokinase activators (GKAs) are not maintained in patients with type 2 diabetes (T2D). Existing preclinical data with GKAs do not explain this loss of sustained glucose-lowering efficacy in patients. Here, we have assessed the effects of chronic (up to 11 months) treatment with two different GKAs in two models of T2D. EXPERIMENTAL APPROACH: Two validated animal models of T2D, insulin-resistant obese Zucker rats and hyperglycaemic gk(wt/del) mice, were treated with two different GKAs for 1 or 11 months respectively at exposures that translate to clinical exposures in humans. Blood glucose, cholesterol, triglycerides and insulin were measured. GKA pharmacokinetics were also determined. KEY RESULTS: Treatment with either GKA provided sustained lowering of blood glucose for up to 1 month in the Zucker rat and up to 11 months in hyperglycaemic gk(wt/del) mice, with maintained compound exposures. This efficacy was achieved without increases in plasma or hepatic triglycerides, accumulation of hepatic glycogen or impairment of glucose-stimulated insulin secretion. CONCLUSIONS AND IMPLICATIONS: Chronic treatment with two GKAs in two animal models of diabetes provided sustained lowering of blood glucose, in marked contrast to clinical findings. Therefore, either these animal models of T2D are not good predictors of responses in human T2D or we need a better understanding of the consequences of GK activation in humans.

Senescent cells: a novel therapeutic target for aging and age-related diseases.

Aging is the main risk factor for most chronic diseases, disabilities, and declining health. It has been proposed that senescent cells--damaged cells that have lost the ability to divide--drive the deterioration that underlies aging and age-related diseases. However, definitive evidence for this relationship has been lacking. The use of a progeroid mouse model (which expresses low amounts of the mitotic checkpoint protein BubR1) has been instrumental in demonstrating that p16(Ink4a)-positive senescent cells drive age-related pathologies and that selective elimination of these cells can prevent or delay age-related deterioration. These studies identify senescent cells as potential therapeutic targets in the treatment of aging and age-related diseases. Here, we describe how senescent cells develop, the experimental evidence that causally implicates senescent cells in age-related dysfunction, the chronic diseases and disorders that are characterized by the accumulation of senescent cells at sites of pathology, and the therapeutic approaches that could specifically target senescent cells.

Possible involvement of GLP-1(9-36) in the regional haemodynamic effects of GLP-1(7-36) in conscious rats.

BACKGROUND AND PURPOSE: The incretin hormone, glucagon-like peptide (GLP)-1(7-36), is rapidly cleaved by dipeptidyl peptidase 4 (DPP-4) into GLP-1(9-36), and although it is agreed that most, if not all, of the metabolic effects are attributable to the intact peptide, the degree to which the cardiovascular effects are due to the cleavage product is unclear. The purpose of this study was to measure the regional haemodynamic effects of GLP-1(7-36), and determine the extent to which the cardiovascular effects of GLP-1(7-36) were influenced by DPP-4 inhibition and reproduced by GLP-1(9-36). Additional experiments investigated the involvement of autonomic mechanisms in the cardiovascular effects of GLP-1(7-36). EXPERIMENTAL APPROACH: Regional haemodynamic effects of bolus doses and 4 h infusions of GLP-1(7-36) amide and GLP-1(9-36) amide were measured in conscious, chronically instrumented rats; the influence of DPP-4 inhibition and autonomic blockade on responses to GLP-1(7-36) were also assessed. KEY RESULTS: Glucagon-like peptide-1(7-36) had clear regional haemodynamic effects comprising tachycardia, a rise in blood pressure, renal and mesenteric vasoconstriction and hindquarters vasodilatation, whereas GLP-1(9-36) was devoid of any cardiovascular actions. The effects of GLP-1(7-36) were enhanced by DPP-4 inhibition, and the tachycardia and hindquarters vasodilatation were beta-adrenoceptor-mediated. CONCLUSIONS AND IMPLICATIONS: In conscious rats, the cardiovascular effects of GLP-1(7-36) resemble those of the GLP analogue, exendin-4, and are attributable to the intact peptide rather than the cleavage product, GLP-1(9-36).

Surface modification of ZnO using triethoxysilane-based molecules.

Zinc oxide (ZnO) is an important material for hybrid inorganic-organic devices in which the characteristics of the interface can dominate both the structural and electronic properties of the system. These characteristics can be modified through chemical functionalization of the ZnO surface. One of the possible strategies involves covalent bonding of the modifier using silane chemistry. Whereas a significant body of work has been published regarding silane attachments to glass and SiO2, there is less information about the efficacy of this method for controlling the surface of metal oxides. Here we report our investigation of molecular layers attached to polycrystalline ZnO through silane bonding, controlled by an amine catalyst. The catalyst enables us to use triethoxysilane precursors and thereby avoid undesirable multilayer formation. The polycrystalline surface is a practical material, grown by sol-gel processing, that is under active exploration for device applications. Our study included terminations with alkyl and phenyl groups. We used water contact angles, infrared spectroscopy, and X-ray photoemission spectroscopy to evaluate the modified surfaces. Alkyltriethoxysilane functionalization of ZnO produced molecular layers with submonolayer coverage and evidence of disorder. Nevertheless, a very stable hydrophobic surface with contact angles approaching 106 degrees resulted. Phenyltriethoxysilane was found to deposit in a similar manner. The resulting surface, however, exhibited significantly different wetting as a result of the nature of the end group. Molecular layers of this type, with a variety of surface terminations that use the same molecular attachment scheme, should enable interface engineering that optimizes the chemical selectivity of ZnO biosensors or the charge-transfer properties of ZnO-polymer interfaces found in oxide-organic electronics.

Mitotic regulation of the anaphase-promoting complex.

Orderly progression through mitosis is regulated by the anaphase-promoting complex/cyclosome (APC/C), a large multiprotein E3 ubiquitin ligase that targets key mitotic regulators for destruction by the proteasome. APC/C has two activating subunits, Cdc20 and Cdh1. The well-established view is that Cdc20 activates APC/C from the onset of mitosis through the metaphase-anaphase transition, and that Cdh1 does so from anaphase through G1. Recent work, however, indicates that Cdh1 also activates APC/C in early mitosis and that this APC/C pool targets the anaphase inhibitor securin. To prevent premature degradation of securin, the nuclear transport factors Nup98 and Rae1 associate with APC/C(Cdh1)-securin complexes. In late metaphase, when all kinetochores are attached to spindle microtubules and the spindle assembly checkpoint is satisfied, Nup98 and Rae1 are released from these complexes, thereby allowing for prompt ubiquitination of securin by APC/C(Cdh1). This, and other mechanisms by which the catalytic activity of APC/C is tightly regulated to ensure proper timing of degradation of each of its mitotic substrates, are highlighted.

The effect of the beta2-adrenoceptor agonist prodrug BRL-47672 on cardiovascular function, skeletal muscle myosin heavy chain, and MyoD expression in the rat.

The intracellular mechanisms that regulate changes in postnatal myosin heavy chain (MHC) expression are not well established. The major objective of this study was to examine the acute and chronic effects of administration of BRL-47672, the prodrug of the beta2-adrenoceptor agonist clenbuterol on MHC and MyoD transcription factor expression to determine whether or not changes in MHC composition are preceded by changes in MyoD protein expression. To assess to what extent the use of BRL-47672 minimized cardiovascular effects, its hemodynamic actions were compared with those of clenbuterol. The effect of BRL-47672 on heart rate, mean arterial blood pressure, and hindquarters vascular conductance was significantly less than that of clenbuterol after a single i.p. injection (250 microg kg(-1) body mass). In the main study, 4-week old rats were given BRL-47672 (900 microg kg(-1) body mass) or an equivalent volume of saline (control) daily for 1, 28, or 56 days. Soleus muscle (SOL) was excised and MHC and MyoD expression analyzed. After 4 weeks, SOL from the BRL-47672-treated animals had significantly faster MHC composition (49 +/- 2% MHCIIA) compared with those from the control animal (39 +/- 3% MHCIIA, P <0.05). MyoD expression increased by 40% after 1 day of BRL-47672 administration (P <0.05) before a change in MHC composition. In conclusion, these data suggest that increased expression of fast-type MHCIIA expression in rat SOL induced by BRL-47672 administration is preceded by changes in the level of MyoD transcription factor expression.

Possible therapeutic benefits of adenosine-potentiating drugs in reducing age-related degenerative disease in dogs and cats.

Adenosine is a ubiquitous, biologically important molecule that is a precursor of other biologically active molecules. It also is a component of some co-factors and has distinct physiological actions in its own right. Levels are maintained by synthesis from dietary precursors and re-cycling. The daily turnover of adenosine is very high. Adenosine can act either as a hormone by binding to adenosine receptors, four adenosine receptor subtypes have been identified, and as an intracellular modulator, after transport into the cell by membrane transporter proteins. One of the principal intracellular actions of adenosine is inhibition of the enzyme phosphodiesterase. Extracellular adenosine also has specific neuromodulatory actions on dopamine and glutamate. Selective and nonselective agonists and antagonists of adenosine are available. The tasks of developing, evaluating and exploiting the therapeutic potential of these compounds is still in its infancy. Adenosine has actions in the central nervous system (CNS), heart and vascular system, skeletal muscle and the immune system and the presence of receptors suggests potential actions in the gonads and other organs. Adenosine agonists improve tissue perfusion through actions on vascular smooth muscle and erythrocyte fluidity and they can be used to improve the quality of life in aged dogs. This article reviews the therapeutic potential of adenosine-potentiating drugs in the treatment of age-related conditions in companion animals, some of which may be exacerbated by castration or spaying at an early age.

Comparative performance of herpes simplex virus type 2-specific serologic assays from Meridian Diagnostics and MRL diagnostics.

MRL Diagnostics and Meridian Diagnostics have recently designed herpes simplex virus type 2 (HSV-2)-specific enzyme immunoassays for HSV-2 antibody detection. Blood donor sera were assayed for HSV-2 antibodies by both methods. The sensitivity, specificity, and efficiency were 97.9, 95.4, and 95.9% for the MRL assay and 83.2, 98.2, and 95.5% for the Meridian assay, respectively.

Six-year study of the incidence of herpes in genital and nongenital cultures in a central Kentucky medical center patient population.

Herpes infections are among the most common sexually transmitted diseases and are the most common cause of genital ulcer disease in the United States. This study addresses the changing distribution of herpes simplex virus type 1 (HSV-1) and HSV-2 in patients presenting for evaluation of herpetic infections. Viral culture results from the University of Kentucky Clinical Microbiology Laboratory were reviewed for a 6-year period (1994 through 1999). Data were collected on patient sex, site of culture, and culture result. These data were analyzed statistically to identify yearly trends. Of the 4,498 cultures analyzed, nearly equal proportions of HSV-1 (13.3%) and HSV-2 (12.0%) were detected for an overall culture positivity rate of 25.3%. Approximately two-thirds of all positive cultures were from women. Although HSV-2 remained the predominant type of genital herpes, over the 6-year span of this study, there was a trend toward increasing proportions of HSV-1 genitalis, with 31.8% of male patients and 44.8% of female patients demonstrating HSV-1 genitalis by 1999. The majority of patients with HSV in nongenital sites grew HSV-1. Although there was significant yearly variation, HSV-2 was isolated from only 9.4% of patients with nongenital HSV for the entire 6-year period. This study therefore concludes that HSV-2 remains primarily a genital pathogen, while HSV-1 is taking on an increasingly important role in causing genital ulcer disease in addition to being the primary nongenital HSV.

Toxic trauma.

Hazardous materials (HAZMAT) carry many inherent dangers. Such materials are distributed widely in industrial and military sites. Toxic trauma (TT) denotes the complex of systemic and organ injury caused by toxic agents. Often, TT is associated with other injuries that also require the application of life-support techniques. Rapid onset of acute respiratory failure and consequent cardiovascular failure are of primary concern. Management of TT casualties is dependent upon the characteristics of the toxic agents involved and on the demographics surrounding the HAZMAT incident. Agents that can produce TT possess two pairs of salient characteristics: (1) causality (toxicity and latency), and (2) EMS system (persistency and transmissibility). Two characteristics of presentations are important: (1) incident presentation, and (2) casualty presentation. In addition, many of these agents complicate the processes associated with anaesthesia and must be dealt with. Failure of recognition of these factors may result in the development of respiratory distress syndromes and multiorgan system failure, or even death.

Evidence for hyaluronan production in the air pouch model in rats.

OBJECTIVE: The aim of our work was to investigate the presence of hyaluronan (HA) in the rat air pouch and its behaviour in response to inflammatory stimuli. METHODS: HA levels (by a microplate assay) and the leucocyte count were determined in the fluid obtained from air pouches in which acute or subacute inflammation had been induced by the injection of monosodium urate crystals (MSU) or high density polyethylene (HDPE) debris respectively and in relative controls. RESULTS: In control pouches of both groups, remarkable levels of HA were found; these levels were higher in the very first hours (2475 and 1850 micrograms/l at 6 hrs) and then gradually decreased. In pouches injected with MSU, HA moderately increased (p < 0.001) after 6 hrs, reached a peak after 12 hrs (p < 0.001) and began to taper at 24 hrs (p < 0.001). The leucocyte count was also increased at 6 hrs (p < 0.001), became higher at 12 hrs (p < 0.001) and tapered at 24 hrs (p < 0.001). In the HDPE pouches, HA levels were significantly reduced with respect to controls after 6 hours (p < 0.001), increasing later (p < 0.001) to reach a peak at 24 hrs (p < 0.001), and returning to the original levels, or even below, in the following 72 hours. CONCLUSIONS: These data confirm that the pouch lining produces fair amounts of HA and provide evidence that, in this system, HA levels seem to be influenced by the degree of inflammation even if with variable behaviour in relation to the different characteristics and phases of phlogosis. The present data suggest that the air pouch is a useful experimental model for studies on HA metabolism in either acute or chronic inflammation.

Resident-directed communication patterns in community homes for persons with disabilities.

A descriptive assessment of environmental variables influencing patterns of staff communication with people living in three community-based residential facilities supporting persons with disabilities was presented. Each of the 16 participating staff persons was observed for 2 hours, and all resident-directed communication behaviors were coded according to staff person, activity context, and resident. Statistical analyses were performed examining frequencies of interaction across these variables. Frequencies of communication were found to differ across activities and residents (communicative partners), but not staff persons or homes. Directions for future research and clinical implications are given, including the development of a model of staff performance and the creation of self-reinforcing social communities in residential settings for persons with disabilities.

Risk factors for equine influenza serum antibody titres in young thoroughbred racehorses given an inactivated vaccine.

Young Thoroughbred racehorses (222 yearlings entering training and 246 2-year-old horses already in training) from eight flat-training yards in Newmarket, UK were used to monitor serological responses to vaccination with an inactivated influenza virus vaccine. Blood samples taken prior to and after vaccination were tested by single radial haemolysis (SRH) to determine antibody titres (expressed as area of haemolysis in mm(2)). Prior to vaccination, yearlings had mean antibody titres (64+/-4 mm(2)) that were approximately half of those of 2-year-olds (115+/-3 mm(2)) and 89% of yearlings and 73% of 2-year-olds had SRH titres <140 mm(2). Extrapolation from experimental and field studies suggests that these levels would not protect against homologous influenza virus infection. Both age-groups showed anamnestic responses to vaccination resulting in similar peak mean titres ( approximately 160+/-2mm(2)) with 67% of yearlings and 73% of 2-year-olds achieving levels > or =140 mm(2). A second dose of vaccine administered a month after the first in yearlings did not increase the mean titre but 75% of horses had levels of antibody > or =140 mm(2). The vaccination history in the official passport of yearlings showed that 23% had no record of previous vaccination and were probably fully susceptible to infection. For yearlings entering training, the important predictors from multiple-regression analyses of SRH titres prior to vaccination were "Time since last vaccination," "Total number of previous vaccines" and "Age at first vaccination." In 2-year-olds and following two doses of vaccine in yearlings, there was no significant relationship between these factors and SRH titre.

Zygomycetes in human disease.

The Zygomycetes represent relatively uncommon isolates in the clinical laboratory, reflecting either environmental contaminants or, less commonly, a clinical disease called zygomycosis. There are two orders of Zygomycetes containing organisms that cause human disease, the Mucorales and the Entomophthorales. The majority of human illness is caused by the Mucorales. While disease is most commonly linked to Rhizopus spp., other organisms are also associated with human infection, including Mucor, Rhizomucor, Absidia, Apophysomyces, Saksenaea, Cunninghamella, Cokeromyces, and Syncephalastrum spp. Although Mortierella spp. do cause disease in animals, there is no longer sufficient evidence to suggest that they are true human pathogens. The spores from these molds are transmitted by inhalation, via a variety of percutaneous routes, or by ingestion of spores. Human zygomycosis caused by the Mucorales generally occurs in immunocompromised hosts as opportunistic infections. Host risk factors include diabetes mellitus, neutropenia, sustained immunosuppressive therapy, chronic prednisone use, iron chelation therapy, broad-spectrum antibiotic use, severe malnutrition, and primary breakdown in the integrity of the cutaneous barrier such as trauma, surgical wounds, needle sticks, or burns. Zygomycosis occurs only rarely in immunocompetent hosts. The disease manifestations reflect the mode of transmission, with rhinocerebral and pulmonary diseases being the most common manifestations. Cutaneous, gastrointestinal, and allergic diseases are also seen. The Mucorales are associated with angioinvasive disease, often leading to thrombosis, infarction of involved tissues, and tissue destruction mediated by a number of fungal proteases, lipases, and mycotoxins. If the diagnosis is not made early, dissemination often occurs. Therapy, if it is to be effective, must be started early and requires combinations of antifungal drugs, surgical intervention, and reversal of the underlying risk factors. The Entomophthorales are closely related to the Mucorales on the basis of sexual growth by production of zygospores and by the production of coenocytic hyphae. Despite these similarities, the Entomophthorales and Mucorales have dramatically different gross morphologies, asexual reproductive characteristics, and disease manifestations. In comparison to the floccose aerial mycelium of the Mucorales, the Entomophthorales produce a compact, glabrous mycelium. The asexually produced spores of the Entomophthorales may be passively released or actively expelled into the environment. Human disease with these organisms occurs predominantly in tropical regions, with transmission occurring by implantation of spores via minor trauma such as insect bites or by inhalation of spores into the sinuses. Conidiobolus typically infects mucocutaneous sites to produce sinusitis disease, while Basidiobolus infections occur as subcutaneous mycosis of the trunk and extremities. The Entomophthorales are true pathogens, infecting primarily immunocompetent hosts. They generally do not invade blood vessels and rarely disseminate. Occasional cases of disseminated and angioinvasive disease have recently been described, primarily in immunocompromised patients, suggesting a possible emerging role for this organism as an opportunist.