Norovirus outbreaks: a systematic review of commonly implicated transmission routes and vehicles.

Causal mechanisms of norovirus outbreaks are often not revealed. Understanding the transmission route (e.g. foodborne, waterborne, or environmental) and vehicle (e.g. shellfish or recreational water) of a norovirus outbreak, however, is of great public health importance; this information can facilitate interventions for an ongoing outbreak and regulatory action to limit future outbreaks. Towards this goal, we conducted a systematic review to examine whether published outbreak information was associated with the implicated transmission route or vehicle. Genogroup distribution was associated with transmission route and food vehicle, but attack rate and the presence of GII.4 strain were not associated with transmission route, food vehicle, or water vehicle. Attack rate, genogroup distribution, and GII.4 strain distribution also varied by other outbreak characteristics (e.g. setting, season, hemisphere). These relationships suggest that different genogroups exploit different environmental conditions and thereby can be used to predict the likelihood of various transmission routes or vehicles.

The epidemiology of published norovirus outbreaks: a review of risk factors associated with attack rate and genogroup.

The purpose of this study was to examine global epidemiological trends in human norovirus (NoV) outbreaks by transmission route and setting, and describe relationships between these characteristics, viral attack rates, and the occurrence of genogroup I (GI) or genogroup II (GII) strains in outbreaks. We analysed data from 902 reverse transcriptase-polymerase chain reaction-confirmed, human NoV outbreaks abstracted from a systematic review of articles published from 1993 to 2011 and indexed under the terms 'norovirus' and 'outbreak'. Multivariate regression analyses demonstrated that foodservice and winter outbreaks were significantly associated with higher attack rates. Foodborne and waterborne outbreaks were associated with multiple strains (GI+GII). Waterborne outbreaks were significantly associated with GI strains, while healthcare-related and winter outbreaks were associated with GII strains. These results identify important trends for epidemic NoV detection, prevention, and control.

Safety, tolerability, pharmacodynamics and pharmacokinetics of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in healthy subjects.

AIMS: Albiglutide is a glucagon-like peptide-1 (GLP-1) mimetic generated by genetic fusion of a dipeptidyl peptidase-IV-resistant GLP-1 dimer to human albumin. Albiglutide was designed to retain the therapeutic effects of native GLP-1 while extending its duration of action. This study was conducted to determine the pharmacokinetics and initial safety/tolerability profile of albiglutide in non-diabetic volunteers. METHODS: In this single-blind, randomized, placebo-controlled trial, 39 subjects (18-60 years, body mass index 19.9-35.0 kg/m(2)) received placebo (n = 10) or escalating doses of albiglutide (n = 29) on days 1 and 8 in the following sequential cohorts: cohort 1: 0.25 + 1 mg; cohort 2: 3 + 6 mg; cohort 3: 16 + 24 mg; cohort 4: 48 + 60 mg; and cohort 5: 80 + 104 mg. Dose proportionality was evaluated based on area under the plasma drug concentration versus time curve [area under the curve (AUC((0-7 days)))] and maximum plasma drug concentration (C(max)) for cohorts 2-5 during week 1. RESULTS: Albiglutide had a terminal elimination half-life (T(1/2)) of 6-8 days and time to maximum observed plasma drug concentration (T(max)) of 3-4 days. A greater-than-dose proportional increase in albiglutide exposure was observed. Albiglutide demonstrated a dose-dependent trend in reductions of glucose weighted mean AUC and fructosamine levels in healthy subjects. The incidence and severity of adverse events (AEs) was similar between placebo and albiglutide groups. Headache was the most frequent drug-related AE, followed by constipation, flatulence and nausea. CONCLUSIONS: Albiglutide has a half-life that favours once weekly or less frequent dosing with an acceptable safety/tolerability profile in non-diabetic subjects.

Sediment influence on congener-specific PCB bioaccumulation by Mytilus edulis: a case study from an intertidal hot spot, Clyde Estuary, UK.

An intertidal site in the Clyde Estuary, UK, was selected to evaluate the role of sediment geochemistry on the bioaccumulation of polychlorinated biphenyls (PCBs) by mussels (Mytilus edulis). The area had previously been identified as showing anomalously high levels of PCB contamination (over 1,500 microg kg(-1) total PCB in sediment, 22 congeners). Samples of surface sediment and M. edulis were collected from two closely located sites, one within the anomalous area and another representing typical PCB contamination in the estuary. Sediment samples were separated into grain size fractions and analysed for a range of biomarker compounds, PCBs and sediment mineralogy. The anomalous site showed an atypical association of PCBs with sediment properties, despite both locations showing influence of both petrogenic and pyrogenic organic contamination. Interrogation of data using correlation and principal component analysis showed that sediment mineralogy as well as organic matter composition influenced PCB congener distribution. One sediment source was found to control the PCB concentration in mussels at both locations and clay mineralogy appears to control PCB uptake by biota with preference for higher molecular weight congeners. Overall bioavailability is determined by sediment TOC.

Food intake inhibition and reduction in body weight gain in lean and obese rodents treated with GW438014A, a potent and selective NPY-Y5 receptor antagonist.

Numerous reports have implicated theY5 receptor as the 'feeding' receptor mediating the orexigenic action of neuropeptide Y (NPY). This notion is supported by the correlation between the in vitro functional and binding activities of different peptide agonists and their potent stimulation of food intake in rodents. We have discovered a series of small molecule heterocycles with high affinity, selectivity, and functional antagonism for Y5 receptors. Intraperitoneal (i.p.) administration of GW438014A into rodents, resulted in a potent reduction of NPY-induced and normal overnight food intake. Brain levels of GW438014A were detected well in excess of its binding IC(50) for up to 3 h post-dosing. Daily (i.p., BID, 10 mg/kg) administration of this compound to Zucker Fatty rats for a period of 4 days resulted in a marked decrease in the rate of weight gain and a reduction in fat mass. No effect on food intake was observed following oral administration of GW438014A (25-100 mg/kg), consistent with the poor oral bioavailability (<3%) and low brain levels observed.

Food intake inhibition and reduction in body weight gain in rats treated with GI264879A, a non-selective NPY-Y1 receptor antagonist.

Neuropeptide Y has been proposed to play a major role in the hypothalamic regulation of feeding behavior through the activation of specific, central NPY receptor(s). In an effort to design small molecule antagonists of NPY receptors, we have synthesized a series of substituted dipeptides based on defined pharmacophores, previously identified by us and others as essential for the interaction with the peptide receptors. GI264879A behaves as a functional antagonist of Y1 receptors while displaying no binding selectivity for the different NPY receptor subtypes. We demonstrate here that administration of GI264879A to rats causes a significant decrease in food intake and body weight partly through a mechanism dependent on the integrity of the vagus nerve.

Novel cypermethrin formulation for the control of sea lice on salmon (Salmo salar)

A novel formulation of cypermethrin was applied as a bath treatment to Atlantic salmon infested with sea lice on a commercial fish farm on the Isle of Skye, Scotland. Twenty 15 m x 15 m cages were treated with cypermethrin at a concentration of 5 micrograms/litre sea water. The numbers of sea lice of all stages were recorded on five fish per cage before the treatment and one, seven and 16 days after treatment. Statistically significant reductions in the numbers of chalimus III and IV pre-adults and adults were recorded over the whole period; the average percentage reductions at one and 16 days after treatment were 59 per cent and 90 per cent (chalimus III and IV), 98 per cent and 95 per cent (pre-adults), and 99 per cent (adults), respectively.

Pharmacological characterization and selectivity of the NPY antagonist GR231118 (1229U91) for different NPY receptors.

Neuropeptide Y (NPY) is widely distributed throughout the central and peripheral nervous system and exerts a wide range of physiological responses by activating specific receptors. In this study we have characterized the potency of the high affinity peptide dimer antagonist, GR231118, to displace radiolabeled NPY/PYY from different tissues and cell lines expressing Y1 or Y2 receptors and from CHO cells stably transfected with human cDNA encoding for Y1, Y2 and Y4 receptors. GR231118 displays high affinity for Y1 and Y4 receptors, equal or better than that of NPY itself, while its activity is several fold weaker for Y2 receptors. Displacement of radiolabeled PYY from rat hypothalamic membranes by GR231118, reveals the existence of high and low affinity binding sites which may be equated to Y1 and Y2 receptors respectively suggesting that the compound maybe used as a tool to dissect central NPY receptors.

Structure-activity relationship of novel pentapeptide neuropeptide Y receptor antagonists is consistent with a noncontinuous epitope for ligand-receptor binding.

We report the first systematic study on short peptide structure affinity and activity for the neuropeptide Y (NPY) receptor. A series of linear pentapeptides has been synthesized that display affinities in the low micromolar range toward rat brain NPY receptors. Furthermore, some of these compounds competitively antagonize the Y1-type NPY receptor-mediated increase in cytosolic Ca2+ in human erythroleukemic (HEL) cells. The inactive NPY carboxyl-terminal pentapeptide (Thr-Arg-Gln-Arg-Tyr-NH2; IC50 > 100 microM) was modified by replacing threonine with an aromatic amino acid and glutamine with leucine. This resulted in a series of pentapeptides with dramatically improved affinity (IC50 = 0.5-4 microM) for the rat brain receptor. The structure-affinity data suggest that these peptides may represent a noncontinuous epitope containing the amino-terminal tyrosine and the carboxyl-terminal residues Arg-35 and Tyr-36 of NPY.

High-affinity neuropeptide Y receptor antagonists.

Neuropeptide Y (NPY) is one of the most abundant peptide transmitters in the mammalian brain. In the periphery it is costored and coreleased with norepinephrine from sympathetic nerve terminals. However, the physiological functions of this peptide remain unclear because of the absence of specific high-affinity receptor antagonists. Three potent NPY receptor antagonists were synthesized and tested for their biological activity in in vitro, ex vivo, and in vivo functional assays. We describe here the effects of these antagonists inhibiting specific radiolabeled NPY binding at Y1 and Y2 receptors and antagonizing the effects of NPY in human erythroleukemia cell intracellular calcium mobilization perfusion pressure in the isolated rat kidney, and mean arterial blood pressure in anesthetized rats.

The role of extracellular calcium in the neuropeptide-Y-induced increase in cytosolic calcium in human erythroleukemic (HEL) cells.

Cytosolic calcium changes were followed in human erythroleukemic (HEL) cells loaded with the fluorescent probe fura-2. Peak increases in cytosolic calcium were reduced by two-thirds in cells suspended in Ca(2+)-free medium, suggesting that calcium entry significantly contributes to the increases in cytosolic calcium after NPY receptor stimulation. To establish if Ca2+ entry was a direct consequence of receptor stimulation or indirectly via depletion of Ca2+ stores, the latter were totally or partially depleted by treatment with cyclopiazonic acid or alpha-thrombin, respectively, in Ca(2+)-free medium. Partial depletion markedly diminished and full depletion suppressed the NPY-induced response in Ca(2+)-free medium. After full depletion, the recovery of the NPY-induced increase in cytosolic calcium was dependent on the length of [Ca2+]e reexposure, suggesting a direct entry of Ca2+ to the storage sites followed by release to the cytosol. After partial depletion, transient reexposure to [Ca2+]e did not by itself increase cytosolic calcium levels or refill the stores as NPY stimulation did not increase cytosolic calcium if [Ca2+]e was chelated prior to stimulation. However, if partially depleted cells were exposed to NPY in the presence of readded [Ca2+]3, the peak calcium response was similar to that of control cells, indicating that partially depleted calcium stores can be refilled from extracellular sources only if NPY receptors are stimulated. Analysis of the data suggests that in HEL cells the entry of calcium and mobilization from intracellular stores are in series processes and that entry is triggered by intracellular levels only under extreme depletion, while under physiological conditions calcium entry is coupled to receptor stimulation.

Characterization of the neuropeptide Y-induced intracellular calcium release in human erythroleukemic cells.

Human erythroleukemic (HEL) cells, loaded with fura-2, respond to neuropeptide Y (NPY) with a fast and transient increase in intracellular calcium. The Y1 receptor-specific agonist (Leu-31,Pro-34)-NPY is 4-fold more potent and the carboxyl-terminal fragment NPY13-36 is 150-fold less potent than NPY. Thus, it is concluded that the response is mediated through the activation of a Y1 type of NPY receptor. HEL cells do not respond to a second addition of NPY but do respond to a further addition of alpha-thrombin (alpha-T). However, in a calcium-free medium, prior stimulation with NPY largely inhibits a subsequent response to alpha-T. Moreover, prior stimulation with alpha-T in the absence of external calcium completely prevents the response to the addition of NPY, indicating a common effector pathway. The latter is further reinforced by using thapsigargin (TG), which has been shown to deplete the Inositol 1,4,5-trisphosphate-dependent calcium pool in other systems. HEL cells preincubated with TG in calcium-free medium fail to respond to either NPY or alpha-T. Likewise, prior stimulation with NPY or alpha-T in calcium-free medium significantly inhibits the response to TG. Preincubation of cells with phorbol esters strongly inhibits the NPY-induced release of intracellular Ca2+ in HEL cells, an effect that is partially prevented by preincubation of the cells with H7, a protein kinase C inhibitor. However, neither the homologous nor the apparent heterologous desensitization of the NPY receptor can be prevented by H7. It is concluded that NPY releases intracellular Ca2+ from an inositol 1,4,5-trisphosphate-sensitive calcium pool, which is restored by external calcium, and that NPY receptor desensitization is protein kinase C independent.

Neuropeptide Y mobilizes intracellular Ca2+ and increases inositol phosphate production in human erythroleukemia cells.

The intracellular concentration of free Ca2+ was monitored by measuring the fluorescence of fura-2 loaded Human Erythroleukemia Cells. Neuropeptide Y (NPY) increased intracellular Ca2+ in a dose-dependent manner and the 50% effective concentration was 2 nM. Chelation of extracellular Ca2+ by EGTA did not reduce the NPY-mediated increase in cytoplasmic Ca2+, indicating that the increase in fluorescence was due to the release of intracellular Ca2+. A second dose of NPY, after intracellular Ca2+ had returned to basal levels, failed to elicit a response, indicating that the NPY receptor had undergone desensitization. In similar experiments, NPY increased the formation of inositol phosphates, suggesting that the mobilization of Ca2+ from intracellular stores in HEL cells was secondary to the generation of inositol phosphates and stimulation of phospholipase C.

Identification of zona binding proteins of rabbit, pig, human, and mouse spermatozoa on nitrocellulose blots.

Mammalian fertilization is a multi-step process with different requirements for specificity at each step. In the present report we have examined the binding of spermatozoa to homologous and heterologous zonae pellucidae. The homologous zona binding proteins (ZBP) of ejaculated rabbit, pig and human spermatozoa and epididymal mouse spermatozoa have been identified. The rabbit's ZBPs have relative molecular weights (MW) of 32K, 18K, 16K and 14K; the pig's major ZBP is 16K while human spermatozoa bind human zona protein at 17K and 18K. Mouse sperm ZBPs are 19K, 18K and 16K.