Flatworm nerve-muscle: structural and functional analysis

Platyhelminthes occupy a unique position in nerve-muscle evolution, being the most primitive of metazoan phyla. Essentially, their nervous system consists of an archaic brain and associated pairs of longitudinal nerve cords cross-linked as an orthogon by transverse commissures. Confocal imaging reveals that these central nervous system elements are in continuity with an array of peripheral nerve plexuses which innervate a well-differentiated grid work of somatic muscle as well as a complexity of myofibres associated with organs of attachment, feeding, and reproduction. Electrophysiological studies of flatworm muscles have exposed a diversity of voltage-activated ion channels that influence muscle contractile events. Neuronal cell types are mainly multi- and bi-polar and highly secretory in nature, producing a heterogeneity of vesicular inclusions whose contents have been identified cytochemically to include all three major types of cholinergic, aminergic, and peptidergic messenger molecules. A landmark discovery in flatworm neurobiology was the biochemical isolation and amino acid sequencing of two groups of native neuropeptides: neuropeptide F and FMRFamide-related peptides (FaRPs). Both families of neuropeptide are abundant and broadly distributed in platyhelminths, occurring in neuronal vesicles in representatives of all major flatworm taxa. Dual localization studies have revealed that peptidergic and cholinergic substances occupy neuronal sets separate from those of serotoninergic components. The physiological actions of neuronal messengers in flatworms are beginning to be established, and where examined, FaRPs and 5-HT are myoexcitatory, while cholinomimetic substances are generally inhibitory. There is immunocytochemical evidence that FaRPs and 5-HT have a regulatory role in the mechanism of egg assembly. Use of muscle strips and (or) muscle fibres from free-living and parasitic flatworms has provided baseline information to indicate that muscle responses to FaRPs are mediated by a G-protein-coupled receptor, and that the signal transduction pathway for contraction involves the second messengers cAMP and protein kinase C.

Child abuse as a complex and wicked problem: Reflecting on policy developments in the United Kingdom in working with children and families with multiple problems

In spite of significant public concern, professional efforts and financial expenditure, there has been a perceived lack of progress in reducing the incidence of child abuse, and in improving the outcomes for children in both the short and longer term. In this article the authors reflect on recent policy developments in the United Kingdom relating to children and families experiencing multiple adversities, and argue that the current conceptualisation of child abuse is flawed. In adopting a rational technical approach to the management of child abuse, there is a tendency to focus on shorter term outcomes for the child, such as immediate safety, that primarily reflect the outputs of the child protection system. However, by viewing child abuse as a wicked problem, that is complex and less amenable to being solved, then child welfare professionals can be supported to focus on achieving longer term outcomes for children that are more likely to meet their needs. The authors argue for an earlier identification of and intervention with children who are experiencing multiple adversity, such as those living with parents misusing substances and exposed to intimate partner violence.

Impact of persistent substance misuse on 1-year outcome in first-episode psychosis

Background: Substance misuse is a common comorbid problem in people presenting with first-episode psychosis and is associated with a poor short-term outcome.

Aims: The aim of this study is to examine differences in baseline characteristics and 1-year outcome between individuals with first-episode psychosis who have never misused substances, those who stop misusing substances after initial presentation and those who persistently misuse substances over the 1-year assessment period.

Method: Patients were recruited to the Northern Ireland First Episode Psychosis Study (n=272). Clinical assessments were performed at baseline and at 1 year (n=194) and data were collected from the case notes.

Results: Individuals with persistent substance misuse had more severe depression, more positive symptoms, poorer functional outcome and greater rates of relapse at 1 year than those who stopped and those who had never misused substances. There were no differences in outcome between people who had never misused substances and those who stopped misusing after presentation.

Conclusions: These results support assertive intervention targeted at comorbid substance misuse in individuals with first-episode psychosis.

British drugs policy: Problematizing the distinction between legal and illegal drugs and the definition of the ‘drugs problem’.

This article draws upon an extensive literature review of the social and medical sciences, official documents and various websites to critically re-evaluate the basis of British drugs policy. The article problematizes the rationale for criminalizing certain substances and questions the distinctions created between legal and illegal drugs; in so doing, the article argues that the definition of the `drugs problem' is the real problem. It shows that the debate on illegal drugs is filled less with factual truths and more with misinformation which creates public fear and provides a questionable basis for public policy. The article questions current thinking regarding the drugs/crime relationship and concludes by exploring some implications for policy and practice.

Neuropeptides Regulate Expression of Angiogenic Growth Factors in Human Dental Pulp Fibroblasts

Abstract
INTRODUCTION:
Neuropeptides play an important role in inflammation and repair and have been implicated in mediating angiogenesis. Pulp fibroblasts express neuropeptide receptors, and the aim of this research was to investigate whether neuropeptides could regulate angiogenic growth factor expression in vitro
METHODS:
An angiogenic array was used to determine the levels of 10 angiogenic growth factors expressed by human pulp fibroblasts.
RESULTS:
Pulp fibroblasts were shown to express angiogenin, angiopoietin-2, epidermal growth factor, basic fibroblast growth factor, heparin-binding epidermal growth factor, hepatocyte growth factor, leptin, platelet-derived growth factor, placental growth factor, and vascular endothelial growth factor. Furthermore, the neuropeptides substance P, calcitonin gene-related peptide, vasoactive intestinal polypeptide, and neuropeptide Y altered angiogenic growth factor expression in vitro.
CONCLUSIONS:
The regulation of angiogenic growth factor expression by neuropeptides suggests a novel role for neuropeptides in pulpal inflammation and repair.

Solutes determine the temperature windows for microbial survival and growth

Microbial cells, and ultimately the Earth's biosphere, function within a narrow range of physicochemical conditions. For the majority of ecosystems, productivity is cold-limited, and it is microbes that represent the failure point. This study was carried out to determine if naturally occurring solutes can extend the temperature windows for activity of microorganisms. We found that substances known to disorder cellular macromolecules (chaotropes) did expand microbial growth windows, fungi preferentially accumulated chaotropic metabolites at low temperature, and chemical activities of solutes determined microbial survival at extremes of temperature as well as pressure. This information can enhance the precision of models used to predict if extraterrestrial and other hostile environments are able to support life; furthermore, chaotropes may be used to extend the growth windows for key microbes, such as saprotrophs, in cold ecosystems and manmade biomes.

Detection of glucocorticoid bioactivity in bovine urine samples using a reporter gene assay.

The illegal use of anabolic substances in the meat producing industry is an ongoing problem due to the continual production of new synthetic compounds and/or the practice of low-level cocktail administration to avoid detection by the surveillance schemes of EU member states National Plan surveillance systems.

We present a highly sensitive reporter gene assay and sample extraction procedure based on a two step solid phase extraction and high performance liquid chromatography, developed for the detection of glucocorticoid abuse in bovine urine. The assay is capable of detecting compounds with glucocorticoid bioactivity and is extremely sensitive with an EC50 of 0.79 ng mL-1 for dexamethasone. New or unknown compounds with glucocorticoid bioactivity and low-level cocktail mixtures are detectable by this assay.

Cross-reactivity data for a range of 11ß-hydroxyglucocorticoids has been provided. This assay shows low interference from the 11-keto prohormones and other steroidal hormones. The assay may be suitable for application in other matrices such as hair. In conclusion this screening assay offers advantages over existing analytical techniques.

The Effect of Volume Shape Factor on the Crystal Size Distribution of Fragments due to Attrition

The effect of volume shape factor on crystal size distribution (CSD) is usually ignored to simplify the analysis of population balance equation. In the present work, the CSD of fragments generated from a mechanically stirred crystallizer as the result of attrition mechanism has been reported when the volume shape factor conforms to normal distribution. The physical model of GAHN and MERSMANN which relates the attrition resistance of a crystalline substances to its mechanical properties has been employed. The simulation of fragment size distribution was performed by Monte Carlo (MC) technique. The results are compared with those reported by GAHN and MERSMANN.

Microneedle-based drug delivery systems: Microfabrication, drug delivery, and safety

Many promising therapeutic agents are limited by their inability to reach the systemic circulation, due to the excellent barrier properties of biological membranes, such as the stratum corneum (SC) of the skin or the sclera/cornea of the eye and others. The outermost layer of the skin, the SC, is the principal barrier to topically-applied medications. The intact SC thus provides the main barrier to exogenous substances, including drugs. Only drugs with very specific physicochemical properties (molecular weight <500 Da, adequate lipophilicity, and low melting point) can be successfully administered transdermally. Transdermal delivery of hydrophilic drugs and macromolecular agents of interest, including peptides, DNA, and small interfering RNA is problematic. Therefore, facilitation of drug penetration through the SC may involve by-pass or reversible disruption of SC molecular architecture. Microneedles (MNs), when used to puncture skin, will by-pass the SC and create transient aqueous transport pathways of micron dimensions and enhance the transdermal permeability. These micropores are orders of magnitude larger than molecular dimensions, and, therefore, should readily permit the transport of hydrophilic macromolecules. Various strategies have been employed by many research groups and pharmaceutical companies worldwide, for the fabrication of MNs. This review details various types of MNs, fabrication methods and, importantly, investigations of clinical safety of MN.

Interstitial Cells in the Urinary Bladder-Localization and Function

Aims: This review summarizes the currently available literature on the localization and proposed functions of a novel group of cells in the urinary bladder known as interstitial cells or interstitial cells of Cajal (ICC).

Methods: On-line searches of "Pubmed" for bladder, c-Kit, ICC, interstitial cell and myofibroblast were performed to identify relevant studies for the review.

Results: The literature contains substantial data that several sub-populations of ICC are present in the wall of the mammalian urinary bladder. These are located in the lamina propria and within the detrusor with distinctive cell shapes and morphological arrangements. Bladder ICC are identified with transmission electron microscopy or by immunohistochemical labeling using antibodies to the Kit receptor which is an established ICC marker. Lamina propria-ICC form a loose network connected via Cx43 gap junctions and are associated with mucosal nerves. Detrusor ICC track the smooth muscle bundles and make frequent contacts with intramural nerves. Both groups of ICC exhibit spontaneous electrical and Ca²⁺-signalling and also respond to application of neurotransmitter substances including ATP and carbachol. There is emerging evidence that the expression of ICC is upregulated in pathophysiological conditions including the overactive bladder.

Conclusions: There is now a convincing body of evidence that specialized ICC are present in the urinary bladder making important associations with other cells that make up the bladder wall and possessing physiological properties consistent with a role of bladder activity modulation. Neurourol. Urodynam. 29: 82–87, 2010. © 2009 Wiley-Liss, Inc.

Antibody Targeting of Camptothecin-Loaded PLGA Nanoparticles to Tumor Cells

Antibody targeting of drug substances can improve the efficacy of the active molecule, improving distribution and concentration of the drug at the site of injury/disease. Encapsulation of drug substances into polymeric nanoparticles can also improve the therapeutic effects of such compounds by protecting the molecule until its action is required. In this current study, we have brought together these two rationales to develop a novel immunonanoparticle with improved therapeutic effect against colorectal tumor cells. This nanoparticle comprised a layer of peripheral antibodies (Ab) directed toward the Fas receptor (CD95/Apo-1) covalently attached to poly(lactide-co-glycolide) nanoparticles (NP) loaded with camptothecin. Variations in surface carboxyl density permitted up to 48.5 mu g coupled Ab per mg of NP and analysis of nanoparticulate cores showed efficient camptothecin loading. Fluorescence visualization studies confirmed internalization of nanoconstructs into endocytic compartments of HCT 116 cells, an effect not evident in NP without superficial Ab. Cytotoxicity studies were then carried out against HCT116 cells. After 72 h, camptothecin solution resulted in an IC50 of 21.8 ng mL(-1). Ab-directed delivery of NP-encapsulated camptothecin was shown to be considerably more effective with an IC50 of 0.37 ng mL(-1). Calculation of synergistic ratios for these nanoconstructs demonstrated synergy of pharmacological relevance. Indeed, the results in this paper suggest that the attachment of anti-Fas antibodies to camptothecin-loaded nanoparticles may result in a therapeutic strategy that could have potential in the treatment of tumors expressing death receptors.

Sex, drugs and STDs: Preliminary findings from the Belfast Youth Development Study

Young people's participation in sexual risk behaviours is commonly linked with participation in a range of other risky behaviours, and in particular with substance use behaviours. This cross-sectional analysis of the sixth sweep of the Belfast Youth Development Study aimed to examine associations between substance use and sexual activity and related risks among 17-19-year olds in Northern Ireland. Being sexual activity and participating in sexual risk behaviours was associated with the use of a range of licit and illicit substances particularly alcohol and ecstasy. Additionally, females were more likely to have been tested for a sexually transmitted disease (STD). The findings add to the existing research body suggesting that substance misuse and sexual risk behaviours tend to co-occur in adolescence and highlight a need to develop appropriate interventions and initiatives for school aged young people.

Evidence of natural occurrence of the banned antibiotic chloramphenicol in herbs and grass

Chloramphenicol (CAP), a broad-spectrum antibiotic, was detected in several herb and grass samples from different geographic origins. Due to its suspected carcino-genicity and linkages with the development of aplastic anemia in humans, CAP is banned for use in food-producing animals in the European Union (EU) and many other countries. However, products of animal origin originating from Asian countries entering the European market are still found noncompliant (containing CAP) on a regular basis, even when there is no history of chloramphenicol use in these countries. A possible explanation for the continued detection of these residues is the natural occurrence of CAP in plant material which is used as animal feed, with the consequent transfer of the substance to the animal tissues. Approximately 110 samples were analyzed using liquid chromatography coupled with mass spectrometric detection. In 26 samples, the presence of CAP was confirmed using the criteria for banned substances defined by the EU. Among other plant materials, samples of the Artemisia family retrieved from Mongolia and from Utah, USA, and a therapeutic herb mixture obtained from local stores in the Netherlands proved to contain CAP at levels ranging from 0.1 to 450 mu g/kg. These findings may have a major impact in relation to international trade and safety to the consumer. The results of this study demonstrate that noncompliant findings in animal-derived food products may in part be due to the natural occurrence of chloramphenicol in plant material. This has implications for the application of current EU, USA, and other legislation and the interpretation of analytical results with respect to the consideration of CAP as a xenobiotic veterinary drug residue and the regulatory actions taken upon its detection in food.