Triglyceride Blisters in Lipid Bilayers: Implications for Lipid Droplet Biogenesis and the Mobile Lipid Signal in Cancer Cell Membranes

Triglycerides have a limited solubility, around 3%, in phosphatidylcholine lipid bilayers. Using millisecond-scale course grained molecular dynamics simulations, we show that the model lipid bilayer can accommodate a higher concentration of triolein (TO) than earlier anticipated, by sequestering triolein molecules to the bilayer center in the form of a disordered, isotropic, mobile neutral lipid aggregate, at least 17 nm in diameter, which forms spontaneously, and remains stable on at least the microsecond time scale. The results give credence to the hotly debated existence of mobile neutral lipid aggregates of unknown function present in malignant cells, and to the early biogenesis of lipid droplets accommodated between the two leaflets of the endoplasmic reticulum membrane. The TO aggregates give the bilayer a blister-like appearance, and will hinder the formation of multi-lamellar phases in model, and possibly living membranes. The blisters will result in anomalous membrane probe partitioning, which should be accounted for in the interpretation of probe-related measurements

Pharmacokinetics and transcriptional effects of the anti-salmon lice drug emamectin benzoate in Atlantic salmon (Salmo salar L.)

Background Emamectin benzoate (EB) is a dominating pharmaceutical drug used for the treatment and control of infections by sea lice (Lepeophtheirus salmonis) on Atlantic salmon (Salmo salar L). Fish with an initial mean weight of 132 g were experimentally medicated by a standard seven-day EB treatment, and the concentrations of drug in liver, muscle and skin were examined. To investigate how EB affects Atlantic salmon transcription in liver, tissues were assessed by microarray and qPCR at 7, 14 and 35 days after the initiation of medication. Results The pharmacokinetic examination revealed highest EB concentrations in all three tissues at day 14, seven days after the end of the medication period. Only modest effects were seen on the transcriptional levels in liver, with small fold-change alterations in transcription throughout the experimental period. Gene set enrichment analysis (GSEA) indicated that EB treatment induced oxidative stress at day 7 and inflammation at day 14. The qPCR examinations showed that medication by EB significantly increased the transcription of both HSP70 and glutathione-S-transferase (GST) in liver during a period of 35 days, compared to un-treated fish, possibly via activation of enzymes involved in phase II conjugation of metabolism in the liver. Conclusion This study has shown that a standard seven-day EB treatment has only a modest effect on the transcription of genes in liver of Atlantic salmon. Based on GSEA, the medication seems to have produced a temporary oxidative stress response that might have affected protein stability and folding, followed by a secondary inflammatory response.publishedVersio

Withdrawal symptoms in children after long-term administration of sedatives and/or analgesics: A literature review. "Assessment remains troublesome"

Background: Prolonged administration of benzodiazepines and/or opioids to children in a pediatric intensive care unit (PICU) may induce physiological dependence and withdrawal symptoms. Objective: We reviewed the literature for relevant contributions on the nature of these withdrawal symptoms and on availability of valid scoring systems to assess the extent of symptoms. Methods: The databases PubMed, CINAHL, and Psychinfo (1980-June 2006) were searched using relevant key terms. Results: Symptoms of benzodiazepine and opioid withdrawal can be classified in two groups: central nervous system effects and autonomic dysfunction. However, symptoms of the two types show a large overlap for benzodiazepine and opioid withdrawal. Symptoms of gastrointestinal dysfunction in the PICU population have been described for opioid withdrawal only. Six assessment tools for withdrawal symptoms are used in children. Four of these have been validated for neonates only. Two instruments are available to specifically determine withdrawal symptoms in the PICU: the Sedation Withdrawal Score (SWS) and the Opioid Benzodiazepine Withdrawal Scale (OBWS). The OBWS is the only available assessment tool with prospective validation; however, the sensitivity is low. Conclusions: Withdrawal symptoms for benzodiazepines and opioids largely overlap. A sufficiently sensitive instrument for assessing withdrawal symptoms in PICU patients needs to be developed

Natural products as starting points for future anti-malarial therapies: going back to our roots?

Abstract Background The discovery and development of new anti-malarials are at a crossroads. Fixed dose artemisinin combination therapy is now being used to treat a hundred million children each year, with a cost as low as 30 cents per child, with cure rates of over 95%. However, as with all anti-infective strategies, this triumph brings with it the seeds of its own downfall, the emergence of resistance. It takes ten years to develop a new medicine. New classes of medicines to combat malaria, as a result of infection by Plasmodium falciparum and Plasmodium vivax are urgently needed. Results Natural product scaffolds have been the basis of the majority of current anti-malarial medicines. Molecules such as quinine, lapachol and artemisinin were originally isolated from herbal medicinal products. After improvement with medicinal chemistry and formulation technologies, and combination with other active ingredients, they now make up the current armamentarium of medicines. In recent years advances in screening technologies have allowed testing of millions of compounds from pharmaceutical diversity for anti-malarial activity in cellular assays. These initiatives have resulted in thousands of new sub-micromolar active compounds – starting points for new drug discovery programmes. Against this backdrop, the paucity of potent natural products identified has been disappointing. Now is a good time to reflect on the current approach to screening herbal medicinal products and suggest revisions. Nearly sixty years ago, the Chinese doctor Chen Guofu, suggested natural products should be approached by dao-xing-ni-shi or ‘acting in the reversed order’, starting with observational clinical studies. Natural products based on herbal remedies are in use in the community, and have the potential unique advantage that clinical observational data exist, or can be generated. The first step should be the confirmation and definition of the clinical activity of herbal medicinal products already used by the community. This first step forms a solid basis of observations, before moving to in vivo pharmacological characterization and ultimately identifying the active ingredient. A large part of the population uses herbal medicinal products despite limited numbers of well-controlled clinical studies. Increased awareness by the regulators and public health bodies of the need for safety information on herbal medicinal products also lends support to obtaining more clinical data on such products. Conclusions The relative paucity of new herbal medicinal product scaffolds active against malaria results discovered in recent years suggest it is time to re-evaluate the ‘smash and grab’ approach of randomly testing purified natural products and replace it with a patient-data led approach. This will require a change of perspective form many in the field. It will require an investment in standardisation in several areas, including: the ethnopharmacology and design and reporting of clinical observation studies, systems for characterizing anti-malarial activity of patient plasma samples ex vivo followed by chemical and pharmacological characterisation of extracts from promising sources. Such work falls outside of the core mandate of the product development partnerships, such as MMV, and so will require additional support. This call is timely, given the strong interest from researchers in disease endemic countries to support the research arm of a malaria eradication agenda. Para-national institutions such as the African Network for Drugs and Diagnostics Innovation (ANDi) will play a major role in facilitating the development of their natural products patrimony and possibly clinical best practice to bring forward new therapeutics. As in the past, with quinine, lapinone and artemisinin, once the activity of herbal medicinal products in humans is characterised, it can be used to identify new molecular scaffolds which will form the basis of the next generation of anti-malarial therapies.</p

Carotid intima-medial thickness measured on multiple ultrasound frames: evaluation of a DICOM-based software system

United Kingdo

Effective healthcare teams require effective team members: defining teamwork competencies

BACKGROUND: Although effective teamwork has been consistently identified as a requirement for enhanced clinical outcomes in the provision of healthcare, there is limited knowledge of what makes health professionals effective team members, and even less information on how to develop skills for teamwork. This study identified critical teamwork competencies for health service managers. METHODS: Members of a state branch of the professional association of Australian health service managers participated in a teamwork survey. RESULTS: The 37% response rate enabled identification of a management teamwork competency set comprising leadership, knowledge of organizational goals and strategies and organizational commitment, respect for others, commitment to working collaboratively and to achieving a quality outcome. CONCLUSION: Although not part of the research question the data suggested that the competencies for effective teamwork are perceived to be different for management and clinical teams, and there are differences in the perceptions of effective teamwork competencies between male and female health service managers. This study adds to the growing evidence that the focus on individual skill development and individual accountability and achievement that results from existing models of health professional training, and which is continually reinforced by human resource management practices within healthcare systems, is not consistent with the competencies required for effective teamwork

Brugia malayi Excreted/Secreted Proteins at the Host/Parasite Interface: Stage- and Gender-Specific Proteomic Profiling

Relatively little is known about the filarial proteins that interact with the human host. Although the filarial genome has recently been completed, protein profiles have been limited to only a few recombinants or purified proteins of interest. Here, we describe a large-scale proteomic analysis using microcapillary reverse-phase liquid chromatography-tandem-mass spectrometry to identify the excretory-secretory (ES) products of the L3, L3 to L4 molting ES, adult male, adult female, and microfilarial stages of the filarial parasite Brugia malayi. The analysis of the ES products from adult male, adult female, microfilariae (Mf), L3, and molting L3 larvae identified 852 proteins. Annotation suggests that the functional and component distribution was very similar across each of the stages studied; however, the Mf contributed a higher proportion to the total number of identified proteins than the other stages. Of the 852 proteins identified in the ES, only 229 had previous confirmatory expressed sequence tags (ESTs) in the available databases. Moreover, this analysis was able to confirm the presence of 274 “hypothetical” proteins inferred from gene prediction algorithms applied to the B. malayi (Bm) genome. Not surprisingly, the majority (160/274) of these “hypothetical” proteins were predicted to be secreted by Signal IP and/or SecretomeP 2.0 analysis. Of major interest is the abundance of previously characterized immunomodulatory proteins such as ES-62 (leucyl aminopeptidase), MIF-1, SERPIN, glutathione peroxidase, and galectin in the ES of microfilariae (and Mf-containing adult females) compared to the adult males. In addition, searching the ES protein spectra against the Wolbachia database resulted in the identification of 90 Wolbachia-specific proteins, most of which were metabolic enzymes that have not been shown to be immunogenic. This proteomic analysis extends our knowledge of the ES and provides insight into the host–parasite interaction

Therapeutic strategies to slow chronic kidney disease progression

Childhood chronic kidney disease commonly progresses toward end-stage renal failure, largely independent of the underlying disorder, once a critical impairment of renal function has occurred. Hypertension and proteinuria are the most important independent risk factors for renal disease progression. Therefore, current therapeutic strategies to prevent progression aim at controlling blood pressure and reducing urinary protein excretion. Renin-angiotensin-system (RAS) antagonists preserve kidney function not only by lowering blood pressure but also by their antiproteinuric, antifibrotic, and anti-inflammatory properties. Intensified blood pressure control, probably aiming for a target blood pressure below the 75th percentile, may exert additional renoprotective effects. Other factors contributing in a multifactorial manner to renal disease progression include dyslipidemia, anemia, and disorders of mineral metabolism. Measures to preserve renal function should therefore also comprise the maintenance of hemoglobin, serum lipid, and calcium-phosphorus ion product levels in the normal range