Identification of high-affinity binding sites for the insulin sensitizer rosiglitazone (BRL-49653) in rodent and human adipocytes using a radioiodinated ligand for peroxisomal proliferator-activated receptor gamma.

A radioiodinated ligand, [125I]SB-236636 [(S)-(-)3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]3-[125I]iodophenyl]2-ethoxy propanoic acid], which is specific for the ? isoform of the peroxisomal proliferator activated receptor (PPAR?), was developed. [125I]SB-236636 binds with high affinity to full-length human recombinant PPAR?1 and to a GST (glutathione S-transferase) fusion protein contg. the ligand binding domain of human PPAR?1 (KD = 70 nM). Using this ligand, the authors characterized binding sites in adipose-derived cells from rat, mouse and humans. In competition expts., rosiglitazone (BRL-49653), a potent antihyperglycemic agent, binds with high affinity to sites in intact adipocytes (IC50 = 12, 4 and 9 nM for rat, 3T3-L1 and human adipocytes, resp.). Binding affinities (IC50) of other thiazolidinediones for the ligand binding domain of PPAR?1 were comparable with those detd. in adipocytes and reflected the rank order of potencies of these agents as stimulants of glucose transport in 3T3-L1 adipocytes and antihyperglycemic agents in vivo: rosiglitazone > pioglitazone > troglitazone. Competition of [125I]SB-236636 binding was stereoselective in that the IC50 value of SB-219994, the (S)-enantiomer of an ?-trifluoroethoxy propanoic acid insulin sensitizer, was 770-fold lower than that of SB-219993 [(R)-enantiomer] at recombinant human PPAR?1. The higher binding affinity of SB-219994 also was evident in intact adipocytes and reflected its 100-fold greater potency as an antidiabetic agent. The results strongly suggest that the high-affinity binding site for [125I]SB-236636 in intact adipocytes is PPAR? and that the pharmacol. of insulin-sensitizer binding in rodent and human adipocytes is very similar and, moreover, predictive of antihyperglycemic activity in vivo.

Championing the interface between mental health and child protection: evaluation of a service initiative to improve joint working in Northern Ireland

The importance of establishing effective interagency working between adult mental health services and child care services in order to safeguard children has been repeatedly identified by research, policy, inquiries and inspection reports. This article reports on the evaluation of an initiative in one Health and Social Care Trust in Northern Ireland that aimed to facilitate joint working and so improve service provision and protection for children and families. The Champions Initiative involved identifying a champion in each multi-disciplinary community mental health team and in each family and child care team who would have responsibility for providing information, promoting joint working and identifying any obstacles to better co-operation. The evaluation of this initiative assessed levels of experience, training, confidence, understanding and awareness in the Champions and their team members at baseline. The Champions and their Team Leaders were then followed-up after six months to obtain their qualitative views of the impact of the initiative. The results include comparisons between mental health and child care staff, and crucially, views about whether the initiative has had any impact on working together. This study also generated recommendations for further service development in this complex and important area of practice.

Will Antiangiogenic Agents be a Future for Mesothelioma Therapy?

Background: Malignant mesothelioma (MM) is an aggressive disease that is diagnosed mostly in locally advanced or metastatic stage. In this condition chemotherapy with the combination cisplatin and pemetrexed or ralitrexed represents the standard treatment as supported by a phase III study. However, chemotherapy has very limited effect on the improvement of survival of patients and very few of the MM patients survive more than 2 years. A better understanding of molecular mechanisms and pathways involved in angiogenesis in MM is the basis for the development of new drugs targeted against these pathways responsible for the proliferation and survival of tumor cells.

Does airways inflammation pre-exist before late onset wheeze in children?

Epidemiological studies show that some children develop wheezing after 3 yr of age which tends to persist. It is unknown how this starts or whether there is a period of asymptomatic inflammation. The aim of this study is to determine whether lower airway allergic inflammation pre-exists in late onset childhood wheeze (LOCW). Follow-up study of children below 5 yr who had a non-bronchoscopic bronchoalveolar lavage (BAL) performed during elective surgery. The children had acted as normal controls. A modified ISAAC questionnaire was sent out at least 7 yr following the initial BAL, and this was used to ascertain whether any children had subsequently developed wheezing or other atopic disease (eczema, allergic rhinitis). Cellular and cytokine data from the original BAL were compared between those who never wheezed (NW) and those who had developed LOCW. Eighty-one normal non-asthmatic children were recruited with a median age of 3.2 . Of the 65 children contactable, 9 (16.7%) had developed wheeze, 11 (18.5%) developed eczema and 14 (22.2%) developed hay fever. In five patients, wheeze symptoms developed mean 3.3- yr (range: 2–5 yr) post-BAL. Serum IgE and blood eosinophils were not different in the LOCW and NW, although the blood white cell count was lower in the LOCW group. The median BAL eosinophil % was significantly increased in the patients with LOCW (1.55%, IQR: 0.33 to 3.92) compared to the children who never wheezed, NW (0.1, IQR: 0.0 to 0.3, p = 0.01). No differences were detected for other cell types. There are no significant differences in BAL cytokine concentrations between children with LOCW and NW children. Before late onset childhood wheezing developed, we found evidence of elevated eosinophils in the airways. These data suggest pre-existent airways inflammation in childhood asthma some years before clinical presentation.

Data mining approach identifies research priorities and data requirements for resolving the red algal tree of life

Background. The assembly of the tree of life has seen significant progress in recent years but algae and protists have been largely overlooked in this effort. Many groups of algae and protists have ancient roots and it is unclear how much data will be required to resolve their phylogenetic relationships for incorporation in the tree of life. The red algae, a group of primary photosynthetic eukaryotes of more than a billion years old, provide the earliest fossil evidence for eukaryotic multicellularity and sexual reproduction. Despite this evolutionary significance, their phylogenetic relationships are understudied. This study aims to infer a comprehensive red algal tree of life at the family level from a supermatrix containing data mined from GenBank. We aim to locate remaining regions of low support in the topology, evaluate their causes and estimate the amount of data required to resolve them. Results. Phylogenetic analysis of a supermatrix of 14 loci and 98 red algal families yielded the most complete red algal tree of life to date. Visualization of statistical support showed the presence of five poorly supported regions. Causes for low support were identified with statistics about the age of the region, data availability and node density, showing that poor support has different origins in different parts of the tree. Parametric simulation experiments yielded optimistic estimates of how much data will be needed to resolve the poorly supported regions (ca. 103 to ca. 104 nucleotides for the different regions). Nonparametric simulations gave a markedly more pessimistic image, some regions requiring more than 2.8 105 nucleotides or not achieving the desired level of support at all. The discrepancies between parametric and nonparametric simulations are discussed in light of our dataset and known attributes of both approaches. Conclusions. Our study takes the red algae one step closer to meaningful inclusion in the tree of life. In addition to the recovery of stable relationships, the recognition of five regions in need of further study is a significant outcome of this work. Based on our analyses of current availability and future requirements of data, we make clear recommendations for forthcoming research.

Fasciola hepatica: Histological changes in the reproductive structures of triclabendazole (TCBZ)-sensitive and TCBZ-resistant flukes after treatment in vivo with TCBZ and the related benzimidazole derivative, Compound Alpha

Twenty-four shed-reared lambs were each infected orally with 250 metacercariae of Fasciola hepatica, using either the triclabendazole (TCBZ)-sensitive Cullompton isolate or the TCBZ-resistant Sligo isolate. Twelve weeks after infection the lambs were treated with TCBZ (10 mg/kg) or with the experimental fasciolicide, Compound Alpha (Cpd alpha), a benzimidazole derivative of TCBZ (15 mg/kg). The lambs were euthanised 48,72 and 96 h after TCBZ treatment, or 24, 48 and 72 h after Cpd a treatment, and flukes were collected from the liver and/or gall bladder of each animal. Untreated animals harbouring 12-week infections were euthanised 24 h after administration of anthelmintic to the treatment groups, and the untreated flukes provided control material. A semi-quantitative assessment of the degree of histological change induced by the two drugs after different times of exposure was achieved by scoring the intensity of three well-defined lesions that developed in the testes and uteri of a representative sample of flukes from each lamb. In general, it was found that in those tissues where active meiosis and/or mitosis occurred (testis, ovary, and vitelline follicles), there was progressive loss of cell content due to apparent failure of cell division to keep pace with expulsion of the mature or effete products. Further, actively dividing cell types tended to become individualised, rounded and condensed, characteristic of apoptotic cell death. Protein synthetic activity was apparently inhibited in the Mehlis' secretory cells. In the uterus, where successful formation of shelled eggs represents the culmination of a complex sequence of cytokinetic, cytological and synthetic activity involving the vitelline follicles, the ovary and the Mehlis' gland, histological evidence indicating failure of ovigenesis was evident from 24 h post-treatment onwards. The development of these lesions may be related to the known antitubulin activity of the benzimidazole class of anthelmintics, to the induction of apoptosis in cells where mitosis or meiosis has aborted due to failure of spindle formation, and to drug-induced inhibition of protein synthesis. The semi-quantitative findings indicated that Cpd a is slightly less efficacious than TCBZ itself in causing histological damage to the reproductive structures of TCBZ-sensitive flukes, and that, like TCBZ, it caused no histological damage in flukes of the TCBZ-resistant isolate. This study illustrates the potential utility of histological techniques for conveniently screening representative samples of flukes in field trials designed to validate instances of drug resistance or to test the efficacy of new products against known drug-resistant and drug-susceptible fluke isolates. It also provides reference criteria for drug-induced histopathological changes in fluke reproductive structures which may aid interpretation of TEM findings. (C) 2009 Elsevier B.V. All rights reserved.

Benzylguanidines and Other Galegine Analogues Inducing Weight Loss in Mice

Dimethylallylguanidine, also known as galegine, isolated from Galega officinalis, has been shown to have weight reducing properties in vivo. Substitution of the guanidine group with an N-cyano group and replacement of guanidine with amidine, pyrimidine, pyridine, or the imidazole moieties removed the weight reducing properties when evaluated in BALB/c mice. However, retention of the guanidine and replacement of the dimethylallyl group by a series of functionalized benzyl substituents was shown to exhibit, and in some cases significantly improve, the weight reducing properties of these molecules in BALB/c, ob/ob, and diet induced obesity (DIO) mice models. The lead compound identified, across all models, was 1-(4-chlorobenzyl)guanidine hemisulfate, which gave an average daily weight difference (% from time-matched controls; +/- SEM) of -19.7 +/- 1.0, -11.0 +/- 0.7, and -7.3 +/- 0.8 in BALB/c, ob/ob, and DIO models, respectively.

Ion acceleration from the shock front induced by hole boring in ultraintense laser-plasma interactions

Ion-acceleration processes have been studied in ultraintense laser plasma interactions for normal incidence irradiation of solid deuterated targets via neutron spectroscopy. The experimental neutron spectra strongly suggest that the ions are preferentially accelerated radially, rather than into the bulk of the material from three-dimensional Monte Carlo fitting of the neutron spectra. Although the laser system has a 10(-7) contrast ratio, a two-dimensional magnetic hydrodynamics simulation shows that the laser pedestal generates a 10 mum scale length in the coronal plasma with a 3 mum scale-length plasma near the critical density. Two-dimensional particle-in-cell simulations, incorporating this realistic density profile, indicate that the acceleration of the ions is caused by a collisionless shock formation. This has implications for modeling energy transport in solid is caused by a collisionless shock formation. This has implications for modeling energy transport in solid density plasmas as well as cone-focused fast ignition using the next generation PW lasers currently under construction.