Gifts, Drug Samples, and other Items Given to Medical Specialists by Pharmaceutical Companies

Aim  To ascertain the quantity and nature of gifts and items provided by the pharmaceutical industry in Australia to medical specialists and to consider whether these are appropriate in terms of justifiable ethical standards, empirical research and views expressed in the literature.Design and Setting  Fifty-one medical Sydney specialists were asked to collect all gifts, offers, invitations, and items received from pharmaceutical companies in an eight-week period.Main Outcome Measures  The items received were categorised as promotional/educational, drug samples, clinical practice aids, office gifts, personal gifts, and invitations; and were analysed in relation to the pharmaceutical industry Code of Conduct.Results  A large number (mean = 42/participant) and wide range of gifts and items were received. These included promotional/educational items (mean = 21), drug samples (mean = 8), office gifts (mean = 5) and personal gifts (mean = 1), clinical aids (mean = 3), and invitations (mean = 3) to meals, meetings, and conferences. Most gifts and items complied with the Code with a few breaches including offers of entertainment (sporting event and cabaret), items of high monetary value (in competitions with prizes unrelated to medicine), unbranded gifts, and promotional documents presented as journal articles.Conclusions  Medical specialists received many gifts and items from pharmaceutical companies and a few that infringed the Code current at the time of the study. The findings were considered in the light of changes that have since been made to the industry Code of Conduct and professional medical guidelines on ethical relationships between physicians and the industry. In large measure, these changes are supported although some suggestions are made for stricter standards.Competing Interest  Graham Macdonald is employed by Merck Sharp & Dohme (Australia). Richard Day serves as an Advisory Board member for Merck Sharp & Dohme (Australia) (rofecoxib, etoricoxib), Merck Sharp & Dohme (Asia) (rofecoxib), Abbott Australia (adalimumab), Schering–Plough Australia (infliximab), Amgen Australia (anakinra), GlaxoSmithKline Consumer Australia (paracetamol) and, previously, Pfizer Australia (celecoxib). Any honoraria for these activities are placed in audited trust funds of St Vincent’s Hospital, Sydney, to be used to support academic activities within the Department of Clinical Pharmacology.     

Antibodies to Toxoplasma gondii in Eurasian badgers

Antibodies to Toxoplasma gondii were detected in samples collected from 90 live-trapped adult Eurasian badgers (Meles meles) sampled at three sites (two agricultural and one woodland) in southern England. Serum was tested using a qualitative latex agglutination test procedure and 63 of 90 (70%) badgers tested positive for T. gondii antibodies. Antibody prevalence varied between the sites; 67% and 77% of badgers from agricultural sites and 39% from a nonagricultural site tested positive.     

A targeted proteomic approach for the identification of tumor-associated membrane antigens using the ProteomeLab PF-2D in tandem with mass spectrometry

Mapping differential expression of soluble proteins has become fairly routine using chromatofocusing in combination with the reversed-phase HPLC (ProteomeLab PF-2D by Beckman Coulter Inc.); however, identification of membrane antigens has not been reported thus far. In this report, we demonstrate a targeted proteomic approach employing immunoprecipitation, prior to 2D-LC separation, in tandem with MS/MS that can be used to identify tumor-associated membrane antigens. This system is very sensitive and reproducible in that only 1/4th the amount of starting material is required for analysis as compared to gel-based analysis, and permits a focused environment for eliminating non-specific interactions leading to an accurate resolution of the cognate antigen. This system also circumvents the well-known limitations associated with gel-based approaches. This approach has been validated in the identification of ErB2/HER-2 and was subsequently used to identify CD44E as the cognate antigen for VB1-008, one of our fully human, tumor-specific, monoclonal antibodies.     

High-risk human papillomavirus E5 oncoprotein displays channel-forming activity sensitive to small-molecule inhibitors

High-risk human papillomavirus type 16 (HPV16) is the primary causative agent of cervical cancer and therefore is responsible for significant morbidity and mortality worldwide. Cellular transformation is mediated directly by the expression of viral oncogenes, the least characterized of which, E5, subverts cellular proliferation and immune recognition processes. Despite a growing catalogue of E5-specific host interactions, little is understood regarding the molecular basis of its function. Here we describe a novel function for HPV16 E5 as an oligomeric channel-forming protein, placing it within the virus-encoded "viroporin" family. The development of a novel recombinant E5 expression system showed that E5 formed oligomeric assemblies of a defined luminal diameter and stoichiometry in membranous environments and that such channels mediated fluorescent dye release from liposomes. Hexameric E5 channel stoichiometry was suggested by native PAGE studies. In lieu of high-resolution structural information, established de novo molecular modeling and design methods permitted the development of the first specific small-molecule E5 inhibitor, capable of both abrogating channel activity in vitro and reducing E5-mediated effects on cell signaling pathways. The identification of channel activity should enhance the future understanding of the physiological function of E5 and could represent an important target for antiviral intervention.     

Acute pantothenic acid and cysteine supplementation does not affect muscle coenzyme A content, fuel selection, or exercise performance in healthy humans

Reduced skeletal muscle free coenzyme A (CoASH) availability may decrease the contribution of fat oxidation to ATP production during high-intensity, submaximal exercise or, alternatively, limit pyruvate dehydrogenase complex (PDC) flux and thereby carbohydrate oxidation. Here we attempted to increase the muscle CoASH pool in humans, via pantothenic acid and cysteine feeding, in order to elucidate the role of CoASH availability on muscle fuel metabolism during exercise. On three occasions, eight healthy male volunteers (age 22.9 ± 1.4 yr, body mass index 24.2 ± 1.5 kg/m(2)) cycled at 75% maximal oxygen uptake (Vo(2max)) to exhaustion, followed by a 15-min work output performance test. Muscle biopsies were obtained at rest, and after 60 min and 91.3 ± 3.1 min of exercise (time to exhaustion on baseline visit) on each occasion. Two weeks following the first visit (baseline), 1 wk of oral supplementation with either 3 g/day of a placebo control (glucose polymer; CON) or 1.5 g/day each of d-pantothenic acid and l-cysteine (CP) was carried out prior to the second and third visits in a randomized, counterbalanced, double-blind manner, leaving a 3-wk gap in total between each visit. Resting muscle CoASH content was not altered by supplementation in any visit. Following 60 min of exercise, muscle CoASH content was reduced by 13% from rest in all three visits (P < 0.05), and similar changes in the respiratory exchange ratio, glycogenolysis (～235 mmol/kg dry muscle), PCr degradation (～57 mmol/kg dry muscle), and lactate (～25 mmol/kg dry muscle) and acetylcarnitine (～12 mmol(.)kg/dry muscle) accumulation was observed during exercise when comparing visits. Furthermore, no difference in work output was observed when comparing CON and CP. Acute feeding with pantothenic acid and cysteine does not alter muscle CoASH content and consequently does not impact on muscle fuel metabolism or performance during exercise in humans.     

A functional interaction between the MAGUK protein hDlg and the gap junction protein connexin 43 in cervical tumour cells

Gap junctions, composed of Cxs (connexins), allow direct intercellular communication. Gap junctions are often lost during the development of malignancy, although the processes behind this are not fully understood. Cx43 is a widely expressed Cx with a long cytoplasmic C-terminal tail that contains several potential protein-interaction domains. Previously, in a model of cervical carcinogenesis, we showed that the loss of gap junctional communication correlated with relocalization of Cx43 to the cytoplasm late in tumorigenesis. In the present study, we demonstrate a similar pattern of altered expression for the hDlg (human discs large) MAGUK (membrane-associated guanylate kinase) family tumour suppressor protein in cervical tumour cells, with partial co-localization of Cx43 and hDlg in an endosomal/lysosomal compartment. Relocalization of these proteins is not due to a general disruption of cell membrane integrity or Cx targeting. Cx43 (via its C-terminus) and hDlg interact directly in vitro and can form a complex in cells. This novel interaction requires the N- and C-termini of hDlg. hDlg is not required for Cx43 internalization in W12GPXY cells. Instead, hDlg appears to have a role in maintaining a cytoplasmic pool of Cx43. These results demonstrate that hDlg is a physiologically relevant regulator of Cx43?in transformed epithelial cells.     

Draft genome sequence of Novosphingobium nitrogenifigens Y88(T)

Novosphingobium nitrogenifigens was originally isolated from pulp and paper mill wastewater, a low-nitrogen, high-carbon environment. N. nitrogenifigens is the first known nitrogen-fixing, polyhydroxyalkanoate-accumulating sphingomonad, and we report the annotated draft genome sequence of the type strain Y88(T) here.