The Paradise Conspiracy

A death, missing computer disks, a wineboxfull of secret files, a tax haven in the Cook Islands, alleged extortion, arms dealing, corruption, coverups and criminal fraud, billion dollar deals, kidnap attempts ... and an investigative television team's struggle to expose the truth.&nbsp

Studies on the genus Bordetella

The genus Bordetella as defined by Lopez (1952) consists of the three organisms Bordetella pertussis, Bordetella parapertussis and Bordetella bronchiseptica. These species were formerly classified in the genus Haemophilus, but their inclusion in a new genus was suggested on the grounds of cultural and antigenic differences from other Haemophilus species.Bord. pertussis was first isolated by Bordet and Gengou (1906) from children suffering from the disease known as whooping cough. Eldering and ILendrick (1937) isolated a second organism, Bord. hparapertussis, which was also a cause of whooping cough, although the infection was generally of a mild type. The third member of the genus, Bord. bronchiseptica, has frequently been found in respiratory -tract infections of rabbits, guinea igs, cats and dogs and has also been isolated from a few cases of whooping cough (Brown, 1926; Medical esearch Council, 1951). The isolation of these species has never been easy, even using complex edia rendered selective by the addition of penicillin, and few diagnostic laboratories obtain igh percentage isolations of Bordetella strains from cases of whooping cough. Problems are also encountered in the laboratory culture of Bord. ertussis. This organism is difficult to grow and maintain in a virulent state, but the other two species are rriore easily grown and can be cultured on most,simple laboratory media. Cultur problems are also reflected in vaccine production.Whooping cough in young children causes high morbidity and since the discovery of the causal organisms, attempts have been made to develop suitable prophylactic agents. Whole cell vaccines are commonly used but possess many disadvantages, the most serious being the occasional occurrence of encephalopathy following vaccination. L1uch research has been carried out to obtain a satisfactory prophylactic material, without such disadvantages.The present work is an attempt to prepare a medium giving optimal growth of virulent Bord. pertussis, and, using this medium, to obtain a better knowledge of the chemical and immunological properties of Bord. pertussis antigens. An attempt is also made to clarify some of the antigenic relationships within the genus, using modern techniques of serological analysis such as gel diffusion and immunoelectrophoresis.A historical introduction to the work is presented, to show the difficulties which earlier workers have encountered with this genus and to give an outline of our present knowledge.1). A liquid medium supporting growth of virulent Bordetella pertussis has been described. It contains casamino acids, nicotinamide, glutathione tris buffer and inorganic salts as well as an anion exchange resin. The medium is reproducable, giving good yields of bacteria and is also cheap and easy to prepare. After the resin has been removed by decantation or filtration, the medium contains only dialysable components. Cells grown in this medium produce haemagglutinin and protective antigen. The liquid medium can be solidified by the addition of agar and then compares favourably with Bordet- Gengou medium for the growth of Bordetella species.2). The protective activity of Bordetella pertussis cells grown in tris -resin medium was assayed by intracerebral challenge in mice and was shown to reside in the cell wall. The activity was not destroyed by treatment of the cell wall with trypsin, lipase or detergent, although these removed adherant cytoplasmic material and trypsin destroyed the histamine -sensitising factor. The lipopolysaccharide moiety of the cell wall had no major role in protection.3). The lipopolysaccharides from Bordetella pertussis, Bordetella parapertussis and Bordetella bronchiseptica showed some chemical similarities, containing hexosamine, heptose and hexose in varying proportions. The lipopolysacch- -arides were species specific, but that isolated from Bord.pertussis was present in virulent and avirulent strains.4). Agglutination tests showed some similarities between strains of the same Bordetella species. Precipitation tests in agar gel revealed a large number of antigens common to all three species. The only antigens which could be identified were the species specific lipopolysaccharides. Two antigens were found to be common to the Bordetella and Haemophilus genera.5). Soluble haemagglutinins were prepared from Bord. Pertussis and Bord. parapertussis. They were reversibly inactivated by oxygen and all activity was rapidly lost on dialysis. They were destroyed by the proteolytic enzyme trypsin. An inhibitor to haemagglutination was found in cooked meat medium, and an inhibitory material, removable by treatment with neuraminidase, was found on ox erythrocytes. Most red cell species were agglutinated to the same titre.6). Two previously unknown pigments have been isolated from Bordetella species. A blue pigment, for which the name azurin is suggested, has been obtained from virulent strains of all three species. Azurin is a protein of low molecular weight, approximately 16,500, containing copper (0.156%). It has absorption maxima at 280 mμ and 625 mμ in the oxidised form, but the peak in the visible wavelengths disappears on reduction with cysteine or thioglycollate. Azurin is autoxidisable.A cytochrome of the c type has been isolated from Bord.pertussis and Bord. bronchiseptica. It has absorption maxima at 408 mµ in the oxidised form and at 416 mµ, 522 mμ. and 550 mp, in the reduced form. The method used for the purification of the bacterial cytochrome could also be applied to mammalian cytochrome c

Plasma ATP concentration and venous oxygen content in the forearm during dynamic handgrip exercise

Background It has been proposed that adenosine triphosphate (ATP) released from red blood cells (RBCs) may contribute to the tight coupling between blood flow and oxygen demand in contracting skeletal muscle. To determine whether ATP may contribute to the vasodilatory response to exercise in the forearm, we measured arterialised and venous plasma ATP concentration and venous oxygen content in 10 healthy young males at rest, and at 30 and 180 seconds during dynamic handgrip exercise at 45% of maximum voluntary contraction (MVC). Results Venous plasma ATP concentration was elevated above rest after 30 seconds of exercise (P < 0.05), and remained at this higher level 180 seconds into exercise (P < 0.05 versus rest). The increase in ATP was mirrored by a decrease in venous oxygen content. While there was no significant relationship between ATP concentration and venous oxygen content at 30 seconds of exercise, they were moderately and inversely correlated at 180 seconds of exercise (r = -0.651, P = 0.021). Arterial ATP concentration remained unchanged throughout exercise, resulting in an increase in the venous-arterial ATP difference. Conclusions Collectively these results indicate that ATP in the plasma originated from the muscle microcirculation, and are consistent with the notion that deoxygenation of the blood perfusing the muscle acts as a stimulus for ATP release. That ATP concentration was elevated just 30 seconds after the onset of exercise also suggests that ATP may be a contributing factor to the blood flow response in the transition from rest to steady state exercise

Medical educators' perspectives of teaching physical examinations using ultrasonography at the undergraduate level

Background: Ultrasonography is increasingly used for teaching physical examination in medical schools. This study seeks the opinions of educators as to which physical examinations would be most enhanced by the addition of ultrasonography. We also asked when ultrasound-aided physical examination teaching could have deleterious effects if used outside its intended scope. Methods: All of the educators from the University of Calgary Master Teacher Program were invited to complete a 22-item paper-based survey. Survey items were generated independently by two investigators, with input from an expert panel (N = 5). Results: Of the 36 educators, 27 (75%) completed the survey. Examinations identified to be potentially most useful included: measuring the size of the abdominal aorta, identifying the presence/absence of ascites, identifying the presence/absence of pleural effusions, and measuring the size of the bladder. Examinations thought to be potentially most harmful included: identifying the presence/absence of intrauterine pregnancy, measuring the size of the abdominal aorta, and identifying the presence/absence of pericardial effusion. Conclusions: Examinations that are potentially the most useful may also be potentially the most harmful. When initiating an ultrasound curriculum for physical examinations, educators should weigh the risks and benefits of examinations chosen.

Inclusion of KI67 significantly improves performance of the PREDICT prognostication and prediction model for early breast cancer.

BACKGROUND: PREDICT (http://www.predict.nhs.uk) is a prognostication and treatment benefit tool for early breast cancer (EBC). The aim of this study was to incorporate the prognostic effect of KI67 status in a new version (v3), and compare performance with the Predict model that includes HER2 status (v2). METHODS: The validation study was based on 1,726 patients with EBC treated in Nottingham between 1989 and 1998. KI67 positivity for PREDICT is defined as >10% of tumour cells staining positive. ROC curves were constructed for Predict models with (v3) and without (v2) KI67 input. Comparison was made using the method of DeLong. RESULTS: In 1274 ER+ patients the predicted number of events at 10 years increased from 196 for v2 to 204 for v3 compared to 221 observed. The area under the ROC curve (AUC) improved from 0.7611 to 0.7676 (p=0.005) in ER+ patients and from 0.7546 to 0.7595 (p=0.0008) in all 1726 patients (ER+ and ER-). CONCLUSION: Addition of KI67 to PREDICT has led to a statistically significant improvement in the model performance for ER+ patients and will aid clinical decision making in these patients. Further studies should determine whether other markers including gene expression profiling provide additional prognostic information to that provided by PREDICT.SEARCH was funded through a programme grant from Cancer Research UK (C490/A10124) and this work is supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge.This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/1471-2407-14-90

An updated PREDICT breast cancer prognostication and treatment benefit prediction model with independent validation

BACKGROUND PREDICT is a breast cancer prognostic and treatment benefit model implemented online. The overall fit of the model has been good in multiple independent case series, but PREDICT has been shown to underestimate breast cancer specific mortality in women diagnosed under the age of 40. Another limitation is the use of discrete categories for tumour size and node status resulting in 'step' changes in risk estimates on moving between categories. We have refitted the PREDICT prognostic model using the original cohort of cases from East Anglia with updated survival time in order to take into account age at diagnosis and to smooth out the survival function for tumour size and node status. METHODS Multivariable Cox regression models were used to fit separate models for ER negative and ER positive disease. Continuous variables were fitted using fractional polynomials and a smoothed baseline hazard was obtained by regressing the baseline cumulative hazard for each patients against time using fractional polynomials. The fit of the prognostic models were then tested in three independent data sets that had also been used to validate the original version of PREDICT. RESULTS In the model fitting data, after adjusting for other prognostic variables, there is an increase in risk of breast cancer specific mortality in younger and older patients with ER positive disease, with a substantial increase in risk for women diagnosed before the age of 35. In ER negative disease the risk increases slightly with age. The association between breast cancer specific mortality and both tumour size and number of positive nodes was non-linear with a more marked increase in risk with increasing size and increasing number of nodes in ER positive disease. The overall calibration and discrimination of the new version of PREDICT (v2) was good and comparable to that of the previous version in both model development and validation data sets. However, the calibration of v2 improved over v1 in patients diagnosed under the age of 40. CONCLUSIONS The PREDICT v2 is an improved prognostication and treatment benefit model compared with v1. The online version should continue to aid clinical decision making in women with early breast cancer

HMDB: the Human Metabolome Database

The Human Metabolome Database (HMDB) is currently the most complete and comprehensive curated collection of human metabolite and human metabolism data in the world. It contains records for more than 2180 endogenous metabolites with information gathered from thousands of books, journal articles and electronic databases. In addition to its comprehensive literature-derived data, the HMDB also contains an extensive collection of experimental metabolite concentration data compiled from hundreds of mass spectra (MS) and Nuclear Magnetic resonance (NMR) metabolomic analyses performed on urine, blood and cerebrospinal fluid samples. This is further supplemented with thousands of NMR and MS spectra collected on purified, reference metabolites. Each metabolite entry in the HMDB contains an average of 90 separate data fields including a comprehensive compound description, names and synonyms, structural information, physico-chemical data, reference NMR and MS spectra, biofluid concentrations, disease associations, pathway information, enzyme data, gene sequence data, SNP and mutation data as well as extensive links to images, references and other public databases. Extensive searching, relational querying and data browsing tools are also provided. The HMDB is designed to address the broad needs of biochemists, clinical chemists, physicians, medical geneticists, nutritionists and members of the metabolomics community. The HMDB is available at

The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups.

The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in ~40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, we identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4. Unsupervised analysis of paired DNA–RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the ‘CNA-devoid’ subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome

Shouldn't enantiomeric purity be included in the minimum information about a bioactive entity? Response from the MIABE group

[Reply to Letter