David J M Wright

Variable major lipoprotein is a principal TNF-inducing factor of louse-borne relapsing fever.

Massive release of tumor necrosis factor is responsible for the potentially fatal Jarisch-Herxheimer reaction that follows antibiotic treatment of relapsing fever due to Borrelia recurrentis. We have undertaken the quantitative purification of the components of B. recurrentis that stimulate human monocytes to produce tumor necrosis factor. We show that the predominant factor inducing tumor necrosis factor is a variable lipoprotein homologous to the variable major protein of B. hermsii. We found antibodies to different forms of variable major protein in two patients with louse-borne relapsing fever. The three purified variable major proteins studied here differ in their ability to induce tumor necrosis factor production, which may partly explain the variable clinical severity of borrelial infection. These results may be of considerable relevance for the pathogenesis of Lyme disease and other forms of human borreliosis.

Selection of in vitro mutants of pyrazinamide-resistant Mycobacterium tuberculosis

Mutations within the pncA gene coding for pyrazinamidase of Mycobacterium tuberculosis can cause pyrazinamide (PZA) resistance. The effect of drug concentrations on PZA resistance in a clinical isolate of M. tuberculosis was studied in vitro. Serial passage at gradually increased concentrations of PZA from 200 to 500 microg/ml was performed using BACTEC radiometric method. Thirteen in vitro-selected variant strains were assembled and sequence analysis showed that 12 of the 13 variants had a novel single point mutation within the pncA gene by deletion at nucleotide 381 (G), codon 127. This lead to a frameshift that affected the function of the pyrazinamidase resulting in PZA resistance regardless of different PZA concentrations used. One variant had a silent mutation at nucleotide 6 (G-->A) and remains PZA sensitive. We conclude that the mutation location found is an important position for full resistance, at least in this strain. The lack of further mutations even after exposure to higher PZA concentrations implies a critical value for development of resistance-a level exceeded in tissues in clinical treatment regimes.

Self-Reported Allergy-Related Symptoms and Psychological Morbidity in Primary Care

Objective: To examine the relationship between allergy-related symptoms, food intolerance and psychological distress in primary care. Methods: Two thousand three hundred and thirty two adults in five General Practices in the South of England completed questionnaires regarding allergy and psychological health. Results: There was a weak link between allergy-related symptoms and psychological symptoms, but no association was demonstrated between a history of diagnosed or treated asthma, eczema or hay fever and psychological morbidity. Cases of food intolerance had lower levels of psychological distress than expected compared to hospital samples. Current, but not past wheezing and eczema, was associated with an excess of life stresses in the previous six months. Conclusions: The association between psychological distress and the label of food allergy/intolerance found in specialist care does not extend to primary care.

Neuropharmacological agents modifying endotoxin-induced changes in mice.

A variety of neuropharmacological agents were tested to elucidate how chlorpromazine influenced an endotoxin-induced reaction. The results obtained, particularly with beta-adrenergic blocking agents, reserpine and fusaric acid, suggested that the primary locus of chlorpromazines action was mediated by peripheral beta-adrenergic receptor blockade. Such a locus is compatible with the low doses of propranolol which suppress the reaction, and with successful treatment of shock with dopamine.

Dysentery in World War 1: Shigella a century on

www.thelancet.com Vol 384 November 8, 2014 1651 induction and the subsequent combination with a proliferation signal inhibitor could potentially generate protolerogenic immunological eff ects (like so-called prope, or near, tolerance and upregulated T regulatory cells). Prevention of cumulative alloimmunological injury to the graft from subclinical rejection and acute and chronic (donor-specifi c) antibody-mediated rejection could potentially translate into measurably better graft function and survival after 5 years. Alemtuzumab with sirolimus could reduce nephrotoxicity and cardiovascular and metabolic adverse eff ects through avoidance of calcineurin inhibitors. However, given the complexity of cardiovascular morbidity and mortality after renal transplantation, improvement in a few laboratory results in a clinical trial is a long way from achievement of improvements in the disease course over 5 years. Ideally, these goals would all be achieved without excess malignancies and opportunistic infections. Irrespective of the current and anticipated long-term results of the 3C Study, investigators will question the cause of the results. This will be a diffi cult question to answer because the 3C investigators changed all parts of the standard of care immunosuppressive regimen (the type of induction drug, the dose of calcineurin inhibitor and mycophenolate, and even the use of corticosteroids) rather than one element only. 6 months later, they changed the regimen again. Therefore, the 3C Study will not only address its own predefi ned hypotheses, but will also represent a test case for what type of trials in clinical transplantation are needed to regain some of the academic vigour and pharmaceutical impetus towards development of new pipelines for novel immunosuppressive drugs. Dirk R J Kuypers Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven B-3000, Belgium dirk.kuypers@uzleuven.be

An assessment of a multiplex PCR assay for differentiating clinically important mycobacteria based on pncA gene variation.

The pncA genes in mycobacteria are responsible for the production of pyrazinamidase (PZase). In Mycobacterium tuberculosis, PZase hydrolyses pyrazinamide (PZA) to pyrazonic acid, a compound that possesses bactericidal activity against tubercle bacilli. Nucleotide sequences of pncA genes found within mycobacteria where aligned in an effort to ascertain the significance of any variability in sequence. Three sets of primers (one degenerate and five consensus sequences) were designed and employed in a multiplex PCR assay to amplify the pncA region in seven clinically common mycobacteria. The banding patterns generated from each species in conjunction with PZase activity tests demonstrated that the mycobacterial species examined could be clearly identified and differentiated from one another. Although not yet tested with clinical isolates, the combination of these two assays has provided a promising discriminatory tool for the identification of commonly encountered clinical mycobacteria species.

Book Review: Monoclonal and Anti-Idiotypic Antibodies: Probes for Receptor Structure and FunctionMonoclonal and Anti-idiotypic Antibodies: Probes for Receptor Structure and Function (Receptor Biochemistry and Methodology, vol 4) VenterJ C (ed) pp 194£35 ISBN 0-8451-3703-4New York: Alan R Liss1984

who wish to have some insight into medical terminology, its structure and how this relates to diseases and patients. Doctors who have an interest in information and want to become aware of the issues in medical information-processing might also find it helpful. The bibliography of 143 papers, if used selectively, will also be useful. This book should not be taken seriously, but can be used to bring out current issues in the interface between information and medicine.