Bacteria lacking a multidrug pump: a sensitive tool for drug discovery

Microorganisms express multidrug resistance pumps (MDRs) that can confound antibiotic discovery. We propose the use of mutants deficient in MDRs to overcome this problem. Sensitivity to quinolones and to amphipathic cations (norfloxacin, benzalkonium chloride, cetrimide, pentamidine, etc.) was increased 5- to 30-fold in a Staphylococcus aureus mutant with a disrupted chromosomal copy of the NorA MDR. NorA was required both for increased sensitivity to drugs in the presence of an MDR inhibitor and for increased rate of cation efflux. This requirement suggests that NorA is the major MDR protecting S. aureus from the antimicrobials studied. A 15- to 60-fold increase in sensitivity to antimicrobials also was observed in wild-type cells at an alkaline pH that favors accumulation of cations and weak bases. This effect was synergistic with a norA mutation, resulting in an increase up to 1,000-fold in sensitivity to antimicrobials. The usefulness of applying MDR mutants for natural product screening was demonstrated further by increased sensitivity of the norA- strain to plant alkaloid antimicrobials, which might be natural MDR substrates.     

Statistical methods in psychiatric genetics

Most psychiatric disorders are determined by the complex interplay between genetic and environmental factors. Aetiological research into these complex disorders raises many different questions which require a variety of statistical methods. These include survival analysis for the estimation of morbid risk, structural equation models for the partitioning of phenotypic variances and covariances into genetic and other components, complex segregation analysis to detect loci of major effect, and linkage and association analysis for the localisation and identification of susceptibility genes. Future developments in psychiatric genetics will involve the integration of genetic and epidemiological statistics in order to study the interplay between genetic and environmental factors in the complex pathways which lead to mental disorders.     

William James and emotion: is a century of fame worth a century of misunderstanding?

During his lifetime William James's complex ideas about emotion were oversimplified to the point of caricature, and for the next half century scientific research on emotion was driven by the oversimplified version--by the idea that emotions are merely the sensation of bodily changes. In fact, the interpretation of the stimulus was an essential feature of James's ideas, but one that seemed so obvious that it did not require explanation. Three damaging scientific consequences of the mischaracterization of James's views were (a) the nearly exclusive focus on bodily process, (b) the reification of emotions as entities rather than processes, and (c) the linear thinking produced by the concern with the sequence of affect, interpretation, and bodily response.     

Subcutaneous nodules as a manifestation of onchocerciasis. A rare condition in the United States

Although infection with tissue nematodes is a significant health problem in many parts of the world, such cases are unusual in the continental United States. This report describes a case of Onchocerca volvulus infection, acquired by a 38-year-old female missionary in northern Brazil, that manifested as subcutaneous nodules in the groin and flank two years after the patient's return to the United States. A year previously, a wrong diagnosis of Wuchereria bancrofti was made at biopsy. At that time, treatment with diethylcarbamazine citrate had to be discontinued because of intense pruritus. Examination of a wet saline impression smear of a new biopsy specimen showed the adult worms to have regularly arranged outer annular ridges, which, together with the pruritus after treatment with diethylcarbamazine (a positive Mazzotti test), led to the diagnosis of onchocerciasis. Retreatment with diethylcarbamazine again caused pruritus, but this was tolerated as were subsequent treatments.     

Seasonal variations in urinary crystals

Individual urine samples from normal subjects and stone-formers with idiopathic hypercalciuria have been examined for crystals both qualitatively and quantitatively at 37 degrees C. The group as a whole showed a rise in incidence of urinary crystals in the summer months of June to August inclusive. This rise was seen most clearly in overnight urines, collected on rising in the morning, and the patients appeared to be at risk overnight during the summer. In the untreated patients the summer rise in incidence of phosphate crystals was quite dramatic but was only small in the cellulose phosphate treated group, who showed a rather constant and raised incidence of oxalate crystals right through the year. Seasonal crystal incidence has been compared with seasonal changes in urinary composition. The rise in crystal incidence during the summer was associated with increased creatinine concentration in the same urine samples and with increased oxalate concentration in 24-hour urine collections.     

Preclinical evaluation of a novel group B meningococcal conjugate vaccine that elicits bactericidal activity in both mice and nonhuman primates

Group B meningococcal (GBM) conjugate vaccines were prepared using chemically modified N-propionylated polysialic acid, from Escherichia coli K1 polysaccharide capsule, coupled by reductive amination to tetanus toxoid and purified recombinant GBM porin (rPorB). All conjugates elicited high antibody levels in mice with good booster responses. However, only rPorB conjugates elicited bactericidal activity specific against a broad spectrum of five different GBM serotypes. Bactericial activity was completely inhibited by free N-propionylated polysaccharide. In baboons and rhesus monkeys, rPorB conjugates elicited high antibody titers, with IgG booster responses 9- to 15-fold higher than primary responses. Bactericial activity increased 19- to 39-fold over preimmune values, using rabbit complement; increased bactericial activity was also confirmed with human and monkey complement. IgG cross-reactivity for unmodified N-acetyl polysaccharide was <5% for 79% of mice and <10% for 80% of primates. These studies strongly suggest that the N-propionylated polysialic acid-rPorB conjugate is an excellent vaccine candidate for human use.