Bronchiectasis is associated with delayed diagnosis and adverse outcomes in the New Zealand Common Variable Immunodeficiency Disorders cohort study.

Common variable immunodeficiency disorders (CVID) are multi-system disorders where target organ damage is mediated by infective, autoimmune and inflammatory processes. Bronchiectasis is probably the most common disabling complication of CVID. The risk factors for bronchiectasis in CVID patients are incompletely understood. The New Zealand CVID study (NZCS) is a nationwide longitudinal observational study of adults, which commenced in 2006. In this analysis, the prevalence and risk factors for bronchiectasis were examined in the NZCS. After informed consent, clinical and demographic data were obtained with an interviewer-assisted questionnaire. Linked electronic clinical records and laboratory results were also reviewed. Statistical methods were applied to determine if variables such as early-onset disease, delay in diagnosis and increased numbers of infections were associated with greater risk of bronchiectasis. One hundred and seven adult patients with a diagnosis of CVID are currently enrolled in the NZCS, comprising approximately 70% of patients known to have CVID in New Zealand. Fifty patients (46·7%) had radiologically proven bronchiectasis. This study has shown that patients with compared to those without bronchiectasis have an increased mortality at a younger age. CVID patients with bronchiectasis had a greater number of severe infections consequent to early-onset disease and delayed diagnosis. Indigenous Maori have a high prevalence of CVID and a much greater burden of bronchiectasis compared to New Zealand Europeans. Diagnostic latency has not improved during the study period. Exposure to large numbers of infections because of early-onset disease and delayed diagnosis was associated with an increased risk of bronchiectasis. Earlier diagnosis and treatment of CVID may reduce the risk of bronchiectasis and premature death in some patients.

The C. elegans glutamate receptor subunit NMR-1 is required for slow NMDA-activated currents that regulate reversal frequency during locomotion.

The N-methyl-D-aspartate (NMDA) subtype of glutamate receptor is important for synaptic plasticity and nervous system development and function. We have used genetic and electrophysiological methods to demonstrate that NMR-1, a Caenorhabditis elegans NMDA-type ionotropic glutamate receptor subunit, plays a role in the control of movement and foraging behavior. nmr-1 mutants show a lower probability of switching from forward to backward movement and a reduced ability to navigate a complex environment. Electrical recordings from the interneuron AVA show that NMDA-dependent currents are selectively disrupted in nmr-1 mutants. We also show that a slowly desensitizing variant of a non-NMDA receptor can rescue the nmr-1 mutant phenotype. We propose that NMDA receptors in C. elegans provide long-lived currents that modulate the frequency of movement reversals during foraging behavior.

Analysis of the capsule biosynthetic locus of Mannheimia (Pasteurella) haemolytica A1 and proposal of a nomenclature system.

A 16-kbp DNA region that contains genes involved in the biosynthesis of the capsule of Mannheimia (Pasteurella) haemolytica A1 has been characterized. The gene cluster can be divided into three regions like those of the typical group II capsule biosynthetic clusters in gram-negative bacteria. Region 1 contains four genes (wzt, wzm, wzf, and wza) which code for an ATP-binding cassette transport apparatus for the secretion of the capsule materials across the membranes. The M. haemolytica A1 wzt and wzm genes were able to complement Escherichia coli kpsT and kpsM mutants, respectively. Further, the ATP binding activity of Wzt was demonstrated by its affinity for ATP-agarose, and the lipoprotein nature of Wza was supported by [(3)H]palmitate labeling. Region 2 contains six genes; four genes (orf1/2/3/4) code for unique functions for which no homologues have been identified to date. The remaining two genes (nmaA and nmaB) code for homologues of UDP-N-acetylglucosamine-2-epimerase and UDP-N-acetylmannosamine dehydrogenase, respectively. These two proteins are highly homologous to the E. coli WecB and WecC proteins (formerly known as RffE and RffD), which are involved in the biosynthesis of enterobacterial common antigen (ECA). Complementation of an E. coli rffE/D mutant with the M. haemolytica A1 nmaA/B genes resulted in the restoration of ECA biosynthesis. Region 3 contains two genes (wbrA and wbrB) which are suggested to be involved in the phospholipid modification of capsular materials.

Electrophysiological evidence for two transduction pathways within a bitter-sensitive taste receptor.

Among the sapid stimuli, those that elicit bitter taste are the most abundant and structurally diverse. To accommodate this diversity, animals are thought to use multiple bitter transduction pathways. We examined the role of individual taste receptor cells (TRCs) in this transduction process by focusing on one of the taste organs, or chemosensilla, of a caterpillar (Manduca sexta). This chemosensillum (the lateral styloconicum) contains four functionally distinct TRCs: the salt, sugar, inositol, and deterrent TRCs, which are known to respond strongly to, in respective order, salts, sugars, inositol, and compounds humans describe as bitter. Using an extracellular recording technique, we tested three hypotheses for how a structurally diverse array of bitter compounds (salicin, caffeine, and aristolochic acid) could excite the same chemosensillum: several TRCs within the lateral styloconica respond to the bitter compounds; only the deterrent TRC responds to the bitter compounds, through a single transduction pathway; and only the deterrent TRC responds to the bitter compounds, but through multiple transduction pathways. To discriminate among these hypotheses, we tested five predictions. The first addressed how many TRCs within the lateral styloconica responded to the bitter compounds. Subsequent predictions were based on the results of the test of the first prediction and assumed that only the deterrent TRC responded to these compounds. These latter predictions addressed whether the bitter compounds acted through one or multiple transduction pathways. We obtained evidence consistent with the third hypothesis: only the deterrent TRC responded to the bitter compounds; the temporal patterns of firing and concentration-response curves elicited by caffeine and salicin were similar to each other, but different from those elicited by aristolochic acid; the patterns of sensory adaptation and disadaptation elicited by caffeine and salicin were similar to each another, but different from those elicited by aristolochic acid; reciprocal cross-adaptation occurred between caffeine and salicin, but not between aristolochic acid and caffeine or aristolochic acid and salicin; and the responsiveness of individual deterrent TRCs to caffeine and salicin correlated significantly, whereas that to aristolochic acid and caffeine or aristolochic acid and salicin did not. Taken together, these results indicate that the deterrent TRC contains at least two excitatory transduction pathways: one responds to caffeine and salicin and the other to aristolochic acid. To our knowledge, this is the first direct support for the existence of two bitter transduction pathways within a single TRC.