The treatment and prevention of chronic otorrhoea in the Northland health district.

The operation of a mobile ear clinic within the school medical service in Northland is described. The major justification for the use of a sophisticated unit lies in the opportunity which it affords for the education of children and adults on aural health. The higher costs of treatment may well be more than offset by the long-term benefits resulting from increased awareness and better understanding in our population on the causation of supporative otitis media.     

Diurnal cycle of emission of induced volatile terpenoids by herbivore-injured cotton plant

Cotton plants attacked by herbivorous insect pests emit relatively large amounts of characteristic volatile terpenoids that have been implicated in the attraction of natural enemies of the herbivores. However, the composition of the blend of volatile terpenes released by the plants varies remarkably throughout the photoperiod. Some components are emitted in at least 10-fold greater quantities during the photophase than during the scotophase, whereas others are released continuously, without conforming to a pattern, during the entire time that the plants are under herbivore attack. The diurnal pattern of emission of volatile terpenoids was determined by collecting and analyzing the volatile compounds emitted by cotton plants subjected to feeding damage by beet armyworm larvae in situ. The damage was allowed to proceed for 3 days, and volatile emission was monitored continuously. During early stages of damage high levels of lipoxygenase-derived volatile compounds [e.g., (Z)-3-hexenal, (Z)-3-hexenyl acetate] and several terpene hydrocarbons [e.g., alpha-pinene, caryophyllene] were emitted. As damage proceeded, high levels of other terpenes, all acyclic [e.g., (E)-beta-ocimene, (E)-beta-farnesene], were emitted in a pronounced diurnal fashion; maximal emissions occurred in the afternoon. These acyclic terpenes followed this diurnal pattern of emission, even after removal of the caterpillars, although emission was in somewhat smaller amounts. In contrast, the emission of cyclic terpenes almost ceased after the caterpillars were removed.     

Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation

Although circulating memory T cells provide enhanced protection against pathogen challenge, they often fail to do so if infection is localized to peripheral or extralymphoid compartments. In those cases, it is T cells already resident at the site of virus challenge that offer superior immune protection. These tissue-resident memory T (T(RM)) cells are identified by their expression of the α-chain from the integrin α(E)(CD103)β(7), and can exist in disequilibrium with the blood, remaining in the local environment long after peripheral infections subside. In this study, we demonstrate that long-lived intraepithelial CD103(+)CD8(+) T(RM) cells can be generated in the absence of in situ antigen recognition. Local inflammation in skin and mucosa alone resulted in enhanced recruitment of effector populations and their conversion to the T(RM) phenotype. The CD8(+) T(RM) cells lodged in these barrier tissues provided long-lived protection against local challenge with herpes simplex virus in skin and vagina challenge models, and were clearly superior to the circulating memory T-cell cohort. The results demonstrate that peripheral T(RM) cells can be generated and survive in the absence of local antigen presentation and provide a powerful means of achieving immune protection against peripheral infection.     

Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense

A coding polymorphism (Thr300Ala) in the essential autophagy gene, autophagy related 16-like 1 (ATG16L1), confers increased risk for the development of Crohn disease, although the mechanisms by which single disease-associated polymorphisms contribute to pathogenesis have been difficult to dissect given that environmental factors likely influence disease initiation in these patients. Here we introduce a knock-in mouse model expressing the Atg16L1 T300A variant. Consistent with the human polymorphism, T300A knock-in mice do not develop spontaneous intestinal inflammation, but exhibit morphological defects in Paneth and goblet cells. Selective autophagy is reduced in multiple cell types from T300A knock-in mice compared with WT mice. The T300A polymorphism significantly increases caspase 3- and caspase 7-mediated cleavage of Atg16L1, resulting in lower levels of full-length Atg16Ll T300A protein. Moreover, Atg16L1 T300A is associated with decreased antibacterial autophagy and increased IL-1β production in primary cells and in vivo. Quantitative proteomics for protein interactors of ATG16L1 identified previously unknown nonoverlapping sets of proteins involved in ATG16L1-dependent antibacterial autophagy or IL-1β production. These findings demonstrate how the T300A polymorphism leads to cell type- and pathway-specific disruptions of selective autophagy and suggest a mechanism by which this polymorphism contributes to disease.Human genetic studies offer an unbiased approach to identify genes and DNA variants underlying susceptibility to complex diseases. Although this approach has been successful at identifying more than 160 loci associated with Crohn disease (CD), a chronic inflammatory condition affecting the gastrointestinal tract (1, 2), ascribing function to specific risk variants has been difficult. Individuals who harbor a common threonine to alanine coding variant at position 300 in autophagy related 16-like 1 (ATG16L1) (T300A) are at increased risk of developing CD compared with individuals who possess a threonine at this position (T300T) (3, 4). The T300A variant lies within a structurally unclassified region of ATG16L1, making it challenging to identify the effect of this polymorphism.ATG16L1 is a component of the core autophagy machinery that plays a critical role in immunity and inflammation. Initial studies investigating ATG16L1 used hypomorphic Atg16L1 mouse models, which show Paneth cell abnormalities relevant to CD such as abnormal mitochondria, irregular patterns of granule morphology and lysozyme distribution, and increased expression of genes implicated in inflammation (5, 6). Although these studies have been useful in highlighting the important role of autophagy proteins in intestinal cells such as Paneth cells and goblet cells, the precise mechanisms by which ATG16L1 T300A influences pathogenesis remain unclear (7–10).Previous studies have demonstrated that Atg16L1-deficient macrophages produce elevated levels of active caspase 1 and secrete higher levels of the cytokines IL-1β and IL-18 upon stimulation with the endotoxin LPS (5). Consistent with these results, peripheral blood mononuclear cells from patients homozygous for ATG16L1 T300A produce increased levels of IL-1β upon muramyl dipeptide (MDP) stimulation compared with cells expressing T300T (11). Given the diverse roles of ATG16L1 and the canonical autophagy machinery in various cell types, investigating the effects of the T300A polymorphism on intestinal epithelial cells and gut-resident immune cells is critical to understanding the role of this polymorphism in CD pathogenesis.A number of CD-associated genes, including ATG16L1, NOD2 (nucleotide-binding oligomerization domain containing 2), and IRGM, have been associated with impaired intracellular bacterial handling. Previous studies have revealed that the ATG16L1–NOD2 axis is important for maintaining intracellular mucosal homeostasis and that the T300A polymorphism specifically disrupts antibacterial autophagy (12–14). Other studies have reported no association between the T300A polymorphism and antibacterial autophagy in reconstituted Atg16L1-deficient mouse embryonic fibroblasts (MEFs), suggesting that the T300A polymorphism confers cell type-specific effects (15).Here we generated Atg16L1 T300A knock-in mice to examine the effects of the T300A polymorphism on various autophagy-dependent pathways. We show that Atg16L1 T300A is associated with impaired activation of autophagy against intracellular bacteria and increased IL-1β secretion. We identify and analyze previously unidentified ATG16L1 proteomic interactors to reveal ATG16L1-dependent, pathway-specific interactions.     

Communication and Empowerment: A Place for Rich and Multiple Media?

Background Project @pple (Access & Participation for People with intellectual disability in Learning Environments) 1 was about exploring the terms on which young people with intellectual disability access and participate with e‐Learning and the Web. The current study is one of a number of related studies. It explores the culture of information and communication technology (ICT) and the potential to support communication and empowerment. Materials and Methods Semi‐structured interviews were carried out with 20 young people with intellectual disability. The interviews involved a low‐technology, augmentative communication method called Talking Mats ( Murphy & Cameron 2002 ). Findings Information and communication technology and rich and multiple media featured in the participants’ narratives and contributed to self‐concept and inclusive communication. Positive value was attributed to ICT options by many, although some difficulties were expressed with regard to operational aspects of the technology. Conclusions The lives of young people with intellectual disability provide a fertile culture for developments in this area, offering some new opportunities for communication and empowerment.     

Embedding instruction in practice: contingency and collaboration during surgical training

In this paper we address the ways in which surgeons, in collaboration with other members of the surgical team, create occasions for demonstration and instruction within the highly complex and demanding tasks of a surgical operation. Drawing on video recordings of surgical operations, augmented by field studies, we examine how particular phenomena and procedures are made accessible and intelligible to trainees and the ways in which brief episodes of insight and instruction enable complex procedures to be followed and understood. We consider the ways in which demonstration and instruction are achieved, whilst preserving the integrity of medical practice, and explore how trainees are provided with the opportunity to witness, and learn from, the contingent deployment of formal procedures in particular cases. We conclude by considering our observations in the light of recent discussions of practice and situated learning in healthcare training.     

Early cannabis use and DSM‐IV nicotine dependence: a twin study

Background Evidence suggests that cannabis users are at increased risk for cigarette smoking—if so, this may potentially be the single most alarming public health challenge posed by cannabis use. We examine whether cannabis use prior to age 17 years is associated with an increased likelihood of DSM‐IV nicotine dependence and the extent to which genetic and environmental factors contribute to this association. Methods A population‐based cohort of 24–36‐year‐old Australian male and female twins (n = 6257, 286 and 229 discordant pairs) was used. The co‐twin–control method, with twin pairs discordant for early cannabis use, was used to examine whether, after controlling for genetic and familial environmental background, there was evidence for an additional influence of early cannabis use on DSM‐IV nicotine dependence. Bivariate genetic models were fitted to the full data set to quantify the genetic correlation between early cannabis use and nicotine dependence. Results The early cannabis‐using twin was about twice as likely to report nicotine dependence, when compared to their co‐twin who had experimented with cigarettes but had never used cannabis. Even when analyses were restricted to cannabis users, earlier age cannabis use onset conferred greater risk (1.7) for nicotine dependence than did later onset. This association was governed largely by common genetic liability to early cannabis use and nicotine dependence, as demonstrated by genetic correlations of 0.41–0.52. Conclusions Early‐onset cannabis users are at increased risk for nicotine dependence, but this risk is attributable largely to common genetic vulnerability. There is no evidence for a causal relationship between cannabis use and nicotine dependence.     

Bariatric Support Line: A Prospective Study of Support Line Activity

In this prospective study, we examine the workload of the North London Obesity Surgery Service Bariatric telephone support line (BTSL) and its effects on service provision. Over a 3-month period (June to August 2008), a prospective record was kept of all calls, who they were from, whether the patient was presurgery or postsurgery, the type of procedure planned or undertaken, the nature of the enquiry, and the time taken to answer the query. Seventy-five (72%) calls were related to patients who were postsurgery and 29 (28%) presurgery. Patients scheduled for or having undergone Roux-en-Y gastric bypass accounted for 46 (44%) calls; 24 (23%) were preprocedure and 22 (21%) postprocedure. Patients scheduled for or having undergone gastric banding accounted for 56 (54%) calls; five (0.5%) were preprocedure and 51 (49%) postprocedure. Patients undergoing sleeve gastrectomy accounted for two (<1%) calls. Both calls were postprocedure. The reason for the support line enquiry was psychological support in 15 (14%) patients, questions postsurgery in 26 (25%), general enquiries in 27 (26%), and clinical enquiries in 36 (36%). This study of the BTSL has allowed us to identify areas of need within our bariatric population and improve the service we deliver. The changes we have made should lead to a better use of the team’s time, greater patient compliance, and satisfaction as well as reduced complaints and litigation.     

2,2',3,3',6,6'-hexachlorobiphenyl hydroxylation by active site mutants of cytochrome P450 2B1 and 2B11.

The structural basis of species differences in cytochrome P450 2B-mediated hydroxylation of 2,2',3,3',6,6'-hexachlorobiphenyl (236HCB) was evaluated by using 14 site-directed mutants of cytochrome P450 2B1 and three point mutants of 2B11 expressed in Escherichia coli. To facilitate metabolite identification, seven possible products, including three hydroxylated and four dihydroxylated hexachlorobiphenyls, were synthesized by direct functionalization of precursors and Ullmann and crossed Ullmann reactions. HPLC and GC/MS analysis and comparison with authentic standards revealed that 2B1, 2B11, and all their mutants produced 4, 5-dihydroxy-236HCB and 5-hydroxy-236HCB, while 2B11 L363V and 2B1 I114V mutants also catalyzed hydroxylation at the 4-position. The amount of products formed by 2B1 mutants I114V, F206L, L209A, T302S, V363A, V363L, V367A, I477A, I477L, G478S, I480A, and I480L was smaller than that of the wild type. I477V exhibited unaltered 236HCB metabolism, and I480V produced twice as much dihydroxy product as the wild type. For 2B11, substitution of Val-114 or Asp-290 with Ile decreased the product yields. Replacement of Leu-363 with Val dramatically altered the profile of 236HCB metabolites. In addition to an increase in the overall level of hydroxylation, the mutant mainly catalyzed hydroxylation at the 4-position. Incubation of P450 2B1 with 5-hydroxy-236HCB produced 4,5-dihydroxy-236HCB, which indicates that 4,5-dihydroxy-236HCB may be formed by a direct hydroxylation of 5-hydroxy-236HCB. The findings from this study demonstrate the importance of residues 114, 206, 209, 302, 363, 367, 477, 478, and 480 in 2B1 and 114, 290, and 363 in 2B11 for 236HCB metabolism.