Inactivation of human immunodeficiency virus (HIV)-1 envelope-specific CD8+ cytotoxic T lymphocytes by free antigenic peptide: A self-veto mechanism?

Free peptide has been found to inhibit cytotoxic T lymphocyte (CTL) activity, and veto cells bearing peptide-major histocompatibility complex (MHC) complexes have been found to inactivate CTL, but the two phenomenon have not been connected. Here we show that a common mechanism may apply to both CD8+ CTL lines or clones specific for a determinant of the human immunodeficiency virus (HIV)-1 IIIB envelope protein gp160, P18IIIB, are inhibited by as little as 10 min exposure to the minimal 10-mer peptide, 1- 10, within P18IIIB, free in solution, in contrast to peptide already bound to antigen-presenting cells (APC), which does not inhibit. Several lines of evidence suggest that the peptide must be processed and presented by H-2D(d) on the CTL itself to the specific T cell receptor (TCR) to be inhibitory. The inhibition was not killing, in that CTL, did not kill 51Cr-labeled sister CTL in the presence of free peptide, and in missing experiments with CTL lines of different specificities restricted by the same MHC molecule, D(d), the presence of free peptide recognized by one CTL line did not inhibit the activity of the other CTL, line that could present the peptide. Also, partial recovery of activity could be elicited by restimulation with cell-bound peptide, supporting the conclusion that neither fratricide nor suicide (apoptosis) was involved. The classic veto phenomenon was ruled out by failure of peptide-bearing CTL to inactivate others. Using pairs of CTL lines of differing specificity but similar MHC restriction, each pulsed with the peptide for which the other is specific, we showed that the minimal requirement is simultaneous engagement of the TCR and class I MHC molecules of the same cell. This could occur in single cells or pairs of cells presenting peptide to each other. Thus, mechanistically the inhibition is analogous to veto, and might be called self-veto. As a clue to a possible mechanism, we found that free 1-10 peptide induced apparent downregulation of expression of specific TCR as well as interleukin 2 receptor, CD69, lymphocyte function-associated antigen 1, and CD8. This self-veto effect also has implication for in vivo immunization and mechanisms of viral escape from CTL immunity

Post-treatment follow-up study of abdominal cystic echinococcosis in Tibetan communities of northwest Sichuan Province, China

Background: Human cystic echinococcosis (CE), caused by the larval stage of Echinococcus granulosus, with the liver as the most frequently affected organ, is known to be highly endemic in Tibetan communities of northwest Sichuan Province. Antiparasitic treatment with albendazole remains the primary choice for the great majority of patients in this resource-poor remote area, though surgery is the most common approach for CE therapy that has the potential to remove cysts and lead to complete cure. The current prospective study aimed to assess the effectiveness of community based use of cyclic albendazole treatment in Tibetan CE cases, and concurrently monitor the changes of serum specific antibody levels during treatment. Methodology/Principal Findings: Ultrasonography was applied for diagnosis and follow-up of CE cases after cyclic albendazole treatment in Tibetan communities of Sichuan Province during 2006 to 2008, and serum specific IgG antibody levels against Echinococcus granulosus recombinant antigen B in ELISA was concurrently monitored in these cases. A total of 196 CE cases were identified by ultrasound, of which 37 (18.9%) showed evidence of spontaneous healing/involution of hepatic cyst(s) with CE4 or CE5 presentations. Of 49 enrolled CE cases for treatment follow-up, 32.7% (16) were considered to be cured based on B-ultrasound after 6 months to 30 months regular albendazole treatment, 49.0% (24) were improved, 14.3% (7) remained unchanged, and 4.1% (2) became aggravated. In general, patients with CE2 type cysts (daughter cysts present) needed a longer treatment course for cure (26.4 months), compared to cases with CE1 (univesicular cysts) (20.4 months) or CE3 type (detached cyst membrane or partial degeneration of daughter cysts) (9 months). In addition, the curative duration was longer in patients with large (.10 cm) cysts (22.3 months), compared to cases with medium (5– 10 cm) cysts (17.3 months) or patients with small (,5 cm) cysts (6 months). At diagnosis, seven (53.8%) of 13 cases with CE1 type cysts without any previous intervention showed negative specific IgG antibody response to E. granulosus recombinant antigen B (rAgB). However, following 3 months to 18 months albendazole therapy, six of these 7 initially seronegative CE1 cases sero-converted to be specific IgG antibody positive, and concurrently ultrasound scan showed that cysts changed to CE3a from CE1 type in all the six CE cases. Two major profiles of serum specific IgG antibody dynamics during albendazole treatment were apparent in CE cases: (i) presenting as initial elevation followed by subsequent decline, or (ii) a persistent decline. Despite a decline, however, specific antibody levels remained positive in most improved or cured CE cases. Conclusions: This was the first attempt to follow up community-screened cystic echinococcosis patients after albendazole therapy using ultrasonography and serology in an endemic Tibetan region. Cyclic albendazole treatment proved to be effective in the great majority of CE cases in this resource-poor area, but periodic abdominal ultrasound examination was necessary to guide appropriate treatment. Oral albendazole for over 18 months was more likely to result in CE cure. Poor drug compliance resulted in less good outcomes. Serology with recombinant antigen B could provide additional limited information about the effectiveness of albendazole in CE cases. Post-treatment positive specific IgG antibody seroconversion, in initially seronegative, CE1 patients was considered a good indication for positive therapeutic efficacy of albendazole

Comparative indicators for cancer network management in England: Availability, characteristics and presentation

BACKGROUND: In 2000, the national cancer plan for England created 34 cancer networks, new organisational structures to coordinate services across populations varying between a half and three million people. We investigated the availability of data sets reflecting measures of structure, process and outcome that could be used to support network management. METHODS: We investigated the properties of national data sets relating to four common cancers - breast, colorectal, lung and prostate. We reviewed the availability and completeness of these data sets, identified leading items within each set and put them into tables of the 34 cancer networks. We also investigated methods of presentation. RESULTS: The Acute Hospitals Portfolio and the Cancer Standards Peer Review recorded structural characteristics at hospital and cancer service level. Process measures included Hospital Episode Statistics, recording admissions, and Hospital Waiting-List data. Patient outcome measures included the National Survey of Patient Satisfaction for cancer, and cancer survival, drawn from cancer registration. Data were drawn together to provide an exemplar indicator set a single network, and methods of graphical presentation were considered. CONCLUSION: While not as yet used together in practice, comparative indicators are available within the National Health Service in England for use in performance assessment by cancer networks

Understanding organisational development, sustainability, and diffusion of innovations within hospitals participating in a multilevel quality collaborative

<p>Abstract</p> <p>Background</p> <p>Between 2004 and 2008, 24 Dutch hospitals participated in a two-year multilevel quality collaborative (MQC) comprised of (a) a leadership programme for hospital executives, (b) six quality-improvement collaboratives (QICs) for healthcare professionals and other staff, and (c) an internal programme organisation to help senior management monitor and coordinate team progress. The MQC aimed to stimulate the development of quality-management systems and the spread of methods to improve patient safety and logistics. The objective of this study is to describe how the first group of eight MQC hospitals sustained and disseminated improvements made and the quality methods used.</p> <p>Methods</p> <p>The approach followed by the hospitals was described using interview and questionnaire data gathered from eight programme coordinators.</p> <p>Results</p> <p>MQC hospitals followed a systematic strategy of diffusion and sustainability. Hospital quality-management systems are further developed according to a model linking plan-do-study-act cycles at the unit and hospital level. The model involves quality norms based on realised successes, performance agreements with unit heads, organisational support, monitoring, and quarterly accountability reports.</p> <p>Conclusions</p> <p>It is concluded from this study that the MQC contributed to organisational development and dissemination within participating hospitals. Organisational learning effects were demonstrated. System changes affect the context factors in the theory of organisational readiness: organisational culture, policies and procedures, past experience, organisational resources, and organisational structure. Programme coordinator responses indicate that these factors are utilised to manage spread and sustainability. Further research is needed to assess long-term effects.</p

Residual stress in laser cladded rail

To improve the fatigue life of components subject to loads with high surface strain gradients, it is possible to coat them with an alloy of higher durability. The present study focuses on the effect of cladding high value track components, made of a standard rail steel UIC 900A/grade 260, with a layer of a premium martensitic stainless steel to reduce wear and fatigue. The laser cladding process inevitably generates residual stresses in the clad and parent metal, which could be detrimental to the integrity of the component. Therefore, measurements to determine the residual stress state of cladded rail were performed using semi-destructive centre-hole and deep hole drilling and non-destructive neutron diffraction techniques. Subsequently, the effects of cycling loading and wear, representative of typical service loads, on the redistribution of the residual stress field were investigated. It was observed that laser cladding causes a triaxial compressive residual stress field in the clad and near the interface and a tensile stress field in the parent material. The stress field is shown to change when the first cycle of load is applied but reaches a steady state after only 10 cycles: After the 10th cycle there is no evidence that the clad continues accumulating strain which could indicate that there is low risk of ratcheting. Wear effect on residual stress redistribution was found to be local on the surface of the specimen only

Ploidy elicits a whole-genome dosage effect: growth of triploid Atlantic salmon is linked to the genetic origin of the second maternal chromosome set

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Standing genetic variation and compensatory evolution in transgenic organisms: a growth-enhanced salmon simulation

Genetically modified strains usually are generated within defined genetic backgrounds to minimize variation for the engineered characteristic in order to facilitate basic research investigations or for commercial application. However, interactions between transgenes and genetic background have been documented in both model and commercial agricultural species, indicating that allelic variation at transgene-modifying loci are not uncommon in genomes. Engineered organisms that have the potential to allow entry of transgenes into natural populations may cause changes to ecosystems via the interaction of their specific phenotypes with ecosystem components and services. A transgene introgressing through natural populations is likely to encounter a range of natural genetic variation (among individuals or sub-populations) that could result in changes in phenotype, concomitant with effects on fitness and ecosystem consequences that differ from that seen in the progenitor transgenic strain. In the present study, using a growth hormone transgenic salmon example, we have modeled selection of modifier loci (single and multiple) in the presence of a transgene and have found that accounting for genetic background can significantly affect the persistence of transgenes in populations, potentially reducing or reversing a “Trojan gene” effect. Influences from altered life history characteristics (e.g., developmental timing, age of maturation) and compensatory demographic/ecosystem controls (e.g., density dependence) also were found to have a strong influence on transgene effects. Further, with the presence of a transgene in a population, genetic backgrounds were found to shift in non-transgenic individuals as well, an effect expected to direct phenotypes away from naturally selected optima. The present model has revealed the importance of understanding effects of selection for background genetics on the evolution of phenotypes in populations harbouring transgenes

Valuable Journalism: The search for quality from the vantage point of the user

Many professional journalists and journalism scholars consider the increasing attention paid to audiences as one of the causes of the gradual loss of journalistic quality. They reason if ratings, circulation figures, hits and shares determine the content of journalism, the core values of journalism become jeopardized. This article argues how and why studies of journalistic quality should take the actual readers, listeners and viewers of journalistic texts seriously. It reports on a different kind of research for measuring the public's news interests and preferences; one that concentrates on value - what makes journalism precious for people and how news organizations can provide this. By zooming in on the professionals' and public's experience of quality information instead of their views on the topic, the article shows how pleasing the audience might be compatible with producing excellent journalism. © The Author(s) 2012