Modulation of TCR avidity of primary HIV-1-specific CD8 T-cell responses by early and potent antiviral therapy responses

Background: CD8 T-cells play a critical role in antiviral immunity. However, mechanisms of virus control and immune correlates of protection are still not fully understood. Among other factors, TCR avidity (antigen sensitivity) is thought to play a critical role. Whereas there is a large consensus that high TCR avidity T-cell responses are correlated to higher efficacy against cancer and acute viral infections, it may be not the case in chronic persistent viral infections. Methods: TCR avidity (measured by the effect concentration 50% [EC50]) of HIV-1-specific CD8 T-cell responses directed against optimal epitopes was investigated in different cohorts of HIV-1- infected subjects (n¼114) including early acute and chronic (progressive and non-progressive) HIV-1-infection. Overall, TCR avidity was investigated in 245 HIV-1-specific CD8 T-cell responses. The relationships between TCR avidity, T-cell differentiation and functional profile including cytokine secretion, proliferation and cytotoxic potential (determined by polychromatic flow cytometry) were analyzed. Results: HIV-1-specific CD8 T-cell responses from patients with acute infection had significantly lower TCR avidity as compared to patients with chronic (progressive or non-progressive) HIVinfection (P¼0.03 and 0.003, respectively). These differences remained significant when the analyses were restricted to common epitopes (same epitopes restricted by the same class I HLA). Interestingly, some patients treated during acute infection underwent spontaneous treatment interruption. Re-exposure to high viral load induced two major effects: a) the increase in TCR avidity of pre-existing high avidity (EC50<0.01) T-cell responses (P<0.02) and b) the generation of new T-cell responses with higher TCR avidity as compared to the average pre-existing T-cell responses. Conclusion: These results suggest that high TCR avidity T-cell responses are selected during the course of HIV-1 infection and that one of the potential driving mechanisms is continuous exposure to HIV-1 antigens. These results advance our understanding of the relationship between TCR avidity and Ag exposure of antiviral memory CD8 T-cells.

Effets secondaires meconnus des glucocorticoi'des: prevention et traitement spécifiques requis [Some less well known side effects of glucocorticoids: specific prevention and treatment?]

Steroid treatment is required in many clinical settings and if prolonged can be associated with serious side effects. Certain less well-known side effects may require specific prevention, diagnosis and treatment. The risk of developing hyperglycemia, psychiatric disorders and opportunistic infections associated with immunosuppression is often forgotten. We present herein some evidence on the prevalence, preventive measures and treatment of some of these side effects. Large controlled trials are lacking and do not allow to provide strong recommendations. Nevertheless, we try to provide some suggestions based on a review of the literature.

APPROACH AND TREATMENT OF SUICIDAL BEHAVIOR IN THE CLINICAL PRACTICE OF DIFFERENT GROUPS OF HEALTH PROFESSIONALS IN SPAIN: RESULTS OF THE PROJECT EUREGENA.

According to the WHO (World Health Organization) and the European Union, suicide is considered to be a health problem of prime importance and to be one of the principal causes of unnatural death. In Spain, the number of suicides has increased 12% since 2005 . The Research Project “European Regions Enforcing Actions against Suicide (EUREGENAS), funded by the Health Program 2008-2013, has as main objective the description of an integrated model of Mental Health orientated to the prevention of suicide. The differences that allow distinguishing the meaning of prevention in suicide behavior are described and explained through a qualitative methodological strategy and through the creation of discussion groups formed by different groups of health professionals. The results highlight the existing differences between the diverse health professionals who come more in contact with this problem and it shows as well the coincidence of meaning that suicide has to be considered as a priority in the field of health.

EORTC-ROG expert opinion: radiotherapy volume and treatment guidelines for neoadjuvant radiation of adenocarcinomas of the gastroesophageal junction and the stomach.

PURPOSE: The Gastro-Intestinal Working Party of the EORTC Radiation Oncology Group (GIWP-ROG) developed guidelines for target volume definition in neoadjuvant radiation of adenocarcinomas of the gastroesophageal junction (GEJ) and the stomach. METHODS AND MATERIALS: Guidelines about the definition of the clinical target volume (CTV) are based on a systematic literature review of the location and frequency of local recurrences and lymph node involvement in adenocarcinomas of the GEJ and the stomach. Therefore, MEDLINE was searched up to August 2008. Guidelines concerning prescription, planning and treatment delivery are based on a consensus between the members of the GIWP-ROG. RESULTS: In order to support a curative resection of GEJ and gastric cancer, an individualized preoperative treatment volume based on tumour location has to include the primary tumour and the draining regional lymph nodes area. Therefore we recommend to use the 2nd English Edition of the Japanese Classification of Gastric Carcinoma of the Japanese Gastric Cancer Association which developed the concept of assigning tumours of the GEJ and the stomach to anatomically defined sub-sites corresponding respectively to a distinct lymphatic spread pattern. CONCLUSION: The GIWP-ROG defined guidelines for preoperative irradiation of adenocarcinomas of the GEJ and the stomach to reduce variability in the framework of future clinical trials.

Sagopilone (ZK-EPO, ZK 219477) for recurrent glioblastoma. A phase II multicenter trial by the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group.

Background: Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood-brain barrier has demonstrated preclinical activity in glioma models.Patients and methods: Patients with first recurrence/progression of glioblastoma were eligible for this early phase II and pharmacokinetic study exploring single-agent sagopilone (16 mg/m(2) over 3 h every 21 days). Primary end point was a composite of either tumor response or being alive and progression free at 6 months. Overall survival, toxicity and safety and pharmacokinetics were secondary end points.Results: Thirty-eight (evaluable 37) patients were included. Treatment was well tolerated, and neuropathy occurred in 46% patients [mild (grade 1) : 32%]. No objective responses were seen. The progression-free survival (PFS) rate at 6 months was 6.7% [95% confidence interval (CI) 1.3-18.7], the median PFS was just over 6 weeks, and the median overall survival was 7.6 months (95% CI 5.3-12.3), with a 1-year survival rate of 31.6% (95% CI 17.7-46.4). Maximum plasma concentrations were reached at the end of the 3-h infusion, with rapid declines within 30 min after termination.Conclusions: No evidence of relevant clinical antitumor activity against recurrent glioblastoma could be detected. Sagopilone was well tolerated, and moderate-to-severe peripheral neuropathy was observed in despite prolonged administration.

Integrating novel agents into multiple myeloma treatment - current status in Switzerland and treatment recommendations.

The treatment of multiple myeloma has undergone significant changes in the recent past. The arrival of novel agents, especially thalidomide, bortezomib and lenalidomide, has expanded treatment options and patient outcomes are improving significantly. This article summarises the discussions of an expert meeting which was held to debate current treatment practices for multiple myeloma in Switzerland concerning the role of the novel agents and to provide recommendations for their use in different treatment stages based on currently available clinical data. Novel agent combinations for the treatment of newly diagnosed, as well as relapsed multiple myeloma are examined. In addition, the role of novel agents in patients with cytogenetic abnormalities and renal impairment, as well as the management of the most frequent side effects of the novel agents are discussed. The aim of this article is to assist in treatment decisions in daily clinical practice to achieve the best possible outcome for patients with multiple myeloma.

Body, Disease and Treatment in a Changing World. Latin texts and contexts in ancient and medieval medicine (Proceedings of the ninth International Conference «Ancient Latin Medical Texts», Hulme Hall, University of Manchester, 5th-8th September 2007),

This volume reflects a variegated and fruitful dialogue between classical and medieval philologists and historians of science, philosophy, literature and language as well as of medicine - the diverse range of interests that the history of medicine in the Graeco-Roman world and the medieval West continues to stimulate and draw on. A recurrent theme is the transformation of medical knowledge in different languages, literary forms and cultural milieux. Several papers concern editorial work in progress on unpublished texts, available only in manuscript or early printed editions. Ce recueil met en dialogue des spécialistes des textes médicaux latins de l'Antiquité et du Moyen Âge. Certaines analyses adoptent une approche sociolinguistique, d'autres s'intéressent à des questions de transmission et de réception, d'autres enfin livrent des études sur le lexique médical. Mais toutes concourent à éclairer une histoire culturelle de la médecine qui s'inscrit dans un monde en mutation. With a preface by D. R. Langslow, and contributions by M. Baldin, J. P. Barragán Nieto, P. P. Conde Parrado, D. Crismani, M. Cronier, C. de la Rosa Cubo, A. Ferraces Rodríguez, K.-D. Fischer, P. Gaillard-Seux, A. García González, V. Gitton-Ripoll, G. Haverling, F. Le Blay, B. Maire, G. Marasco, A. I. Martín Ferreira, I. Mazzini, F. Messina, Ph. Mudry, V. Nutton, M. Pardon-Labonnelie, R. Passarella, M. J. Pérez Ibáñez, S. Sconocchia, A. M. Urso, M. E. Vázquez Buján, and H. von Staden.

Iowa Department of Corrections Iowa State Penitentiary Final Operational and Architectural Program

The planning effort for ISP began in 2006 when the IDOC retained the Durrant/PBA team of architects and planners to review the Iowa correctional system. The team conducted two studies in the following two years, the first being the April 2007 Iowa Department of Corrections Systemic Master Plan. Both studies addressed myriad aspects of the correctional system including treatment and re-entry needs and programs, security and training, and staffing.

Effect of olive oil on early and late events of colon carcinogenesis in rats: modulation of arachidonic acid metabolism and local prostaglandin E2 synthesis.

BACKGROUND Animal model studies have shown that the colon tumour promoting effect of dietary fat depends not only on the amount but on its fatty acid composition. With respect to this, the effect of n9 fatty acids, present in olive oil, on colon carcinogenesis has been scarcely investigated. AIMS To assess the effect of an n9 fat diet on precancer events, carcinoma development, and changes in mucosal fatty acid composition and prostaglandin (PG)E2 formation in male Sprague-Dawley rats with azoxymethane induced colon cancer. METHODS Rats were divided into three groups to receive isocaloric diets (5% of the energy as fat) rich in n9, n3, or n6 fat, and were administered azoxymethane subcutaneously once a week for 11 weeks at a dose rate of 7.4 mg/kg body weight. Vehicle treated groups received an equal volume of normal saline. Groups of animals were colectomised at weeks 12 and 19 after the first dose of azoxymethane or saline. Mucosal fatty acids were assessed at 12 and 19 weeks. Aberrant crypt foci and the in vivo intracolonic release of PGE2 were assessed at week 12, and tumour formation at week 19. RESULTS Rats on the n6 diet were found to have colonic aberrant crypt foci and adenocarcinomas more often than those consuming either the n9 or n3 diet. There were no differences between the rats on the n9 and n3 diets. On the other hand, administration of both n9 and n3 diets was associated with a decrease in mucosal arachidonate concentrations as compared with the n6 diet. Carcinogen treatment induced an appreciable increase in PGE2 formation in rats fed the n6 diet, but not in those fed the n3 and n9 diets. CONCLUSIONS Dietary olive oil prevented the development of aberrant crypt foci and colon carcinomas in rats, suggesting that olive oil may have chemopreventive activity against colon carcinogenesis. These effects may be partly due to modulation of arachidonic acid metabolism and local PGE2synthesis.

Molecular genetics and treatment of narcolepsy.

Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness and cataplexy. The hypocretin/orexin deficiency is likely to be the key to its pathophysiology in most of cases although the cause of human narcolepsy remains elusive. Acting on a specific genetic background, an autoimmune process targeting hypocretin neurons in response to yet unknown environmental factors is the most probable hypothesis in most cases of human narcolepsy with cataplexy. Although narcolepsy presents one of the tightest associations with a specific human leukocyte antigen (HLA) (DQB1*0602), there is strong evidence that non-HLA genes also confer susceptibility. In addition to a point mutation in the prepro-hypocretin gene discovered in an atypical case, a few polymorphisms in monoaminergic and immune-related genes have been reported associated with narcolepsy. The treatment of narcolepsy has evolved significantly over the last few years. Available treatments include stimulants for hypersomnia with the quite recent widespread use of modafinil, antidepressants for cataplexy, and gamma-hydroxybutyrate for both symptoms. Recent pilot open trials with intravenous immunoglobulins appear an effective treatment of cataplexy if applied at early stages of narcolepsy. Finally, the discovery of hypocretin deficiency might open up new treatment perspectives.

Characteristics and early and long-term outcome in patients with acute ischemic stroke and low ejection fraction.

OBJECTIVES: We assessed the clinical characteristics of patients with acute ischemic stroke (AIS) with left ventricular ejection fraction (EF) ≤ 35% and investigated the association of low EF with early and long-term outcome. METHODS: A total of 2439 patients of the Acute Stroke Registry and Analysis of Lausanne (ASTRAL) were selected. Demographics, risk factors, pre-stroke treatment, and clinical, radiological and metabolic variables in patients with and without low EF were compared. Functional independence (modified Rankin Score ≤ 2) and mortality were recorded 1 week up to 12 months from admission. RESULTS: Low EF patients (n=119) were more commonly men, older, had higher rates of coronary artery disease and atrial fibrillation (AF), and more frequent pretreatment with anticoagulants, antiplatelets and antihypertensive agents. On admission, they presented with higher stroke severity and had lower values of systolic blood pressure, higher heart rate, and worse estimated glomerular filtration rate. Stroke-related disability and death rates were higher in low EF patients during follow-up (19.5% vs. 7.8% at 1 week, and 36.1% vs. 16.5% at 12 months). Increasing age, stroke severity, and AF were independent predictors of one-year mortality in these patients while prior use of statins had a favorable effect on early mortality. CONCLUSIONS: AIS in patients with low EF is associated with older age, cardiac comorbidities, and more severe clinical presentation. Low EF can identify a subset of AIS patients at high risk of early and long-term functional disability and mortality.

Osteoid osteoma-like lesions: MDCT features and treatment by radiofrequency ablation : 46

Purpose: To assess the MDCT features of bone lesions that mimic osteoid osteoma (OO-like lesions) and evaluate their treatment by radiofrequency (RF) ablation. Methods and materials: All percutaneous RF ablations performed between May 2002 and June 2009 for a presumed (clinical and MDCT features) diagnosis of OO were retrospectively reviewed. Per-procedural biopsies were always performed and histopathological diagnoses were noted. The following MDCT features of all bone lesions were assessed by two musculoskeletal radiologists in consensus: skeletal distribution and location within the bone, size, central calcification, surrounding osteosclerosis and periosteal reaction. Clinical success was also evaluated. Results: Eighty patients (54 males, 26 females, mean age 24.1 years, range 5-48) underwent RF ablation. The histopathological diagnoses were: 54 non-contributory biopsies, 16 OO, 10 OO-like lesions (5 chronic osteomyelitis, 3 chondroblastoma, 1 eosinophilic granuloma, 1 fibrous dysplasia). The OO-like lesions were significantly greater in size (p = 0.001) and exhibited trends toward medullary location within the bone, moderate surrounding osteosclerosis and less periosteal reaction, compared to OO. Primary clinical success for OO-like lesions was 100% at 1 month, 85.7% at 6 and 12 months, and 66.7% at 24 months. Secondary success was 100%. Conclusion: Greater size, medullary location within the bone, lesser surrounding osteosclerosis and periosteal reaction on MDCT may help differentiate OO-like lesions from OO. OO-like lesions are safely and successfully treated by RF ablation.

Partnership for fragility bone fracture care provision and prevention program (P4Bones): study protocol for a secondary fracture prevention pragmatic controlled trial.

ABSTRACT: BACKGROUND: Fractures associated with bone fragility in older adults signal the potential for secondary fracture. Fragility fractures often precipitate further decline in health and loss of mobility, with high associated costs for patients, families, society and the healthcare system. Promptly initiating a coordinated, comprehensive pharmacological bone health and falls prevention program post-fracture may improve osteoporosis treatment compliance; and reduce rates of falls and secondary fractures, and associated morbidity, mortality and costs.Methods/design: This pragmatic, controlled trial at 11 hospital sites in eight regions in Quebec, Canada, will recruit community-dwelling patients over age 50 who have sustained a fragility fracture to an intervention coordinated program or to standard care, according to the site. Site study coordinators will identify and recruit 1,596 participants for each study arm. Coordinators at intervention sites will facilitate continuity of care for bone health, and arrange fall prevention programs including physical exercise. The intervention teams include medical bone specialists, primary care physicians, pharmacists, nurses, rehabilitation clinicians, and community program organizers.The primary outcome of this study is the incidence of secondary fragility fractures within an 18-month follow-up period. Secondary outcomes include initiation and compliance with bone health medication; time to first fall and number of clinically significant falls; fall-related hospitalization and mortality; physical activity; quality of life; fragility fracture-related costs; admission to a long term care facility; participants' perceptions of care integration, expectations and satisfaction with the program; and participants' compliance with the fall prevention program. Finally, professionals at intervention sites will participate in focus groups to identify barriers and facilitating factors for the integrated fragility fracture prevention program.This integrated program will facilitate knowledge translation and dissemination via the following: involvement of various collaborators during the development and set-up of the integrated program; distribution of pamphlets about osteoporosis and fall prevention strategies to primary care physicians in the intervention group and patients in the control group; participation in evaluation activities; and eventual dissemination of study results.Study/trial registration: Clinical Trial.Gov NCT01745068Study ID number: CIHR grant # 267395.

Coping with an HIV infection. A multicenter qualitative survey on HIV positive adolescents' perceptions of their disease, therapeutic adherence and treatment.

HIV-positive adolescents face a number of challenges in dealing with their disease and its treatment. In this qualitative study, twenty-nine HIV-positive adolescents aged 13 to 20 years (22 girls), who live in Switzerland, were asked, in a semi-structured interview (duration of 40-110 minutes), to describe their perceptions and experiences with the disease itself and with therapeutic adherence. While younger adolescents most often thought of their disease as fate, older adolescents usually knew that they had received it through vertical transmission, although the topic appeared to be particularly difficult to discuss for those living with their HIV-positive mothers. Based on their attending physician's assessment, 18 subjects were judged highly adherent, 4 fairly and 7 poorly adherent. High adherence appeared linked with adequate psychological adjustment and effective coping mechanisms, as well as with the discussion and adoption of explicit medication-taking strategies. The setting and organisation of health care teams should allow for ongoing discussions with HIV-positive adolescents that focus on their perceptions of their disease, how they cope with it and with the treatment, and how they could improve their adherence.

Cumulative Costs of Caries Prevention and Treatment in Children - with Special Reference to Work Division and Cohort Effect

Lapsen karieshoidon kustannuskertymän muutokset ja karieshoidon toimintakäytäntöjen yhteys kustannuksiin Tutkimuksen tavoitteena oli mitata terveyskeskuksessa hoidettavien lasten karieshoidon kumulatiivisia kustannuksia ja verrata niitä kahden erilaisen toimintatavan välillä. Lisäksi tarkasteltiin lasten hampaiden terveyttä. Tutkimus tehtiin julkisen palvelutuottajan näkökulmasta. Tutkimusaineisto kerättiin Kemin ja Tornion terveyskeskusten suun terveydenhuollon potilaskertomuksista. Kemin kohortit 1980, 1983 ja 1986 (n = 600) ja Tornion kohortit 1980 ja 1992 (n = 400) edustivat perinteistä ja Kemin kohortit 1989, 1992 ja 1995 (n = 600) uutta toimintatapaa työnjaon ja ehkäisyn ajoituksen suhteen. Kohortteja ja kaupunkeja verrattiin hampaiden terveyden (dmft/DMFT = 0 ja dmft ja DMFT keskiarvot 5 ja 12 vuoden iässä) ja voimavarojen käytön suhteen. Panoskäyttö johdettiin käyntimäärien avulla laskennallisen työajan kautta. Kustannuskertymät muodostettiin käyttämällä henkilöstömenoista laskettuja suorittajakohtaisia yksikkökustannuksia. Panoskäytön ja yksikkökustannusten kautta muodostettiin kustannuskertymät. Kustannusten ja terveysvaikutusten suhteita arvioitiin kustannus-vaikuttavuusanalyysissä. Suuhygienistien työpanosta hyödyntävällä varhaisen ehkäisyn toimintamallilla saavutettiin vähäisemmin kustannuksin alle kouluiässä parempi ja kouluiässä yhtä hyvä hammasterveys kuin perinteisellä, enemmän hammaslääkärien työpanokseen perustuvalla tavalla. Karieksen hoitoon liittyvien käyntien määrä oli nuorimmissa syntymävuosikohorteissa pienempi kuin vanhimmissa kohorteissa. Käynnit hammaslääkärissä vähenivät eniten. Toimintatavalla oli merkittävä vaikutus lapsen karieshoidon kokonaiskustannuksiin. Herkkyysanalyysin mukaan karieshoidon kustannukset olivat työnjakoa hyödyntämällä kolmanneksen pienemmät, kuin jos hoidon suorittajana olisi ollut ainoastaan hammaslääkäri-hoitaja työpari. Lasten karieshoidon kustannusvaikuttavuus kohentui molemmissa terveyskeskuksissa nuoremmissa kohorteissa vanhempiin verrattuna. Suun terveydenhuollon potilaskertomuksia olisi hyödynnettävä toiminnan kehittämisessä. Varhaisen ehkäisyn avulla voitaisiin kaikkien suun terveydenhuollon ammattihenkilöiden työpanos kohdentaa kustannustehokkaasti.