IL-33-mediated protection against experimental cerebral malaria is linked to induction of Type 2 innate lymphoid cells, M2 macrophages and regulatory T cells

Author Summary Cerebral malaria (CM) caused by the parasite Plasmodium sp . is a fatal disease, especially in children. Currently there is no effective treatment. We report here our investigation on the role of a recently discovered cytokine IL-33, in treating experimental cerebral malaria (ECM) in the susceptible C57BL/6 mice. IL-33 protects the mice against ECM. The protection is accompanied by a reduction of Th1 response and the enhancement of type 2 cytokine response. We also found that IL-33 mediates its protective effect by inducing a population of type 2 innate lymphoid cells (ILC2), which then polarize macrophages to alternatively-activated phenotypes (M2). M2 in turn expand regulatory T cells (Tregs) which suppress the deleterious Th1 response. Our report therefore reveals hitherto unrecognised mechanisms of the regulation of ECM and provide a novel function of IL-33

CD4+ Natural Regulatory T Cells Prevent Experimental Cerebral Malaria via CTLA-4 When Expanded In Vivo

Studies in malaria patients indicate that higher frequencies of peripheral blood CD4+ Foxp3+ CD25+ regulatory T (Treg) cells correlate with increased blood parasitemia. This observation implies that Treg cells impair pathogen clearance and thus may be detrimental to the host during infection. In C57BL/6 mice infected with Plasmodium berghei ANKA, depletion of Foxp3+ cells did not improve parasite control or disease outcome. In contrast, elevating frequencies of natural Treg cells in vivo using IL-2/anti-IL-2 complexes resulted in complete protection against severe disease. This protection was entirely dependent upon Foxp3+ cells and resulted in lower parasite biomass, impaired antigen-specific CD4+ T and CD8+ T cell responses that would normally promote parasite tissue sequestration in this model, and reduced recruitment of conventional T cells to the brain. Furthermore, Foxp3+ cell-mediated protection was dependent upon CTLA-4 but not IL-10. These data show that T cell-mediated parasite tissue sequestration can be reduced by regulatory T cells in a mouse model of malaria, thereby limiting malaria-induced immune pathology

Tailored Print Communication and Telephone Motivational Interviewing Are Equally Successful in Improving Multiple Lifestyle Behaviors in a Randomized Controlled Trial

Background: Computer tailoring and motivational interviewing show promise in promoting lifestyle change, despite few head-to-head comparative studies. Purpose: Vitalum is a randomized controlled trial in which the efficacy of these methods was compared in changing physical activity and fruit and vegetable consumption in middle-aged Dutch adults. Methods: Participants (n?=?1,629) were recruited via 23 general practices and randomly received either four tailored print letters, four motivational telephone calls, two of each type of intervention, or no information. The primary outcomes were absolute change in self-reported physical activity and fruit and vegetable consumption. Results: All three intervention groups (i.e., the tailored letters, the motivational calls, and the combined version) were equally and significantly more effective than the control group in increasing physical activity (hours/day), intake of fruit (servings/day), and consumption of vegetables (grams/day) from baseline to the intermediate measurement (week 25), follow-up 1 (week 47) and 2 (week 73). Effect sizes (Cohen's d) ranged from 0.15 to 0.18. Participants rated the interventions positively; interviews were more positively evaluated than letters. Conclusions: Tailored print communication and telephone motivational interviewing or their combination are equally successful in changing multiple behaviors. © 2010 The Author(s)

The credit crunch: the collapse of Lehman Brothers - and a Hong Kong scheme to handle Lehman claims

Anthony Connerty (Barrister and Chartered Arbitrator) looks at the Lehman collapse - considering the background to the collapse of Lehman Brothers investment bank, claims related to the collapse, an example of a credit crunch claim, a criminal prosecution and a Hong Kong mediation and arbitration scheme aimed at dealing speedily with Lehman Brothers-related claims. Versions of this article have been published in Hong Kong in the January 2010 edition of Asian Dispute Review and in London in the July 9, 2010 edition of New Law Journal. Published in Amicus Curiae – Journal of the Society for Advanced Legal Studies at the Institute of Advanced Legal Studies. The Journal is produced by SALS at the IALS (Institute of Advanced Legal Studies, School of Advanced Study, University of London)

Defective DNA replication impairs mitochondrial biogenesis in human failing hearts

Mitochondrial dysfunction plays a pivotal role in the development of heart failure. Animal studies suggest that impaired mitochondrial biogenesis attributable to downregulation of the peroxisome proliferator-activated receptor gamma coactivator (PGC)-1 transcriptional pathway is integral of mitochondrial dysfunction in heart failure. OBJECTIVE: The study sought to define mechanisms underlying the impaired mitochondrial biogenesis and function in human heart failure. METHODS AND RESULTS: We collected left ventricular tissue from end-stage heart failure patients and from nonfailing hearts (n=23, and 19, respectively). The mitochondrial DNA (mtDNA) content was decreased by >40% in the failing hearts, after normalization for a moderate decrease in citrate synthase activity (P<0.05). This was accompanied by reductions in mtDNA-encoded proteins (by 25% to 80%) at both mRNA and protein level (P<0.05). The mRNA levels of PGC-1alpha/beta and PRC (PGC-1-related coactivator) were unchanged, whereas PGC-1alpha protein increased by 58% in the failing hearts. Among the PGC-1 coactivating targets, the expression of estrogen-related receptor alpha and its downstream genes decreased by up to 50% (P<0.05), whereas peroxisome proliferator-activated receptor alpha and its downstream gene expression were unchanged in the failing hearts. The formation of D-loop in the mtDNA was normal but D-loop extension, which dictates the replication process of mtDNA, was decreased by 75% in the failing hearts. Furthermore, DNA oxidative damage was increased by 50% in the failing hearts. CONCLUSIONS: Mitochondrial biogenesis is severely impaired as evidenced by reduced mtDNA replication and depletion of mtDNA in the human failing heart. These defects are independent of the downregulation of the PGC-1 expression suggesting novel mechanisms for mitochondrial dysfunction in heart failure

Minimally invasive direct access heart valve surgery

We review our experience with minimally invasive direct access (MIDA) heart valve surgery in 518 patients. Two hundred fifty-two patients underwent MIDA aortic valve replacement (AVR) or repair and 266 underwent MIDA mitral valve repair or replacement. Among the 250 AVRs, 157 (63%) were men, aged 63.2 ± 14.6 years, NYHA functional Class 2.4 ± 0.8. The surgical approach was right parasternal in 36 (14%) or upper hemisternotomy in 216 (86%). There were four (2%) operative deaths. Perioperative complications included 14 (5.6%) reexplorations for bleeding, 7 (3%) chest wound infections, 5 (2%) strokes, and 1 (0.4%) external iliac vein injury. Follow-up was complete in 193 (77%) patients, with a mean follow-up of 12 ± 8 months. Late complications included 2 (0.8%) nonfatal myocardial infarctions, 4 (2%) reoperations for, respectively, 2 pericardial complications, 1 paravalvar leak, and 1 infected valve. There were five (2%) late deaths from congestive heart failure, pneumonia, hemorrhage, aneurysm, and cancer. Mean follow-up NYHA Class was 1.4 ± 0.6. For the 266 mitral patients, 145 (54.5%) were men, age 58.7 ± 13.6 years, functional Class 2.3 ± 0.5. The surgical approach was right parasternal in 195 (73%), lower hemisternotomy in 53 (20%), right submammary thoracotomy in 9 (3.4%), or full sternotomy through a small skin incision in 9 (3.4%). There were 2 (0.8%) operative deaths. Perioperative complications included 4 (1.5%) reoperations for bleeding, 4 (1.5%) strokes, and 5 (2%) wound infections, and 3 (1%) ascending aortic complications. Follow-up was complete in 202 (76%) patients with a mean follow-up of 9.5 ± 6.4 months. Late complications included one (0.4%) nonfatal myocardial infarction and three (1%) reoperations all converting repairs to replacements. There were three (1%) late deaths from suicide, pneumonia, and sudden death, respectively. Mean follow-up NYHA functional Class was 1.3 ± 0.5. We conclude that MIDA heart valve surgery is safe and effective for the majority of patients requiring isolated elective aortic or mitral valve surgery.link_to_subscribed_fulltex