Abstract

Prevention of cardiovascular disease in high risk diabetic patients:impact of multifactorial intervention

Hans-Henrik Parving

Morbidity and mortality in diabetes are caused chiefly by its vascular complications, both in the microcirculation and in the large vessels. Diabetic nephropathy and retinopathy are the clinical hallmarks for microangiopathy, which may lead to end stage renal failure and blindness. The cardiovascular complications in diabetes consist mainly of an accelerated form of atherosclerosis. It should be recalled that diabetic nephropathy is strongly associated with other severe complications such as proliferative retinopathy, neuropathy, macroangiopathy, and hypertension. The cumulative incidence of diabetic nephropathy both in type 1 and type 2 is approximately 40%. Multiple modifiable risk factors for late complications in patients with type 2 diabetes, including hyperglycemia, hypertension, and dyslipidemia, increase the risk of a poor outcome. Randomized trials that investigated the effect of intensified intervention involving a single risk factor in patients with type 2 diabetes demonstrated benefits in terms of both macrovascular and microvascular complications in kidneys, eyes, and nerves. On the basis of the results of these trials, recent guidelines from the American Diabetes Association and other national guidelines recommend an intensified multifactorial treatment approach, although the effect of this approach has not been confirmed in long-term studies. We undertook a randomized study - the Steno-2 Study - to evaluate the effect on cardiovascular disease of an intensified, targeted, multifactorial intervention comprising behaviour modification and polypharmacologic therapy aimed at several modifiable risk factors (hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with secondary prevention of cardiovascular disease with aspirin) in patients with type 2 diabetes and microalbuminuria; we compared this approach with a conventional intervention involving multiple risk factors. The mean age of the patients was 55.1 years, and the mean follow-up was 7.8 years. The decline in glycosylated hemoglobin values, systolic and diastolic blood pressure, serum cholesterol and triglyceride levels measured after an overnight fast, and urinary albumin excretion rate were all significantly greater in the intensive-therapy group than in the conventional-therapy group. Patients receiving intensive therapy also had a significantly lower risk of cardiovascular disease (hazard ratio, 0.47; 95 percent con-fidence interval, 0.24 to 0.73), nephropathy (hazard ratio, 0.39; 95 percent confidence interval, 0.17 to 0.87), retinopathy (hazard ratio, 0.42; 95 percent confidence interval, 0.21 to 0.86), and autonomic neuropathy (hazard ratio, 0.37; 95 percent confidence interval, 0.18 to 0.79). In conclusions, a target-driven, long-term, intensified intervention aimed at multiple risk factors in patients with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular and microvascular events by about 50 percent.

Immunotherapy of cancer: lessons learned from melanoma

Suzanne L. Topalian

The promise of antigen-specific immunotherapy has not yet been fully realized, perhaps due to the choice of target molecules. Most current information on the nature of immunogenic cancer antigens is derived from studies of melanoma, and therefore the majority of clinical efforts have focused on this disease. Using commonly expressed nonmutated antigens such as tyrosinase, gp100, and MART-1/MelanA as targets for immunotherapy provides access for the majority of melanoma patients, and yet loss of expression of these non-essential molecules provides an escape route for treatment-refractory tumors. Identification and targeting of tumor-associated molecules vital to maintaining the malignant phenotype will be critical to realizing the full potential of cancer immunotherapy. These molecules may be encoded by native or mutant sequences. For example, a constitutively activating somatic mutation in the signaling molecule B-Raf is frequently expressed in melanomas and may play an important role in the biology of this disease. Because of its tumor specificity, shared expression, functional significance, and ability to stimulate CD4+ T cells from melanoma patients, mutant B-Raf typifies targets that may be ideal for immunotherapy. Another important component of cancer immunology is immune regulation. Treatment of melanoma patients with anti-CTLA4, a monoclonal antibody designed to block inhibitory T cell signaling, has resulted in tumor regressions in select patients, but non specific immune enhancement caused by this drug has also caused autoimmune complications. Current research aims to develop new immunomodulatory drugs with enhanced anti-tumor specificity. One attractive target is B7-H1, a B7 family member expressed on most melanomas and also on common epithelial cancers, which ligates the inhibitory PD-1 receptor on activated T cells. Evidence from animal models suggests that tumor-associated B7-H1 is important for immune evasion. The potential for B7-H1 blockade in humans to augment the effects of immunotherapy is an area of ongoing investigation.

Sensing and recognition of bacteria by NKT cells

Mitchell Kronenberg, Yuki Kinjo, Niranjana Nagarajan, Douglass Wu, Guo-wen Xing, Chi-Huey Wong, Kazuyoshi Kawahara, Michael Poles and Moriya Tsuji

NKT cells recognize glycolipids presented by CD1d, a class I-like antigen-presenting molecule. They rapidly produce cytokines, and they play an important role in regulating a variety of immune responses. However, the ability of these cells to recognize microbial antigens has been controversial, and in fact the true physiologic role of these cells has been uncertain. Recent data from our group and others, however, indicate that NKT cells are adapted for the sensing of microbes. These cells produce IFNg but not IL-4 in response to bacterial products such as LPS. This response is not dependent on direct recognition of LPS by the T cell antigen receptor (TCR) nor on toll like receptor expression by NKT cells, but it requires IL-12 and IL-18 produced by activated DCs. We have also demonstrated that the majority of NKT cells also can recognize microbial antigens in a TCR mediated fashion, leading to the production of both IFNγ and IL-4. These microbial antigens are glycosphingolipids from Sphingomonas bacteria, which are gram-negative bacteria that do not contain LPS. NKT cells are activated in vivo after exposure to bacterial antigens or bacteria, and mice deficient for NKT cells exhibit a dramatic defect in the clearance of Sphingomonas from the liver. Moreover, this response is conserved when human NKT cells are analyzed. These data suggest that NKT cells are T lymphocytes that use TCR-mediated recognition, as well as mechanisms that do not depend on the TCR, to provide an innate-type immune response and protection from certain microorganisms.

Stem cell regulation: niche and signaling

Linheng Li

How stem cells are maintained in vivo and the signal pathways that regulate the delicate balance between self-renewal and differentiation are fundamental questions in the study of stem cells and cancer biology. If self-renewal overpowers differentiation, the result is tumorigenesis. In contrast, if differentiation overpowers self-renewal, the number of stem cells decreases, resulting in early maturation of the corresponding tissues. Here we describe our studies regarding the role of BMP signaling in regulating stem cell behavior: 1) how stem cells are maintained in the hematopoietic and intestinal systems by their microenvironment (niche), and 2) how BMP and Wnt signaling control the balance between self-renewal and differentiation. We provide evidence that demonstrates the essential function of the niche in maintenance of stem cells, and show that multiple signals are required to maintain a balanced control of stem cell self-renewal.

Gastric inflammation and oxidative stress in the pathogenesis of Helicobacter pylori-associated diseases

Ann M. O'Hara, Song-Ze Ding and Sheila E. Crowe

Oxidative stress results when cellular homeostatic mechanisms are overwhelmed by changes in intracellular ROS levels and may lead to oxidative damage of protein, lipid and DNA and activation of cell signaling pathways, which in turn stimulate aberrant cell proliferation and/or cell death. Helicobacter pylori infection leads to an accumulation of ROS within the gastric epithelium secondary to phagocytic inflammatory cells, direct bacterial effects and certain inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) that signal via ROS. H. pylori infection is associated with increased oxidative DNA damage, proliferation and apoptosis. Accumulation of ROS and apoptosis can be inhibited by antioxidants in experimental studies and in vivo studies suggest that antioxidants reduce bacterial load, inflammation, apoptosis and even gastric cancer precursor lesions. Epidemiological data suggest that diets high in naturally occurring antioxidants found in fruits and vegetables are associated with lower rates of gastric cancer. As ROS regulate expression of apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE-1/Ref-1), a multifunctional protein that repairs DNA and activates transcription factors including activating protein (AP)- 1, our laboratory has examined expression and function of APE-1/Ref-1 in human gastric epithelial cells during H. pylori infection. APE-1/Ref-1 is constitutively expressed with enhanced expression and nuclear translocation after exposure to H. pylori or ROS. Overexpression or siRNA inhibition studies demonstrate that APE-1/Ref-1 activates AP-1 and nuclear factor (NF)-κ B and modulates expression of interleukin (IL)- 8 under basal conditions and in response to H. pylori infection. These findings suggest that the effect of oxidative stress on the epithelial response to H. pylori infection is mediated by APE-1/Ref-1. Further studies are needed to better define the role oxidative stress plays in H. pylori associated disorders.

Issues in early intervention and recovery from first-episode psychosis

Eric YH Chen, Christy LM Hui and Cindy PY Chiu

Recent developments in early psychosis intervention have emphasized the reduction of the delay before diagnoses, as well as the provision of comprehensive pharmacological and psychosocial treatments. They aim to optimize the outcome in the first two to three years of the illness, which may have a pivotal influence over longer term outcome. The early intervention programme in Hong Kong (the Early Assessment Service for Young People with Psychosis, EASY) made use of intensive media activities to introduce a novel Chinese phrase for "early psychosis" that was less stigmatizing and more acceptable to the public. Media activities are supported by an open hotline referral system which provides screening. From around seven million people, each year around seven hundred first onset cases (under 25) were identified. The pattern of recovery in first episode psychosis patients in Hong Kong was studied. Most patients achieved remission within the first three years of the illness. Only 13% fail to remit in positive symptoms. However if recovery is considered in terms of positive, negative symptoms, and functioning, the proportion of patients who achieved recovery is only around 17%. We also studied the subjective perception of recovery among first episode patients using a self administered questionnaire (the Psychosis Recovery Inventory, PRI). Concurring with the above findings, only about ten percent of patients felt they had made a near complete recovery. Among the reasons for not feeling adequately recovered, the need to continue with maintenance medication, and subjective cognitive impairments, were rated as most important by patients.

Anorexia nervosa and the brain

Bryan Lask

Anorexia nervosa is a severe and life threatening condition, manifested by an excessive preoccupation with weight and shape, distorted body image and determined and persistent weight loss. The causation is complex and includes psychological, social and neurobiological factors. Neuroimaging research from our group and others has consistently pointed to altered functioning of networks within the temporal region in about 75% of patients with early onset anorexia nervosa using measures of cerebral blood flow. There appears to be no association between this reduction in blood flow and cerebral dominance, nutritional status, length of illness, mood or eating disorder psychopathology. However there is a significant association between reduced blood flow and neuropsychological measures. Using this empirical evidence, we have developed a neurobiological hypothesis to explain the common features of anorexia nervosa. We suggest that the Insular Cortex within the temporal region, sometimes called the hidden fifth lobe of the brain, serves a unique role integrating body image, eating behaviour and fear networks. This presentation aims to give an accessible overview of the research leading to this hypothesis, so that colleagues not otherwise immersed in the neurosciences can participate in the debate. It describes the journey towards a testable model of this hypothesis, and shares how emerging technologies in functional neuroimaging will help to revolutionise our understanding and treatment of young people with anorexia nervosa.