Showing papers in "Journal of Internal Medicine in 2008"

The epidemiology of obesity: the size of the problem.

Abstract: The epidemic of obesity took off from about 1980 and in almost all countries has been rising inexorably ever since. Only in 1997 did WHO accept that this was a major public health problem and, even then, there was no accepted method for monitoring the problem in children. It was soon evident, however, that the optimum population body mass index is about 21 and this is particularly true in Asia and Latin America where the populations are very prone to developing abdominal obesity, type 2 diabetes and hypertension. These features are now being increasingly linked to epigenetic programming of gene expression and body composition in utero and early childhood, both in terms of fat/lean tissue ratios and also in terms of organ size and metabolic pathway regulation. New Indian evidence suggests that insulin resistance at birth seems linked to low birth weight and a higher proportion of body fat with selective B12 deficiency and abnormalities of one carbon pool metabolism potentially responsible and affecting 75% of Indians and many populations in the developing world. Biologically there are also adaptive biological mechanisms which limit weight loss after weight gain and thereby in part account for the continuing epidemic despite the widespread desire to slim. Logically, the burden of disease induced by inappropriate diets and widespread physical inactivity can be addressed by increasing physical activity (PA), but simply advocating more leisure time activity is unrealistic. Substantial changes in urban planning and diet are needed to counter the removal of any every day need for PA and the decades of misdirected food policies which with free market forces have induced our current 'toxic environment'. Counteracting this requires unusual policy initiatives.

NF‐κB in inflammatory bowel disease

Abstract: Apart from genetic and environmental factors, the mucosal immune system of the gut plays a central role in the pathogenesis of inflammatory bowel disease (IBD). In the healthy gut, the mucosal immune system ensures the balance between pro- and anti-inflammatory mediators and thereby allows an effective defence against luminal pathogens but at the same time prevents an overwhelming immune reaction directed against the huge amount of harmless luminal antigens (for example, components of food or nonpathological bacteria). In both entities of IBD (Crohn's disease and ulcerative colitis) this immunological balance is severely impaired and shifted towards the pro-inflammatory side. The chronic mucosal inflammation in IBD is caused by hyperactivation of effector immune cells, which produce high levels of pro-inflammatory cytokines like tumour necrosis factor-alpha, interleukin-6 and interferon-gamma, resulting in colonic tissue damage. The nuclear transcription factor kappaB (NF-kappaB) was identified as one of the key regulators in this immunological setting. Its activation is markedly induced in IBD patients and through its ability to promote the expression of various pro-inflammatory genes, NF-kappaB strongly influences the course of mucosal inflammation. Considering the different cell-type specific effects which are mediated by NF-kappaB, this review aims at describing the complex role of NF-kappaB in IBD and discusses existing pharmacological attempts to block the activation of NF-kappaB to develop new therapeutic strategies in IBD.

Renin-angiotensin system revisited.

Abstract: New components and functions of the renin-angiotensin system (RAS) are still being unravelled. The classical RAS as it looked in the middle 1970s consisted of circulating renin, acting on angiotensinogen to produce angiotensin I, which in turn was converted into angiotensin II (Ang II) by angiotensin-converting enzyme (ACE). Ang II, still considered the main effector of RAS was believed to act only as a circulating hormone via angiotensin receptors, AT1 and AT2. Since then, an expanded view of RAS has gradually emerged. Local tissue RAS systems have been identified in most organs. Recently, evidence for an intracellular RAS has been reported. The new expanded view of RAS therefore covers both endocrine, paracrine and intracrine functions. Other peptides of RAS have been shown to have biological actions; angiotensin 2-8 heptapeptide (Ang III) has actions similar to those of Ang II. Further, the angiotensin 3-8 hexapeptide (Ang IV) exerts its actions via insulin-regulated amino peptidase receptors. Finally, angiotensin 1-7 (Ang 1-7) acts via mas receptors. The discovery of another ACE2 was an important complement to this picture. The recent discovery of renin receptors has made our view of RAS unexpectedly complex and multilayered. The importance of RAS in cardiovascular disease has been demonstrated by the clinical benefits of ACE inhibitors and AT1 receptor blockers. Great expectations are now generated by the introduction of renin inhibitors. Indeed, RAS regulates much more and diverse physiological functions than previously believed.

Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial

Abstract: . Objectives. The objective of the present study was to examine the cross-sectional relation between serum 25-hydoxyvitamin D [25-(OH) D] levels and depression in overweight and obese subjects and to assess the effect of vitamin D supplementation on depressive symptoms. Design. Cross-sectional study and randomized double blind controlled trial of 20.000 or 40.000 IU vitamin D per week versus placebo for 1 year. Setting. A total of 441 subjects (body mass index 28–47 kg m−2, 159 men and 282 women, aged 21–70 years) recruited by advertisements or from the out-patient clinic at the University Hospital of North Norway. Main outcome measures. Beck Depression Inventory (BDI) score with subscales 1–13 and 14–21. Results. Subjects with serum 25(OH)D levels <40 nmol L−1 scored significantly higher (more depressive traits) than those with serum 25(OH)D levels ≥40 nmol L−1 on the BDI total [6.0 (0–23) versus 4.5 (0–28) (median and range)] and the BDI subscale 1–13 [2.0 (0–15) versus 1.0 (0–29.5)] (P < 0.05). In the two groups given vitamin D, but not in the placebo group, there was a significant improvement in BDI scores after 1 year. There was a significant decrease in serum parathyroid hormone in the two vitamin D groups without a concomitant increase in serum calcium. Conclusions. It appears to be a relation between serum levels of 25(OH)D and symptoms of depression. Supplementation with high doses of vitamin D seems to ameliorate these symptoms indicating a possible causal relationship.

Cholesterol efflux pathways and other potential mechanisms involved in the athero‐protective effect of high density lipoproteins

Abstract: Plasma high density lipoprotein (HDL) levels bear a strong independent inverse relationship with atherosclerotic cardiovascular disease. Although HDL has anti-oxidant, anti-inflammatory, vasodilating and anti-thrombotic properties, the central anti-atherogenic activity of HDL is likely to be its ability to remove cholesterol and oxysterols from macrophage foam cells, smooth muscle cells and endothelial cells in the arterial wall. To some extent, the pleotropic athero-protective properties of HDL may be related to its ability to promote sterol and oxysterol efflux from arterial wall cells, as well as to detoxify oxidized phospholipids. In cholesterol-loaded macrophages, activation of liver X receptors (LXRs) leads to increased expression of adenosine triphosphate (ATP) binding cassetter transporter (ABCA1), ATP binding cassetter transporter gene (ABCG1) and apoE and promotes cholesterol efflux. ABCA1 stimulates cholesterol efflux to lipid-poor apolipoproteins, whilst ABCG1 promotes efflux of cholesterol and oxysterols to HDL. Despite some recent setbacks in the clinical arena, there is still intense interest in therapeutically targeting HDL and macrophage cholesterol efflux pathways, via treatments with niacin, cholesterol ester transfer protein inhibitors, LXR activators and infusions of apoA-1, phospholipids and peptides.

C-reactive protein and coronary heart disease: a critical review.

Abstract: Modestly elevated baseline concentrations of C-reactive protein (CRP), the classical acute phase protein, are associated with the long-term risk of coronary heart disease in general populations, whilst the major acute phase response of CRP following myocardial infarction is associated with death and cardiac complications. The pathogenic and clinical significance of these associations is controversial. Here we critically review the evidence and describe large-scale epidemiological studies, novel experiments and possible specific therapies which will rigorously inform the debate. We distinguish between the potential pathogenicity of high acute phase circulating CRP concentrations in individuals with substantial tissue damage and modest but persistent increases in baseline values in generally healthy subjects.

Mitochondrial dysfunction as a cause of ageing.

Abstract: Mitochondrial dysfunction is heavily implicated in the ageing process. Increasing age in mammals correlates with accumulation of somatic mitochondrial DNA (mtDNA) mutations and decline in respiratory chain function. The age-associated respiratory chain deficiency is typically unevenly distributed and affects only a subset of cells in various human tissues, such as heart, skeletal muscle, colonic crypts and neurons. Studies of mtDNA mutator mice has shown that increased levels of somatic mtDNA mutations directly can cause a variety of ageing phenotypes, such as osteoporosis, hair loss, greying of the hair, weight reduction and decreased fertility. Respiratory-chain-deficient cells are apoptosis prone and increased cell loss is therefore likely an important consequence of age-associated mitochondrial dysfunction. There is a tendency to automatically link mitochondrial dysfunction to increased generation of reactive oxygen species (ROS), however, the experimental support for this concept is rather weak. In fact, respiratory-chain-deficient mice with tissue-specific mtDNA depletion or massive increase of point mutations in mtDNA typically have minor or no increase of oxidative stress. Mitochondrial dysfunction is clearly involved in the human ageing process, but its relative importance for mammalian ageing remains to be established.

Erythropoietin-mediated tissue protection: reducing collateral damage from the primary injury response.

Abstract: In its classic hormonal role, erythropoietin (EPO) is produced by the kidney and regulates the number of erythrocytes within the circulation to provide adequate tissue oxygenation. EPO also mediates other effects directed towards optimizing oxygen delivery to tissues, e.g. modulating regional blood flow and reducing blood loss by promoting thrombosis within damaged vessels. Over the past 15 years, many unexpected nonhaematopoietic functions of EPO have been identified. In these more recently appreciated nonhormonal roles, locally-produced EPO signals through a different receptor isoform and is a major molecular component of the injury response, in which it counteracts the effects of pro-inflammatory cytokines. Acutely, EPO prevents programmed cell death and reduces the development of secondary, pro-inflammatory cytokine-induced injury. Within a longer time frame, EPO provides trophic support to enable regeneration and healing. As the region immediately surrounding damage is typically relatively deficient in endogenous EPO, administration of recombinant EPO can provide increased tissue protection. However, effective use of EPO as therapy for tissue injury requires higher doses than for haematopoiesis, potentially triggering serious adverse effects. The identification of a tissue-protective receptor isoform has facilitated the engineering of nonhaematopoietic, tissue-protective EPO derivatives, e.g. carbamyl EPO, that avoid these complications. Recently, regions within the EPO molecule mediating tissue protection have been identified and this has enabled the development of potent tissue-protective peptides, including some mimicking EPO's tertiary structure but unrelated in primary sequence.

The molecular mechanisms of the thrombotic complications of atherosclerosis.

Abstract: Our evolving knowledge of the cellular and molecular mechanisms underlying atherosclerosis has helped uncover the underlying causes behind thrombotic complications of this disease. Most fatal coronary thrombosis result from fibrous cap rupture or superficial erosion. Recent research has established a role for matrix metalloproteinases in the regulation of aspects of plaque structure related to propensity to disrupt and provoke thrombosis. Inflammatory pathways impinge on proteinase activity and aspects of oxidative stress that may favour plaque disruption. Novel molecular imaging strategies may permit visualization of proteinase activity in vivo, providing a new functional window on pathophysiology.

Physician gender is associated with the quality of type 2 diabetes care

Abstract: . Objectives. Patient gender influences the quality of medical care whilst the role of physician gender is not well established. To investigate the influence of physician gender on quality of care in patients with type 2 diabetes. Design and methods. Cross-sectional study in 51 053 outpatients (48.6% male), treated by 3096 office-based physicians (66.3% male; 74.0% general practitioners, 21.8% internists and 4.2% diabetologists). Outcome measures included processes of care, intermediate outcomes and medical management. Quality of care measures were based on current ADA guidelines. Hierarchical regression models were used to avoid case-mix bias and to correct for physician-level clustering. Adjusted odds ratios were calculated controlling for age, gender, disease duration and presence of atherosclerotic disease. Results. The patients of female physicians were more often women, more obese, older and had more often atherosclerotic disease (34% in the total cohort). The patients of female physicians more often reached target values in glycaemic control (HbA1c < 6.5%; OR 1.14; 1.05–1.24, P = 0.002), blood lipoproteins (LDL-C < 100 mg dL−1; OR 1.16; 1.06–1.27, P = 0.002), and blood pressure (systolic values < 130 mmHg; OR 1.11; 1.02–1.22, P = 0.018). They were more likely to receive antihypertensive drug therapy in general (OR 1.35; 1.24–1.46, P < 0.0001) and angiotensin converting enzyme (ACE) inhibitors in particular (OR 1.17; 1.09–1.25, P < 0.0001). The patients of female physicians less often performed glucose self-monitoring (OR 0.83; 0.76–0.91, P < 0.0001) and less often received oral hypoglycaemic agents (OR 0.88; 0.82–0.95, P = 0.001). Conclusions. Physician gender influences quality of care in patients with type 2 diabetes. Female physicians provide an overall better quality of care, especially in prognostically important risk management.

Telomere attrition is associated with inflammation, low fetuin-A levels and high mortality in prevalent haemodialysis patients.

Abstract: . Introduction. Chronic kidney disease (CKD) predisposes to a 10- to 20-fold increased cardiovascular risk. Patients undergo accelerated atherogenesis and vascular ageing. We investigated whether telomere attrition, a marker of cell senescence, contributes to this increased mortality risk. Methods. This is a cross-sectional study in prevalent haemodialysis patients [n = 175; 98 Males; median (range) age: 66 (23–86) years]. Biochemical markers of oxidative stress and inflammatory status were measured in relation to the patient’s leucocyte telomere length. Overall mortality was assessed after a median of 31 (range 2–42) months. Results. Telomere length was shorter in CKD men, despite women being older (average ± SD 6.41 ± 1.23 vs. 6.96 ± 1.48 kb, P = 0.002). Telomere length was associated with age (rho = −0.18, P = 0.01), fetuin-A (rho = 0.26, P = 0.0004), high-sensitivity C-reactive protein (rho = −0.21, P = 0.005) and IL-6 (rho = −0.17, P = 0.02). In a multivariate logistic regression (pseudo r2 = 0.14), telomere length was associated with age >65 years (odds ratio: 2.11; 95% CI: 1.10, 4.06), sex (2.01; 1.05, 3.86), fetuin-A (1.85; 0.97, 3.50) and white blood cell count (2.04; 1.02, 4.09). Receiver operating characteristic curves identified a telomere length < 6.28 kb as a fair predictor of mortality. Finally, reduced telomere length was associated with increased mortality, independently of age, gender and inflammation (likelihood ratio 41.6, P < 0.0001), but dependently on fetuin-A levels. Conclusion. Age and male gender seem to be important contributors to reduced telomere length in CKD patients, possibly via persistent inflammation. Reduced telomere length also contributes to the mortality risk of these patients through pathways that could involve circulating levels of fetuin-A.

Microenvironmental influences in chronic lymphocytic leukaemia: the role of antigen stimulation.

Abstract: Several studies suggest that immune-mediated pathways are important in the pathogenesis of chronic lymphocytic leukaemia (CLL). The in vivo accumulation of leukaemic lymphocytes is facilitated by interactions of CLL cells with other cells and soluble factors that probably occur more often within the microenvironment through classical receptor-ligand interactions. These include CD40L-CD40 and chemokine-chemokine receptor interactions as well as B cell receptor (BCR) engagement by (auto)antigens. Indeed, the categorizations of CLL patients based on immunoglobulin heavy variable (IGHV) gene mutations and structure of the clone's BCR suggest that CLL patient outcome could be a reflection of ongoing BCR signalling in the context of other co-signals.

Oxidation-specific epitopes are important targets of innate immunity.

Abstract: During the oxidation of LDL, a central pathophysiological component of atherogenesis, a wide variety of chemical and physical changes occur leading to the generation of oxidation-specific neoepitopes. These epitopes are not only immunogenic, leading to adaptive humoral responses, but are also a prominent target of multiple arcs of innate immunity. The pattern recognition receptors (PRRs) of innate immunity are germ line encoded, conserved by natural selection, and bind to pathogen-associated molecular patterns (PAMPs) common on multiple structures. However, it is not intuitive as to why they should recognize oxidation-specific neoepitopes. Yet it is clear that multiple macrophage scavenger receptors, which are classic PRRs, recognize oxidation-specific epitopes, such as those found on oxidized LDL (OxLDL). Other innate proteins, such as C-reactive protein, also bind to OxLDL. Natural antibodies (NAbs), the humoral arc of innate immunity, provide a nonredundant role in the first line of defence against pathogens, but are also believed to provide important homeostatic house-keeping functions against self-antigens. Our work demonstrates that oxidation-specific epitopes, as found on OxLDL, are a major target of NAbs. In this review, we will discuss the specific example of the prototypic NAb T15/E06, which is increased in atherosclerotic mice and mediates atheroprotection, and discuss the potential role of NAbs in atherogenesis, and in inflammation in general. We also review data that oxidation-specific epitopes are generated whenever cells undergo programmed cell death, forming a common set of PAMPs recognized by oxidation-specific PRRs on macrophages, NAbs and innate proteins. We present the hypothesis that oxidation-specific epitopes on apoptotic cells exerted evolutionary pressure for the conservation of these PRRs and also serve to maintain the expansion of a substantial proportion of NAbs directed to these stress-induced self-antigens.

Interplay of commensal and pathogenic bacteria, genetic mutations, and immunoregulatory defects in the pathogenesis of inflammatory bowel diseases.

Abstract: Enteric microbiota can contribute to Crohn's disease and ulcerative colitis in several ways. Pathogenic or functionally altered commensal bacteria with increased mucosal adherence, invasion and intracellular persistence can activate pathogenic T cells and chronic intestinal inflammation. Compositional changes in intestinal microbiota can lead to decreased protective and increased aggressive species. Genetic polymorphisms resulting in increased mucosal permeability, decreased microbial killing, ineffective clearance of bacteria, biased TH1 and TH17 immune responses and loss of immunological tolerance are probably key contributors to IBD. Future therapies for these heterogeneous diseases should be individualized based on the patient-specific subset.

Virulence blockers as alternatives to antibiotics : type III secretion inhibitors against Gram-negative bacteria

Abstract: In recent years mounting problems related to antibiotic-resistant bacteria have resulted in the prediction that we are entering the preantibiotic era. A way of preventing such a development would be to introduce novel antibacterial medicines with modes of action distinct from conventional antibiotics. Recent studies of bacterial virulence factors and toxins have resulted in increased understanding of the way in which pathogenic bacteria manipulate host cellular processes. This knowledge may now be used to develop novel antibacterial medicines that disarm pathogenic bacteria. The type III secretion system (T3SS) is known to be a potent virulence mechanism shared by a broad spectrum of pathogenic Gram-negative bacteria that interact with human, animal and plant hosts by injecting effector proteins into the cytosol of host cells. Diseases, such as bubonic plague, shigellosis, salmonellosis, typhoid fever, pulmonary infections, sexually transmitted chlamydia and diarrhoea largely depend on the bacterial proteins injected by the T3SS machinery. Recently a number of T3SS inhibitors have been identified using screening-based approaches. One class of inhibitors, the salicylidene acylhydrazides, has been subjected to chemical optimization and evaluation in several in vitro and ex vivo assays in multiple bacterial species including Yersinia spp., Chlamydia spp., Salmonella spp. and Pseudotuberculosis aeruginosa. Reports published up to date indicate that T3SS inhibitors have the potential to be developed into novel antibacterial therapeutics.

Separating cause from effect: how does insulin/IGF signalling control lifespan in worms, flies and mice?

Abstract: Ageing research has been revolutionized by the use of model organisms to discover genetic alterations that can extend lifespan. In the last 5 years alone, it has become apparent that single gene mutations in the insulin and insulin-like growth-factor signalling pathways can lengthen lifespan in worms, flies and mice, implying evolutionary conservation of mechanisms. Importantly, this research has also shown that these mutations can keep the animals healthy and disease-free for longer and can alleviate specific ageing-related pathologies. These findings are striking in view of the negative effects that disruption of these signalling pathways can also produce. Here, we summarize the body of work that has lead to these discoveries and point out areas of interest for future work in characterizing the genetic, molecular and biochemical details of the mechanisms to achieving a longer and healthier life.

The first postmodern pandemic: 25 years of HIV/ AIDS.

Abstract: Science responded to the challenge of AIDS by rapidly identifying aetiology, describing pathogenesis and transmission routes, and developing diagnostic tests and treatment. However, this did not prevent the global spread of HIV, with 25 million fatal cases so far, another 33 million infected, and disastrous socioeconomic and demographic consequences. In spite of unprecedented political attention and financial resources, the response is falling further behind the growth of the epidemic. This is partly due to the unique characteristics of the virus, such as persistent infection, vertical transmission and a variability that allows it to escape immunity and antiretroviral drugs, and partly due to human characteristics such as a strong procreative instinct, drug use and ostracism. Denial, myths and complacency are major obstacles to rational measures. With no cure or vaccine in sight, scaling up prevention is of paramount importance. To meet the goal of universal access to prevention, treatment and care by 2010 would require a quadrupling of funding to an estimated US$42 billion by 2010, including adequate overall strengthening of healthcare systems, but in any case, the world will have to learn to live with HIV for the foreseeable future.

Autoimmunity in atherosclerosis: a protective response losing control?

Abstract: Atherosclerosis is a chronic inflammatory disease characterized by accumulation of oxidized lipoproteins, increased cell death and hypertrophic degeneration of the arterial intima. The disease process is associated with local formation of modified self antigens that are targeted by both innate and adaptive immune responses. Although it remains to be firmly established it is likely that these autoimmune responses initially have a beneficial effect facilitating the removal of potentially harmful rest products from oxidized LDL and dying cells. However, studies performed on hypercholesterolaemic mice deficient in different components of the immune system uniformly suggest that the net effect of immune activation is pro-atherogenic and that atherosclerosis, at least to some extent, should be regarded as an autoimmune disease. These observations point to the possibility of developing new treatments for atherosclerosis based on modulation of immune responses against plaque antigens, an approach presently tested clinically for several other chronic inflammatory diseases with autoimmune components. Pilot studies in animals have provided promising results for both parental and oral vaccines based on oxidized LDL antigens. The time when this concept is ready for clinical testing is rapidly approaching but it will be important not to underestimate the difficulties that will be encountered in transferring the promising results from experimental animals into humans.

SIRT6 in DNA repair, metabolism and ageing

Abstract: Ageing, or increased mortality with time, coupled with physiologic decline, is a nearly universal yet poorly understood biological phenomenon. Studies in model organisms suggest that two conserved pathways modulate longevity: DNA damage repair and Insulin/Igf1-like signalling. In addition, homologs of yeast Sir2 - the sirtuins - regulate lifespan in diverse organisms. Here, we focus on one particular sirtuin, SIRT6. Mice lacking SIRT6 develop a degenerative disorder that in some respects mimics models of accelerated ageing [Cell (2006) 124:315]. We discuss how sirtuins in general and SIRT6 specifically relate to other evolutionarily conserved pathways affecting ageing, and how SIRT6 might function to ensure organismal homeostasis and normal lifespan.

Understanding ageing from an evolutionary perspective.

Abstract: There is clear heritability of human longevity. However, the genetics of ageing is likely to be complex. Evolution theory tells us not to expect genes that have been selected to promote ageing. Ageing is not programmed but results from accumulation of somatic damage, owing to limited investments in maintenance and repair. Genes controlling the levels of activities, such as DNA repair and antioxidant defence, thus regulate longevity. In addition, there may be contributions either from late-acting deleterious genes that escape the force of natural selection or that trade benefit at an early age against harm at older ages. In some species, there is evidence that genes have evolved to detect and respond to changes in the environment, e.g. food supply. Evolutionary understanding can also help to understand important features of the human life history such as menopause.

Autoimmune and inflammatory disorders and risk of malignant lymphomas – an update

Abstract: As specific autoimmune disorders now constitute established risk factors for malignant lymphomas, we describe this association We review reported risk levels, risk determinants, lymphoma subtypes and biological mechanisms in autoimmunity/inflammation, emphasizing on recent findings Whilst numerous reports describe average lymphoma risks in large patient groups, there's a recent shift of focus to risk determinants and the role of inflammatory activity Studies highlight associations with diffuse large B-cell lymphoma, apart from lymphoma development in target organs of inflammation Future studies of high-risk patient subsets using detailed assessments of autoimmunity/inflammation and lymphoma may give important clues to lymphomagenesis

From vulnerable plaque to atherothrombosis.

Abstract: Plaque rupture precipitates approximately 75% of all fatal coronary thrombi. Therefore, the plaque prone to rupture is the primary focus of this review. The lipid-rich core and fibrous cap are pivotal in the understanding of plaque rupture. Plaque rupture is a localized process within the plaque caused by degradation of a tiny fibrous cap rather than by diffuse inflammation of the plaque. Atherosclerosis is a multifocal disease, but plaques prone to rupture seem to be oligofocal at most.

Fruit and vegetable consumption in the prevention of cancer: an update: REVIEW: FRUIT, VEGETABLES AND CANCER

Abstract: Abstract. Terry P, Terry JB, Wolk A (The Karolinska Institute, Stockholm, Sweden; Albert Einstein College of Medicine, Bronx, NY, USA; and National Food Administration, Uppsala, Sweden). Fruit and vegetable consumption in the prevention of cancer: an update (Review). J Intern Med 2001; 250: 280–290.

Infectious aetiology of Hodgkin and non‐Hodgkin lymphomas: a review of the epidemiological evidence

Abstract: Lymphomas constitute a heterogeneous group of malignant disorders with different clinical behaviours, pathological features and epidemiological characteristics. For some lymphoma subtypes, epidemiological evidence has long pointed to infectious aetiologies. A subset of Hodgkin lymphoma is strongly linked to Epstein-Barr virus (EBV) infection. In addition, infectious agents can directly infect and transform lymphocytes (e.g. EBV, human herpesvirus 8), induce immunosuppression (human immunodeficiency virus), or cause chronic immune stimulation (hepatitis C virus, Helicobacter pylori), all of which may play a role in the development of various non-Hodgkin lymphoma subtypes. Here, we review the epidemiological evidence linking infections with malignant lymphoma.

Biological functions and clinical implications of oestrogen receptors alfa and beta in epithelial tissues

Abstract: Morani A, Warner M, Gustafsson J-A ˚ (Karolinska Institutet, Novum, Huddinge, Sweden). Biological functions and clinical implications of oestrogen receptors alfa and beta in epithelial tissues (Review). J Intern Med 2008; 264: 128-142. For the past 10 years it is known that oestrogen func- tions through the activation of two oestrogen recep- tors (ERa and ERb). To the great surprise of endocrinologists, ERb was found to be widely distrib- uted in tissues throughout the body including tissues previously considered as 'oestrogen insensitive'. The epithelium of the ventral prostate and lung as well as ovarian granulosa cells are ERa-negative but ERb- positive and in these tissues ERb seems to be involved in important physiological processes, like differentiation, extracellular matrix organization and stromal-epithelial communication. In tissues where both ERs are expressed, the two receptors seem to counteract each other. In the uterus, mammary gland and immune system, ERa promotes proliferation whereas ERb has pro-apoptotic and pro-differentiating functions. The challenge of the future will be to develop specific agonists, which can selectively acti- vate ⁄ inactivate either ERa or ERb. These pharmaceu- ticals are likely to be of clinical importance in the prevention or treatment of various diseases.

Ventilation/Perfusion SPECT for diagnostics of pulmonary embolism in clinical practice.

Abstract: AIM: The aim of this retrospective study is to illustrate clinical utility and impact of pulmonary embolism (PE) diagnostics of up to date Ventilation/Perfusion SPECT (V/P (SPECT)) applying holistic interpretation criteria. MATERIAL AND METHODS: During a 2-year period 2328 consecutive patients referred to V/P(SPECT) for clinically suspected PE were examined. Final diagnosis was established by physicians clinically responsible for patient care. To establish the performance of V/P(SPECT) negative for PE, patients were followed up by medical records for 6 months. RESULTS: Ventilation/Perfusion SPECT was feasible in 99% of the patients. Data for follow-up were available in 1785 patients (77%). PE was reported in 607 patients (34%). Normal pattern was described in 420 patients (25%). Pathology other than PE such as a pneumonia, left heart failure, obstructive lung disease, tumour was described in 724 patients (41%). Report was nondiagnostic in 19 patients (1%). Six cases were classified as falsely negative because PE was diagnosed at follow-up and was fatal in one case. Six cases were classified as falsely positive because the clinician decided not to treat. In 608 patients with final PE diagnosis, 601 patients had positive V/P(SPECT) (99%). In 1177 patients without final PE diagnosis 1153 patients had negative V/P(SPECT) (98%). CONCLUSIONS: Holistic interpretation of V/P(SPECT,) yields high negative and positive predictive values and only 1% of nondiagnostic findings and was feasible in 99% of patients. It is a responsibility and a challenge of nuclear medicine to provide optimal care of patients with suspected PE by making V/P(SPECT) available. (Less)

MicroRNAs and cancer.

Abstract: The Nobel Prize in Medicine and Physiology was awarded to the RNA interference (RNAi) field in 2006 because of the huge therapeutic potential this technique harbours. However, the RNAi technology is based on a natural mechanism that utilizes short noncoding RNA molecules (microRNAs) to regulate gene expression. This paper reviews our current knowledge about microRNAs focusing on their involvement in cancer and their potential as diagnostics and therapeutics.

The Interleukin-23 / Interleukin-17 axis in intestinal inflammation.

Abstract: Although the precise aetiology of inflammatory bowel disease (IBD) remains unclear, recent discoveries have led to an improved understanding of disease pathogenesis. Whilst these findings have underscored the central role of innate and adaptive immune responses in intestinal inflammation, they have also precipitated a paradigm shift in the key cytokine pathways that drive disease. The prevailing dogma that IBD was mediated by interleukin (IL)-12-driven T-helper (Th)1 CD4 T cell responses towards the bacterial flora has been largely dispelled by findings that the closely related cytokine IL-23 appears to be the key mediator of intestinal inflammation. IL-23 is associated with a novel subset of IL-17-secreting CD4 T cells termed Th17 cells and rodent studies have implicated the IL-23/IL-17 axis in autoimmune inflammation. Genome-wide association studies in IBD patients have confirmed the predominant role of the IL-23 pathway, indicating that this could represent an important future therapeutic target.

Predictable and unpredictable evolution of antibiotic resistance.

Abstract: Evolution of bacteria towards antibiotic resistance is unavoidable as it represents a particular aspect of the general evolution of bacteria. Thus, at the very best, the only hope we can have in the field of resistance is to delay dissemination of resistant bacteria or resistance genes. Resistance to antibiotics in bacteria can result from mutations in resident structural or regulatory genes or from horizontal acquisition of foreign genetic information. In this review, we will consider the predictable future of the relationship between bacteria and antibiotics.

Cardiovascular disease in type 2 diabetes: challenge for treatment and prevention: REVIEW: CVD IN TYPE 2 DIABETES

Abstract: Abstract. Laakso M (University of Kuopio, Kuopio, Finland). Cardiovascular disease in type 2 diabetes: challenge for treatment and prevention (Review). J Intern Med 2001; 249: 225–235.