New insights into the hygiene hypothesis in allergic diseases

There is convincing evidence from both human and animal studies suggesting that the infant intestinal microbiota plays an important role in regulating immune responses associated with the development of allergic diseases. To date there are, however, still no definite bacterial taxa or particular subsets of the microbiota that have been consistently associated with allergic diseases, which is mainly attributable to the methodological dissimilarities between studies. As such there is a need to apply different methodological concepts to enhance a deeper and more refined understanding of the relationship between the gut microbiota and allergies. Within our recent studies we reported that colonization by clostridia in early infancy increased the risk of atopic dermatitis. Using subsequent mediation analysis, we demonstrated that birth mode and having older siblings strongly impacted the infant microbiota which in turn affected the risk of atopic dermatitis. The results of these mediation analyses contributed stronger evidence for a causal link of birth mode and birth order on allergy risk through modulation of the microbiota composition.     

New insights into mechanism of inflammatory and allergic diseases in mucosal tissues

The gastrointestinal immune system is a major component of the mucosal barrier to foreign antigens including microbial and dietary antigens. Under normal circumstances, the mucosal immune system employs tightly regulated dynamic mucosal intra- and internets for the maintenance of an appropriate immunological balance between the host and gut environments. For example, mucosally induced tolerance is usually induced against enteric commensal bacterial and/or dietary antigens. However, in some cases, the break down of these tightly regulated mucosal immune responses led to hyper-responsiveness against these gut environmental antigens. To this end, numerous disorders could evoke in the gastrointestinal tissues, such as inflammatory bowel disease (IBD) and allergic gastroenteropathy. Recently, many studies have described possible molecular and cellular mechanisms of those dysfunctions in the gastrointestinal tissues. In this review, we have briefly summarized some of the current interesting and exciting findings for gastrointestinal diseases, especially IBD and intestinal allergic diseases from our group, which can be applied for the development of new mucosal immune therapy.     

New insights into the pathophysiology of allergic rhinitis.

The immune response to an allergen is dependent on an initial sensitization process, with future exposures triggering a two-part allergic response including an early and a late phase. The process by which an allergen is recognized as such, including which cell types and cytokines are involved in the sensitization process, has become clearer over the last several years. Similarly, the roles of the different preformed mediators responsible for many of the signs and symptoms of the early phase response have been elucidated. Recent work also has shed some light on the multitude of cells and mediators involved in the late-phase reactions, which can lead to priming and long-term inflammation. This article will discuss some of this recent work as well as review the basics behind all of the stages of the allergic response, especially as they apply to the nose and upper airway.     

New insights into autoimmune liver diseases.

Autoinflammatory liver disease represents an important aspect of global hepatological practice. The three principal disease divisions recognized are autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis. Largely, but not exclusively, these diseases are considered to be autoimmune in origin. Increased recognition of outlier and overlap syndromes, changes in presentation and natural history, as well as the increased awareness of IgG4-associated sclerosing cholangitis, all highlight the limitations of the classic terminology. New insights continue to improve the care given to patients, and have arisen from carefully conducted clinical studies, therapeutic trials, as well as genetic and laboratory investigations. The challenges remain to treat patients before liver injury becomes permanent and to prevent the development of organ failure.     

New insights into the hygiene hypothesis in allergic diseases: Mediation of sibling and birth mode effects by the gut microbiota

There is convincing evidence from both human and animal studies suggesting that the infant intestinal microbiota plays an important role in regulating immune responses associated with the development of allergic diseases. To date there are, however, still no definite bacterial taxa or particular subsets of the microbiota that have been consistently associated with allergic diseases, which is mainly attributable to the methodological dissimilarities between studies. As such there is a need to apply different methodological concepts to enhance a deeper and more refined understanding of the relationship between the gut microbiota and allergies. Within our recent studies we reported that colonization by clostridia in early infancy increased the risk of atopic dermatitis. Using subsequent mediation analysis, we demonstrated that birth mode and having older siblings strongly impacted the infant microbiota which in turn affected the risk of atopic dermatitis. The results of these mediation analyses contributed stronger evidence for a causal link of birth mode and birth order on allergy risk through modulation of the microbiota composition.     

New insights into sexual functioning and fertility in rheumatic diseases

Sexuality is an often neglected area of quality of life in patients with rheumatic disease. Manifestations and symptoms of disease can impair sexual functioning, but this can be much improved by adequate intervention and counseling. Fertility is in general not reduced in rheumatic diseases, however, the time taken to achieve a pregnancy is often increased. An increased rate of pregnancy loss is observed in systemic lupus erythematosus and the antiphospholipid syndrome contributing to a reduced family size. Autoantibodies are present in most of the rheumatic diseases and can interfere with fertilization, implantation, embryonic development and placental function. Active disease disturbs the hypothalamic-pituitary-axis, giving rise to periods of gonadal dysfunction. Toxic effects of immunosuppressive drugs can induce transient or permanent gonadal failure in women and men.     

Dysfunctional ryanodine receptors in the heart: New insights into complex cardiovascular diseases

Calcium dependent signaling is highly regulated in cardiomyocytes and determines the force of cardiac muscle contraction. The cardiac ryanodine receptors (RyR2) play important roles in health and disease. Modulation of RyR2 by phosphorylation is required for sympathetic regulation of cardiac function. Abnormal regulation of RyR2 contributes to heart failure, and atrial and ventricular arrhythmias. RyR2 channels are oxidized, nitrosylated, and hyperphosphorylated by protein kinase A (PKA) in heart failure, resulting in “leaky” channels. These leaky RyR2 channels contribute to depletion of calcium from the sarcoplasmic reticulum, resulting in defective cardiac excitation–contraction coupling. In this review, we discuss both the importance of PKA and calcium/calmodulin-dependent kinase II (CaMKII) regulation of RyR2 in health, and how altered phosphorylation, nitrosylation and oxidation of RyR2 channels lead to cardiac disease. Correcting these defects using either genetic manipulation (knock-in) in mice, or specific and novel small molecules ameliorates the RyR2 dysfunction, reducing the progression to heart failure and the incidence of arrhythmias. This article is part of a Special Issue entitled “Calcium Signaling in Heart”.     

New insights into the treatment of obesity

Obesity is a chronic, progressive and relapsing disease with a rising global prevalence associated with increased morbidity and mortality and reduced quality of life. Treatment of obesity requires a comprehensive medical approach that includes behavioural interventions, pharmacotherapy and bariatric surgery. The degree of weight loss with all approaches is highly heterogeneous, and long-term weight maintenance remains challenging. For years, antiobesity medications have been limited in number, often delivering meagre efficacy and raising numerous safety concerns. Therefore, there is a need for the development of highly efficacious and safe new agents. Recent insights into the complex pathophysiology of obesity have increased our understanding of intervenable targets for pharmacotherapies to treat obesity and improve weight-related cardiometabolic complications, namely, type 2 diabetes, hyperlipidaemia and hypertension. As a result, novel potent therapies have emerged, such as semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) recently approved for the treatment of obesity. Semaglutide 2.4 mg once weekly significantly reduces body weight by approximately 15%, with simultaneous improvement in cardiometabolic risk factors and physical functioning in people with obesity. Tirzepatide, the first dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RA, has recently demonstrated that body weight reduction exceeding 20% in people with obesity and coupled with improved cardiometabolic measures is feasible. Thus, these novel agents promise to narrow the gap between the weight-loss effects of behaviour interventions, previous pharmacotherapies, and bariatric surgery. In this narrative review, we highlight established and emerging therapeutic treatments for long-term obesity management and position them in a framework according to their weight loss effects.     

New aspects on inflammation in allergic diseases

BackgroundAllergic disease has currently reached epidemic proportions, with a high percentage of individuals in the developed world exhibiting an allergic response after exposure to some common environmental factors. Although new strategies for the treatment and management of allergic diseases have decreased the mortality rate, a high percentage of affected persons still require frequent hospitalization and experience decreased quality of life.MethodsAn internet-based literature search was performed for recent contributions on the underlying mechanisms provoking an allergic response and their potential for therapeutic approaches.ResultsNovel concepts on allergic responses have emerged: allergic disease may result from an imbalance between allergen activation of regulatory T cells and effector T helper 2 cells (Th2), a process in which dendritic cells are key players. Cytokines such as interleukin (IL)-6, IL-21, IL-25, and human thymic stromal lymphopoietin (TSLP) seem to be important contributors in allergic processes. New data on IgE effector responses and on the IgE-independent mechanisms involved in allergic reactions have resolved some unanswered questions about these reactions.ConclusionsThese new findings on allergic diseases have important implications for diagnosis and management, with potential improvements in prevention and treatment, which could provide a cure in the future.     

New insights into the cellular immunology of the intestine in relation to the pathophysiology of inflammatory bowel diseases

The authors review advances about altered immunological cellular mechanisms in inflammatory bowel diseases (IBD). The innate immune response might play a role in the inductive phase : epithelial barrier defect, production of inflammatory cytokines and defective neutrophil function. Dendritic cells have a pivotal role, since they sense the nature of the micro-organisms in the intestine in order to drive either adaptive immune responses through IL-12 or IL-4 and co-stimulatory molecules, or immunotolerance through regulatory T cells (Tr). T helper(Th)1 cytokines (IFNgamma, TNF-alpha, IL-12) are secreted in excess in Crohn's disease (CD) whereas in ulcerative colitis an atypical Th2 immune response (IL-4, TGFbeta) has been reported. However, activation of Th can only lead to effective immune response if co-stimulatory molecules expressed on activated T cells bind to their specific ligands on the antigen-presenting-cells, mesenchymal and endothe-, lial cells. This binding is necessary to generate an effective immune response, to enhance expression of adhesion molecules and T cell recruitment, promoting chronic inflammation in IBD. A defective function of Tr might contribute to excessive T cell response. Innate CD4 + CD25 + Tr derived from the thymus represent 5-10% of T cells in peripheral lymphoid organs. Acquired peripheral Tr downregulate the immune response through IL-10 and TGF-beta production. In IBD effector T cells might downregulate the development of Tr cells in the thymus. Another defective mechanism in CD is T cell resistance to apoptosis, leading to inappropriate immune homeostasis and accumulation of T cells in the tissues. New therapeutic agents have been proposed for correcting deficiencies of innate immunity or reducing excessive immune responses, with promising results confirmed by randomized controlled trials.     

New insights into pneumococcal disease

Streptococcus pneumoniae (pneumococcus) remains a common cause of disease and death throughout the world. Despite considerable research into various aspects of this infection, there still remain a number of unresolved issues, as well as considerable ongoing controversies, particularly with regard to its optimal management. Among the risk factors for pneumococcal pneumonia, cigarette smoking has been shown to play a major role, more recently among HIV-infected individuals. Considerable recent research has focused on determining the role of the various protein virulence factors in disease pathogenesis. Among the ongoing controversies has been an appreciation of the true impact of antimicrobial resistance on the outcome of pneumococcal infections, as well an understanding of the role of combination antibiotic therapy in the more severely ill hospitalized cases. An important advance in the prevention of pneumococcal infections has been the introduction of the pneumococcal protein conjugate vaccine.     

对动脉粥样硬化斑块的新认识

粥样硬化性动脉狭窄是脑梗死的主要病理生理基础。现代观点认为,脑梗死的发生与粥样斑块的活跃状态密切相关,而与斑块体积大小的关系不大。斑块的不稳定性或脆性决定于斑块内的脂质核心、巨噬细胞及斑块纤维帽。     

New insights into hereditary pancreatitis

The recent discovery that mutations in the trypsinogen gene are responsible for acute and chronic pancreatitis, and that patients with hereditary pancreatitis are at great risk for pancreatic cancer, has opened the door to understanding many aspects of pancreatic disease. This review focuses on the clinical presentation of hereditary pancreatitis, the mechanism of disease, and implications of this disease on understanding acute and chronic pancreatitis.