Prolonged inflammation following critical illness may impair long-term survival: a hypothesis with potential therapeutic implications

Despite successful intensive care a substantial portion of critically ill patients dies after discharge from the intensive care unit or hospital. Observational studies investigating long-term survival of critically ill patients reported that most deaths occur during the first months or year after discharge. Only limited data on the causes of impaired quality of life and post-intensive care unit deaths exist in the current literature. In this manuscript we hypothesize that the acute inflammatory response which characteristically accompanies critical illness is ensued by a prolonged imbalance or activation of the immune system. Such a chronic low-grade inflammatory response to critical illness may be sub-clinical and persist for a variable period of time after discharge from the intensive care unit and hospital. Chronic inflammation is a well-recognized risk factor for long-term morbidity and mortality, particularly from cardiovascular causes, and may thus partly contribute to the impaired quality of life as well as increased morbidity and mortality following intensive care unit and hospital discharge of critically ill patients. Assuming that critical illness is indeed followed by a prolonged inflammatory response, important implications for treatment would arise. An interesting and potentially beneficial therapy could be the administration of immune-modulating drugs during the time after intensive care unit or hospital discharge until chronic inflammation has subsided. Statins are well-investigated and effective drugs to attenuate chronic inflammation and could potentially also improve long-term outcome of critically ill patients after intensive care unit or hospital discharge. Future studies evaluating the course of inflammation during and after critical illness as well as its response to statin therapy are required.

Therapeutic ultrasound for osteoarthritis of the knee or hip

Osteoarthritis is the most common form of joint disease and the leading cause of pain and physical disability in the elderly. Therapeutic ultrasound is one of several physical therapy modalities suggested for the management of pain and loss of function due to osteoarthritis (OA).

[The effect of stress-relieving interventions on inflammatory bowel disease: quality assessment of 10 therapeutic studies]

Patient comments and empirical studies suggest an influence of stress on inflammatory bowel diseases (IBD). We performed a quality assessment of previous studies on the effect of stress reduction on IBD in order to formulate recommendations for future studies and to evaluate their potential for improvement.

Preclinical testing of strategies for therapeutic targeting of human T-cell trafficking in vivo

Naive T cells are migratory cells that continuously recirculate between blood and lymphoid tissues. Antigen-specific stimulation of T cells within the lymph nodes reprograms the trafficking properties of T cells by inducing a specific set of adhesion molecules and chemokine receptors on their surface which allow these activated and effector T cells to effectively and specifically home to extralymphoid organs. The observations of organ-specific homing of T cells initiated the development of therapeutic strategies targeting adhesion receptors for organ-specific inhibition of chronic inflammation. As most adhesion receptors have additional immune functions besides mediating leukocyte trafficking, these drugs may have additional immunomodulatory effects. Therapeutic targeting of T-cell trafficking to the central nervous system is the underlying concept of a novel treatment of relapsing remitting multiple sclerosis with the humanized anti-alpha-4-integrin antibody natalizumab. In this chapter, we describe a possible preclinical in vivo approach to directly visualize the therapeutic efficacy of a given drug in inhibiting T-cell homing to a certain organ at the example of the potential of natalizumab to inhibit the trafficking of human T cells to the inflamed central nervous system in an animal model of multiple sclerosis.

Stem cell-based therapeutic applications in retinal degenerative diseases

Retinal degenerative diseases that target photoreceptors or the adjacent retinal pigment epithelium (RPE) affect millions of people worldwide. Retinal degeneration (RD) is found in many different forms of retinal diseases including retinitis pigmentosa (RP), age-related macular degeneration (AMD), diabetic retinopathy, cataracts, and glaucoma. Effective treatment for retinal degeneration has been widely investigated. Gene-replacement therapy has been shown to improve visual function in inherited retinal disease. However, this treatment was less effective with advanced disease. Stem cell-based therapy is being pursued as a potential alternative approach in the treatment of retinal degenerative diseases. In this review, we will focus on stem cell-based therapies in the pipeline and summarize progress in treatment of retinal degenerative disease.

betaARKct: a therapeutic approach for improved adrenergic signaling and function in heart disease

One of the most powerful regulators of cardiovascular function is catecholamine-stimulated adrenergic receptor (AR) signaling. The failing heart is characterized by desensitization and impaired beta-AR responsiveness as a result of upregulated G protein-coupled receptor kinase-2 (GRK2) present in injured myocardium. Deterioration of cardiac function is progressively enhanced by chronic adrenergic over-stimulation due to increased levels of circulating catecholamines. Increased GRK2 activity contributes to this pathological cycle of over-stimulation but lowered responsiveness. Over the past two decades the GRK2 inhibitory peptide betaARKct has been identified as a potential therapy that is able to break this vicious cycle of self-perpetuating deregulation of the beta-AR system and subsequent myocardial malfunction, thus halting development of cardiac failure. The betaARKct has been shown to interfere with GRK2 binding to the betagamma subunits of the heterotrimeric G protein, therefore inhibiting its recruitment to the plasma membrane that normally leads to phosphorylation and internalization of the receptor. In this article we summarize the current data on the therapeutic effects of betaARKct in cardiovascular disease and report on recent and ongoing studies that may pave the way for this peptide towards therapeutic application in heart failure and other states of cardiovascular disease.