Honoring 50 Years of Clinical Heart Transplantation in Circulation: In-Depth State-of-the-Art Review.

Heart transplantation has become a standard therapy option for advanced heart failure. The translation of heart transplantation from innovative experiments to long-term clinical success has married prescient insights with discipline and organization in the domains of surgical techniques, organ preservation, immunosuppression, organ donation and transplantation logistics, infection control, and long-term graft surveillance. This review explores the key milestones of the past 50 years of heart transplantation and discusses current challenges and promising innovations on the clinical horizon.

An Amazing Turn of Events.

How the master regulator of cell growth, TOR, came to be identified and understood, from the perspective of its discoverer, Michael N. Hall.

Thiopurines and inflammatory bowel disease: Current evidence and a historical perspective.

The use of thiopurines in inflammatory bowel disease (IBD) has been examined in numerous prospective, controlled trials, with a majority demonstrating a clinical benefit. We conducted this review to describe the historical and current evidence in the use of thiopurines in IBD. A systematic search was performed on MEDLINE between 1965 and 2016 to identify studies on thiopurines in IBD. The most robust evidence for thiopurines in IBD includes induction of remission in combination with anti-tumor necrosis factor (anti-TNF) agents, and maintenance of remission and post-operative maintenance in Crohn's disease. Less evidence exists for thiopurine monotherapy in induction of remission, maintenance of ulcerative colitis, chemoprevention of colorectal cancer, and in preventing immunogenicity to anti-TNF. Evidence was often limited by trial design. Overall, thiopurines have demonstrated efficacy in a broad range of presentations of IBD. With more efficacious novel therapeutic agents, the positioning of thiopurines in the management of IBD will change and future studies will analyze the benefit of thiopurines alone and in conjunction with these new medications.

Multiple sclerosis-a quiet revolution.

Multiple sclerosis (MS) has been thought to be a complex and indecipherable disease, and poorly understood with regards to aetiology. Here, we suggest an emphatically positive view of progress over several decades in the understanding and treatment of MS, particularly focusing on advances made within the past 20 years. As with virtually all complex disorders, MS is caused by the interaction of genetic and environmental factors. In recent years, formidable biochemical, bioinformatic, epidemiological and neuroimaging tools have been brought to bear on research into the causes of MS. While susceptibility to the disease is now relatively well accounted for, disease course is not and remains a salient challenge. In the therapeutic realm, numerous agents have become available, reflecting the fact that the disease can be attacked successfully at many levels and using varied strategies. Tailoring therapies to individuals, risk mitigation and selection of first-line as compared with second-line medications remain to be completed. In our view, the MS landscape has been comprehensively and irreversibly transformed by this progress. Here we focus on MS therapeutics-the most meaningful outcome of research efforts.

Transplantation: a brief history.

Developments in transplantation have progressed dramatically over the past century. Current research is underway to optimize immune modulation, genetically engineering animals for xenografting, and breakthroughs are occurring in regenerative medicine. However, pioneering live-donor transplantation has transformed transplantation in the organ shortage, and these contribute an increased proportion of transplanted organs. Live-donor transplantation is associated with better long-term outcomes, and techniques to recover organs have become less invasive. We set out to examine the evolution of transplantation from its historic beginnings to the developments that make it successful today.

From defining antigens to new therapies in multiple sclerosis: honoring the contributions of Ruth Arnon and Michael Sela.

Ruth Arnon and Michael Sela profoundly influenced the development of a model system to test new therapies in multiple sclerosis (MS). Their application of the animal model, known as experimental autoimmune encephalomyelitis (EAE), for the discovery of Copaxone, opened a new path for testing of drug candidates in MS. By measuring clinical, pathologic, and immunologic outcomes, the biological implications of new drugs could be elucidated. Using EAE they established the efficacy of Copaxone as a therapy for preventing and reducing paralysis and inflammation in the central nervous system without massive immune suppression. This had a huge impact on the field of drug discovery for MS. Much like the use of parabiosis to discover soluble factors associated with obesity, or the replica plating system to probe antibiotic resistance in bacteria, the pioneering research on Copaxone using the EAE model, paved the way for the discovery of other therapeutics in MS, including Natalizumab and Fingolimod. Future applications of this approach may well elucidate novel therapies for the neurodegenerative phase of multiple sclerosis associated with disease progression.

The history and progression of treatments for allergic rhinitis.

This article intends to place new treatments in the context of allergic rhinitis (AR) treatment history. The medical literature was searched for significant advances and changes in AR treatment. Historical data on AR treatment options and management were selected. Reviews of AR management published throughout the 20th century were included to provide context for treatment advances. Modern AR treatment began in the early 20th century with immunotherapy and was soon followed by the emergence of antihistamine therapy in the 1930s. Numerous treatments for AR have been used over the ensuing decades, including decongestants, mast cell stabilizers, and leukotriene receptor antagonists. Topical corticosteroid options were developed the 1950s, and, added to baseline antihistamine therapy, became the foundation of AR treatment. Treatment options were significantly impacted after the 1987 Montreal Protocol, which phased out the use of chlorofluorocarbon propellant aerosols because of environmental concerns. From the mid-1990s until recently, this left only aqueous solution options for intranasal corticosteroids (INSs). The approval of the first hydrofluoroalkane propellant aerosol INSs for AR in 2012 restored a "dry" aerosol treatment option. The first combination intranasal antihistamine/INSs was also approved in 2012, providing a novel treatment option for AR. Treatment of AR has progressed with new therapeutic options now available. This should continue to move forward with agents to alter the allergic mechanism itself and impact the disease burden that has a significant impact on patient outcomes.

An Overview of Transplant Immunosuppression--History, Principles, and Current Practices in Kidney Transplantation.

From the historical first transplant in 1954 to the current transplant era, tremendous strides have been made in transplant immunology and immunosuppression. The most common immunosuppressive regimens use a combination of agents with differing modes of action to maximize efficacy and minimize the toxicities associated with each class of agent. The general categories of immunosuppressives are glucocorticoids, antimetabolites, calcineurin inhibitors, anti-lymphocyte antibody therapies (monoclonal and polyclonal), costimulation blockers, and mTOR inhibitors. This article reviews immunosuppressant medications, their actions, and significant side effects; discusses clinical management issues of immunosuppression; and describes future directions for the development of immunosuppressive medications.

Calcineurin inhibitors: 40 years later, can't live without ...

Calcineurin inhibitors (CNIs) revolutionized the field of organ transplantation and remain the standard of care 40 years after the discovery of cyclosporine. The early impressive results of cyclosporine in kidney transplant recipients led to its subsequent use in other organ transplant recipients and for treatment of a variety of autoimmune diseases as well. In this review, we examine the discovery of CNIs, their mechanism of action, preclinical and clinical studies with CNIs, and the usage of CNIs in nontransplant recipients. We review the mechanisms of renal toxicity associated with CNIs and the recent efforts to avoid or reduce usage of these drugs. Although minimization strategies are possible, safe, and of potential long-term benefit, complete avoidance of CNIs has proven to be more challenging than initially thought.

Historical overview of transplantation.

Except for legends and claims of miracles, most histories of transplantation cover only the last 60 years because there were no earlier successes. However, the story of even this era has been documented in such rich detail that a full account would fill several volumes. Thus, this brief summary must be limited to highly selected "landmarks." Some landmarks had an immediate impact, but the importance of others went unrecognized for decades. Some findings that deserved landmark status were overlooked or forgotten, whereas others of no biological significance had major impact. Placing these events in perspective is challenging. Several of transplantation's pioneers are still alive, and most of the others are within living memory. Virtually all of them have produced their own accounts. For the most part, they agree on what the "landmarks" are, but their differences in emphasis and perspective make an interesting story.

[Inflammatory bowel disease - the past 50 years]. / Chronisch entzündliche Darmerkrankungen - die letzten 50 Jahre.

Since ancient times chronic inflammatory bowel diseases have been known as non-contagious colitis and remain as an unsolved enigma of internal medicine. In the past 50 years it became clear that the incidence is increasing, the cause is multifactorial genetics as well as environment and the intestinal immune reaction is directed against the intestinal microbiota and not tissue antigens. Based on groundbreaking genetic studies the focus has moved from adaptive to innate immunity and thus from autoimmunity to a barrier defect. This paradigm shift will have a major impact on therapies which are traditionally immunosuppressive and will be developed to improve the antibacterial mucosal barrier in the future.

Hartmann Stahelin (1925-2011) and the contested history of cyclosporin A.

The aims of this study are twofold: (i) to pay tribute to Hartmann Stahelin for his scientific research on cyclosporin A; and (ii) to consider possible lessons for future pharmacological innovation by revisiting Stahelin's personal struggles to obtain fair recognition for his contribution to transplantation medicine.

[The 50th anniversary of the first liver transplantation: from myth to reality. Tributes to Thomas Starzl, 2012 Lasker Prize]. / Le cinquantenaire de la première transplantation hépatique: du mythe à la réalité. Hommages à Thomas Starzl, Prix Lasker 2012.

Chemical immunosuppression and the reversal of rejection permit to develop kidney transplantation and were incitative to start liver transplantation in 1963. However, the difficulties were many: wrong operative indications, inadequate immunosuppression, difficulty of etiologic diagnosis of jaundice, poor preservation of the graft. Cyclosporine was the key-step of the success.