Beyond the increase in medical knowledge and biotechnology during the last decades, doctors have adopted professional norms that would have been considered heretical only two generations ago. The changes transpired between the 1970s and 1990s, and generated controversies between those who upheld the traditional values of patient care, and those who welcomed the new professional norms. Professor Dr Johannes Juda Groen (1903–1990) predicted and promoted some of these changes. As early as the 1940s through the 1960s, he recognized the need to teach interviewing skills and advocated an orientation to patients, rather than to diseases; he supported decision-making based on evidence, rather than on personal experience and pathophysiologic rationale; and he demonstrated that psychosocial determinants predict, rather than only correlate with, disease. These views led to confrontations with the medical establishments in the Netherlands and in Israel. Still, many of his colleagues recognized the value of his contributions. The author, for one, admires Groen’s commitment in challenging the prevailing clinical wisdom after the end of World War 2, and his courage in opposing the views of his colleagues.
Anti-citrullinated protein antibodies (ACPAs) are highly specific serologic markers for rheumatoid arthritis (RA) and can pre-date clinical disease onset by up to 10 years, also predicting erosive disease. The process of citrullination, the post-translational conversion of arginine to citrulline residues, is mediated by peptidylarginine deiminase (PAD) enzymes present in polymorphonuclear cells (PMNs). Calcium ions (Ca2+) are required for PAD activation, but the intracellular Ca2+ concentration in normal cells is much lower than the optimal Ca2+ concentration needed for PAD activation. For this reason, it has been proposed that PAD activation, and thus citrullination, occurs only during PMN cell death when PAD enzymes leak out of the cells into the extracellular matrix, or extracellular Ca2+ enters the cells, with the high Ca2+ concentration activating PAD. Recently, using artificial in vitro systems to corroborate their hypothesis, Romero et al. demonstrated that “hypercitrullination,” citrullination of multiple intracellular proteins, occurs within synovial fluid (SF) cells of RA patients, and that only modes of death leading to membranolysis such as perforin-granzyme pathway or complement membrane attack complex activation cause hypercitrullination. In order for Romero’s hypothesis to hold, it is reasonable to surmise that PMN-directed lysis should occur in the rheumatoid joint or the circulation of RA patients. Research conducted thus far has shown that immunoglobulin G (IgG) targeting PMNs are present in RA SF and mediate PMN activation. However, the role of anti-PMN IgG in mediating complement activation and subsequent PMN lysis and hypercitrullination has not been fully evaluated.
Osteoporosis is a common condition with significant health care costs. First-line therapy is with bisphosphonates, which have proven anti-fracture efficacy. Around 10 years after the introduction of bisphosphonates reports began to be published of atypical femoral fractures (AFFs) that may be associated with this therapy. These fractures are associated with significant morbidity although lower mortality than the more common osteoporotic neck-of-femur fractures. A case definition has been described to allow identification of this class of fracture. Further work has established a high relative risk of AFFs in patients treated with bisphosphonates, but a low absolute risk in comparison to that of osteoporotic fractures. Proposed pathological mechanisms include low bone turnover states leading to stress/insufficiency fractures. Clinicians should be aware of the risk of AFFs and in particular the high rate of prodromal thigh/groin pain that warrants investigation in a patient receiving a bisphosphonate. If an incomplete fracture is diagnosed then bisphosphonate therapy needs to be stopped and prophylactic surgery may be considered. Due to these rare side effects patients on bisphosphonates require regular review, and this is particularly advised after 5 years of oral or 3 years of intravenous therapy.
Sacroiliitis, inflammation of the sacroiliac joint (SIJ), is the hallmark of ankylosing spondylitis and spondyloarthritis (SpA) in general. The arsenal of recommended diagnostic modalities for imaging of the SIJ is scanty and, in practice, includes only conventional X-rays and magnetic resonance imaging (MRI). This review suggests that bone scintigraphy, particularly single-photon emission computed tomography (SPECT) with calculation of indices, or SPECT in combination with low-dose computed tomography (CT) can be a sensitive and specific tool for the diagnosis of sacroiliitis and can be used as part of the individualized approach to the diagnosis of axial SpA. In addition, [18F]fluoride positron emission tomography (PET)/CT imaging and immunoscintigraphy, using labeled monoclonal anti-cytokine anti-bodies, are promising methods of current scientific interest in this field.
Epidemiological studies have shown that patients with psoriatic arthritis (PsA) are often affected by numerous comorbidities that carry significant morbidity and mortality. Reported comorbidities include diabetes mellitus, obesity, metabolic syndrome, cardiovascular diseases, osteoporosis, inflammatory bowel disease, autoimmune eye disease, non-alcoholic fatty liver disease, depression, and fibromyalgia. All health care providers for patients with PsA should recognize and monitor those comorbidities, as well as understand their effect on patient management to ensure an optimal clinical outcome.
Dr Gerald Loewi was Senior Research Scientist and Consultant Pathologist at the Medical Research Council (MRC) Rheumatism Research Unit at Taplow, England and subsequently the MRC Clinical Research Centre, Harrow, England. An immunologist with a background in pathology, he made major contributions to our understanding of the immunopathology of rheumatoid arthritis and other rheumatic disorders. With his colleagues, he developed a more sophisticated concept of what were initially thought to be primary autoimmune or degenerative diseases but are now recognized as much more complex disease processes. He was one of the first to initiate close collaboration between clinicians and scientists in rheumatology research and practice.
Autoinflammatory diseases (AID) are characterized by seemingly unprovoked self-limited attacks of fever and systemic inflammation potentially leading to amyloidosis. Familial Mediterranean fever (FMF) is the most common AID and therefore the most studied. Besides FMF, the other main hereditary AID are tumor necrosis factor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD), and cryopyrin-associated periodic fever syndrome (CAPS). These hereditary diseases result from a mutant gene that is involved in the regulation of inflammation, resulting in a characteristic clinical phenotype. The differential diagnosis of AID can be challenging due to a wide overlap in clinical manifestations. Moreover, a considerable proportion of patients present with autoinflammatory symptoms but without a pathogenetic variant on genetic analysis. Furthermore, non-hereditary AID, such as the periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome, which is the most common AID in children worldwide, must be excluded in certain circumstances. Herein we shall review the main AID and describe a practical approach to diagnosis in a patient with a clinical suspicion of AID.
Long-standing diabetes leads to structural and functional alterations in both the micro- and the macro-vasculature. Designing therapies to repair these abnormalities present unique and sophisticated challenges. Vascular endothelial cells are the primary cells damaged by hyperglycemia-induced adverse effects. Vascular stem cells that give rise to endothelial progenitor cells and mesenchymal progenitor cells represent an attractive target for cell therapy for diabetic patients. In this review, we shed light on challenges and recent advances surrounding stem cell therapies for diabetes vascular complications and discuss limitations for their clinical adoption.
We are proud to introduce you to the Thirteenth Rambam Research Day, now established as a key annual event at Rambam Health Care Campus (Rambam), reflecting the diverse research activities on our campus...
Objective: To examine the relationship between duration of fetal hypoxia, nucleated red blood cell (NRBC) count, and fetal growth.
Methods: Pregnant rats were exposed to a severe hypoxia (9.5%–10% O2) for varying time intervals (2, 6, 12, 24, 48, and 120 hours; n=4 for each time interval) immediately prior to delivery at term. Normoxic controls were exposed to room air (21% O2) and matched for all other study variables (n=4 rats for each time interval). Pups were delivered via hysterotomy while maintaining exposure gas concentrations. Blood gas analysis and NRBC counts were performed, and fetal body and liver weights were recorded. Student’s t test and simple regression were used for statistical analysis.
Results: As the duration of hypoxia increased, fetal weight, liver weight, blood bicarbonate, and base excess levels decreased significantly; concomitantly, NRBC counts increased. This increase in NRBCs became statistically significant after 24 hours of exposure. After 48 hours of hypoxia there was a 2.5-fold rise in NRBC count, and after 120 hours of hypoxia there was a 4.5-fold rise in NRBC count over control levels. After 12 or more hours of hypoxia, fetal body weights were significantly reduced; 120 hours of hypoxia resulted in a 35% reduction in fetal body weight, a 34% reduction in fetal liver weight, and 356% increase in NRBC count.
Conclusion: In a pregnant rat model, chronic maternal hypoxia (≥24 hours) results in a significant increase in fetal NRBC counts as well as reduced fetal body weight and organ growth.
