Between the 1950s and 1980s, scientists were focusing mostly on how the genetic code was transcribed to RNA and translated to proteins, but how proteins were degraded had remained a neglected research area. With the discovery of the lysosome by Christian de Duve it was assumed that cellular proteins are degraded within this organelle. Yet, several independent lines of experimental evidence strongly suggested that intracellular proteolysis was largely non-lysosomal, but the mechanisms involved have remained obscure. The discovery of the ubiquitin-proteasome system resolved the enigma. We now recognize that degradation of intracellular proteins is involved in regulation of a broad array of cellular processes, such as cell cycle and division, regulation of transcription factors, and assurance of the cellular quality control. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of human disease, such as malignancies and neurodegenerative disorders, which led subsequently to an increasing effort to develop mechanism-based drugs.
This paper is provided for the convenience of our readers and represents a full edited transcription of the Rambam Grand Rounds Lecture by Dr. Richard Horton, Editor-in-Chief of The Lancet. The lecture was given on October 2, 2014. The Editorial Board wishes to express its gratitude to Dr. Horton for giving permission to present his Rambam Grand Rounds lecture in Rambam Maimonides Medical Journal, in both the original video format and in this printed form.
The Jewish principle concerning a decision with regard to a dangerous treatment is as following: A patient who is estimated to die within 12 months because of a fatal illness is permitted to undergo a treatment that on the one hand may extend his life beyond 12 months, but on the other hand may hasten his death. There are, however, several limitations to this ruling related to the chances of success with the proposed treatment, the nature of the treatment, whether it is intended to be curative or merely to postpone the danger and death, whether the treatment is absolutely necessary, and others. One is not obligated to undergo a dangerous treatment, but one is permitted to do so. The permissibility to forfeit a short life expectancy in order to achieve more prolonged life applies only with the patient’s consent. That consent is valid and is not considered a form of attempted suicide. Neither is a refusal to submit to treatment considered an act of suicide; the patient has the right to refuse a dangerous procedure. In all situations where a permissive ruling is granted for a patient to endanger his short life expectancy, the ruling should be arrived at after careful reflection and with the approval of the rabbinic authorities acting on the recommendation of the most expert physicians.
Suicidal phenomena in the general hospital can take a variety of forms that can be parsed by taking into account whether or not the patient 1) intended to hasten death, and 2) included collaborators, including family and health care providers, in the decision to act. These two criteria can be used to distinguish entities as diverse as true suicide, non-compliance, euthanasia/physician-assisted suicide, and hospice/palliative care. Characterizing the nature of “suicide” events facilitates appropriate decision-making around management and disposition.
The human body hosts rich and diverse microbial communities. Our microbiota affects the normal human physiology, and compositional changes might alter host homeostasis and, therefore, disease risk. The microbial community structure may sometimes occupy discrete configurations and under certain circumstances vary continuously. The ability to characterize accurately the ecology of human-associated microbial communities became possible by advances in deep sequencing and bioinformatics analyses.
On May 28, 2014, colleagues from the Mayo Clinic visited Rambam Health Care Campus to gather and exchange ideas and knowledge. American and Israeli caregivers and scientists shared with each other the daily challenges of their practice in many and varied settings. This issue is dedicated to the presentations given and the collaborative efforts we are building as a result of that visit. We hope this issue will serve as an example of the fruitfulness of international collaboration to enhance and propagate medical knowledge worldwide.
In rare cases, the monoclonal immunoglobulin that characterizes essential monoclonal gammopathy interacts with a self-antigen with functional consequences and a resulting clinical syndrome. This event is presumably random and results from the clone of B lymphocytes making a monoclonal immunoglobulin that simulates an autoimmune antibody. Thus, by chance, the monoclonal immunoglobulin has sufficient affinity for an epitope on a normal protein that functional consequences ensue. One such rare event is the synthesis and secretion of a monoclonal immunoglobulin that binds to human insulin. Inactivation of insulin by antibody results in (1) an early postprandial hyperglycemia, (2) followed by either or both (i) a reactive overshot in insulin secretion, as a result of hypertrophied or hyperplastic islet beta cells, later falling glucose levels, and (ii) an unpredictable dissociation of insulin from the complex, and, several hours later, (3) a resultant increase in free insulin levels and severe hypoglycemia with clinical consequences, ranging from sweating, dizziness, headache, and tremors to confusion, seizures, and unconsciousness. These attacks are invariably responsive to glucose administration. This very uncommon manifestation of a monoclonal gammopathy can occur in patients with essential monoclonal gammopathy or myeloma. The monoclonal anti-insulin immunoglobulin in monoclonal gammopathy has a low affinity for insulin, but has a high capacity for insulin-binding, resulting in the syndrome of episodic hypoglycemic attacks. This phenomenon of an insulin-binding monoclonal immunoglobulin simulates the acquired insulin autoimmune syndrome, although the latter is mediated by a polyclonal antibody response in the majority of cases studied, and has linkage to HLA class II alleles.
The transition of new biotechnologies into clinical trials is a critical step in approving a new drug or therapy in health care. Ethically recruiting appropriate volunteers for these clinical trials can be a challenging task for both the pharmaceutical companies and the US Food and Drug Administration. In this paper we analyze the Jewish halachic perspectives of volunteering for clinical trials by focusing on an innovative technology in reproductive medicine, mitochondrial replacement therapy. The halachic perspective encourages individuals to volunteer for such clinical trials under the ethical principles of beneficence and social responsibility, when animal studies have shown that health risks are minimal.
An anniversary is not only a point of memory—it provides the opportunity for self-examination and paves the way to the future. Every anniversary marks a starting-point that was preceded by a vision. The beginning of any vision is a personal dream—someone wants to improve or repair the world as far as he is able. The vision motivates action; in its aftermath comes the reality. This is the 21st issue of Rambam Maimonides Medical Journal. This issue is particularly important as it marks the completion of five years of creative work pursuing our vision for a high-caliber scientific medical journal. Our vision has become reality.
As I shared in my January 2015 editorial, the furor surrounding publication in The Lancet of the open letter by P. Manduca et al. carried potential for bad and for good. Here at Rambam Health Care Campus, we have chosen and will continue to look for the good.
