CD4+CD25+Foxp3+ regulatory T cells (Treg) are critical to the maintenance of immune tolerance. Treg are known to utilize a number of molecular pathways to control immune responses and maintain immune homeostasis. Fibrinogen-like protein 2 (FGL2) has been identified by a number of investigators as an important immunosuppressive effector of Treg, which exerts its immunoregulatory activity by binding to inhibitory FcγRIIB receptors expressed on antigen-presenting cells including dendritic cells, endothelial cells, and B cells. More recently, it has been suggested that FGL2 accounts for the immunosuppressive activity of a highly suppressive subset of Treg that express T cell immunoreceptor with Ig and ITIM domains (TIGIT). Here we discuss the important role of Treg and FGL2 in preventing alloimmune and autoimmune disease. The FGL2–FcγRIIB pathway is also known to be utilized by viruses and tumor cells to evade immune surveillance. Moving forward, therapies based on modulation of the FGL2–FcγRIIB pathway hold promise for the treatment of a wide variety of conditions ranging from autoimmunity to cancer.
Chronic hepatitis C virus (HCV) infection is a leading cause of liver disease worldwide and remains the most common indication for liver transplantation. The current standard of care leads to a sustained vir-al response of roughly 50% of treated patients at best. Furthermore, anti-viral therapy is expensive, pro-longed, and associated with serious side-effects. Evidence suggests that a poor response to treatment may be the result of a suppressed anti-viral immunity due to the presence of increased numbers and activity of CD4+CD25+Foxp3+ regulatory T cells (Treg cells). We and others have recently identified fi-brinogen-like protein 2 (FGL2) as a putative effector of Treg cells, which accounts for their suppressive function through binding to Fc gamma receptors (FcγR). In an experimental model of fulminant viral hepatitis, our laboratory showed that increased plasma levels of FGL2 pre- and post-viral infection were predictive of susceptibility and severity of disease. Moreover, treatment with antibody to FGL2 fully protected susceptible animals from the lethality of the virus, and adoptive transfer of wild-type Treg cells into resistant fgl2-deficient animals accelerated their mortality post-infection. In patients with HCV infection, plasma levels of FGL2 and expression of FGL2 in the liver correlated with the course and severity of the disease. Collectively, these studies suggest that FGL2 may be used as a biomarker to pre-dict disease progression in HCV patients and be a logical target for the development of novel therapeu-tic approaches for the treatment of patients with HCV infection.
Objective: To compare the results of treating patients with common bile duct (CBD) stones by endoscopic sphincterotomy (ES), surgical exploration, or a combination of ES and surgical CBD exploration (the rendezvous technique).
Methods: A narrative review of the literature.
Summary of Data: Before 1990, 17 cohort studies indicated that ES cleared CBD stones in 92.0% of patients, with a mortality rate of 1.5%. Surgery removed CBD stones in 90.2% of patients, with a 2.1% mortality rate. A single randomized controlled trial in 1987 showed that ES removed CBD stones in 91% of 55 patients, with a 3.6% mortality rate and a 27% complication rate, whereas surgical CBD exploration removed CBD stones in 92%, with a 1.8% mortality rate and a 22% complication rate. Since 1991, 26 randomized controlled trials have shown that laparoscopic–ES rendezvous is as effective as ES alone and laparoscopic surgery alone but is associated with fewer complications, a reduced need for additional procedures, and a shorter hospital stay.
Conclusions: A laparoscopic–ES rendezvous appears to be the optimal approach to the treatment of CBD stones in younger and fit patients. The choice between ES alone and laparoscopic–ES rendezvous in older or high-risk patients remains uncertain.
The world, as a global village, is currently taking part in a real-time public health, medical, socio-cultural, and economic experiment on how best to combat the COVID-19 pandemic. Extraordinary times demand extraordinary measures. Depending on the time from the outbreak, strategies have ranged from minimal intervention to mitigation by quarantine for high-risk groups (elderly with chronic illnesses) to containment and lockdown. Adherence to such restrictions have depended on the individual and national psyche and culture. One can understand and forgive governments for being over-cautious, but not for being ill-prepared. It seems that Singapore after SARS (2003) and South Korea after MERS (2015) learnt from their experiences and have fared relatively well with minimal disruption to daily routines. Coping with the challenge of COVID-19 is an urgent global task. We use the Sociotype ecological framework to analyze different coping responses at three levels: Context (government and leadership, social context, health services, and media); Relationships; and the Individual. We describe the many negative outcomes (e.g. mortality [obviously], unemployment, economic damage, food insecurity, threat to democracy, claustrophobia) and the positive ones (e.g. new, remote teaching, working, and medical routines; social bonding and solidarity; redefining existential values and priorities) of this surreal situation, which is still evolving. We highlight the importance of humor in stress reduction. Regular and reliable communication to the public has to be improved, acknowledging incomplete data, and learning to deal with fake news, misinformation, and conspiracy theories. Excess mortality is the preferred statistic to follow and compare outcomes. When the health risks are over, the economic recovery responses will vary according to the financial state of countries. If world order is to be reshaped, then a massive economic aid plan should be launched by the rich countries—akin to the Marshall plan after the Second World War. It should be led preferably by the USA and China. The results of the tradeoffs between health and economic lockdowns will only become apparent in the months to come. The experiences and lessons learned from this emergency should be used as a rehearsal for the next epi-/pandemic, which will surely take place in the foreseeable future.
The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has markedly increased over the last three decades mostly due to human papillomavirus (HPV)-related infections. Cancers resulting from HPV infection bear a better prognosis than those that are smoking-related. Because HPV-positive patients are often younger, with lower rates of co-morbid illness and longer overall life expectancies, long-term sequelae of therapy have become an important issue. Treatment of oropharyngeal cancers has typically involved the use of radiation and chemotherapy to avoid the morbidity of open surgery which included mandibulotomy and composite resection. Transoral robotic surgery (TORS) is an emerging treatment option for this disease, avoiding the morbidity of open approaches while providing excellent oncologic and functional outcomes. With overall survival rate at 2 years exceeding 80%, and local failure rate of less than 3%, patients receiving TORS report relatively good health-related quality of life (QOL) scores. The aim of the current review is to provide a summary of the current literature with regard to the oncologic and functional outcomes following treatment of OPSCC with TORS.
Combat trauma may affect servicemen from indigenous, traditional communities in ways that warrant special attention. The Bedouins, who enlist in the Israel Defense Forces (IDF) voluntarily, represent a unique, closed, collectivist cultural minority, potentially in a predicament in light of ongoing sociopolitical events. This paper summarizes findings and lessons learned from a community study of Bedouin IDF servicemen and their families residing in Israel’s Western Galilee. This is the only research endeavor to have addressed trauma exposure and posttraumatic reactions in this community. The sampling strategies and interview schedule were designed in consideration of participation barriers typical of hard-to-reach populations. Data collection followed an extended phase of liaising with key informants and building trust. Study limitations are discussed in terms of the challenges presented by this type of research. Interviews conducted with 317 men, 129 wives, and 67 mothers revealed high levels of trauma exposure and posttraumatic stress disorder (PTSD) in the men, and related distress in wives and mothers, but not in the children. The role of aggression in mediating the impact of PTSD and concepts such as shame, the loss of personal resources, and beliefs about retribution are highlighted as key issues for a culturally relevant understanding of traumatized indigenous communities.
During the past 50 years, a dramatic reduction in the mortality rate associated with cardiovascular disease has occurred in the US and other countries. Statistical modeling has revealed that approximately half of this reduction is the result of risk factor mitigation. The successful identification of such risk factors was pioneered and has continued with the Framingham Heart Study, which began in 1949 as a project of the US National Heart Institute (now part of the National Heart, Lung, and Blood Institute). Decreases in total cholesterol, blood pressure, smoking, and physical inactivity account for 24%, 20%, 12%, and 5% reductions in the mortality rate, respectively. Nephrology was designated as a recognized medical professional specialty a few years later. Hemodialysis was first performed in 1943. The US Medicare End-Stage Renal Disease (ESRD) Program was established in 1972. The number of patients in the program increased from 5,000 in the first year to more than 500,000 in recent years. Only recently have efforts for risk factor identification, early diagnosis, and prevention of chronic kidney disease (CKD) been undertaken. By applying the approach of the Framingham Heart Study to address CKD risk factors, we hope to mirror the success of cardiology; we aim to prevent progression to ESRD and to avoid the cardiovascular complications associated with CKD. In this paper, we present conceptual examples of risk factor modification for CKD, in the setting of this historical framework.
This Supplement of Rambam Maimonides Medical Journal presents the abstracts from the Fourteenth Annual Rambam Research Day. These abstracts represent the newest basic and clinical research coming out of Rambam Health Care Campus—research that is the oxygen for education and development of tomorrow’s generation of physicians. Hence, the research presented on Rambam Research Day is the foundation for understanding patient needs and improving treatment modalities. Bringing research from the bench to the bedside and from the bedside to the community is at the heart of Maimonides’ scholarly and ethical legacy.
Squamous cell carcinoma of the larynx continues to be the commonest head and neck cancer in many Western countries. The larynx plays a key role for many essential functions, including breathing, voice production, airway protection, and swallowing. The goals of laryngeal cancer treatment are thus to provide best possible oncologic control, while optimizing functional outcomes.
In recent decades, the treatment paradigm for advanced laryngeal cancer has shifted from one of primary surgery (total laryngectomy) as gold standard, toward non-surgical organ-preserving treatment using radiotherapy or chemoradiotherapy. However, concerns have emerged regarding functional outcomes after chemoradiotherapy, as well as possible decreased overall survival in patients with laryngeal cancer.
The purpose of the present review is to review surgical and non-surgical options for treatment of advanced laryngeal cancer, as well as the evidence supporting each of these.
Achievement of complete response (CR) to therapy in chronic lymphocytic leukemia (CLL) has become a feasible goal, directly correlating with prolonged survival. It has been established that the classic definition of CR actually encompasses a variety of disease loads, and more sensitive multiparameter flow cytometry and polymerase chain reaction methods can detect the disease burden with a much higher sensitivity. Detection of malignant cells with a sensitivity of 1 tumor cell in 10,000 cells (10–4), using the above-mentioned sophisticated techniques, is the current cutoff for minimal residual disease (MRD). Tumor burdens lower than 10–4 are defined as MRD-negative. Several studies in CLL have determined the achievement of MRD negativity as an independent favorable prognostic factor, leading to prolonged disease-free and overall survival, regardless of the treatment protocol or the presence of other pre-existing prognostic indicators. Minimal residual disease evaluation using flow cytometry is a sensitive and applicable approach which is expected to become an integral part of future prospective trials in CLL designed to assess the role of MRD surveillance in treatment tailoring.
