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Introduction: Fibromyalgia syndrome (FMS) is a chronic pain syndrome, prevalent in women more than men. The main symptoms are widespread musculoskeletal pain, fatigue, and weakness. To date, the pathophysiological mechanisms are unclear, and there are several pathogenic theories elucidating this condition. In this review, we summarized articles published in the past few years, regarding the effect of musculoskeletal dysfunction on FMS. We focused on the musculoskeletal system and central nervous system (CNS) disarrays.

Background: We welcome the readers of Harefuah to the following issue that deals with the research and clinical practice that was carried out in this challenging year of the COVID-19 pandemic. Despite the high hospitalization rates throughout the country in these times, our clinicians found the spirit to continue and conduct their research activities. The following issue presents the essence of the good clinical practice along with interesting research outcomes.

Introduction: Besides its role in iron homeostasis and storage, ferritin is also regarded as an acute-phase reactant. Extreme Hyperferritinemia is seen in severe inflammatory conditions, severe infections, iron storage diseases and malignancies. A direct linkage between high ferritin levels and poor prognosis has been observed., Objectives: To characterize patients with extreme high ferritin levels in the serum for possible etiologies and assessment of the correlation between ferritin levels, prognosis and mortality., Methods: We conducted a retrospective cohort study between the years 2002-2016 using the large database of Clalit Health Services. Patients older than 18 years with ferritin levels above 10,000 ng/ml that were taken during hospitalization and ambulatory visits were included in the study. After examining the medical files of each patient, we evaluated the demographic characteristics, etiologies, clinical presentation and relevant laboratory parameters. We calculated the proportion of this data and compared it to the general population by using chi square test., Results: The incidence of extreme hyperferritinemia was statistically significant in patients with autoimmune and rheumatologic diseases in particular adult onset Still's disease compared to the general population. Among hospitalized patients, bacterial and viral infections were the leading cause in 62% of cases. In ambulatory patients, hyperferritinemia was mainly secondary to chronic blood transfusions in patients with hemoglobinopathies and poor compliance to iron chelators. Among 21 biopsies from involved organs including lymph nodes, bone marrow and liver, hemophagocytosis was only observed in 5 cases (6.8%)., Conclusions: Extreme hyperferritinemia with values higher than 10,000 ng/ml can be attributed to many inflammatory autoimmune conditions.

Introduction: Silicone is a foreign material to our body and therefore, has been found to stimulate the immune system. Silicone breast implants (SBIs), made of silicone polymer, have been used for aesthetic and medical purposes since the 1960s, and were found to trigger acute/chronic inflammation, eventually leading to the formation of fibrotic capsules on the surface of the implant. Silicone implants have been found to be associated with the development of severe and sometimes unexplained clinical manifestations such as: chronic fatigue, sleep and memory problems, widespread pain, dry mouth and eye, depression, arthralgia, myalgia, palpitations, tinnitus and hearing loss, skin rash, hair loss, vision problems, hyperhidrosis, allergic reactions, etc. Furthermore, SBIs have been found to be associated with the development of rheumatologic/autoimmune diseases and the development of rare lymphoma. The FDA has expressed concern over the years about the implications of SBIs and requested that the companies involved provide data of any concern regarding the implants. However, the companies continued to sell the implants without reporting data, as agreed. In October 2019, the FDA recommended boxed warnings describing the dangers facing women applying for SBIs such as lymphoma. Importantly, our lab recently found the presence of autoantibodies against the autonomic nervous system in the blood of women with SBIs, which might explain some of the patients' severe symptoms. Owing to the numerous data that had been accumulated (since 1960s) indicating a direct link between silicone, autoimmune diseases and cancer, we believe that the use of SBIs has been a historical medical error.

Introduction: In this case-report, a young female patient presented with a systemic inflammatory disease, accompanied by an extremely elevated ferritin blood level (Hyperferritinemia).The combination of high fever with extremely elevated ferritin level is considered to be a medical emergency being associated with the following four life threating conditions: Adult-onset Still's disease, catastrophic antiphospholipid syndrome, septic shock and macrophage activating syndrome. These conditions were recently bundled under the umbrella term of Hyperferritinemia Syndrome. During the patient's hospitalization, after empiric board spectrum antibiotics did not appear to improve the patient's condition, she was diagnosed with Adult-onset Still's disease and treated with steroids and methotrexate, resulting in gradual clinical improvement. This patient exemplifies a diagnostic challenge, recurring in the patients' milieu of internal medicine departments. Therefore, we discuss the differential diagnosis of Hyperferritinemia syndrome and treatment options for refectory adult's Still disease.

Aims: This study aimed to examine a possible association between BMI levels, smoking and socio-economic status and the existence of fibromyalgia., Background: Obesity is a worldwide epidemic with devastating impacts on the public's health. There are several indications that obesity might also be involved in the pathogenesis of chronic pain syndromes such as fibromyalgia., Methods: Patients who were diagnosed with fibromyalgia were compared to population-based controls, matched in age and gender (by a ratio of 1:5). Body mass indices, smoking status and socioeconomic strata were retrieved from computerized medical records of the Clalit Health Services database. Body mass index was classified in WHO categories of underweight, normal, overweight and obese (<18.5, 18.5-<25, 25.0-<30, ≥30.0 kg/m2); χ2, t-tests, and logistic regression models were used to compare the study groups and assess the association between obesity and fibromyalgia., Results: The study included 14,296 patients with fibromyalgia and 71,324 controls. Among patients with fibromyalgia the average BMI (body mass index) was higher than that of the controls 29.1± 6.2 vs. 28.0± 6.01, p<0.001) with every increment of 1 unit of the BMI score, there was an increment of 2.7% of the odds of having coexistent fibromyalgia. The chances of having fibromyalgia was 56% higher among subjects with obesity compared to individuals of normal weight. The data revealed that patients with fibromyalgia smoke more and belong to lower socioeconomic levels., Conclusions: Our findings demonstrate that obesity is significantly associated with a higher proportion of fibromyalgia. This finding underlines the role that obesity plays in inflammation and chronic pain.

Introduction: Prolonged hospitalizations are a major challenge for any society and to the Israeli health system in particular. Identifications of predictors underlines the areas that require comprehensive interventions to prevent long hospital stays. Analysis of the literature points out that discharges from internal medicine wards should be preplanned and coordinated. It is obvious that the care of those with special needs such as the elderly, dependent, lonely, disabled and patients with comorbidities mandates the development of proper community-based care that will be a continuation of in-hospital therapy. It seems inevitable that this urgent need will require a medical professional whose main task will be coordination of care in and out of the hospital.

Background: Mounting data are indicating that major depression is related to diverse functions of the immune system. Several observations indicate that cytokine concentrations might also relate to the intensity of depressive manifestations. In this study we assessed whether inflammatory and anti-inflammatory cytokine concentrations are associated with the intensity of the depressive features in a cohort of patients with major depression and in healthy normal controls., Methods: A group of 25 patients with major depression all suffering from an acute deterioration of their mental status and all hospitalized in a psychiatric ward were assessed for the intensity of their depressive manifestations according to the Hamilton rating scale for depression and by the clinical global impression scale (CGI). In parallel, concentrations of serum IL-2R, IL-6, IL-8, IL-10 were analyzed by commercial ELISA kits. As comparators, a group of 25 healthy controls was analyzed., Results: The levels of IL-6 were higher among patients with depression. A high degree of correlation was found between the scores measured by the Hamilton and CGI scales by which the intensity of depressive symptoms were ranked. Interestingly, within the group of patients with depression a negative correlation was detected between the IL-6 concentrations and the CGI scores while a positive correlation was found between the IL-10 concentration and IL-6 concentration., Conclusions: Our data indicate that the patients with depression differ from healthy individuals by their cytokine profile. Within this group of patients depressive features have a specific pattern and linkage to inflammatory and anti-inflammatory scores.

Introduction: This review deals with the neuropsychiatric disorders resulting from systemic lupus erythematosus (SLE). SLE is a chronic autoimmune disease that impacts all systems in the human body, including the central nervous system. Neuropsychiatric symptoms in SLE are a common complication of the disease. This complication has significant implications for the severity of the illness. In most cases no thorough psychiatric assessment is performed during initial evaluation of the disease and no protocol or clear guidelines for treating the psychiatric symptoms in SLE are available. Early diagnosis of the psychiatric symptoms in SLE is critical since absence of treatment may result in severe psychiatric complications. Clinical pharmacological studies are needed in order to develop guidelines for treating psychiatric symptoms in SLE.

The immune system carefully distinguishes between self and non-self-components. Therefore, any small deviation of this balanced function may result in an autoimmune activity and harm against self-antigens (autoantigens). The link between autoimmune diseases and various heredity and environmental factors has been discussed in numerous studies. The infectious factor is still considered to be the most important environmental factor leading to the development of autoimmune disease. Recent studies associated new environmental factors to autoimmunity, such as excessive salt consumption. In this paper, we summarize the relationship between environmental factors and autoimmune diseases covering innovations in this field.

Syphilis is an infectious disease. It is unique and interesting, and even to this day it continues to be a major challenge to the medical community in the prevention of the spread, the diagnosis and treatment of the disease. In recent years in Israel, 200 new cases have been revealed annually. During this period, several reports were published on the outbreaks of the disease. We believe that due to the increase in the rate of patients with the disease there is a strong need to educate the medical staff about the disease and to raise awareness regarding the symptoms of the disease, methods of diagnosis, increased risk populations, and methods of treatment. In this article we present four cases of syphilis that we encountered in our institution, which presented relatively in different ways. Furthermore, in these cases the diagnosis was not simple. So it is important to be aware that this disease still exists and must be recognized in order to know how to diagnose it.

A 91 year old patient presented with constipation, abdominal distension, weakness and anorexia lasting for two days. Computed tomography revealed multiple peritoneal masses with significant growth within days and local invasiveness without regard to anatomical boundaries. No lymphadenopathy or hepatosplenomegaly were found. Abdominal paracentesis showed 60,000 cells/mm3 presumed to be neutrophils. During follow-up, there were no clinical or radiographic signs of peritonitis. Trans-abdominal true-cut biopsy from the peritoneal masses was consistent with diffuse large B cell lymphoma germinal center B cell type, clinically presenting as peritoneal lymphomatosis. FISH cytogenetic study identified single BLC-6 gene in the tumor infiltrating lymphocytes. We speculated that this aberration in the patient's immune system cells contributed to this rare, unusual and aggressive lymphoma presentation in an otherwise non-immune compromised patient.

Over the past years, considerable progress has been made in understanding the pathogenesis of the fibromyatgia syndrome and the evidence based approach to the diagnosis and management has been significantty extended. The purpose of the current project is to develop practicat and evidence based guidetine recommendations for the Israeli health care system. A panet of physicians with clinical and research experience in the fibromyalgia field was convened under the auspices of the Israeli Rheumatology Association. A systematic review was performed on the current literature regarding the diagnosis and treatment of fibromyalgia. Using an interactive discussion procedure, recommendations were reached and expert opinion was introduced where evidence was considered incomplete. The panel recommendations underline the importance of concomitant and integrated medical therapy, such as serotonin and noradrenaline reuptake inhibitor (SNRI) anti-depressants or gamma-aminobutyric acid (GABA) related anti-epileptics, with regular aerobic physical exercise.

Cancer of unknown primary site (CUP) is defined as a metastatic disease, identified on biopsy, with it's origin remaining unknown despite extensive clinical, laboratory and imaging studies. As much as 3% to 10% of all cancers can be defined as CUP. The primary workup includes history taking, a full physical examination, basic laboratory studies, imaging studies and immunohistochemical staining or genetic analysis of biopsy material. The diagnostic yield of such studies is about 20% to 30% of cases. New advanced techniques can be used to define the genetic profile of the tumor cells. Comparing such profiles to those originating from known tumors may markedly improve our ability to detect the origin of CUP in up to 90% of cases. The treatment of CUP is based on the regimen given for cancer of the presumed origin, and in many cases is completely empiric. The prognosis for patients with CUP is dismal partially due to the late stages in which the disease is diagnosed and the aggressiveness of the tumor. The median survival is 10-12 months and the 2 year survival is 20%-25%. This is a case report demonstrating the dilemmas in managing such patients, followed by a review of the recent medical literature covering the topic.

This clinical-pathological conference took place at the Sourasky Medical Center, Tel Aviv, on February 21, 2001. We present the case of a young and previously healthy soldier who developed multi-organ failure with predominant liver dysfunction following exertional heatstroke. The patient's clinical course consisted of an early phase of transient encephalopathy, associated with hyperthermia, hypophosphatemia, mild laboratory indications of renal failure, rhabdomyolysis and consumption coagulopathy. Following an intermediate convalescing phase that lasted a single day the patient deteriorated into a catastrophic course with hemodynamic instability, fulminant hepatic failure, respiratory distress, kidney failure, rhabdomyolysis, coagulopathy and coma. He died 4 days later. In this article we elaborate on the association of heatstroke with multiple organ dysfunction syndrome in general, and fulminant liver failure in particular. The nature of hypophosphatemia and the possible role of additional injury from acetaminophen are discussed.