[IMATINIB INDUCED EDEMA].

INTRODUCTION: Imatinib is a tyrosine kinase inhibitor and is used for the treatment of chronic myeloid leukemia (CML) since 2002. We present a patient who suffered from fluid retention and periorbital edema secondary to this drug.

[ETHICAL CHALLENGES IN TREATING CRITICAL CORONAVIRUS PATIENTS: EXPERIENCE FROM THE SHEBA MEDICAL CENTER ON THE FIRST COVID-19 PANDEMIC OUTBREAK].

INTRODUCTION: As the coronavirus pandemic emerged in late 2019, a task force was founded in the Sheba Medical Center and began preparing for the arrival of the pandemic to Israel. Several wards were put in charge of isolated COVID-19 patients. A new intensive care unit was formed for the most critical COVID-19 patients, requiring mechanical ventilation and multi-organ treatment. The Corona ICU began operating in March 2020, with a multi-disciplinary team, gathered from ICU units, an internal medicine ward, an anesthesiology department, social workers and psychologists. Simultaneously, the routine medical center functions in non-corona sections were maintained, as much as possible. The coronavirus pandemic entails challenges of many aspects: an unfamiliar pathogen causing an unknown illness, a necessity for social distancing, ambiguity regarding the risk factors for contamination and illness severity, and medical crews put at risk. Consequently, the pandemic involves ethical, social, economic and moral aspects, affecting the medical crew members and system, the patients and their families, and our society as a whole. In this article we review our joint experience in the Sheba Medical Center Corona ICU, of the medical, ethical and moral dilemmas that emerged from the first COVID-19 wave.

Assessing the effects of beta-blockers on pancreatic cancer risk: A nested case-control study.

PURPOSE: Both ß1- and ß2-adrenoceptor proteins were detected on the cell surface of pancreatic ductal adenocarcinoma. The current study evaluated the association between beta-blocker use and pancreatic cancer risk. METHODS: We conducted a nested case-control study in a large population representative database. Each pancreatic cancer case was matched with four controls based on age, sex, practice site, and duration of follow-up using incidence density sampling. Beta-blocker use was defined as any prescription prior to index date and was stratified into non-selective and selective ß1 -blockers. The odds ratios (ORs) and 95% confidence intervals (95% CIs) for pancreatic cancer risk associated with beta-blocker use was estimated using conditional logistic regression. RESULTS: The study included 4113 patients with pancreatic cancer and 16 072 matched controls. When compared to never users, there was no association between any beta-blocker use and pancreatic cancer risk (adjusted OR 1.06, 95% CI 0.97-1.16, P = .16). Analysis by receptor selectivity showed use of non-selective beta-blockers for more than 2 years was associated with a reduced pancreatic cancer risk (OR 0.75, 95% CI 0.57-1.00, P = .05). When compared to former users both users of selective ß1-blockers and non-selective beta-blockers had a reduced pancreatic cancer risk (OR 0.78, 95% CI 0.67-0.90, P = .001) and (OR 0.67, 95% CI 0.49-0.92, P = .01), respectively. CONCLUSION: Beta-blocker use was not associated with increased pancreatic cancer risk. However, long-term use of beta-blockers may be associated with decreased pancreatic cancer risk.

[ACUTE RENAL FAILURE INDUCED BY METAMIZOLE].

INTRODUCTION: Sodium metamizole (Optalgin) is one of the most prevalent analgesic and anti-pyretic medications used in Israel. We describe a case of acute kidney injury subsequent to the use of metamizole in a healthy young patient. Metamizole may cause kidney injury in a number of different mechanisms and it is vital that this fact will be emphasized due to the widespread use of this medication.

Polyneuropathy, Myocardial Dysfunction and Pericardial Effusion Following Duodenal Switch.

Duodenal Switch procedure is a type of bariatric surgery that was reserved for severely morbid obese people. Patients undergoing this procedure are at high risk for nutrient deficiencies. In this report we present a case of a patient who had developed polyneuropathy, generalized muscle weakness, Wernicke encephalopathy, myocardial dysfunction and pericardial effusion six years following this operation. He was treated by multivitamins and trace elements with a complete resolution of all of these disturbances. The patient was fully rehabilitated.

[Peripheral arthritis in polymyalgia rheumatica].

Polymyalgia rheumatica is characterized by aching and stiffness of the shoulder, the pelvic girdles and the neck. Peripheral joint involvement is less recognized by the medical community as a sign of the disease. In this article we present two patients whose disease was manifested by peripheral symptoms. The frequency, manifestations and the pathogenesis of the disorder are discussed and the importance of recognition of these symptoms and signs of the disease is stressed.

[Allergic reaction induced by steroid therapy].

Glucocorticoids are widely used for the treatment of allergies and various inflammatory conditions. However, steroids can cause allergic reactions, even anaphylaxis. The incidence of adverse reactions induced by steroids is up to 0.3%. The most commonly reported steroids causing anaphylaxis are hydrocortisone, prednisone and methylprednisotone. In this report we describe an 86 years old patient who developed stridor and respiratory failure immediately after treatment with hydrocortisone. The risk factors and the management of these reactions are discussed. It is important that the medical community should recognize and be aware of such reactions.

Prevalence and clinical implication of thrombocytopenia and heparin-induced thrombocytopenia in patients who are critically ill with COVID-19.

As the COVID-19 pandemic continues to evolve, different clinical manifestations are better understood and studied. These include various haematologic disorders that have been shown to be associated with increased morbidity and mortality. We studied the prevalence of one unusual manifestation, heparin-induced thrombocytopenia (HIT) and its clinical implications in patients who are severely ill with COVID-19 in a single tertiary centre in Israel. The presence of thrombocytopenia, disseminated intravascular coagulation (DIC) and HIT, and their association with clinical course and outcomes were studied. One-hundred and seven patients with COVID-19 were included. Fifty-seven (53.2%) patients developed thrombocytopenia, which was associated with the worst outcomes (ventilation, DIC and increased mortality). Sixteen (28.0%) patients with thrombocytopenia were positive for HIT, all of which were supported by extracorporeal devices. HIT was independently associated with ventilation days, blood product transfusions, longer hospitalisation and mortality.Platelet abnormalities and HIT are common in patients who are critically ill with COVID-19 and are associated with the worst clinical outcomes. The mechanisms underlying HIT in COVID-19 are yet to be studied; HIT may contribute to the dysregulated immunologic response associated with COVID-19 critical illness and may play a significant part in the coagulopathy seen in these patients. As many patients with COVID-19 require aggressive thromboprophylaxis, further understanding of HIT and the implementation of appropriate protocols are important.

Management and outcome of patients with non-ST elevation myocardial infarction and intercurrent non-coronary precipitating events.

AIMS: To evaluate the effect of an intercurrent non-coronary illness on the management and outcome of patients with non-ST-segment elevation myocardial infarction (NSTEMI). METHODS AND RESULTS: Consecutive hospitalized patients with a primary diagnosis of NSTEMI between August 2008 and December 2019 at Sheba Medical Center. All patients' records were reviewed for the presence of a non-coronary precipitating event (NCPE): a major intercurrent acute non-coronary illness or condition, either cardiac or non-cardiac. The primary outcome was all-cause mortality. Cox regression with interaction analysis was applied. Final study population comprised 6491 patients, of whom 2621 (40%) had NCPEs. Patients with NCPEs were older (77 vs. 69 years) and more likely to have comorbidities. The most prevalent event was infection (35%, n = 922). During a median follow-up of 30 months, 2529 patients died. Patients with NCPEs were 43% more likely to die during follow-up in a multivariable model (95% CI: 1.31-1.55). Invasive strategy was associated with a 55% lower mortality among patients without NCPE and only 44% among patients with NCPE (P for interaction < 0.001). Dual antiplatelet therapy (DAPT) was associated with a 20% lower mortality in patients without NCEP and a non-significant mortality difference among patients with NCPE (P for interaction = 0.014). Sub-analysis by the specific NCPE showed the highest mortality risk among patients with infectious precipitant. The lower mortality associated with invasive strategy was not observed in this subgroup. CONCLUSION: Among NSTEMI patients, the presence of an NCPE is associated with poor survival and modifies the effect of management strategies.

Kikuchi-Fujimoto disease.

BACKGROUND: Kikuchi-Fujimoto disease is a benign and self-limited disease, first reported in Japan in 1972. The characteristic features of this disorder include lymphadenopathy and fever. OBJECTIVES: To summarize our experience with Kikuchi disease with regard to clinical manifestations and outcome. METHODS: The patients included in the study were those diagnosed with Kikuchi disease during the years 2005-2008 in two departments of internal medicine at Sheba Medical Center. RESULTS: We identified five patients with Kikuchi disease; four were women and the mean age was 22.6 years. All the patients had cervical lymphadenopathy; three had other sites of lymphadenopathy. Four of the patients had fever higher than 39 degrees C. Two of them had splenomegaly and three reported weight loss. Three of the five patients experienced a relapse of the disease and were treated with steroids or non-steroidal anti-inflammatory agents. The diagnosis was confirmed in all the patients by an excisional biopsy of lymph node. CONCLUSIONS: Kikuchi disease must be considered in every young patient with fever and lymphadenopathy. The disease usually has a benign course.

Flare-up of ulcerative colitis after systemic corticosteroids: a strong case for Strongyloides.

Super-imposed infection with intestinal organisms can mimic a flare-up of underlying disease in patients with inflammatory bowel disease (IBD). We report a case of patient with long standing ulcerative colitis (UC), who presented with abdominal pain, diarrhea and low-grade fever after receiving systemic corticosteroids for an unrelated disorder. Despite a negative stool examination, a peripheral eosinophilia reappeared upon tapering down of a corticosteroid dose. Subsequently, duodenal biopsies showed evidence for Strongyloides, presumably acquired 20 years ago when the patient was residing in Brazil. The patient fully recovered following anti-helmintic therapy. This case underscores the importance of considering Strongyloides in the work-up of flaring-up IBD patients, even if a history of residing or traveling to endemic areas is in the distant past.

West Nile virus-induced pancreatitis.

West Nile Virus (WNV) infection is a fairly common infection in Israel, especially during the summer season. Common manifestations are fever, headaches, malaise and myalgia. Pancreatitis had been described only twice previously as a complication of WNV infection in the medical literature. In this report, an 88-year-old patient is described, who was admitted to hospital with fever, confusion and general deterioration in her condition, accompanied by severe abdominal pain. WNV infection was diagnosed by a lumbar puncture and serological tests. The laboratory results demonstrated elevated amylase and lipase levels. The patient was treated conservatively and the symptoms regressed slowly until full recovery. WNV infection and its complications are described, along with descriptions of previous reports of pancreatitis associated with WNV infection.

[Costeff syndrome: a syndrome that was described in Israel and the responsible gene discovered by an Israeli doctor].

Costeff syndrome or 3-methylglutaconic aciduria type 3, was described by a group of Israeli doctors in 1989. Since then more than 40 patients were described. Most of the patients are of Iraqi-Jewish origin. The clinical abnormalities are bilateral optic atrophy, extrapyramidal signs, spasticity ataxia, dysarthria and mild cognitive deficit. Recently, the gene responsible for this disorder, OPA3 gene was identified. This gene was also discovered by an Israeli doctor. This is a case history of a patient with Costeff syndrome presenting the characteristics of this syndrome and the gene that causes this disease.

Gastroenteritis-associated hyperamylasemia: prevalence and clinical significance.

BACKGROUND: Serum amylase levels can be elevated in various pathological conditions. However, acute gastroenteritis has not been widely recognized as a cause for hyperamylasemia. PATIENTS AND METHODS: We conducted a retrospective study of amylase results for all patients hospitalized or discharged from the emergency department with a diagnosis of gastroenteritis from April through November 1999. Patients with other possible medical causes for elevated amylase levels were excluded. We also compared the clinical and laboratory parameters of hyperamylasemic vs. normoamylasemic hospitalized patients with gastroenteritis. RESULTS: A total of 1041 patients with acute gastroenteritis were identified. Serum amylase levels were determined in 701 patients and were abnormally elevated in 66 of them. In 15 patients, other possible causes of hyperamylasemia were present, and these patients were excluded. The mean serum amylase level among the remaining 51 patients (7.4% of the remaining 686 patients with gastroenteritis) was 1.32 of the upper normal level, with a range of up to 2.2 times the upper normal range. Clinicians tended to admit more hyperamylasemic patients than normoamylasemic patients (10 of 51 vs. 65 of 635; P =.03, 1 sided). However, the course of gastroenteritis in the hospitalized hyperamylasemic patients did not differ significantly from that in the hospitalized normoamylasemic patients, as judged by the clinical signs and symptoms, laboratory results, length of hospital stay, and need for antibiotics. CONCLUSIONS: Gastroenteritis is associated with a mild to moderate elevation of serum amylase levels in a significant portion of patients and should be included in the differential diagnosis of hyperamylasemia. Such elevation, however, does not seem to bear clinical significance in terms of the severity of disease.

[Streptococcus group C bacteremia and meningitis].

Group C streptococci are common causative agents of infections in animals, but a rare cause of bacteremia and meningitis in humans. Severe infections caused by this bacterium are associated with high morbidity and mortality rates. This article presents a case study of a young patient who suffered from bacteremia and meningitis that were caused by streptococcus group C. The clinical manifestations, prognosis and treatment options of this kind of infection are discussed.

Pseudohypoaldosteronism type II: marked sensitivity to thiazides, hypercalciuria, normomagnesemia, and low bone mineral density.

Mutations in WNK kinases cause pseudohypoaldosteronism type II (PHA II) and may represent a novel signaling pathway regulating blood pressure and K(+) and H(+) homeostasis. PHA II is an autosomal dominant disorder characterized by hypertension, hyperkalemia, and metabolic acidosis, with normal glomerular filtration rate. Thiazide diuretics correct all abnormalities. Inactivating mutations in the thiazide-sensitive NaCl cotransporter cause Gitelman syndrome, featuring hypotension, hypokalemia, and metabolic alkalosis plus hypocalciuria and hypomagnesemia. We investigated whether hypercalciuria and hypermagnesemia occurred in a large family with PHA II. Eight affected and eight unaffected members of a PHA II family with the Q565E WNK 4 mutation were studied. In affected members blood and urinary chemistry were measured on and off hydrochlorothiazide (HCTZ), and bone mineral density was determined. Marked sensitivity to HCTZ was found. A mean dose of 20 mg/d reduced mean blood pressure in the six hypertensive subjects by 54.3 (systolic) and 24.5 (diastolic) mm Hg. In affected subjects, HCTZ reduced mean serum K(+) by 1.12 mmol/liter, mean serum Cl(-) by 6.2 mmol/liter, and mean urinary calcium by 65% and elevated mean serum calcium by 0.11 mmol/liter and mean serum urate by 118 micromol/liter. Compared with the literature, this represents an increase of 6-7 in HCTZ potency. Affected members had normomagnesemia, hypercalciuria (336 +/- 113 vs. 155 +/- 39 mg/d in unaffected relatives, P = 0.0002), and decreased bone mineral density. In PHA II the observed marked sensitivity to thiazides and the hypercalciuria are consistent with increased NaCl cotransporter activity. PHA II may serve as a model to investigate thiazides' beneficial effects and side effects.

Hypercalciuria in familial hyperkalemia and hypertension accompanies hyperkalemia and precedes hypertension: description of a large family with the Q565E WNK4 mutation.

Familial hyperkalemia and hypertension (FHH; pseudohypoaldosteronism type II) is an autosomal dominant disorder characterized by hyperkalemia, hypertension, and low renin. WNK1 kinase overexpression and WNK4 kinase inactivating missense mutations cause FHH. When expressed in frog oocyte, WNK4 inhibits Na-Cl cotransporter surface expression, and WNK1 relieves this inhibition. We have reported hypercalciuria in subjects with the WNK4 Q565E mutation. In contrast, in subjects with WNK1 overexpression, normocalciuria was found. Here we report a major extension of our previously described kindred that contains 34 subjects, 18 of them affected by the mutation. Hypertension was diagnosed in 13 affected subjects at the age of 31 +/- 12 yr. Five of the affected or obligatory affected subjects had stroke, in four at the age of 50-62 yr. Seven subjects with FHH were diagnosed 27 yr previously. All four subjects who were normotensive at diagnosis became hypertensive during follow-up. The mean time between detection of hyperkalemia and appearance of hypertension was 13 yr. In the extended kindred, compared with the unaffected subjects, affected subjects had hyperkalemia, low transtubular potassium gradient, hyperchloremia, low bicarbonate, higher aldosterone, and marked suppression of renin. Urinary calcium levels in affected and unaffected subjects were 0.85 +/- 0.27 and 0.28 +/- 0.12 mmol/mmol creatinine, respectively (P < 0.0001). Hypercalciuria was accompanied by lower serum calcium levels [9.44 +/- 0.15 vs. 9.81 +/- 0.31 mg/dl (2.36 +/- 0.04 vs. 2.45 +/- 0.08 mmol/liter); P = 0.01], supporting a mechanism of renal calcium leak. The six affected, currently normotensive subjects had the same degree of hyperkalemia, hypercalciuria, and low renin as the affected hypertensive subjects. We conclude that in FHH with WNK4 mutations, with time all affected subjects will apparently develop hypertension. Hypercalciuria accompanies hyperkalemia, and both precede hypertension. Based on the recent findings that WNK4 regulates the renal outer medullary potassium channel as well as epithelial Cl(-)/base exchanger and the Na(+)-K(+)-2Cl(-) cotransporter, we suggest that WNK4 interacts with a calcium channel or transporter.