Israel Medical Association Journal

Background: Emergency room triage of patients presenting with chest pain syndromes may be difficult. Under-diagnosis may be dangerous, while over0diagnosis may be costly.

Objectives: To report our initial experience with an emergency room cardiologist-based chest pain unit in Israel.

Methods: During a 5 week pilot study, we examined resource utilization and ER [1] diagnosis in 124 patients with chest pain of uncertain etiology or non-high risk acute coronary syndrome. First assessment was performed by the ER physicians and was followed by a second assessment by the CPU[2] team. Assessment was based on the following parameters: medical history and examination, serial electrocardiography, hematology, biochemistry and biomarkers for ACS[3], exercise stress testing and/or 64-slice multi-detector cardiac computed tomography angiography. Changes in decision between initial assessment and final CPU assessment with regard to hospitalization and utilization of resources were recorded.

Results: All patients had at least two cardiac troponin T measurements, 19 underwent EST[4], 9 echocardiography and 29 cardiac MDCT[5]. Fourteen patients were referred for early cardiac catheterization (same/next day). Specific working diagnosis was reached in 71/84 patients hospitalized, including unstable angina in 39 (31%) and non-ST elevation myocardial infarction in 12 (10%). Following CPU assessment, 40/124 patients (32%) were discharged, 49 (39%) were admitted to Internal Medicine and 35 (28%) to the Cardiology departments. CPU assessment and extended resources allowed discharge of 30/101 patients (30%) who were initially identified as candidates for hospitalization after ER assessment. Furthermore, 13/23 (56%) of patients who were candidates for discharge after initial ER assessment were eventually hospitalized. Use of non-invasive tests was significantly greater in patients discharged from the ER (85% vs. 38% patients hospitalized) (P < 0.0001). The mean ER stay tended to be longer (14.9 ± 8.6 hours vs. 12.9 ± 11, P = NS) for patients discharged. At 30 days follow-up, there were no adverse events (myocardial infarction or death) in any of the 40 patients discharged from the ER after CPU assessment. One patient returned to the ER because of chest pain and was discharged after re-assessment. 

Conclusions: Our initial experience showed that an ER cardiologist-based chest pain unit improved assessment of patients presenting to the ER with chest pain, and enhanced appropriate use of diagnostic tests prior to decision regarding admission/discharge from the ER.

Background: The current methods for pre‑ and post‑chemotherapy examination of the extent of disease in the breast and lymph nodes do not provide sufficiently accurate information and, not infrequently, the surgeon has to re‑operate.

Objectives: To correlate the findings between three methods of examination (physical examination, ultrasonography, mammography), all performed by the same oncologic and radiologic team, in patients with locally advanced breast cancer or a tumor/breast tissue ratio that precludes breast-conserving surgery.

Methods: Forty patients (median age 48 years, range 24–73) with locally advanced breast cancer or with a tumor/breast ratio that precluded breast‑conserving surgery were evaluated by the same medical team and received neoadjuvant chemotherapy. Surgery was performed in all, and the pathologic specimen was correlated with the results of the other examinations.

Results: In the pre‑chemotherapy evaluation, the imaging findings of the breast correlated with the physical findings in 78% of the patients and with the axilla examination in 66.7%. In the post‑chemotherapy analysis, imaging agreed with the physical findings of the breast in 62.2% and in 76.3% of the axilla. Sonography best detected occult breast disease and axillary lymph nodes but correlated with pathology in only 58% of the patients in diagnosing breast tumor and in 65.8% in diagnosing axillary lymph nodes. Mammography correlated with breast and lymph node pathology in half the patients.

Conclusions: None of the classical methods of post‑neoadjuvant chemotherapy evaluations could adequately delineate the actual extent of the disease in the breast and axillary lymph nodes. More exacting techniques of imaging combined with the classical methods are required.

Ubiquitin-proteasome degradation is a key cellular process involved in almost every aspect of cell life. According to the current concept, proteins are stable unless they are marked by poly-ubiquitination for degradation by the 26S proteasomes. A new twist in the concept became evident while studying the degradation of the tumor suppressor p53, a protein that appeared to satisfy this principle. We have discovered that native p53 is also prone to ubiquitin-independent 20S proteasomal degradation, suggesting that certain proteins are inherently unstable. We further found that this process of degradation is mediated by 20S proteasomes and inhibited by NADH quinone oxidoreductase 1. Our recent findings together with previous observations of ubiquitin-independent degradation suggest the existence of ubiquitin-independent mechanisms for proteasomal protein degradation in the cells.

Polyubiquitylation of cellular proteins has long been recognized as a prelude to a degradative fate in proteasomes. In recent years, however, ubiquitin conjugation has emerged as a regulatory strategy of considerable versatility. Most notably, monoubiquitylation is attributed an intimate role in trafficking of membrane proteins between various cellular compartments. Diverse classes of transmembrane proteins from across the eukaryotic spectrum (e.g., epidermal growth factor-receptor and other receptor tyrosine kinases) become modified with monoubiquitin molecules. Monoubiquitylation of substrates, in turn, regulates both their endocytosis at the plasma membrane and sorting in endosomes for delivery to lysosomes or vacuoles. A mechanistic rationale lies in the identification of a growing list of ubiquitin-binding domains carried by a variety of endocytic adaptor proteins. Thus, ubiquitin-conjugated membrane proteins may form extensive contacts with the endocytic machinery. Further, ubiquitin-binding adaptors and other endocytic components are, likewise, often monoubiquitylated. In this case, ubiquitin conjugation may serve to enhance intermolecular avidity in cargo-bound endocytic complexes, or alternatively, to mediate timely inactivation of ubiquitin-binding adaptors. Interestingly, the ubiquitin/endocytosis interface is appropriated by pathogenic organisms, for instance, during budding of viruses from host-infected cells. Moreover, compromised ubiquitin-mediated transport of certain signaling receptors is associated with disease states, including oncogenic transformation.

The Ink4a-Arf locus, which encodes two distinct tumor suppressor proteins, is inactivated in many cancers. Whereas p16^Ink4a is an inhibitor of cyclin D-dependent kinases, p19^Arf (p14^ARF in humans) antagonizes the E3 ubiquitin protein ligase activity of Mdm2 to activate p53. We now recognize that Arf functions in both p53-dependent and -independent modes to counteract hyper-proliferative signals originating from proto-oncogene activation, but its p53-independent activities remain poorly understood. Arf proteins are highly basic (> 20% arginine content, pI > 12) and predominantly localize within nucleoli in physical association with an abundant acidic protein, nucleophosmin (NPM/B23). When bound to NPM[1], Arf proteins are relatively stable with half-lives of 6–8 hours. Although mouse p19^Arf contains only a single lysine residue and human p14^ARF has none, both proteins are N-terminally ubiquitinated and degraded in proteasomes. Through as yet uncharacterized mechanisms, p19^Arf induces p53-independent sumoylation of a variety of cellular target proteins with which it interacts, including both Mdm2 and NPM. A naturally occurring NPM mutant (NPMc) expressed in myeloid leukemia cells redirects both wild-type NPM and p19^Arf to the cytoplasm, inhibits Arf-induced sumoylation, and attenuates p53 activity. Thus, ubiquitination and sumoylation can each influence Arf tumor suppressor activity.

Background: Metastatic melanoma is an aggressive and highly malignant cancer. The 5 year survival rate of patients with metastatic disease is less than 5% with a median survival of only 6–10 months. Drugs like dacarbazin (DTIC) as a single agent or in combination with other chemotherapy agents have a response rate of 15–30%, but the duration of response is usually short with no impact on survival. Interleukin-2-based immunotherapy has shown more promising results. The National Institutes of Health recently reported that lymphodepleting chemotherapy, followed by an adoptive transfer of large numbers of anti-tumor specific tumor-infiltrating lymphocytes, resulted in an objective regression in 51% of patients.

Objectives: To introduce the TIL[1] technology to advanced metastatic melanoma patients in Israel.

Methods: We generated TIL cultures from tumor tissue, choosing those with specific activity against melanoma and expanding them to large numbers.

Results: TIL cultures from nine patients were established and examined for their specific activity against the patients' autologous tumor cells. Twelve TIL cultures derived from 5 different patients showed the desired anti-tumor activity, making those 5 patients potential candidates for the therapy.

Conclusions: Pre-clinical studies of the TIL technology in a clinical laboratory set-up were performed successfully and this modality is ready for treating metastatic melanoma patients at the Sheba Medical Center's Ella Institute.

Three decades have elapsed since the inception of Level I trauma centers as the final link in the trauma system "chain of survival".

Background: During the last decade, Israel, a country with low tuberculosis rates, absorbed some 900,000 new immigrants from TB[1]-endemic countries.

Objectives: To analyze the specific impact of our screening procedures on active TB among children in Israel.

Methods: We conducted a retrospective analysis of epidemiologic and clinical data of all children (aged 0–17) with TB notified to the Ministry of Health between 1990 and 1999.

Results: There were 479 children with TB (male/female ratio 1.36). Most cases (81.8%) were foreign born, predominantly (88.2%) immigrants from Ethiopia and, therefore, huge differences existed in TB incidence rates according to countries of origin. Some 80% were diagnosed within 3 years of arrival, mainly due to active case-finding. Pulmonary TB, with infiltrates on chest X-ray, was found in 49.5%. Extra-pulmonary TB sites were: intra-thoracic lymphadenitis (31.1%), extra-thoracic lymphadenitis (12.5%), bones (3.6%), pleura (1.3%), meninges (1%), and others (1%). Seventy percent had a tuberculin skin test reaction ≥10 mm in size. Two (non-immigrant) children died of TB meningitis.

Conclusions: Most of the pediatric TB cases occurred in recent immigrants and were diagnosed within 3 years of immigration. These data support our policy of active case-finding among new immigrants from Ethiopia and extensive contact evaluation for all TB cases.

"Surviving severe injury depends very heavily upon the time it takes to receive trauma services. The risk of death increases three fold after one hour without the uniqe surgical care of a trauma center. This is often referred to as the 'golden hour'..."

Background: In Japan, helicopters have rarely been used for emergency medical services. The use of helicopters not only ensures rapid evacuation but may also serve to provide emergency management to patients with life-threatening injuries in the prehospital setting.

Objectives: To evaluate a Japanese helicopter-based emergency medical system including an onboard physician, particularly in terms of probability of survival.

Methods: We conducted a retrospective review of trauma victims, and calculated two estimates of PS[1] – at the scene and on arrival at the emergency department – based on patient age, Injury Severity Score, and Revised Trauma Score.

Results: We identified trauma victims who had an ISS[2] above 15 and were transported from the scene by helicopter. Excluding cardiopulmonary arrest at the scene, 151 cases were studied. Thirty-two patients had hemodynamic instability with systolic blood pressures below 90 mmHg, caused by hemorrhagic shock (29 cases) or obstructive shock (3 cases). Their PS values were 0.56 ± 0.38 in the prehospital setting and 0.65 ± 0.38 on arrival at the ED[3], representing a significant difference (P = 0.0003). Twenty-four of these patients survived, reflecting successful resuscitation during prehospital and ED management.

Conclusions: A doctor-helicopter system was shown to improve probability of survival for life-threatening trauma in the Japanese emergency medical system.

Objective: To assess the effect of establishing a new dedicated acute stroke unit within a department of neurology on indicators of process of care and outcome of acute stroke in a routine clinical setting in Israel.

Methods: Stroke patients admitted to the Sheba Medical Center during the period March 2001 to June 2002 were included in a prospective study according to selection criteria. Data on demographics, risk factors, co-morbidities and stroke severity were collected. Indicators of process of care and outcome were assessed at hospital discharge and 30 days follow-up. Comparison between outcome variables by hospitalization ward was conducted using logistic regression analysis adjusting for confounders.

Results: Of 616 acute stroke patients (mean age 70 years, 61% men, 84% ischemic stroke), 353 (57%) were admitted to general wards and 263 (43%) to the stroke unit. Diagnostic procedures were performed more often, and infection rate was lower in the setting of the stroke unit. Poor outcome (modified Rankin scale ≥3 or death) was present less often in patients managed in the stroke unit both at hospital discharge (adjusted odds ratio 0.5, 95% confidence interval 0.3–0.8) and at 30 day follow-up (adjusted OR[1] 0.6, 95%CI[2] 0.3–0.9). A Functional Independence Measure score ≤90 or death at 30 day follow-up was less frequent among patients managed in the stroke unit than in general wards (adjusted OR 0.5, 95%CI 0.2–0.8).

Conclusions: Improved outcomes and higher adherence to guidelines were observed in patients treated in a stroke unit within a department of neurology. The results suggest that patients with acute stroke should have access to treatment in a dedicated stroke unit.