Israel Medical Association Journal

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: Anesthesiology is a vital specialty that permits the safe and humane performance of painful procedures. Most Israeli anesthesiologist are immigrants, while only a minimal number of Israeli medical school graduates enter the specialty. Unfortunately, the supply of immigrant physicians is declining due to falling immigration rates.

Objectives: To examine the current Israeli anesthesiology workforce and project future needs.

Methods: Demographic and professional information about Israeli hospital anesthesiologists was solicited from anesthesiology department heads. Data were also gathered about the past, present and projected future growth, age distribution and birth rate of the Israeli population. Needs and demand-based analyses were used to project future anesthesiology workforce requirements.

Results: Data about 711 anesthesiologists were obtained from 30 hospital anesthesiology department heads. Eighty-seven anesthesiologists (12.2%) graduated from Israeli medical schools and 459 (64.6%) graduated from medical schools in the former Soviet Union. Among the 154 anesthesiology residents were ≤ 40 years old, and only 13 (8.4%) graduated from Israeli medical schools There are approximately 10.8 anesthesiologists per 100,000 population. Projections for 2005–2015 revealed a need for 250–300 new anesthesiologists.
Conclusions: The anesthesiology workforce is predominantly composed of immigrants. This has vast implications for the future viability of the specialty because of the continuing reduction in immigration, the lack of interest in the specialty by Israeli medical school graduates, and the projected need for many new anesthesiologists to replace retirees and to provide care to a growing and aging population

Background: The contribution of the abnormal DNA mismatch repair system to non-small cell lung cancer tumorigenesis is controversial and has not been reported in Jewish Israeli patients. Similarly, the involvement of 3p deletions in NSCLC[1] in the same population has not been assessed.

Objectives: To assess the contribution of the DNA-MMR[2] system to NSCLC pathogenesis by analyzing microsatellite instability, and evaluate loss of heterozygosity at 3p rates in Israeli NSCLC patients.

Methods: Paired DNA from tumorous and non-tumorous tissue was extracted, and genotyping for MSI[3] determination was carried out using the five Bethesda markers and for determining LOH[4] two 3p markers were used. Genotyping was performed using polymerase chain reaction amplification and size separation on an ABI semiautomatic DNA sequencer, and the allelic patterns of tumorous and non-tumorous tissue were compared.

Results: Forty-four NSCLCs from 35 smokers and 9 non-smokers were analyzed, with 26 of the 44 (59%) at stage I disease. Using five microsatellite markers (D17S250, D5S346, D2S123, BAT-25, BAT-26) (known as Bethesda markers) for MSI determination, 6 of the 44 tumors (13.6%) exhibited MSI in at least one marker. Similarly, genotyping for LOH at chromosome 3p was performed using two markers (D3S4103, D3S1234) located at 3p14.2 l. With D3S4103, 33 of the 44 patients successfully analyzed were homozygous and therefore non-informative with respect to LOH. Using D3S1234, 33 of 36 patients (91.7%) were heterozygous, and 23 of these individuals' tumors (69.7%) displayed LOH. Unexpectedly, 4 of 33 tumors (12.1%) genotyped by D3S4103, and 16 of 36 tumors (44.5%) genotyped by D3S1234 showed a pattern of MSI, even though only one of these tumors showed a similar pattern when genotyped with the five consensus markers. Overall, 23 of 44 tumors (52.3%) demonstrated MSI on at least one marker, and 5 of these 23 tumors (21.7%) had MSI on two or more markers.

Conclusions: MSI using 3p markers and not the Bethesda markers occurs at a high rate and in early stages in Jewish NSCLC patients.

Background: The contribution of drugs and alcohol to current trauma‑related morbidity and mortality in Israel is not known. Identification of these factors in the fast-changing demographics of the Israeli population might lead to better care and, no less importantly, to targeted prevention measures.

Objectives: To determine the incidence of alcohol‑related trauma, and to specify the time of day, the cause of trauma, and the morbidity and mortality rates as compared to non-alcohol‑associated trauma in the tertiary trauma unit of a large medical center in Tel Aviv.

Methods: Data were obtained from the Israel National Trauma Registry, based on patient records in our institution (Tel Aviv Sourasky Medical Center) from January 2001 to December 2003.

Results: Of the 5,529 patients who were enrolled in the study, 170 had high alcohol blood levels (> 50 mg/dl). Patients intoxicated with alcohol had higher rates of road accident injuries (35% versus 24% non‑intoxicated) and stab wounds (29% vs. 7%). The Injury Severity Score of the alcohol‑intoxicated patients was higher (32% ³ 16 vs. 12% ³ 16). The alcohol‑intoxicated patients were more likely to be non-Jewish (34% vs. 9%), young (82% aged 15–44 years) and males (91%). Most of the alcohol‑related injuries occurred during the weekend (47%) and during evening‑late night hours (from 7 a.m. to 11 p.m.; 55%).

Conclusions: Alcohol‑associated trauma differs from non-alcohol‑associated trauma in many ways. Since the population at risk can be identified, it is important that legislative, social, enforcement and educational measures be adopted to reduce the extent of alcohol abuse and thereby improve the level of public safety.
 

Diabetic retinopathy is one of the leading causes of blindness worldwide.

The care of the trauma victim can be divided into five to six phases, none of which can be bypassed.

Chronic periaortitis is a rare disease affecting the abdominal aorta, usually below the level of the renal arteries.

Background: Sentinel lymph node mapping is the standard of care for patients with malignant melanoma and breast cancer. Recently, SLN[1] mapping was introduced to the field of gastric cancer.

Objectives: To evaluate SLN mapping in patients with gastric cancer.

Methods: In 43 patients with gastric cancer, open intraoperative subserosal dye injection in four opposing peritumoral points was used. Ten minutes following dye injection, stained LNs were located, marked and examined postoperatively from the surgical specimen.

Results: SLN mapping was performed in 43 with gastric cancer; 782 lymph nodes were harvested and evaluated. SLNs were stained in 34 of the patients (79.1%) with a mean of 2.85 SLNs per patient. The false negative rate was 20.9%, the positive predictive value 100%, the negative predictive value 78.6% and the sensitivity 86.9%.

Conclusions: SLN mapping in patients with gastric cancer is feasible and easy to perform. SLN mapping may mainly affect the extent of lymph node dissection, and to a lesser degree gastric resection. However, more data are needed.

The pulmonary microbiology is a dominant element in cystic fibrosis and the main cause of death. Contemporary consensus accords an exclusive role in this to a single microorganism, Pseudomonas aeruginosa. The evidence convincingly shows that the microbiology consists of a multiplicity of species living in perpetual interaction and in a variety of forms – planktonic, sessile, anaerobic – and in organized communities as microcosms, biofilms and ecosystem. This compound microbiology, the essence of the pulmonary disease, is of necessity exposed to constant influence both from without (the air) and within (via the blood), leading to a perpetual state of flux with consequent impact on the clinical course. It is perhaps significant that to date, most or all microbiologic studies were probably conducted, classically, with inert instruments (glass? plastic?), whereas in real life the CF[1] microbiology lives in “test-tubes” of live mucosa with which it maintains a permanent “cross-talk.” The difference to microbial life between these two media may well be very important. It therefore justifies study and may be far-reaching in its effect. There is persuasive argument to strive for a novel holistic view of the totality of the complex microbiology of CF, and to initiate fresh concepts, strategies and methods.

Objectives: To characterize the academic background of graduates, evaluate their attitudes towards current and alternative medical education programs, and examine subgroups among graduates according to gender, medical school, high school education, etc.

Methods: The survey included graduates from all four Israeli medical schools who graduated between the years 1981 and 2000 in a sample of 1:3. A questionnaire and stamped return envelope were sent to every third graduate; the questionnaire included open and quantitative questions graded on a scale of 1 to 5. The data were processed for the entire graduate population and further analyzed according to subgroups such as medical schools, gender, high school education, etc.

Results: The response rate was 41.3%. The survey provided a demographic profile of graduates over a 20 year period, their previous educational and academic background, additional academic degrees achieved, satisfaction, and suggestions for future medical education programs.

Conclusions: The profile of the medical graduates in Israel is mostly homogenous in terms of demographics, with small differences among the four medical schools. In line with recommendations of the graduates, and as an expression of the changing requirements in the healthcare system and the medical profession, the medical schools should consider alternative medical education programs such as a bachelor’s degree in life sciences followed by MD studies, or education programs that combine medicine with disciplines such as law, engineering, computer science, etc.

Objectives: To assess the effect of a vaginal ring delivering estradiol and progesterone in postmenopausal women and to determine whether continuous administration can relieve climacteric symptoms, produce an acceptable pattern of vaginal bleeding and control endometrial proliferation.

Methods: Twenty-nine postmenopausal women with an intact uterus were studied. All had climacteric symptoms. The vaginal rings contained 0.36 g estradiol and either 3.6 g progesterone (high dose progesterone) or 1.8 g (low dose progesterone), and were kept in place for 4–6 months. Serum progesterone, estradiol and estrone were measured and endometrial thickness determined. All women kept a daily diary of bleeding/spotting and completed a questionnaire on climacteric symptoms at monthly intervals. The low dose progesterone group comprised 14 women and the high dose progesterone group 15 women.

Results: A total of 18 patients (9 in each group) completed the study. Mean levels of estradiol, estrone and progesterone were at their peak after 2 to 4 weeks. All rings were effective in alleviating vasomotor symptoms, although there was evidence of the "escape from effect" in month 6. Endometrial thickness increased in 6 of the 29 women but biopsy in each case showed no evidence of hyperplasia. Of the 18 women who completed the study, 5 had amenorrhea throughout, 7 had amenorrhea after 3 months, and the remainder had one or two bleeding episodes after 3 months. Therapy was discontinued in 11 women.

Conclusions: A vaginal ring delivering estradiol and progesterone controlled climacteric symptoms, prevented endometrial proliferation, and provided an acceptable bleeding pattern. It should be viewed as a promising alternative for short-term estrogen-progesterone therapy.