Israel Medical Association Journal

Background: Matrix metalloproteinases are proteolytic enzymes that degrade extracellular matrix components. Numerous studies have demonstrated that individual MMPs[1] play a crucial role in tumor invasion and metastasis.

Objective: To examine the expression of MMPs and their inhibitor TIMP-2 in neoplastic and normal thyroid tissues.

Methods: We examined 33 cases of thyroid tumor (papillary, follicular and medullary carcinoma, follicular adenoma and multinodular goiter). MMP protein content and activity were measured by enzyme-linked immunosorbent assay and gel zymography. Immunohistochemistry was also performed.

Results: The thyroid tissues examined secreted MMP-2 and 9 as well as TIMP-2, but only MMP-2 was significantly higher in papillary carcinoma cases compared to the adjacent normal tissue or to the other tumor entities. Increased MMP-2 immunohistochemical staining was demonstrated in the neoplastic papillary epithelial component. No significant difference was seen between papillary carcinomas with lymph node metastases and those without.

Conclusions: Increased MMP-2 expression may be useful as a diagnostic marker to differentiate papillary carcinoma from other thyroid neoplasms, but it cannot serve as a useful prognostic marker.

Background: Recent years have brought significant progress to the development of hormonal therapies for the treatment of breast cancer. Several new agents have been approved for the treatment of breast cancer in the metastatic setting, among which is the new non-steroidal aromatase inhibitor, anastrozole, introduced for clinical use in Israel in March 1997.

Objectives: To evaluate the response rate and survival duration of patients treated with anastrozole for metastatic breast cancer, who had previously received at least one line of hormonal therapy.

Methods: Anastrozole was administered to 37 patients with metastatic breast cancer. The median age was 64 years. Estrogen receptor was positive in 20 patients, negative in 10 and unknown in 7. All patients were previously treated with tamoxifen in the adjuvant setting or as first-line hormonal therapy for metastatic disease. Anastrozole was given orally, 1 mg/day. Response was evaluated 2 months after the initiation of treatment and reevaluated every 2 months. Therapy was given until disease progression. Ten ER[1]-negative patients were excluded from the final analysis.

Results: Twenty-seven patients were eligible for response and toxicity analysis. The median follow-up was 20 months. One patient (3.7%) achieved complete response and remains free of disease 28 months after start of therapy. No partial responses were seen. Twenty patients (74%) had stable disease. Two year actuarial survival was 57%. Median survival was 26.5 months after starting therapy and median progression free survival was 11 months. The toxicity was mild: one patient (3.7%) complained of weight gain and one patient (3.7%) had mild fatigue.

Conclusion: Although the response rate was low, hormonal therapy with anastrozole seems to be beneficial in terms of disease stabilization, freedom from progression, and overall survival without serious toxicity.  

Background: Visual interpretation of fetal heart rare monitoring is subject to intra and inter observer variability.

Objective: To examine the effect of intrapartum administration of meperidine and promethazine on fetal heart activity measured by a computerized system.

Methods: Fourteen healthy women with normal pregnancies at term were studied during the active phase of labor. Fetal heart rate was recorded with the Oxford Sonicaid system 8000. Recordings were performed for 40 minutes prior to and after maternal intravenous administration of meperidine 50 mg with promethazine 25 mg.

Results: The combination of meperidine and promethazine caused a significant decrease in the number of accelerations of 10 beats per minute (9.7 versus 2.6, P = 0.002) and 15 beats per minute (5.2 vs. l.4, P = 0.003), time spent in episodes of high variation (14.8 vs. 2.0, P = 0.005) and short-term variation (7.8 vs. 5.0, P = 0.003). On the other hand there was an increase in the time spent in episodes of low variation (5.3 vs. 19.7, P = 0.009).

Conclusions: Maternal administration of meperidine with promethazine has a significant effect on FHR[1] indices during the active phase of normal labor.

Background: Previous studies have demonstrated myocardial salvage by basic fibroblast growth factor administration following chronic myocardial ischemia or acute myocardial infarction.

Objectives: To study the effect of bFGF[1] on left ventricular morphometry following coronary occlusion and reperfusion episode in rats.

Methods: bFGF (0.5 mg) or placebo was continuously administered for a period of one week using an implanted osmotic pump. Animals were sacrificed 6 weeks after surgery and myocardial cross-sections were stained with Masson-trichrome and with anti-proliferating cell nuclear antigen antibody.

Results: LV[2] area, LV cavity diameter, LV cavity/wall thickness ratio, and injury size were unchanged compared with control animals. Proliferating endothelial cells were significantly more abundant in injured compared with normal myocardium, but with no differences between animals treated or not treated with bFGF.

Conclusions: One week of systemic bFGF administration following coronary occlusion and reperfusion had no additional effect on LV geometry or cellular proliferation in rats.

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[1] bFGF = basic fibroblast growth factor

[2] LV = left ventricular

Background: The rapidly increasing costs of healthcare pose a major challenge to many governments, particularly those of developed countries. Health policy makers in some Western European countries have adopted the policy of a strong primary healthcare system, partly due to their recognition of the value of primary care medicine as a means to restrain costs while maintaining the quality and equity of healthcare services. In these countries there is a growing comprehension that the role of the family physician should be central, with responsibility for assessing the overall health needs of the individual, for coordination of medical care and, as the primary caregiver, for most of the individual’s medical problems in the framework of the family and the community.

Objectives: To describe primary care physicians in Israel from their own perception, health policy makers' opinion on the role PCPs should play, and patients' view on their role as gatekeepers.

Methods: The study was based on three research tools: a) a questionnaire mailed to a representative sample of all PCPs employed by the four sick funds in Israel in 1997, b) in-depth semi-structured interviews with key professionals and policy makers in the healthcare system, and c) a national telephone survey of a random representative sample of patients conducted in 1997.

Results: PCPs were asked to rank the importance of 12 primary functions. A total of 95% considered coordination of all patient care to be a very important function, but only 43% thought that weighing economic considerations in patient management is important, and 30.6% thought that 24 hour responsibility for patients is important. Also, 60% of PCPs have undergone specialty training and 94% thought that this training is essential. With regard to the policy makers, most preferred highly trained PCPs (board-certified family physicians, pediatricians and internists) and believed they should play a central role in the healthcare system, acting as coordinators, highly accessible and able to weigh cost considerations. Yet, half opposed a full gatekeeper model. They also felt that the general population has lost faith in PCPs, and that most have a low status and do not have adequate training. Regarding the patients’ viewpoint, 40% preferred that the PCP function as their “personal physician” coordinating all aspects of their care and fully in charge of their referrals; 30% preferred self-referral to sub-specialists, and 19% preferred their PCP to coordinate their care but wanted to be able to refer themselves to specialists.

Conclusions: In order to maintain high quality primary care, it is important that all PCPs have board certification. In addition, PCP training systems should emphasize preventive medicine, health promotion, health economy, and cost-effectiveness issues. Efforts should be make to render PCPs a central role in the healthcare system by gradually implementing the elements of the gatekeeper model through incentives rather than regulations.
 

Background: The prevalence of attention deficit-hyperactivity disorder and its pharmacologic treatment have increased dramatically in the past decade in the United States and Britain. We examined the use of methylphenidate hydrochloride for the treatment of ADHD in children in northern Israel.

Methods: We evaluated all prescriptions for methylphenidate filled in 1999 for children aged 5–18 years residing in northern Israel who were insured by Clalit Health Services, a health maintenance organization that covers approximately 70% of the population.

Results: Methylphenidate was prescribed to 1.45% of the children in northern Israel in 1999, an increase of 20% in the overall prevalence of methylphenidate use since 1992. Eighty-two percent were boys. The rate of prescription varied widely by type of settlement, from 0.2% in Arab cities and towns to 5.7% in kibbutzim. Primary care physicians wrote 78% of all the prescriptions.

Conclusions: The increase in methylphenidate use was much smaller in northern Israel than in most other developed regions and countries. More efforts at diagnosis and treatment of attention deficit disorders may need to be directed at Arab populations and those with inadequate medical services.

Background: Most of the published documents proposing teaching objectives for undergraduate clerkships were prepared by expert bodies. Seldom have the clinical teachers, who are critical to the learning process and to the implementationof the  teaching objectives, been the actual proponents of its core content.

Objective: To develop a national-scale proposal of teaching, objectives for the family medicine clerckship in medical school, using a consensus method and the actual, community-based teachers as the expert body.

Method: The Delphi method was chosen for that purpose. In the first round all 189 family medicine teachers in Israeli medical schools were asked to propose five teaching objectives. In the second round the objectives, which were generatedin the first round, were characterized by key words and were send to the participants as a second round for ranking according to their importance.

Results: A total of 116 family medicine teachers (61.38%) responded in the first round and 91 of the 116 (78.5%) in the second round. They formulated 51 teaching objectives listed in order of importance, covering a wide array of themes and including knowledge, attitude and skills objectives. The most important objectives were common problems in primary care, recognition of the biopsychosocial model, and understanding the importance of the doctor-patient relationship. The structure of the list provides a uniqe insight into the relative importance of each objective in the context of the whole core content of the clerkship.

Conclusions: Constructing a proposal for teaching objectives is feasible using the Delphi method and the field instructors as the selecting body. The process and its results can provide faculty with relevant and important suggestions on the content and structure of the family medicine clerkship.
 

Background: The neurosteroids dehydroepiandrosterone (DHEA) and its sulfated metabolite (DHEAS) have been reported to possess neuroprotective as well as anti-tumoral activity in vitro and in vivo.

Objectives: To compare the effect of the two neurohor­mones on cell viability in primary whole-brain fetal mouse culture and isolated neuronal culture, as well as in a human neuroblastoma cell line (SK-N-SH).

Methods: Cell viability and cell proliferation were deter­mined with the neutral red and ³H-thymidine uptake methods, Apoptosis in propidium iodide-stained neuroblastoma cells was determined using flow cytometry.

Results: DHEA (1 nM-10 ìM) decreased the viability of selected primary neuronal cells (33-95% after 24 and 72 hours) but not of whole-brain cultured cells (neuron+glia). DHEAS did not significantly modify cell viability in either primary culture. In a human neuroblastoma cell line, DHEA (1 nM- 1 ìM) decreased ³H-thymidine uptake (30-60%) and cell viability (23-52%) after 24 hours. DHEAS did not significantly modify, or only slightly stimulated, cell viability and uptake of  ³H-thymidine (132% of controls). The combination of DHEA and DHEAS neutralized the toxic effect of DHEA in both primary neuronal culture and neuroblastoma cell line. Flow cytometric analysis of DNA fragmentation in neuroblastoma cells treated with 100 nM DHEA/DHEAS for 24 hours showed an increase in apoptotic events (31.9% and 26.3%. respec­tively, vs. control 2.54%).

Conclusions: Our results do not confirm a neuroprotective role for DHEA and suggest that DHEA and DHEAS have a differential role: DHEA possesses a neurotoxic (expressed only in isolated neurons) and anti-proliferative effect DHEAS demonstrates only a slight neuroprotective effect.
 

There is accumulating evidence that tumor necrosis factor plays a major role in the pathogenesis of rheumatoid arthritis. Recent biotechnological advances have allowed for the development of agents that directly target TNF, a pro-inflammatory cytokine. In the last 2 years, the U.S. Food and Drug Administration and the European Union’s Commission of the European Communities have approved two biological agents for the treatment of refractory RA, etanercept and infliximab. Etanercept is a fusion protein, composed of the Fc portion of immunoglobulin G1 and the extracellular domain of a TNF receptor (p75). Infliximab is a chimeric monoclonal antibody composed of murine variable and human constant regions. In placebo-controlled trials, both agents have proven to be effective and well tolerated in PA patients.

Background: Previous studies have documented that reduction in QT dispersion after thrombolytic treatment in acute myocardial infarction depends on reperfusion status as well as infarct site. Primary percutaneous transluminal coronary angioplasty as compared with thrombolytic therapy has been shown to result in higher patency rates of the infarct vessel.

Objectives: To evaluate whether primary PTCA has a more favorable effect on reducing QT dispersion in patients with acute MI as compared to thrombolytic treatment.

Methods: The study population included 42 consecutive patients (33 men, mean age 58 ± 11 years) with acute Ml (24 anterior wall, 18 inferior wall) who were treated with primary PTCA (group A, n 21) or thrombolytic therapy (group B, n = 21) at 3.9+2 hours after symptom onset. QT intervals were measured before and 24 hours after treatment.

Results: On the admission electrocardiogram, patients with anterior Ml had higher values of QT and QTc dispersions than patients with inferior Ml (52±9 vs. 36±9 msec, R<0.05 and 61+4 vs. 56+4 msec, P=0.002, respectively). There was a significant reduction in QT and QTc dispersions from admission to 24 hours in all patients (from 50+9 to 37+9 msec, P<0.001 and from 59+5 to 42+5 msec, P<0.001. respectively), and also in group A (from 49±8 to 32±5 msec. P<0.001 and from 58+5 to 38+3 msec, P<0.001, respec­tively) and in group B patients (from 51+10 to 42+10 msec. P<0.01 and from 60±4 to 46±5 msec, P<0.001, respec­tively). QT and QTc dispersions were found to be shorter in group A at 24 hours after treatment than in group B (32 + 5 vs. 42+10 msec, P<0.001 and 38+3 vs. 46+5 msec, P<0.001. respectively).

Conclusions: Reperfusion therapy with primary PTCA or thrombolytic agents reduces QT and QTc dispersions in acute Ml. QT and QTc dispersions after reperfusion treatment are shorter with primary PTCA than with thrombolytic therapy.