Israel Medical Association Journal

Background: Oral contraceptive users are at increased risk for both arterial and venous thrombosis, some of which can be fatal. Studies are consistent with the existence of a synergism between cigarette smoking and OC[1] use in the pathogenesis of myocardial infarction in young women.

Objectives: To study the relationship between OC use, cigarette smoking and other cardiovascular risk factors among young women.

Methods: A systematic sample of military personnel, upon discharge from service in the Israel Defense Forces, was asked to complete a research questionnaire. Body weight and height were measured and body mass index computed.

Results: Overall, 16,258 questionnaires were collected and analyzed during this 20 year study. There was a gradual, significant increase in OC use until the mid-1980s, from approximately 45% to 60% (P < 0.001), followed by steady rates of 58–64% since then. In contrast, the rates of smoking decreased significantly in the mid-1980s, from approximately 42% to a nadir of 22% in 1991. Since then, the rate of smoking has increased slowly but steadily, to reach a level of 35% in 1999. The OC users were more often of western (Ashkenazi) origin and came from families with more education and fewer siblings. They were more often smokers than non-OC users, and started smoking at a younger age. They had significantly lower BMI[2] than non-users. OC use was nearly identical in groups with or without multiple cardiovascular risk factors (smoking, obesity, family history).

Conclusions: Smoking and OC use are strongly associated. Other cardiovascular risk factors (smoking, obesity, family history) do not prevent OC users from smoking or smokers to use OC. We suggest that primary care physicians discourage smoking among adolescent females who wish to start using OC. A thorough medical history should be obtained to recognize all risk factors for cardiovascular disease and to provide for appropriate contraception counseling.

Background: Elevated fibrinogen levels are considered a risk factor for the development of atherosclerosis and might be used as a predictor of risk for the development of atherothrombotic events. Several studies have reached equivocal conclusions regarding the effect of statins on fibrinogen.

Objectives: To evaluate the effect of atorvastatin on plasma fibrinogen levels in patients with severe hypercholesterolemia and no other risk factors.

Methods: Twenty-two patients with low density lipoprotein-cholesterol levels above 170 mg/dl (4.40 mmol/L) and with no other risk factors were included in the study. None of the patients had ever received hypolipidemic medication. Patients were followed for 24 weeks (6 office visits 4 weeks apart). During office visits, lipid profile, complete blood count, fibrinogen and C-reactive protein levels were measured.

Results: After 24 weeks of follow-up, total cholesterol decreased by 33% (287 ± 10 to 192 ± 8 mg/dl, P < 0.001), LDL-C[1] by 45% (198 ± 8 to 111 ± 7 mg/dl, P < 0.001) and triglycerides by 21% (189 ± 26 to 138 ± 15 mg/dl, P <0.001). Fibrinogen levels dropped by 18% (355 ± 26 to 275 ± 7 mg/dl, P = 0.01). CRP[2] levels decreased from 0.51 ± 0.15 to 0.28 ± 0.10 mg/dl, but the difference was not statistically significant (P = 0.09). High density lipoprotein, hemoglobin, white blood cell and platelet counts did not change.

Conclusions: We found that atorvastatin reduces plasma fibrinogen in patients with hypercholesterolemia.

Background: The indication for aortic valve replacement in patients with significant aortic stenosis is symptomatology. Aortic stenosis may be associated with bleeding from colonic angiodysplasia, resulting in anemia. Persistent anemia in such patients, despite lack of an identifiable source of bleeding, is not considered an indication for valve replacement.

Objectives: To report our experience with two elderly female patients who suffered from severe asymptomatic aortic stenosis, low levels of large von Willebrand factor multimer (10% and 5% respectively) and persistent anemia requiring multiple blood transfusions.

Methods: Both patients underwent an intensive work-up, but a source of bleeding could not be identified. Aortic valve replacement was performed in both patients.

Results: Aortic valve replacement abolished the need for further blood transfusions during a follow-up period of 20 months with normalization of the vWF[1] multimer level (20% and 30% respectively).

Conclusion: We suggest that aortic valve replacement be considered in selected patients with severe, otherwise asymptomatic aortic stenosis, who suffer from persistent anemia requiring multiple blood transfusions, lack an identifiable source of bleeding and have low levels of large vWF multimers.

The ubiquitin-proteasome pathway has a central role in selective degradation of intracellular proteins. Among the key proteins degraded by the system are those involved in the control of inflammation, cell cycle regulation and gene expression. With numerous important cellular pathways affected, derangements in the ubiquitin system were shown to result in a variety of human diseases including malignancies, neurodegenerative diseases and hereditary syndromes, and proteasome inhibition was implicated as a potential treatment for cancer and inflammatory conditions. Two proteasome inhibitors are currently under clinical evaluation for multiple myeloma and acute ischemic stroke. The ubiquitin system also has an important function in the immune and inflammatory response. It is involved in antigen processing and presentation to cytotoxic T cells, and the activation of nuclear factor-kappa B – the central transcription factor of the immune system. Since the proteasome is the central source of antigenic peptides that are presented to the immune system, some viruses, such as the Epstein-Barr virus, developed escape mechanisms that manipulate the ubiquitin-proteasome system in order to persist in the infected host. Understanding the mechanisms underlying the production of viral antigens by the ubiquitin-proteasome system may have therapeutic applications such as future development of vaccines.

Background: The Israeli Blood Pressure Control program was initiated to enhance the control of modifiable risk factors among high risk hypertensive patients followed by general practitioners in Israel.

Objective: To report the baseline results of the state of the treatment regarding blood pressure management, lipid and glucose control as well as obesity and smoking cessation among the patients.

Methods: Hypertensive patients were screened in 30 general practice clinics supervised by family medicine specialists seeing 1,000–5,000 patients each. Between 50 and 250 hypertensive patients were diagnosed at each participating clinic. Blood pressure levels, body mass index, lipid and glucose levels, as well as target organ damage and medications were recorded for all patients.

Results: Of the 4,948 patients registered, 2,079 were males (42%). Mean age was 64.8 ± 12. Blood pressure control was achieved in only 33.1% of total hypertensive patients. Low density lipoprotein control was achieved in 31.1% of all patients, and glucose control in only 28.5%% of diabetic patients (glucose < 126 mg/dl); 20.7% of the diabetics had glucose levels above 200 mg/dl. In this group of patients 38.9% were obese (BMI[1] >30 kg/m²). While there were more obese females than males (48.0% vs. 35.6%), no difference was found in blood pressure, lipid or glucose control between the genders.

Conclusion: Risk factor management of hypertensive patients attending general practice clinics in Israel is not optimal, especially among those with diabetes or in need of secondary prevention measures. A long-term intervention program for high risk patients in the community is needed to improve the current situation.

Background: The ¹³C-urea breath test is the best non-invasive test to validate Helicobacter pylori eradication. Serology is unreliable for this purpose due to the slow and unpredictable decline in the antibodies titer.

Objectives: To characterize a specific group of patients who were treated for H. pylori and tested for successful eradication by ¹³C-UBT[1] in our central laboratory and to correlate the eradication success rate with specific drug combinations, and to evaluate other factors that may influence eradication success.

Methods: ¹³C-UBT for H. pylori was performed in the central laboratory of Clalit Health Services. The breath test was performed by dedicated nurses in 25 regional laboratories and the samples were analyzed by a mass spectrometer (Analytical Precision 2003, UK). The physician who ordered the test completed a questionnaire computing demographic data (age, gender, origin), indication, use of non-steroidal anti-inflammatory drugs or proton pump inhibitor, and combination of eradication therapy.

Results: Of the 1,986 patients tested to validate successful H. pylori eradication, 539 (27%) had a positive test (treatment failure group) and 1,447 (73%) had a negative test (successful treatment group). Male gender, older age and European-American origin predicted better eradication rates. Dyspeptic symptoms and chronic PPI[2] therapy predicted treatment failure. Combination therapy that included clarithromycin had a higher eradication rate than a combination containing metronidazole. The combination of omeprazole, amoxicillin and clarithromycin achieved an eradication rate of 81.3%, which was better than the combination of omeprazole, metronidazole and clarithromycin (77.2%) (not significant), or of omeprazole, amoxicillin and metronidazole (66.1%) (P < 0.01).

Conclusion: Gender, age, origin, dyspepsia and PPI therapy may predict H. pylori eradication results. Our findings also support an increase in metronidazole resistance of H. pylori strains in Israel, as described in other countries. We recommend combination therapy with omeprazole, amoxicillin and clarithromycin and avoidance of metronidazole as one of the first-line eradication drugs.

Background: The implementation of treatment guidelines is lacking worldwide.

Objectives: To examine whether follow-up in a specialized lipid clinic improves the achievement rate of the treatment guidelines, as formulated by the National Cholesterol Education Program and the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

Methods: The study group included patients who were referred to the lipid clinic because of hyperlipidemia. At each of five visits over a 12 month period, lipid levels, liver and creatine kinase levels, body mass index, and adherence to diet and medications were measured, and achievement of the NCEP[1] target level was assessed.

Results: A total of 1,133 patients (mean age 61.3 years, 60% males) were studied. Additional risk factors for atherosclerosis included hypertension (41%), type II diabetes mellitus (21%), smoking (17%), and a positive family history of coronary artery disease (32%). All patients had evidence of atherosclerotic vascular disease (coronary, cerebrovascular or peripheral vascular diseases). The low density lipoprotein target of <100 mg was present in only 22% of patients before enrollment, with improvement of up to 57% after the follow-up period. During follow-up, blood pressure control was improved (from 38% at the time of referral to 88% after 12 months, P < 0.001), as was glycemic control in diabetic patients (HgA₁C improved from 8.2% to 7.1% after 12 months, P < 0.001). Improved risk factor control was due to increased compliance to medication treatment (from 66% at enrollment to more than 90% after 12 months), as well as careful attention to risk factor management that translated into a change in the treatment profile during the follow-up. There was an increase in the use of the following medications: aspirin from 68% to 96%, statins from 42% to 88%, beta blockers from 20% to 40%, and angiotensin-converting enzyme inhibitors from 28% to 42%; while calcium channel blocker use decreased from 40% to 30% in patients during follow-up.

Conclusion: Follow-up of patients in a specialized clinic enhances the achievement of LDL[2]-cholesterol treatment goals as well as other risk factor treatment goals, due to increased patient compliance and increased use of medications.

________________________________________________

The threat of a disease outbreak resulting from biologic warfare has been of concern for the Israeli health system for many years. In order to be prepared for such an event the health system has formulated doctrines for various biologic agents and defined the logistic elements for the procurement of drugs. During the last 4 years, and especially after the West Nile fever epidemic in 2000, efforts to prepare the healthcare system and the relevant organizations were accelerated. The Director-General of the Ministry of Health nominated a Supreme Steering Committee to fill in the gaps and upgrade the preparedness of the health system for an unusual disease outbreak. This committee and its seven subcommittees established appropriate guidelines, communication routes among different organizations, and training programs for medical personnel. The anthrax outbreak in the United States found the healthcare system in the hub of the preparation process, and all modes of action were intensified. Further work by hospitals, primary care clinics and all other institutes should be initiated to maintain a state of proper preparedness.

Atropine is the drug of choice for treatment of organophosphate (OP) nerve agent and insecticide intoxication and has been used for this indication for several decades. Adverse reactions to atropine may occur, and are of two types: toxic and allergic. Toxic reaction, the most common form, results from the anti-muscarinic effects of the drug. Since it is most probably related to interpersonal variation in sensitivity to atropine, toxic effects may appear at the usual therapeutic doses. The second type, allergic reaction, includes local manifestations, usually after the administration of eyedrops, and systemic reaction in the form of anaphylaxis. Since most patients manifest only a mild reaction, allergy testing is not performed and the prevalence of allergy to atropine is therefore not known. Severe allergic reaction to atropine is rare, as evidenced by the small number of case reports in the literature despite the drug's extensive use. Alternative anti-muscarinic drugs recommended for OP poisoning include glycopyrrolate and scopolamine. Glycopyrrolate is a peripheral anti-muscarinic drug that has been studied in comparison to atropine for many clinical indications, while scopolamine is an anti-muscarinic drug with both peripheral and central effects. An acceptable alternative regimen for patients with proven allergy to atropine is a combination of glycopyrrolate with centrally active drugs such as benzodiazepines or scopolamine.

Recent events have significantly increased concern about the use of biologic and chemical weapons by terrorists and other countries. Since weapons of mass destruction could result in a huge number of casualties, optimizing our diagnostic and therapeutic skills may help to minimize the morbidity and mortality. The national demands for training in medical aspects of nuclear, biologic and chemical warfare have increased dramatically. While Israeli medical preparedness for non-conventional warfare has improved substantially in recent years especially due to extensive training programs, a standardized course and course materials were not available until recently. We have developed a core curriculum and teaching materials for a 1 or 2 day modular course, including printed materials.

Background: Hyperlipidemia is a major risk factor for coronary heart disease. Reducing low density lipoprotein-cholesterol can significantly reduce the risk of CHD[1], but many patients fail to reach the target LDL-C[2] goals due to low doses of statins or low compliance.

Objectives: To treat high risk patients with atorvastatin in order to reach LDL-C goals (either primary or secondary prevention) of the Israel Atherosclerosis Society.

Methods: In this open-label study of 3,276 patients (1,698 of whom were males, 52%), atorvastatin 10 mg was given as a first dose, with follow-up and adjustment of the dose every 6 weeks. While 1,670 patients did not receive prior hypolipidemic treatment, 1,606 were treated with other statins, fibrates or the combination of both.

Results: After 6 weeks of treatment, 70% of the patients who did not receive prior hypolipidemic medications and who needed primary prevention reached target LDL-C levels. Interestingly, a similar number of patients on prior hypolipidemic treatment reached the LDL-C goals for primary prevention. The patients treated with other statins, fibrates or both did not reach the LDL-C treatment goals. Only 34% of all patients who needed secondary prevention reached the ISA[3] LDL-C target of 100 mg/dl. Atorvastatin proved to be completely safe; only two patients had creatine kinase elevation above 500 U/L, and another six had mild CK[4] elevation (<500 U/L). None of the patients had clinical myopathy, and only one had to be withdrawn from the study.

Conclusion: Atorvastatin is a safe and effective drug that enables most patients requiring primary prevention to reach LDL-C goal levels, even with a low dose of 10 mg. Patients in need of secondary prevention usually require higher doses of statins.

__________________________________