Israel Medical Association Journal

Background: Primary pulmonary hypertension is a rare disorder, characterized by progressive pulmonary hypertension and right heart failure. It may be familial or sporadic. Mutations in bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor-beta receptor superfamily of receptors, underlie many cases of the disorder.

Objectives: To perform molecular analysis of a patient with familial PPH[1] and provide her and her family with suitable genetic counseling.

Methods: DNA was extracted from 10 ml whole blood, and the BMPR2 gene was screened for mutations. Individual exons were amplified by polymerase chain reaction and sequenced. Mutation confirmation and molecular characterization of additional family members was performed using restriction enzyme analysis followed by appropriate genetic counseling.

Results: We identified a novel T to C missense mutation expected to result in substitution of arginine for a conserved cysteine in the ligand-binding domain of BMPR2. Screening of family members demonstrated the presence of the mutation in the father and a younger asymptomatic sister of the index patient.

Conclusions: Molecular diagnosis in PPH allows for identification of at-risk family members and raises the option of earlier diagnosis and possibly instituting earlier treatment in affected individuals. However, molecular screening of asymptomatic family members raises difficult ethical questions that can only be resolved by conducting large multicenter prospective studies in BMPR2 carriers.

Background: Intravenous recombinant tissue plasminogen activator therapy within 3 hours of stroke onset is a proven effective treatment for acute ischemic stroke.

Objectives: To assess the feasibility and safety of rt-PA[1] therapy for reperfusion in routine clinical practice in Israel, in a setting of a dedicated stroke unit.

Methods: Consecutive patients presenting within less than 3 hours of stroke onset were evaluated by an emergency physician and the neurology stroke team. After brain computerized tomography eligible patients were treated with intravenous rt-PA (0.9 mg/kg; maximum dose 90 mg) according to an in-hospital protocol corresponding to recommended criteria. Patients were admitted to the acute stroke unit. Safety and clinical outcome were routinely assessed. Re-canalization was assessed by serial transcranial Doppler.

Results: The study group comprised 16 patients, mean age 61 years (range 47–80 years), male to female ratio 10:6, whose median baseline National Institutes of Health stroke scale was 13 (range 6–24). They were treated within a mean door-to-CT time of 39 minutes (range 17–62 min), door-to-drug time 101 minutes (range 72–150), and stroke onset-to-drug time 151 minutes (range 90–180). There was an early improvement within 24 hours (of ≥ 4 points in the NIHSS[2] score) in 7 patients (44%) and no early deteriorations. There were no protocol deviations, no symptomatic intracranial hemorrhages, and no major systemic hemorrhage within 36 hours of rt-PA treatment. Three asymptomatic hemorrhagic transformations of the infarct were noted on routine follow-up brain CT associated with neurologic improvement. Outcome data were comparable to the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study.

Conclusion: Intravenous rt-PA treatment within 3 hours of stroke onset in routine clinical practice in Israel is feasible and appears safe in the setting of a neurology stroke unit and team. Careful implementation of rt-PA therapy for selected patients in Israel is encouraged.

Background:  Physicians’ decisions regarding provision of life-sustaining treatment may be influenced considerably by non-medical variables.

Objectives: To examine physicians’ attitudes towards end-of-life decisions in Israel, comparing them to those found in the United States.

Methods: A survey was conducted among members of the Israel Society of Critical Care Medicine using a questionnaire analogous to that used in a similar study in the USA.       

Results: Forty-three physicians (45%) responded, the majority of whom hold responsibility for withholding or withdrawing life-sustaining treatments. Preservation of life was considered the most important factor by 31 respondents (72%). The quality of life as viewed by the patient was generally considered less important than the quality of life as viewed by the physician. Twenty-one respondents (49%) considered withholding treatment more acceptable than withdrawing it. The main factors for decisions to withhold or withdraw therapy were a very low probability of survival of hospitalization, an irreversible acute disorder, and prior existence of chronic disorders. An almost similar percent of physicians (93% for Israel and 94% for the U.S.) apply Do Not Resuscitate orders in their intensive care units, but much less (28% vs. 95%) actually discuss these orders with the families of their patients.

Conclusions:  Critical care physicians in Israel place similar emphasis on the value of life as do their U.S. counterparts and assign DNR[1] orders with an incidence equaling that of the U.S. They differ from their U.S. counterparts in that they confer less significance to the will of the patient, and do not consult as much with families of patients regarding DNR orders.

Background: In the emergency department the physician is often confronted with the decision of where to hospitalize a patient presenting with chest pain and a possible acute myocardial infarction – in the cardiac care unit or in the internal medicine ward.

Objective: To characterize the clinical factors involved in the triage disposition of patients hospitalized with AMI[1] in Israel to either CCUs[2] or IMWs[3] and to determine to what extent the perceived probability of ischemia influenced the disposition decision.

Methods: During a 2 month nationwide prospective survey in the 26 CCUs and 82 of the 94 IMWs in Israel, we reviewed the charts of 1,648 patients with a discharge diagnosis of AMI. The probability of ischemia at admission was determined retrospectively by the Acute Coronary Ischemia Time-Insensitive Predictive Instrument. Co-morbidity was coded using the Index of Coexistent Diseases.

Results: The ACI-TIPI[4] score for patients admitted to CCUs or to IMWs was 76.2% and 57.7% respectively (P < 0.001). Multivariate analysis showed that young patients with a high probability of ischemia and low co-morbidity or functional impairment were more likely to be hospitalized in CCUs than in IMWs.

Conclusion: In Israel, the factors that strongly influence the initial triage disposition of patients with AMI to CCUs or IMWs are age, perceived probability of ischemia, status of co-morbid conditions and functional impairment.

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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: Previously reported results of total hip arthroplasty in patients younger than 30 years of age indicate a high complication rate and questionable durability.

Objectives: To estimate the results of THA[1] in extremely young patients.

Methods: We report the results of 69 THA procedures in 56 patients who were under the age of 30 at the time of surgery (mean age 23.23 ± 4.31 years) and were followed-up postoperatively for 2–23 years (mean 7.4 ± 3.79 years).

Results: Loosening of the cup (11/69) and early traumatic dislocation (5/69) accounted for the majority of complications.

Conclusion: The final average Harris hip scores of 90.59 ± 9.36 in these patients indicated that THA is a successful and durable treatment modality for young patients with disabling diseases affecting the hip joint. However, due to the likelihood of complications it should be used with caution in this patient group. Efforts should be made to diminish the complication rate.

Background: The precise genes involved in conferring prostate cancer risk in sporadic and familial cases are not fully known.

Objectives: To evlauate the genetic profile within several candidate genes of unselected prostate cancer cases and to correlate this profile with disease parameters.

Methods: Jewish Israeli prostate cancer patients (n=224) were genotyped for polymorphisms within candidate genes: p53, ER, VDR, GSTT1, CYP1A1, GSTP1, GSTM1, EPHX and HPC2/ELAC2, followed by analysis of the genotype with relevant clinical and pathologic parameters.

Results: The EPHX gene His113 allele was detected in 21.4% (33/154) of patients in whom disease was diagnosed above 61 years, compared with 5.7% (4/70) in earlier onset disease (P < 0.001). Within the group of late-onset disease, the same allele was noted in 5.5% (2/36) with grade I tumors compared with 18% (34/188) with grade II and up (P = 0.004). All other tested polymorphisms were not associated with a distinct clinical or pathologic feature in a statistically significant manner.

Conclusions: In Israeli prostate cancer patients, the EPHX His113 allele is seemingly associated with a more advanced, late-onset disease. These preliminary data need to be confirmed by a larger and more ethnically diverse study.

Background: The osteoporosis-pseudoglioma syndrome is a rare autosomal recessive disorder characterized by severe juvenile-onset osteoporosis and congenital or early-onset blindness. Other manifestations include muscular hypotonia, ligamentous laxity, mild mental retardation and seizures. The gene responsible was recently identified to be the low density lipoprotein receptor-related family member LRP5 on chromosome 11q11-12.

Objective: To measure bone density in two siblings with the OPPG[1] syndrome as well as in their family members (parents and siblings).

Methods: Bone mineral density was determined in the lumbar spine (antero-posterior), femoral neck, two-thirds distal forearm (>95% cortical bone) and ultradistal forearm (predominantly trabecular bone) by dual-energy X-ray absorptiometry.

Results: The studies revealed osteoporotic changes both in the patients and the carriers.

Conclusion: The findings demonstrate that OPPG carriers have reduced bone mass, which is a risk factor for development of early osteoporotic changes.

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In 2001 the number of residents aged 65 and over in Israel was 639,000, or 10% of the population. The rate of increase of the elderly population is twice that of the general population, thus the predicted number of elderly for 2020 is around 1,025,000, representing a 60% increase. While this process is determined by a decline in both fertility and mortality, in Israel, immigration has also been a central factor in the process of aging. Life expectancy stands at 76.7 for men and 80.9 for women; at age 65 it is 16.4 years for men and 18.5 for women. The major factor influencing the increase in life expectancy during the past two decades has been the prevention of death among older people. Population aging, or “the demographic transition,” also represents an "epidemiological transition” – from high rates of infectious and communicable diseases, to high rates of chronic diseases among older people. During the past two decades, the number of disabled elderly has increased more than 2.5 times. In 2001, there were about 97,400 disabled elderly in Israel, constituting about 15% of all elderly. By the year 2010, the number of disabled elderly is expected to reach 120,100. The rate of increase of the disabled elderly population is almost double that of the total elderly population, due to changes in this population’s composition. However, recent research indicates that new cohorts of elderly are healthier than earlier cohorts but experience a decline in health at older ages. While advances in standard of living, medicine, and technology have made this possible, a greater allocation of resources is required to prevent disability and maintain the quality of life.

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.