Israel Medical Association Journal

Background: Familial Mediterranean fever (FMF) is a recessively inherited disease with a variety of clinical presentations. The disease is associated with mutations in the FMF gene (MEFV), which encodes for the pyrin protein. The role of the E148Q pyrin mutation in the FMF phenotype remains inconclusive, and some authors even view it as a disease-insignificant polymorphism. The calculated change, imposed by this mutation on pyrin structure, may help to understand the role of this mutation

Objectives: To calculate the relative electrochemical effect of the E148Q mutation on the structure of pyrin protein.

Methods: The electronic properties of the wild-type pyrin molecule and its common mutated forms were computed for the full-length molecule and its segments, encoded by exons 2 and 10, using the HyperChem 7.5 program with one of the molecular mechanical methods (MM+). The change in the structure of the molecule, expressed as a change in energy gain, conferred by the mutations was determined.

Results: The E148Q mutation caused deviation from the wild-type pyrin segment encoded by exon 2 by 1.15% and from the whole pyrin molecule by 0.75%, comparable to the R202Q mutation and less than the M694V mutation which caused a deviation from the wild-type structure of the whole pyrin molecule by 1.5%.

Conclusions: A quantum-chemistry based model suggests that the structural effect of the E148Q mutation is indeed low, but not zero. 
 

Background: Since the identification of the MEFV gene 198 mutations have been identified, not all of which are pathologic. The screening methods used in Israel to test patients suspected of having FMF include a kit that tests for the five main mutations (M694V, V726A, M680Ic/g, M694I, E148Q), and the sequencing of MEFV exon 10 in combination with restriction analysis for detecting additional mutations.

Objectives: To determine the contribution of testing for five additional mutations – A744S, K695R, M680Ic/t, R761H and P369S – to the molecular diagnosis of patients clinically suspected of having FMF.

Methods: A total of 1637 patients were tested for FMF mutations by sequencing exon 10 and performing restriction analysis for mutations E148Q and P369S.

Results: Nearly half the patients (812, 49.6%) did not have any detectable mutations, 581 (35.5%) had one mutation, 241 (14.7%) had two mutations, of whom 122 were homozygous and 119 compound heterozygous, and 3 had three mutations. Testing for the additional five mutations enabled us to identify 46 patients who would have been missed by the molecular diagnosis kit and 22 patients who would have been found to have only one mutation. Altogether, 4.3% of the patients would not have been diagnosed correctly by using only the kit that tests for the five main mutations.

Conclusions: This study suggests that testing for the additional five mutations as well as the five main mutations in patients with a clinical presentation of FMF adds significantly to the molecular diagnosis of FMF in the Israeli population.
 

Background: The age-standardized incidence rate of invasive cervical cancer in Israeli Jewish women is persistently low. Selected demographic characteristics of Israeli Jewish women with cervical squamous cell carcinoma (SCC) were reported recently. 

Objectives: To assess selected clinical characteristics of Israeli Jewish women with cervical SCC.

Methods: Included were all Israeli Jewish women with SCC diagnosed during the 3-year period 2002­–2004. Data were obtained from the Israel National Cancer Registry and the Central Population Registry. Discharge summaries of the patients were reviewed and clinical data were abstracted.

Results: The study was based on 350 Israeli Jewish women with histologically confirmed cervical SCC diagnosed during the 3-year study period. The median age of the patients was 50.3 years. The most common main complaint was discharge/bleeding (35.7%) and only a small percentage (7.4%) was diagnosed subsequent to an abnormal cytological smear. The rate of patients diagnosed in stage I was 47.7%. The overall absolute 5-year survival and survival in stage I was 70% and 83.8% respectively. The rate of Israeli born patients diagnosed in stage I and their overall absolute 5-year survival was significantly higher than in the other ethnic groups.

Conclusions: Age, the most frequent main complaint, the percent of patients diagnosed in stage I and the 5-year survival (overall and in stage I) are similar to data in other countries. The survival of Israeli born women seems to be better than that of other ethnic groups.
 

Objectives: To assess our experience with perichondritis in a large group of patients hospitalized with this entity.

Methods: We retrospectively studied 114 patients who were admitted with perichondritis during 1987–2004, including their demographic details, medical history, current illness, etiology, pathogens and treatments. 

Results: The patients’ mean age was 41.8 ± 20.7 years. In more than half of the patients the etiology could not be determined. Forty-seven patients (41%) were treated prior to hospitalization for an average of 2.5 ± 1.9 days. Eight patients (7%) required surgical intervention. Pseudomonas aeruginosa was found to be the predominant organism (69% of available isolates) and was associated with a more advanced clinical presentation and longer hospitalization (P = 0.008). 

Conclusions:  Perichondritis develops in many cases after apparent minor trauma. Since P. aeruginosa is probably the predominant pathogen, initial treatment should include anti-pseudomonal antibiotics.

Background: The term chronic multi-symptom illness refers to a spectrum of pain disorders, such as fibromyalgia and chronic fatigue syndrome, that are characterized by unexplained chronic pain, fatigue, and cognitive and mood complaints

Objectives: To examine the hypothesis that exercise cessation is associated with symptoms similar to CMI[1] in well-trained amateur athletes.

Methods: The study, conducted in running and triathlon clubs in Israel, involved 26 asymptomatic healthy athletes who regularly exercise 6.75 ± 3.65 hours a week. All athletes were instructed to refrain from physical activity for 7 days. All underwent a complete physical exam, rheumatological assessment including non-articular tenderness threshold (using dolorimeter) and tender points. In addition they completed the SF-36 quality of life questionnaire. Assessments were conducted before exercise cessation and 7 days later.

Results: Seven days after sports deprivation all subjects were significantly more tender by all tender measures (P < 0.001) (dolorimeter thresholds and tender point count). There was also a significant reduction in the scores for physical role function (P < 0.001), emotional role function (P < 0.001) and summary subscales of the SF-36 questionnaire after exercise cessation.

Conclusions: Exercise deprivation is associated with change in non-articular tenderness threshold and reduction in quality of life scores. This may be associated with the development of chronic multi-symptom illness.

Background: The European Quality of Life 5-Dimensions questionnaire is one of the most commonly used measures of health-related quality of life.

Objectives: To present the feasibility, reliability, and validity of the Hebrew version of the EQ-5D[1].

Methods: We conducted face-to-face interviews with a representative sample (n=1666) of the Israeli Jewish population. The data collected included demographic and medical information, and self-valuation of health using the EQ-5D descriptive system, Visual Analogue Scale and Time Trade-Off. Construct validity was assessed by assuming that older individuals, those with a greater burden of diseases, and those reporting experience with their own severe illness would have lower EQ-5D indexes, VAS[2] and TTO[3] values. Test-retest reliability was assessed in a small sample (n=50) that was reevaluated after a 3 week interval.

Results: Test-retest reliability of the EQ-5D and VAS was very high (r ≥ 0.85). Reliability of the TTO was moderate (r = 0.48). There were significant differences in the EQ-5D index, profiles, VAS and TTO between healthy and sick respondents and younger and older respondents, indicating good validity of the instrument.

Conclusions: The Hebrew translation of the EQ-5D is a practical, reliable and valid instrument for assessing the health-related quality of life of the general Israeli Jewish population.

Background: Traditionally, medication dosage was based on clinical and demographic parameters, but drug metabolism was recently recognized as an important factor for proper dosing and prediction of side effects. Metabolic considerations are crucial when administering drugs with a narrow therapeutic index, such as those of the thioguanides family (azathioprine and 6-MP). These can cause life-threatening myelosuppression due to low activity of a critical metabolic enzyme, thiopurine S-methyl transferase. A number of single nucleotide substitutions encoding variant enzymes account for most enzyme deficiencies.

Objectives: To determine the frequency of individuals from different Israeli ethnic groups who may be at risk for drug toxicity from drugs of the thioguanide family due to enzymatic variants.

Methods: DNA analysis was performed using polymerase chain reaction methods. We tested TPMT[1] allelic variants TPMT*3A (G460A, A719G), TPMT*3B (G460A) and TPMT*3C (A719G) in five subpopulations in Israel: mixed-origin Israeli Jews, Arabs, Druze, Jews of Kurdish extraction, and Ethiopian Jews.

Results: The Druze (P = 0.0002) and Ethiopian Jewish (P = 0.015) subpopulations had a significantly unique distribution of allelic variants compared to the rest of the Israeli population. The Druze subpopulation showed a high number of TPMT variants with decreased activity, and a homozygote for TPMT*3A/ *3A was detected.  Ethiopian Jews were found to carry mainly the TPMT*3C variant, also observed in other studies of African populations.

Conclusions: It is advisable that Druze patients be tested for the TPMT enzyme before starting treatment with 6-MP or azathioprine. Such testing may also be considered for other Israeli ethnic subgroups.

Background: Open repair of the Achilles tendon is still the gold standard for treating rupture. This technique has the disadvantage of a long and problematic operative scar and thickly scarred Achilles tendon. To improve the surgical outcome minimally invasive techniques have been developed.

Objectives: To analyze our results of Achilles tendon repair using the Achillon® device and compare them with published studies.

Methods: We performed surgical repair of the Achilles tendon in 28 patients during a 4 year period (2004–2008): 14 patients were treated with the Achillon device, 12 with the open suture technique and 2 with the percutaneous method. Fourteen patients were available for follow-up: the tendon was repaired in 9 patients with the Achillon device, in 3 patients with open suturing and in 2 patients with the percutaneous technique. Follow-up ranged from 1 to 4 years.

Results: The average score of the AOFAS Ankle-Hindfoot Scale for the group treated with the Achillon device was 95.6 points (range 84–100) and for the group treated with the open method, 90 points (range 84–98). The length of the scar in patients operated with a minimally invasive technique was 3.81 cm (range 1–6 cm) as compared to 9.16 cm (range 8–10.5 cm) with the open suture.

Conclusions: This is the first review on this procedure in Israel. Excellent functional results were achieved with this technique. Our outcomes were similar to those of two other studies.
 

Background: A survey conducted among Israel Defense Force primary care physicians in 2001 revealed that they consider patients' needs more than they do organizational needs and that the education PCPs[1] currently receive is inadequate. In 2003 the medical corps initiated a multi-format continuous medical education program aimed at improving skills in primary care medicine.

Objectives: To measure and analyze the effect of the tailored-made CME[2] program on PCPs’ self-perception 3 years after its implementation and correlate it to clinical performance.

Methods: In 2006 a questionnaire was delivered to a representative sample of PCPs in the IDF[3]. The questionnaire included items on demographic and professional background, statements on self-perception issues, and ranking of roles. We compared the follow-up survey (2006) to the results of the original study (2001) and correlated the survey results with clinical performance as measured through objective indicators.

Results: In the 2006 follow-up survey PCPs scored higher on questions dealing with their perception of themselves as case managers (3.8 compared to 4.0 on the 2001 survey on a 5 point scale, P = 0.046), perceived quality of care and education (3.5 vs. 3.8, P = 0.06), and on questions dealing with organizational commitment (3.5 vs. 3.8, P=0.01). PCPs received higher scores on clinical indicators in the later study (odds ratio 2.05, P < 0.001).

Conclusions: PCPs in the IDF perceive themselves more as case managers as compared to the 2001 survey. A tailor-made CME program may have contributed to the improvement in skills and quality of care.

Background: Trans-aortic pressure gradient in patients with aortic stenosis and left ventricular systolic dysfunction is typically low but occasionally high.

Objectives: To examine the distribution of trans-aortic PG[1] in patients with severe AS[2] and severe LV[3] dysfunction and compare the clinical and echocardiographic characteristics and outcome of patients with high versus low PG.

Methods: Using the echocardiographic laboratory database at our institution, 72 patients with severe AS (aortic valve area ≤ 1.0 cm²) and severe LV dysfunction (LV ejection fraction ≤ 30%) were identified. The characteristics and outcome of these patients were compared.

Results: PG was high (mean PG ≥ 35 mmHg) in 32 patients (44.4%) and low (< 35 mmHg) in 40 (55.6%). Aortic valve area was slightly smaller in patients with high PG (0.63 ± 0.15 vs. 0.75 ± 0.16 cm² in patients with low PG, P = 0.003), and LV ejection fraction was slightly higher in patients with high PG (26 ± 5 vs. 22 ± 5% in patients with low PG, P = 0.005). During a median follow-up period of 9 months 14 patients (19%) underwent aortic valve replacement and 46 patients (64%) died. Aortic valve replacement was associated with lower mortality (age and gender-adjusted hazard ratio 0.19, 95% confidence interval 0.05–0.82), whereas trans-aortic PG was not (P = 0.41).

Conclusions: A large proportion of patients with severe AS have relatively high trans-aortic PG despite severe LV dysfunction, a finding partially related to more severe AS and better LV function. Trans-aortic PG is not related to outcome in these patients.

Background: Simulation-based medical education has become a powerful tool in improving the quality of care provided by health professionals.

Objectives: To evaluate the effect of a simulated patient-based educational program for military recruitment center physicians on the quality of medical encounters with adolescent candidates for military service.

Methods: Twelve physicians participated in an educational intervention that included a one day SP[1]-based workshop, where simulations of eight typical candidates for military service were conducted. Assessment of the physicians' performance before and after the intervention was based on questionnaires filled by 697 and 508 military candidates respectively, upon completion of their medical examination by these physicians. The questionnaire explored health topics raised by the examining physician as well as the atmosphere during the encounter. The candidates were also asked whether they had omitted important medical information during the medical encounter.

Results: Pre- and post-intervention comparison revealed significant changes in the percentages of candidates who reported that they were asked questions related to psychosocial topics: school problems – 59.7% and 68.9% (P = 0.01), protected sex – 29.6% and 36.4% (P = 0.01), mood changes – 46.9% and 52.2% (P = 0.05) respectively. Physicians were perceived as being interested in the candidates by 68.2% of the candidates before the intervention and 77.5% after (P < 0.01). The percentage of candidates who reported omitting medical information decreased from 6.6% before the intervention to 2.4% after (P < 0.01).

Conclusions: A simulated patient-based educational program for military physicians improved the quality of physician-candidate encounters. Such programs may serve as an effective instrument for training physicians to communicate with adolescents.