Israel Medical Association Journal

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: Gastric cancer continues to be a leading cause of cancer death. The treatment approach varies, and preoperative staging is therefore crucial since an exploratory laparotomy for unresectable gastric cancer will be followed by an unacceptably high morbidity and mortality rate.

Objectives: To assess the added value of diagnostic laparoscopy to conventional methods of diagnosis such as computed tomography in avoiding unnecessary laparotomies.

Methods: A retrospective study on 78 patients scheduled for curative gastrectomy based on CT staging was conducted. DL[1] was performed prior to exploratory laparotomy.

Results: In 23 of 78 patients (29.5%), unexpected peritoneal spread not detected on preoperative CT was found. Fifty-five patients underwent radical gastrectomy, 15 patients were referred for downstaging and 8 patients underwent a palliative procedure.

Conclusions: Based on our results, DL should be considered in all gastric cancer patients scheduled for curative gastrectomy.

Background: Hypovitaminosis D has been shown to be extremely common in various regions around the world, mostly at high latitudes. Israel is characterized by certain features – cultural (e.g., ethnic isolates) and geographic (e.g., sunny climate) – that have been identified for their possible association with vitamin D status.

Objectives: To conduct an ecological study on a representative sample of the population of Israel, testing vitamin D status across age groups, genders, ethnic groups, and seasons.

Methods: We obtained serum samples from 195 healthy Israeli volunteers representing a broad demographic spectrum. Serum concentrations of 25(OH)D were measured with the commercial kit Liaison 25(OH)D Assay (DiaSorin, Italy).

Results: The mean vitamin D level for the entire cohort was surprisingly low (22.9 ± 10.1 ng/ml), with 149 subjects (78%) suffering from vitamin D insufficiency (< 30 ng/ml). Vitamin D status was better in infants than in older age groups. Differences by gender were significant only in the infant age group (i.e., vitamin D status was worse among females) and were not prominent across older ages. Israelis of Ashkenazi origin had higher vitamin D mean levels than those of Sephardic origin, who, in turn, had higher vitamin D levels than Arab subjects (31.4 ± 12, 24.1 ± 10, and 17.6 ± 9 ng/ml respectively). With regard to season, there were no differences between the samples collected in winter and the samples collected in summer.

Conclusions: The results suggest that hypovitaminosis D is common across all ages, genders and seasons in Israel, a country characterized by a sunny Mediterranean climate. Specific ethnic groups may be at especially high risk.

Background: The incidence of cutaneous leishmaniasis in northern Israel began to rise in 2000, peaking at 41.0 per 100,000 in the Kinneret subdistrict during the first half of 2003.

Objectives: To examine the morbidity rates of CL[1] in northern Israel during the period 1999–2003, which would indicate whether new endemic areas were emerging in this district, and to identify suspicious hosts.

Methods: The demographic and epidemiologic data for the reported cases (n=93) were analyzed using the GIS and SPSS software, including mapping habitats of suspicious hosts and localizing sites of infected sand flies.

Results: The maximal incidence rate in the district was found in the city Tiberias in 2003: 62.5/100,000 compared to 0–1.5/100,000 in other towns. The cases in Tiberias were centered on the peripheral line of two neighborhoods, close to the habitats of the rock hyraxes. Sand flies infected with Leishmania tropica were captured around the residence of those affected. Results of polymerase chain reaction were positive for Leishmania tropica in 14 of 15 tested patients.

Conclusions: A new endemic CL area has emerged in Tiberias. The most suspicious reservoir of the disease is the rock hyrax.

Background: ST-elevation myocardial infarction is caused by occlusive coronary thrombosis where antecedent plaque disruption occurs. When treating STEMI[1] the main goal is to achieve prompt reperfusion of the infarction area. Several studies have demonstrated the efficacy of an aspiration device before percutaneous coronary intervention in patients with acute myocardial infarction.

Objectives: To determine the added value of thrombus aspiration prior to primary PCI[2] by comparing AMI[3] patients with totally occluded infarct-related artery treated with routine primary PCI to those treated with extraction device prior to primary PCI.

Methods: The study group comprised 122 consecutive patients with AMI and a totally occluded infarct artery (TIMI flow 0) who underwent primary PCI. The patients were divided into two groups: 68 who underwent primary PCI only (control group) and 54 who underwent primary thrombus extraction with an extraction device before PCI (extraction group). Baseline clinical and lesion characteristics were similar in both groups. Final TIMI grade flow and myocardial blush as well as 1 year mortality, target lesion revascularization, recurrent myocardial infarction, unstable angina and stroke were compared between the two groups.

Results: Primary angiographic results were better for the extraction group versus the control group: final grade 3 TIMI flow was 100% vs. 95.6% (P = 0.03) and final grade 3 myocardial blush grade 50% vs. 41.18% (although P was not significant). Long-term follow-up total MACE[4] showed a non-significant positive trend in the extraction group (12.96% vs. 24.71%, P = 0.26).

Conclusions: The use of extraction devices for intracoronary thrombectomy during primary PCI in patients with totally occluded infarct artery significantly improved epicardial reperfusion in the infarct-related vessel and showed a trend for more favorable long-term outcome.

Background: A pandemic (H1N1) influenza A virus was identified in 2009.

Objectives: To investigate predictors for pandemic (H1N1) 2009 virus infection among hospitalized patients with a flu-like illness and to identify parameters suggesting a severe clinical course.

Methods: We analyzed a cohort of all patients hospitalized during a 2 month period with a flu-like syndrome who were tested for pandemic (H1N1) 2009 infection. Demographic, clinical and laboratory, along with outcome parameters, were recorded and compared between pandemic (H1N1) 2009 virus-positive and negative hospitalized patients.

Results: Of the 179 examined hospitalized patients suspected of having pandemic (H1N1) 2009 infection 65 (36%) were found positive. These patients tended to be younger and had significantly fewer comorbidities. In addition, they had a significantly higher frequency of fever (94%), cough (86%) and myalgia (29%). Furthermore, age < 65 years and cough were independent predictors for pandemic (H1N1) 2009 virus positivity in a multivariate regression analysis. Notably, 14 of the 65 positive patients (21.5%) had acute respiratory insufficiency requiring treatment in the intensive care unit. These patients were neither older nor previously sicker than patients with non-severe disease, but were distinguished by augmented inflammatory markers, significant lymphopenia associated with disease severity, and overall mortality of 21.4%.

Conclusions: Pandemic (H1N1) 2009 virus-positive hospitalized patients tend to be younger and have fewer comorbidities as compared to compatible negative patients. A significant number of relatively young and previously healthy positive patients might develop severe disease associated with a robust inflammatory reaction and significant lymphopenia.

Background: Enteral nutrition in the critically ill patient is often complicated by gastrointestinal intolerance, manifested by a large gastric residual volume. The frequency of GRV[1] assessment and the intolerant level above which feeding is stopped is controversial.

Objectives: To evaluate a novel approach to EN[2] by allowing high GRV and once-daily assessment that was correlated with the paracetamol absorption test.

Methods: We conducted a pilot prospective study in an 18 bed general intensive care unit. The study group comprised 52 consecutive critically ill mechanically ventilated patients. Enteral nutrition was started at full delivery rate. Once-daily assessment of GRV with three consecutively repeated threshold volumes of 500 ml was performed before stopping EN. The paracetamol absorption test was performed and correlated to GRV. Patients were divided into two groups: low GRV (< 500 ml), and high GRV (at least one measurement of GRV > 500 ml). Clinical outcome included maximal calories delivered, incidence of pneumonia, ICU[3] length of stay, and ICU and hospital mortality.

Results: There were 4 patients (9.5%) with ventilator-associated pneumonia in the low GRV group and 3 (30%) in the high GRV group (P = 0.12). GRV was inversely correlated to paracetamol absorption; however, neither GRV nor paracetamol absorption was associated with the development of pneumonia. Both groups had similar ICU length of stay (11.0 ± 8.2 vs. 13.8 ± 14.4 days, P = 0.41), and similar ICU (21% vs. 40%, P = 0.24) and hospital mortality (35% vs. 40%, P = 1.0).

Conclusions: In critically ill mechanically ventilated patients, allowing larger gastric residual volumes, measured once daily, enables enteral feeding with fewer interruptions which results in high calorie intake without significant complications or side effects.

Background: Patients with multiple (< 100) colorectal adenomatous polyps are at increased risk for colorectal cancer. Genetic evaluation of those patients who test negative for APC gene mutation is both a clinical and economic burden but is critical for counseling and surveillance. In Israel, this is confounded by the fact that national health insurance does not fully cover genetic evaluation of APC gene exon 16.

Objectives: To perform a comprehensive genetic evaluation of APC gene mutation-negative polyposis patients with the aim of developing a future evaluation protocol.

Methods: Genetic analyses were performed in 29 APC gene mutation-negative Jewish individuals with 5 to ≥ 40 colonic adenomas who did not fulfill Amsterdam (clinical) criteria for Lynch syndrome. Analyses included completion of APC gene exon 16 sequencing, analysis for APC gene copy number variations (deletions or duplications), MUTYH gene sequencing, and microsatellite instability in CRC[1] patients fulfilling “Bethesda” (laboratory investigation) criteria for Lynch syndrome.

Results: Completion of APC gene exon 16 sequencing revealed one patient with the E1317Q polymorphism. All were normal by APC multiplex ligation-dependent probe amplification analysis. Pathogenic MUTYH mutations were found in three patients, all of North African origin; two additional patients had variants of unknown significance. One of six patients with Bethesda-positive criteria was MSI²-High with immunohistology consistent with MLH1 mutation.

Conclusions: Based on this small but well-characterized cohort with multiple colorectal adenomas, Lynch syndrome needs to be excluded if there are compatible criteria; otherwise MUTYH sequencing is probably the first step in evaluating APC-negative patients, especially for Jews of North African descent. Completing APC exon 16 sequencing and copy number variations analysis should probably be the last evaluations.

Background: Poisonings are a significant cause of pediatric morbidity and mortality. The Israel Poison Information Center provides clinical consultations on poisonings and drug information 24 hours a day.

Objective: To evaluate epidemiologic characteristics of pediatric poison exposures in Israel.

Methods: We reviewed computerized queries and performed a descriptive analysis of the Poison Center database pertaining to patients less than 18 years old during 2007.

Results: A total of 15,005 pediatric poison exposures were recorded, 80.3% of them occurring in children under 6 years old. Of the calls to the Poison Center, 78.6% were made by the public, 20.7% by physicians, and in 74.4% the call was within 2 hours of exposure. Most exposures occurred at home (89.3%) and were unintentional (89.5%). Among adolescents, most exposures were intentional (49.3%, 38.2% suicides), the time lapse until consultation was longer (37% > 2 hours), and more physicians (54.8%) consulted the Poison Center. Most cases were asymptomatic or mildly affected (92.3%), 54.4% in adolescents. The commonest substances involved in single poison exposure were detergents, antimicrobials, topical preparations, acetaminophen and scale removers; in adolescents the most common substances were acetaminophen, methylphenidate, non-steroidal anti-inflammatory drugs, atropine and ethanol. Moderate to severe toxicity was commonly associated with organophosphates, alkali, ethanol, Vipera palaestinae and neuroleptics. Most patients could be observed at home (66.6%), while more adolescents were referred to emergency departments (42.2% vs. 9.9%) or hospitalized (14.5% vs. 1.9%).

Conclusions: Pediatric poisonings are a significant health problem. The magnitude of the problem is greater in the young age group but more severe in adolescence, probably due to deliberate self-poisoning. Greater national efforts should be directed towards improved poison prevention, rational management of pediatric poisoning, and creating a national poisoning registry.
 

Background: The prevalence of aortic stenosis increases with advancing age. Once symptoms occur the prognosis in patients with severe aortic stenosis is poor. The current and recommended treatment of choice for these patients is surgical aortic valve replacement. However, many patients, mainly the very elderly and those with major comorbidities, are considered to be at high surgical risk and are therefore denied treatment. Recently, a transcatheter alternative to surgical AVR[1] has emerged.

Objectives: To describe the first year experience and 30 day outcome of transcatheter aortic self-expandable CoreValve implantation in Israel.

Methods: Transcatheter aortic valve implantation using the CoreValve system has been performed in Israel since September 2008. In the following year 55 patients underwent CoreValve TAVI[2] in four Israeli centers.

Results: Patients' mean age was 81.7 ± 7.1 years; there were 35 females and 20 males. The mean valve area by echocardiogram was 0.63 ± 0.16 cm². The calculated mean logistic Euroscore was 19.3 ± 8%. Following TAVI, mean transvalvular gradient decreased from baseline levels of 51 ± 13 to 9 ± 3 mmHg. The rate of procedural success was 98%. One patient died on the first day post-procedure (1.8%) and all-cause 30 day mortality was 5.5% (3 of 55 patients). One patient had a significant post-procedural aortic regurgitation of > grade 2. Symptomatic improvement was evident in most patients, with reduction in functional capacity grade from 3.2 ± 0.6 at baseline to 1.4 ± 0.7. The most common post-procedural complication was complete heart block, which necessitated permanent pacemaker implantation in 37% of patients.

Conclusions: The Israeli first year experience of transcatheter aortic valve implantation using the CoreValve self-expandable system demonstrates an effective and safe procedure for the treatment of severe aortic stenosis in patients at high surgical risk.

Background: Community-acquired pneumonia is a common infection and is associated with high rates of morbidity and mortality. Most patients with CAP[1] are treated empirically.

Objectives: To identify common pathogens causing CAP in hospitalized patients in northern Israel and to evaluate the correlation between etiology and disease severity.

Methods: We conducted a prospective study of patients with CAP hospitalized at HaEmek Medical Center, Afula. We collected demographic, clinical and laboratory data (blood and sputum cultures, serology, pneumococcal urinary antigen test, and respiratory multiplex-polymerase chain reaction from nasopharyngeal swab), and radiologic evaluation was performed.

Results: A total of 126 patients and 24 controls were enrolled. At least one pathogen was identified in 84 cases (66.7%), more than one in 43 patients (34.1%), and no pathogens in 42 (33.3%). Typical bacteria were found in 23 (18.3%), atypical bacteria in 66 (52.4%), and viruses in 42 (33.3%). The number (%) of patients with pathogens isolated was: Chlamydophila pneumoniae 26 (20.6%), Streptococcus pneumoniae 23 (18.3%), Mycoplasma pneumoniae 23 (18.3%), influenza virus A-B 20 (15.9%), Coxiella burnetti 8 (6.3%), and parainfluenza and adenovirus 13 (10.3%) each. A correlation was found only between a high PORT score on admission and S. pneumoniae, although atypical pathogens did not show class predominance.

Conclusions: S. pneumoniae, M. pneumoniae and C. pneumoniae were the most common pathogens isolated, while co-infection was very frequent. PORT score did not predict any of the pathogens involved. The choice of empiric antimicrobial treatment for CAP should be made according to local epidemiologic data.

Background: Guidelines are frequently under-implemented in older patients with heart failure. Octogenerians are often excluded from clinical trials.

Objectives: To characterize the clinical profile of the oldest-old (age ≥ 80 years) heart failure patients hospitalized in a subacute geriatric hospital and to evaluate their management and 1 year outcome.

Methods: Patient characteristics and in-hospital course were retrospectively collected. Diagnosis of heart failure was based mainly on clinical evaluation in addition to chest X-ray results and echocardiographic findings when available.

Results: The study population comprised 96 consecutive unselected heart failure patients hospitalized from January to June 2003. The patients were predominantly women (67%), aged 85 ± 5 years, fully dependent or frail with a high rate of comorbidities. Adherence to guidelines and recommended heart failure medications was poor. Their 1 year mortality was 57%. According to logistic regression analysis, predictors of 1 year mortality were lower body mass index (odds ratio 0.86, 95% confidence interval 0.78–0.96) and high urea levels (OR[1] 1.04, 95% CI[2] 1.02–1.06).

Conclusions: Our study confirms that the management of oldest-old heart failure patients hospitalized in a subacute geriatric hospital was suboptimal and their mortality was exceptionally high.