Ilya Novikov

Clopidogrel Resistance Is Associated With Increased Risk of Recurrent Atherothrombotic Events in Patients With Acute Myocardial Infarction

Background— Although clopidogrel reduces the risk of cardiovascular episodes after coronary events and stenting, a substantial number of incidents continue to occur. Methods and Results— The antiplatelet effect of clopidogrel was studied prospectively in 60 consecutive patients who underwent primary angioplasty (percutaneous coronary intervention [PCI]) with stenting for acute ST-segment–elevation myocardial infarction (STEMI) to determine whether variability in response to clopidogrel affects clinical outcomes. Patients were stratified into 4 quartiles according to the percentage reduction of ADP-induced platelet aggregation. Although patients in the first quartile were resistant to the effects of clopidogrel (ADP-induced platelet aggregation at day 6, 103±8% of baseline), ADP-induced aggregation was reduced to 69±3%, 58±7%, and 33±12% of baseline, respectively, in patients in quartiles 2 through 4 (P <0.01 for all). In addition, epinephrine-induced platelet aggregation and platelet aggregation under flow conditions, assessed by the cone-and-plate(let) analyzer method, were reduced significantly less in the first quartile than in quartiles 2 through 4. Whereas 40% of patients in the first quartile sustained a recurrent cardiovascular event during a 6-month follow-up, only 1 patient (6.7%) in the second quartile and none in the third and fourth quartiles suffered a cardiovascular event (P =0.007). Conclusions— Up to 25% of STEMI patients undergoing primary PCI with stenting are resistant to clopidogrel and therefore may be at increased risk for recurrent cardiovascular events.

Long-Term Follow-up for Brain Tumor Development after Childhood Exposure to Ionizing Radiation for Tinea Capitis

Abstract Sadetzki, S., Chetrit, A., Freedman, L., Stovall, M., Modan, B. and Novikov, I. Long-Term Follow-up for Brain Tumor Development after Childhood Exposure to Ionizing Radiation for Tinea Capitis. Radiat. Res. 163, 424–432 (2005). Ionizing radiation is an established risk factor for brain tumors, yet quantitative information on the long-term risk of different types of brain tumors is sparse. Our aims were to assess the risk of radiation-induced malignant brain tumors and benign meningiomas after childhood exposure and to investigate the role of potential modifiers of that risk. The study population included 10,834 individuals who were treated for tinea capitis with X rays in the 1950s and two matched nonirradiated groups, comprising population and sibling comparison groups. The mean estimated radiation dose to the brain was 1.5 Gy. Survival analysis using Poisson regression was performed to estimate the excess relative and absolute risks (ERR, EAR) for brain tumors. After a median follow-up of 40 years, an ERR/Gy of 4.63 and 1.98 (95% CI = 2.43–9.12 and 0.73–4.69) and an EAR/Gy per 104 PY of 0.48 and 0.31 (95% CI = 0.28–0.73 and 0.12–0.53) were observed for benign meningiomas and malignant brain tumors, respectively. The risk of both types of tumors was positively associated with dose. The estimated ERR/Gy for malignant brain tumors decreased with increasing age at irradiation from 3.56 to 0.47 (P = 0.037), while no trend with age was seen for benign meningiomas. The ERR for both types of tumor remains elevated at 30-plus years after exposure.

Pregnancy Outcome after Laparoscopy or Laparotomy in Pregnancy

STUDY OBJECTIVE To assess obstetric performance and fetal outcomes after laparoscopy or laparotomy performed during pregnancy. DESIGN Nationwide, multicenter, retrospective chart review (Canadian Task Force classification II-2). SETTING Seventeen hospitals throughout Israel: 12 university or university-affiliated hospitals and 5 general hospitals. PATIENTS Three hundred eighty-nine pregnant women. INTERVENTION Laparoscopy or laparotomy for various indications. MEASUREMENTS AND MAIN RESULTS Of 192 laparoscopies performed, 141 were during the first, 46 during the second, and 5 during the third trimester; respective figures for 197 laparotomies were 63, 110, and 24. No intraoperative complications were reported for either procedure. Six and 25 women had complications after laparoscopy and laparotomy, respectively. There was no significant difference in abortion rates between groups. Mean gestational age at delivery and mean birthweight were comparable between groups. No significant difference was found in frequency of fetal anomalies between groups or when compared with the Israel register of anomalies. CONCLUSION Operative laparoscopy seems to be as safe as laparotomy in pregnancy.

Genotyping of patients with sporadic and radiation-associated meningiomas.

Ionizing radiation is the most established risk factor for meningioma formation. Our aim was to evaluate the main effect of selected candidate genes on the development of meningioma and their possible interaction with ionizing radiation in the causation of this tumor. The total study population included 440 cases and controls: 150 meningioma patients who were irradiated for tinea capitis in childhood, 129 individuals who were similarly irradiated but did not develop meningioma, 69 meningioma patients with no previous history of irradiation, and 92 asymptomatic population controls. DNA from peripheral blood samples was genotyped for single nucleotide polymorphisms (SNP) in 12 genes: NF2, XRCC1, XRCC3, XRCC5, ERCC2, Ki-ras, p16, cyclin D1, PTEN, E-cadherin, TGFB1, and TGFBR2. SNP analysis was done using the MassArray system (Sequenom, San Diego, CA) and computerized analysis by SpectroTYPER. Logistic regressions were applied to evaluate main effect of each gene on meningioma formation and interaction between gene and radiation. Intragenic SNPs in the Ki-ras and ERCC2 genes were associated with meningioma risk (odds ratio, 1.76; 95% confidence interval, 1.07-2.92 and odds ratio, 1.68; 95% confidence interval, 1.00-2.84, respectively). A significant interaction was found between radiation and cyclin D1 and p16 SNPs (P for interaction = 0.005 and 0.057, respectively). Our findings suggest that Ki-ras and ERCC2 SNPs are possible markers for meningioma formation, whereas cyclin D1 and p16 SNPs may be markers of genes that have an inverse effect on the risk to develop meningioma in irradiated and nonirradiated populations.

The distinction between coronary and myocardial reperfusion after thrombolytic therapy by clinical markers of reperfusion.

OBJECTIVES We sought to examine the hypothesis that rapid resolution of ST-segment elevation in acute myocardial infarction (AMI) patients with early peak creatine kinase (CK) after thrombolytic therapy differentiates among patients with early recanalization between those with and those without adequate tissue (myocardial) reperfusion. BACKGROUND Early recanalization of the epicardial infarct-related artery (IRA) during AMI does not ensure adequate reperfusion on the myocardial level. While early peak CK after thrombolysis results from early and abrupt restoration of the coronary flow to the infarcted area, rapid ST-segment resolution, which is another clinical marker of successful reperfusion, reflects changes of the myocardial tissue itself. METHODS We compared the clinical and the angiographic results of 162 AMI patients with early peak CK (< or =12 h) after thrombolytic therapy with (group A) and without (group B) concomitant rapid resolution of ST-segment elevation. RESULTS Patients in groups A and B had similar patency rates of the IRA on angiography (anterior infarction: 93% vs. 93%; inferior infarction: 89% vs. 77%). Nevertheless, group A versus B patients had lower peak CK (anterior infarction: 1,083+/-585 IU/ml vs. 1,950+/-1,216, p < 0.01; and inferior infarction: 940+/-750 IU/ml vs. 1,350+/-820, p=0.18) and better left ventricular ejection fraction (anterior infarction: 49+/-8, vs. 44+/-8, p < 0.01; inferior infarction: 56+/-12 vs. 51+/-10, p=0.1). In a 2-year follow-up, group A as compared with group B patients had a lower rate of congestive heart failure (1% vs. 13%, p < 0.01) and mortality (2% vs. 13%, p < 0.01). CONCLUSIONS Among patients in whom reperfusion appears to have taken place using an early peak CK as a marker, the coexistence of rapid resolution of ST-segment elevation further differentiates among patients with an opened culprit artery between the ones with and without adequate myocardial reperfusion.

Standardization criteria for the detection of BCR/ABL fusion in interphase nuclei of chronic myelogenous leukemia patients by fluorescence in situ hybridization

Fluorescence in situ hybridization (FISH), as a new clinical test, is not presently standardized. For practical reasons, each laboratory must build its own criteria. In this work, we present our standardization criteria for clinical practice, which include not only the methods for cell fixation, specimen preparation, and hybridization conditions, but mainly the definition of false-positive range and the scoring criteria of microscopic analysis. These include signal assessment, difference between individual microscopists, evaluation of specimen homogeneity, and the minimum number of scored nuclei required for a clinically reliable result. For this purpose, we analyzed by FISH 24 healthy volunteer donors, 31 patients affected by non-chronic myelogenous leukemia (CML) hematological malignancies, 47 CML patients at diagnosis, and 82 CML patients during treatment for the BCR/ABL fusion. In this article, we present several quality control and assurance methods that can be useful in providing standardization of the FISH technique.

Waist circumference vs body mass index in association with cardiorespiratory fitness in healthy men and women: a cross sectional analysis of 403 subjects

ObjectiveBody mass index (BMI) is more commonly used than waist circumference as a measure of adiposity in clinical and research settings. The purpose of this study was to compare the associations of BMI and waist circumference with cardiorespiratory fitness.MethodsIn a cross-sectional study of 403 healthy men and women aged 50 ± 8.8 years, BMI and waist circumference were measured. Cardiorespiratory fitness was assessed from estimated maximal O2 uptake (VO2max), as calculated from a maximal fitness test.ResultsMean BMI (kg/m2) was 27.8 ± 3.7 and 25.5 ± 4.6; and mean waist circumference (cm) 94.1 ± 9.7 and 84.3 ± 10.4 for men and women, respectively. Both men and women reported an average of 2.5 hours of weekly sports related physical activity, and 18% were current smokers. Correlation coefficients between both BMI and waist circumference, and VO2max were statistically significant in men (r = −0.280 and r = −0.377, respectively, p > 0.05 for both) and in women (r = −0.514 and r = −0.491, respectively, p > 0.05 for both). In women, the contribution of BMI to the level of VO2max in a regression model was greater, while in men waist circumference contributed more to the final model. In these models, age, hours of training per week, and weekly caloric expenditure in sport activity, significantly associated with VO2max, while smoking did not.ConclusionThe differences observed between the sexes in the associations of BMI and waist circumference with VO2max support the clinical use of both obesity measures for assessment of cardiorespiratory fitness.

Second primary breast and thyroid cancers (Israel).

Objective: To evaluate the risk for developing second primary thyroid cancer (TC) following breast cancer (BC) and second primary BC following TC on a nationwide basis. Methods: All BC and TC Jewish females diagnosed in Israel during 1960–1998 were identified through the Israel Cancer Registry. The expected second primaries were calculated using cancer incidence rates stratified by age, country of birth and period of diagnosis among the Jewish population in Israel. Standardized incidence ratios (SIRs) were estimated using Poisson regression. Results: A total of 49,207 breast and 4911 thyroid neoplasms were identified. After the exclusion of concomitant disease (diagnosed within 1 year), 59 and 70 second primaries TC and BC yielded SIRs of 1.34 (95% CI: 1.03, 1.72) and 1.07 (95% CI: 0.84, 1.34), respectively. Younger age and earlier calendar year of first primary diagnosis and shorter follow-up period were associated with increased risk for developing second primary neoplasm. Conclusions: Considering the long latency required for carcinogenesis, excess risk of second primary diagnoses soon after the first cancer, argues against the hypothesis of first primary treatment as an initiator for the second cancer. A detection bias of meticulously followed cancer patients, early exposure to common risk factors or genetic susceptibility of certain subpopulations for both malignancies seem plausible.

Expression of topoisomerase II and Ki‐67 in cervical carcinoma — clinicopathological study using immunohistochemistry

Aim. To study the correlation between the expression of topoisomerase II and Ki‐67 antigen and disease outcome in cervical squamous cell carcinomas.

Occupational risks for the development of brain tumors

Occupationally related risk factors were assessed in a population-based, case-control study of 139 patients with primary brain tumors (BT), carried out in central Israel between 1987-1991. For each case, two control groups were matched by age (+/-5 years), sex, and ethnic origin. The interview schedule included questions about lifelong occupational history before diagnosis. Odds ratios (OR) for BT, according to industrial categories, showed a significantly increased risk among blue-collar workers, especially among those employed in the textile industry, and among drivers and motor vehicle operators. When histologic tumor types were assessed separately, a significantly increased risk for malignant BT was found among drivers and motor vehicle operator occupations, while for meningiomas, an increased risk was found among weavers and tailors. Our results may provide clues for etiology and prevention measures.