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OBJECTIVE: Intrauterine pressure catheter (IUPC) is the primary device used to evaluate uterine activity. In contrast to the IUPC, electrical uterine myography (EUM) enables noninvasive measurement of frequency, intensity, and tone of contractions. The aim of this study was to determine the accuracy of EUM compared to IUPC. STUDY DESIGN: EUM measured myometrial electrical activity using a multichannel amplifier and a noninvasive position sensor. In all, 47 women in labor were monitored simultaneously with an IUPC and EUM. We compared the frequency, intensity, and tone of uterine contractions between the methods. RESULTS: The correlation of the frequency, intensity, and tone of contractions between uterine electromyography and IUPC was strong with significant r values of 0.808-1 (P < .0001). CONCLUSION: Electrical uterine electromyography yields information about uterine contractility comparable to that obtained with IUPC. [ABSTRACT FROM AUTHOR]

Purpose: The rise in the rate of cesarean deliveries highlights complications related to adhesion formation. This study evaluated whether the incidence and severity of adhesions secondary to repeat cesarean deliveries are a consequence of repeated surgeries or due to an individual's propensity to develop adhesions., Methods: A retrospective chart review was conducted for 160 patients who had more than two repeat cesarean deliveries in a single teaching hospital. Data regarding intra-abdominal adhesions were collected. The severity, location, density and amount of adhesions were evaluated based on standard operative reports. Adhesion progression in subsequent cesarean deliveries was evaluated for each individual patient., Results: 69/160 (43 %) patients developed significant adhesions following the primary cesarean delivery. Of these, 46 (67 %) had significant adhesions at the second surgery. Of the 91 (57 %) patients, who did not develop significant adhesions after the primary cesarean delivery, 34 (37 %) had significant adhesions at the third surgery. A patient presenting with significant adhesions at her second cesarean had a 1.88-fold risk for significant adhesions at her third cesarean (95 % CI 1.3-2.7)., Conclusions: Our results suggest that adhesion development might be influenced by individual factors more than by the number of cesarean deliveries.

Objective: To evaluate whether carriers of group B streptococcus (GBS) have adverse obstetric and neonatal outcomes when preterm premature rupture of membranes (PPROM) occurs., Methods: In a retrospective study, data were reviewed for women with a singleton pregnancy and PPROM before 34 weeks who attended the Meir Medical Center, Kfar Saba, Israel, between 2005 and 2012. All women received roxithromycin for 1 week, and ampicillin until GBS culture results were available. Ampicillin was continued to 1 week if the GBS culture was positive. The primary study outcome measure was the latency period (time from rupture of membranes to active/induced labor)., Results: Among 116 eligible patients, 21 (18.1%) were GBS carriers and 95 (81.9%) noncarriers. The latency period was 11.2 ± 18.1 days for GBS carriers versus 7.5 ± 9.6 days for noncarriers (P=0.93). However, there was a correlation between the length of ampicillin treatment and the latency period (Spearman correlation coefficient 0.7; P<0.001). There were no differences in early neonatal outcomes., Conclusion: GBS carriers with PPROM did not have adverse outcomes. Longer treatment with ampicillin among GBS carriers prolonged the latency period., (Copyright © 2014 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: Compare mechanical and pharmacological ripening for patients with oligohydramnios at term., Study Design: Fifty-two patients with oligohydramnios ⩽ 5 cm and Bishop score ⩽ 6 were randomized for labor induction with a vaginal insert containing 10 mg timed-release dinoprostone (PGE2) or double-balloon catheter. The primary outcome was time from induction to active labor. Time to labor, neonatal outcomes and maternal satisfaction were also compared., Result: Baseline characteristics were similar. Time from induction to active labor (13 with PGE2 vs 19.5 h with double-balloon catheter; P = 0.243) was comparable, with no differences in cesarean rates (15.4 vs 7.7%; P = 0.668) or neonatal outcomes. The PGE2 group had higher incidence of early device removal (76.9 vs 26.9%; P = 0.0001), mostly because of active labor or non-reassuring fetal heart rate. Fewer PGE2 patients required oxytocin augmentation for labor induction (53.8 vs 84.6% P = 0.034). Time to delivery was significantly shorter with PGE2 (16 vs 20.5 h; P = 0. 045)., Conclusion: Intravaginal PGE2 and double-balloon catheter are comparable methods for cervical ripening in term pregnancies with oligohydramnios.

Introduction: Placentas from pregnancies complicated with IUGR (intrauterine growth restriction) express altered telomere homeostasis. In the current study, we examined mechanisms of telomere shortening in these placentas., Methods: Placental biopsies from 15 IUGR and 15 healthy control pregnancies were examined. The percentage of trophoblasts with fragmented nuclei: senescence-associated heterochromatin foci (SAHF), was calculated using DAPI staining. The amount of human telomerase reverse transcriptase (hTERT) mRNA was evaluated using RtPCR levels of telomere capture using FISH in those samples were estimated., Results: The percentage of trophoblasts with SAHF was higher in IUGR compared to control samples, (25±13.4% vs. 1.6±1.6%, P<0.0001), hTERT mRNA was decreased (0.5±0.2 vs. 0.9±0.1, P<0.0001) and telomere capture was increased (13.2±9.7% vs.1.3±2.5%, P<0.001)., Conclusions: We suggest that IUGR placentas express increased signs of senescence as part of the impaired telomere homeostasis. One factor that mediates telomere shortening in these placentas is decreased hTERT mRNA, leading to decreased protein expression and therefore, reduced telomere elongation. Telomere capture, which is a healing process, is increased in IUGR trophoblasts as a compensatory mechanism., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Removal of retained placental tissue postpartum and retained products of conception (RPOC) abortion is done by uterine curettage or hysteroscopy. Trauma to the endometrium from surgical procedures, primarily curettage, can cause intrauterine adhesions (Asherman's syndrome) and subsequent infertility. The incidence of malpractice claims relating to intrauterine adhesions is rising, justifying reevaluation of the optimal way of handling these complications., Objectives: To review malpractice claims regarding intrauterine adhesions, and to explore the clinical approach that might reduce those claims or improve their medical and legal outcomes., Methods: We examined 42 Asherman's syndrome claims handled by MCI, the largest professional liability insurer in Israel. The clinical chart of each case was reviewed and analyzed by the event preceding the adhesion formations, timing and mode of diagnosis, and outcome. We also assessed whether the adverse outcome was caused by substandard care and it it could have been avoided by different clinical practice. The legal outcome was also evaluated., Results: Forty-seven percent of the cases occurred following vaginal delivery, 19% followed cesarean section, 28% were RPOC following a first-trimester pregnancy termination, and 2% followed a second-trimester pregnancy termination., Conclusions: It is apparent that due to the lack of an accepted management protocol for cases of RPOC, it is difficult to legally defend those cases when the complication of Asherman syndrome develops.

Objective: Senescence has been described as a stable cell proliferation arrest resulting from the progression of primary human fibroblasts through a finite number of population doublings in vitro. Accelerated telomere shortening was observed in pregnancies complicated by intrauterine growth restriction, in placentas of diabetic mothers and trisomy 21 amniocytes. We hypothesized that under conditions of stress, telomeres in placentas will be shorter and there will be more cells with the senescence phenotype., Methods: The two study groups included placental biopsies from 7 cases of trisomy 21 and amniocytes from 10 cases of trisomy 21. The control groups consisted of placental biopsies from 6 cases and amniocytes from 10 pregnancies with a normal karyotype. The samples were analyzed for the presence of senescent cells based on the number of fragments in each cell., Results: A significantly higher percentage of cells in the senescent state, based on a higher percentage of cells with more fragmentations, were found in the amniocytes (20.8%) and in trophoblasts (94.3%) from placentas with trisomy 21 compared to the control groups., Conclusion: Among other genetic instability parameters, trisomy 21 amniocytes and trophoblasts express a higher prevalence of senescent cells than were previously reported.

Objective: Fetal cells represented by extravillous trophoblasts (EVT) obtained from the cervix by a minimally invasive procedure are important for prenatal diagnosis in early pregnancies. Endoreduplication is a duplication of chromosomes without mitosis, leading to polyploidy that might represent increased cellular metabolic activity. In this study, we estimated the normal prevalence of polyploid trophoblasts exfoliated to the cervix between 5 and 13 weeks of gestation., Methods: Cervical samples were obtained by cytobrush, between 5 and 13 weeks of gestation from 36 randomly selected, singleton pregnancies. FISH was done with X, Y and two 21 probes., Results: We diagnosed 21 pregnancies with female and 15 pregnancies with male fetal karyotypes. A mean of 15.2 (0.02%) tetraploid cells were found in pregnancies with a female fetus and a mean of 2.0 (0.003%) tetraploid cells were found in pregnancies with a male fetus. The tetraploid cells (endoreduplicated trophoblasts) were two to three times larger than the normal cells usually seen in the cervix., Conclusions: Extravillus trophoblasts tend to form endoreduplication to the ploidy level of 4c-8c of DNA. Those cells may represent a typical phenomenon in the growing placenta. Extravillus trophoblasts from female fetuses tend to form higher rates of endoreduplication.

Objectives: Infants with intrauterine growth restriction (IUGR) have increased morbidity and mortality. The decision whether to induce labor at term or to expectantly manage these pregnancies is controversial. The aim of this study was to assess the outcomes of these two management strategies in term pregnancies., Study Design: This retrospective cohort study compared neonatal and maternal morbidity and mortality of IUGR fetuses (estimated fetal weight below the 10th percentile) between induced and spontaneous labors., Results: Records of 669 IUGR newborns were reviewed; 499 were delivered through spontaneous labor and 170 were delivered through induced labor. Epidemiology and early perinatal outcomes between the two groups were similar. The cesarean section rate was significantly higher (P<0.005) in the induced group., Conclusions: Expectant management for term IUGR pregnancies seems to be safe, with lower rates of cesarean deliveries. A large, prospective, randomized controlled trial with long-term neonatal follow-up is indicated.

Introduction: intrauterine growth restriction (IUGR) is a significant cause of both short- and long-term morbidity and mortality. IUGR secondary to placental dysfunction is correlated with telomere shortening. Telomerase is an enzyme complex that elongates telomeres. One of its components is encoded by the telomerase RNA component gene (TERC), which serves as the RNA template for the addition of telomeric repeats. We hypothesized decreased TERC gene copy number in IUGR placentas as part of the mechanism of telomere shortening in placental dysfunction., Methods: we estimated the gene copy number of the TERC gene at 3q26 by applying FISH to trophoblasts of placental biopsies from five pregnancies with IUGR caused by placental insufficiency and compared them to placentas from five gestational-age matched, uncomplicated pregnancies., Results: significantly lower TERC gene copy number was observed in IUGR trophoblasts on the same chromosome and on other chromosomes, compared to the control samples (p<0.05)., Conclusions: the TERC gene copy number is decreased in IUGR trophoblasts. These results support the observations of telomere shortening and decreased telomerase activity in IUGR placentas. We suggest that these findings might play a role in the pathophysiology of IUGR, perhaps by promoting senescence in trophoblasts of IUGR placentas., (2010 Elsevier Ireland Ltd. All rights reserved.)

Individuals with trisomy 21 have an increased risk of developing leukemia and premature dementia. They also have a higher rate of telomere loss. The aim of the study was to compare telomere length and the hTERC gene copy number, which encodes the telomerase RNA subunit, in amniocytes of trisomy 21 conceptions and normal pregnancies. A quantitative fluorescence-in-situ protocol (Q-FISH) was used to compare telomere length in amniocytes cultured from 11 trisomy 21 conceptions and from 14 normal pregnancies. Quantification was conducted using novel computer software. Fluorescence in situ hybridization (FISH) was used to assess the percentage of cells with additional copies of hTERC. We found that the immunofluorescence intensity, which represents telomere length, was significantly lower in amniocytes from trisomy 21 conceptions compared to the control group. The trisomy 21 group had a higher number of cells with additional copies of hTERC. This observation could be one of the cytogenetic parameters that represent a state of genetic instability and might play a role in the pathomechanism of typical features of Down syndrome, such as dementia and malignancy., (Copyright © 2011 S. Karger AG, Basel.)

Telomeres are TTAGGG repetitions at the ends of chromosomes. Functioning telomeres are essential for normal segregation and maintenance of chromosomes during mitotic and meiotic divisions. Dysfunctional telomeres support the survival of aneuploid cells, a characteristic of many human malignancies. In contrast to the non-overlapping nature of telomeres in normal nuclei, telomeres of tumor nuclei tend to form aggregates. In this study, our objective was to evaluate the number of telomere aggregates (TAs) in karyotype-balanced structural rearrangements. This is an additional parameter of genetic instability, which might suggest a possible increased risk for diseases related to genomic instability, such as cancer. Twenty-six amniotic fluid cell cultures were established following genetic amniocentesis. Telomere FISH protocol was applied to the samples. Telomere aggregates were counted using a 2D microscope. The results were statistically tested by analysis of variance (ANOVA) and Kruskal-Wallis tests. More telomere aggregates in the structural balanced rearrangements were found in both study groups (balanced translocations and inversions) compared to the control group (P < 0.05). The persistence of TAs in cells is probably related to Breakage-Bridge-Fusion (BBF) cycles, a mechanism of TAs described by Muller and McClintock, resulting in end-to-end fusion that contributes to the onset of genomic instability. BBF cycles contribute to deletions, gene amplification, non-reciprocal translocations, and overall genetic changes associated with tumor genesis. According to our studies, the individuals who are carriers of balanced structural chromosomal rearrangements show some of the genetic instability parameters that appear in other circumstances, such as premalignant and malignant conditions.

Objective: Telomeres shorten and aggregate with cellular senescence and oxidative stress. Telomerase and its catalytic component human telomerase reverse-transcriptase regulate telomere length. The pathogenesis of preeclampsia and intrauterine growth restriction involves hypoxic stress. We aimed to assess telomere length in trophoblasts from pregnancies with those complications., Study Design: Placental specimens from 4 groups of patients were studied: severe preeclampsia, intrauterine growth restriction, preeclampsia combined with intrauterine growth restriction, and uncomplicated (control). Telomere length and human telomerase reverse-transcriptase expression were assessed by using quantitative fluorescence-in-situ protocol and immunohistochemistry., Results: Telomere length was significantly lower in preeclampsia, intrauterine growth restriction, and preeclampsia plus intrauterine growth restriction placentas. More aggregates were found in preeclampsia, but not in intrauterine growth restriction placentas. Human telomerase reverse-transcriptase was significantly higher in the controls compared with the other groups., Conclusion: Telomeres are shorter in placentas from preeclampsia and intrauterine growth restriction pregnancies. Increased telomere aggregate formation in preeclampsia but not in intrauterine growth restriction pregnancies, implies different placental stress-related mechanisms in preeclampsia with or without intrauterine growth restriction., (Copyright 2010 Mosby, Inc. All rights reserved.)

ABSTRACT Focal amplification of specific regions of the genome creates high copy number and expression of oncogenes in tumors. By applying fluorescence in situ hybridization (FISH) to leukocytes of hepatitis C (HCV) patients and non-Hodgkin lymphoma (NHL) patients, we estimated gene dosage of the TERC gene at 3q26.3. Higher TERC copy numbers were found in NHL at diagnosis compared to HCV patient groups. Higher TERC copy numbers were also observed in NHL patient at diagnosis and relapse compared to patients in remission. We believe that the TERC gene amplification is involved in the process of genetic instability leading to tumor genesis such as in NHL.

Background: Although the comprehensive evaluation of the fetal heart includes echocardiography by an experienced pediatric cardiologist, economic constraints sometimes dictate the need to select patients., Objectives: To analyze the usefulness of fetal echocardiography in the detection of congenital heart disease according to the referral indication., Methods: This retrospective survey relates to all 3965 FE studies performed in our center from January 2000 to December 2004. The diagnosed cardiac anomalies were classified as significant and non-significant malformations. All FE studies were done by a single operator (A.L.) at Meir Medical Center, a referral center for a population of about 400,000. The 3965 FE studies were performed for the following indications: abnormal obstetric ultrasound scans, maternal and family history of cardiac malformations, medication use during the pregnancy, and maternal request. The relative risk of detecting CHD was calculated according to the various referral indications., Results: Overall, 228 (5.8%) cases of CHD were found. The most common indication for referral was suspicion of CHD during a four-chamber view scan in a basic system survey or during a level II ultrasound survey. No correlation was found between maternal age and gestational age at the time of scanning and the likelihood of finding CHD., Conclusions: Our data suggest that a suspicious level II ultrasound orthe presence of polyhydramnios is an important indication for FE in the detection of significant CHD.

Telomeres of tumor nuclei tend to form aggregates (TA). The aim of this study was to estimate the TA formation in leukocytes of patients with chronic hepatitis C (HCV) which is considered to be premalignant disease, in patients of HCV who eradicated the virus. PNA Telomere kit (Dako) was used to evaluate the TA formation with the utilization of 2D fluorescence microscopy. A higher rate of TA was found in both HCV groups as compared to controls. Our results indicate that HCV patients have some of the components that create the cascade of events leading to malignancies.

Broken chromosomes can acquire new telomeres by "telomere capture" (TC), and it has become possible to investigate the terminus in cytogenetically visible telomere rearrangements. The TC phenomenon was observed in malignant conditions. We evaluated the TC rate in hepatitis C virus (HCV) patients compared to non-Hodgkin's lymphoma patients, as well as relative to a control group. For this purpose, we used two Cytocell probes, 15qter and 13qter. Higher TC rates were found in the three study groups relative to the control group. Our results showed that HCV patients have some of the components that can initiate the cascade of events leading to malignancies.

Telomeres are nucleoprotein structures located at the termini of chromosomes that protect the chromosomes from fusion and degradation. Hepatocyte cell-cycle turnover may be a primary mechanism of telomere shortening in hepatitis C virus (HCV) infection, inducing fibrosis and cellular senescence. HCV infection has been recognized as potential cause of B-cell lymphoma and hepatocellular carcinoma. The present study sought to assess relative telomere length in leukocytes from patients with chronic HCV infection, patients after eradication of HCV infection (in remission), and healthy controls. A novel method of manual evaluation was applied. Leukocytes derived from 22 patients with chronic HCV infection and age- and sex-matched patients in remission and healthy control subjects were subjected to a fluorescence-in-situ protocol (DAKO) to determine telomere fluorescence intensity and number. The relative, manual, analysis of telomere length was validated against findings on applied spectral imaging (ASI) in a random sample of study and control subjects. Leukocytes from patients with chronic HCV infection had shorter telomeres than leukocytes from patients in remission and healthy controls. On statistical analysis, more cells with low signal intensity on telomere FISH had shorter telomeres whereas more cells with high signal intensity had longer telomeres. The findings were corroborated by the ASI telomere software. Telomere shortening in leukocytes from patients with active HCV infection is probably due to the lower overall telomere level rather than higher cell cycle turnover. Manual evaluation is an accurate and valid method of assessing relative telomere length between patients with chronic HCV infection and healthy subjects.

Telomeres of tumor nuclei tend to form aggregates (TA). The same phenomenon was also observed in premalignant states. The aim of this study was to estimate TA formation in leukocytes of patients with non-Hodgkin lymphoma (NHL) at different disease stages (diagnosis, treatment, relapse, and remission). The peptide nucleic acid Telomere Kit was used to evaluate TA formation, using two-dimensional fluorescence microscopy. A higher rate of TA was found in all the NHL stages (including remission) than in the control group. Significantly higher TA formation was also observed in the relapse group, compared to the diagnosis group. It may be possible that patients with higher TA numbers are prone to relapse. From our previous results involving replication pattern, random aneuploidy rate, and (recently) TA formation, it can be concluded that the patients in remission are at higher risk of developing relapse than the normal population throughout their life span. The genetic instability parameters remain in the cells of these patients, who must continue to be monitored throughout their life.

Chronic immune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by a low platelet count and mucocutaneous bleeding. Pregnancy does not increase the incidence of ITP nor does it exacerbate a preexisting disease. Although pregnant women with ITP may experience several maternal and fetal complications, in most cases even with a very low platelet count, there is neither maternal nor fetal morbidity or mortality. Corticosteroids are the first line of therapy in pregnant women; intravenous immune globulin is commonly used in steroid resistant patients. Other treatments such as intravenously administered anti-D (Rhogam) and splenectomy during pregnancy have been reported. Antiplatelet IgG antibodies can cross the placenta and can induce fetal thrombocytopenia. In most women there is no indication to assess fetal platelet counts during the pregnancy. The mode of delivery is determined by obstetrical considerations.

Hepatitis C virus (HCV) has been recently recognized as a potential cause of B-cell lymphoma. Both chronic hepatitis B and C with or without cirrhosis represent major preneoplastic conditions, and the majority of hepatocellular carcinomas arise in these pathological settings. According to the aneuploidy-cancer theory, carcinogenesis is initiated by random aneuploidy, which is either induced by carcinogens or arises spontaneously. The aim of this study was to evaluate random aneuploidy rate in HCV patients during chronic infection and remission (past infection eradicated), compared with non-Hodgkin lymphoma (NHL) patients and healthy controls. To determine random aneuploidy, we applied the FISH technique with probes for chromosomes 9 and 18. Significantly higher random aneuploidy rate was found in the HCV-infected and lymphoma patients than in the control group; the past HCV group in remission had intermediate rates, between those of the control group and the chronically infected patients. Patients who have eradicated HCV infection may nonetheless carry higher risk for future malignancy and therefore need long-term follow-up.

B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia of adults in Western countries. The most frequent recurring chromosomal aberrations identified in B-CLL patients are trisomy 12 and deletions of 13q, 17p, and 11q. Cases with deletions of 11q and 17p have a poor prognosis, whereas cases with deletions in 13q have a favorable prognosis. It was previously shown that CLL patients with trisomy 12 and del(13)(q14) have a higher rate of asynchronous replication of normal structural genes when compared to those with normal karyotypes. We studied the replication pattern of the structural locus 21q22 and the imprinted gene SNRPN and its telomere (15qter) and the random aneuploidy of chromosomes 9 and 18 in CLL patients with trisomy 12 and deletions of 11q and 17p, and compared the results to those of CLL patients without these aberrations and to healthy controls. Random aneuploidy rate was higher in the group of patients with trisomy 12 as compared to all other groups. The replication pattern with higher asynchronous pattern was found in both aberration groups compared to the CLL patients without the aberrations and to the control group with involvement of 21q22 and 15qter, whereas the highest synchronous group was found in the 2 aberrations CLL patient groups compared to the other groups with the imprinted locus SNRPN. The existence and significance of chromosomal aberrations in CLL have a deleterious effect on the processes of cell cycle and gene replication and may have biological and prognostic implications.

Unlabelled: The cause of aneuploidy in fetuses of young women is not fully understood. As such women are considered to be at risk of repeating the "error", it is customary to recommend chromosomal evaluation (karyotyping) in subsequent pregnancies. Individuals predisposed to meiotic nondisjunction exhibit aneuploidy in their mitotic cells (mosaicism). The aim of this study was to assess the actual risk for repeated aneuploidy in patients who had a previous pregnancy with aneuploidy by estimating the rate of somatic random aneuploidy in their normal pregnancy and to assess whether this risk is heritable. With utilization of FISH, we assessed the number of chromosomes 9 and 18 in amniocytes from the following pregnancies: 1. Fourteen of the women had a history of chromosomal aneuploidy in a previous pregnancy (study group). 2. Ten women had previous normal pregnancies (control). 3. Nine samples were assessed in amniocytes taken from aneuploid pregnancies (positive controls). A mean of 458+/-65.66 amniocytes were evaluated (range 97-500 nuclei). There was no significant difference in the rate of aneuploidy of both chromosomes between the study and control groups. However, this rate was significantly higher in the aneuploid pregnancies (p < 0.05)., Conclusion: The known tendency for repeated nondisjunction shown in women with previous aneuploid babies could not be demonstrated in their offsprings.

Down syndrome (DS) is a multifactorial disorder with a high predisposition to leukemia and other malignancies. A change in the replication pattern from synchronous in normal genes to asynchronous in DS amniocytes has previously been reported. The objective of this study was to evaluate additional molecular cytogenetic factors which could re-emphasize the high correlation between DS cells and genetic instability. We found a higher rate of random aneuploidy in chromosomes 9 and 18 and a higher rate of asynchronous replication in the subtelomeric region or DS leukocytes than in cells from normal newborns. In addition, the telomere capture phenomenon was observed in the DS leukocytes but not in normal controls. The molecular cytogenetic factors observed in the DS individuals are known to correlate with genomic instability and with predisposition to cancer.

Telomeric regions of the human genome are of particular interest, because rearrangements of these regions are difficult to identify by conventional chromosome banding technology. With the advent of molecular cytogenetic techniques such as fluorescence in situ hybridization (FISH), it has been possible to investigate the terminus in cytogenetically visible terminal deletions and telomere rearrangements. We investigated telomere capture and aneuploidy rates in chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML) patients, as well as in healthy control subsets. Using a FISH technique, we estimated the random aneuploidy and telomere capture of the 21q22, SNRPN, and 15qter loci. Higher aneuploidy rates were found in the leukocytes of CLL and CML patients, compared with the control group, for the 21q22 and SNRPN loci. There was no difference in the aneuploidy rate between the CML and CLL groups. Telomere capture was found in the two groups (CLL and CML), but not in the control group. We propose that the telomere capture phenomenon is much more common than has been reported in the literature; however, its prognostic significance is yet to be established.

In this study we evaluated the aneuploidy rate of cells from patients considered to have a premalignant condition (monoclonal gammopathy or MGUS) and patients with multiple myeloma, as well as healthy controls. By applying a fluorescence situ hybridization technique, we estimated the random aneuploidy rate of alpha-satellite (centromeres) probes from chromosomes 9 and 18. The monosomy and total aneuploidy rates were higher in the two study groups compared to the control group. The monosomy rate was significantly higher in the MGUS group compared to the group with chromosome 18 alpha-satellite probes, a finding that was reported before in preneoplastic conditions. Our results support the cancer aneuploidy theory that carcinogenesis is initiated by a random aneuploidy, which is induced either spontaneously or by a carcinogen. The resulting karyotype instability sets a chain reaction of aneuploidization, which generates even more abnormal and eventually cancer-specific combinations and rearrangements of chromosomes.

Objective: In this study, we applied the fluorescent in situ hybridization (FISH) technique and compared the common numerical abnormalities with chromosomes 13, 16, 18, 21, X, and Y in spontaneous to artificial abortion. This would cover about 75% of the common aneuploidy in spontaneous abortion., Methods: Placentas were taken from 59 patients with a first trimester spontaneous abortion and 61 patients who underwent an elective first trimester pregnancy termination. The range of growth was from 5 to 12 gestational weeks. Placentas were processed according to direct chorionic villi preparation. Direct dual color FISH was performed according to Vysis protocol with the probes for the following chromosomes: 13, 16, 18, 21, X, and Y., Results: The aneuploidy rate in spontaneous abortion was 55.9% and in artificial abortion 8.2%. There was a significant difference between the two groups in the aneuploidy rate (P = 6 x 10(-9))., Conclusion: FISH is a rapid, efficient, and relatively inexpensive tool in detecting aneuploidy in placentas from cases of spontaneous abortions. Our rate of detected aneuploidy is compatible with other reports in which conventional cytogenetics was utilized.

The possibility that environmental effects are associated with chromosome aberrations and various congenital pathologies has been discussed previously. Recent advances in the collection and computerization of data make studying these potential associations more feasible. The aim of this study was to investigate a possible link between the number of Down syndrome (DS) cases detected prenatally or at birth yearly in Israel over a 10-year period compared with the levels of solar and cosmic ray activity 1 year before the detection or birth of each affected child. Information about 1,108,449 births was collected for the years 1990-2000, excluding 1991, when data were unavailable. A total of 1,310 cases of DS were detected prenatally or at birth--138 in the non-Jewish community and 1,172 in the Jewish population. Solar activity indices--sunspot number and solar radio flux 2,800 MHz at 10.7 cm wavelength for 1989-1999--were compared with the number of DS cases detected. Pearson correlation coefficients (r) and their probabilities (P) were established for the percentage of DS cases in the whole population. There was a significant inverse correlation between the indices of solar activity and the number of cases of DS detected--r=-0.78, P=0.008 for sunspot number and r=-0.76, P=0.01 for solar flux. The possibility that cosmophysical factors inversely related to solar activity play a role in the pathogenesis of chromosome aberrations should be considered. We have confirmed a strong trend towards an association between the cosmic ray activity level and the incidence of DS.

A 33-year-old healthy woman, gravida 1 with twins pregnancy was admitted with mild preeclampsia and unusual hyponatremia which resolved promptly postpartum. This is the seventh reported case of hyponatremia complicating preeclampsia, four of the patients carried twins and four had nephrotic syndrome.

Ataxia telangiectasia (AT) is a pleiotropic and rare (1:40,000 to 1:100,000) recessive disease. Laboratory investigations have failed to detect any consistent anomaly in cells from AT heterozygotes. To estimate random aneuploidy, we applied a fluorescence in situ hybridization technique with alpha-satellite probes for chromosomes 8 and 9 and replication pattern for RB-1, HER-2/neu, and the imprinted SNRPN loci on primary AT carrier fibroblasts. Higher random aneuploidy was not found in the carrier fibroblasts compared to control amniocytic cells. The asynchrony pattern was higher in the AT carrier cells with the RB-1 locus (P=0.057) and significantly higher with the HER-2/neu locus (P < 0.001) compared to control cells. As for the imprinted locus SNRPN, there was a significantly lower asynchrony rate in the AT carriers (P < 10(-5)) compared to the control group. Molecular cytogenetic parameters of random aneuploidy and replication pattern may reflect predisposition for the development of cancer. It is possible that in some AT carriers the genetic instability phenomena associated with the abnormal replication pattern may represent their potential for developing malignancies.

Multiple myeloma represents a malignant proliferation of plasma cells derived from a single clone. It is well known that alkylating agents are capable of inducing myelodysplastic syndromes (MDS) and acute myelocytic leukemias (AML). This risk of both diseases in patients with multiple myeloma has been estimated to be 10-20% after 10 years. We aimed to evaluate the time course and the type of genetic abnormalities in melphalan-treated patients in the chronic stage of the disease. We applied fluorescence in situ hybridization methods with probes to 5q31 and 7q31 to mononuclear peripheral blood leukocytes of 18 melphalan-treated patients and compared the results to those of 8 untreated myeloma patients. We found three patients (17%) with a 5q31 deletion in their peripheral white blood cells, but no 7q31 deletion. These findings suggest that 5q- occurs before the overt development of MDS/AML and raise important concerns regarding long-term treatment of myeloma patients with alkylating agents. Also, the performance of cytogenetic evaluation should be considered before autologous transplantation. The clinical and biological implications of these findings should be evaluated in larger clinical and laboratory studies.

Xeroderma pigmentosum (XP) is a rare autosomal recessive syndrome. Laboratory investigations have failed to detect any consistent anomaly in cells from XP heterozygotic subjects, although examples of behavior intermediate between normal and XP cells have been reported. To estimate random aneuploidy we applied fluorescence in situ hybridization (FISH) with alpha-satellite probes for chromosomes 8 and 9 and replication pattern for TP53 (p53), ERBB2 (HER-2/neu), and MYCN (N-MYC) loci and for the imprinted SNRPN locus. A significantly higher rate of aneuploidy rate was observed in XP patients and carriers than in controls. The asynchrony pattern was significantly higher in XP carriers and patients with all three coding loci analyzed and significantly lower in XP patients and carriers with the imprinted locus SNRPN than in the control group. Molecular cytogenetic parameters such as random aneuploidy and replication pattern, which are known to reflect chromosomal instability, may be part of the tumorigenesis process. In XP patients and carriers, this genetic instability may represent a potential for developing malignancies.

Objectives: To examine the assumption that amniotic fluid alpha-fetoprotein (AFAFP) levels are different in female and male twin fetuses., Design: Amniotic fluid levels of AFP in pregnancies with female and male fetuses in gender-concordant and gender-discordant twins were compared. A t test of p < 0.05 was considered significant., Material and Methods: Between 1995 and 1999, 332 genetic amniocenteses on twin pregnancies were performed at Meir Hospital, Kfar Saba, and Rambam Hospital, Haifa, Israel. One hundred and sixty-six were concordant for gender (84 females and 82 males) while 166 pairs differed in their gender. The amniotic fluid AFP levels of each sac were measured using fluorescent immunoassay methods by an AutoDELFIA machine., Results: The mean levels of AFAFP were lower in female twins compared to their male counterparts in same-gender twins (p = 0.07), although the difference was quite small. Nevertheless, there was no such difference between AFAFP of male versus female fetuses in gender-discordant twins., Conclusions: The levels of AFAFP were higher in the male twins of gender-concordant twins in comparison to female twins. No such difference was found between female versus male fetuses in gender-disconcordant twins., (Copyright 2003 S. Karger AG, Basel)

Benign cystic teratoma, also known as dermoid cyst, is the most common of all ovarian neoplasms accounting for 10%-20% of all ovarian cysts. Most have a normal 46,XX karyotype. Less than 2% can undergo malignant transformation. By using the comparative genomic hybridization technique on nine benign ovarian cysts we were able to show two cases with chromosomal aberrations not seen before in dermoid cysts but known to be involved in malignant ovarian tumors. We speculate that these are the tumors carrying the potential for malignant transformation.

The most common treatment of chronic lymphocytic leukemia (CLL) is the alkylating agent chlorambucil (CLB), with or without prednisone. In the present study, our aim was to evaluate whether treatment with CLB for more than one year induced genetic changes manifested by comparative genomic hybridization (CGH) as new chromosomal aberrations. We also studied whether CLB affected the pattern of replication by using fluorescence in situ hybridization (FISH). We found a similar rate of asynchronous pattern of replication in both treated and untreated patients with CLL. Most of the aberrations found with CGH were previously reported in CLL. More prognostically unfavorable aberrations and more cases with genetic changes were found in the treated group. The changes found were not typical of the secondary genetic aberrations associated with alkylating agents. Thus, we conclude that treatment of CLL with CLB for at least a year does not affect the parameters analyzed in this study. Longer studies are needed to further explore the effects of alkylating agents on normal and malignant cells.

We applied a comparative genomic hybridization (CGH) technique to paraffin-embedded tissue samples taken from fibroadenomas, benign breast tumors, to detect possible numerical and unbalanced genetic changes. We compared the results to those from previous cytogenetic studies of fibroadenomas. In concurrence with previous cytogenetic studies of fibroadenomas, we detected genetic aberrations in chromosomes 4-6, 8-13, 16, 18, 19, 20, and 22. In addition, with the CGH technique we were able to find two new aberrations, 15q+ and 16p-. Because these aberrations have also been reported to be present in breast cancer, the importance of this finding is yet to be determined.

Background: While most allelic pairs of DNA replicate synchronously during the S phase of the cell cycle, some genes normally replicate asynchronously, i.e., genes on the X chromosome and imprinted genes. The replication control mechanism is unknown but was shown to be impaired in malignancies and chromosomal trisomies where replication pattern becomes asynchronous., Objectives: To determine the level of asynchronization in replication timing of cells from patients with microdeleted genomes., Methods: We applied monocolor fluorescent in situ hybridization with different probes on leukocytes from microdeleted genomes., Results: All samples derived from the microdeleted genomes showed significantly higher levels of an asynchronized pattern compared to normal individuals., Conclusions: Even a "small" genetic imbalance (microdeletion) can interfere with gene replication and cell cycle progression, as previously shown in full trisomies.

Comparative genomic hybridization (CGH) was applied to samples taken from various sites of placentas originating from complicated pregnancies: 24 with intrauterine growth restriction (IUGR), one with multiple fetal malformation, one with toxemia, one with hydrocephalus and two with undetectable maternal serum alpha-fetoprotein (MSAFP). One of the most common aberrations in the IUGR cases was the addition of a whole or part of the X chromosome. Other aberrations such as additional Y chromosome or of 13(q22) or loss of chromosome 17 also appeared in different cases. In one IUGR case trisomy 8 (in one site) and 47,XXY (in all sites) were detected. In the two cases with undetectable MSAFP monosomy 16 was found. Some of the results were also confirmed by the FISH technique. In all the control cases (six normal and five with aneuploidy) CGH concurred with the known karyotype. Our results demonstrate the usefulness of the CGH technique in the genetic evaluation of fresh and paraffin embedded placentas in problematic pregnancies even when morphology is normal. However, it is very important to take multiple samples from different sites of the placenta., (Copyright 2002 John Wiley & Sons, Ltd.)

The replication status of malignant cells is usually asynchronous. However, to date the pattern of replication has not been studied in myeloproliferative disorders nor has the effect of chemotherapy been systematically evaluated. Therefore, we used fluorescence in situ hybridization to interphase nuclei in PHA-stimulated peripheral blood lymphocytes to examine replication timing of three alleles associated with the malignant process. The study group comprised hydroxyurea treated and untreated patients with essential thrombocytosis (ET) or polycythemia vera (PV). A significantly higher rate of the asynchronous pattern of replication in both treated and untreated patients was found as compared to healthy controls. The highest rate of asynchronous replication was observed in untreated patients. Also, the frequency of the two doublets pattern was significantly higher in the untreated group compared to the treated patients and to the control groups. In conclusion, patients with PV and ET have a higher rate of asynchronous pattern of replication. A possible correlation between disease activity and the pattern of replication is suggested. The effect of hydroxyurea on the pattern of replication is variable.

Objective: A study was conducted to evaluate the sensitivity of combining a second trimester triple test and targeted ultrasound in order to detect Down syndrome in women undergoing amniocentesis over 35 years of age., Methods: Women over 35 years of age underwent a triple test and an ultrasound examination for chromosomal markers immediately prior to genetic amniocentesis., Results: One thousand and six women were examined. Four hundred and thirty seven were triple test-positive and in 195 cases ultrasonographic abnormalities were observed. Thirteen had Down syndrome and eight had other chromosomal abnormalities. All women with Down syndrome babies were triple test-positive and seven also had ultrasonographic markers. Three of eight women who had babies with chromosomal aberrations other then Down syndrome were also triple test-positive., Conclusions: The use of the triple test as a screening tool in our population would reduce the number of amniocenteses by 60%, while no cases of Down syndrome would be missed. Ultrasonographic markers have added little to this population. Three non-Down syndrome chromosomal abnormalities and two Down syndrome mosaic cases would be missed by this approach., (Copyright 2002 John Wiley & Sons, Ltd.)

We assessed possible inter- and intraindividual variations in the frequency of disomy in sperm cells from three men with abnormal sperm analysis parameters. Mono- and dual-color fluorescence in situ hybridization (FISH) was applied to sperm cells from different samples of the men. Four men with a normal sperm profile were used as controls. The samples were taken separately over a period of 6 months. FISH probes used for the disomy rate analysis were clones from the satellite region of chromosomes 8, 18, X, and Y. The study group showed a significantly higher disomy rate compared with the control group, whereas there was no significant difference in the disomy rate between three different samples from the same individuals. These results suggest that the sampling time has no importance in assessing the rate of nondisjunction in sperm cells.

Hepatocellular carcinoma (HCC) is a very common and highly malignant tumor, associated mainly with chronic viral hepatitis, cirrhosis of any cause, aflatoxin exposure and ethanol consumption. The aim of this study was to map genomic aberrations in HCC by a recently developed technique: comparative genomic hybridization (CGH). We applied CGH on 17 liver specimens, of which seven were HCCs. The rest were benign liver tumors, cirrhotic and normal livers, and other liver malignancies. Our study included mainly large tumors (mean size 10.5 cm) unrelated to viral hepatitis or cirrhosis. Our CGH analysis detected genomic imbalances in 42% of HCCs. The common aberrations included DNA gains of 1q, 9p, and 8q and DNA losses of 17p, 13q, 9q, 4q, and 11q. Also, we detected trisomies 8, 9, 18 and 21, which have not been reported previously. Gains and losses of DNA found in this study probably involve oncogenes and tumor suppressor genes that play a role in the puzzle of hepatocarcinogenesis. This study also suggests a possible link between the size of the tumor and the burden of genetic changes.

Various non-invasive techniques for prenatal diagnosis have been under investigation. We evaluated the success of fetal sexing using a non-invasive technique for obtaining fetal cells, uterine cervix brushing, in combination with FISH. Thirty pregnant women who completed between 6 and 10 weeks of gestation and who were scheduled to undergo pregnancy termination were included in the study. A Pap smear cytobrush was inserted through the external os to a maximum depth of 2 cm and removed while rotating it a full turn. The material that was caught on the brush was spread on four microscope slides. Two-color FISH was used for fetal sexing. Following pregnancy termination, a placental sample was used for full karyotyping. In 29/30 cases FISH diagnosis was confirmed by chromosomal analysis. The only male case in which a Y chromosome was not seen was from a pregnancy of 6 weeks 6 days gestational age. One case was mosaic of 46,XY/47,XXY (25%). In most cases (7/13) the Y chromosome was already identified in the first analyzed slide. With the use of a cytobrush fetal cells can be easily obtained for the purpose of prenatal diagnosis of chromosomal disorders., (Copyright 2001 John Wiley & Sons, Ltd.)

Polycythemia vera (PV) and essential thrombocytosis (ET) are clonal chronic myeloproliferative disorders originating from a multipotent stem cell. Bone marrow examinations reveal chromosomal abnormalities in 15-43% of PV patients and 5% of ET patients, but no specific recurring abnormality has been found to date. We aimed to find cytogenetic aberrations in PV and ET by comparative genomic hybridization (CGH), a relatively new molecular cytogenetic technique. In this study, CGH analysis was performed on peripheral blood leukocytes of 12 PV patients and 8 ET patients. One patient (8.3%) with PV had an abnormal karyotype with a deletion in 7q11.2 and one patient with ET (12.5%) had a gain in 18p. Peripheral blood analysis by CGH revealed a low frequency of cytogenetic abnormalities in PV and ET patients. However, using CGH we were able to detect two cytogenetic aberrations that were not reported previously in these disorders.

Asynchronous replication of homologous loci was reported in lymphocytes of patients with lymphoma, ovarian and renal cancer as well as in lymphocytes of patients with premalignant conditions, for example, essential mixed cryoglobulinemia associated with hepatitis C virus and in monoclonal gammopathy of unknown significance. In the present study we evaluated the replication pattern in lymphocytes of four groups of patients with intermediate grade of non-Hodgkin lymphoma at various stages of their disease: 1) at diagnosis; 2) during cytotoxic treatment; 3) in remission; and 4) in relapse. A significantly higher proportion of the asynchronous pattern of replication at diagnosis, during cytotoxic treatment, and in relapse was noted as compared to healthy controls and to patients who achieved remission of their lymphoma. Also, the frequency of the two doublets (DD) pattern in every group studied was significantly lower than in the controls. If our findings can be confirmed in larger, long-term prospective studies, it may allow the use of a simple and inexpensive tool to closely observe patients with lymphoma who are at high risk for relapse.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in humans, with the major cytogenetic aberrations of trisomy 12 and deletion of 13q14. This study examined the influence of these aberrations on general gene replication. The study group included three subgroups: (1) 15 CLL patients, (2) 4 CLL patients with trisomy 12, (3) 3 CLL patients with deletions in 13q14. Five healthy individuals served as a control group. Monocolor fluorescence in situ hybridization (FISH) with probes for c-myc, HER-2/neu, and p53 was applied to lymphocyte nuclei for the evaluation of replication timing. Asynchronous replication (SD) rate was significantly higher in all CLL patients (P < 0.01) when compared to the control group and was even higher in the group of CLL patients with trisomy 12 and 13q14 deletion (P < 0.01). The asynchrony rate was significantly higher in cells with trisomy 12 for all three probes analyzed, compared to "healthy" cells in the same patients (P < 0.001). To conclude, in CLL patients with a chromosomal aberration such as trisomy 12 and 13q14 deletion we were able to demonstrate a high rate of asynchrony of replication. The high correlation between cells with trisomy 12 and SD pattern could reflect direct influence of the aberration on gene replication and cell cycle control.

Objective: To examine the theory that the postpartum shivering phenomenon is related to feto-maternal bleed during the third stage of labor., Methods: One hundred laboring low-risk women who had a normal vaginal delivery were observed for the presence of postpartum chills. The duration of the first and second stages of labor changes in body temperature, maternal and fetal blood types and the use of epidural anesthesia were recorded. Following the delivery maternal blood was examined for the presence of fetal red blood cells using the Kleihauer-Betke stain., Results: Complete data was available in 97 patients. Post-partum chills occurred in 31 of them (32%). Women with and without chills were similar in their maternal and gestational age, the use of epidural anesthesia, and length of second stage of labor. Women with chills delivered smaller babies but the difference did not reach significance. Maternal-fetal blood group incompatibility was significantly more common among shivering than non-shivering women (48% vs. 20% respectively, p=0.006). Kleihauer-Betke test was positive in 11 women. The only two women in this group who experienced chills had maternal-fetal blood group incompatibility., Conclusion: Post-partum chills are a common phenomenon. It may be the clinical presentation of feto-maternal transfusion reaction. The small number of positive Kleihauer-Betke tests may reflect its low sensitivity in the detection of small feto-maternal bleeds.