Biomedical subjects

Ilana Ariel

Publications and source records attributed to Ilana Ariel.

15 recordsLinked to original sources

PubMed2006

Adult hypertension in intrauterine growth-restricted offspring of hyperinsulinemic rats: evidence of subtle renal damage.

In humans, intrauterine growth-restricted newborns are prone to develop hypertension as adults. We studied a rat model of pregnancy-induced hypertension associated with intrauterine growth restriction (IUGR) produced by chronic administration of insulin. Fetuses of hyperinsulinemic dams (HDs) were smaller than those of normal dams (5.1+/-0.4 g versus 5.6+/-0.1 g, respectively; P<0.05). At 16 weeks of age, tail-cuff systolic blood pressure was measured, the rats were placed in metabolic cages and euthanized, and the kidneys were examined. Male but not female offspring of HDs (n=9) had higher blood pressure than normal-pregnancy offspring (n=12; 148+/-11 mm Hg versus 118+/-14 mm Hg; P<0.004). In contrast to other models, there was no difference in ours in the number and volume of glomeruli. However, there were significantly greater glomerular, tubulointerstitial, and vascular damage indices in the kidneys of male HD offspring versus controls (2.01+/-0.34 versus 1.08+/-0.16, 1.80+/-0.34 versus 0.76+/-0.12, and 2.13+/-0.81 versus 0.78+/-0.16, respectively; P<0.0001), with similar tubulointerstitial findings in females. Increased expression of collagen type IV, a kidney damage marker indicating fibrosis, was found in the tubulointerstitium. This may be associated with downregulation of bone morphogenetic protein 6, a presumptive antifibrogenic agent, at the end of gestation. In conclusion, male offspring of HDs displayed IUGR and adult hypertension accompanied by several indices of renal fibrosing damage, mainly in the renal tubulointerstitium. Our findings suggest that there is >1 pathway of fetal programming leading from IUGR to development of hypertension in later life.

Animals↗

PubMed2005

Fibroblast growth factor-10 and fibroblast growth factor receptors 1-4: expression and peptide localization in human decidua and placenta.

The development of the chorionic villous tree into a complex and organized ramified tubular network can be termed branching morphogenesis. Studying the molecular mechanisms involved in this process may contribute to the understanding of pregnancy complications such as preeclampsia. We hypothesized that fibroblast growth factor-10 (FGF-10) and fibroblast growth factor receptors 1-4 (FGFR 1-4) are expressed in human decidual and placental tissues. We analyzed the expression of FGF-10 and FGFRs 1-4 in 1st, 2nd and 3rd trimester placentas, as well as in decidua. RT-PCR and immunohistochemistry were employed to study mRNA and protein expression. FGF-10 was expressed by decidual cells and by cytotrophoblasts of the cytotrophoblast columns during all three trimesters. FGFR 1-4 were expressed in the placenta but not in the decidua. Placental expression of FGFRs was temporally regulated: In 1st trimester placentas, FGFR 1-4 were expressed by Hofbauer cells, FGFR-1 and FGFR-4 were expressed in cytotrophoblast columns, and the latter was also expressed by syncytiotrophoblasts. Similar expression was seen in 2nd trimester placentas with additional expression of FGFR-1 in blood vessel walls. The expression of FGFR-1 and FGFR-4 in the 3rd trimester was comparable to that seen in the 2nd trimester. The expression of FGF-10, FGFR-1 and FGFR-4 in the maternal-fetal interphase suggests their role in decidual-trophoblast interaction. The abundance of FGFR expression in Hofbauer cells implies that mesenchymal-trophoblast interaction is important for regulation of villous development.

Decidua↗

PubMed2005

Growth factor receptor-protein bound 2 (GRB2) upregulation in the placenta in preeclampsia implies a possible role for ras signalling.

OBJECTIVES: To screen for genes with altered expression in placentas from pregnancies complicated by preeclampsia. STUDY DESIGN: To corroborate gene expression profile of preeclamptic and normal placentas (ATLAS Clontech), by dot blot, Northern blot analysis and RT-PCR for growth factor receptor bound-protein 2 (GRB2), using immunohistochemistry to localize its expression in the placenta. RESULTS: Increased expression of GRB2 upregulated in the microarrays was found in preeclampsia by Dot blot and Northern blot analysis. RT-PCR performed with primers specific for GRB2 and its alternatively spliced isoform GRB3-3 showed that most of the cDNA represented in the array was GRB2. The protein was localized to the smooth muscle wall of stem vessels by immunohistochemistry. CONCLUSION: The ras signalling activated by placental receptor tyrosine kinases may play a role in the segmental thickening of the stem vascular wall in preeclamptic placentas, resulting in reduced blood flow to the developing fetus.

Adaptor Proteins, Signal Transducing↗

PubMed2005

p57Kip2 (cdkn1c): sequence, splice variants and unique temporal and spatial expression pattern in the rat pancreas.

The cyclin-dependent kinase (CDK) inhibitor p57Kip2 (CDKN1C) is a negative regulator of cell proliferation, binding to a variety of cyclin-CDK complexes and inhibiting their kinase activities in vitro. The p57Kip2 gene is imprinted and the maternal allele is expressed in terminally differentiated cells, including human beta-cells. Somatic loss of p57Kip2 expression is associated with increased beta-cell proliferation in the focal form of Hyperinsulinism of Infancy. We cloned and sequenced the rat ortholog of p57Kip2, and demonstrate that it is highly homologous to the mouse gene. However, the human and rodent genes are quite divergent. Despite having highly homologous C- and N-terminal domains, the mid-portion of the human gene is entirely different from that of its rodent counterparts. Expression of p57Kip2 was evaluated during fetal and postnatal development, and a highly cell-specific, temporal and spatial expression profile was found. In contrast to other tissues, the expression pattern in rat pancreas was entirely opposite from that previously reported in man, with high levels of expression in rodent exocrine cells, but no expression in beta-cells during any stage of development. These findings demonstrate that p57Kip2 expression is highly regulated. In the pancreas, the functional significance of this gene appears to be quite different in humans when compared with rodents, suggesting that a better understanding of the function of this protein may provide new insights into the mechanisms involved in the control of human beta-cell mass.

Alternative Splicing↗

PubMed2005

Relative expression and localization of the insulin-like growth factor system components in the fetal, child and adult intestine.

BACKGROUND: The insulin-like growth factors (IGFs) are important in the development and maintenance of the gastrointestinal tract. OBJECTIVES: To compare the expression of IGFs and their receptors in the stomach and duodenum of the fetus, the child and the adult. To identify the cells mainly responsible for the production of the members of the IGF system. METHODS: Tissue was obtained from fetus after abortion and from children and adults during diagnostic endoscopy and biopsy. The expression of the IGFs and their receptors was estimated by an RNAse protection assay and sections were stained with antisera to the components of IGF system. RESULTS: The tissues from the stomach and the duodenum expressed the two IGFs and their receptors at all stages of life. The fetal IGF receptors I and II, were approximately ten times higher than in the child and IGF-II was five times higher. Immunohistochemical staining showed the components of the IGF system to be localized to the gastric glands and to the basotlateral border of the gastric epithelial cells. In the duodenum, they were concentrated at the apical portion of the epithelial tissue. They could also be identified in ganglion cells and nerves. CONCLUSIONS: The IGFs and their receptors in the stomach and duodenum are expressed in all age groups and mostly are highest in the fetus. The IGF system proteins were located in the gastric glands and epithelium and in the apical portion of the villous epithelium of the duodenum.

Aborted Fetus↗

PubMed2004

Fetal vascular obstructive lesions: nosology and reproducibility of placental reaction patterns.

The purpose of this study was to assemble and test the reliability of a complete set of the placental reaction patterns seen with chronic fetal vascular obstruction in the hope that this might provide a standardized diagnostic framework useful for practicing pathologists. Study cases (14 with fetal vascular obstructive lesions, 6 controls) were reviewed blindly by seven pathologists after agreement on a standard set of diagnostic criteria. Majority vote served as the gold standard and 80% of the 180 diagnoses rendered (9 diagnoses each for 20 cases) were agreed upon by at least six of the seven scores. The sensitivity of individual diagnosis relative to the group consensus averaged 83% (range, 69-100%) and specificity averaged 91% (range, 86-100%). Reproducibility was measured by unweighted kappa-values and interpreted as follows: < 0.2, poor; 0.2-0.6, fair/moderate; > 0.6, substantial. Kappa values for lesions of distal villi were generally superior to those for lesions involving large fetal vessels: avascular villi (0.49), villous stromal-vascular karyorrhexis (0.58), and villitis of unknown etiology (VUE) with stem villitis and avascular villi (0.65) versus large vessel thrombi (any vessel, 0.34; chorionic plate vessel, 0.40) and intimal fibrin cushions (recent, 0.47; remote, 0.78). Reproducibility for a global impression of any villous change consistent with chronic fetal vascular obstruction was substantial (0.63), while that for a more severe subgroup was moderate (0.44). Three points are worthy of emphasis. Our system separately recognizes, but later combines, uniformly avascular villi and villous stromal-vascular karyorrhexis as manifestations of the same underlying process. We propose that this combined group of villous lesions be dichotomized with the terms fetal thrombotic vasculopathy or extensive avascular villi (and/or villous stromal-vascular karyorrhexis) being reserved for the group with 15 or more affected terminal villi per section. Scattered foci of avascular villi (and/or villous stromal-vascular karyorrhexis) could be used to describe less severe cases. Finally, we distinguish VUE with stem villitis and avascular villi (obliterative fetal vasculopathy) as a distinct process with substantial perinatal morbidity.

Blood Vessels↗

PubMed2004

Gene expression in the bladder carcinoma rat model.

We investigated gene expression in N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced rat bladder carcinoma in order to test its applicability as a model for the study of novel therapeutic modalities, particularly gene therapy. We administered BBN in the drinking water to Wistar rats for up to 30 wk and induced papillary transitional cell carcinoma (TCC), which is similar to the most prevalent type of human bladder cancer. Tumor evolution was similar to that found in previous studies. However, we described the morphological stages according to modern human bladder carcinoma terminology. Our main goal was to examine the expression levels of the H19 gene, of the insulin-like growth factor 2 (Igf2) transcripts expressed from promoters P2 and P3 and of the telomerase subunits that we had previously investigated as tools for targeted gene therapy of bladder cancer. We detected at 30 wk of BBN exposure significant upregulation of these sequences in the rat bladder tumors, similar to our previous findings in human bladder cancer. To reinforce the similarity of this model to the corresponding human disease, we searched for additional tumor-specific genes documented as having altered expression in human bladder carcinoma, using cDNA expression arrays (Clontech). We suggest that BBN-induced rat bladder cancer has morphological, biological, and molecular parallels to human bladder cancer and is an attractive model for studying novel alternatives of therapeutic intervention.

Animals↗

PubMed2004

Placental pathology in fetal thrombophilia.

The aim of this study was to test the hypothesis that placental vascular lesions of the fetal circulation are caused by fetal thrombophilic mutations. The study included 64 newborns of women with one or more of the following pregnancy complications: preeclampsia, placental abruption, and intrauterine growth restriction. The most prevalent inherited thrombophilias--factor V Leiden, factor II (prothrombin) G20210A, and homozygosity for methyltetrahydrofolate reductase C677T--were examined in maternal blood and fetal umbilical cord blood. One pathologist reviewed all of the slides for fetal vascular lesions. Associations between fetal thrombotic vasculopathy and fetal thrombophilia were tested for using Fisher's exact test; Z scores and gestational age were compared using the Student t-test. Fetal thrombophilic mutations were diagnosed in 19 of 64 newborns, 15 of whom had coexistent maternal thrombophilia. There was no statistical difference in the prevalence of thrombotic lesions of the fetal circulation between newborns with and without thrombophilia. The combination of maternal and fetal thrombophilia was also not associated with increased fetal vascular lesions. The results indicate that fetal thrombophilia alone, even in the context of maternal underperfusion, is not associated with fetal vascular lesions of the placenta, although it may represent an underlying risk factor for lesions triggered by other process(es).

Female↗

PubMed2004

An unusual composite endometrial tumor combining papillary serous carcinoma and small cell carcinoma.

This is the first report in the English literature of a composite endometrial tumor composed of papillary serous carcinoma and small cell carcinoma. A 79-year-old woman underwent total abdominal hysterectomy and left salpingo-oophorectomy due to endometrial carcinoma. Grossly, the uterus was enlarged with an irregular and nodular serosal surface, thickened myometrium, and irregular endometrium. Microscopic examination revealed an endometrial carcinoma composed of papillary serous carcinoma and small cell carcinoma. There was a differential immunoreactivity between the two components: the cells of the papillary serous carcinoma were positive for cytokeratin, CA-125, CEA, and HER-2/Neu, whereas these markers were negative in the small cell carcinoma. Various neuroendocrine markers were positive in the small cell carcinoma and negative in the papillary serous carcinoma. Fluorescence in situ hybridization analysis using 4, 8, and 10 centromeric probes revealed hyperploidy (6-8 signals) in the small cell carcinoma cells. Most of the serous carcinoma cells were euploid, with scattered trisomies and tetrasomies of these chromosomes. The patient died of progressive disease 5 months after surgery. We suggest that the small cell carcinoma may have arisen from the endometrial papillary serous carcinoma undergoing tumor progression with neuroendocrine differentiation.

Aged↗

PubMed2003

Transgenic mouse with the herpes simplex virus type 1 latency-associated gene: expression and function of the transgene.

During herpes simplex virus type 1 (HSV-1) latent infection in human peripheral sensory ganglia, the major viral gene transcribed is the latency-associated transcript (LAT) gene. In order to facilitate the study of this gene, we generated a transgenic mouse that contains the DNA fragment that transcribes the LAT RNAs (2.0 kb and its 1.5-kb spliced transcript) under control of the cytomegalovirus promoter. The tissue distribution of these transcripts and their effects upon HSV-1 replication, latency, and reactivation in the transgenic-mouse model were examined. Different steady-state amounts of both transcripts were found in various tissues. While the highest levels of the 2.0-kb RNA were detected in heart and skeletal muscle, the 1.5-kb transcript was found at elevated levels in the brain and at much higher levels in the trigeminal ganglia (TG). Replication of both the wild-type and a LAT-negative mutant virus was suppressed in primary embryonic fibroblasts obtained from LAT-expressing transgenic mice compared to that in cells obtained from normal mice. HSV-1 DNA amounts in latently infected TG of transgenic mice were similar to those in normal mice. Reactivation of latent HSV-1 LAT-negative mutants by explant cocultivation of TG from transgenic mice was more efficient than reactivation from normal-mouse TG. Considering our present and previous results, we propose that the significantly higher steady-state level of the 1.5-kb RNA in the TG may link this transcript to latency functions and that by inhibition of virus replication, the LAT gene may protect ganglion cells and thereby increase the probability of reactivation.

Animals↗

PubMed2002

Use of H19 regulatory sequences for targeted gene therapy in cancer.

We present a tumor gene therapy approach based on the use of regulatory sequences of the H19 gene that are differentially expressed between normal and cancer cells. We constructed expression vectors carrying the gene for the A fragment of diphtheria toxin (DT-A) or herpes simplex virus thymidine kinase (HSV-tk), under the control of a 814 bp 5'-flanking region of the H19 gene. The cell killing activity of these constructs was in accordance with the relative activity of the H19 regulatory sequences in the transfected cells. We evaluated the therapeutic potential of the gene expression constructs driven by H19 regulatory sequences in an animal model of bladder cancer induced by subcutaneous injection of syngeneic bladder tumor cell lines. Intratumoral injection of these constructs caused a significant suppression of subcutaneous tumor growth, with no obvious toxicity toward the host.

Animals↗

PubMed2002

Single umbilical artery stenosis associated with intrauterine fetal death post-transfusion.

Single umbilical artery is among the most common funicular vascular anomalies. In contrast, umbilical artery stenosis is rare, and has only been reported in three-vessel cords. We describe a case of single umbilical artery stenosis in a fetus with no associated malformations. Intrauterine fetal death occurred at 28 weeks' gestation following cordocentesis and intravascular transfusion for Rhesus alloimmunization. Single umbilical artery stenosis may place the fetus at increased risk, particularly in cases requiring interventions involving cord manipulation.

Adult↗

PubMed2002

Analysis of differentially expressed genes in hepatocellular carcinoma using cDNA arrays.

Hepatocellular carcinoma (HCC) is characterized by multiple somatic mutations, including DNA rearrangements, that affect many cell-growth regulatory pathways. Many genes differentially expressed in HCC have been reported previously, but the patterns of expression varied significantly between patients who bore different risk factors for HCC. To identify genes whose differential expression could serve as a "signature" for diagnosis and prognosis of HCC, we performed analyses of differentially expressed genes in three cases of HCC with different risk factors using the Atlas Human Cancer cDNA Expression Arrays. Among all 597 genes present on the array, only three were found to be coordinately differentially expressed in all three HCC cases, in agreement with published data. These three genes, Cu/Zn superoxide dismutase, osteonectin/secreted protein acidic and rich in cysteine, and matrix metalloproteinase 14, could serve as candidates for the HCC "signature." Ten genes were found to be coordinately differentially expressed in only two of three tested HCC cases. On the other hand, many genes that had been reported previously as differentially expressed in HCC failed to show the described pattern of expression in this group. The results of this study confirm the great variability in gene-expression patterns in HCC and establish the utility of the array technology for identifying both the HCC signature genes and individual gene-expression patterns for purposes of patient-oriented therapy.

Aged↗

PubMed2002

Extreme caudal agenesis. Possible drug-related etiology?

BACKGROUND: Caudal regression syndrome (CRS) is a rare anomaly of the lower body pole that represents a continuum of congenital malformations ranging from isolated sacral agenesis to absence of the lumbosacral spine and major visceral anomalies. While the exact etiology of this syndrome is unclear, maternal diabetes, genetic factors, teratogens and vascular anomalies altering blood flow have been hypothesized to play a role in its pathogenesis. CASE: A fetus had extreme hypotrophy of the caudal body pole, aplasia of the lower spine and complete renal agenesis diagnosed in the second trimester by ultrasound. Maternal history revealed the use of minoxidil solution for preventing hair loss for four years prior to and during gestation. Also, the mother had taken trimethoprim-sulfamethoxazole during the first trimester for treatment of upper respiratory disease. No maternal diabetes or history of familial genetic diseases was evident. CONCLUSION: In an extreme form of CRS consisting of complete aplasia of the lower body pole and viscera and additional malformations, a possible drug-related etiology was suggested but should be confirmed by more studies.

Abnormalities, Multiple↗

PubMed2002

Listeria infection during pregnancy: a 10 year experience.

BACKGROUND: Although Listeria monocytogenes is widely distributed in nature, it rarely causes clinical infection in previously healthy people. This microorganism, however, may cause severe invasive disease in pregnant women and newborns. OBJECTIVES: To investigate--in our pregnant population--the impact, severity and outcome of listeriosis on both mother and fetus. METHOD: The study was carried out at a level III, university two-hospital complex. In a retrospective chart review of 65,022 parturients during a 10 year period (1990-1999), we identified and evaluated 11 pregnant patients and their offspring with Listeria infection. RESULTS: Chorioamnionitis with multiple placental abscesses were observed in all five placentae examined. Clinically, 4 of 11 parturients had a cesarean section for fetal distress (36.3%), as compared to the 14% mean CS rate in our general population. Two of 11 had a late abortion (18.1%), as compared with the 4% rate in our hospital. Four of 11 had premature labor (36%), which was about four times the rate in our population. Finally, although no intrauterine fetal death was recorded in our series, there was one neonatal death of a term infant (1/11, 9%), which is about 10 times higher than our corrected perinatal mortality rate. CONCLUSIONS: If not promptly and adequately treated, listeriosis in pregnancy may present serious hazards to the fetus and newborn through direct infection of the placenta and chorioamnionitis.

Adult↗