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Biomedical subjects

A Ornoy

Publications and source records attributed to A Ornoy.

At least 37 records · Page 2Linked to original sources
PubMed2001

The newly inbred cohen diabetic rat: a nonobese normolipidemic genetic model of diet-induced type 2 diabetes expressing sex differences.

The newly inbred Cohen diabetic rat is an exceptional experimental model of diet-induced type 2 diabetes mellitus that is the result of secondary inbreeding nearly 30 years after it originally had been established. Animals from the original colony were selectively inbred by stringent criteria for 10 additional generations, bringing overall inbreeding to >50 generations. The metabolic phenotypes of the resulting contrasting strains, designated as the Cohen diabetic-sensitive (CDs) and -resistant (CDr) rats, were characterized. The phenotype of the CDs strain that was fed a regular diet consisted of fasting normoglycemia, normal glucose tolerance to intraperitoneal glucose loading, normal fasting insulin levels, and a normal insulin response to glucose loading. In contrast, CDs rats that were fed a custom-prepared high-sucrose low-copper diabetogenic diet became overtly diabetic: fasting glucose levels were normal or elevated, and the blood glucose insulin response to glucose loading was markedly abnormal. CDr rats that were fed a regular or diabetogenic diet did not develop diabetes and maintained normal glucose tolerance and insulin secretion. A striking sex difference was observed in CDs rats that were fed a diabetogenic diet: males had a lower growth rate and a more severe glucose intolerance pattern than females. Gonadectomy shortly after weaning did not prevent the development of the diabetic phenotype in its early phase in either sex but markedly attenuated its expression in males at a later phase, abolishing the sex differences. Alternate-day feeding, as opposed to daily feeding, also attenuated the metabolic phenotype in males. The development of the diabetic phenotype in CDs rats that were fed a diabetogenic diet was not accompanied by obesity or hyperlipidemia. The genetic profile of the strains was established using 550 microsatellite markers evenly distributed throughout the rat genome. The rate of homozygosity within strain was > or = 96%. The rate of polymorphism between the contrasting strains was 43%. We conclude that the metabolic phenotypes of the rebred colony of CDs and CDr rats and their genetic makeup render the Cohen diabetic rat a useful experimental model that is highly suitable for studying the interaction between nutritional-metabolic environmental factors and genetic susceptibility (sensitivity and resistance) for the development of type 2 diabetes. The model is also distinctively useful for investigating the effect of sex on the expression of the diabetic phenotype.

Animals↗
PubMed2000

Spontaneous language of children with specific neurological syndromes.

This paper presents data concerning the early phases of language development in 8 children with congenital neurological syndromes (NS) who are cognitively impaired. The children are native speakers of Hebrew, and their verbal achievements assessed on normative tests are below their age level. The children's spontaneous speech was analyzed with respect to 13 different language variables known to be diagnostic of a child's developmental level. No differences were found between the children and their language-matched controls on 10 grammatical variables. The groups differed, however, in number of pragmatic errors, errors of word choice, and errors of gender marking on animate nouns. Profile analysis was done through the use of POSAC (partial order scalogram analysis by base coordinates; Shye, 1985; Shye, Elizur, & Hoffman, 1994). The analysis did not reveal differences between the children with NS and the controls. These findings suggest the possibility of a mechanism that is functionally akin to brain plasticity. Such a mechanism will guarantee the preservation of basic linguistic skills in children with NS.

Brain Diseases↗
PubMed2000

Early motor development of blind children.

OBJECTIVES: The purpose of this study was to assess the characteristic motor developmental pattern in blind children in Israel. METHODOLOGY: The study compared the developmental data concerning 10 motor skills of 40 blind children to a control group of sighted children and to the motor developmental milestones of the Bayley Developmental Scale and the Revised Denver Developmental Screening Test. RESULTS: The motor development of blind children was delayed, the delay being significant in all 10 motor skills that were examined. This delay emphasizes the major importance of vision as a sensory input modality for the process of sensory- motor development. CONCLUSION: An adequate stimulating environment and proper parental handling could potentially shorten the motor developmental delay but probably not eliminate it entirely.

Blindness↗
PubMed2000

Prospective, controlled, multicentre study of loperamide in pregnancy.

BACKGROUND: Loperamide is a synthetic piperidine derivative used for the treatment of both acute and chronic diarrhea. Little is known about its safety and risk in pregnancy. Human data are limited to one surveillance study of Michigan Medicaid patients, with 108 women exposed in the first trimester. In this study there were six major birth defects, three of which were cardiovascular anomalies. OBJECTIVES: To determine whether loperamide use in pregnancy is associated with an increased risk of major malformations. The secondary end points were rates of minor malformations, spontaneous and therapeutic abortions, and premature births, and mean birth weights. PATIENTS AND METHODS: Women counselled by five teratogen information centres on the safety and risk of loperamide in pregnancy were followed after delivery and compared with a similar group of women matched for age, smoking, alcohol and other exposures. RESULTS: One hundred and five follow-ups were completed; 89 of the women were exposed to loperamide in the first trimester of pregnancy. There were no statistically significant differences between the study group and the control group in any of the end points that were analyzed. However, of women who took loperamide throughout their pregnancy, 21 of 105 had babies who were 200 g smaller than babies in the control group. CONCLUSIONS: The results of this study suggest that the use of loperamide during pregnancy is not associated with an increased risk of major malformations.

Abnormalities, Drug-Induced↗
PubMed2000

Oophorectomy-induced osteopenia in rats in relation to age and time postoophorectomy.

Oophorectomized (OVX) rats served for many years as a popular model for 'postmenopausal' osteoporosis in spite of the fact that the rat continues to grow during these experiments. We performed OVX in rats at 1, 3, 6 and 10 months of age and compared the histomorphometric (bone size, bone trabecular and cartilage volume in different areas) and chemical (ash, Ca, P and Mg content) parameters at 2, 6, 8 and 20 weeks post-OVX (2-20 weeks) to those of sham-operated rats. Significant differences were observed only in the animals that were OVX at a young or young-mature age, i.e. mainly at 1 and 3 months and some of the rats at 6 months of age. There were no changes in bone ash and mineral contents in the OVX animals in comparison to sham-operated rats, except 2 weeks post-OVX in the 1-month-old rats where these variables were reduced. The most significant finding was a reduction in the metaphyseal bone volume. This was observed in the rats OVX at 1, 3 and 6 months of age, but not in those OVX at 10 months. In the young OVX rats there was also an increase in epiphyseal cartilage volume. The epiphyseal and diaphyseal bone volumes were not different between the groups at any time postsurgery, explaining the lack of differences in bone ash and mineral contents. There were no significant changes in the results of the histomorphometric studies between OVX and sham-operated rats when surgery was performed at 10 months of age. Since OVX exerts significant changes only in young rapidly growing rats, this approach is an inappropriate model for postmenopausal osteoporosis, which occurs long after bone growth has ended.

Age Factors↗
PubMed2000

The use of psychiatric drugs in pregnancy and lactation.

To help determine which drugs can be used with relative safety during pregnancy, we reviewed the literature on the possible teratogenic, perinatal, behavioral or developmental effects of the various groups of commonly used psychiatric drugs, and their effects on lactation. Tricyclic antidepressants, fluoxetine, phenothiazines, and most benzodiazepines are not considered to be teratogenic and may be used during pregnancy. All anti-epileptic drugs seem to have an embryotoxic and teratogenic potential and we recommend, if possible, avoiding these drugs. Lithium administration during the first trimester of pregnancy increases the risk of cardiac malformations, but the risk is not as high as originally reported. Therefore lithium may be continued whenever it seems to be the "drug of choice" if fetal echocardiography and ultrasonography are performed. There is a lack of information on the teratogenic effect of the newer drugs, and in spite of the fact that similar "older" drugs do not seem to adversely affect the fetus, they should be used with care. Although the data on the development of children following in-utero exposure to psychiatric drugs is limited, there seems to be no evidence of any long-term adverse effects on the development of children exposed to most psychotropic medications. However, children exposed in utero to anti-epileptic drugs may exhibit long-term developmental problems. Most of the drugs are detected in breast milk only at low concentrations. In nursing women taking these drugs, breastfeeding is possible. The infant should be carefully monitored for any clinical side effects and whenever observed, nursing should be discontinued. In light of our knowledge today, there seems to be only rarely an indication for pregnancy interruption following maternal exposure to psychiatric drugs during pregnancy.

Abnormalities, Drug-Induced↗
PubMed2000

Comparison of the motor development of school-age children born to mothers with and without diabetes mellitus.

The objectives of this study were to examine the effects of diabetes during pregnancy on the long-term motor development of the offspring and to study possible correlations between glycemic control and motor development. We compared the motor development of 57 children, 5- to 12-years-of-age, born to 48 mothers with well-controlled diabetes, to the motor development of 57 control children matched by age, birth order, and parental socio-economic status. Children born to mothers with diabetes performed less well than controls in fine and gross motor functions on the Bruininks-Oseretsky Test of Motor Proficiency. A negative correlation existed between the test scores of the children whose mothers had diabetes and the severity of hyperglycemia as assessed by blood glycosylated hemoglobin levels and acetonuria. Motor ability of the children of mothers with diabetes had a high correlation with biological and environmental variables. These results suggest that diabetes during pregnancy may affect the developing brain, inducing long-term mild motor deficiency. The effects seem to result from the adverse effects of diabetic metabolic factors, and the effects correlate with the degree of diabetes control. The combination of metabolic functioning of women with diabetes and home environment may affect the motor development of their children.

Adolescent↗
PubMed2000

The development of antioxidant defense mechanism in young rat embryos in vivo and in vitro.

Reactive oxygen species (ROS) are involved in the etiology of numerous diseases and are suggested to be one of the mechanisms of action of several teratogens such as cocaine, high concentrations of glucose and ketone bodies. We studied the antioxidant capacity of 9.5-12.5 day old rat embryos and their yolk sacs both in vivo and in vitro. We measured the activity of superoxide dismutase (SOD) and the hydrogen peroxide removing activity (mainly due to catalase (CAT) and glutathione peroxidase (GSH -Px) and found significant activity of these enzymes already at day 9.5 in the embryos and their yolk sac, both in vivo and in vitro. A gradual increase in the activity was found with the advancement of embryonic age. The reducing power, that reflects the concentration of low molecular weight antioxidants (LMWA) was measured by cyclic voltammetry. LMWA were found in the embryos and their yolk sacs on days 9.5-11.5 of gestation with the peak potential of 0.56- 0.62 Volts. On day 12.5 an additional group of LMWA appeared at a peak potential of 0.95-0.97 Volts. There was a gradual increase in the concentration of LMWA with the increase in embryonic age. Generally, the concentration of LMWA was higher in the embryo than in its yolk sac but it was similar in vivo and in vitro at the same developmental stage. The gradual development of the embryonic antioxidant capacity implies that under normal conditions the developing embryo is capable of coping with oxidative stress, but this may fail under various pathological conditions, leading to embryonic damage.

Animals↗
PubMed1999

Vitamin D3 metabolites regulate LTBP1 and latent TGF-beta1 expression and latent TGF-beta1 incorporation in the extracellular matrix of chondrocytes.

Growth plate chondrocytes make TGF-beta1 in latent form (LTGF-beta1) and store it in the extracellular matrix via LTGF-beta1 binding protein (LTBP1). 1,25-(OH)2D3 (1,25) regulates matrix protein production in growth zone (GC) chondrocyte cultures, whereas 24,25-(OH)2D3 (24,25) does so in resting zone (RC) cell cultures. The aim of this study was to determine if 24,25 and 1,25 regulate LTBP1 expression as well as the LTBP1 -mediated storage of TGF-beta1 in the extracellular matrix of RC and GC cells. Expression of LTBP1 and TGF-beta1 in the growth plate and in cultured RC and GC cells was determined by in situ hybridization using sense and antisense oligonucleotide probes based on the published rat LTBP1 and TGF-beta1 cDNA sequences. Fourth passage male rat costochondral RC and GC chondrocytes were treated for 24 h with 10(-7)-10(-9) M 24,25 and 10(-8)-10(-10) M 1,25, respectively. LTBP1 and TGF-beta1 mRNA levels were measured by in situ hybridization; production of LTGF-beta1, LTGF-beta2, and LTBP1 protein in the conditioned media was verified by immunoassays of FPLC-purified fractions. In addition, ELISA assays were used to measure the effect of 1,25 and 24,25 on the level of TGF-beta1 in the media and matrix of the cultures. Matrix-bound LTGF-beta1 was released by digesting isolated matrices with 1 U/ml plasmin for 3 h at 37 degrees C. LTBP1 and TGF-beta1 mRNAs are co-expressed throughout the growth plate, except in the lower hypertrophic area. Cultured GC cells express more LTBP1 and TGF-beta1 mRNAs than RC cells. FPLC purification of the conditioned media confirmed that RC cells produce LTGF-beta1, LTGF-beta2, and LTBP1. GC cells also produce LTGF-beta2, but at lower concentrations. 1,25 dose-dependently increased the number of GC cells with high LTBP1 expression, as seen by in situ hybridization. 24,25 had a similar, but less pronounced, effect on RC cells. 1,25 also caused a dose-dependent increase in the amount of TGF-beta1 protein found in the matrix, significant at 10(-8) and 10(-9) M, and a corresponding decrease in TGF-beta1 in the media. 24,25 had no effect on the level of TGF-beta1 in the matrix or media produced by RC cells. This indicates that 1,25 induces the production of LTBP1 by GC cells and suggests that the TGF-beta1 content of the media is reduced through the formation of latent TGF-beta1 -LTBP1 complexes which mediates storage in the matrix. Although 24,25 induced the expression of LTBP1 by RCs, TGF-beta1 incorporation into the matrix is not regulated by this vitamin D3 metabolite. Thus, vitamin D3 metabolites may play a role in regulating the availability of TGF-beta1 by modulating LTBP1 production.

24,25-Dihydroxyvitamin D 3↗
PubMed1999

[The Israel Teratogen Information Service: a report of the last ten years with 20,613 calls].

The Israel Teratogen Information Service (TIS) was established 10 years ago with the help of the Ministry of Health and the Hebrew University-Hadassah Medical School. During these 10 years we have had 20,631 calls. We describe the results of our experience in counseling. There was a gradual increase in the number of calls, which in 1997 reached 4,447. Most calls (84.5%) were during pregnancy, while 12% were prior to pregnancy. In 75.7% the calls were due to drug exposure during pregnancy; 10.9% were due to exposure to X-rays; there was maternal infection in 6.6% and in 5% immunization during pregnancy. The callers were: physicians in 46.6%, nurses 18.9%, pregnant women 39.5%, and 4.8% others. In 76.6% there was no additional risk to the embryo or fetus and in 17.4% there was a small additional risk of less than 1%; a significant additional risk to the fetus was expected in only 6%. In 3625 pregnant women with known outcome there were 8.9% spontaneous and 9.2% induced abortions. Of the 2968 live-born children, 2.3% were malformed, a rate similar to that among controls. The information provided by the TIS alleviated the fears most pregnant women have, and reduced unnecessary terminations of pregnancy planned because of unjustified fear of the teratogenic effects of agents to which women were exposed. It reduced the number of children born with congenital anomalies, since pregnancies were interrupted whenever there was a high risk for congenital anomalies.

Female↗
PubMed1999

High vitamin A intake in early pregnancy and major malformations: a multicenter prospective controlled study.

The European Network of the Teratology Information Services (ENTIS) collected and evaluated data on 423 pregnancies exposed during the first 9 weeks of gestation to a "high" dose of vitamin A (10,000 IU per day or more). Data were collected prospectively; 394 women (93.1%) were followed by telephone interview up to the first few weeks after the expected date of delivery, using standardized procedures. The presence of major structural malformations, excluding chromosomal and genetic diseases, was evaluated in 311 infants exposed to a median daily dose of vitamin A of 50,000 IU per day (range, 10,000-300,000 IU per day; interquartile range, 25,000-60,000 IU per day). Three infants with a major malformation were reported: pulmonary stenosis, stenotic anus with fistula, and bilateral inguinal hernia. No congenital malformations were reported among 120 infants exposed to more than 50,000 IU per day of vitamin A. When the birth prevalence rate of major malformations in the study group was compared with two internal control groups of infants exposed to: 1) "high" vitamin A exposure later in pregnancy, and 2) nonteratogenic agent exposures, the rate ratio was, respectively, 0.28 (CI 95% interval, 0.06, 1.23) and 0.50 (CI 95% interval, 0.14, 1.76). The studied sample did not provide evidence for an increased risk of major malformations, associated with "high" vitamin A intake during the organogenetic period, higher than 2.76 above the control reference risk of 1.91% (power 80%, alpha 0.10).

Abnormalities, Drug-Induced↗
PubMed1999

Transplacental effects of bisphosphonates on fetal skeletal ossification and mineralization in rats.

Bisphosphonates are clinically used mainly to reduce bone resorption. We studied the transplacental effects of two bisphosphonates on the fetal skeleton in rats. Pregnant rats were treated during days 11-20 of pregnancy with daily subcutaneous injections of 0.1 mg/kg of alendronate or a newly synthesized bisphosphonate, VS-b6. This period of pregnancy was chosen because the active development of bones from mesenchyme through cartilaginous models occurs during that time. Histological examination of midlongitudinal sections of the 21-day-old fetuses showed an increase in the amount of diaphyseal bone trabeculae with slight shortening of the diaphysis in the experimental fetuses, in comparison to controls. Computerized histomorphometric studies similarly showed an increase in the amount of diaphyseal bone trabeculae with a concomitant decrease in bone marrow volume, but no change in cartilage volume. In addition, chemical analysis of the fetal bones showed an increase in calcium content in the treated fetuses. 14C-alendronate was shown to pass through the rat placenta and accumulate in the fetuses, most probably in their bones. This is presumed because bisphosphonates are known to accumulate in bone, being stored there for long periods of time. It is important, in light of our results, to give careful consideration to the treatment of women with bisphosphonates at childbearing age, whenever this is needed.

Alendronate↗
PubMed1999

Role of reactive oxygen species (ROS) in the diabetes-induced anomalies in rat embryos in vitro: reduction in antioxidant enzymes and low-molecular-weight antioxidants (LMWA) may be the causative factor for increased anomalies.

A disturbed embryonic antioxidant defense mechanism may play a major role in diabetes-induced teratogenesis. We therefore studied the antioxidant capacity of 10.5-day-old rat embryos and their yolk sacs after culture for 28 hr in vitro under diabetic conditions (3 mg/ml glucose, 2 mg/ml beta-hydroxybutyrate (BHOB) and 10 microg/ml of acetoacetate), as compared with control embryos in vitro. We found a high rate of congenital anomalies, decreased growth and protein content, and a decrease in the activity of both superoxide dismutase (SOD) and catalase (CAT) under diabetic conditions, as compared with controls. The reducing power, which reflects the concentration and type of water-soluble and of lipid-soluble low-molecular-weight antioxidants (LMWA), was measured by cyclic voltammetry. Generally, LMWA were reduced in the embryos and yolk sacs under diabetic conditions. In the water-soluble fraction of control embryos and yolk sacs, two peak potentials were found, indicating two major groups of LMWA, while only one peak potential was found under diabetic conditions, indicating that an entire group of LMWA is missing. HPLC studies have demonstrated a decrease in vitamin C (water-soluble fraction) and in vitamin E (lipid-soluble fraction) under diabetic culture conditions, and an increase in uric acid. Generally, the concentration of LMWA was higher in the embryos than in the yolk sac. LMWA concentration, protein content, and antioxidant enzyme activity were lower in the malformed experimental embryos than in experimental embryos without anomalies. The addition of vitamins C and E to the diabetic culture medium abolished the deleterious effects of the diabetic serum on the embryos. The disturbed antioxidant defense mechanism under diabetic conditions may be explained, at least in part, by a direct effect of diabetic metabolic factors on the activity of antioxidant enzymes and on the concentration of reducing equivalents. This, in turn, may be embryotoxic.

3-Hydroxybutyric Acid↗
PubMed1999

Isolation and hormonal responsiveness of primary cultures of human bone-derived cells: gender and age differences.

We present a model for isolating human cell culture derived from biopsies obtained during orthopedic surgery. Four donor groups were defined by gender and age: pre- and postmenopausal women (<50 and >55 years, respectively), and younger (30-55 years) and older (>60 years) men. Bone-derived cells were identified as osteoblasts by major osteoblastic characteristics; that is, high alkaline phosphatase (ALP) activity, dose-dependent increase of ALP by 1,25(OH)2D3, high levels of parathyroid hormone (PTH)-induced cyclic AMP, and 1,25-(OH)2D3-induced osteocalcin. In all cells, levels of osteocalcin were significantly elevated (p < 0.05 and 0.01). In cells derived from men, no significant age differences were found in ALP and osteocalcin values of basal activity and in fold stimulation 1,25(OH)2D3. Cells from postmenopausal women showed a nonsignificant lower basal ALP activity than premenopausal cells. In postmenopausal cells, ALP responded less to 1,25(OH)2D3 (33% increase, p < 0.05) than the premenopausal cells (100% increase, p < 0.05). In cells from either age group, ALP did not respond to the gonadal steroids 17beta-estradiol (E2) and dihydrotestosterone (DHT) or progesterone. Basal levels of osteocalcin were higher in cells of premenopausal origin as compared with postmenopausal cells (p = 0.05), but response to 1,25(OH)2D3 was the same. PTH significantly stimulated cAMP (p = 0.001) in all age and gender groups analyzed. In all groups, no differences were found in either basal activity or in PTH response. Unlike men, cells derived from the bone of women were more susceptible to age changes. We postulate that the postmenopausal cell population had a decreased number of osteoblasts, or cells in a lower differentiation stage. These results extend our knowledge of bone biology found in animal models and reveal that human osteoblasts from men do not show the same age-dependent differences observed in women.

Alkaline Phosphatase↗