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Biomedical subjects

L Nathan

Publications and source records attributed to L Nathan.

At least 19 recordsLinked to original sources
PubMed2001

Testosterone inhibits early atherogenesis by conversion to estradiol: critical role of aromatase.

The effects of testosterone on early atherogenesis and the role of aromatase, an enzyme that converts testosterone to estrogens, were assessed in low density lipoprotein receptor-deficient male mice fed a Western diet. Castration of male mice increased the extent of fatty streak lesion formation in the aortic origin compared with testes-intact animals. Administration of anastrazole, a selective aromatase inhibitor, to testes-intact males increased lesion formation to the same extent as that observed with orchidectomized animals. Testosterone supplementation of orchidectomized animals reduced lesion formation when compared with orchidectomized animals receiving the placebo. This attenuating effect of testosterone was not observed when the animals were treated simultaneously with the aromatase inhibitor. The beneficial effects of testosterone on early atherogenesis were not explained by changes in lipid levels. Estradiol administration to orchidectomized males attenuated lesion formation to the same extent as testosterone administration. Aromatase was expressed in the aorta of these animals as assessed by reverse transcription-PCR and immunohistochemistry. These results indicate that testosterone attenuates early atherogenesis most likely by being converted to estrogens by the enzyme aromatase expressed in the vessel wall.

Animals↗
PubMed2001

Missed opportunities for congenital syphilis prevention in an urban southeastern hospital.

BACKGROUND: Despite recent declines in syphilis rates nationally, recent outbreaks suggest that prevention of congenital syphilis remains an ongoing public health problem. GOALS: To identify missed opportunities for congenital syphilis prevention during prenatal care. STUDY DESIGN: Retrospective medical record review of 157 live birth or stillbirth deliveries that involved cases of congenital syphilis from Grady Memorial Hospital (Atlanta, GA). RESULTS: The hospital congenital syphilis prevalence was 8.2 cases per 1,000 live births. Six percent of case patients were HIV positive. Opportunities for earlier maternal screening, treatment, or diagnosis were missed in 60% of case patients who received timely prenatal care. Congenital syphilis cases attributable to preventable missed opportunities were significantly more common among case patients with fewer prenatal visits (66% versus 28%, P = 0.01). CONCLUSION: Provider efforts to reduce congenital syphilis in high-risk populations receiving prenatal care should focus on (1) screening patients at the first opportunity, at both the first prenatal visit and during the third trimester (i.e., 28 weeks); (2) performing on-site testing and same-day treatment; (3) providing appropriate treatment to infected women with penicillin allergy; (4) referring sex partners for treatment to prevent reinfection; and (5) screening all pregnant women attending emergency clinics.

Adult↗
PubMed2001

E2 and not P4 increases NO release from NANC nerves of the gastrointestinal tract: implications in pregnancy.

In women, during pregnancy, there is decreased motility of the gastrointestinal tract leading to a delay in gastric emptying and an increase in colonic transit time. Whether the rise in estradiol (E2) or progesterone (P4) is responsible for this effect is controversial. As the nitrergic component of the nonadrenergic, noncholinergic (NANC) nerves is responsible for modulating gastrointestinal motility in vivo, the purpose of this study was to evaluate whether the increased release of nitric oxide (NO) from the nitrergic component of the NANC nerves innervating the gastric fundus and colon that occurs during late pregnancy in rats is mediated by E2 or P4. Ovariectomized rats treated with E2 or P4 alone or in combination were used for our studies. We also wanted to assess the cellular and molecular mechanisms involved. The NANC activity was studied by assessing changes in tone after application of electric field stimulation (EFS). The role of NO was determined by observing the effects of EFS in the presence and absence of the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) and the reversibility of the effects of L-NAME by L-arginine. Our studies indicated that there was increased magnitude of relaxation of isolated strips of rat gastric fundus and rat colon after application of EFS to tissues obtained from animals treated with E2 alone or a combination of E2 + P4 but not from those treated with P4 alone. L-NAME attenuated relaxation responses in E2- and E2 + P4-treated animals. To elucidate whether the increased NO release may be due to an increase in neuronal NOS (nNOS) protein, we used both Western blot analysis and immunohistochemistry. We also used RT-PCR to determine whether there was an increase in nNOS mRNA after treatment with sex steroids. In nonpregnant animals, nNOS was detected by Western blot in the fundus and the colon and was barely detectable in the ileum. In pregnancy, there was an increase in nNOS in both the gastric fundus and the colon. The nNOS protein was also increased in ovariectomized animals treated with either E2 alone or E2 + P4 but not P4 alone when compared with ovariectomized animals receiving vehicle. Our results indicated that there was an increase in nNOS protein that was localized to the neurons of the myenteric plexus in the gastric fundus and colon in E2- and E2 + P4-treated animals, but this increase was not observed in animals treated with P4 alone. This increase in nNOS protein was accompanied by an increase in nNOS mRNA. These results suggest the possibility that E2, rather than P4, may be responsible for the delay in gastric emptying and increase in colonic transit time observed in pregnancy.

Animals↗
PubMed2000

Production and excretion of nitrate by human newborn infants: neonates are not little adults.

Endothelium-derived relaxing factor, identified as nitric oxide or its adducts, is metabolized to nitrate and excreted in the urine. Since blood pressures are lower in newborn infants compared to adults, we hypothesized that newborn infants would have increased excretion of nitrate on the day of birth. Neonatal urine was collected before 24 h of age when exogenous intake of nitrate was low. Two different analytical methods showed that nitrate accounted for >99% of nitrogen oxides in urine of healthy neonates and adults. The absolute micromolar concentration of nitrate in urine from infants was significantly below that of adults. When nitrate content was standardized for the reduced renal function in the newborn infant (creatinine content) and body mass (kilogram weight), the concentration of nitrate in neonatal urine was significantly higher than that of adults. Nitrate concentrations in the urine of prematurely born infants were twice that of nitrate measured in urine from term infants. These findings suggested that nitric oxide is produced in larger intravascular quantities in newborn infants versus adults. Thus, we postulated that nitric oxide released from a nitrosothiol would be metabolized to nitrate more readily by neonatal erythrocytes compared to red blood cells obtained from adults. Neonatal erythrocytes, suspended at concentrations of 8, 12, or 16 g per deciliter of hemoglobin, produced 1.7- to 2.1-fold more nitrate than equivalent hemoglobin concentrations of adult erythrocytes that were each incubated with S-nitroso-N-acetylpenicillamine (100 microM) over a 2-h period. Taken together, the studies of urinary nitrate in newborn infants and the ability of neonatal erythrocytes to generate nitrate are consistent with a robust production of nitric oxide immediately after birth.

Adult↗
PubMed2000

Correlation between amniotic fluid glucose concentration and amniotic fluid volume in pregnancy complicated by diabetes.

OBJECTIVE: Pregnancies complicated by diabetes are frequently characterized by an increased volume of amniotic fluid, and the pathophysiologic mechanism of this increase is not known. Our goal was to evaluate the relationship between amniotic fluid glucose concentration and the amniotic fluid index in pregnancies complicated by insulin-treated diabetes and to compare it with that seen in normal pregnancies. STUDY DESIGN: Amniotic fluid index and amniotic fluid glucose levels were measured before elective repeated cesarean delivery in 41 women with insulin-treated diabetes and in 35 women without diabetes. Only singleton gestations without anomalous fetuses were included. Women with diabetes were hospitalized for approximately 4 weeks before delivery, during which time glycemic control was optimized. Amniotic fluid index and amniotic fluid glucose concentration were correlated with each other and were compared between the groups with and without diabetes. RESULTS: The mean amniotic fluid index was significantly increased in the diabetes group (16.6 +/- 5.0 cm in the diabetes group vs 13.4 +/- 3.5 cm in the control group; P =.002). The amniotic fluid glucose concentration was also significantly greater in the diabetes group than in the control group (39 +/- 17 mg/dL in the diabetes group vs 24 +/- 11 mg/dL in the control group; P <.001). Among women with diabetes the amniotic fluid glucose concentration was significantly correlated with the amniotic fluid index (r = 0.32; P =.04), a correlation not found among the control women. The mean fasting blood glucose concentration among the women with diabetes for the week before amniocentesis was 82 +/- 11 mg/dL. CONCLUSION: The amniotic fluid index parallels the amniotic fluid glucose level among women with diabetes. This finding raises the possibility that the hydramnios associated with diabetes is a result of increased amniotic fluid glucose concentration.

Adult↗
PubMed1999

Estradiol inhibits leukocyte adhesion and transendothelial migration in rabbits in vivo : possible mechanisms for gender differences in atherosclerosis.

The mechanism by which estrogens protect against atherosclerosis is not known. We evaluated in vivo whether there is a gender difference in monocyte adhesion and subendothelial migration in hypercholesterolemic rabbits and whether any gender differences observed are due to estradiol. Monocyte adhesion and subendothelial migration were assessed in a blinded fashion by analyzing a standardized segment of aorta using a scanning electron microscope. We also assessed whether estradiol modulates induction of vascular cell adhesion molecule-1 (VCAM-1) protein using Western blot and flow cytometric analyses. We observed that male rabbits develop more monocyte adhesion and subendothelial migration than do female rabbits during hypercholesterolemia. We also observed that oophorectomized rabbits given physiological estradiol supplementation demonstrate fewer adherent and subendothelial monocytes than do oophorectomized rabbits given placebo. VCAM-1 protein expression was increased in aortae obtained from hypercholesterolemic, oophorectomized animals supplemented with placebo, and this increase was attenuated by estradiol. Finally, in cultured rabbit aortic endothelial cells stimulated with lysophosphatidylcholine, we observed an increase in VCAM-1 protein that was inhibited in a concentration-dependent fashion by estradiol. We have demonstrated in vivo that there is a gender difference in monocyte adhesion to endothelial cells and transendothelial migration after hypercholesterolemia and that this gender difference is due in part to estradiol. Our results also suggest that estradiol inhibits monocyte adhesion by inhibiting expression of VCAM-1.

Animals↗
PubMed1999

Effects of calcitonin gene-related peptide on vascular resistance in rats: role of sex steroids.

It has been demonstrated in reflex-intact animals that the sensitivity to calcitonin gene-related peptide (CGRP) is increased during pregnancy and that this action is mediated by sex steroids but not by nitric oxide (NO). We assessed the effects of CGRP in the following groups of anesthetized ganglion-blocked rats: 1) pregnant, 2) ovariectomized, and 3) ovariectomized and treated with estradiol and progesterone. Changes in mean arterial pressure (MAP) were assessed after the administration of varying doses of CGRP. Decreases in MAP after CGRP administration were significantly greater in pregnant rats and ovariectomized rats administered sex steroids than in ovariectomized controls. The CGRP antagonist CGRP8-37 produced a pressor response of similar magnitude in both pregnant and ovariectomized rats. We also assessed the effects of CGRP and the modulating role of NO in the isolated uterine vascular bed preparation. CGRP reduced perfusion pressure to a greater degree in ovariectomized animals treated with sex steroids than in ovariectomized animals. This response was attenuated by pretreatment with an NO synthesis inhibitor. CGRP8-37 produced a similar increase in perfusion pressure in both groups. We conclude that 1) the increased vascular sensitivity observed during pregnancy or after treatment with sex steroids is in part mediated by NO, and 2) CGRP8-37 has a vasoconstrictor action of its own.

Animals↗
PubMed1998

Initial and repeat screening for Chlamydia trachomatis during pregnancy.

OBJECTIVES: The objective of this study is to determine the prevalence of Chlamydia trachomatis and risk factors for positive repeat tests in a high-risk population presenting for early prenatal care. METHODS: We completed a retrospective cohort study of 2,484 women who initiated prenatal care prior to 20 weeks gestation, delivered, and received testing for cervical C. trachomatis at Grady Memorial Hospital or a Grady-affiliated clinic between July 1, 1993 and December 31, 1994. We calculated adjusted odds ratios (OR) for selected risk factors for a positive initial test and for a positive subsequent test after an initial negative test. RESULTS: The prevalence of C. trachomatis was 14.8%. At initial testing, 10.4% of the women were positive. If the initial test was negative, 5.7% had a positive subsequent test; but if the initial test was positive, 32.0% had a positive subsequent test (P < 0.001). The variables significantly and independently associated with a positive initial test were black race/ethnicity, age less than 25, unmarried, and less than a high-school education (adjusted OR of 1.66, 3.53, 2.18, and 1.81, respectively). Variables significantly and independently associated with a positive subsequent test after a negative initial test were white race/ethnicity, black race/ethnicity, age less than 25, and less than a high-school education (adjusted OR 8.69, 7.77, 4.12, and 2.27, respectively). CONCLUSIONS: In our inner-city population, most pregnant women have risk factors suggesting the need to rescreen for C. trachomatis in the second half of pregnancy.

Adolescent↗
PubMed1998

Children's comprehension of unfamiliar regional accents: a preliminary investigation.

The effect of regional accent on children's processing of speech is a theoretically and practically important aspect of phonological development that has been little researched. 48 children from London, aged four and seven years old, were tested on their ability to repeat and define single words presented in their own accent and in a Glaswegian accent. Results showed that word comprehension was significantly reduced in the Glaswegian condition and that four-year-olds performed less successfully than seven-year-olds. Both groups made similar numbers of lexical misidentifications, but the younger children were more likely to fail to access any word at all. On the repetition task, the younger children showed a different pattern of errors to the older children, their productions being apparently more influenced by the phonetics of the Glaswegian stimuli. It is suggested that such phonetic responses are related to the younger children's failure to map the unfamiliar accent onto their own phonological representations. It is proposed that the lexical misidentifications, common to both age groups, are more likely to be induced by lack of context. The paper concludes with discussion of implications of these findings for our understanding of how children develop the ability to process unfamiliar regional accents.

Child↗
PubMed1998

Antioxidant and prooxidant actions of estrogens: potential physiological and clinical implications.

Oxidative stress and free radical-mediated cell death have been linked to diseases such as atherosclerosis, Alzheimer's disease, and cancer. Estrogens may promote, or offer protection against these conditions, by acting both as an antioxidant and prooxidant. Estrogens are converted to catecholestrogens via an oxidation step. Catecholestrogens are precursors of quinones that undergo a reversible oxidation-reduction reaction yielding semiquinones and reactive oxygen species. These semiquinones and reactive oxygen species may act as prooxidants and result in DNA and protein damage that may play a role in initiating tumor growth. Estrogen may also stimulate the peroxidase reaction, thereby promoting prooxidant reactions catalyzed by estrogen. Such reactions may be involved in enhancing the oxidizability of low-density lipoproteins (LDL). This mechanism of oxidation of LDL in plasma may actually lead to increased clearance of LDL by the liver and thereby contribute to estrogens' antiatherogenic action. On the other hand, participation of catecholestrogens in iron redox cycling may contribute to the antioxidant action of estrogens. This action might be important in sites such as the subendothelial space where estrogens are thought to inhibit LDL oxidation. Estrogens may also exert antioxidant effects by acting on genes with response elements for antioxidants. This may in turn inhibit expression of certain proteins involved in disease processes such as atherogenesis. Thus, by acting as an antioxidant and prooxidant, estrogen may produce both beneficial and adverse effects important in the prevention and pathogenesis of disease.

Alzheimer Disease↗
PubMed1998

Estradiol suppresses MCP-1 expression In vivo : implications for atherosclerosis.

The mechanisms by which 17beta-estradiol retards atherogenesis are not known. The adhesion of monocytes to endothelial cells followed by the migration of monocytes into the artery wall are key cellular events that occur throughout the entire atherogenic process and may be responsive to estradiol. Monocyte chemoattractant protein-1 (MCP-1), a chemokine that is expressed in atherosclerotic lesions, is thought to play a major role in stimulating the migration of blood monocytes into developing atherosclerotic lesions. We therefore assessed the effects of estradiol in vivo on MCP-1 protein and mRNA expression in the descending thoracic aorta of rabbits fed a cholesterol-enriched (0.5%) diet for 6 weeks and in animals fed normal chow. MCP-1 protein was quantified by Western blot analysis and monocyte chemotaxis bioassay, and reverse transcription-polymerase chain reaction was used to ascertain the level of MCP-1 mRNA expression. We observed that in both ovary-intact and ovariectomized (OVX) animals, MCP-1 protein and mRNA expression were significantly increased by 6 weeks in animals fed a high-cholesterol diet. The cholesterol-induced increase in MCP-1 protein and mRNA expression was significantly attenuated in OVX rabbits supplemented with estradiol pellets (1.5- and 10.0-mg 60-day-release pellets), which yielded a range of estradiol concentrations encompassing the physiological levels. MCP-1 protein and mRNA expression were increased in normocholesterolemic OVX rabbits compared with normocholesterolemic ovary-intact animals, and this increase was prevented in OVX animals supplemented with estradiol pellets. Our observations indicate that both basal and hypercholesterolemia-induced increases in MCP-1 protein are modulated by physiological concentrations of estradiol.

Animals↗
PubMed1998

Speech processing abilities in children with speech vs speech and language difficulties.

This paper reports on the speech processing skills of a group of four year old children with specific speech difficulties and examines the impact of an additional language impairment on these skills. Forty seven children with speech difficulties were tested on two speech output measures and one speech input measure to assess the accuracy of their phonological representations. Their performance was compared to a matched control group n = 47 and analysed according to the presence/absence of an additional language impairment. It was found that children with both speech and language difficulties had poorer speech processing abilities compared to both the normal controls and the children with speech-only difficulties. The clinical implications of these findings are outlined.

Analysis of Variance↗
PubMed1997

In utero infection with Treponema pallidum in early pregnancy.

Amniocentesis was performed under sonographic guidance in gravidas (< 20 weeks' gestation) with untreated syphilis. Five to ten millilitres of amniotic fluid from each patient was used for rabbit infectivity testing (RIT) and polymerase chain reaction (PCR) to detect amniotic fluid infection with Treponema pallidum. Gravidas were treated with benzathine penicillin G. Newborns were examined for clinical and laboratory signs of congenital syphilis including immunoglobulin M (IgM) antibody to T. pallidum by Western blotting (immunoblotting). Eleven patients were enrolled at a mean gestational age of 16.8 weeks. T. pallidum was recovered from amniotic fluid by RIT in four cases (36 per cent), and PCR was positive in three of the amniotic fluid specimens (27 per cent). There were no false-positive PCR results. None of the newborns had clinical evidence of congenital syphilis and their sera lacked IgM reactivity to T. pallidum antigens by immunoblotting. These findings confirm in utero infection with T. pallidum in continuing early pregnancy and indicate that in utero treponemal infection can be eradicated by maternal treatment.

Adolescent↗
PubMed1997

Estrogens and atherosclerosis.

Estrogens prevent heart disease in women and have also been shown to retard atherogenesis in animal models. Estrogens may act at several steps in the atherogenic process to prevent cardiovascular disease. Some of the benefits of estrogens can be ascribed to their ability to favorably alter the lipoprotein profile, i.e. increase high-density lipoprotein and decrease low-density lipoprotein, and also to their ability to prevent oxidative modification of low-density lipoprotein. Other beneficial effects of estrogens include direct actions on the vascular endothelium and vascular smooth muscle, leading to a decrease in the expression of adhesion molecules involved in monocyte adhesion to endothelial cells, and to a decrease in certain chemokines involved in monocyte migration into the subendothelial space. Estrogens may also affect the later stages of atherogenesis. Finally, estrogens may modify the behavior of atherosclerotic vessels by altering their reactivity and thereby promoting vasodilation, and this may also partly account for their ability to prevent clinical events due to cardiovascular disease.

Animals↗
PubMed1996

Mixed mesodermal sarcoma of the ovary in a young patient.

Mixed mesodermal tumors (MMT) of the ovary are rare and have a poor prognosis. This ovarian malignancy usually occurs in postmenopausal women. We report an unusual ovarian MMT in a young woman given treatment similar to one used for ovarian germ cell malignancies. We believe this is the youngest patient reported with an homologous MMT of the ovary.

Adult↗
PubMed1996

Inhibition of GH in maternal separation may be mediated through altered serotonergic activity at 5-HT2A and 5-HT2C receptors.

The hyposecretion of growth hormone (GH) in maternal separation (MS) of rat pups is remarkably similar to the specific suppression of GH secretion to evocative tests in infants diagnosed with Reactive Attachment Disorder of Infancy (RADI). Growth hormone-releasing factor (GRF) and somatostatin (SS) provide opposing regulation of GH secretion, and both are modified by noradrenergic and serotonergic stimuli in neonatal and adult rats. In this study, GRF administration reversed MS-induced suppression of GH secretion in 10-day-old pups, but this action of GRF was prevented by pretreatment with cyproheptadine (Cypro), a serotonergic antagonist. The normalization of GH secretion after return to the dam was not altered by pretreatment with SS. Indirect 5-HT agonists, fluoxetine (FLX) and 5-HTP, both stimulated GH secretion in 10-day-old pups. All mixed serotonin- and 5-HT1A-receptor agonists suppressed GH secretion in 10-day-old pups. Antagonists Cypro and ketanserin (Ket) suppressed FLX-induced GH secretion. In contrast, only Cypro suppressed 5-HTP-induced GH secretion. Maternal separation inhibited GH secretion stimulated by 5-HTP, but not by FLX. The serotonergic pathway acting on 5-HT2A receptors may be obligatory for GRF-mediated stimulation and is sensitive to inhibition by Cypro. In addition, a Ket-sensitive serotonergic parallel pathway acting on 5-HT2C receptors may also stimulate GH secretion by acting on GRF or SS. However, only the obligate 5-HT2A pathway appears to be suppressed in MS. These data and observations by others indicate that specific suppression of GH secretion in MS may derive from a reduction in GRF release through noradrenergic neurons, possibly impinging upon serotonergic terminals in the hypothalamus. This study may also provide insight into mechanisms by which GH secretion is suppressed in humans with RADI.

Animals↗
PubMed1995

The role of nitric oxide in the altered vascular reactivity of pregnancy in the rat.

1. Pregnancy is characterized by a decrease in systemic vascular resistance and a blunting of the angiotensin II (AII) pressor response. We studied the role of nitric oxide (NO) and prostanoids in these vascular changes of pregnancy in anaesthesized, ganglion blocked non-pregnant and pregnant rats. 2. Inhibition of NO synthesis with NG-nitro-L-arginine methyl ester (L-NAME) led to an increase in mean arterial pressure (MAP) which was of a significantly greater magnitude in pregnant rats in late gestation than in non-pregnant rats, or rats in mid-gestation. 3. The pressor response to varying doses of AII was attenuated during late pregnancy, and this attenuation was partially reversed by L-NAME. 4. The pressor response to varying doses of a vasoconstrictor, phenylephrine (PE), was also attenuated in late pregnancy. However, this attenuation was not reversed by L-NAME. 5. Inhibition of prostanoid biosynthesis with meclofenamate did not alter basal MAP, nor the pressor response to varying doses of AII or PE in pregnant and non-pregnant animals. 6. It is concluded that (a) increased NO synthesis occurs during late gestation and contributes both to the decrease in systemic vascular resistance, as well as the blunting of the pressor response to AII during pregnancy, and (b) prostaglandins are not important in the maintenance of basal vascular tone, or the blunting of the pressor response to AII during pregnancy.

Angiotensin II↗