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James M Roberts

Publications and source records attributed to James M Roberts.

At least 55 records · Page 3Linked to original sources
PubMed2004

Moderate hyperhomocysteinemia decreases endothelial-dependent vasorelaxation in pregnant but not nonpregnant mice.

Increased homocysteine is associated with the pregnancy complication preeclampsia and with later-life cardiovascular disease. Although elevated homocysteine persists after pregnancy, the vascular changes of preeclampsia abate with delivery, and cardiovascular disease occurs decades later. This suggests the vasculature during pregnancy may manifest increased sensitivity to homocysteine. We used the cystathionine-beta synthase (CBS)-deficient transgenic mouse to investigate whether hyperhomocysteinemia would differentially affect vascular function in nonpregnant and pregnant animals. Mesenteric arteries from nonpregnant and midpregnant (14 to 16 days) wild-type, heterozygous, and homozygous CBS-deficient transgenic mice were investigated for their response to vasoconstriction, endothelial-dependent, and endothelial-independent relaxation using an isometric wire myograph system. Endothelial-dependent vasodilation was similar in arteries from nonpregnant heterozygous and wild-type mice. In contrast, endothelial-dependent relaxation was reduced significantly in arteries from pregnant heterozygous animals compared with wild-type mice. Inhibition of NO synthesis blunted relaxation in arteries from pregnant wild-type but not pregnant heterozygous mice. Endothelial-dependent relaxation was restored by in vitro pretreatment with the tetrahydrobiopterin precursor sepiapterin. These data indicate that in pregnant mice, endothelial-dependent vasodilation is more sensitive to the effect of increased homocysteine than arteries from nonpregnant mice. This effect appears to result from a loss in NO-mediated relaxation that may be mediated by the oxidative inactivation of the NO synthase cofactor tetrahydrobiopterin.

Animals↗
PubMed2004

Homocysteine and folic acid are inversely related in black women with preeclampsia.

Black women have an increased risk of preeclampsia compared with white women. Plasma homocysteine is increased in preeclampsia. Homocysteine concentrations are affected by nutritional deficiencies, particularly decreased folic acid and B12, leading to increased homocysteine. Previous studies have reported racial differences in nutritional intake including folic acid. Therefore, we investigated whether there were racial differences in plasma homocysteine, folic acid, and vitamin B12 among women with preeclampsia. We tested for an association between homocysteine and folic acid and B12, and we hypothesized an inverse relationship of homocysteine and folic acid in preeclampsia, more so in black women in whom preeclampsia developed. Black women with preeclampsia (n=26) had elevated homocysteine concentrations (8.7+/-1.4 micromol/L) compared with black women with normal pregnancy (n=52, 7.6+/-0.5 micromol/L), white women with preeclampsia (n=34, 7.5+/-0.6 micromol/L), and white women with normal pregnancy (n=48, 5.5+/-0.3 micromol/L). Folic acid concentrations were lower in black women (14.1+/-0.8 ng/mL) compared with white women (18.5+/-0.9 ng/mL, P<0.01). However, plasma homocysteine was inversely related to folic acid only among black women with preeclampsia (r=-0.23, P=0.01). These racial differences may have implications for the higher rates of preeclampsia in this group and may have long-term implications for future cardiovascular risk. Racial differences in diet, adherence to folic acid supplementation, or interactions of nutritional and maternal factors warrant further study by race and pregnancy status.

Adolescent↗
PubMed2004

p27Kip1 modulates cell migration through the regulation of RhoA activation.

The tumor suppressor p27(Kip1) is an inhibitor of cyclin/cyclin-dependent kinase (CDK) complexes and plays a crucial role in cell cycle regulation. However, p27(Kip1) also has cell cycle-independent functions. Indeed, we find that p27(Kip1) regulates cell migration, as p27(Kip1)-null fibroblasts exhibit a dramatic decrease in motility compared with wild-type cells. The regulation of motility by p27(Kip1) is independent of its cell-cycle regulatory functions, as re-expression of both wild-type p27(Kip1) and a mutant p27(Kip1) (p27CK(-)) that cannot bind to cyclins and CDKs rescues migration of p27(-/-) cells. p27(-/-) cells have increased numbers of actin stress fibers and focal adhesions. This is reminiscent of cells in which the Rho pathway is activated. Indeed, active RhoA levels were increased in cells lacking p27(Kip1). Moreover, inhibition of ROCK, a downstream effector of Rho, was able to rescue the migration defect of p27(-/-) cells in response to growth factors. Finally, we found that p27(Kip1) binds to RhoA, thereby inhibiting RhoA activation by interfering with the interaction between RhoA and its activators, the guanine-nucleotide exchange factors (GEFs). Together, the data suggest a novel role for p27(Kip1) in regulating cell migration via modulation of the Rho pathway.

Actins↗
PubMed2004

Regulation of cyclin-dependent kinase activity during mitotic exit and maintenance of genome stability by p21, p27, and p107.

To study the regulation of cyclin-dependent kinase (CDK) activity during mitotic exit in mammalian cells, we constructed murine cell lines that constitutively express a stabilized mutant of cyclin A (cyclin A47). Even though cyclin A47 was expressed throughout mitosis and in G1 cells, its associated CDK activity was inactivated after the transition from metaphase to anaphase. Cyclin A47 associated with both p21 and p27 during mitotic exit, implicating these proteins in CDK inactivation. However, cyclin A47 was fully inhibited during the M-to-G1 transition in p21(-/-) p27(-/-) fibroblasts. Also, the CDKs associated with cyclin A47 were not inactivated by phosphorylation at tyrosines. The protein responsible for CDK inactivation during mitotic exit in p21/p27 null cells was the Rb family member, p107. p107 bound to cyclin A47 when p21 and p27 were absent, and cyclin A47-CDK activity was not inactivated during the M-to-G1 transition in p21(-/-) p27(-/-) p107(-/-) null fibroblasts. Enforced expression of cyclin A in cells lacking all three CDK inhibitors induced rapid tetraploidization, indicative of mitotic failure/endoreduplication. We concluded that cyclin proteolysis and CDK inhibitors constitute redundant pathways that control cyclin A-CDK activity during mitotic exit in mammalian cells and that loss of these pathways can cause genetic instability.

3T3 Cells↗
PubMed2004

The Trp64Arg polymorphism of the beta3-adrenergic receptor is not increased in women with preeclampsia.

OBJECTIVE: Insulin resistance is greater and obesity is more common in women with preeclampsia. The Trp64Arg polymorphism in the beta(3)-adrenergic receptor is associated with these metabolic changes. This study investigated whether the Trp64Arg polymorphism is more common in women with preeclampsia. STUDY DESIGN: beta(3)-Adrenergic receptor genotypes were determined in 177 women with a history of preeclampsia and in 179 normal pregnancies. We also compared prepregnancy body mass index (BMI), length of gestation, baby weight percentile, and glucose values during an oral tolerance test in women with and without the polymorphism. RESULTS: The genotypes and allele frequency did not differ significantly between women with preeclamptic and normal pregnancies (P=.17). Women with and without the polymorphism had similar prepregnancy BMI, glucose at 1-hour screening, gestational age at delivery, and adjusted baby weight. CONCLUSION: The Trp64Arg polymorphism of the beta(3)-receptor does not predispose to preeclampsia, and it is it not associated with obesity and carbohydrate intolerance in a population of young pregnant women.

Adult↗
PubMed2004

Serum homocysteine levels after preterm premature rupture of the membranes.

OBJECTIVE: Preterm premature rupture of the membranes (PPROM) is believed to be caused, in part, by abnormalities of collagen and increased levels of oxidative stress. Elevated homocysteine levels have been shown to induce these same pathophysiologic changes. We tested the hypothesis that serum homocysteine levels would be higher in women with PPROM when compared with matched control women. STUDY DESIGN: A secondary analysis derived from 2 previously completed studies performed in the National Institutes of Child Health and Human Development Maternal-Fetal Medicine Units (MFMU) Network. We identified 99 study cases with PPROM (24 to 32 weeks' gestation) and matched them with 99 asymptomatic control women from an observational study of preterm birth prediction. Cases and control women were matched for race, gestational age at sampling, and MFMU Network center. Serum homocysteine levels were determined by immunoassay in batch fashion by personnel masked to study arm and clinical outcomes. Serum homocysteine levels were compared between groups, as were the baseline characteristics of maternal age, cigarette smoking, nulliparity, infections during pregnancy, and body mass index (BMI) <19.8 kg/m 2. Serum homocysteine levels were dichotomized as >75th, 90th, and 95th %ile of control women, and the likelihood of elevated homocysteine levels was determined in women who smoked, had a BMI <19.8 kg/m 2, or who had PPROM. Statistical analyses included the Wilcoxon rank sum, chi-square, and Pearson correlation coefficient, where appropriate. Baseline characteristics were controlled with a logistic regression model. RESULTS: Serum homocysteine levels measured in patients with PPROM were not significantly different from matched control women: median and (25th to 75th %ile): 4.9 (3.5-6.2) vs 4.8 (3.9-6.2 micromol/L), P =.73. In our population, neither the number of cigarettes smoked ( r = -0.08, P =.57), nor BMI ( r = -0.08, P =.24) correlated with serum homocysteine levels. The strongest association was seen in women with PPROM having serum homocysteine levels >95th %ile of control women (odds ratio [OR] 2.7, P =.10). After adjusting for baseline characteristics, no correlation between serum homocysteine level and the presence of PPROM was seen, OR 1.0 (.9-1.1); P =.99. CONCLUSION: Women presenting with PPROM did not have significantly increased serum homocysteine levels when compared with control women.

Adult↗
PubMed2004

Antioxidant therapy to prevent preeclampsia.

Preeclampsia is a 2-stage disorder. Stage 1 is decreased placental perfusion and generates stage 2 of the disorder, the maternal syndrome characteristic of preeclampsia. How the 2 stages are linked has been a topic of intense investigation for many years. One candidate phenomenon, which includes many other suggested linkages, is oxidative stress. This hypothesis predicts that the administration of antioxidants would decrease oxidative stress and modify stage 2. Experience with the treatment of preeclampsia including a small trial of antioxidants in women with manifest preeclampsia makes it clear that the use of any therapy once preeclampsia is evident will not be successful. Trials evaluating prophylactic aspirin and supplemental calcium from early pregnancy suggest that therapy before evident preeclampsia may be successful in selected populations. Guided by these concepts and by experience with antioxidant therapy in other settings, 1 small study (<80 women in the treatment arm) was very encouraging with an almost two-thirds reduction of the frequency of preeclampsia in high-risk women. Antioxidants currently are being evaluated in several larger trials in the United States, Canada, Mexico, England, and in several developing nations. These studies should definitively establish the efficacy and safety of this therapy for the mother and fetus.

Antioxidants↗
PubMed2004

Regulation of the cytoskeleton: an oncogenic function for CDK inhibitors?

Cyclin-dependent kinase inhibitors (CKIs) are well known inhibitors of cell proliferation. Their activity is disrupted in many tumour types. Recent studies show that some of these proteins have interesting alternative functions, acting in the cytoplasm to regulate Rho signalling and thereby controlling cytoskeletal organization and cell migration. The upregulation of CKIs in the cytoplasm of many cancer cells indicates that although loss of nuclear CKIs is important for cancer cell proliferation, gain of cytoplasmic CKI function might be involved in tumour invasion and metastasis.

Cell Division↗
PubMed2004

Evidence of increased oxidative stress, unexplained by lipid changes, is present in nulliparous black women from early gestation.

OBJECTIVE: We tested the hypothesis that race-specific lipid changes in pregnancy could predispose to oxidative stress and might increase the risk of preeclampsia for black women. STUDY DESIGN: Blood samples were obtained at five time points in pregnancy and postpartum for 15 black and 15 white women with normal pregnancy. Serum or plasma samples were analyzed for cholesterol, triglycerides, LDL cholesterol, HDL total and subfractions, free fatty acids, uric acid, and malondialdehyde (MDA). RESULTS: Cholesterol and LDL-cholesterol values were higher in white women than in black women (RMANOVA, p = 0.04) while MDA values were higher in blacks throughout pregnancy (RMANOVA, p = 0.03). Although not significantly different, black women had lower mean triglycerides, while mean total HDL and subfractions HDL2 and HDL3 were higher for black women. Both races evidenced smaller, denser LDL particle size with advancing gestation and a return to early pregnancy LDL particle size by 6 weeks' gestation. CONCLUSION: These data do not support quantitative lipid change as the explanation for the increased incidence of preeclampsia in black women. Despite this, black women manifest increased evidence of oxidative stress, postulated to be an important contributor to the pathogenesis of preeclampsia from early gestation.

Adult↗
PubMed2004

Cooperative regulation of the cell division cycle by the protein kinases RAF and AKT.

The RAS-activated RAF-->MEK-->extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3'-kinase (PI3'-kinase)-->PDK1-->AKT signaling pathways are believed to cooperate to promote the proliferation of normal cells and the aberrant proliferation of cancer cells. To explore the mechanisms that underlie such cooperation, we have derived cells harboring conditionally active, steroid hormone-regulated forms of RAF and AKT. These cells permit the assessment of the biological and biochemical effects of activation of these protein kinases either alone or in combination with one another. Under conditions where activation of neither RAF nor AKT alone promoted S-phase progression, coactivation of both kinases elicited a robust proliferative response. Moreover, under conditions where high-level activation of RAF induced G(1) cell cycle arrest, activation of AKT bypassed the arrest and promoted S-phase progression. At the level of the cell cycle machinery, RAF and AKT cooperated to induce cyclin D1 and repress p27(Kip1) expression. Repression of p27(Kip1) was accompanied by a dramatic reduction in KIP1 mRNA and was observed in primary mouse embryo fibroblasts derived from mice either lacking SKP2 or expressing a T187A mutated form of p27(Kip1). Consistent with these observations, pharmacological inhibition of MEK or PI3'-kinase inhibited the effects of activated RAS on the expression of p27(Kip1) in NIH 3T3 fibroblasts and in a panel of bona fide human pancreatic cancer cell lines. Furthermore, we demonstrated that AKT activation led to sustained activation of cyclin/cdk2 complexes that occurred concomitantly with the removal of RAF-induced p21(Cip1) from cyclin E/cdk2 complexes. Cumulatively, these data strongly suggest that the RAF-->MEK-->ERK and PI3'K-->PDK-->AKT signaling pathways can cooperate to promote G(0)-->G(1)-->S-phase cell cycle progression in both normal and cancer cells.

Animals↗
PubMed2004

Impairment of endothelial function in women with a history of preeclampsia: an indicator of cardiovascular risk.

Preeclampsia is a disorder of pregnancy diagnosed by gestational hypertension and proteinuria. Epidemiological evidence suggests that women who experience preeclampsia are at a greater risk of hypertension and heart disease later in life compared with women who had normal pregnancies. Our objective was to determine whether endothelial function is impaired in postpartum women with a history of preeclampsia in their first pregnancy. We measured forearm blood flow (FBF) by venous occlusion plethysmography in 50 healthy women: 16 with prior preeclampsia, 14 with a prior normotensive pregnancy, and 20 never pregnant controls. The postpartum women participated 6-12 mo after delivery. Heart rate (HR) and blood pressure (BP) were concurrently monitored on the contralateral arm. Hemodynamic variables were assessed at baseline and during a mental stress test known to elicit endothelium-dependent vasodilatation. We found that baseline FBF, HR, systolic BP, and diastolic BP did not significantly differ among the groups, whereas mean arterial pressure in the preeclamptic group was greater than that of the normal pregnancy group (P = 0.03). Stress-induced FBF (percent change over baseline) was reduced in the preeclamptic group compared with both the normal pregnancy and never pregnant groups (P = 0.06) and was significantly attenuated compared with women with prior normal pregnancies (91% vs. 147%, P = 0.006). These data demonstrate that women with a history of preeclampsia exhibit impaired endothelial function up to 1 yr postpartum. This observation may explain their increased risk for hypertension and cardiovascular disease.

Adolescent↗
PubMed2004

Preeclampsia and future cardiovascular disease: potential role of altered angiogenesis and insulin resistance.

Altered angiogenesis and insulin resistance are associated with preeclampsia and cardiovascular disease (CVD), and women with preeclampsia appear to be at increased risk of future CVD. We hypothesized that these factors are detectable in asymptomatic postpartum women with a history of preeclampsia and may represent pathophysiological mechanisms bridging preeclampsia and future CVD. We measured fasting insulin, glucose, vascular endothelial growth factor, and its circulating inhibitor, soluble fms-like tyrosine kinase (sFlt-1) in 29 normotensive women with a history of preeclampsia and 32 women with prior normotensive pregnancies at 18.0 +/- 9.7 months postpartum. The homeostasis model of insulin resistance (HOMA(IR)) [(insulin [microunits per milliliter] x glucose [millimoles per liter])/22.5] was calculated. Compared with women with normal pregnancies, women with prior preeclampsia had significantly increased levels of sFlt-1 (41.6 +/- 6.7 vs. 30.4 +/- 10.2; P < 0.01) and median HOMA(IR) (2.8 vs. 1.9; P = 0.04). Membership in the upper quartile of either sFlt-1 or HOMA(IR) was associated with prior preeclampsia (odds ratio 5.7; 95% confidence interval 1.7, 20.0; P < 0.01), and all five women in the upper quartiles of both sFlt-1 and HOMA(IR) had a history of preeclampsia. Women with a history of preeclampsia demonstrate altered expression of angiogenesis-related proteins and increased HOMA(IR) more than 1 yr postpartum. These factors may contribute to their risk of future CVD.

Adult↗
PubMed2003

Critical pathways for the management of preeclampsia and severe preeclampsia in institutionalised health care settings.

BACKGROUND: Preeclampsia is a complex disease in which several providers should interact continuously and in a coordinated manner to provide proper health care. However, standardizing criteria to treat patients with preeclampsia is problematical and severe flaws have been observed in the management of the disease. This paper describes a set of critical pathways (CPs) designed to provide uniform criteria for clinical decision-making at different levels of care of pregnant patients with preeclampsia or severe preeclampsia. METHODS: Clinicians and researchers from different countries participated in the construction of the CPs. The CPs were developed using the following steps: a) Definition of the conceptual framework; b) Identification of potential users: primary care physicians and maternal and child health nurses in ambulatory settings; ob/gyn and intensive care physicians in secondary and tertiary care levels. c) Structural development. RESULTS: The CPs address the following care processes: 1. Screening for preeclampsia, risk assessment and classification according to the level of risk. 2. Management of preeclampsia at primary care clinics. 3. Evaluation and management of preeclampsia at secondary and tertiary care hospitals: 4. Criteria for clinical decision-making between conservative management and expedited delivery of patients with severe preeclampsia. CONCLUSION: Since preeclampsia continues to be one of the primary causes of maternal deaths and morbidity worldwide, the expected impact of these CPs is the contribution to improving health care quality in both developed and developing countries. The CPs are designed to be applied in a complex health care system, where different physicians and health providers at different levels of care should interact continuously and in a coordinated manner to provide care to all preeclamptic women. Although the CPs were developed using evidence-based criteria, they could require careful evaluation and remodelling according to each system's demands. Additionally, the CPs need to be tested in large-scale, multi-level studies in order to thoroughly examine and evaluate their efficacy and effectiveness.

Journal Article↗
PubMed2003

Summary of the NHLBI Working Group on Research on Hypertension During Pregnancy.

A Working Group on Research in Hypertension in Pregnancy was recently convened by the National Heart, Lung, and Blood Institute to determine the state of knowledge in this area and suggest appropriate directions for research. Hypertensive disorders in pregnancy, especially preeclampsia, are a leading cause of maternal death worldwide and even in developed countries increase perinatal mortality rates 5-fold. Much has been learned about preeclampsia, but gaps in the knowledge necessary to direct therapeutic strategies remain. Oxidative stress is a biologically plausible contributor to the disorder that may be amenable to intervention. Hypertension that antedates pregnancy (chronic hypertension) bears many similarities to hypertension in nonpregnant women, but the special setting of pregnancy demands information to guide evidence-based therapy. The recommendations of the Working Group are to attempt a clinical trial of antioxidant therapy to prevent preeclampsia that is be complemented by mechanistic research to increase understanding of the genetics and pathogenesis of the disorder. For chronic hypertension, clinical trials are recommended to direct choice of drugs, evaluate degree of control, and assess implications to the mother and fetus. Recommendations to increase participation in this research are also presented.

Antioxidants↗
PubMed2003

Family history of hypertension, heart disease, and stroke among women who develop hypertension in pregnancy.

OBJECTIVE: To assess familial cardiovascular risk factors in women developing hypertension in pregnancy. METHOD: Of 2211 women delivering live births after enrollment in a pregnancy cohort study, 85 (3.8%) developed preeclampsia (antepartum systolic blood pressure greater than 140 or diastolic blood pressure greater than 90 plus proteinuria) and 142 (6.4%) developed transient hypertension of pregnancy (antepartum blood pressure elevation without proteinuria). At a mean of 10.2 weeks' gestation, women were asked about first-degree family members with heart disease or stroke, hypertension, diabetes, renal disease, or any of these, which defined familial cardiovascular risk. RESULTS: After adjustment for age and body size, having two or more family members, versus no family members, with cardiovascular risk imparted a 1.9-fold (95% confidence interval [CI] 1.1, 3.2) elevated risk for developing preeclampsia and a 1.7-fold (95% CI 1.1, 2.6) risk for developing transient hypertension of pregnancy. Having two or more family members with hypertension also imparted a significant, two-fold elevation in risk of preeclampsia and transient hypertension of pregnancy, and having two or more family members with heart disease or stroke imparted a 3.2-fold (95% CI 1.4, 7.7) elevation in the risk for preeclampsia. CONCLUSION: A strong family history of aggregate cardiovascular risk increased the likelihood for developing preeclampsia and transient hypertension of pregnancy. These findings support the theory that a preexisting tendency to cardiovascular risk, and particularly hypertension, increases a women's susceptibility to developing hypertension in pregnancy.

Adult↗
PubMed2003

Seroprevalence of antibodies to Chlamydia pneumoniae in women with preeclampsia.

OBJECTIVE: Preeclampsia shares many risk factors and pathophysiologic features with coronary heart disease. We studied whether, like atherosclerosis, preeclampsia is related to seroprevalence of immunoglobulin (Ig) G antibodies to Chlamydia pneumoniae. METHODS: Cross-sectional comparisons were made for 37 women with preeclampsia and 37 women with normal pregnancies at term. In these two groups, antibody titers for IgG, IgM, and IgA seroprevalence to C pneumoniae and IgG to Chlamydia trachomatis and Chlamydia psittaci were compared. RESULTS: Immunoglobulin G antibodies to C pneumoniae at a titer of at least 1:16 were more common in women with preeclampsia (25 of 37) than in women without (15 of 37) (odds ratio 3.1; 95% confidence interval 1.2, 7.9). There were no significant differences in the seroprevalence of IgA or IgM antibodies to C pneumoniae. Women with preeclampsia were also no more likely to have IgG antibodies to C trachomatis or C psittaci. CONCLUSION: Women with preeclampsia had an increased IgG seroprevalence to C pneumoniae but not to C trachomatis or C psittaci. These preliminary data suggest a specific association between infection with C pneumoniae and preeclampsia.

Antibodies, Bacterial↗