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Biomedical subjects

J M Roberts

Publications and source records attributed to J M Roberts.

At least 181 records · Page 10Linked to original sources
PubMed1995

Plasma from women with preeclampsia increases endothelial cell nitric oxide production.

In preeclampsia, a factor in the maternal circulation alters endothelial function via a reduction in nitric oxide synthesis. We measured the in vitro effects of 2% plasma from women with preeclampsia, compared with 2% plasma from normotensive pregnant women, on cultured endothelial cell nitrite production and nitric oxide synthase activity. On finding differential effects, we measured the effects on cellular viability (assessed by lactate dehydrogenase levels) and performed a time course study. Endothelial cell nitrite production was found to be higher after exposure to plasma from the preeclamptic group than the normotensive pregnant group. The effects of long-term exposure (120 hours) were similar to those of short-term exposure (24 hours). In addition, nitric oxide synthase activity was significantly greater after exposure to preeclamptic plasma than after exposure to normotensive pregnant plasma. No differential effect on cellular viability was found. Contrary to our hypothesis, exposure of endothelial cells to preeclamptic plasma resulted in increased nitric oxide production and nitric oxide synthase activity.

Adult↗
PubMed1995

Nitric oxide produced by endothelial cells increases production of eicosanoids through activation of prostaglandin H synthase.

The endothelium serves many functional roles, including the modulation of vascular smooth muscle tone through the release of vasoactive agents such as nitric oxide (NO) and the eicosanoids. We proposed that NO produced by endothelial cells would increase the production of eicosanoids through enhanced expression and/or activation of prostaglandin H synthase. NO and eicosanoid synthesis were stimulated in a bovine coronary microvessel endothelial cell line with the calcium ionophore A23187 (1 mumol/L). Our data demonstrated the following: (1) A23187 stimulated NO synthesis along with prostacyclin and thromboxane production. (2) Inhibition of NO synthesis with NG-nitro-L-arginine methyl ester (0.1 mmol/L) significantly diminished both prostacyclin and thromboxane production. (3) Cells incubated with hemoglobin (2 micrograms/mL), which inactivates NO, decreased A23187-stimulated prostacyclin production, whereas cells incubated with superoxide dismutase (20 U/mL), which protects NO from superoxide anions, enhanced prostacyclin production. (4) Exogenous NO stimulated prostacyclin production. (5) The interaction of NO with prostacyclin persisted in the presence of excess exogenous arachidonic acid (100 mumol/L). (6) Cyclooxygenase activity in cell lysates increased in the first hour of NO stimulation. (7) NO stimulation of prostacyclin occurred within 1 hour and continued for 8 hours. (8) Neither constitutive nor inducible prostaglandin H synthase enzyme expression was altered by NO. (9) Cycloheximide (10 mumol/L) had no effect on A23187 stimulation of prostacyclin production. (10) Exogenous cGMP (10 mumol/L) or a phosphodiesterase inhibitor (1 mmol/L) did not affect prostacyclin production. These data indicate that stimulating synthesis of endogenous NO in cultured endothelial cells increased eicosanoid production through activation of prostaglandin H synthase.

Animals↗
PubMed1995

Dexamethasone for the treatment of depression: a randomized, placebo-controlled, double-blind trial.

OBJECTIVE: The authors' goal was to assess dexamethasone for the treatment of depression. METHOD: Thirty-seven outpatients (11 men and 26 women) meeting DSM-III-R criteria for major depressive disorder were randomly assigned to receive either placebo or 4 mg/day of oral dexamethasone for 4 days. Baseline Hamilton depression scale scores were compared with scores obtained 14 days after the first dose of study medication. Data were analyzed by using two-sample t tests, chi-square methods, and Fisher's exact test. RESULTS: Seven (37%) of the 19 patients given dexamethasone but only one (6%) of the 18 patients given placebo responded positively. No adverse events or side effects were reported, and all patients who entered the study completed it. CONCLUSIONS: A brief course of oral dexamethasone (4 days) was significantly more effective than placebo within 14 days for the treatment of depression in a randomized, double-blind study of depressed outpatients.

Administration, Oral↗
PubMed1995

Antibodies to a Plasmodium falciparum blood-stage antigen as a tool for predicting the protection levels of two malaria-exposed populations.

To evaluate the ability of antibodies to Plasmodium falciparum ring-infected erythrocyte surface antigen (Pf155/RESA) epitopes to discriminate between individuals well protected or poorly protected against malaria, a receiver operating characteristic analysis was performed in two populations living in Madagascar and Malawi. The definition of protection was based on longitudinal measurements of clinical malarial attacks during the season of high malaria transmission in the Madagascar study, and on a cross-sectional measurement of parasitemia in the Malawi study. Antibodies to peptides reproducing the 4-mer, 8-mer, and 11-mer of the Pf155/RESA were tested for their reactivities using the Falcon assay screening test-enzyme-linked immunosorbent assay. Maximal detection of poorly protected individuals (specificity = 100%) corresponded to high cutoff antibody titers (range = 1.65-3.0 optical density [OD] units in the Madagascar study and 0.67-1.42 OD units in the Malawi study) and a sensitivity less than 50%. For a given sensitivity of 50%, specificity ranged from 55% to 62% in the Madagascar study, and from 67% to 94% in the Malawi study. The antibody cutoff titers corresponding to minimal misclassification rates ranged from 0.24 to 1.73 OD units in the Madagascar study and from 0.15 to 0.55 OD units in the Malawi study. For each antibody, the highest detectability value as measured by the area under the curve was obtained for anti-R11 in the Malawi study (0.838). In demonstrating such qualities, antibodies to Pf155/RESA epitopes could be used for screening poorly protected populations in which malaria control programs have to be implemented.

Amino Acid Sequence↗
PubMed1995

Sertraline treatment of comorbid posttraumatic stress disorder and alcohol dependence.

BACKGROUND: Posttraumatic stress disorder (PTSD) often co-occurs with alcohol dependence, yet little is known about treatment of this comorbidity. The serotonin selective reuptake inhibitors have been shown preliminarily to be effective in decreasing symptoms of PTSD but have not been studied in individuals with comorbid alcohol dependence. This is of particular interest as the SSRIs also have a modest effect in decreasing alcohol consumption. METHOD: In this preliminary trial, nine subjects with comorbid PTSD and alcohol dependence were treated in an open-label trial with sertraline for a 12-week period. Symptoms of PTSD and depression were monitored monthly with the Impact of Event Scale and the Hamilton Rating Scale for Depression (HAM-D). Alcohol consumption was monitored by a self-report instrument (Time-Line Follow-Back). RESULTS: There were significant decreases in all three symptom clusters of PTSD measured by overall PTSD symptom scores (p < or = .001) and in HAM-D scores (p < or = .001) during the follow-up period. Days of abstinence increased and average number of drinks decreased during the follow-up period. Four subjects claimed total abstinence during the follow-up period. CONCLUSION: While limited by small sample size and the open-label, nonblinded study design, this study suggests that sertraline may be useful in the treatment of PTSD complicated by alcoholism. The medication was well tolerated and subjects showed improvement in PTSD symptoms as well as decreased alcohol consumption. A controlled trial of sertraline in this population would be of interest.

1-Naphthylamine↗
PubMed1994

Interleukin-2-mediated elimination of the p27Kip1 cyclin-dependent kinase inhibitor prevented by rapamycin.

The cyclin-dependent kinase (Cdk) enzymes, when associated with the G1 cyclins D and E, are rate-limiting for entry into the S phase of the cell cycle. During T-cell mitogenesis, antigen-receptor signalling promotes synthesis of cyclin E and its catalytic partner, Cdk2, and interleukin-2 (IL-2) signalling activates cyclin E/Cdk2 complexes. Rapamycin is a potent immunosuppressant which specifically inhibits G1-to-S-phase progression, leading to cell-cycle arrest in yeast and mammals. Here we report that IL-2 allows Cdk activation by causing the elimination of the Cdk inhibitor protein p27Kip1, and that this is prevented by rapamycin. By contrast, the Cdk inhibitor p21 is induced by IL-2 and this induction is blocked by rapamycin. Our results show that p27Kip1 governs Cdk activity during the transition from quiescence to S phase in T lymphocytes and that p21 function may be restricted to cycling cells.

Animals↗
PubMed1994

Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals.

We cloned p27Kip1, a cyclin-dependent kinase inhibitor implicated in G1 phase arrest by TGF beta and cell-cell contact. p27Kip1 associates with cyclin E-Cdk2 complexes in vivo and in vitro, prevents their activation, and inhibits previously activated complexes, and p27Kip1 overexpression obstructs cell entry into S phase. p27Kip1 potently inhibits Rb phosphorylation by cyclin E-Cdk2, cyclin A-Cdk2, and cyclin D2-Cdk4. p27Kip1 is highly conserved and broadly expressed in human tissues, and its mRNA levels are similar in proliferating and quiescent cells. p27Kip1 has a region of sequence similarity to p21Cip1/WAF1, the Cdk inhibitor whose transcription is stimulated by p53. A p27Kip1 peptide corresponding to this region retains Cdk inhibitory activity. We suggest that cell contact, TGF beta, and p53 all restrain cell proliferation through related Cdk inhibitors.

Amino Acid Sequence↗
PubMed1994

Plasma cellular fibronectin as a measure of endothelial involvement in preeclampsia and intrauterine growth retardation.

OBJECTIVE: Our purpose was to determine the presence and degree of endothelial injury, by measuring plasma concentrations of cellular fibronectin, in pregnancies complicated by preeclampsia or intrauterine growth retardation. STUDY DESIGN: A matched, nested, case-control study design was used. Plasma was collected prospectively from pregnant women throughout gestation. At least 12 weeks after delivery women with preeclampsia, both preeclampsia and intrauterine growth retardation, or intrauterine growth retardation alone were identified. Normal controls were matched to these patients by age, race, and gestational age. Stored plasma, which had been obtained in the third trimester, was assayed for cellular fibronectin by means of a sensitive and specific enzyme immunoassay. After an appropriate transformation of the data results were compared with one-way analysis of variance with Fisher's post hoc test. RESULTS: Patients with preeclampsia (n = 18) had higher plasma cellular fibronectin concentrations than did control patients (n = 68) with median values of 2.8 and 1.4 micrograms/ml, respectively (p < 0.001, using transformed data). Patients with intrauterine growth retardation alone (n = 10) had 2.3 micrograms/ml cellular fibronectin, significantly higher than values of controls (p < 0.02 using transformed data) and significantly lower than those of patients with preeclampsia (p < 0.05 using transformed data). CONCLUSION: Pregnancies complicated by preeclampsia had significantly higher plasma cellular fibronectin concentrations than did pregnancies with intrauterine growth retardation alone, which in turn had significantly higher plasma cellular fibronectin concentrations than did control pregnancies. We speculate that endothelial involvement in intrauterine growth retardation is confined to the uteroplacental circulation, whereas it is systemic in preeclampsia.

Adult↗
PubMed1994

p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest.

Cell-cell contact and TGF-beta can arrest the cell cycle in G1. Mv1Lu mink epithelial cells arrested by either mechanism are incapable of assembling active complexes containing the G1 cyclin, cyclin E, and its catalytic subunit, Cdk2. These growth inhibitory signals block Cdk2 activation by raising the threshold level of cyclin E necessary to activate Cdk2. In arrested cells the threshold is set higher than physiological cyclin E levels and is determined by an inhibitor that binds to cyclin E-Cdk2 complexes. A 27-kD protein that binds to and prevents the activation of cyclin E-Cdk2 complexes can be purified from arrested cells but not from proliferating cells, using cyclin E-Cdk2 affinity chromatography. p27 is present in proliferating cells, but it is sequestered and unavailable to interact with cyclin E-Cdk2 complexes. Cyclin D2-Cdk4 complexes bind competitively to and down-regulate the activity of p27 and may thereby act in a pathway that reverses Cdk2 inhibition and enables G1 progression.

Animals↗
PubMed1994

Reduced susceptibility of Anopheles gambiae to permethrin associated with the use of permethrin-impregnated bednets and curtains in Kenya.

Susceptibility of the malaria vector Anopheles gambiae to permethrin decreased following the installation of mosquito nets impregnated with 0.5 g permethrin per square metre in four villages near Kisumu, Kenya. During the first year that permethrin-impregnated bednets and curtains were in place, the exposure time to 50% mortality (LT50) increased 2.5-fold from 13 to 33 min, while the LT50 for An.gambiae was unchanged in two other villages where no intervention measures were used. Two years after permethrin-impregnated mosquito nets were distributed the LT50s for An.gambiae were 28, 28 and 16 min, respectively, in the villages with bednets, curtains and with no such intervention. Using a colony of An.gambiae derived from females collected in the villages using permethrin-impregnated mosquito nets, we lengthened the LT50 from 28 to 41 min in two generations by exposing all females to permethrin-treated papers for 60 min and rearing offspring of the survivors. Permethrin-impregnated bednets and curtains are intended to reduce vectorial capacity. Reduced susceptibility to permethrin could counter this beneficial effect.

Animals↗
PubMed1994

Inactivation of a Cdk2 inhibitor during interleukin 2-induced proliferation of human T lymphocytes.

Peripheral blood T lymphocytes require two sequential mitogenic signals to reenter the cell cycle from their natural, quiescent state. One signal is provided by stimulation of the T-cell antigen receptor, and this induces the synthesis of both cyclins and cyclin-dependent kinases (CDKs) that are necessary for progression through G1. Antigen receptor stimulation alone, however, is insufficient to promote activation of G1 cyclin-Cdk2 complexes. This is because quiescent lymphocytes contain an inhibitor of Cdk2 that binds directly to this kinase and prevents its activation by cyclins. The second mitogenic signal, which can be provided by the cytokine interleukin 2, leads to inactivation of this inhibitor, thereby allowing Cdk2 activation and progression into S phase. Enrichment of the Cdk2 inhibitor from G1 lymphocytes by cyclin-CDK affinity chromatography indicates that it may be p27Kip1. These observations show how sequentially acting mitogenic signals can combine to promote activation of cell cycle proteins and thereby cause cell proliferation to start. CDK inhibitors have been shown previously to be induced by signals that negatively regulate cell proliferation. Our new observations show that similar proteins are down-regulated by positively acting signals, such as interleukin 2. This finding suggests that both positive and negative growth signals converge on common targets which are regulators of G1 cyclin-CDK complexes. Inactivation of G1 cyclin-CDK inhibitors by mitogenic growth factors may be one biochemical pathway underlying cell cycle commitment at the restriction point in G1.

Adult↗