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Biomedical subjects

J M Roberts

Publications and source records attributed to J M Roberts.

At least 163 records · Page 9Linked to original sources
PubMed1996

Malaria parasite infection during pregnancy and at delivery in mother, placenta, and newborn: efficacy of chloroquine and mefloquine in rural Malawi.

Despite international recommendations to use malaria treatment and prevention in pregnant women in malaria-endemic areas, few studies have evaluated the efficacy of available antimalarial regimens. This issue is of particular concern in the face of spreading chloroquine (CQ)-resistance of Plasmodium falciparum in malarious areas of sub-Saharan Africa. In a prospective trial in rural Malawian pregnant women, we examined three regimens using CQ (including the existing national policy regimen) and one regimen using mefloquine (MQ). The efficacy of the regimens was determined by comparing rates of clearance of initial parasitemia; prevention of breakthrough infection; and parasitemia at delivery in maternal peripheral blood, placental blood, and in infant umbilical cord blood. Among 1,528 parasitemic women at enrollment, 281 (18.4%) had persistent infections; and among 1,852 initially aparasitemic women, 320 (17.3%) had breakthrough parasitemia on one or more follow-up visits. Compared with women on MQ, women on a CQ regimen were at significantly greater risk of persistent and breakthrough infection (odds ratios [OR] = 30.9 and 11.1, respectively, P < 10(-6)). Other significant risk factors for persistent and breakthrough infections in a multivariate model included first pregnancy; enrollment in the rainy or postrainy season; maternal age < or = 25 years; seropositivity to the human immunodeficiency virus (HIV) (persistent infections only); and no use of antimalarial prophylaxis before enrollment (breakthrough infections only). At delivery, compared with women on MQ, women on a CQ regimen were at significantly greater risk of peripheral, placental, or umbilical cord blood parasitemia (OR = 8.7, 7.4, and 4.1, respectively, P < 10(-6)). Additional risk factors for parasitemia at delivery in multivariate models included first pregnancy; delivery in the rainy or postrainy season; HIV-seropositivity; and maternal age < or = 25 years (risk for peripheral and placental blood parasitemia only). Maternal anemia (hematocrit < 30%) at enrollment or at delivery was not associated with persistent or breakthrough parasitemia or parasitemia at deliver in these multivariate models. While factors leading to increased malaria parasite exposure (high transmission seasons) and lowered or altered host immune response (low pregnancy number, young age, and HIV infection) are important risk factors for malaria in pregnant women, the use of an ineffective intervention (CQ in a setting with CQ-resistant parasites) was the most important determinant of P. falciparum parasitemia in these pregnant women. Strategies to reduce the impact of malaria in pregnant women must use efficacious interventions and may need to consider targeting the intervention to the most susceptible women during the seasons of high malaria exposure.

Adolescent↗
PubMed1995

Preeclampsia: not simply pregnancy-induced hypertension.

Once classified as a seizure disorder and later as a hypertensive condition, preeclampsia is actually a multisystem disease. It remains a leading cause of maternal and neonatal morbidity. Clinical challenges include identifying patients who are at risk of serious complications and deciding whether it is safer for the fetus to be delivered or to remain in the uterus.

Adolescent↗
PubMed1995

Malaria surveillance--United States, 1992.

PROBLEM/CONDITION: Malaria is caused by one of four species of Plasmodium (i.e., P. falciparum, P. vivax, P. ovale, or P. malariae) and is transmitted by the bite of an infective female Anopheles sp. mosquito. Most malaria cases in the United States occur among persons who have traveled to areas that have ongoing transmission. However, cases are transmitted occasionally through exposure to infected blood products, by congenital transmission, or by local mosquito-borne transmission. Malaria surveillance is conducted to identify episodes of local transmission and to guide prevention recommendations. REPORTING PERIOD COVERED: Cases with onset of illness during 1992. DESCRIPTION OF SYSTEM: Malaria cases were identified at the local level (i.e., by healthcare providers or through laboratory-based surveillance). All suspected cases were confirmed by slide diagnosis and then reported to the respective state health department and to CDC. RESULTS: CDC received reports of 910 cases of malaria that had onset of symptoms during 1992 among persons in the United States and its territories. In comparison, 1,046 cases were reported for 1991, representing a decrease of 13% in 1992. P. vivax, P. falciparum, P. malariae, and P. ovale were identified in 51%, 33%, 4%, and 3% of cases, respectively. The species was not identified in the remaining 9% of cases. The number of reported malaria cases that had been acquired in Africa by U.S. civilians decreased 38%, primarily because the number of P. falciparum cases declined. Of U.S. civilians whose illnesses were diagnosed as malaria, 81% had not taken a chemoprophylactic regimen recommended by CDC. Seven patients had acquired their infections in the United States. Seven deaths were attributed to malaria. INTERPRETATION: The decrease in the number of P. falciparum cases in U.S. civilians could have resulted from a change in travel patterns, reporting errors, or increased use of more effective chemoprophylaxis regimens. ACTIONS TAKEN: Additional information was obtained concerning the seven fatal cases and the seven cases acquired in the United States. Malaria prevention guidelines were updated and disseminated to health-care providers. Persons traveling to a malaria-endemic area should take the recommended chemoprophylaxis regimen and use personal protection measures to prevent mosquito bites. Any person who has been to a malarious area and who subsequently develops a fever or influenza-like symptoms should seek medical care, which should include a blood smear for malaria. The disease can be fatal if not diagnosed and treated at an early stage of infection. Recommendations concerning prevention and treatment of malaria can be obtained from CDC.

Female↗
PubMed1995

TEL and KIP1 define the smallest region of deletions on 12p13 in hematopoietic malignancies.

Unbalanced translocations as well as interstitial deletions of the short arm of chromosome 12 [del(12p)] are found as recurring chromosomal changes in a broad spectrum of hematopoietic malignancies. These changes result in the hemizygous deletion of genetic material from 12p. We mapped a yeast artificial chromosome containing the TEL gene, a cosmid contig containing part of TEL and a P1 contig containing the KIP1 gene to 12p13. These probes were used for fluorescence in situ hybridization to analyze samples from 47 patients with various hematologic malignancies who had unbalanced translocations (25 patients) leading to loss of 12p or deletions (22 patients) involving 12p13. The patients had acute lymphoblastic leukemia (8 cases), myelodysplastic syndrome (MDS; 11 cases), acute myeloid leukemia (AML; 10 cases), myeloproliferative disorders (4 cases), therapy-related MDS or AML (7 cases), non-Hodgkin's lymphoma (2 cases), and other hematopoietic malignancies (5 cases). All three probes were hemizygously detected in 26 cases and were completely retained in only 9 cases. In 12 cases probes for one of the two genes were deleted, allowing us to map the smallest region of overlap of these deletions to a small genomic region that is bordered on the telomeric side by the TEL gene and on the centromeric side by KIP1. The genomic distance between TEL and KIP1 is estimated to be about 1 to 2 Mbp.

Adolescent↗
PubMed1995

Assignment of the human p27Kip1 gene to 12p13 and its analysis in leukemias.

The p27Kip1 (p27) gene encodes an inducible inhibitor of cyclin-dependent kinase activity. Using a murine p27 cDNA as probe, we obtained a human cDNA clone and subsequently used it to isolate a genomic clone of this gene. The coding region of the human p27 gene was contained in two exons. Both the amino acid sequence and intron-exon organization of p27 were similar to those previously found for the related cyclin-dependent kinase inhibitor p21Waf1 (p21). The p27 gene was localized to chromosome band 12p13 by a combination of somatic cell hybrid and fluorescence in situ hybridization analyses. The p27 gene product is thought to control the leukocyte cell cycle and the 12p13 chromosomal band is known to be deleted in leukemias, suggesting that the p27 gene may act as a tumor suppressor gene in leukemias. Although p27 was found to reside in the minimal region of chromosomal loss in hematological malignancies, no mutations of p27 were observed in leukemia samples. Haploinsufficiency of p27 may confer a growth advantage to leukemia cells.

Base Sequence↗
PubMed1995

Plasma from preeclamptic women increases human endothelial cell prostacyclin production without changes in cellular enzyme activity or mass.

OBJECTIVE: We investigated differences in prostacyclin production by endothelial cells exposed to plasma from either preeclamptic women or normal pregnant women. STUDY DESIGN: A case-control study of matched preeclamptic and normal pregnancies was used to compare prostacyclin synthesis by human umbilical vein endothelial cells incubated with pregnancy plasma for 24 hours. Prostacyclin concentrations in conditioned media were measured by radioimmunoassay of its stable metabolite (6-keto-prostaglandin F1 alpha). Human umbilical vein endothelial cell lysates were used to determine concentrations of the enzymes cyclooxygenase and prostacyclin synthase. RESULTS: Prostacyclin production by human umbilical vein endothelial cells incubated with plasma from preeclamptic women was significantly greater than that by cells exposed to normal pregnancy plasma. Differences in prostacyclin production under the two experimental conditions could be explained neither by differences in enzyme mass nor activities of cyclooxygenase and prostacyclin synthase. CONCLUSION: The stimulatory effect of preeclampsia plasma on prostacyclin biosynthesis in human umbilical vein endothelial cells appears to be manifested at a step(s) proximal to the activation of cyclooxygenase. Possible mechanisms are increased phospholipase A2, lipoprotein, or lipid peroxide activities in preeclampsia.

Case-Control Studies↗
PubMed1995

Mitogenic effect of basic fibroblast growth factor and estradiol on cultured human myometrial and leiomyoma cells.

OBJECTIVE: We compared the mitogenic effect of basic fibroblast growth factor with and without estradiol on myometrial and leiomyometrial cells. STUDY DESIGN: The mitogenic effect of basic fibroblast growth factor on myometrial cells was measured by thymidine incorporation and cell count. The mitogenic effect of basic fibroblast growth factor with and without estradiol as measured by thymidine incorporation was compared between myometrial and leiomyometrial cells. RESULTS: Both human myometrial and leiomyometrial cells showed significant (p = 0.004 and p = 0.001, respectively), dose-dependent incorporation of thymidine in response to basic fibroblast growth factor. Leiomyometrial cells showed significantly (p = 0.04) less thymidine incorporation compared with matched normal myometrial cells. The addition of estradiol with basic fibroblast growth factor did not result in a further increase in thymidine incorporation. CONCLUSIONS: Both myometrial and leiomyometrial cells respond to basic fibroblast growth factor with increased thymidine incorporation; however leiomyometrial cells are less responsive than are matched normal myometrial cells. The addition of estradiol is not synergistic with basic fibroblast growth factor.

Adult↗
PubMed1995

Elevated serum levels of vascular endothelial growth factor in patients with preeclampsia.

OBJECTIVE: To determine whether altered levels of vascular endothelial growth factor (VEGF) may be implicated in the pathogenesis of preeclampsia, and whether VEGF mediates the endothelial cell activation that is involved in the pathogenesis of the clinical syndrome. METHODS: In a cross-sectional study, maternal serum samples in late pregnancy (at the time of clinical disease) were collected from 78 nulliparous women. These subjects were subdivided into those with preeclampsia (n = 27), nonproteinuric pregnancy-induced hypertension (n = 15), and normal pregnant women (n = 36). In a nested case-control study, in addition to samples taken before delivery, samples were obtained in early pregnancy (before clinical disease) and 24-48 hours postpartum from 12 of the patients with preeclampsia, 12 of those with nonproteinuric pregnancy-induced hypertension, and 12 of the normal pregnant subjects. Umbilical cord blood was sampled from 14 of the preeclamptic and 16 of the normal pregnant subjects. We measured VEGF levels in all samples using an immunofluorometric assay. RESULTS: In most samples collected before delivery, VEGF levels were below the lower limit of detection. However, the proportion of detectable levels was higher in the preeclampsia group (seven of 27) than in the normotensive group (one of 36, P < .05). The proportion in the nonproteinuric pregnancy-induced hypertension group (two of 15) did not differ significantly from the other groups. Levels in the patients with preeclampsia were not elevated before clinical disease. Levels of VEGF in umbilical blood samples were higher than in maternal venous blood, although there were no significant differences between groups. CONCLUSION: Serum VEGF levels were elevated in patients with preeclampsia, which suggests that the growth factor has a role in the endothelial cell activation that occurs in the disease.

Adult↗
PubMed1995

Human cyclin E, a nuclear protein essential for the G1-to-S phase transition.

Cyclin E was first identified by screening human cDNA libraries for genes that would complement G1 cyclin mutations in Saccharomyces cerevisiae and has subsequently been found to have specific biochemical and physiological properties that are consistent with it performing a G1 function in mammalian cells. Most significantly, the cyclin E-Cdk2 complex is maximally active at the G1/S transition, and overexpression of cyclin E decreases the time it takes the cell to complete G1 and enter S phase. We have now found that mammalian cells express two forms of cyclin E protein which differ from each other by the presence or absence of a 15-amino-acid amino-terminal domain. These proteins are encoded by alternatively spliced mRNAs and are localized to the nucleus during late G1 and early S phase. Fibroblasts engineered to constitutively overexpress either form of cyclin E showed elevated cyclin E-dependent kinase activity and a shortened G1 phase of the cell cycle. The overexpressed cyclin E protein was detected in the nucleus during all cell cycle phases, including G0. Although the cyclin E protein could be overexpressed in quiescent cells, the cyclin E-Cdk2 complex was inactive. It was not activated until 6 to 8 h after readdition of serum, 4 h earlier than the endogenous cyclin E-Cdk2. This premature activation of cyclin E-Cdk2 was consistent with the extent of G1 shortening caused by cyclin E overexpression. Microinjection of affinity-purified anti-cyclin E antibodies during G1 inhibited entry into S phase, whereas microinjection performed near the G1/S transition was ineffective. These results demonstrate that cyclin E is necessary for entry into S phase. Moreover, we found that cyclin E, in contrast to cyclin D1, was required for the G1/S transition even in cells lacking retinoblastoma protein function. Therefore, cyclins E and D1 control two different transitions within the human cell cycle.

Alternative Splicing↗
PubMed1995

Human endothelial cell morphology and autacoid expression.

Human umbilical vein endothelial (HUVE) cells plated on plastic or gelatin-coated dishes grow as a "cobblestone" monolayer. By contrast, endothelial cells cultured on a complex matrix (e.g., Matrigel) form three-dimensional, capillary-like structures. In the current study, we verified the capillary phenotype of the latter structures and asked whether the morphological changes induced by extracellular matrix also affect human endothelial gene expression and function in vitro. Concentrations of cellular fibronectin, prostacyclin, and endothelin-1 were measured in the conditioned media by enzyme-linked immunosorbent and radioimmunoassays. Steady-state concentrations of HUVE mRNA were estimated by reverse transcription-polymerase chain reaction and quantified by Northern analyses to assess fibronectin and endothelin-1 gene expression. We found that the subjacent extracellular matrix affects the morphology, proliferation, and differentiation of HUVE cells in vitro. Cells cultured on gelatin were more mitotically active, expressed significantly less cellular fibronectin, made similar amounts of prostacyclin, and secreted significantly more endothelin-1 compared with the same cells grown on a Matrigel substrate.

Autacoids↗
PubMed1995

NOS expression is increased in endothelial cells exposed to plasma from women with preeclampsia.

Endothelial cell function is proposed to be altered by a factor(s) in the maternal circulation of women with the pregnancy disorder preeclampsia. Our initial hypothesis was that in preeclampsia, such factor(s) would reduce synthesis of nitric oxide (NO) by endothelial cells. However, we previously observed increased NO synthase activity in endothelial cells exposed to plasma from preeclamptic women. This study tested whether exposing cells to plasma from preeclamptic women increased transcription and/or translation of endothelial NO synthase. Cultured bovine coronary microvascular endothelial cells were exposed to 2% plasma from patients with preeclampsia and patients with uncomplicated pregnancies. Nitrite production was greater in endothelial cells exposed to plasma from preeclamptic women (8.97 +/- 0.54 vs. 6.39 +/- 0.59 nmol nitrites.10(6) cells-1 x 24 h-1; P < 0.05). Similarly, endothelial NO synthase mass as measured by Western immunoblotting was significantly increased (20,980 +/- 1,406 vs. 15,047 +/- 1,003 absorbancy units; P < 0.02). There was no detectable difference in mRNA for endothelial NO synthase. However, actinomycin (3 micrograms/ml), a transcription inhibitor, significantly decreased nitrite production only in cells exposed to plasma from preeclamptic women (5.28 +/- 0.52 vs. 3.56 +/- 0.36 nmol.10(6) cells-1 x 24 h-1, P < 0.05). These findings indicate a regulation of the "constitutive" isoform of NO synthase by factor(s) in the blood of preeclamptic women, which may have significance in this pathological condition of pregnancy.

Adult↗