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Biomedical subjects

M A Williams

Publications and source records attributed to M A Williams.

At least 19 recordsLinked to original sources
PubMed2007

Association of gestational diabetes mellitus and low-density lipoprotein (LDL) particle size.

A predominance of small, dense low-density lipoproteins (LDL) is characteristic of the dyslipidemic state seen in type 2 diabetes. However, no study has investigated the association in gestational diabetes mellitus (GDM), which is pathophysiologically similar to type 2 diabetes. We hypothesized that LDL particle size is reduced in GDM cases compared with controls. Gradient gel electrophoresis was used to characterize LDL subclass phenotypes in non-fasting intrapartum plasma from 105 GDM cases and 96 controls. All participants were free of pre-existing diabetes or hypertension. The authors used logistic regression to estimate odds ratios (OR) and 95 % confidence intervals (CI) adjusted for confounders. Women with this phenotype had a significant 4.9-fold (95 % CI: 1.1-23.2) increased risk of GDM compared with those with the large, buoyant phenotype. The magnitude of this association was attenuated when plasma triglyceride and other confounders were included in the model (OR=4.2, 95 % CI: 0.5-39.5). Mean LDL particle size in GDM cases was smaller compared with controls (270.1 vs. 272.7A, p=0.003). The OR of GDM risk was 1.8 (95 % CI: 0.9-3.3) for every 10-A reduction in LDL particle size. Large prospective studies are needed to evaluate the association between smaller LDL particle size in early pregnancy with subsequent GDM risk.

Adult↗
PubMed2007

Ankyloblepharon filiforme adnatum.

Two cases of a rare congenital eyelid abnormality, ankyloblepharon filiforme adnatum, are presented, and novel aspects of treatment, associations and classification are discussed.

Abnormalities, Multiple↗
PubMed2006

Neurologic prognosis and withdrawal of life support after resuscitation from cardiac arrest.

OBJECTIVE: To study the impact of neurologic prognostication on the decision to withdraw life-sustaining therapies (LST) in comatose patients resuscitated after cardiac arrest. METHODS: The authors prospectively studied a consecutive series of post-resuscitation comatose patients referred for neurologic prognostication at a single center for 4 years. For most patients, neurologic prognostication was not sought due to early death or rapid return to consciousness. Prognostication was based on Glasgow Coma Score (GCS) and Brainstem Reflex Score (BRS), with EEG and cortical evoked potentials (CEP), which were graded as benign, uncertain, and malignant. The outcomes were as follows: survivors (Group S), brain or cardiac death (Group D), and death from withdrawal of life sustaining therapy (Group W). In Group W, the time interval to withdrawal of LST was analyzed by EEG and CEP grades. RESULTS: Of 58 patients studied, 10 were in Group S, 8 in Group D, and 40 in Group W. Initial median GCS and BRS was similar for all groups with significant improvement noted in Group S, but not in Group D or Group W. In Group W, CEP grade correlated with the median duration of continued therapy before a decision to withdraw LST: 7 days for benign CEP, 2 days for uncertain CEP, and 1 day for malignant CEP, p = 0.0004. CONCLUSION: In patients with poor neurologic recovery early after resuscitation from cardiac arrest, physicians appear to use the cortical evoked potential grade to estimate prognosis. Cortical evoked potential grade correlated with the waiting time until life sustaining therapies were withdrawn after no improvement in neurologic examination was seen.

Adult↗
PubMed2006

Cardiovascular monkey telemetry: sensitivity to detect QT interval prolongation.

INTRODUCTION: Preclinical evaluation of delayed ventricular repolarization manifests electrocardiographically as QT interval prolongation and is routinely used as an indicator of potential risk for pro-arrhythmia (potential to cause Torsades de Pointes) of novel human pharmaceuticals. In accordance with ICH S7A and S7B guidelines we evaluated the sensitivity and validity of the monkey telemetry model as a preclinical predictor of QT interval prolongation in humans. METHODS: Cardiovascular monitoring was conducted for 2 h pre-dose and 24 h post-dosing with Moxifloxacin (MOX), with a toxicokinetic (TK) evaluation in a separate group of monkeys. In both studies, MOX was administered orally by gavage in 0.5% methylcellulose at 0, 10, 30, 100, 175 mg/kg. Each monkey received all 5 doses using a dose-escalation paradigm. Inherent variability of the model was assessed with administration of vehicle alone for 4 days in all 4 monkeys (0.5% methylcellulose in deionized water). RESULTS: MOX had no significant effect on mean arterial pressure, heart rate, PR or QRS intervals. MOX produced significant dose-related increases in QTc at doses of 30 (Cmax=5.5+/-0.6 microM), 100 (Cmax=16.5+/-1.6 microM), and 175 (Cmax=17.3+/-0.7 microM) mg/kg with peak increases of 22 (8%), 27 (10%), and 47 (18%) ms, respectively (p<or=0.05; compared to vehicle). DISCUSSION: In conclusion, we have developed a reproducible, sensitive and reliable primate telemetry model in rhesus monkeys, which exhibits low inherent intra-animal variability and high sensitivity to detect small but significant increases in QT/QTc interval (approximately 4%) with MOX in the same range of therapeutic plasma concentrations attained in humans. Therefore, the primate telemetry model should be considered an important preclinical predictor of QT prolongation of novel human pharmaceuticals.

Algorithms↗
PubMed2006

Erythrocyte omega-3, omega-6 and trans fatty acids in relation to risk of preeclampsia among women delivering at Harare Maternity Hospital, Zimbabwe.

We sought to examine the association between maternal erythrocyte omega-3, omega-6 and trans fatty acids and risk of preeclampsia. We conducted a case-control study of 170 women with proteinuric, pregnancy-induced hypertension and 185 normotensive pregnant women who delivered at Harare Maternity Hospital, Harare, Zimbabwe. We measured erythrocyte omega-3, omega-6 and trans fatty acid as the percentage of total fatty acids using gas chromatography. After multivariate adjustment for confounding factors, women in the highest quartile group for total omega-3 fatty acids compared with women in the lowest quartile experienced a 14% reduction in risk of preeclampsia (odds ratio 0.86, 95% confidence interval 0.45 to 1.63). For total omega-6 fatty acids the odds ratio was 0.46 (95% confidence interval 0.23 to 0.92), although there was suggestion of a slight increase in risk of preeclampsia associated with high levels of arachidonic acid. Among women in the highest quartile for arachidonic acid the odds ratio was 1.29 (95% confidence interval 0.66 to 2.54). A strong statistically significant positive association of diunsaturated fatty acids with a trans double bond with risk of preeclampsia was observed. Women in the upper quartile of 9-cis 12-trans octadecanoic acid (C(18:2n6ct)) compared with those in the lowest quartile experienced a 3-fold higher risk of preeclampsia (odds ratio = 3.02, 95% confidence interval 1.41 to 6.45). Among women in the highest quartile for 9-trans 12-cis octadecanoic acid (C(18:2n6tc)) the odds ratio was 3.32 (95% confidence interval 1.55 to 7.13). Monounsaturated trans fatty acids were also positively associated with the risk of preeclampsia, although of much reduced magnitude. We observed a strong positive association of trans fatty acids, particularly diunsaturated trans fatty acids, with the risk of preeclampsia. We found little support for the hypothesized inverse association between omega-3 fatty acids and preeclampsia risk in this population. Polyunsaturated fatty acids, particularly omega-3 fatty acids, were comparatively lower in Zimbabwean than among US pregnant women. Given the limited inter-person variation in omega-3 fatty acids among Zimbabwean women, our sample size may be too small to adequately assess the relation in this population.

Adult↗
PubMed2006

Functional variants of the lipoprotein lipase gene and the risk of preeclampsia among non-Hispanic Caucasian women.

Hypertriglyceridemia is an important pathophysiologic feature of preeclampsia, a common vascular disorder of pregnancy. Three well-documented functional variants (N291S, S447X, and D9N) of the lipoprotein lipase gene were related to hypertriglyceridemia. Results from the only two studies concerning the relationship between these variants and preeclampsia risk have been inconsistent. We investigated this relationship in a case-control study including 144 preeclamptic and 290 normotensive pregnant women (all non-Hispanic Caucasians). We estimated odds ratios (OR) and 95% confidence intervals (CI) adjusted for maternal age, pre-pregnancy body mass index, and parity. After adjusting for covariates, women with the 291 N/S or S/S genotype had significantly increased risk of preeclampsia (OR 6.9, 95% CI 1.9-25.4) compared with women with the common 291N/N genotype. The 447 S/X or X/X genotype was not significantly associated with preeclampsia risk. The frequency of the 9N variant allele was 1.8% in controls, while this allele was not observed among cases. Haplotype 9D/291S/447S was strongly associated with higher risk of preeclampsia as compared with the most common haplotype 9D/291N/447S (adjusted OR 6.6, 95% CI 1.7-25.0). Results from our study support the thesis that abnormal lipid metabolism is important in the pathogenesis of preeclampsia.

Adult↗
PubMed2006

Prevalence and correlates of migraine among women attending a prenatal care clinic in Lima, Peru.

Migraine headaches are among the leading causes of disability in the world. The burden of migraines is highest in women of reproductive age. This cross-sectional study characterized the prevalence, symptoms and correlates of migrainous headaches in 154 pregnant women attending a prenatal care clinic in Lima, Peru. Lifetime prevalence of migraine defined by modified IHS criteria was 9.1% (95% CI 4.6-13.6). When probable migraines were included, the lifetime prevalence of migraine in this population was 29.2% (95% CI 22.0-36.4). Migraine headaches were associated with a maternal history of headache, childhood carsickness, a diagnosis of allergies, and a high frequency of fatigue. Although headache-related disability was low in terms of missed work and recreation, high rates of headache pain and medicinal use reflect the true impact on this population.

Adolescent↗
PubMed2006

A morphometric study on the endometrium of rat uterus in hypothyroid and thyroxine treated hypothyroid rats.

Hypothyroidism increases the rate of pregnancy loss. Other manifestations include menstrual disorder, and infertility. Serum levels of gonadotropins are low in hypothyroid patients. Though studies of uterine ultrastructure are well established as approaches to investigating the pathophysiology of infertility, they have scarcely been extended to the study of hypothyroid related infertility. The present study investigates the effect of hypothyroidism on the ultrastructure of uterine epithelium. Three groups of Wistar rats were studied. Two groups were initially made hypothyroid using methimazole, and the third group was an untreated control. One hypothyroid group was given daily injections of thyroxine for six weeks. The uteri were removed in all three groups, and processed for transmission electron microscopy and morphometry. It was found that absolute epithelial cell volume was decreased in hypothyroidism. The volume of the nucleus had decreased though its relative volume in the cell had increased. The height of the luminal epithelium in hypothyroid rats also decreased by (33.8%) as compared with controls. Basement membrane thickness was significantly increased in hypothyroidism. The changes were all substantially abrogated by the administration of thyroxine. This study suggests that thyroid hormones might be importantly concerned in the maintenance of the normal structure of uterine epithelial cells.

Animals↗
PubMed2005

Oxidized low-density lipoprotein (Oxidized LDL) and the risk of preeclampsia.

Oxidative stress plays an important role in the pathophysiology of preeclampsia. In a case-control study of 99 women with preeclampsia and 99 controls, we assessed maternal plasma oxidized low-density lipoprotein (oxidized LDL) in relation to preeclampsia risk. Logistic regression procedures were used to derive odds ratios (OR) and 95 % confidence intervals (CI). Plasma oxidized LDL was determined using enzyme immunoassay. Maternal plasma oxidized LDL was significantly positively correlated with lipids in both cases and controls. After adjusting for nulliparity, pre-pregnancy body mass index, physical inactivity, family history of chronic hypertension and plasma vitamin C concentrations, women who had elevated oxidized LDL concentrations ( > or = 50 U/l) experienced a 2.9-fold increased risk of preeclampsia when compared with women having lower oxidized LDL concentrations (95 % CI 1.4-5.9). The risk of preeclampsia was markedly increased in women who had both elevated oxidized LDL and elevated triglyceride concentrations (OR=8.9, 95 % CI 3.1-26.2). Women with both elevated oxidized LDL and low vitamin C concentrations experienced a 9.8-fold increased risk of preeclampsia (95 % CI 3.0-32.2). Our results confirm the role of oxidative stress in the pathogenesis of preeclampsia. Prospective studies are needed to determine if elevated oxidized LDL concentrations can predict the occurrence of preeclampsia.

Adolescent↗
PubMed2005

Changes in placental adipocytokine gene expression associated with gestational diabetes mellitus.

Leptin and adiponectin, two adipocytokines, may work together in regulating energy homeostasis and insulin action. Leptin gene expression has been investigated in term placental tissue complicated by gestational diabetes mellitus (GDM), but never in conjunction with all isoforms of the leptin receptor (LEPR A-D), or with adiponectin receptors (ADIPOR1 and 2). In this study we examined the association between changes in expression of these genes in placental tissue and GDM risk. We assessed placental gene expression of leptin, LEPR A-D and ADIPOR1 and 2 by real time PCR using mRNA from maternal and fetal biopsies. Tissues were collected from uncomplicated pregnancies (n=28) and those complicated by GDM (n=19). Gene expression was normalized to three endogenous housekeeping genes. Relative gene expression values were reported as fold change between groups. Adiponectin gene expression was out of the sensitive range of our assay. There were increases in leptin mRNA expression in GDM cases compared with controls for maternal-side (p=0.06), and fetal-side (p=0.09) placental biopsies. No significant changes were seen in GDM cases compared with controls in LEPR A-D or ADIPOR1 and 2. mRNA derived from maternal-side tissue was positively correlated with tissue from the fetal side for all genes studied (all p<0.01). Finally, we noted that absence or presence of GDM was a major factor in leptin mRNA expression after adjusting for maternal age, mode of delivery, parity and smoking status. In conclusion, increases in leptin mRNA expression in term placenta, but not that of its receptors, are associated with the diagnosis of GDM. Changes seen in the ligand, but not the receptor, of the leptin pathway in GDM-complicated pregnancies may also apply to the adiponectin pathway, as the ADIPOR1 and 2 mRNAs do not change with GDM diagnosis.

Adult↗
PubMed2005

Maternal plasma VEGF, sVEGF-R1, and PlGF concentrations in preeclamptic and normotensive pregnant Zimbabwean women.

Vascular endothelial growth factor (VEGF), a disulphide-linked homodimeric glycoprotein that is selectively mitogenic for endothelial cells, plays an important role in vasculogenesis and angiogenesis. Preeclampsia, a relatively common complication of pregnancy that is characterized by diffuse endothelial dysfunction possibly secondary to impaired trophoblast invasion of the spiral arteries during implantation, has recently been associated with alterations in maternal serum/plasma concentrations of VEGF, and other related growth factors and their receptors. We examined the relationship of maternal plasma VEGF, sVEGF-R1 and PlGF levels to the risk of preeclampsia among women delivering at Harare Maternity Hospital, Zimbabwe. 131 pregnant women with preeclampsia and 175 controls were included in a case-control study. Maternal plasma concentrations of each biomarker were measured using enzymatic methods. We used logistic regression to calculate odds ratios (OR) and 95 % confidence intervals (CI). Preeclampsia risk was inversely related with quartiles of plasma VEGF (OR: 1.0, 1.0, 0.7, and 0.5, with the lowest quartile as reference; p for trend=0.06). We noted a strong positive association between preeclampsia risk and sVEGF-R1 concentrations (OR: 1.0, 6.5, 9.7, 31.6, with the first quartile as the referent group; p for trend<0.001). After adjusting for confounders, we noted that women with sVEGF-R1 concentrations in the highest quartile (>or=496 pg/ml), as compared with those in the lowest quartile (<62 pg/ml) had a 31.6-fold increased risk of preeclampsia (OR=31.6, 95 % CI 7.7-128.9). There was no clear evidence of a linear relation in risk of preeclampsia with PlGF concentrations. In conclusion, plasma VEGF, sVEGF-R1 and PlGF concentrations (measured at delivery) were altered among Zimbabwean women with preeclampsia as compared with normotensive women. Our results are consistent with some, though not all, previous reports. Prospective studies are needed to: 1) identify modifiable determinants of maternal plasma concentrations VEGF, sVEGF-R1, and PlGF; and 2) evaluate the temporal relationship between observed alterations of these biological markers in preeclamptic pregnancies.

Adult↗
PubMed2004

Maternal recreational physical activity is associated with plasma leptin concentrations in early pregnancy.

BACKGROUND: A limited amount of literature suggests that plasma leptin concentrations are reduced with habitual physical activity in men and non-pregnant women. We investigated the relationship between maternal physical activity and plasma leptin during early pregnancy. METHODS: The study population included 879 normotensive, non-diabetic pregnant women who reported physical activity type, frequency, and duration in early pregnancy. Plasma leptin, measured in blood samples collected <16 weeks gestation, were determined using enzyme immunoassays. Weekly duration (h/week) and energy expended on recreational physical activity [metabolic equivalent score (MET)-h/week] were categorized by tertiles among active women. Physical activity intensity was categorized as none, moderate (<6 MET) and vigorous (> or =6 MET). Differences in leptin concentrations across categories were estimated using linear regression procedures. RESULTS: Mean leptin was 5.8 ng/ml lower among active versus inactive women (P=0.001). Mean leptin was lower among women in the highest levels (>12.8 h/week) of time performing physical activity (-8.1 ng/ml, P<0.001) and energy expenditure (>70.4 MET-h/week) (-8.3 ng/ml, P=0.001) compared with inactive women. Leptin was inversely associated with the intensity of physical activity. CONCLUSIONS: Our findings are consistent with other reports suggesting an independent inverse relationship between habitual physical activity and leptin concentrations. Our findings extend the literature to include pregnant women.

Adult↗
PubMed2004

Leptin, soluble leptin receptor and leptin gene polymorphism in relation to preeclampsia risk.

Few investigators have simultaneously evaluated leptin, soluble leptin receptor (SLR) and leptin gene polymorphisms in preeclampsia cases and controls. We examined these three biomolecular markers in 40 preeclampsia cases and 39 controls. Plasma leptin and SLR concentrations were determined using immunoassays. Genotype for the tetranucleotide repeat (TTTC)(n), polymorphism in the 3 -flanking region of the leptin gene was determined using PCR. Alleles of the polymorphism were characterized by size distributions [short repeats (class I); and long repeats (class II)]. Logistic regression was used to calculate odds ratios (OR) and 95 % confidence intervals (CI). Leptin concentrations were higher in our cases than in the controls (53.1 4.7 vs. 17.7+/-2.4 ng/ml, p<0.05). SLR concentrations were slightly lower in our patients than in the controls (25.7+/-1.9 vs. 29.1+/-1.1 ng/ml, p>0.05). Elevated leptin (? 14.5 ng/ml) was associated with a 3.8-fold (CI 1.0-14.4) increased risk; whereas low SLR (< 28.5 ng/ml) was associated with a 6.3-fold (CI 1.7-23.2) increased risk of preeclampsia. The I/II genotype was associated with a 3.8-fold increased risk of preeclampsia (OR=3.8; 95 % CI 0.8-18.0); and the II/II genotype was not observed among our cases (0 % vs. 33 % p<0.001). Larger studies would be needed to confirm and further clarify the relations between functional variants in the leptin gene and preeclampsia risk.

Adult↗
PubMed2004

E1A-based determinants of oncogenicity in human adenovirus groups A and C.

A broad spectrum of genetic and molecular investigations carried out with group C, Ad2 and Ad5, and with group A, Ad12, have shown that early region1 (E1) gene products are sufficient for complete transformation of rodent cells in vitro by these viruses. During the past quarter century, the processes by which E1A proteins, in cooperation with E1B proteins, perturb the cell cycle and induce the transformed phenotype, have become well defined. Somewhat less understood is the basis for the differential oncogenicity of these two groups of viruses, and the processes by which the E1A proteins of Ad12 induce a tumorigenic phenotype in transformants resulting from infection of cells in vivo and in vitro. In this chapter we review previous findings and present new evidence which demonstrates that Ad12 E1A possesses two or more independent functions enabling it to induce tumors. One of these functions lies in its capacity to repress transcription of MHC class I genes, allowing the tumor cells to avoid lysis by cytotoxic T lymphocytes. We have shown that class I repression is mediated through increased binding of repressor COUP-TF and decreased binding of NF-kB to the class I enhancer. In addition to mediating immune escape, E1A also determines the susceptibility of transformants to Natural Killer (NK) cell lysis, and in this case, also, Ad12 transformants are not susceptible. By using Ad12 mutants containing chimeric E1A Ad12-Ad5 genes, point mutations, or a specific deletion, we have shown that the unique spacer region of Ad12 E1A is an oncogenic determinant, but is not required for transformation in vitro. Given that the E1A regions responsible for class I repression are first exon encoded, we have examined a set of cell lines transformed by these altered viruses, and have found that while they display greatly reduced tumorigenicity, they maintain a wildtype capacity to repress class I transcription. Whether the spacer contributes to NK evasion remains unresolved. Lastly, we discuss the properties of the Ad2/Ad5 E1A C-terminal negative modulator of tumorigenicity, and examine the effects on transformation, tumor induction and transformant tumorigenicity, when the Ad5 negative modulator is placed by chimeric construction in Ad12 E1A.

Adenovirus E1A Proteins↗