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M A Williams

Publications and source records attributed to M A Williams.

At least 37 records · Page 2Linked to original sources
PubMed2004

Relationship of maternal plasma leptin and risk of pre-eclampsia: a prospective study.

OBJECTIVE: We measured maternal plasma leptin concentrations in 55 women with pre-eclampsia and 487 normotensive women to determine whether elevated leptin concentrations were associated with the occurrence of pre-eclampsia. METHODS: Maternal blood samples were collected at 13 weeks' gestation, on average. Plasma leptin concentrations were determined using immunoassay. Logistic regression procedures were used to calculate odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: Leptin concentrations were 78% higher in cases than control subjects (median 34.6 vs. 19.5 ng/ml; p < 0.001). Relative to women with leptin concentrations of < 27.4 ng/ml, those with elevated leptin concentrations (> or = 27.4 ng/ml) experienced a 2.3-fold increased risk of pre-eclampsia (OR 2.3; 95% CI 1.1-4.6). We observed evidence of a strong linear component of trend in risk of pre-eclampsia with increasing maternal plasma leptin concentration. Each 10-ng/ml increase in leptin concentration was associated with a 30% increase in pre-eclampsia risk (OR 1.3; 95% CI 1.1-1.5). Overweight women with elevated leptin concentrations experienced the highest risk of pre-eclampsia (OR 6.4; 95% CI 3.1-13.2) as compared with lean women with no leptin elevations. CONCLUSION: Elevated plasma leptin concentration and maternal overweight status appear to be independently associated with an increased risk of pre-eclampsia.

Female↗
PubMed2004

Methylenetetrahydrofolate reductase 677 C-->T polymorphism and plasma folate in relation to pre-eclampsia risk among Peruvian women.

OBJECTIVES: Pre-eclampsia is an important cause of maternal and fetal morbidity and mortality worldwide. Hyperhomocyst(e)inemia in pregnancy is associated with an increased risk of pre-eclampsia in most studies. Nutritional and genetic factors regulate homocyst(e)ine levels. A missense mutation 677 C-->T in the gene for methylenetetrahydrofolate reductase (MTHFR) has been associated with an increased pre-eclampsia risk in some, although not most, previously studied populations. METHODS: To further understand the role of this polymorphism in the etiology of pre-eclampsia, we genotyped a total of 125 pre-eclamptics and 179 normotensive pregnant Peruvian women. RESULTS: The wild-type allele frequency among cases and controls was 54% and 58%, respectively. Twenty percent of cases and 17% of controls were homozygous for the 677 C-->T MTHFR genotype (T/T). After adjustment for confounding by covariates including maternal age, nulliparity, pre-pregnancy body mass index and use of prenatal vitamins, women homozygous for the 677 C-->T MTHFR genotype (T/T) experienced a modest, statistically non-significant increased risk of pre-eclampsia (adjusted OR 1.6, 95% CI 0.7, 3.8). Maternal folate deficiency was associated with a statistically non-significant doubling in risk of pre-eclampsia in this population (adjusted OR 2.0, 95% CI 0.9, 4.3). CONCLUSIONS: There was no evidence to suggest that pre-eclampsia risk is positively associated with the T/T genotype overall, or in the context of folate deficiency.

Adult↗
PubMed2004

Utility of CSF pressure monitoring to identify idiopathic intracranial hypertension without papilledema in patients with chronic daily headache.

The aim of the present study was to report on the utility of continuous Pcsf monitoring in establishing the diagnosis of idiopathic intracranial hypertension without papilledema (IIHWOP) in chronic daily headache (CDH) patients. We report a series of patients (n = 10) with refractory headaches and suspected IIHWOP referred to us for continuous Pcsf monitoring between 1991 and 2000. Pcsf was measured via a lumbar catheter and analysed for mean, peak, highest pulse amplitude and abnormal waveforms. A 1-2 day trial of continuous controlled CSF drainage (10 cc/ h) followed Pcsf monitoring. Response to CSF drainage was defined as improvement in headache symptoms. Patients with abnormal waveforms underwent a ventriculoperitoneal (VPS) or lumboperitoneal (LPS) shunt insertion. All patients had normal resting Pcsf (8 +/- 1 mmHg) defined as ICP < 15 mmHg. During sleep, all patients had B-waves and 90% had plateau waves or near plateau waves. All patients underwent either a VPS or LPS procedure. All reported improvement of their headache after surgery. Demonstration of pathological Pcsf patterns by continuous Pcsf monitoring was essential in confirming the diagnosis of IIHWOP, and provided objective evidence to support the decision for shunt surgery. Increased Pcsf was seen mostly during sleep and was intermittent, suggesting that Pcsf elevation may be missed by a single spot-check LP measurement. The similarity between IIHWOP and CDH suggests that continuous Pcsf monitoring in CDH patients may have an important diagnostic role that should be further investigated.

Adult↗
PubMed2003

Halophilic adaptation of protein-DNA interactions.

Pyrococcus woesei ( Pw ) is an archaeal organism adapted to living in conditions of elevated salt and temperature. Thermodynamic data reveal that the interaction between the TATA-box-binding protein (TBP) from this organism and DNA has an entirely different character to the same interaction in mesophilic counterparts. In the case of the Pw TBP, the affinity of its interaction with DNA increases with increasing salt concentration. The opposite effect is observed in all known mesophilic protein-DNA interactions. The halophilic behaviour can be attributed to sequestration of cations into the protein-DNA complex. By mutating residues in the Pw TBP DNA-binding site, potential sites of cation interaction can be removed. These mutations have a significant effect on the binding characteristics, and the halophilic nature of the Pw TBP-DNA interaction can be reversed, and made to resemble that of a mesophile, in just three mutations. The genes of functionally homologous proteins in organisms existing in different environments show that adaptation is most often accompanied by mutation of an existing protein. However, the importance of any individual residue to a phenotypic characteristic is usually difficult to assess amongst the multitude of changes that occur over evolutionary time. Since the halophilic nature of this protein can be attributed to only three mutations, this reveals that the important phenotype of halophilicity could be rapidly acquired in evolutionary time.

Archaeal Proteins↗
PubMed2003

Influence of pre-eclampsia on fetal growth.

OBJECTIVE: We examined the effect of pre-eclampsia on fetal growth in a cohort of pregnant women delivering singleton infants. METHODS: Analyses were restricted to 155 women with pre-eclampsia and 5570 normotensive women. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) after adjusting for confounders. We estimated ORs for very low birth weight (VLBW; < 1500 g), low birth weight (LBW; < 2500 g), and small for gestational age (SGA; weight < or = 10th centile by each gestational age, race, sex and parity strata) in relation to maternal pre-eclampsia status. RESULTS: After adjusting for maternal age, race, smoking, Medicaid status and gestational age, the OR for VLBW was 30.7 (95% CI 7.0-134.9). Pre-eclampsia was associated with a 3.8-fold increased risk of LBW (95% CI 1.9-7.5). Women with pre-eclampsia were 3.6 times more likely to deliver an SGA newborn as compared with normotensive women (95% CI 2.3-5.7). Advanced maternal age, African-American race, parity or smoking status did not modify the associations of pre-eclampsia with LBW and SGA. CONCLUSIONS: Our results are consistent with other reports that have documented a strong relationship between pre-eclampsia and restricted fetal growth. Further, our results expand the literature by documenting a particularly strong association between pre-eclampsia and VLBW. However, our findings regarding the relationship between pre-eclampsia and fetal growth may be confounded by unmeasured factors including maternal weight prior to pregnancy and pregnancy weight gain.

Adult↗
PubMed2003

The influence of maternal triglyceride levels on infant birth weight in Peruvian women with pre-eclampsia.

OBJECTIVE: Hypertriglyceridemia is an important pathophysiological feature of pre-eclampsia, a complication associated with retarded fetal growth. We studied the relation between third-trimester maternal triglyceride levels and infant birth weight in 113 pre-eclamptic and 150 normotensive women. METHODS: Plasma triglyceride concentrations were determined using enzymatic methods. The relative risk of infant low birth weight (LBW, < 2500 g) was determined using logistic regression to calculate the odds ratio (OR) and 95% confidence interval (CI). RESULTS: Approximately 12% of normotensive and 32% of pre-eclamptic mothers delivered LBW infants. After adjusting for maternal age, parity, pre-pregnancy adiposity and gestational age at delivery, pre-eclamptics were 2.3 times more likely to deliver a LBW infant as compared with normotensive mothers (95% CI 1.1-5.0). There was no association between plasma triglyceride level and infant birth weight. Pearson correlation coefficients for birth weight and triglyceride were r = 0.10 (p = 0.24) and r = 0.06 (p = 0.49) for normotensive and pre-eclamptic women, respectively. The OR for LBW associated with high triglyceride level (> or = 233 mg/dl) was 0.8 (95% CI 0.2-3.1) and 0.9 (95% CI 0.4-2.0) for the two groups. Triglyceride levels did not modify the pre-eclampsia and LBW association. Compared to normotensive women with low triglyceride level (< 233 mg/dl), the ORs for LBW were 1.2 (95% CI 0.4-4.0), 3.6 (95% CI 1.0-12.5) and 2.8 (95% CI 1.0-8.0) for normotensive and high triglyceride, pre-eclamptic and low triglyceride, and pre-eclamptic and high triglyceride mothers, respectively. CONCLUSIONS: Hypertriglyceridemia in late pregnancy, considered a maternal adaptation to maintain stable fuel distribution to the fetus, was not related to birth weight.

Adult↗
PubMed2003

Correlates of recreational physical activity in early pregnancy.

OBJECTIVE: Despite the well-documented benefits of a physically active lifestyle, over 25% of American adults report that they never engage in regular recreational physical activity. Little is known about the determinants of physical activity among pregnant women. We investigated the predictors of physical activity in 386 normotensive pregnant women. METHODS: Participants provided information about the type, frequency and duration of each physical activity performed during the first 20 weeks of pregnancy. We calculated odd ratios (OR) for active compared with inactive women using logistic regression models. RESULTS: Approximately 61% of women reported participating in some regular physical activity during pregnancy. Walking, swimming, gardening and jogging were the most common activities. Physical activity as an adolescent (OR 4.0) and during the year before pregnancy (OR 48.9) were the strongest predictors of physical activity in pregnancy. Active women who continued to exercise during pregnancy decreased the average intensity of their exercise and the weekly duration of exercise compared with the year before pregnancy. Nulliparas were twice as likely to engage in physical activity as compared with multiparas. Education and income were positively related with physical activity. Non-White women were 40-60% less likely to engage in physical activity as compared with White women. Smokers were also less likely to engage in physical activity. High protein intake was positively associated with physical activity, while the opposite was true for high carbohydrate intake. CONCLUSIONS: The identification of determinants of physical activity in pregnancy has important implications for developing strategies aimed at promoting a physically active lifestyle among young women.

Adult↗
PubMed2003

Specific immunotherapy of experimental myasthenia by genetically engineered APCs: the "guided missile" strategy.

Although treatment of MG with general immunosuppressive agents is often effective, it has important drawbacks, including suppression of the immune system as a whole, with the risks of infection and neoplasia, and numerous other adverse side effects. Ideally, treatment of MG should eliminate the specific pathogenic autoimmune response to AChR, without otherwise suppressing the immune system or producing other adverse side effects. Although antibodies to AChR are directly responsible for the loss of AChRs at neuromuscular junctions in MG, the AChR antibody response is T cell-dependent, and immunotherapy directed at T cells can abrogate the autoantibody response, with resulting benefit. As in other autoimmune diseases, the T cell response in MG is highly heterogeneous. The design of specific immunotherapy must take this heterogeneity into account and target the entire repertoire of AChR-specific T cells. We describe our investigation of a novel strategy for specific immunotherapy of MG, involving gene transfer to convert antigen-presenting cells (APCs) to "guided missiles" that target AChR-specific T cells, and that induce apoptosis and elimination of those T cells. This strategy uses the ability of APCs from a given individual to present the entire spectrum of AChR epitopes unique for that individual, and thereby to target the entire repertoire of antigen-specific T cells of the same individual. Using viral vectors, we have genetically engineered the APCs to process and present the most important domain of the AChR molecule, and to express a "warhead" of Fas ligand (FasL) to eliminate the activated AChR-specific T cells with which they interact. Our results show that the APCs express the appropriate gene products, and effectively and specifically eliminate AChR-specific T cells by the Fas/FasL pathway, while sparing T cells of other specificities.

Animals↗
PubMed2002

In vitro studies of gadolinium-DTPA conjugated with monoclonal antibodies as cancer-specific magnetic resonance imaging contrast agents.

The monoclonal antibodies, 9.2.27 against human melanoma cell lines and WM53 against leukemia cell lines, were conjugated with cyclic anhydride gadolinium-diethylenetriaminepenta-acetic acid (Gd-cDTPAa) and used as tumor-specific contrast agents in magnetic resonance imaging (MRI). The data indicate that Gd-DTPA-9.2.27 in solution decreased the T1 relaxation of water protons at 7.0 Tesla (300 MHz) in direct proportion to the gadolinium concentration, and this effect was greater than in Gd-DTPA solutions. These conjugates show high specificity for melanoma and leukemia cell lines. T1 relaxation time at 7.0 Tesla, measured for the melanoma cell line (MM-138) and leukemia cell line (HL-60) after incubation at 37 degrees C for 4 hr, were significantly decreased (approximately 25%) relative to controls. The gadolinium concentration in cells and washing solutions was measured by inductively coupled plasma atomic emission spectroscopy (ICP-AES). A linear relationship was observed between T1 relaxation rates and gadolinium concentrations obtained by ICP-AES. The ICP-AES results showed no gadolinium uptake in the non-targeted HT-29 colorectal cancer cells.

Animals↗
PubMed2002

Low pressure hydrocephalus and ventriculomegaly: hysteresis, non-linear dynamics, and the benefits of CSF diversion.

Low pressure hydrocephalus (LPH) is a rare clinical condition. We report our experience with 10 patients treated at the Johns Hopkins Hospital. We reviewed the records of 10 patients (five men, five women; mean age 43 years) treated between 1996 and 2000. All underwent intracranial pressure (ICP) monitoring and subatmospheric cerebrospinal fluid (CSF) drainage with an intraventricular or lumbar catheter. All patients developed ventriculomegaly: five following aneurysmal subarachnoid haemorrhage; one after meningitis; one after intraventricular haemorrhage. Three patients presented with chronic aqueductal stenosis. Ventriculomegaly was clinically detected on average 12 days after presentation. Mean ICP was 4.8 mmHg (range 0-10). All patients improved only in the setting of negative pressure CSF drainage, and were subsequently treated with low pressure ventriculo- or lumboperitoneal shunts. At 1 year, eight patients (80%) showed good recovery to minimal disability; seven patients (70%) had resolving ventriculomegaly. The mechanism of low pressure hydrocephalus remains unclear. In our cohort, different aetiologies were responsible for the change in compliance/elastance of the brain parenchyma and subsequent development of ventriculomegaly. We propose that while ventriculomegaly (and therefore neuronal dysfunction) can be initiated in the setting of high ICP, the maintenance of ventriculomegaly at normal or low ICP is a physiological example of hysteresis. This behaviour, which has been characterized by the chaos theory of non-linear dynamics as a Hopf bifurcation, explains how a system can exhibit two different states (ventricular size) at a single parameter value (ICP). Most importantly, it helps to explain how lowering ICP in the setting of LPH can resolve ventriculomegaly and its neurologic sequelae.

Adult↗
PubMed2001

Ventriculitis complicating use of intraventricular catheters in adult neurosurgical patients.

Ventriculitis is a serious complication of intraventricular catheter (IVC) use, with rates of IVC-related infections ranging from 0% to 45% and gram-positive organisms predominating. We prospectively analyzed ventriculostomy-related infections occurring among 157 adult neurosurgical patients (mean age, 54.9 years; 90 [57%] were women) from 1995 through 1998, to determine the incidence of, risk factors for, and organisms that cause ventriculitis. A total of 196 IVC events resulted in 11 infections (5.6%; 9 were caused by gram-negative organisms and 2 by coagulase-negative staphylococci). Independent risk factors for IVC-related infection include length of IVC placement (8.5 days [infected] vs. 5.1 days [uninfected]; P=.007) and cerebrospinal fluid leakage about the IVC (P=.003). The length of hospital stay (30.8 days vs. 22.6 days; P=.03) and mean total hospital charges ($85,674.27 vs. $55,339.21; P=.009) were greater for infected patients than for uninfected patients. In addition, a microbiologic shift from gram-positive organisms toward gram-negative organisms was noted. This study suggests that IVC-related infections remain serious infections that increase the length of hospitalization.

Adult↗
PubMed2001

Characterization of virus-mediated inhibition of mixed chimerism and allospecific tolerance.

Simultaneous blockade of the CD28 and CD40 T cell costimulatory pathways has been shown to effectively promote skin allograft survival in mice. Furthermore, blockade of one or both of these pathways has played a central role in the development of strategies to induce mixed hematopoietic chimerism and allospecific tolerance. It has recently been observed that the beneficial effects of CD40 blockade and donor splenocytes in prolonging skin graft survival can be abrogated by some viral infections, including lymphocytic choriomeningitis virus (LCMV). In this study, we show that LCMV infection prevents prolonged allograft survival following CD28/CD40 combined blockade. We further show that LCMV prevents the induction of allospecific tolerance and mixed hematopoietic chimerism, while delay of infection for 3-4 wk posttransplant has no effect on tolerance induction. Because of reports of anti-H-2(d) activity following LCMV infection, we assayed the ability of LCMV-specific T cells to respond to alloantigen at a single cell level. Although we confirm that LCMV infection induces the generation of alloreactive cells, we also demonstrate that LCMV-specific T cells do not divide in response to alloantigen. The alloresponse suppressed by costimulation blockade is restored by LCMV infection and correlates with increased dendritic cell maturation. We hypothesize that the costimulation blockade-resistant rejection mediated by LCMV could be partly attributable to the up-regulation of alternative costimulatory pathways subsequent to LCMV-induced dendritic cell maturation.

Animals↗
PubMed2001

Simulation of endo-PG digest patterns and implications for the determination of pectin fine structure.

Novel stepwise approaches to the calculation of enzyme digest patterns are described and used in the validation of a computer simulation. Results obtained using the simulation show that, while a previously proposed model of endo-PG action captures some of the salient features of this enzymes behaviour, it is not sufficient to successfully predict experimental digest patterns from pectic substrates. Subsequently, it has been shown that a modified model incorporating existing information regarding subsite architecture and speculative site tolerances for esterified residues, goes someway towards improving the situation.

Computer Simulation↗
PubMed2001

Costimulation blockade, busulfan, and bone marrow promote titratable macrochimerism, induce transplantation tolerance, and correct genetic hemoglobinopathies with minimal myelosuppression.

Mixed hemopoietic chimerism has the potential to correct genetic hemological diseases (sickle cell anemia, thalassemia) and eliminate chronic immunosuppressive therapy following organ transplantation. To date, most strategies require either recipient conditioning (gamma-irradiation, depletion of the peripheral immune system) or administration of "mega" doses of bone marrow to facilitate reliable engraftment. Although encouraging, many issues remain that may restrict or prevent clinical application of such strategies. We describe an alternative, nonirradiation based strategy using a single dose of busulfan, costimulation blockade, and T cell-depleted donor bone marrow, which promotes titratable macrochimerism and a reshaping of the T cell repertoire. Chimeras exhibit robust donor-specific tolerance, evidenced by acceptance of fully allogeneic skin grafts and failure to generate donor-specific proliferative responses in an in vivo graft-versus-host disease model of alloreactivity. In this model, donor cell infusion and costimulation blockade without busulfan were insufficient for tolerance induction as donor-specific IFN-gamma-producing T cells re-emerged and skin grafts were rejected at approximately 100 days. When applied to a murine beta-thalassemia model, this approach allows for the normalization of hemologic parameters and replacement of the diseased red cell compartment. Such a protocol may allow for clinical application of mixed chimerism strategies in patients with end-stage organ disease or hemoglobinopathies.

Animals↗
PubMed2001

The solution structure of the disulphide-linked homodimer of the human trefoil protein TFF1.

The trefoil factor family protein, TFF1, forms a homodimer, via a disulphide linkage, that has greater activity in wound healing assays than the monomer. Having previously determined a high-resolution solution structure of a monomeric analogue of TFF1, we now investigate the structure of the homodimer formed by the native sequence. The two putative receptor/ligand recognition domains are found to be well separated, at opposite ends of a flexible linker. This contrasts sharply with the known fixed and compact arrangement of the two trefoil domains of the closely related TFF2, and has significant implications for the mechanism of action and functional specificity of the TFF of proteins.

Amino Acid Sequence↗
PubMed2001

Plasma concentrations of carotenoids, retinol, and tocopherols in preeclamptic and normotensive pregnant women.

This case-control study was conducted in Lima, Peru, from June 1997 through January 1998 to assess whether plasma concentrations of carotenoids (alpha-carotene, beta-carotene, lycopene, lutein, zeaxanthin, beta-cryptoxanthin), retinol, and tocopherols (alpha-tocopherol and gamma-tocopherol) are decreased in women with preeclampsia. A total of 125 pregnant women with preeclampsia and 179 normotensive pregnant women were included. Plasma concentrations of antioxidants were determined using high performance liquid chromatography. After adjusting for maternal demographic, behavioral, and reproductive characteristics and total plasma lipid concentrations, the authors found a linear increase in risk of preeclampsia with increasing concentrations of alpha-tocopherol (odds ratio of the highest quartile = 3.13; 95% confidence interval: 1.06, 9.23, with the lowest quartile as the reference group; p value of the test of linear trend = 0.040). The risk of preeclampsia decreased across increasing quartiles of concentrations for retinol (odds ratio of the highest quartile = 0.32; 95% confidence interval: 0.15, 0.69, with the lowest quartile as the reference group; p value of the test of linear trend = 0.001). Some of these results are inconsistent with the prevailing hypothesis that preeclampsia is an antioxidant-deficient state. Preliminary findings confirm an earlier observation of increased plasma concentrations of alpha-tocopherol among women with preeclampsia as compared with normotensive pregnant women.

Adolescent↗
PubMed2001

Plasma folate, vitamin B(12), and homocyst(e)ine concentrations in preeclamptic and normotensive Peruvian women.

The authors measured maternal third trimester plasma folate, vitamin B(12), and homocyst(e)ine concentrations among 125 women with preeclampsia and 179 normotensive women in Lima, Peru (1997-1998), to determine whether these analytes were associated with the occurrence of preeclampsia. Logistic regression procedures were used to calculate maximum likelihood estimates of odds ratios and 95% confidence intervals. Relative to women in the upper quartile of the control distribution of maternal plasma folate concentrations, women with values in the lowest quartile experienced a 1.6-fold increased risk of preeclampsia (odds ratio = 1.6; 95% confidence interval: 0.8, 3.2). There was no evidence of an increased risk of preeclampsia associated with low plasma vitamin B(12) concentrations. The unadjusted relative risk of preeclampsia increased across successively higher quartiles of plasma homocyst(e)ine level (odds ratios were 1.0, 1.0, 1.5, and 2.9, respectively, with the lowest quartile used as the referent; p for linear trend = 0.0004). After adjustment for maternal age, parity, gestational age, use of prenatal vitamins, whether the pregnancy had been planned, and educational attainment, the relative risk between extreme quartiles was 4.0 (95% confidence interval: 1.8, 8.9). These findings are consistent with earlier reports suggesting that hyperhomocyst(e)inemia in pregnancy may be a risk factor for preeclampsia.

Adult↗