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Biomedical subjects

M C Walker

Publications and source records attributed to M C Walker.

At least 37 records · Page 2Linked to original sources
PubMed1999

Changes in homocysteine levels during normal pregnancy.

OBJECTIVE: The objective of this study was to determine the changes in total plasma homocysteine concentration that occur during normal pregnancy. STUDY DESIGN: In this cross-sectional study homocysteine was measured in 155 normal women in the first, second, and third trimesters and in nonpregnant controls. In addition, albumin, serum B12, serum folate, and red blood cell folate concentrations were measured and correlated to homocysteine values. RESULTS: The mean homocysteine concentration (in micromoles per liter) was 5.6 (95% confidence interval 3.9-7.3) at 8-16 weeks' gestation, 4.3 (95% confidence interval 3.5-5.3) at 20-28 weeks' gestation, 5.5 (95% confidence interval 3.3-7.5) at 36-42 weeks' gestation, and 7.9 (95% confidence interval 6.2-9.6) in the nonpregnant control group. Homocysteine was significantly lower in all 3 trimesters of pregnancy compared with nonpregnant controls (P <.001). Homocysteine levels were directly correlated with albumin levels, which decreased during pregnancy. Homocysteine concentrations were decreased in subjects taking folic acid supplementation. CONCLUSION: Serum concentrations of homocysteine decrease during pregnancy. This occurs in association with the physiologic fall in albumin during pregnancy, as well as with folic acid supplementation.

Adult↗
PubMed1999

A canarypox vaccine expressing multiple human immunodeficiency virus type 1 genes given alone or with rgp120 elicits broad and durable CD8+ cytotoxic T lymphocyte responses in seronegative volunteers.

Induction of CD8+ cytotoxic T cells is considered one of the important correlates for the protective efficacy of candidate human immunodeficiency virus type 1 (HIV-1) vaccines. To induce CD8+ cytotoxic T lymphocytes (CTLs) along with neutralizing antibody and CD4+ T cell help, a live canarypox virus construct expressing gp120, transmembrane gp41, the gag and protease genes, and sequences containing CTL epitopes in nef and pol was given simultaneously with, or followed by, rgp120 SF2. CD8+ CTLs were detected in 61% of volunteers at some time during the trial. Three to 6 months after the last immunization, the gene-specific responses were gag, 26/81; env, 17/77; nef, 12/77; and pol, 3/16. Simultaneous immunization with the canarypox vector and the subunit, beginning with the initial immunization, resulted in earlier antibody responses. In summary, a strategy of immunization with a canarypox vector expressing multiple genes of HIV-1 given with gp120 results in durable CD8+ CTL responses to a broad range of epitopes.

AIDS Vaccines↗
PubMed1999

Randomised, double-blind, placebo controlled pilot study assessing nitroglycerin as a tocolytic.

Thirty-three women in preterm labour were randomised in a double-blind fashion to receive either transdermal nitroglycerin (n = 17) or placebo (n = 16). Both groups had significant (P < 0.001) change in the cervix prior to randomisation. The primary outcome measure was delivery within 48 hours of randomisation. Fewer women randomised to nitroglycerin treatment (6/17) were delivered within 48 hours, compared with the placebo treatment (10/16) (RR 0.56, 95% CI 0.27 to 1.19). This pilot study lends support to two case series published that suggest that transdermal nitroglycerin may be promising as a safe, effective means for tocolysis.

Administration, Cutaneous↗
PubMed1999

Halothane as a neuroprotectant during constant stimulation of the perforant path.

PURPOSE: To determine the neuroprotective effects of halothane during constant stimulation of the perforant path. METHODS: Male Sprague-Dawley rats had electrodes implanted into the perforant path and dentate granule cell layer under halothane anaesthesia (1-2% in oxygen). They were then divided into four groups. In group 1 (n = 9), the perforant path was stimulated at 20 Hz for 2 h under halothane anaesthesia (1-2%). In group 2 (n = 3), the animals were unstimulated but maintained under halothane anaesthesia (1-2%) for 2 h with the electrodes in place. Both groups 1 and 2 had the electrodes removed and were then allowed to recover fully from the anaesthetic. In groups 3 and 4, the electrodes were held in place with dental acrylic. Both of these groups were allowed to recover fully from anaesthesia. In group 3 (n = 3), 24-48 h after recovery from anaesthesia, the perforant path was stimulated at 20 Hz for 2 h. Group 4 (n = 3) received no stimulation. After 14-17 days, the rats were killed, and morphometry and cell counts were performed on the hippocampi from rats in groups 1 and 2. RESULTS: Cell densities were not significantly different between control (group 2), unstimulated rats, and animals stimulated under halothane anaesthesia (group 1). Stimulation in the unanaesthetised rats resulted in severe neuronal loss in hilus, CA1, and CA3. CONCLUSIONS: Halothane protects hippocampal neurons against damage induced by constant stimulation of the perforant path.

Anesthesia, Inhalation↗
PubMed1999

Vertebral physitis with epiphyseal sequestration and a portosystemic shunt in a Pekingese dog.

Vertebral physitis with bone sequestration and a portosystemic shunt were diagnosed in an 18-month-old female Pekingese dog. The latter was determined by the presence of low blood urea nitrogen, elevated serum bile acids, microhepatica and an increased portosystemic shunt fraction. It was managed with a home-cooked low protein diet. Vertebral physitis and bone sequestration was diagnosed by the presence of thoracolumbar hyperaesthesia, radiographic and scintigraphic changes, isolation of Staphylococcus intermedius from blood and the third lumbar vertebra, and histopathological examination of a surgical biopsy. A partial sequestrectomy was performed and a six-month course of amoxycillin-clavulanate was prescribed. The dog was pain-free and showed partial resolution of the radiographic signs four months after the discontinuation of antibiotics.

Animals↗
PubMed1999

Rapid onset transverse myelitis in adolescence: implications for pathogenesis and prognosis.

Five adolescents with transverse myelitis were reviewed. All presented with a rapid onset paralysis of the lower limbs and impairment of bladder control. The maximum disability developed between 10 minutes and six hours. There was no history of trauma, asthma, or prodromal illness. Investigations failed to demonstrate a vascular cause. Extensive spinal cord abnormalities were observed on magnetic resonance imaging. Electrophysiological investigations, performed in four cases, were all consistent with anterior horn cell damage. In all five adolescents there was poor recovery. The underlying pathogenesis of this rapid onset condition remains a subject of debate. Similarities with both transverse myelitis and fibrocartilaginous emboli are evident, widening the spectrum of conditions within the transverse myelitis umbrella. These observations suggest that in rapid onset "transverse myelitis" the combination of extensive hyperintensity on spinal cord neuroimaging with electrophysiological evidence of anterior horn cell involvement might have adverse prognostic significance.

Adolescent↗
PubMed1998

Modulation of immunologic responses to HIV-1MN recombinant gp160 vaccine by dose and schedule of administration. National Institute of Allergy and Infectious Diseases AIDS Vaccine Evaluation Group.

The safety and immunogenicity of HIV-1MN recombinant gp160 (MN rgp160) vaccine in healthy, uninfected volunteers was tested in a double-blind study with a factorial design. By random assignment, 20 volunteers received three 200 micrograms doses of MN rgp160 and four volunteers received placebo at days 0, 28, and 168 or 0, 56, and 224. Of the 24 volunteers, 16 received 200 micrograms or 800 micrograms of MN rgp160 and two received placebo at day 532 (month 18). The vaccine was safe. It induced T cell memory measured by Th1 cytokine production and lymphocyte proliferation, and serum anti-MN rgp160 IgG (all subclasses) and IgA antibodies. Fifteen of 20 vaccinees developed neutralizing antibody. The regimen including immunizations on days 0, 28, and 168 followed by the 800 micrograms fourth dose was most immunogenic.

AIDS Vaccines↗
PubMed1998

Immune responses to human immunodeficiency virus (HIV) type 1 induced by canarypox expressing HIV-1MN gp120, HIV-1SF2 recombinant gp120, or both vaccines in seronegative adults. NIAID AIDS Vaccine Evaluation Group.

A safety and immunogenicity trial was conducted in vaccinia-immune and vaccinia-naive human immunodeficiency virus (HIV)-uninfected adults who were randomized to receive 10(6) or 10(7) TCID50 of canarypox (ALVAC) vector expressing HIV-1MN gp160 or 10(5.5) TCID50 of ALVAC-rabies virus glycoprotein control at 0 and 1 or 2 months and ALVAC-gp160 or 50 microg of HIV-1SF2 recombinant (r) gp120 in microfluidized emulsion at 9 and 12 months; others received rgp120 at 0, 1, 6, and 12 months. All vaccines were well-tolerated. Neither vaccinia-immune status before vaccination nor ALVAC dose affected HIV immune responses. HIV-1MN and HIV-1SF2 neutralizing antibodies were detected more often (100%) in ALVAC-gp160/rgp120 recipients than in recipients of ALVAC-gp160 (<65%) or rgp120 (89%) alone. ALVAC-gp160/rgp120 also elicited more frequent HIV V3-specific and fusion-inhibition antibodies, antibody-dependent cellular cytotoxicity, lymphoproliferation, and cytotoxic CD8+ T cell activity than did either vaccine alone. Trials with ALVAC expressing additional HIV components and rgp120 are underway.

AIDS Vaccines↗
PubMed1998

The epidemiology and management of status epilepticus.

Status epilepticus refers to a prolonged seizure state, usually taken as lasting 30 min or longer. This review considers recent studies of the epidemiology of status epilepticus; these have confirmed the high incidence and the high associated mortality and morbidity. Advances in the management of status epilepticus are also reviewed but despite these advances there is still a lack of good comparative studies on which to base treatment regimens.

Anesthetics↗
PubMed1998

Comparison of single- and repeated-dose pharmacokinetics of diazepam.

PURPOSE: To determine whether repeat boluses of diazepam (DZP) lead to significant accumulation in the central nervous system and/or peripheral compartments, as repeat intravenous boluses of diazepam are commonly used in the treatment of status epilepticus (SE). METHODS: In a rat model that permits simultaneous serum and cerebrospinal fluid (CSF) sampling, we characterized the pharmacokinetics of DZP and its metabolite, desmethyldiazepam, in CSF and blood using HPLC. DZP was administered by intraperitoneal injection as either a single dose (20 or 30 mg/kg) or repeat doses (10 or 20 mg/kg x 3, 1 h apart). RESULTS: After a single intraperitoneal dose, DZP was rapidly absorbed with a time to maximum concentration of 10 min. The serum concentrations then declined biexponentially. DZP rapidly entered the CSF, the CSF to serum ratio reached equilibrium within 10 min, and was equivalent to the ratio of free to total serum concentration. Repeated DZP dosing resulted in a threefold decrease in volume of distribution and clearance (p < 0.001). This was reflected in the CSF concentration data; however, after the third dose, the ratio of CSF to serum concentration, also increased greatly, representing further persistence of DZP in the CSF compartment. CONCLUSIONS: Repeat dosing of DZP leads to substantial accumulation, and high, persistent serum and CSF concentrations, which may explain the toxic effects of repeat DZP dosing. Repeat dosing of DZP using a tapering protocol, however, may increase the effectiveness of DZP in treating SE by preventing relapses without substantially increasing toxicity.

Animals↗
PubMed1997

Changes in activated protein C resistance during normal pregnancy.

OBJECTIVE: The objective of this study was to determine the changes in activated protein C resistance that occur during normal pregnancy. STUDY DESIGN: In this cross-sectional study activated protein C was measured in 128 women with normal pregnancies in the first, second, and third trimesters and in nonpregnant control subjects with 24 to 39 women in each group. In addition, factor V, factor VIII, free protein S, and functional protein C were measured and correlated with activated protein C levels. Polymerase chain reaction for factor V Leiden mutation was performed. RESULTS: There was a significant fall in the activity of activated protein C in the second and third trimesters of pregnancy (p < 0.05). This was related to increased factor VIII and decreased free protein S levels (p = 0.002, R2 = 0.20). The prevalence of the factor V Leiden mutation was 7.3%. CONCLUSION: Resistance to activated protein C is increased in the second and third trimesters of pregnancy. This is related to the alterations in other coagulation proteins, a phenomenon normally occurring during pregnancy.

Adult↗
PubMed1997

New aromatic inhibitors of EPSP synthase incorporating hydroxymalonates as novel 3-phosphate replacements.

A new, aromatic analogue of the EPSP synthase enzyme reaction intermediate 1 has been identified, which contains a 3-hydroxymalonate moiety in place of the usual 3-phosphate group. This simplified inhibitor was readily prepared in five steps from ethyl 3,4-dihydroxybenzoate. The resulting tetrahedral intermediate mimic 9 is an effective, competitive inhibitor versus S3P with an apparent Ki of 0.57 +/- 0.06 microM. This result demonstrates that 3-hydroxymalonates exhibit potencies comparable to aromatic inhibitors containing the previously identified 3-malonate ether replacements and can thus function as suitable 3-phosphate mimics in this system. These new compounds provide another example in which a simple benzene ring can be used effectively in place of the more complex shikimate ring in the design of EPSP synthase inhibitors. Furthermore, the greater potency of 9 versus the glycolate derivative 10 and the 5-deoxy-analog 11, again confirms the requirement for multiple anionic charges at the dihydroxybenzoate 5-position in order to attain effective inhibition of this enzyme.

3-Phosphoshikimate 1-Carboxyvinyltransferase↗
PubMed1997

Neutralization of a clade B primary isolate by sera from human immunodeficiency virus-uninfected recipients of candidate AIDS vaccines.

The inability of antibodies induced by experimental human immunodeficiency virus type 1 (HIV-1) vaccines to neutralize HIV-1 primary isolates may be due to a failure to elicit such antibodies, antigenic differences between the vaccine and the strains tested, insensitivity of the assays used, or to a combination of factors. New neutralization assays were used to determine the ability of candidate AIDS vaccines to generate neutralizing antibodies for clade B primary isolate BZ167, which is closely related in portions of its envelope to the immunizing strains. Sera from HIV-uninfected volunteers in vaccine trials were tested, and neutralizing activity was found in recipients of recombinant (r) gp120MN or of rgp160MN-containing canarypox boosted with rgp120SF-2. Detection of antibodies that neutralize primary isolate BZ167 correlated with neutralizing activity for homologous vaccine strains. These data demonstrate that certain candidate AIDS vaccines can elicit antibodies that neutralize a primary isolate of HIV-1.

AIDS Vaccines↗
PubMed1997

Antibody to human immunodeficiency virus type 1 (HIV-1) gp160 in mucosal specimens of asymptomatic HIV-1-infected volunteers parenterally immunized with an experimental recombinant HIV-1 IIIB gp160 vaccine. The National Institute of Allergy and Infectious Diseases-sponsored AIDS Vaccine Evaluation Group.

Twenty-two human immunodeficiency virus type 1 (HIV-1)-infected, asymptomatic volunteers with CD4 cell counts of >600 cells/mm3 who were enrolled in a phase I immunotherapy trial comparing two schedules of immunization of an HIV-1 IIIB-based recombinant gp160 (rgp160) experimental vaccine were evaluated for rgp160-specific antibodies in parotid saliva, genital secretions, and serum. When the study was unblinded, it was determined that five volunteers had received rgp160 on a month 0, 1, 2, 3, 4, and 5 immunization schedule, seven volunteers had received rgp160 on a month 0, 1, 2, and 5 schedule, five had received alum/deoxycholate placebo, and seven had received a licensed hepatitis B virus vaccine. Five volunteers consented to the donation of parotid saliva but not genital secretions. Prior to immunization, parotid saliva specimens were available for 11 of 22 volunteers, seminal plasma (SP) specimens were available for 7 of 22 volunteers, cervicovaginal lavage (CVL) specimens were available for 5 of 22 volunteers, and serum was available for 22 of 22 volunteers. These baseline specimens and specimens collected at 1 and 7 months after the final immunizations were assessed by enzyme-linked immunosorbent assay for immunoglobulin G (IgG) and IgA antibodies specific for HIV-1 LAI rgp160 or HIV-1 MN rgp160. No augmentation in HIV rgp160-specific IgG or IgA antibody production in either parotid saliva or serum specimens of vaccinees compared to that in controls was observed after immunization. There were insufficient numbers of SP or CVL specimens available for statistical comparisons between vaccinees and controls. Overall, anti-LAI rgp160 IgG antibodies were detected in the parotid saliva specimens of 20 of 22 volunteers, the seminal plasma specimens of 11 of 11 volunteers, and the CVL specimens of 6 of 6 volunteers and in 21 of 22 serum specimens. Fewer volunteers expressed anti-LAI rgp160 IgA antibodies in mucosal or serum specimens: 11 of 22 parotid saliva specimens, 3 of 11 SP specimens, 3 of 5 CVL samples, and 12 of 22 sera.

AIDS Vaccines↗
PubMed1997

Difficulties in extrapolating from clinical trial data to clinical practice: the case of antiepileptic drugs.

Effective new antiepileptic drugs (AEDs) are needed for the treatment of those with refractory epilepsy. However, with the growing number of these drugs being licensed and marketed, a rational approach to the treatment of epilepsy is becoming essential. New AED trials can determine appropriate use of AEDs but ultimately fail to determine the best use of AEDs and their exact role in treating patients. New AED trials rarely use clinically applicable measures of efficacy, and it is difficult to extrapolate the data from populations used in AED trials to the wider population of patients with epilepsy. Furthermore, AED trials ignore the factors that are most likely to determine prognosis: the etiology, seizure types, and epilepsy syndrome. To resolve these issues, we need large multicenter studies in well-defined populations with well-characterized seizures, epilepsy syndromes, and etiologies. Being seizure free should be the primary measure of efficacy rather than meta-analyses and guidelines based upon incomplete data.

Anticonvulsants↗