Biomedical subjects
Publications and source records attributed to W Jones.
Explore the source record for details and available documents.
PURPOSE: Two recombinant IFN-beta products have been approved for the treatment of multiple sclerosis, a glycosylated form with the predicted natural amino acid sequence (IFN-beta-1a) and a non-glycosylated form that has a Met-1 deletion and a Cys-17 to Ser mutation (IFN-beta-1b). The structural basis for activity differences between IFN-beta-1a and IFN-beta-1b, is determined. METHODS: In vitro antiviral, antiproliferative and immunomodulatory assays were used to directly compare the two IFN-beta products. Size exclusion chromatography (SEC), SDS-PAGE, thermal denaturation, and X-ray crystallography were used to examine structural differences. RESULTS: IFN-beta-1a was 10 times more active than IFN-beta-1b with specific activities in a standard antiviral assay of 20 x 10(7) IU/mg for IFN-beta-1a and 2 x 10(7) IU/mg for IFN-beta-1b. Of the known structural differences between IFN-beta-1a and IFN-beta-1b, only glycosylation affected in vitro activity. Deglycosylation of IFN-beta-1a produced a decrease in total activity that was primarily caused by the formation of an insoluble disulfide-linked IFN precipitate. Deglycosylation also resulted in an increased sensitivity to thermal denaturation. SEC data for IFN-beta-1b revealed large, soluble aggregates that had reduced antiviral activity (approximated at 0.7 x 10(7) IU/mg). Crystallographic data for IFN-beta-1a revealed that the glycan formed H-bonds with the peptide backbone and shielded an uncharged surface from solvent exposure. CONCLUSIONS: Together these results suggest that the greater biological activity of IFN-beta-1a is due to a stabilizing effect of the carbohydrate on structure.
This study aimed to assess the effect of a hospital-based smoking cessation intervention delivered by midwives during routine antenatal and postnatal care on the smoking habits of pregnant women and their partners. At the first antenatal visit, women in the intervention group (n = 110) were given a demonstration of the immediate effects of smoking on foetal heart rate, brief smoking cessation advice and smoking cessation booklets for themselves and their partners; at delivery, they were given brief advice and a booklet about postpartum cessation. Compared with an historical control group who received usual care (n = 110) and assuming those lost to follow-up continued to smoke, biochemically-verified maternal cessation sustained from at least 24 weeks gestation to late pregnancy was 6.4% in the intervention group and 1.8% in the comparison group. However, there was no difference between maternal quit rates at six months postpartum. Partners were more likely to try to quit in the intervention group, but quit rates did not differ. Exposure to the intervention was not associated with increased levels of psychological distress, as measured by the 12-item General Health Questionnaire. We conclude that this type of intervention, when implemented by staff during routine care, is probably associated with a small improvement in maternal cessation in pregnancy, similar to that produced by minimal advice to quit smoking.
BACKGROUND: Interferon beta is an effective treatment for relapsing multiple sclerosis (MS). As with other protein drugs, neutralizing antibodies (NAB) can develop that reduce the effectiveness of treatment. OBJECTIVES: To determine the incidence and biological significance of NAB to interferon beta-la (IFN-beta-1a; Avonex; Biogen, Cambridge, MA) in MS patients. METHODS: A two-step assay for NAB to IFN-beta-1a was developed and used to assay serum samples from participants in the phase III clinical trial of IFN-beta-1a, and from patients in an ongoing open-label study of IFN-beta-1a. The biological significance of NAB to IFN-beta-1a was determined by relating the NAB assay result to in vivo induction of the IFN-inducible molecules neopterin and beta-2 microglobulin, and the clinical significance was determined by comparing clinical and MRI measures of disease activity after 2 years of IFN-beta-1a therapy in patients who were NAB+ and NAB-. The incidence of NAB was compared in MS patients who had used only IFN-beta-1a with the incidence in MS patients who had used only IFN-beta-1b. RESULTS: In patients in the open-label study, development of NAB to IFN-beta-1a resulted in a titer-dependent reduction in neopterin induction after interferon injections. In patients in the phase III study, development of NAB was associated with a reduction in beta-2 microglobulin induction. In the phase III study, a trend toward reduced benefit of IFN-beta-1a on MRI activity in NAB+ versus NAB- patients was observed. The incidence of NAB to IFN-beta-1a in the open-label study was approximately 5% over 24 months of treatment of IFN-beta-1a therapy, but was four- to sixfold higher using the same assay for patients exposed only to IFN-beta-1b for a similar duration. There were no clinical, MRI, or CSF characteristics that were predictive of which patients would develop NAB. CONCLUSIONS: NAB directed against IFN-beta have in vivo biological consequences in patients with MS. The frequency with which MS patients develop NAB against IFN-beta is significantly greater with IFN-beta-1b therapy compared with IFN-beta-1a therapy. Treatment decisions in MS patients treated with IFN-beta should take into account development of NAB.
Explore the source record for details and available documents.
Coronafacic acid, the polyketide component of the phytotoxin coronatine, is activated and coupled to coronamic acid via amide bond formation, a biosynthetic step presumably catalyzed by the coronafacate ligase (cfl) gene product. In the present study, cfl was fused to the carboxy terminus of malE, which encodes the maltose-binding protein (MBP), and overexpressed in Escherichia coli. Immunoblot analysis indicated that Cfl contained an ATP-binding region, a motif conserved in enzymes which activate their substrates by adenylation. MBP-Cfl was overproduced and purified from Pseudomonas syringae and the protein fusion was used to generate antisera. Anti-MBP-Cfl antibodies and a transcriptional fusion of the cfl promoter to a promoterless glucuronidase gene were used to follow the temporal expression of coronafacate ligase. The results indicated that transcription of cfl is temperature-sensitive. Furthermore, a nonpolar mutation in cfl suggested that the gene may have a role in coronafacic acid biosynthesis.
The pulmonary toxicity of the respirable dusts silica, coal, carbonyl iron, and titanium dioxide on alveolar macrophage (AM) and neutrophil (PMN) inducible nitric oxide synthase (iNOS) gene expression and nitric oxide (NO) production was investigated. Rats were intratracheally instilled with 5 mg/100 g body weight of silica, coal, carbonyl iron, or titanium dioxide. The dust particles averaged less than 5 microns in diameter. Bronchoalveolar lavage was performed 24 h later. Bronchoalveolar lavage cell (BALC) differentials, iNOS gene expression and NO production by BALC (measured indirectly as NO-dependent chemiluminescence), and lavageable lung protein levels were measured. Analyzed on an equal mass basis, silica, coal, and titanium dioxide dusts increased the production of iNOS-dependent NO by AM. Silica and titanium dioxide both increased the levels of iNOS mRNA while carbonyl iron and coal did not. Each dust caused an increase in PMN, indicating an inflammatory response. Carbonyl iron and titanium dioxide decreased the numbers of AM. Levels of acellular lavageable lung protein were increased by silica, carbonyl iron, and titanium dioxide. When exposure was normalized for an equal number of particles, the pneumotoxic dusts, silica and coal, caused more inflammation and NO production than the nuisance dusts, carbonyl iron and titanium dioxide. Therefore, it appears that particle number is a more appropriate metric of exposure than mass when comparing the relative pathogenicity of dusts of different sizes. Furthermore, since the potency of these dusts (on a particle number basis) to increase iNOS gene expression reflects their inflammatory and pathogenic potential, it is proposed that NO may contribute to the early inflammatory damage observed in the lung following dust exposure.
Hand and arm posture while keying is frequently mentioned as a risk factor for upper extremity musculoskeletal disorders (UEMSDs) among video display terminal (VDT) operators. However, many epidemiologic studies have not included measures of posture of VDT operators, in part, because of the difficulty of assessing posture rapidly and reliably among large numbers of subjects. For a single measure of posture to be useful for estimating dose-response relationships between posture and risk of UEMSDs, the within-subject variability of the postural measure must be smaller than the between-subject variability of the postural measure. In addition, the measure must be stable over time. We estimate the ratio of between- to within-subject variability for manual goniometry by measuring six postural angles on six occasions among 19 subjects using VDTs. For each postural angle, between-subject variability was substantially and statistically significantly larger than within-subject variability. Stability of postural measures over time was sufficient to justify a single postural measurement in epidemiologic studies. We conclude that manual goniometry can provide useful information about upper extremity posture among VDT users for use in epidemiologic studies of UEMSDs.
Explore the source record for details and available documents.
OBJECTIVE: To determine the neurological outcome of a cohort of premature babies having ultrasound diagnoses of severe cystic periventricular leukomalacia. METHODOLOGY: All neonatal intensive care unit admissions born at less than 35 weeks gestation or weighing less than 1500 g underwent serial cranial ultrasounds. Those developing severe bilateral cystic periventricular leukomalacia (12 patients) were then followed clinically to a mean age of 27.3 months. RESULTS: Ten of the 12 patients fulfilling strict ultrasound criteria survived. All had a major neurological handicap, all having spastic quadriparesis and visual impairments, with most suffering global developmental delay and epilepsy. CONCLUSIONS: Severe bilateral cystic periventricular leukomalacia results in major permanent handicap. It is currently impossible to identify most patients with this condition while they are being ventilated. Non-ultrasound techniques are needed to diagnose the condition earlier, and to give guidance to management.
The aim of the article is to clarify the research term 'triangulation'. Examples are given to illustrate the use of triangulation in clinical practice. The strength of using triangulation in both the design and analysis stages are highlighted.
The documented release of carbon fines from granular activated carbon filters is a concern for drinking water utilities, since these particles may carry coliform and even pathogenic bacteria through the disinfection barrier. Such a breakthrough could have an impact on distribution system biofilms. Using total cell counts, specific monoclonal antibody staining, and computerized image analysis, we monitored the colonization of introduced Klebsiella pneumoniae associated with carbon fines in mixed-population biofilms. The particles transported the coliforms to the biofilms and allowed successful colonization. Chlorine (0.5 mg/liter) was then applied as a disinfectant. Most K. pneumoniae along with the carbon fines left the biofilm under these conditions. The impact of chlorine was greater on the coliform bacteria and carbon fines than on the general fixed bacterial population. However, 10% of the introduced coliforms and 20% of the fines remained in the biofilm. The possibility that this represents a mechanism for bacteria of public health concern to be involved in regrowth events is discussed.
A set of uncoordinated (Unc) cold-sensitive (cs) mutants was isolated at a stringent condition of 11 degrees C. About half of the 13 independently isolated cs-Unc mutants were alleles of three X-linked Unc mutants that exhibited the "kinker" phenotype. The remaining four isolates identified new mutants that exhibited "kinker," "coiler," or severe paralytic phenotypes. The temperature-sensitive period (TSP) for each gene was determined. As a homozygous or heterozygous dominant, unc-125 exhibited a TSP throughout all stages of development. Its severe paralysis was immediately observed upon a shift down to 11 degrees C and reversed upon a shift up to 23 degrees C. The reversible thermolability of the unc-125 gene product indicated that it may function in a multicomponent process involved in neuro-excitation.
The objective of this study was to explore the use of alveolar macrophage culture to evaluate the cytotoxicity of two glass fiber materials, a building insulation fiberglass (a relatively long and thick fiber) and a glass microfiber (a short and thin fiber). Alveolar macrophages were obtained from male Sprague-Dawley rats by bronchoalveolar lavage and were cultured with varying fiber concentrations for up to 3 d. Fiber toxicity was assessed by assaying cell viability, membrane integrity, and phagocyte function. The microfibers exhibited a concentration-dependent cytotoxicity shown by the loss of cell viability and function. The building insulation fiberglass had little effect on cell viability and did not change macrophage function in this assay system. The results of this study show that short and thin glass fibers are more toxic than long and thick fibers in vitro, supporting a role of fiber dimension in toxicity.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
The pharmacodynamic interaction between mizolastine, a new H1 antihistamine, and ethanol was assessed in a randomized, double-blind, three-way crossover, placebo-controlled study. Eighteen healthy young male volunteers received mizolastine 10 mg, or cetirizine 10 mg or placebo once daily for 7 days with a 1-week wash-out interval. An oral dose of ethanol or ethanol placebo, given 2 h after dosing on days 5 or 7 of each treatment period, was administered to achieve a peak blood alcohol concentration (BAC) of 0.7 g/l then maintained for 1 h by two further doses of ethanol. Driving ability and psychomotor performance were evaluated using actual and simulated driving tests, critical flicker fusion threshold (CFF), adaptive tracking and divided attention (DAT) tasks. Ethanol produced a significant decrement in all tasks up to 5.5 h after administration: an increase in steering movements of 4.6, in lateral deviation of 0.45 m, in braking reaction time of 80 ms, in driving test and DAT performance of + 3.2; and a decrease in CFF and in tracking speed of 2.6 m.s-1. Neither mizolastine nor cetirizine significantly impaired driving ability or arousal (CFF) compared with the placebo. However, both drugs significantly impaired DAT performance 6:00 h post-dose (increase of + 2.1 for mizolastine and + 2.4 for cetirizine). The tracking speed was significantly decreased 7:50 h after mizolastine administration (-1.3 m.s-1) and more consistently from 1:30 to 7:50 h after cetirizine administration (-1.4 m.s-1). No significant adverse interaction, i.e. potentiation, occurred between ethanol and either antihistamine.(ABSTRACT TRUNCATED AT 250 WORDS)
OBJECTIVE: Our purpose was to analyze (1) the effects of prevalent lower reproductive tract infections and (2) the effect of systematic diagnosis and treatment to reduce risks of early pregnancy loss (< 22 weeks), preterm premature rupture of membrances, and overall preterm birth. STUDY DESIGN: A prospective, controlled treatment trial was conducted on 1260 women. During the first 7 months of the program (observation, phase I), women were examined at initiation of prenatal care for a panel of lower genital tract microorganisms and bacterial vaginosis. Women were followed up with reexaminations at 22 to 29 weeks and after 32 weeks' gestation. The recommended treatments of the Centers for Disease Control (i.e., 300 mg of clindamycin orally twice daily for 7 days for bacterial vaginosis) were used for infected women during the second 8 months of the study (treatment, phase II). Data were analyzed according to intent to treat by means of univariate and multivariate methods. RESULTS: Overall, presence of bacterial vaginosis (32.5%) at enrollment was associated with pregnancy loss at < 22 weeks' gestation (relative risk 3.1, 95% confidence interval 1.4 to 6.9). Among women in the observation phase bacterial vaginosis was associated with increased risk of both preterm birth (relative risk 1.9, 95% confidence interval 1.2 to 3.0) and preterm premature rupture of membranes (relative risk 3.5, 95% confidence interval 1.4 to 8.9). Within this population (phase I) 21.9% of preterm birth overall (43.8% premature rupture of membranes) is estimated as attributable to bacterial vaginosis. Among women with bacterial vaginosis phase II (treatment) was associated with reduced preterm birth (relative risk 0.5, 95% confidence interval 0.3 to 0.9); there was a similar reduction for women with preterm premature rupture of membranes (relative risk 0.5, 95% confidence interval 0.2 to 1.4). Women with both bacterial vaginosis and trichomoniasis were at highest risk of preterm birth (28%); treatment of both conditions (phase II) reduced preterm birth (17%) but did not eliminate this risk. Earlier patient enrollment and oral antibiotic treatment were associated with reduced preterm birth. CONCLUSIONS: This prospective, controlled trial confirms that the presence of bacterial vaginosis is associated with increased risks of pregnancy loss at < 22 weeks, preterm premature rupture of membranes, and preterm birth. Orally administered clindamycin treatment is associated with a 50% reduction of bacterial vaginosis-linked preterm birth and preterm premature rupture of membranes. Women at risk for preterm birth or preterm premature rupture of membranes because of bacterial vaginosis or common genital tract infections should be screened, treated, reevaluated for cure, and re-treated if necessary.