Job strain and cardiovascular disease.
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Bias↗
Biomedical subjects
D Baker
Publications and source records attributed to D Baker.
Emergence of T-lymphocytes, eosinophils and dendritic cells in the bronchi of actively sensitized guinea pigs after antigenic challenge.
Bronchi from guinea pigs actively sensitized to ovalbumin and boosted two weeks later display increased numbers of CD4+ T-lymphocytes and eosinophils. We have further investigated immunopathological changes in sensitized guinea pigs 2 or 24 h after antigenic challenge with ovalbumin. Lungs were resected, frozen and cryostat sections stained with monoclonal antibodies that recognize relevant guinea pig epitopes. Cyanide-resistant peroxidase activity was used to stain eosinophils. No further increase in T-lymphocytes or eosinophils was observed 2 h after challenge. At 24 h, a marked increase in EPO+ eosinophils was found, and this was accompanied by severe mucosal damage characterized by epithelial shedding and ulceration. The numbers of T-lymphocytes remained stable but a novel population of cells with the appearance of dendritic cells was seen in the bronchial wall. They were negative for macrophage markers but were strongly Class II positive. These findings suggest that antigenic challenge results in further recruitment of eosinophils, their activation and release of toxic substances to the epithelium. Furthermore, other cell types, possibly dendritic cells, are attracted to the bronchi and could play a role in maintaining allergic inflammation via antigen presentation.
Animals↗
Opioid antagonist effects on self-injury in adults with mental retardation: response form and location as determinants of medication effects.
The opioid antagonist naltrexone was administered to 8 adults with severe or profound mental retardation and extensive histories of self-injurious behavior. Five-minute behavioral samples were observed randomly out of every hour from 8 a.m. through 3 p.m., Monday through Friday, for four 2-week phases (baseline, placebo, 50 mg, and 100 mg). During naltrexone administration, there were fewer days with frequent head-banging and self-biting, whereas there were more days on which blows to the head or self-biting were infrequent. Self-injurious participants slept 1.38 hours less per night during baseline, which was unaffected by naltrexone.
Adult↗
Impact of the 1990 contract for general practitioners on night visiting.
BACKGROUND: The 1990 contract for general practitioners extended the hours of eligibility for night visiting claims by 25% and introduced financial incentives to discourage the use of deputizing services. AIM: This study set out to examine the impact of these contract changes on the rate and pattern of night visiting. METHOD: Family health services authority data were used to compare trends in night visiting before and after the introduction of the new contract. Rates were calculated separately for those authorities which might be expected to have a high rate of visiting because of their demographic structure and those that might be expected to have a high rate because of their socioeconomic composition, thus separating out these two sets of factors combined in the Jarman index. RESULTS: Rates of night visiting increased by 33% between 1989 and 1990 while the proportion of visits made by deputies fell by 19%. These changes could not simply be explained either by the extension of eligible hours or the success of financial incentives in changing behaviour in the appropriate direction. It was found that the effect of the new contract was to increase visiting most in family health services authorities with a high proportion of elderly people living alone, that is, where demand would be expected to be higher. In previous years there had been little variation in visiting rates between authorities with a high proportion of those aged 65 years and over living alone and those with a low proportion. The effect of the contract was also to increase rates of visiting most in affluent authorities, that is, where demand would be predicted to be lower. This again marked a sharp break with trends in previous years in that the gap between the high rates in the deprived family health services authorities and lower rates in the most affluent authorities narrowed. CONCLUSION: The 1990 contract achieved the government's policy aims of promoting night visiting by principals and discouraging the use of deputies in its first year. However, the finding that doctors responded more to demand from elderly people and affluent people than from deprived people presents a challenge both for analysis and for policy. It underlines the importance of disaggregating the Jarman index when examining the impact of policy change on local populations and suggests that general practitioners in the most deprived family health services authorities may lack the capacity or the incentive to respond to the changes introduced in the 1990 contract.
Adolescent↗
Retroviral-mediated gene transfer of a mutant H-ras gene into normal human bone marrow alters myeloid cell proliferation and differentiation.
To investigate the effects of mutant ras expression on the growth and differentiation of normal human bone marrow, we used retrovirus-mediated gene transfer. A retrovirus (HR-1) containing a mutant ras gene (H12-ras) in addition to the selectable neo gene was transferred by cocultivation of a packaging cell line with long-term cultures of normal human bone marrow. Controls were established by cocultivating aliquots of the same bone marrow with a retrovirus (VSN-2) containing only neo. The efficiency of gene transfer, as determined by the percentage of G418-resistant colony-forming units-granulocyte/macrophage (CFU-GM) immediately after termination of cocultivation, was similar: 8 +/- 4% with HR-1 and 5 +/- 3% with VSN-2. After a further week in long-term culture, there was an increase in the number and percentage of G418-resistant CFU-GM in both the HR-1-infected and VSN-2-infected marrows. Thereafter, the numbers of G418-resistant CFU-GM declined, becoming undetectable at 4 weeks. The time course of the production of G418-resistant colonies was not significantly different in HR-1- and VSN-2-infected marrows, indicating that H12-ras did not alter the proliferation of normal CFU-GM. However, the total cellularity of HR-1-infected marrow cultures was significantly greater than that of VSN-2-infected marrow cultures. This was due to increased cellular proliferation of HR-1-infected cultured cells, since differential counts showed a significant increase in myeloid blast cells together with a slight reduction in mature myeloid cells in HR-1-infected marrow compared to baseline and to VSN-2-infected marrow. No leukemic blast cell colonies were grown from HR-1-infected marrows or control marrows, and HR-1 infection did not confer serum independence. These data show successful retroviral infection of normal bone marrow progenitor cells and suggest that expression of mutant H12-ras in such cells results in enhanced proliferation of early myeloid cells at the expense of differentiation.
Animals↗
PRISM: application to the solution of two protein structures.
The previous paper described a phase-refinement strategy for protein crystallography which exploited the information that proteins consist of connected linear chains of atoms. Here the method is applied to a molecular-replacement problem, the structure of the protease inhibitor ecotin bound to trypsin, and a single isomorphous replacement problem, the structure of the N-terminal domain of apolipoprotein E. The starting phases for the ecotin-trypsin complex were based on a partial model (trypsin) containing 61% of the atoms in the complex. Iterative skeletonization gave better results than either solvent flattening or twofold non-crystallographic symmetry averaging as measured by the reduction in the free R factor [Brünger (1992). Nature (London), 355, 472-474]. Protection of the trypsin density during the course of the refinement greatly improved the performance of both skeletonizing and solvent flattening. In the case of apolipoprotein E, previous attempts using solvent flattening had failed to improve the SIR phases to the point of obtaining an interpretable map. The combination of iterative skeletonization and solvent flattening decreased the phase error with respect to the final refined structure, significantly more than solvent flattening alone. The final maps generated by the skeletonization procedure for both the ecotin-trypsin complex and apolipoprotein E were readily interpretable.
Journal Article↗
PRISM: topologically constrained phased refinement for macromolecular crystallography.
We describe the further development of phase refinement by iterative skeletonization (PRISM), a recently introduced phase-refinement strategy [Wilson & Agard (1993). Acta Cryst. A49, 97-104] which makes use of the information that proteins consist of connected linear chains of atoms. An initial electron-density map is generated with inaccurate phases derived from a partial structure or from isomorphous replacement. A linear connected skeleton is then constructed from the map using a modified version of Greer's algorithm [Greer (1985). Methods Enzymol. 115, 206-226] and a new map is created from the skeleton. This 'skeletonized' map is Fourier transformed to obtained new phases, which are combined with any starting-phase information and the experimental structure-factor amplitudes to produce a new map. The procedure is iterated until convergence is reached. In this paper significant improvements to the method are described as is a challenging molecular-replacement test case in which initial phases are calculated from a model containing only one third of the atoms of the intact protein. Application of the skeletonization procedure yields an easily interpretable map. In contrast, application of solvent flattening does not significantly improve the starting map. The iterative skeletonization procedure performs well in the presence of random noise and missing data, but requires Fourier data to at least 3.0 A. The constraints of linearity and connectedness prove strong enough to restore not only missing phase information, but also missing amplitudes. This enables the use of a powerful statistical test, analogous to the 'free R factor' of conventional refinement [Brünger (1992). Nature (London), 355, 472-474], for optimizing the performance of the skeletonization procedure. In the accompanying paper, we describe the application of the method to the solution of the structure of the protease inhibitor ecotin bound to trypsin and to a single isomorphous replacement problem.
Journal Article↗
A point mutation associated with leukocyte adhesion deficiency type 1 of moderate severity.
Leukocyte adhesion deficiency (LAD) is a genetic disease characterized clinically by severe bacterial infections, and biochemically by a deficiency in the surface expression of the CD11/CD18 leukocyte integrins. We studied a teenage girl with the moderate deficiency phenotype of LAD. B-lymphoblastoid cells from this patient displayed approximately 5% of normal levels of CD11/CD18 on the cell surface. Although a normal sized CD18 mRNA was detectable on Northern blotting, a small CD18 protein was present on Western blotting. Sequencing of the RNA revealed a single base pair substitution resulting in a glycine to serine amino acid substitution at amino acid 284. This amino acid substitution occurs within a highly conserved region of the extracellular domain of CD18 in which several other mutations have been identified in LAD.
Adolescent↗
Identification of a major encephalitogenic epitope of proteolipid protein (residues 56-70) for the induction of experimental allergic encephalomyelitis in Biozzi AB/H and nonobese diabetic mice.
Native proteolipid (PLP) and synthetic 15- or 16-mer peptides of the whole PLP molecule, with eight amino acid overlaps, were screened for their ability to induce experimental allergic encephalomyelitis in Biozzi AB/H (H-2dq1) mice. Clinical and histological evidence of experimental allergic encephalomyelitis developed after sensitization with native PLP and with the PLP sequence 56-70 (DYEYLINVIHAFQYV) but not with the other synthetic PLP peptides used. Nonobese diabetic mice that share similar MHC determinants (H-2Anod) with Biozzi AB/H mice, could be induced to develop experimental allergic encephalomyelitis after sensitization with either mouse spinal cord homogenate or the PLP 56-70 peptide. Although the PLP 56-70 overlaps with the encephalitogenic epitope of PLP (residues 43-64) in PL/J (H-2u) mice the Biozzi AB/H mice did not exhibit disease with either PLP 43-64 peptide or the nonapeptide PLP 56-64 that overlaps both the Biozzi AB/H and PL/J encephalitogenic peptides. The identification of a novel major encephalitogenic epitope of PLP for Biozzi AB/H mice, increases the repertoire of encephalitogenic epitopes of PLP and supports a role for PLP as a target Ag in autoimmune demyelinating diseases.
Amino Acid Sequence↗
Spatially localized rhomboid is required for establishment of the dorsal-ventral axis in Drosophila oogenesis.
The establishment of dorsal-ventral asymmetry of the Drosophila embryo requires a group of genes that act maternally. None of the previously identified dorsal-ventral axis genes are known to produce asymmetrically localized gene products during oogenesis. We show that rhomboid (rho), a novel member of this group, encodes a protein that is localized on the apical surface of the dorsal-anterior follicle cells surrounding the oocyte. Loss of rho function causes ventralization of the eggshell and the embryo, whereas ectopic expression leads to dorsalization of both structures. Thus, spatially restricted rho is necessary and sufficient for dorsal-ventral axis formation. We propose, based on these observations and double mutant experiments, that the spatially restricted rho protein leads to selective activation of the epidermal growth factor receptor in the dorsal follicle cells and subsequently the specification of the dorsal follicle cells.
Animals↗
Uniqueness and the ab initio phase problem in macromolecular crystallography.
The crystallographic phase problem is indeterminate in the absence of additional chemical information. A successful ab initio approach to the macromolecular phase problem must employ sufficient chemical constraints to limit the solutions to a manageably small number. Here we show that commonly employed chemical constraints - positivity, atomicity and a solvent boundary - leave the phase problem greatly underdetermined for Fourier data sets of moderate (2.5-3.0 A) resolution. Entropy maximization is also beset by multiple false solutions: electron-density maps are readily generated which satisfy the same Fourier amplitude constraints but have higher entropies than the true solution. We conclude that a successful ab initio approach must make use of high-resolution Fourier data and/or stronger chemical constraints. One such constraint is the connectivity of the macromolecule. We describe a rapid algorithm for measuring the connectivity of a map, and show its utility in reducing the multiplicity of solutions to the phase problem.
Journal Article↗
Isolation and characterization of cells infiltrating the spinal cord during the course of chronic relapsing experimental allergic encephalomyelitis in the Biozzi AB/H mouse.
A novel method for the isolation of leukocytes from the spinal cords of mice during chronic relapsing experimental allergic encephalomyelitis (CREAE) was developed using discontinuous density gradients. Immunostaining of these cells, together with spinal cord sections and peripheral blood leukocytes, with a panel of monoclonal antibodies enabled a detailed profile of the kinetics and cell phenotype during CREAE to be developed. Overall, the kinetics of cell accumulation within the spinal cord correlated with disease severity. The number of cells increased from an average of 5 x 10(4) in unimmunized animals to 40 x 10(4) in paralysed animals during the initial disease episode. The cell numbers rapidly declined with clinical remission (6 x 10(4) cells/cord) and again dramatically increased during clinical relapse. Low numbers of CD3+ lymphocytes (50-150 cells) were consistently isolated from normal mice. However, the number of T cells infiltrating the spinal cord increased following immunization. The numbers of T cells, macrophages, B cells, neutrophils, and Ig-bearing cells all paralleled the clinical disease course, with T cells and macrophages (showing evidence of myelin breakdown) predominating. T cells infiltrating the spinal cord generally failed to express gamma delta T cell receptors and expressed low levels of IL-2 receptors (5% of infiltrating T cells). These cells were phenotypically dissimilar to peripheral blood leukocytes isolated in parallel, with the spinal cord having a consistently higher ratio (9:1) of CD4+ to CD8+ than the peripheral blood (7:3). The low expression of MEL-14 (L-selectin) and 16a antigen (CD45RBhigh) and the higher levels of Pgp-1 (CD44) expressed by the infiltrating T cells, compared with splenocytes, suggest a preferential recruitment/retention of distinct T cell subsets, possibly memory/primed cells, into the central nervous system from the periphery during neuroimmunological disease.
Animals↗
Complete characterization of the expressed immune response genes in Biozzi AB/H mice: structural and functional identity between AB/H and NOD A region molecules.
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Amino Acid Sequence↗
Control of immune-mediated disease of the central nervous system with monoclonal (CD4-specific) antibodies.
Chronic relapsing experimental allergic encephalomyelitis (CREAE) was induced in Biozzi AB/H (H-2dq1) mice by active sensitization with spinal cord antigens. A single i.p. injection of CD8-depleting (YTS169.4) monoclonal antibody (mAb) failed to affect the clinical course of CREAE when administered prior to and during the onset of both the initial clinical and subsequent relapse phase of the disease. By contrast similar treatment with both CD4-depleting (YTS191.1) or CD4-blocking/non-depleting (YTS177.9) mAb significantly inhibited disease progression. Treatment shortly before the anticipated onset of clinical EAE prevented the subsequent development of disease, although disease could be provoked following antigen-rechallenge. In contrast, treatment with these antibodies during post-acute remission phase mainly served to delay the incidence of relapse. This suggests that, unless tolerance can be re-induced, treatment of ongoing neuroimmunological disease will require 'pulse' therapy and thus potentiate the problems of long-term immunosuppresion. Despite the findings that CD4-specific antibodies can rapidly reverse overt clinical disease shortly after the onset of disease exacerbation, once neurological dysfunction becomes established anti-CD4 treatment fails to improve the animals clinically, possibly due to the inability to rapidly reverse established demyelination. Although this study does not exclude the potential central action of the injected mAb, the failure to significantly dissociate therapeutic benefit between mAb administered directly into the CNS and that given systemically suggests that a major action of these agents is probably by selectively removing T cells in the peripheral T cell pool.
Animals↗
The role of pro regions in protein folding.
In vivo, many proteases are synthesized as larger precursors. During the maturation process, the catalytically active protease domain is released from the larger polypeptide or pro-enzyme by one or more proteolytic processing steps. In several well studied cases, amino-terminal pro regions have been shown to play a fundamental role in the folding of the associated protease domains. The mechanism by which pro regions facilitate folding appears to be significantly different from that used by the molecular chaperones. Recent results suggest that the pro region assisted folding mechanism may be used by a wide variety of proteases, and perhaps even by non-proteases.
Bacterial Proteins↗
Chlorpromazine with and without lorazepam as antiemetic therapy in children receiving uniform chemotherapy.
We prospectively studied the efficacy and adverse effects of chlorpromazine (30 mg/m2 given intravenously) plus lorazepam (0.04 mg/kg given intravenously) versus chlorpromazine alone in a controlled, double-blind, randomized, parallel-design investigation in 25 children (1.5 to 17.3 years of age) with acute lymphoblastic leukemia. Response to other antiemetics in eight children refusing random assignment to treatment was also evaluated. All children were receiving intravenous infusions of teniposide plus cytarabine, the pharmacokinetics of which were characterized for each of the one to four courses. There were no differences between the 11 patients randomly assigned to receive chlorpromazine alone and the 14 randomly assigned to receive lorazepam plus chlorpromazine in the number of emesis episodes (6.0 vs 5.9; p = 0.53), frequency of dystonic reactions (3% vs 5%), or akathisia (13 vs 10%). The only serious adverse event, symptomatic hypotension, occurred in a boy receiving chlorpromazine plus lorazepam. An exploratory pharmacodynamic analysis revealed that the only variable that correlated with vomiting was cytarabine 1 1/2-hour plasma concentration (p = 0.007). Children who received either chlorpromazine plus lorazepam or chlorpromazine alone had fewer episodes of vomiting than those who received "conventional" antiemetic therapy (6.0 vs 8.6; p = 0.01). We conclude that the severity of emesis is related to the plasma concentration of cytarabine; that intravenously administered chlorpromazine is as effective as chlorpromazine plus lorazepam in preventing chemotherapy-induced vomiting; and that the potential for adverse effects with the addition of lorazepam may be a disadvantage.
Adolescent↗
Supermarket checker motions and cumulative trauma risk.
The relationship between specific motions and symptoms consistent with upper extremity cumulative trauma disorders (UECTDs) was investigated in 50 supermarket checkers. Each completed a questionnaire concerning UECTD symptoms; four composite symptom indices were derived: any arm symptoms, hand-wrist-lower arm (S-DIST), upper arm, and symptoms specifically associated with carpal tunnel syndrome (S-SPC). Each participant was videotaped on at least two occasions while performing checking work. Analysis of these tapes assigned each subject a composite motion index for each of the following motions: wrist flexion, wrist extension, body (lumbar) flexion, pronation, grip type, and tendency to lift objects. "Positive" symptom status was defined by a score in the upper quartile for the symptom index. Relationships between an individual's motion indices and symptom indices were analyzed by determining the percent of subjects "positive" for symptoms in each quartile of motion index, by rank correlation, and by regression of symptom scores on principal components of motions. Trends toward relationship of wrist flexion and extension, lumbar flexion, and pronation with S-DIST and S-SPC were noted. Principal components regression confirmed that extension and flexion were related to these two symptom outcomes. This study suggests that postural loading can be determined on an individual basis in a meaningful fashion and that interventions that decrease such loading may be beneficial. It supports the role of certain repetitive motions as causes of UECTD symptoms.
Adult↗
Immunopathologic alterations in the bronchi of immunized guinea pigs.
Isolated lungs from guinea pigs actively sensitized to ovalbumin and boosted 2 wk later display an enhanced bronchoconstriction and release larger amounts of secondary mediators as compared with lungs from nonimmunized animals when stimulated by platelet-activating factor or other agonists. We have investigated changes in T lymphocytes and eosinophils found in the bronchial wall of immunized and nonimmunized guinea pigs. The animals received two injections of 10 micrograms ovalbumin in Al(OH)3, at a 2-wk interval. Two studies were performed: (1) the animals were killed 7 days after the booster injection of antigen, (2) they were challenged with ovalbumin at this same day and killed after 2 or 24 h. Lungs were resected and frozen, and cryostat sections stained using monoclonal antibodies that recognize T cells, T cell subsets, or other relevant epitopes. Cyanide-resistant peroxidase activity was used to identify eosinophils. A large number of T cells, mainly of the CD4+ subset, and eosinophils were recruited into the bronchi 7 days after the booster injection of the antigen, compared with nonimmunized or nonboosted animals. In antigen-challenged animals, the numbers of T cells did not change but eosinophils were further increased in number at the 24 h time point. Also at this time point, a population of cells with a dendritic appearance was seen in the bronchial wall, which did not express macrophage markers but was strongly class II positive. Class II positivity was also noted in the bronchial epithelium and on many cells infiltrating the mucosa. These findings suggest that activated T cells and/or their products play an important role in the bronchopulmonary immunopathology associated with this model and possibly with the development of bronchial hyperreactivity.
Animals↗