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D R Wilson

Publications and source records attributed to D R Wilson.

At least 55 records · Page 3Linked to original sources

Evolutionary epidemiology and manic depression.

The reformulation of epidemiological prevalence rates as evolutionary frequency rates puts medical genetics within an explicit framework of Darwinian theory. Yet an enduring and still current assumption of genomic medicine is that genes associated with disease are necessarily maladapted. Indeed, it seems it could hardly be otherwise. However, evolutionary epidemiology has begun to uncover important and surprising counter-exemplary case-studies. Thus, the present aim is to first outline this emerging sub-discipline of 'evolutionary epidemiology'. Then, a major psychopathological syndrome--manic-depression--is examined in some detail within the purview of evolutionary epidemiology. Its medical genetics are those of an adaptive polymorphism in the human genome. Hence, genes associated with what is now a major public health problem accrued as they conferred selective advantage in phylogeny. Why should manic-depressive etiogenes have been selected? A preliminary anatomic-functional model, assembled from facts of human paleoneuropsychiatry, more adequately contextualises manic-depressive genomics and phenotypy. In this model, manic-depression finds its heuristic origins in a hierarchy of behavioural strategies stabilised in phylogeny and embedded at serial levels in the brain (Hawk-Dove ESS). A proportion of the population has variant genotypy which appears to have been favoured in social competition phylogenetically but express more pathogenic phenotypy in the current environment. The paper closes with a brief consideration of clinical practices and ethical issues as alternative considerations emerge with the syndrome recast in a more positive Darwinian light.

Adaptation, Physiological↗

Antigenic analysis of Bordetella pertussis filamentous hemagglutinin with phage display libraries and rabbit anti-filamentous hemagglutinin polyclonal antibodies.

Although substantial advancements have been made in the development of efficacious acellular vaccines against Bordetella pertussis, continued progress requires better understanding of the antigenic makeup of B. pertussis virulence factors, including filamentous hemagglutinin (FHA). To identify antigenic regions of FHA, phage display libraries constructed by using random fragments of the 10-kbp EcoRI fragment of B. pertussis fhaB were affinity selected with rabbit anti-FHA polyclonal antibodies. Characterization of antibody-reactive clones displaying FHA-derived peptides identified 14 antigenic regions, each containing one or more epitopes. A number of clones mapped within regions containing known or putative FHA adhesin domains and may be relevant for the generation of protective antibodies. The immunogenic potential of the phage-displayed peptides was assessed indirectly by comparing their recognition by antibodies elicited by sodium dodecyl sulfate (SDS)-denatured and native FHA and by measuring the inhibition of this recognition by purified FHA. FHA residues 1929 to 2019 may contain the most dominant linear epitope of FHA. Clones mapping to this region accounted for ca. 20% of clones recovered from the initial library selection and screening procedures. They are strongly recognized by sera against both SDS-denatured and native FHA, and this recognition is readily inhibited by purified FHA. Given also that this region includes a factor X homolog (J. Sandros and E. Tuomanen, Trends Microbiol. 1:192-196, 1993) and that the single FHA epitope (residues 2001 to 2015) was unequivocally defined in a comparable study by E. Leininger et al. (J. Infect. Dis. 175:1423-1431, 1997), peptides derived from residues of 1929 to 2019 of FHA are strong candidates for future protection studies.

Adhesins, Bacterial↗

Rhabdomyolysis following moderate exercise.

Raised levels of serum muscle enzyme activity are frequently seen following unaccustomed or prolonged strenuous exercise. Following particularly severe exercise, muscle enzyme levels can be extremely high and are occasionally associated with rhabdomyolysis. A case of rhabdomyolysis following a moderate degree of accustomed exercise in a fit young soldier is reported and discussed.

Adult↗

Preparing for rural practice. Enhanced experience for medical students and residents.

PROBLEM ADDRESSED: Recruitment and retention of physicians appropriately trained for rural practice in Canada continues to be a serious challenge. We describe three integrated educational programs at the University of Alberta that aim to increase students' and residents' participation in rural health care and encourage them to take up practice in rural areas. OBJECTIVES OF PROGRAM: To expand and enrich rural educational experiences at undergraduate and postgraduate levels and to supplement family medicine postgraduate education with a third-year special-skills program for rural practice. MAIN COMPONENTS OF PROGRAM: Main components are sustained, reliable funding from the Government of Alberta for the Rural Physician Action Plan; adequate infrastructure to support the program; and commitment by university faculty, rural physicians, and communities. CONCLUSION: The rural-based educational programs have allowed more than 95% of medical students to gain experience in rural areas. The number of family medicine residents doing rural rotations has doubled, and the length of experiences in rural practice has increased fourfold. The third-year special-skills training for rural practice has expanded greatly, and at least 26 of 49 participants have gone on to enter rural practice. In more than 30 rural Alberta communities, 56 physicians have had an important influence on the training of medical students and family medicine residents.

Alberta↗

Phage display: applications, innovations, and issues in phage and host biology.

In the 7 years since the first publications describing phage-displayed peptide libraries, phage display has been successfully employed in a variety of research. Innovations in vector design and methods to identify target clones account for much of this success. At the same time, not all ventures have been entirely successful and it appears that phage and host biology play important roles in this. A key issue concerns the role played by a displayed peptide or protein in its successful expression and incorporation into virions. While few studies have examined these issues specifically in context of phage display, the literature as a whole provides insight. Accordingly, we review phage biology, relevant aspects of host biology, and phage display applications with the goals of illustrating (i) relevant aspects of the interplay between phage-host biology and successful phage display and (ii) the limitations and considerable potential of this important technology.

Amino Acid Sequence↗

The 'Asx-Pro turn' as a local structural motif stabilized by alternative patterns of hydrogen bonds and a consensus-derived model of the sequence Asn-Pro-Asn.

Analyses of databases derived from the Brookhaven Protein Data Bank have identified a set of related turn structures formed by the sequence Asx-Pro-Xxx(n). In a variety of flanking structural contexts, more than 60% of Asx-Pro sequences adopt a turn conformation stabilized by a set of alternative hydrogen bonds among the side chain O delta and backbone C = O carbonyl oxygens of Asx (residue i) and the backbone NH of residues i + 2, i + 3 and in some cases i + 4. In contrast, the structures adopted by Ser-Pro, His-Pro and other Xxx-Pro sequences reflect more heterogeneous hydrogen-bonding patterns. As expected, structures formed by Asx-Pro-Asx are similar to those formed by Asx-Pro-Xxx(n), but in some cases additional hydrogen bonds are formed between the Asx side chains. Hydrogen bond patterns within Asx-Pro and Asn-Pro-Asn turns are consistent with published NMR studies of helical (Asn-Pro-Asn-Ala)n peptides, indicating that a consensus structure reflecting these hydrogen bonds can serve as a partial model of the Asn-Pro-Asn-Ala tetrapeptide repeats of Plasmodium falciparum circumsporozoite protein.

Amino Acid Sequence↗

Recognition of phage-expressed peptides containing Asx-Pro sequences by monoclonal antibodies produced against Plasmodium falciparum circumsporozoite protein.

The immunodominant region of the Plasmodium falciparum circumsporozoite protein is comprised mainly of a series of tetrapeptide repeats that can, depending on the starting cadence chosen, be described as (NANP)n, (ANPN)n, (NPNA)n or (PNAN)n in one-letter amino acid code. Data from several studies suggest that the NPNA cadence alone is structurally correct, in that each NPNA tetrapeptide effectively forms a structural unit initiated by an Asx-Pro turn. To explore this idea further and to assess the immunological relevance of peptide conformation as it relates to the cadence of these tetrapeptide repeats, we used ELISA to compare the abilities of monoclonal antibodies (MAbs) produced against P. falciparum sporozoites to recognize repeat-related heptapeptides expressed on the surface of filamentous bacteriophage. Having included representatives of both NANP and NPNA cadences and other peptides in which the number and location of Asx-Pro sequences varied, we provide evidence that Asx-Pro sequences play an important role in peptide conformation and antibody recognition, that peptide conformation is influenced by the cadence of the tetrapeptide repeats and that peptide conformation is important to the abilities of these MAbs to recognize their epitopes.

Amino Acid Sequence↗

Impaired energy homeostasis in C/EBP alpha knockout mice.

Mice homozygous for the targeted deletion of the c/ebp alpha gene, which expresses the CCAAT/enhancer-binding protein alpha (C/EBP alpha), did not store hepatic glycogen and died from hypoglycemia within 8 hours after birth. In these mutant mice, the amounts of glycogen synthase messenger RNA were 50 to 70 percent of normal and the transcriptional induction of the genes for two gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, was delayed. The hepatocytes and adipocytes of the mutant mice failed to accumulate lipid and the expression of the gene for uncoupling protein, the defining marker of brown adipose tissue, was reduced. This study demonstrates that C/EBP alpha is critical for the establishment and maintenance of energy homeostasis in neonates.

Adipose Tissue↗

Autoregulation of the human C/EBP alpha gene by stimulation of upstream stimulatory factor binding.

The human C/EBP alpha gene promoter shares significant sequence homology with that of the mouse but has a different mechanism of autoregulation. Activation of the murine promoter by direct binding of C/EBP alpha to a site within 200 bp of the transcriptional start was shown to elevate activity by approximately threefold (R. J. Christy, K. H. Kaestner, D. E. Geiman, and M. D. Lane, Proc. Natl. Acad. Sci. USA 88:2593-2597, 1991; K. Legraverend, P. Antonson, P. Flodby, and K. G. Xanthapoulos, Nucleic Acids Res. 21:1735-1742, 1993). Unlike its murine counterpart, the human C/EBP alpha gene promoter does not contain a cis element that binds the C/EBP alpha protein. Neither C/EBP alpha nor C/EBP beta (NF-Il-6) binds the human C/EBP alpha promoter within 437 bp. However, cotransfection studies show that C/EBP alpha stimulates transcription of a reporter gene driven by 437 bp of the C/EBP alpha promoter. Our studies show that the human C/EBP alpha protein stimulates USF to bind to a USF consensus element within C/EBP alpha promoter and activates it by two- to threefold. We propose that the human gene employs the ubiquitously expressed DNA-binding protein factor USF to carry out autoregulation. Autoregulation of the human C/EBP alpha promoter was abolished by deletion of the USF binding site, CACGTG. Expression of human C/EBP beta following transfection did not stimulate USF binding. These studies suggest a mechanism whereby tissue-specific autoregulation can be achieved via a trans-acting factor that is expressed in all cell types. Thus, direct binding of the C/EBP alpha protein to the promoter of the C/EBP alpha gene is not required for autoregulation.

Amino Acid Sequence↗

Clinical predictors of acute risperidone response in schizophrenia, schizoaffective disorder, and psychotic mood disorders.

BACKGROUND: In studies of patients with schizophrenia, the atypical antipsychotic risperidone has been shown to be comparable in efficacy to haloperidol and, at dosages of 4 to 8 mg/day, to have a lower rate of extrapyramidal side effects. However, little is known about the efficacy of risperidone in patients with schizophrenia refractory to treatment with typical antipsychotics, schizoaffective disorder, and psychotic mood disorders. The purpose of this study was to assess the efficacy of risperidone in the treatment of these disorders and to identify clinical factors associated with risperidone response. METHOD: By surveying treating clinicians and chart data, we assessed response to risperidone and factors associated with response to risperidone in 144 consecutive patients treated with the drug for at least 2 weeks at a regional state psychiatric hospital. RESULTS: Patients displaying a moderate-to-marked response to risperidone were more likely to be younger; receive diagnoses of bipolar disorder or schizoaffective disorder, depressive type; and have a shorter duration of illness and shorter length of stay prior to risperidone treatment. Response to risperidone was sufficient to allow discharge in 26% of patients with treatment-refractory schizophrenia hospitalized for at least 10 weeks prior to risperidone and in 11% of patients with treatment-refractory schizophrenia hospitalized for greater than 1 year. CONCLUSION: Risperidone may be a useful alternative or adjunctive treatment for patients with schizophrenia refractory to treatment with standard antipsychotic agents, schizoaffective disorder (especially the depressive type), and bipolar disorder when used in conjunction with mood stabilizers.

Adult↗

The transcription factor HNF1 acts with C/EBP alpha to synergistically activate the human albumin promoter through a novel domain.

HNF1 and C/EBP alpha are transcription factors that bind to and trans-activate the human albumin gene proximal promoter. Various 5' deletions of the human albumin promoter were coupled to a luciferase reporter gene (alb-luc constructs) and co-electroporated with HNF1 and/or C/EBP alpha expression vectors into HeLa cells. Luciferase activities from co-electroporation of the HNF1 and C/EBP alpha expression vectors with the alb-luc constructs were approximately 10-fold greater than the sum of the activities achieved with HNF1 and C/EBP alpha alone. Analysis of COOH-terminal or internal deletions of the HNF1 expression vector revealed that the domain important for collaborative interaction with C/EBP alpha could be localized to a 157 amino acid region not previously described. This domain is proline and glutamine-rich and is highly homologous (66%) to a portion of vHNF1, an evolutionarily related gene first identified in dedifferentiated hepatoma cells. A construct linking the negatively charged activation domain of herpes simplex virus protein VP16 to the DNA-binding domain of HNF1 showed that it could also synergize with C/EBP alpha to trans-activate the human albumin gene promoter. Our studies delineate a domain in HNF1 important for synergistic activation with C/EBP alpha.

Albumins↗

A comparison of in vitro skin-penetration cells.

A new low-volume flow-through diffusion cell (LVFC) was designed to provide accurate determinations of penetrant flux across skin while minimizing the dilution of penetrant in receptor fluid and eliminating the need for magnetic stirring. The performance of the 0.3-mL LVFC was compared to a magnetically stirred, 4.3-mL high-volume flow cell (HVFC) and to a magnetically stirred, manually sampled 7.5-mL static cell (SC) with hydrophilic and lipophilic penetrants. The clearance of 14C-labeled benzoic acid from the LVFC and HVFC followed an exponential profile expected for complete mixing when the LVFC and HVFC were run at flow rates of 0.4-0.9 and 4.0-5.2 mL/h, respectively. The in vitro dispositions of 14C-labeled benzoic acid and estradiol were determined in the LVFC and HVFC by applying the compounds to split-thickness pig skin at a 4 micrograms/cm2 dose. Additionally, the effects of receptor fluid flow rate (1.2 vs 3.5 cell volumes/h) and method of skin attachment (O-ring vs compression) were determined on disposition in the HVFC. The percutaneous penetration of benzoic acid and the residue of estradiol within skin did not differ between the LVFC and HVFC. However, the percutaneous penetration of benzoic acid increased significantly (p < 0.05) using the O-ring attachment as compared to compression at a flow rate of 1.2 cell volumes/h. The in vitro permeation of benzoic acid-saturated water and 17 beta-estradiol-saturated propylene glycol monolaurate through human epidermis was compared between the LVFC, HVFC, and SC. The LVFC and HVFC had flow rates of 0.9-1.0 mL/h.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

The Darwinian roots of human neurosis.

The paper offers contextual and integrating comments about sex, evolution and psychopathology as a point of departure toward a new and more scientific understanding of human neurosis. The evolved roots of neurotic behavior are firmly linked to theorems of evolution, which is emerging as the basic science of psychopathology. Evolutionary tenets serve to: 1) redefine key aspects of neuroses, 2) place neurotic behavior in a broad and integrated evolutionary context, and 3) pose basic questions for all psychopathology. Readers who wish to expand, clarify or confirm elements of might well consult basic books in either field as a passing familiarity with psychiatry and biology is assumed.

Animals↗

Dietary salt extremes and renal function in rats: effect of atrial natriuretic factor.

1. Chronic reduction of salt intake can reduce the natriuretic effect of exogenously administered atrial natriuretic factor. The purpose of this study was to elucidate the intrarenal site(s) of such atrial natriuretic factor resistance. Renal clearance and collecting duct microcatheterization experiments were made before and during infusion of atrial natriuretic factor in three groups of rats: group 1 consisted of rats fed a high salt diet (8% NaCl) for 1 week before the experiment; group II were fed a low salt diet (< 0.008%); group III received the same low salt diet, but were acutely replenished with salt at the time of experiment. 2. Baseline sodium chloride excretion was 6480 +/- 810 nmol min-1 g-1 kidney weight in group 1 compared to 99 +/- 16 in group 1. Fractional reabsorptions in the medullary collecting duct were 37 +/- 6% and 95 +/- 2% of delivered load, respectively (P < 0.05). The fractions of filtered sodium remaining at the beginning of the medullary duct were 6.6 +/- 1.0% of filtered load in group 1 and 2.7 +/- 0.7% in group II (P < 0.05), indicating increased tubular reabsorption in group II, not only in the medullary duct, but also in upstream nephron segments.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗

Participation of the transcription factor C/EBP delta in the acute-phase regulation of the human gene for complement component C3.

C3, the third component of complement, is critical in the host immune response in that it is involved in both the classical and alternative pathways of complement activation. We have previously shown that a region (bp -127 to -70) within the C3 promoter is indispensable for conferring interleukin 1 (IL-1) responsiveness to this gene. A sequence comparison reveals two CCAAT/enhancer binding protein (C/EBP) consensus sequences, basic DNA binding region and leucine zippers 1 and 2 (bZIP1 and bZIP2), within this region. Site-directed mutagenesis of the more 3' C/EBP site (bZIP1) in the C3 promoter significantly reduced the basal level of expression and the IL-1 responsiveness of the reporter gene, whereas mutation in the second, more 5', C/EBP consensus sequence (bZIP2) had a minimal effect on basal expression and IL-1 inducibility. Electrophoretic-mobility-shift assays, with and without antibodies to the different C/EBP proteins that "supershift" protein-DNA complexes, demonstrated that proteins binding at the 3' C/EBP site formed several complexes. Antibodies to C/EBP alpha supershifted the majority of complexes formed with extracts from control cells. Antibodies directed against C/EBP delta supershifted the major IL-1-inducible complexes. Western immunoblot analyses showed that the level of C/EBP delta protein was increased dramatically in the nuclei of Hep 3B2 cells after 4 h of IL-1 treatment. When Hep 3B2 cells were cotransfected with a C/EBP delta expression vector and a construct with a C3 promoter and a reporter gene, C/EBP delta was able to trans-activate the C3 promoter in an IL-1-responsive manner. The data strongly suggest that C/EBP delta is the major protein responsible for regulating the acute-phase expression of the human C3 gene.

Base Sequence↗