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Biomedical subjects

D J Davidson

Publications and source records attributed to D J Davidson.

At least 19 recordsLinked to original sources
PubMed2006

Immunomodulatory properties of defensins and cathelicidins.

Host defence peptides are a conserved component of the innate immune response in all complex life forms. In humans, the major classes of host defence peptides include the alpha- and beta-defensins and the cathelicidin, hCAP-18/LL-37. These peptides are expressed in the granules of neutrophils and by a wide variety of tissue types. They have many roles in the immune response including both indirect and direct antimicrobial activity, the ability to act as chemokines as well as induce chemokine production leading to recruitment of leukocytes to the site of infection, the promotion of wound healing and an ability to modulate adaptive immunity. It appears that many of these properties are mediated though direct interaction of peptides with the cells of the innate immune response including monocytes, dendritic cells, T cells and epithelial cells. The importance of these peptides in immune responses has been demonstrated since animals defective in the expression of certain host defence peptides show greater susceptibility to bacterial infections. In the very few instances in which human patients have been demonstrated to have defective host defence peptide expression, these individuals suffer from frequent infections. Although studies of the immunomodulatory properties of these peptides are in their infancy, there is a growing body of evidence suggesting that the immunomodulatory properties of these small, naturally occurring molecules might be harnessed for development as novel therapeutic agents.

Amino Acid Sequence↗
PubMed2006

Endogenous pulmonary antibiotics.

The human lung produces a variety of peptides and proteins which have intrinsic antimicrobial activity. In general these molecules have broad spectra of antimicrobial activity, kill micro-organisms rapidly, and evade resistance generated by pathogens. In recent years it has become increasingly apparent that the antimicrobial peptides (AMPs) simultaneously possess immunomodulatory functions, suggesting complex roles for these molecules in regulating the clearance of, and immune response to, invading pathogens. These collective properties have stimulated considerable interest in the potential clinical application of endogenous AMPs. This article outlines the biology of AMPs, their pattern of expression in the lung, and their functions, with reference to both antimicrobial and immunomodulatory activity. We then consider the biological importance of AMPs, before concentrating on the potential to use AMPs to therapeutic effect. The principles discussed in the article apply to innate immune defence throughout the body, but particular emphasis is placed on AMPs in the lung and the potential application to pulmonary infection.

Anti-Bacterial Agents↗
PubMed2001

Syndromes of schizophrenia and smooth-pursuit eye movement dysfunction.

There have been a number of studies on smooth pursuit eye movement (SPEM) dysfunction in schizophrenia. However, the association between SPEM dysfunction and particular clinical symptoms remains unclear. We examined SPEM dysfunction in relation to schizophrenic symptoms using both the positive/negative dichotomy and the three-syndrome model. Subjects included 78 patients with schizophrenia and 60 healthy control subjects. SPEM performance was indexed by root mean square error. Symptom profiles were assessed using the Positive and Negative Syndrome Scale (PANSS), and the three-primary syndromes were identified by factor analysis of PANSS ratings (Psychomotor poverty: deficit negative symptoms; Disorganization: defined primarily by thought disorder; and Reality distortion: hallucinations and delusions). Compared with controls, the schizophrenia group showed significant impairment in global SPEM function. The three-syndrome approach produced more specific findings than the dichotomous model. Of the three syndromes, only the Disorganization dimension showed a significant association with increased global SPEM dysfunction. The specificity of SPEM dysfunction to Disorganization was verified in comparisons among schizophrenia subgroups and the control group. By contrast, the general domains of positive and negative symptoms were both found to be modestly associated with SPEM dysfunction. The separation of positive and negative symptoms that contribute to Disorganization from those that define Reality Distortion and Psychomotor Poverty has revealed significant new associations between SPEM and schizophrenic symptoms. These findings are interpreted in light of the proposal that the Disorganization syndrome is the central form of pathology in schizophrenia.

Adolescent↗
PubMed2001

Mouse models of cystic fibrosis.

The development of mouse models for cystic fibrosis has provided the opportunity to dissect disease pathogenesis, correlate genotype and phenotype, study disease-modifying genes and develop novel therapeutics. This review discusses the successes and the challenges encountered in characterizing and optimizing these models.

Animals↗
PubMed2001

X-ray microanalysis of airway surface liquid collected in cystic fibrosis mice.

The airway surface liquid (ASL) that lines the airway surface epithelium plays a major role in airway antibacterial defense and mucociliary transport efficiency, two key factors in cystic fibrosis (CF) disease. A major difficulty is to collect ASL in native conditions without stimulation or alteration of the underlying airway epithelium. Using a cryoprobe specifically adapted to collect native ASL from the tracheal mouse surface, we analyzed by X-ray microanalysis the complete ASL and plasma ion content in Cftr(tm1Hgu)/Cftr(tm1Hgu) mice compared with that in control littermates. ASL ion content from eight Cftr(tm1Hgu)/Cftr(tm1Hgu) mice and eight control littermates did not appear significantly different. The mean (+/-SE) concentrations were 2,352 +/- 367 and 2,058 +/- 401 mmol/kg dry weight for Na, 1,659 +/- 272 and 1,448 +/- 281 mmol/kg dry weight for Cl, 357 +/- 57 and 337 +/- 38 mmol/kg dry weight for S, 1,066 +/- 220 and 787 +/- 182 mmol/kg dry weight for K, 400 +/- 82 and 301 +/- 58 mmol/kg dry weight for Ca, 105 +/- 31 and 105 +/- 20 mmol/kg dry weight for Mg, 33 +/- 15 and 29 +/- 9 mmol/kg dry weight for P in non-CF and CF mice, respectively. This cryotechnique appears to be a promising technique for analyzing the complete elemental composition of native ASL in CF and non-CF tissues.

Animals↗
PubMed2001

Processing of threat-related affect is delayed in delusion-prone individuals.

OBJECTIVES: On the basis of previous reports of an attentional bias for threat-related emotional material in deluded schizophrenics (e.g. Bentall & Kaney, 1989), the present study examined the proposal that a similar bias would be demonstrated by delusion-prone individuals, reflected by longer response latencies for the task of processing threat-related facially displayed affects (e.g. anger, fear). DESIGN: A non-randomized matched group design was employed to examine the performance of delusion-prone individuals in comparison with a control group. METHODS: 50 psychiatrically healthy participants completed the Peters et al. Delusions Inventory (PDI) as an index of delusional ideation (Peters, Day, & Garety, 1996; Peters, Joseph, & Garety, 1999). Subjects were presented with a standard set of facial stimuli depicting happy, sad, neutral, fearful and angry emotion expressions (Mazurski & Bond, 1993). Reaction times for the task of identifying each type of affect were compared between groups of high and low scorers on the PDI. RESULTS: Highly delusion-prone individuals displayed a significant delay in processing angry facial expressions in comparison with low scorers on the PDI. CONCLUSIONS: The increased response latency for processing angry expressions was interpreted as evidence of attentional bias for material posing a threat to the self, supporting previous cognitive data in relation to deluded patients. Threatening facial expressions may be regarded with increased significance by delusion-prone individuals, and it is possible that this bias is involved in the formation of delusional beliefs.

Adolescent↗
PubMed2000

Bacterial DNA is implicated in the inflammatory response to delivery of DNA/DOTAP to mouse lungs.

Phase 1 clinical trials of liposome-mediated gene therapy for cystic fibrosis have been completed and in all cases the expression level achieved has been low and transient. Clearly, improvements in the efficiency of gene transfer are required. It is now being recognised that delivery of high doses of DNA/liposomes to the mouse airway epithelium can achieve reproducible evidence of transgene, but is often associated with an unacceptable level of inflammation/ toxicity. It has recently been shown that instillation of bacterial DNA causes inflammation in the lower respiratory tract of rodents. The increased number and unmethylated status of CpG motifs, particularly when present in a particular base context, was identified as an important factor in this response. It was suggested that the immune system recognises this molecular pattern as 'foreign' thus activating appropriate immune responses. We have found that methylation of DNA decreases the level of several inflammatory cytokines in lavage fluid and surprisingly has a differential effect on expression of the plasmids pCMV CFTR-int6ab and pCMV CAT which only differ in the actual transcription cassette. The severe lung pathology observed did not show a corresponding decrease with methylation suggesting that these cytokines are not the only contributors to the toxicity/inflammation observed. Gene Therapy (2000) 7, 384-392.

Animals↗
PubMed2000

A primary culture model of differentiated murine tracheal epithelium.

The goal of this study was to develop a primary culture model of differentiated murine tracheal epithelium. When grown on semipermeable membranes at an air interface, dissociated murine tracheal epithelial cells formed confluent polarized epithelia with high transepithelial resistances ( approximately 12 kOmega. cm(2)) that remained viable for up to 80 days. Immunohistochemistry and light and electron microscopy demonstrated that the cells were epithelial in nature (cytokeratin positive, vimentin and alpha-smooth muscle actin negative) and differentiated to form ciliated and secretory cells from day 8 after seeding onward. With RT-PCR, expression of the cystic fibrosis transmembrane conductance regulator (Cftr) and murine beta-defensin (Defb) genes was detected (Defb-1 was constitutively expressed, whereas Defb-2 expression was induced by exposure to lipopolysaccharide). Finally, Ussing chamber experiments demonstrated an electrophysiological profile compatible with functional amiloride-sensitive sodium channels and cAMP-stimulated CFTR chloride channels. These data indicate that primary cultures of murine tracheal epithelium have many characteristics similar to those of murine tracheal epithelium in vivo. This method will facilitate the establishment of primary cultures of airway epithelium from transgenic mouse models of human diseases.

Amiloride↗
PubMed1999

A novel mouse beta defensin, Defb2, which is upregulated in the airways by lipopolysaccharide.

Studies have shown that beta defensins are present in the human airways and may be relevant to the pathogenesis of cystic fibrosis lung disease. Here we report the identification of a novel mouse gene, Defb2, which shows sequence similarity to previously described mouse and human airway beta defensins. Defb2 does not appear to be expressed in the airways of untreated mice but it is upregulated in response to lipopolysaccharide. The induced expression of this gene by an inflammatory stimulus strongly suggests that this defensin contributes to host defence at the mucosal surface of the airways.

Amino Acid Sequence↗
PubMed1998

Mouse beta defensin-1 is a functional homolog of human beta defensin-1.

Defensin are 3-4 kDa antimicrobial peptides of which three distinct families have been identified; alpha-defensin, beta-defensins, and insect defensins. Recent investigations have shown that beta-defensins are present in the human airways and may be relevant to the pathogenesis of cystic fibrosis (CF) lung disease. We report here the further characterization of a recently identified mouse beta-defensin gene, Defb1, sometimes referred to as mBD-1, which is homologous to the human airway beta defensin hBD-1. We report that Defb1 is expressed in a variety of tissues including the airways and, similar to hBD-1, is not upregulated by lipopolysaccharide (LPS). Defb1 was found to consist of two small exons separated by a 16-kb intron and cytogenetic, and physical mapping linked it to the alpha defensin gene cluster on mouse Chromosome (Chr) 8. Functional studies demonstrate that, like hBD-1, Defb1 demonstrates a salt-sensitive antimicrobial activity against Pseudomonas aeruginosa. Of relevance to CF lung disease is the fact that neither the hBD-1 nor the mBD-1 peptides are active against Burkholderia cepacia.

Amino Acid Sequence↗
PubMed1997

Risk-taking behaviors among adolescent trauma patients.

BACKGROUND: Alcohol is a major contributing factor in adult trauma and may adversely affect decision-making in other safety areas such as use of seatbelts and motorcycle helmets. The magnitude of risk-taking behavior and poor decision-making among adolescent trauma patients is not fully appreciated. Our objective was to determine the prevalence and pattern of risk-taking behavior among adolescents (age < or = 20 years) admitted to an adult Level I trauma center. METHODS: The trauma registry was used to identify patients. Data collected included age, mechanism of injury, blood alcohol and urine toxicology results, seatbelt and helmet use, Glasgow Coma Score, Injury Severity Score, and outcome. RESULTS: Fifteen percent of all admissions to an adult trauma center were adolescents (648 of 4,291). Twenty-one percent of adolescents (138 of 648) and 30% of adults (1,067 of 3,643) tested positive for blood alcohol on admission. Seatbelts were worn by only 19% of adolescent motor vehicle crash admissions versus 30% of adults. Only 7% of adolescents (6 of 83) with detectable alcohol used restraints, compared with 22% (67 of 310) without documented alcohol ingestion (p < 0.05). Adults were somewhat better at restraint use (16% of alcohol-positive patients and 36% without alcohol). Eight of 23 minors (35%) in motorcycle/bicycle crashes were wearing a helmet, compared with 95 of 168 adults (57%). Overall, 6.7% of adolescents and 8.6% of adults had positive toxicology screens. Adolescents with known alcohol consumption were twice as likely to have a positive toxicology screen for illegal drugs (15 vs. 7%; p < 0.05). Alcohol was also frequently detected among adolescents with mechanisms of injury other than motor vehicle and motorcycle crashes, such as violence (25%) and falls (44%). CONCLUSION: Alcohol is frequently involved in all types of trauma, for adolescents as well as adults. This is often compounded by poor decision-making and multiple risk-taking behaviors.

Adolescent↗
PubMed1996

Differential effects of Lys- and mini-plasminogen on clot lysis induced by recombinant urokinase and recombinant pro-urokinase in a canine thrombosis model.

These studies were conducted to examine the lytic efficacy of recombinant urokinase (r-UK) and pro-urokinase (r-proUK) in the presence and absence of truncated forms of plasminogen. Due to differences in their structures, these modified proteins are more readily activated to plasmin than the circulating form of plasminogen. Use of such modified substrates for plasminogen activators may improve the clinical outcome in patients treated for a variety of thrombotic diseases. Lys-plasminogen (46 units) or mini-plasminogen (in units of equivalent chromogenic activity), in conjunction with r-UK (7,500 units), were administered in the absence of heparin to dogs (9-11 kg) in which a radiolabelled thrombus was formed in a femoral artery. Fibrinolysis was measured as a loss of radioactivity from the clot. After intra-arterial administration of the agents, clot lysis was 48 +/- 8%, 50 +/- 9% and 75 +/- 2% in the presence of r-UK + vehicle, r-UK + lys-plasminogen, and r-UK + mini-plasminogen, respectively. When these treatment groups were examined in the presence of heparin (500 units + 350 units/hour) in a second study, r-UK (2,000 units) produced clot lysis of 54 +/- 3%; addition of lys- or mini-plasminogen to the regimen resulted in lysis of 62 +/- 9% and 46 +/- 10%, respectively. A third phase of the study examined r-proUK (1,000 units) with heparin; in this case, lysis was 51 +/- 9% in the presence of vehicle, but 55 +/- 17% and 10 +/- 5% when lys- and mini-plasminogen were administered, respectively. Flow restoration, measured in the femoral artery in each experiment, generally paralleled the lytic profile. The results indicate that supplementation with mini-plasminogen is only useful when added to a lytic regimen in the absence of heparin, and that lys-plasminogen, in conjunction with either of the lytic agents, does not improve clot lysis in this canine model.

Animals↗
PubMed1995

Prevention of prostate-cancer metastasis in vivo by a novel synthetic inhibitor of urokinase-type plasminogen activator (uPA).

Urokinase-type plasminogen activator (uPA) is a serine protease associated with tissue remodeling, cellular invasiveness, matrix degradation and tumor growth. Over-expression of uPA by the rat prostate-cancer cell line Dunning R3227, Mat LyLu, results in increased tumor metastasis to several non-skeletal and skeletal sites. Histological examination of these skeletal lesions has shown them to be primarily osteoblastic. In the present study we examined the capacity of a selective inhibitor of uPA enzymatic activity, 4-iodo benzo[b]thiophene-2-carboxamidine (B-428), to prevent the development of tumor growth and invasiveness in a syngeneic model of rat prostate cancer using a Dunning R3227 cell line over-expressing rat uPA. Male Copenhagen rats were inoculated s.c. with experimental cells into the right flank and continuously infused i.p. with either vehicle alone or uPA inhibitor for 2 to 3 weeks. Animals were killed at timed intervals and evaluated for the development of tumor growth and metastasis. Serum from these animals was collected to examine any signs of nephrotoxicity. Control animals receiving vehicle alone developed large tumors at the site of inoculation as well as macroscopic metastases in the lungs, kidney, spleen and lymph nodes. In contrast, experimental animals receiving uPA inhibitor showed a marked decrease in primary tumor volume and weight as well as in the development of tumor metastases. The occasional tumor metastases observed after infusion of B-428 were significantly smaller than those observed in vehicle controls. These effects of B-428 were found to be dose-dependent without any adverse effects on the renal function of experimental animals. These studies demonstrate that uPA-specific inhibitors can decrease primary tumor volume and invasiveness as well as metastasis in a model of prostate cancer where uPA has been implicated as a major pathogenetic factor.

Amidines↗
PubMed1995

Decreased beta-adrenergic stimulation of glycoprotein secretion in CF mice submandibular glands: reversal by the methylxanthine, IBMX.

beta-adrenergic stimulation of glycoprotein secretion was shown to be decreased in submandibular glands of Cystic Fibrosis (CF) mice. The defective response was partially restored by the methylxanthine, IBMX or cpt-cyclic AMP. Cholinergic stimulation of pancreatic amylase secretion was not affected in CF mice, demonstrating that this is not a generalised depression of protein secretion. The data are the first to show that the CF mouse mimics the protein secretion defect in CF human submandibular cells and that the mechanism of correction of the CF defect is via elevation of cyclic AMP. The results are therefore invaluable towards devising a rational pharmaceutical therapy for CF patients.

1-Methyl-3-isobutylxanthine↗
PubMed1995

Lung disease in the cystic fibrosis mouse exposed to bacterial pathogens.

Lung disease is the major cause of death in cystic fibrosis (CF), but there is no evidence for overt lung involvement at birth. We show here that the same is true for the gene targeted cftrm1HGU mutant mouse. Furthermore, this CF mouse model demonstrates an impaired capacity to clear Staphylococcus aureus and Burkholderia (Pseudomonas) cepacia, two opportunistic lung pathogens closely associated with lung disease in CF subjects. The cftrm1HGU homozygotes display mucus retention and frank lung disease in response to repeated microbial exposure. Thus, lung disease in the cftrm1HGU mouse develops in response to bacterial infection, establishing a model to dissect the pathogenesis of CF pulmonary disease and providing a clinically relevant end point to assess the efficacy of pharmacologic or genetic interventions.

Animals↗
PubMed1995

Evaluation in vitro and in vivo of cationic liposome-expression construct complexes for cystic fibrosis gene therapy.

We have tested the cationic liposome N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethyl-ammoniummethylsul phate, (DOTAP), for gene delivery in vitro and in vivo with a view to clinical use in gene therapy for cystic fibrosis. Delivery of lacZ cDNA-DOTAP complexes via aerosol showed promoter-dependent differences in the pattern and longevity of expression. Repeated administration was well tolerated. The potential for the transfer of foreign genes into reproductive tissue was investigated by intravenous injection of DNA-DOTAP into female mice. Foreign DNA was undetectable in the ovaries by Southern blot analysis at 1 and 7 days after injection. Our results suggest that DOTAP merits testing in cystic fibrosis patients for delivery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene to the respiratory tract and that substitution of the cytomegalovirus (CMV) promoter for the simian virus (SV) promoter may improve on the transitory response reported previously.

Aerosols↗