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Biomedical subjects

H Dawson

Publications and source records attributed to H Dawson.

At least 19 recordsLinked to original sources
PubMed2006

An apolipoprotein E-based therapeutic improves outcome and reduces Alzheimer's disease pathology following closed head injury: evidence of pharmacogenomic interaction.

Apolipoprotein E (apoE) modifies glial activation and the CNS inflammatory response in an isoform-specific manner. Peptides derived from the receptor-binding region of apoE have been demonstrated to maintain the functional activity of the intact protein, and to improve histological and functional deficits after closed head injury. In the current study, APOE2, APOE3, and APOE4 targeted replacement (TR) mice expressing the human apoE protein isoforms (apoE2, apoE3 and apoE4) were used in a clinically relevant model of closed head injury to assess the interaction between the humanized apoE background and the therapeutic apoE mimetic peptide, apoE(133-149). Treatment with the apoE-mimetic peptide reduced microglial activation and early inflammatory events in all of the targeted replacement animals and was associated with histological and functional improvement in the APOE2TR and APOE3TR animals. Similarly, brain beta amyloid protein (Abeta)(1-42) levels were increased as a function of head injury in all of the targeted replacement mice, while treatment with apoE peptide suppressed Abeta(1-42) levels in the APOE2TR and APOE3TR animals. These results suggest a pharmacogenomic interaction between the therapeutic effects of the apoE mimetic peptide and the human apoE protein isoforms. Furthermore, they suggest that administration of apoE-mimetic peptides may serve as a novel therapeutic strategy for the treatment of acute and chronic neurological disease.

Alzheimer Disease↗
PubMed2006

NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease.

Alzheimer's disease is characterized by two primary pathological features: amyloid plaques and neurofibrillary tangles. The interconnection between amyloid and tau aggregates is of intense interest, but mouse models have yet to reveal a direct interrelationship. We now show that NO may be a key factor that connects amyloid and tau pathologies. Genetic removal of NO synthase 2 in mice expressing mutated amyloid precursor protein results in pathological hyperphosphorylation of mouse tau, its redistribution to the somatodendritic compartment in cortical and hippocampal neurons, and aggregate formation. Lack of NO synthase 2 in the amyloid precursor protein Swedish mutant mouse increased insoluble beta-amyloid peptide levels, neuronal degeneration, caspase-3 activation, and tau cleavage, suggesting that NO acts at a junction point between beta-amyloid peptides, caspase activation, and tau aggregation.

Alzheimer Disease↗
PubMed2003

The Prudhoe Cognitive Function Test, a scale to assess cognitive function in adults with Down's syndrome: inter-rater and test-retest reliability.

BACKGROUND: The Prudhoe Cognitive Function Test (PCFT) was designed to measure cognitive function in subjects with all degrees of intellectual disability (ID) and to be administered by non-specialist raters. The aim of the present study was to measure the test-retest and inter-rater reliability of the PCFT. METHODS: Three raters, one a specialist and two non-specialists, administered the PCFT to 14 subjects with Down's syndrome on two occasions separated by 4 weeks. RESULTS: The intra-class correlation coefficients (ICCs) between the rater pairs (n=3) were 0.99, 0.99 and 0.98 (P<0.01). Floor effects were recorded for two items. The ICC for test-retest reliability was 0.99 (P<0.01). CONCLUSIONS: The PCFT is a highly reliable instrument when used by either specialist or non-specialist raters. It has excellent temporal stability.

Adult↗
PubMed2003

Cytokine gene expression in dams and foetuses after experimental Neospora caninum infection of heifers at 110 days of gestation.

Neospora caninum is a major cause of abortion in cattle. An essential role for Th1 cytokines, such as IFN-gamma and IL-12 in protective immunity against N. caninum in murine models has been indicated. However, little is known about immunity to Neospora in pregnant cattle where a considerable level of immunomodulation may exist. In this study, the immune response of heifers infected early in the second trimester of pregnancy by intravenous inoculation of N. caninum tachyzoites was compared with immune responses in uninfected pregnant heifers. Animals were killed 3 weeks after infection. No abortion was observed in any infected dam, however, transplacental infection was shown to have already taken place. Infection with N. caninum during pregnancy induced significant immune responses in both dams and their foetuses. Infected dams showed significant changes in lymphocyte subpopulations compared with uninfected pregnant animals and these changes were compartmentalized. Increased levels of T lymphocytes were observed in the infected foetuses. Cytokine gene expression analysed by real time RT-PCR showed increased expression of both Th1 and Th2 cytokines in N. caninum infected animals. This cytokine expression could have a role in the transplacental transmission of the parasite and/or mediate tissue damage.

Abortion, Veterinary↗
PubMed2002

Limited effect of recombinant porcine interleukin-12 on porcine lymphocytes due to a low level of IL-12 beta2 receptor.

The cytokine interleukin-12 (IL-12) is a key molecule in the regulation of CD4 + T cell development and specifically potentiates T helper 1 responses in mouse and man. However, biological effects mediated by IL-12 have not been well defined in pigs. Herein, recombinant porcine IL-12 (rPoIL-12) was expressed in a swine poxvirus system as a biologically active heterodimer and used to stimulate bovine or swine lymphoblast cells. After 3 days of incubation, only bovine blasts were responsive to the rPoIL-12 treatment as monitored by cell proliferation in several independent trials. Similarly, i.m. administration of rPoIL-12 in the hind leg of 3-week-old pigs indicated a reduction in the number of interferon-gamma (IFN-gamma) producing lymphocytes isolated from inguinal lymph nodes. The porcine IL-12R beta2 (IL-12Rbeta2) sequence was cloned and results generated by reverse transcriptase polymerase chain reaction (RT-PCR) demonstrated that the expression of IL-12R on porcine blasts as measured by the relative levels of IL-12Rbeta2 mRNA was less than that in bovine blasts and are in agreement with the reduced proliferation response of swine blast cells to rPoIL-12 treatment. Real time PCR analysis demonstrated that after PBMC stimulation, bovine blasts had an 11-fold increase in IL-12Rbeta2 mRNA levels while porcine blasts had almost no change. These data support a mechanism for IL-12 stimulation in swine inconsistent with that observed in conventional models.

Amino Acid Sequence↗
PubMed2001

Age-related changes in cytokine production by leukocytes in rhesus monkeys.

Using a variety of experimental rodent and human models, age-related alterations in cytokine production by immune cells have been described extensively. While the precise mechanism(s) responsible for such age-related changes in cytokine responses remain unclear, it seems likely that these changes may have a significant effect on immune cell function. In an attempt to clarify such changes in aging primates, we examined cytokine production by white cells derived from a controlled colony of rhesus monkeys (Macaca mulatta). Non-fractionated whole blood and peripheral blood mononuclear cells (PBMCs) were obtained from male monkeys of different ages (6-28 years), and were subsequently evaluated for their ability to express mRNA and protein for the cytokines, IL-10, IL-6, IFNgamma, IL-1beta, and TNFalpha, following in vitro stimulation with polyclonal mitogens. Our results suggest that white blood cells derived from aged rhesus monkeys exhibit a significant increase in their ability to produce the Th2-associated cytokine, IL-10, upon stimulation with lipopolysaccharide (LPS) when compared to white cells derived from younger counterparts. Similarly, a significant age-related decrease in the expression of the Th1-associated cytokine, IFNgamma, was also observed using phytohemagglutinin (PHA)-stimulated PBMCs. No significant age-related differences in the production of IL-1beta or TNFalpha were observed in response to any stimulation, but there was limited evidence of an age-related increase in IL-6 production. Overall, our results suggest that a possible systemic change from a Th0/Th1 to a Th2-like cytokine profile occurs in circulating leukocytes derived from aging primates. We believe that such age-related alterations in cytokine production may play a role in the reduced immune responses observed in elderly human populations.

Aging↗
PubMed2000

In vitro polymerization of tau protein monitored by laser light scattering: method and application to the study of FTDP-17 mutants.

Tau polymerization into the filaments that compose neurofibrillary tangles is seminal to the development of many neurodegenerative diseases. It is therefore important to understand the mechanisms involved in this process. However, a consensus method for monitoring tau polymerization in vitro has been lacking. Here we demonstrate that illuminating tau polymerization reactions with laser light and measuring the increased scattering at 90 degrees to the incident beam with a digital camera results in data that closely approximate the mass of tau polymer formation in vitro. The validity of the technique was demonstrated over a range of tau concentrations and through multiple angle scattering measurements. In addition, laser light scattering data closely correlated with quantitative electron microscopy measurements of the mass of tau filaments. Laser light scattering was then used to measure the efficiency with which the mutant tau proteins found in frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) form filamentous structures. Several of these mutant proteins display enhanced polymerization in the presence of arachidonic acid, suggesting a direct role for these mutations in tau the filament formation that characterizes FTDP-17.

Chromosomes, Human, Pair 17↗
PubMed2000

Expression of the apolipoprotein E gene does not affect motor recovery after sensorimotor cortex injury in the mouse.

Motor recovery after unilateral sensorimotor cortex ablation or sham-injury was measured in apolipoprotein E knockout and wild-type mice by testing their abilities to traverse a narrow beam. All mice trained without difficulty. Sham-operated mice performed perfectly regardless of genotype throughout testing. There was no difference in motor scores between lesioned apolipoprotein E knockout and wild-type mice on a first trial 24h after injury (P>0.05). There was a significant overall effect of lesion on motor performance (two-way repeated measures analysis of variance F(1,42)=304, P<0.0001), a significant time effect (F(17,714)=58, P<0.0001) and a lesion by time interaction (F(17,714)=58, P<0.0001). However, there was no effect of apolipoprotein E genotype group on recovery rate (i.e. there was no lesion group by genotype group by time interaction, F(17,714)=0.33, P=1.00) and no effect of genotype on the final level of motor performance 12 days after the lesion (Kruskal-Wallis H=5.79, P=0.12). These data suggest that motor recovery after unilateral injury to the sensorimotor cortex does not vary with apolipoprotein E genotype.

Animals↗
PubMed2000

Workshop to implement the baby-friendly office initiative. Effect on community physicians' offices.

OBJECTIVE: To assess the effect of a self-appraisal questionnaire and a workshop for office staff in promoting the baby-friendly office (BFO). DESIGN: A two-times-three factorial design with a delayed workshop for one of two groups: an early intervention group who attended a workshop for office staff in October 1997 (n = 23) and a late-intervention group who attended in April 1998 (n = 23). Self-appraisals were completed before the workshops by all participants in October 1997, by 37 offices in April 1998, and by 34 offices in October 1998. SETTING: Offices of family physicians and primary care pediatricians in Hamilton-Wentworth, Ont. PARTICIPANTS: Staff of 46 offices; 74% (34/46) completed all three assessments. MAIN OUTCOME MEASURES: Degree of change in implementing each of the "10 Steps to Baby-Friendly Office" and overall average BFO score received by each office. RESULTS: Of the 34 offices completing all assessments, none followed all 10 steps. Initial mean score was 4.4 steps (standard deviation 1.4, n = 46). The workshop intervention improved overall mean scores from 4.3 to 5.6 (P < .001, n = 37). Although office staff completed the BFO self-appraisal tool, it alone had no effect on scores. Areas of improvement were noted in providing information to patients and displaying posters to promote breastfeeding. Key steps, such as not advertising breast milk substitutes and not distributing free formula, did not change. CONCLUSION: The workshop effected a modest but positive change in breastfeeding promotion. The change was maintained at 6 and 12 months after the intervention.

Adult↗
PubMed1999

Treatment with tumor necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor increases epidermal Langerhans' cell numbers in cancer patients.

Dendritic cells (DCs) initiate primary and stimulate secondary T-cell responses. We conducted a phase I trial of tumor necrosis factor (TNF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with cancer to increase DCs in peripheral blood or skin based on in vitro data that showed that CD34(+) hematopoietic precursors require these cytokines to mature into functional antigen-presenting DCs. Eleven patients were treated for 7 days with GM-CSF, 125 microg/m(2) twice daily as subcutaneous injections, and TNF-alpha as a continuous infusion at dose levels of 25, 50, or 100 microg/m(2)/day. The maximum tolerated dose of TNF-alpha was 50 microg/m(2)/day with this dose of GM-CSF; dose-limiting toxicities occurred in both patients treated with 100 microg/m(2)/day. One became thrombocytopenic and the other had transient confusion. Epidermal Langerhans' cells were quantitated by S100 staining of skin biopsies and DC precursors in peripheral blood by colony-forming unit dendritic (CFU-dendritic) assays. S100-positive cells in the epidermis doubled after treatment (2.55 S100(+) cells/high-power field before treatment to 6.05 after treatment, p = 0.029). CFU-dendritic in peripheral blood increased after treatment in 3 colorectal cancer patients but not in 3 patients with melanoma. CD11c(+) or CD123(+), HLA-DR(bright), lineage-negative dendritic cell precursors were not increased in peripheral blood mononuclear cells. This trial demonstrates that treatment with TNF-alpha and GM-CSF can increase the number of DCs in the skin and the number of dendritic cell precursors in the blood of some patients with cancer. This approach may increase the efficacy of vaccination to tumor antigens in cancer patients.

Adult↗
PubMed1999

Analyte comparisons between 2 clinical chemistry analyzers.

The purpose of this study was to assess agreement between a wet reagent and a dry reagent analyzer. Thirteen analytes (albumin, globulin, alkaline phosphatase, alanine aminotransferase, amylase, urea nitrogen, calcium, cholesterol, creatinine, glucose, potassium, total bilirubin, and total protein) for both canine and feline serum were evaluated. Concordance correlations, linear regression, and plots of difference against mean were used to analyze the data. Concordance correlations were excellent for 8 of 13 analytes (r > or = 0.90); the correlations for albumin, potassium, and calcium were clinically unreliable. The linear regression analysis revealed that several analytes had slopes significantly different from unity, which was likely related to methodological differences. Compared to the wet reagent analyzer, the dry reagent analyzer showed excellent agreement for alkaline phosphatase, alanine aminotransferase, amylase (feline), urea nitrogen, cholesterol, creatinine, glucose, total bilirubin (canine), and total protein. However, it showed only slight to substantial agreement for amylase (canine), calcium, albumin, potassium, and total bilirubin (feline).

Animals↗
PubMed1997

Modulation of nitric oxide production in human macrophages by apolipoprotein-E and amyloid-beta peptide.

Induction of oxidative stress has been implicated as a causative factor in chronic neurodegenerative diseases such as Alzheimer's disease. Apolipoprotein-E (apoE) and amyloid-beta peptide (A beta) have been reported to alter the redox state of the brain. Using human monocyte-derived macrophages as a model of brain microglia, physiological levels of apolipoprotein-E were found to stimulate nitric oxide (NO) production in polyinosinic:polycytidylic acid (poly I:C) primed cells. ApoE treatment released 68% more NO than cells treated with poly I:C alone and almost threefold more NO than unprimed cells. In contrast to mouse microglia, human cells failed to generate NO in response to A beta peptides, with or without poly I:C treatments. Furthermore, the combination of A beta plus apoE inhibited the increase in NO production induced by apoE. Since Alzheimer's is strongly associated with the presence of an APOE4 allele, our study predicts a mechanism where apoE and A beta regulate nitric oxide production in human brain.

Adult↗
PubMed1997

Provision of physiotherapy services at the sixth All Africa Games.

The provision of physiotherapy services to guest nations by the host nation, Zimbabwe, at the sixth All Africa Games is examined. There was a high rate of pre-existing injury. Ice, the Cryocuff, and ultrasound were the most frequently used tools, and should be made available to physiotherapists at all multisport events. It is recommended that collection of epidemiological data be standardised to allow comparison between events.

Africa↗
PubMed1996

Bis tertiary amide inhibitors of the HIV-1 protease generated via protein structure-based iterative design.

A series of potent nonpeptide inhibitors of the HIV protease have been identified. Using the structure of compound 3 bound to the HIV protease, bis tertiary amide inhibitor 9 was designed and prepared. Compound 9 was found to be about 17 times more potent than 3, and the structure of the protein-ligand complex of 9 revealed the inhibitor binds in an inverted binding mode relative to 3. Examination of the protein-ligand complex of 9 suggested several modifications in the P1 and P1' pockets. Through these modifications it was possible to improve the activity of the inhibitors another 100-fold, highlighting the utility of crystallographic feedback in inhibitor design. These compounds were found to have good antiviral activity in cell culture, were selective for the HIV protease, and were orally available in three animal models.

Amides↗
PubMed1996

Iron metabolism: a comprehensive review.

Despite its abundance in the earth's crust, iron deficiency is a serious health issue in many parts of the world. Although fundamental observations about iron metabolism and the significance of iron nutriture were first noted some time ago, the molecular mechanisms involved in iron metabolism are just now being defined.

Animals↗
PubMed1995

Protein structure-based design of potent orally bioavailable, nonpeptide inhibitors of human immunodeficiency virus protease.

A class of potent nonpeptidic inhibitors of human immunodeficiency virus protease has been designed by using the three-dimensional structure of the enzyme as a guide. By employing iterative protein cocrystal structure analysis, design, and synthesis the binding affinity of the lead compound was incrementally improved by over four orders of magnitude. An inversion in inhibitor binding mode was observed crystallographically, providing information critical for subsequent design and highlighting the utility of structural feedback in inhibitor optimization. These inhibitors are selective for the viral protease enzyme, possess good antiviral activity, and are orally available in three species.

Administration, Oral↗