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David Wilson

Publications and source records attributed to David Wilson.

At least 19 recordsLinked to original sources
PubMed2026

A workshop considering genetic research and data collection with American Indian and Alaska Native people outside of Tribal jurisdiction.

INTRODUCTION: In the United States (US), Tribes are sovereign nations and have the right to oversee research conducted with Tribal citizens. However, it is unclear who should approve research protocols when data from American Indian and Alaska Native (AIAN) people are collected off Tribal lands. As genetic research continues to advance and transform the delivery of healthcare, equitable inclusion of AIAN people is necessary, but oversight of research needs clarity. METHODS: We held a 3-day workshop with US thought leaders on genetic and other health research with AIAN people in urban areas to explore views and values on this issue and to discuss potential policy and practice solutions. RESULTS: Thirty-six individuals attended. Solidarity surfaced as a foundational motivation for Tribal Nations to review research conducted with AIAN people, whether on Tribal lands or not. Understanding data from Indigenous perspectives was identified as a way to ensure appropriate AIAN community protections are in place. Three discrete areas to improve policy were suggested-Tribal, Academic Institution, and National-to protect AIAN people participating in research both on and off Tribal lands. DISCUSSION: Researchers, whether Indigenous or not, must recognize Tribal sovereignty and operate in solidarity with the applicable and most appropriate ethical principles and regulations.

Alaska Native↗
PubMed2006

A phase I pharmacodynamic study of the effects of the cyclin-dependent kinase-inhibitor AZD5438 on cell cycle markers within the buccal mucosa, plucked scalp hairs and peripheral blood mononucleocytes of healthy male volunteers.

PURPOSE: AZD5438 is a novel, orally bioavailable, cyclin-dependent kinase (CDK) inhibitor demonstrating preclinical pharmacodynamic (PD) effects on CDK substrates and active growth inhibition of human tumour xenografts. Clinical pharmacokinetic (PK) data shows its plasma t1/2 to be 1-3 h. The main purpose of the current study was to evaluate PD activity of single oral doses of AZD5438 in healthy volunteers. Twelve healthy male subjects received 10, 40 or 60 mg AZD5438 or placebo in a rotating placebo crossover study design. Rapidly proliferating normal tissues [buccal mucosa, peripheral blood mononucleocytes (PBMCs) and plucked scalp hair] were sampled pre-dosing, 1.5 h (tmax), +/-6 h post-dosing. The primary PD endpoint, phospho-retinoblastoma protein (pRb) levels in buccal biopsies (unit length labelling index) assessed by immunohistochemistry, was used as a biomarker of CDK activity. RESULTS: Phospho-pRb levels were demonstrated to decrease in an epitope, dose- and time-dependent manner. Statistically significant reductions in the ratio phospho-pRb/total pRb were detected at 1.5 h post-dose compared to placebo for both 40 mg [S807-S811 epitope geometric least-squares mean (glsmean) ratio = 0.75, P = 0.014] and 60 mg AZD5438 (S807-S811 epitope glsmean ratio = 0.74, P = 0.011; T821 epitope glsmean ratio = 0.72, P = 0.031). No statistically significant differences were noted at 6 h post-dosing, indicating a close PK-PD relationship between AZD5438 and target inhibition. No effects attributable to AZD5438 were detectable on phospho-p27, p27, Ki67 in the buccal mucosa; or on phospho-pRb (S249-T252 epitope), phospho-p27 or Ki67 in the sheath cells of plucked scalp hair, raising issues about the appropriateness of different detection methods/tissues for use as PD biomarkers. In ex vivo stimulated PBMCs, statistically and near-statistically significant anti-proliferative effects, with the suggestion of a dose-response effect, were noted on the incorporation of [3H]-thymidine (stimulated/non-stimulated) at 10, 40 and 60 mg, compared to placebo, at 1.5 h post-dosing (glsmean ratio = 0.65, P = 0.019; 0.70, P = 0.056; 0.51, P = 0.001, respectively). CONCLUSIONS: The modest PD effect, short plasma t1/2 and close PK-PD relationship suggest that multiple daily dosing or sustained release formulations at higher doses will be necessary for AZD5438 to achieve sustained inhibition of CDK in human cancers.

Biomarkers↗
PubMed2006

Analysis of data-collection methods for an acute stroke care registry.

This study aims to assess and compare the completeness and reliability of data collected by prospective and retrospective methods for the Paul Coverdell National Acute Stroke Registry. The prototypes consisted of eight states that used the same data elements but differed in their collection approach. Three prototypes employed retrospective case ascertainment (n=1218), and five prototypes used prospective or a combination of prospective and retrospective case ascertainment (n=1602). RTI International performed an audit analysis of the eight prototypes. Completeness, exact match, and discrepancy analyses were performed with data elements grouped into 12 categories for this analysis. A sample of 2820 (37.6%) from a total of 7494 records from 91 hospitals was studied. The "in-hospital complications" section had the highest percentage of completeness (99.6%), followed by "demographic data" (97.7%), and "in-hospital diagnostic procedures" (93.4%). The section with the lowest percentage of completeness was "thrombolytic treatment" (53.5%), followed by "reasons for nontreatment with thrombolytics" (57.1%), and "signs and symptoms onset" (63.5%). Across all prototype elements, exact matches with audit data ranged from 62.8% to 95.9%. Documentation of the date/time of stroke onset and of arrival in the emergency department had a high number of discrepancies with audit data, with exact match percentages of 69.7% and 64.5%, respectively. No significant difference was found between retrospective and prospective case ascertainment in completeness or matching with audit data. Combined retrospective and prospective data-collection approaches for different types of data elements may be best in terms of both completeness and accuracy.

Acute Disease↗
PubMed2006

Synthesis and biophysical evaluation of minor-groove binding C-terminus modified pyrrole and imidazole triamide analogs of distamycin.

Five polyamide derivatives with rationally modified C-terminus moieties were synthesized and their DNA binding specificity and affinity determined. A convergent approach was employed to synthesize polyamides containing an alkylaminopiperazine (4 and 5), a truncated piperazine (6), or an alkyldiamino-C-terminus moiety (7 and 8) with two specific objectives: to investigate the effects of number of potential cationic centers and steric bulk at the C-terminus. CD studies confirmed that compounds 4, 5, 7, and 8 bind in the minor groove of DNA. The alkylpiperazine containing compounds (4 and 5) showed only moderate binding to DNA with DeltaT(m) values of 2.8 and 8.3 degrees C with their cognate sequence, respectively. The alkyldiamino compounds (7 and 8) were more impressive producing a DeltaT(m) of >17 and >22 degrees C, respectively. Compound 6 (truncated piperazine) did not stabilize its cognate DNA sequence. Footprints were observed for all compounds (except compound 6) with their cognate DNA sequence using DNase I footprinting, with compound 7 producing a footprint of 0.1 microM at the expected 5'-ACGCGT-3' site. SPR analysis of compound 7 binding to 5'-ACGCGT-3', 5'-ACCGGT-3', and 5'-AAATTT-3' produced binding affinities of 2.2x10(6), 3.3x10(5), and 1x10(5)M(-1), respectively, indicating a preference for its cognate sequence of 5'-ACGCGT-3'. These results are in good agreement with the footprinting data. The results indicate that steric crowding at the C-terminus is important with respect to binding. However, the number of cationic centers within the molecule may also play a role. The alkyldiamino-containing compounds (7 and 8) warrant further investigation in the field of polyamide research.

Amides↗
PubMed2006

Taxonomy of Australian Funnel-web spiders using rp-HPLC/ESI-MS profiling techniques.

The complex nature of venom from spider species offers a unique natural source of potential pharmacological tools and therapeutic leads. The increased interest in spider venom molecules requires reproducible and precise identification methods. The current taxonomy of the Australian Funnel-web spiders is incomplete, and therefore, accurate identification of these spiders is difficult. Here, we present a study of venom from numerous morphologically similar specimens of the Hadronyche infensa species group collected from a variety of geographic locations in southeast Queensland. Analysis of the crude venoms using online reversed-phase high performance liquid chromatography/electrospray ionisation mass spectrometry (rp-HPLC/ESI-MS) revealed that the venom profiles provide a useful means of specimen identification, from the species level to species variants. Tables defining the descriptor molecules for each group of specimens were constructed and provided a quick reference of the relationship between one specimen and another. The study revealed that the morphologically similar specimens from the southeast Queensland region are a number of different species/species variants. Furthermore, the study supports aspects of the current taxonomy with respect to the H. infensa species group. Analysis of Australian Funnel-web spider venom by rp-HPLC/ESI-MS provides a rapid and accurate method of species/species variant identification.

Animals↗
PubMed2006

Chronic intermittent hypoxia activates nuclear factor-kappaB in cardiovascular tissues in vivo.

Obstructive sleep apnea (OSA) is an important risk factor for cardiovascular morbidity and mortality. The mechanisms through which OSA promotes the development of cardiovascular disease are poorly understood. In this study, we tested the hypotheses that chronic exposure to intermittent hypoxia and reoxygenation (CIH) is a major pathologic factor causing cardiovascular inflammation, and that CIH-induces cardiovascular inflammation and pathology by activating the NF-kappaB pathway. We demonstrated that exposure of mice to CIH activated NF-kappaB in cardiovascular tissues, and that OSA patients had markedly elevated monocyte NF-kappaB activity, which was significantly decreased when obstructive apneas and their resultant CIH were eliminated by nocturnal CPAP therapy. The elevated NF-kappaB activity induced by CIH is accompanied by and temporally correlated to the increased expression of iNOS protein, a putative and important NF-kappaB-dependent gene product. Thus, CIH-mediated NF-kappaB activation may be a molecular mechanism linking OSA and cardiovascular pathologies seen in OSA patients.

Animals↗
PubMed2006

Point-of-care biosensor systems for cancer diagnostics/prognostics.

With the growing number of fatalities resulting from the 100 or so cancer-related diseases, new enabling tools are required to provide extensive molecular profiles of patients to guide the clinician in making viable diagnosis and prognosis. Unfortunately with cancer-related diseases, there is not one molecular marker that can provide sufficient information to assist the clinician in making effective prognoses or even diagnoses. Indeed, large panels of markers must typically be evaluated that cut across several different classes (mutations in certain gene fragments--DNA; over/under-expression of gene activity as monitored by messenger RNAs; the amount of proteins present in serum or circulating tumor cells). The classical biosensor format (dipstick approach for monitoring the presence of a single element) is viewed as a valuable tool in many bioassays, but possesses numerous limitations in cancer due primarily to the single element nature of these sensing platforms. As such, if biosensors are to become valuable tools in the arsenal of the clinician to manage cancer patients, new formats are required. This review seeks to provide an overview of the current thinking on molecular profiling for diagnosis and prognosis of cancers and also, provide insight into the current state-of-the-art in the biosensor field and new strategies that must be considered to bring this important technology into the cancer field.

Biomarkers, Tumor↗
PubMed2006

Association of genital shedding of herpes simplex virus type 2 and HIV-1 among sex workers in rural Zimbabwe.

INTRODUCTION: Herpes simplex virus type 2 (HSV-2) facilitates sexual acquisition of HIV-1 but data on transmission are less clear. In this study the interaction between genital shedding of HIV-1 and HSV-2 was explored among Zimbabwean sex workers. METHODS: Women (n = 214) were interviewed about genital symptoms. Blood samples were analysed for HIV-1 and HSV-2 antibodies, HIV-1 plasma viral load (PVL) and CD4 lymphocyte count and genital swabs for detection of HIV-1 and HSV-2 genital shedding, Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis, and a cervico-vaginal lavage (CVL) for quantitative measurement of HIV-1 shedding. Shedding analyses were undertaken on women co-infected with HSV-2 and HIV-1. RESULTS: A total of 124 women were co-infected with HIV-1 and HSV-2; 58 were infected with HSV-2 alone. Most HIV-1-infected women were co-infected with HSV-2 (95.4%). Genital HIV-1 shedding was detected in 84.3% of co-infected women and was associated with low CD4 cell count and high PVL but not with reported symptoms of genital herpes or genital shedding of HSV-2. There was no difference in HIV-1 shedding among women shedding HSV-2 (79.3%) and women not shedding HSV-2 (83.2%) (P = 0.64). The adjusted odds ratio for HIV-1 shedding between HSV-2 shedders and non-shedders was 0.8 [95% confidence interval (CI), 0.2-3.3]. HIV-1 PVL(log10) and CVL viral load(log10) were correlated (r = 0.38; 95%CI, 0.2-0.5). After adjusting for PVL, genital symptoms and age, HSV-2 shedding had no effect on CVL viral load (P = 0.13). CONCLUSION: Rate and quantity of HIV-1 genital shedding do not appear to be altered by presence of HSV-2 genital shedding.

Adolescent↗
PubMed2006

The Strengthening Washington D.C. Families project: a randomized effectiveness trial of family-based prevention.

The Strengthening Washington DC Families Project (SWFP) examined implementation fidelity and effectiveness when a selective, evidence-based prevention program was implemented with a sample of 715 predominantly African American families across multiple settings in an urban area. Using a true experimental design, this study reports on the differential effectiveness of four conditions (child skills training only, parent skills training only, parent and child skills training plus family skills training, and minimal treatment controls) in reducing child antisocial behavior and its precursors. Major challenges with recruitment and retention of participants and uneven program coverage were documented. No statistically significant positive effects for any of the program conditions were observed, and a statistically significant negative effect on child reports of Negative Peer Associations was observed for children of families assigned to the family skills training condition. Two marginally significant findings were observed: Child's positive adjustment favored families assigned to family skills training condition relative to minimal treatment and child training only, and family supervision and bonding was lower for children in family skills training than in the other three conditions. Hypotheses about potential explanations for the weaker than expected effects of this program are offered, as are thoughts about the infrastructure necessary to successfully implement family strengthening programs and the future of prevention science.

Adult↗
PubMed2006

Activation of nuclear factor kappaB in obstructive sleep apnea: a pathway leading to systemic inflammation.

Apnea-induced hypoxia and reoxygenation, which generates reactive oxygen species, may activate the oxidant-sensitive, proinflammatory transcription factor nuclear factor kappaB (NF-kappaB), increasing systemic inflammation in obstructive sleep apnea. We measured NF-kappaB activity in circulating neutrophils and plasma levels of NF-kappaB-controlled gene products, soluble E (sE)-selectin and soluble vascular cell adhesion molecule-1 (sVCAM-1) in control subjects and in obstructive sleep apnea (OSA) patients. To confirm a causal link with OSA, we reassessed these parameters after nasal continuous positive airway pressure (CPAP) therapy. Twenty-two subjects undergoing evaluation for symptoms of sleep-disordered breathing were grouped by apnea hypopnea index: control, less than 5/h; mild to moderate OSA, 11-40/h; severe OSA, more than 40/h. A morning venous blood sample was obtained. Neutrophils were isolated, and NF-kappaB activity was determined by electrophoretic mobility shift assay. Plasma sE-selectin and sVCAM-1 were assayed by enzyme-linked immunosorbent assay. Neutrophils in mild to moderate and severe OSA patients showed 4.8- and 7.9-fold greater NF-kappaB binding activity compared with control subjects (p<0.0001). The degree of NF-kappaB activation was positively correlated with indices of apnea severity. In five severe OSA patients, 1 month of CPAP therapy decreased neutrophil NF-kappaB activation to control levels. sE-selectin and sVCAM concentrations were reduced by CPAP in four of these five subjects. OSA leads to NF-kappaB activation, which may constitute an important pathway linking OSA with systemic inflammation and cardiovascular disease.

Adult↗
PubMed2006

Nitric oxide modifies the sarcoplasmic reticular calcium release channel in endotoxemia by both guanosine-3',5' (cyclic) phosphate-dependent and independent pathways.

OBJECTIVES: a) To determine whether decreased sarcoplasmic calcium release channel (CRC) activity is a mechanism by which myocardial contractility is reduced in endotoxemia; b) to determine whether nitric oxide modulates CRC activity in endotoxemia; and c) to examine two nitric oxide signaling pathways in relation to CRC function in endotoxemia. DESIGN: Randomized, prospective using a rat model of endotoxemia. SETTING: : Research laboratory. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: Endotoxemia was induced by lipopolysaccharide administration. The effects of nitric oxide were studied using the highly selective inducible nitric oxide synthase inhibitor N-(3-(aminomethyl)benzyl)acetamidine dihydrochloride (1400W) and the specific guanylyl cyclase inhibitor 1-H (1, 2, 4)oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). MEASUREMENTS AND MAIN RESULTS: We assessed myocardial contractility, myocardial nitric oxide content, and guanosine-3',5' (cyclic) phosphate (cGMP) content. We determined CRC activity by calcium release and ryanodine binding assays. We followed these variables at four time points through the course of endotoxemia. We found that myocardial contractility and CRC activity were decreased in late but not in early endotoxemia. Furthermore, inducible nitric oxide synthase inhibition with 1400W restored contractility and CRC activity in late endotoxemia but paradoxically worsened these variables in early endotoxemia. Through the use of the guanylyl cyclase inhibitor ODQ, we demonstrate that nitric oxide acts through cGMP-mediated mechanisms in early and late endotoxemia. We investigated cGMP-independent pathways by assessing the oxidative status of the CRC. We found that in late endotoxemia, nitric oxide decreased the number of free thiols, demonstrating that nitric oxide also acts through cGMP-independent pathways. CONCLUSIONS: Nitric oxide has a dual effect on the CRC in endotoxemia. At low concentrations, as measured in early endotoxemia, nitric oxide stabilizes the CRC through cGMP-mediated mechanisms. In late endotoxemia, high nitric oxide concentrations decrease channel activity through both cGMP-dependent and cGMP-independent mechanisms.

Animals↗
PubMed2006

A mechanical study of ligature security of commercially available pre-tied ligatures versus hand tied ligatures for use in equine laparoscopy.

OBJECTIVE: To determine a hand-tied ligature knot configuration, suture size, and suture type that would be an acceptable substitute to commercially available ligature knots for use in equine laparoscopic surgery. STUDY DESIGN: Three-factor ANOVA with the fixed effects being suture type, suture size, and knot type. The dependent variable was ligature security (load to failure). METHODS: Commercially available Endoloop and 4 hand-tied slipknot ligatures were compared with a 4-layer square knot. The hand tied ligature knots tested were the 4S modified Roeder knot, the Brooks knot, the modified Roeder knot, and the Weston knot. Two suture sizes (0, 2) of each of 2 suture types (polydioxanone, polyglactin 910) were tested with each hand tied knot. Two types (polydioxanone, polyglactin 910) of size 0 Endoloop were tested. Twenty repetitions of each knot suture type were tested for force to yield on a materials testing machine. Statistical analysis consisted of a 3-way ANOVA with individual comparisons made using the Bonferroni method. Significance was P< or = .05. RESULTS: Only the 4S modified Roeder knot in 2 polydioxanone (103 N) was comparable with the breaking strength of the square knots (157 N). All other knot suture combinations tested were significantly weaker than the square knot (range, 2-18 N). CONCLUSION: For equine laparoscopy, a 2 polydioxanone 4S modified Roeder knot would be an acceptable alternative to the commercially available Endoloop. CLINICAL RELEVANCE: Laparoscopic slip knots are commonly used in equine laparoscopic surgery. Various knot configuration and suture size and type combinations will affect the security of the slip knot.

Analysis of Variance↗
PubMed2006

Workgroup report: public health strategies for reducing aflatoxin exposure in developing countries.

Consecutive outbreaks of acute aflatoxicosis in Kenya in 2004 and 2005 caused > 150 deaths. In response, the Centers for Disease Control and Prevention and the World Health Organization convened a workgroup of international experts and health officials in Geneva, Switzerland, in July 2005. After discussions concerning what is known about aflatoxins, the workgroup identified gaps in current knowledge about acute and chronic human health effects of aflatoxins, surveillance and food monitoring, analytic methods, and the efficacy of intervention strategies. The workgroup also identified public health strategies that could be integrated with current agricultural approaches to resolve gaps in current knowledge and ultimately reduce morbidity and mortality associated with the consumption of aflatoxin-contaminated food in the developing world. Four issues that warrant immediate attention were identified: a) quantify the human health impacts and the burden of disease due to aflatoxin exposure; b) compile an inventory, evaluate the efficacy, and disseminate results of ongoing intervention strategies; c) develop and augment the disease surveillance, food monitoring, laboratory, and public health response capacity of affected regions; and d) develop a response protocol that can be used in the event of an outbreak of acute aflatoxicosis. This report expands on the workgroup's discussions concerning aflatoxin in developing countries and summarizes the findings.

Developing Countries↗
PubMed2005

Application of perceptual difference model on regularization techniques of parallel MR imaging.

Parallel magnetic resonance imaging through sensitivity encoding using multiple receiver coils has emerged as an effective tool to reduce imaging time or to improve image SNR. The quality of reconstructed images is limited by the inaccurate estimation of the sensitivity map, noise in the acquired k-space data and the ill-conditioned nature of the coefficient matrix. Tikhonov regularization is a popular method to reduce or eliminate the ill-conditioned nature of the problem. In this approach, selection of the regularization map and the regularization parameter is very important. Perceptual difference model (PDM) is a quantitative image quality evaluation tool that has been successfully applied to varieties of MR applications. High correlation between the human rating and PDM score shows that PDM should be suitable to evaluate image quality in parallel MR imaging. By applying PDM, we compared four methods of selecting the regularization map and four methods of selecting the regularization parameter. We found that a regularization map obtained using generalized series (GS) together with a spatially adaptive regularization parameter gave the best reconstructions. PDM was also used as an objective function for optimizing two important parameters in the spatially adaptive method. We conclude that PDM enables one to do comprehensive experiments and that it is an effective tool for designing and optimizing reconstruction methods in parallel MR imaging.

Brain Mapping↗
PubMed2005

Is sexual contact with sex workers important in driving the HIV epidemic among men in rural Zimbabwe?

OBJECTIVE: To establish the importance of commercial sex in driving the HIV epidemic in the general population by determining risk factors for HIV infection among male mine and farm workers and estimating the fraction of prevalent HIV infections attributable to sexual contact with sex workers (SWs). SETTING: Five commercial farms and 2 mines in Mashonaland West, Zimbabwe. METHODS: A cross-sectional interviewer-administered questionnaire and urine survey of 1405 male workers. Urine samples were tested for HIV antibodies by a particle agglutination test and enzyme-linked immunosorbent assay and for Chlamydia trachomatis and Neisseria gonorrhoeae using a polymerase chain reaction assay. RESULTS: The overall prevalence of HIV antibodies was 27.3% (95% confidence interval [CI]: 24.8 to 29.5), that of C. trachomatis was 1.5% (95% CI: 1.0 to 2.1), and that of N. gonorrhoeae was 0.5% (95% CI: 0.1 to 0.9). A total of 48.4% (95% CI: 45.8 to 51.0) of men reported ever having had sexual contact with an SW, and 29.3% (95% CI: 26.9 to 31.7) reported contact in the past year. HIV was more common among men who reported SW contact on univariate (1.9% [95% CI: 1.5 to 2.4]) and multivariate (1.4% [95% CI: 1.0 to 1.8]) analysis after adjusting for confounding. HIV was also strongly associated with self-reported genital ulceration in the previous 6 months (adjusted odds ratio [OR] = 3.1, 95% CI: 2.2 to 4.3). Genital ulceration and SW contact were highly correlated. A total of 19.6% of HIV infections in men could be attributed to ever having had sexual contact with an SW (95% CI: 10.8 to 27.6). CONCLUSIONS: An appreciable proportion of HIV infection in men is attributable to sexual contact with SWs. Consideration should be given to developing interventions that target male clients of SWs.

Adult↗