Biomedical subjects
Publications and source records attributed to David Wood.
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Severe acute respiratory syndrome (SARS) emerged in the Guangdong province of China in late 2002 and spread to 29 countries. By the end of the outbreak in July 2003, the CDC and WHO reported 8437 cases with a 9.6% case fatality rate. The disease was caused by a previously unrecognized coronavirus, SARS-CoV. Drawing on experience with animal coronavirus vaccines, several vaccine candidates have been developed and evaluated in pre-clinical trials. Available data suggest that vaccines should be based on the the 180kDa viral spike protein, S, the only significant neutralization antigen capable of inducing protective immune responses in animals. In the absence of clinical cases of SARS, candidate vaccines should be evaluated for efficacy in animal models, and although it is uncertain whether the United States Food and Drug Administration's "animal rule" would apply to licensure of a SARS vaccine, it is important to develop standardized animal models and immunological assays in preparation for this eventuality. This report summarizes the recommendations from a WHO Technical Meeting on Animal Models and Antibody Assays for Evaluating Candidate SARS Vaccines held on 25-26 August 2005 in South Mimms, UK, provides guidance on the use of animal models, and outlines the steps to develop standard reagents and assays for immunological evaluation of candidate SARS vaccines.
The literature contains limited yet controversial information regarding whether a fixed or a mobile bearing implant should be used in unicompartmental knee arthroplasty (UKA). This randomized study was to further document the performance and comparison of the two designs. Fifty-six knees in 48 patients (mean age of 72 years) undergoing medial UKA were randomized into a fixed bearing (Miller/Galante) or a mobile bearing (Oxford) UKA. The 2 year clinical outcomes (clinical scores), radiographic findings, and weight bearing knee kinematics (assessed using RSA) were compared between the two groups. The mobile bearing knees displayed a larger and an incrementally increased tibial internal rotation (4.3 degrees, 7.6 degrees, 9.5 degrees vs. 3.0 degrees, 3.0 degrees, 4.2 degrees respectively at 30 degrees, 60 degrees, 90 degrees of knee flexion) compared to the fixed ones. The medial femoral condyle in the mobile bearing knees remained 2 mm from the initial position vs. a 4.2 mm anterior translation in the fixed bearing knees during knee flexion. The contact point in the mobile bearing implant moved 2 mm posteriorly vs. a 6 mm anterior movement in the other group. The mobile bearing knees had a lower incidence of radiolucency at the bone implant interface (8% vs. 37%, p < 0.05). The incidence of lateral compartment OA and progression of OA at patello-femoral joint were equal. No differences were found regarding Knee Society Scores, WOMAC, and SF-36 scores (p > 0.05). This study indicates that mobile bearing knees had a better kinematics, a lower incidence of radiolucency but not yet a better knee function at 2 years.
The potential of human papillomavirus (HPV) vaccines will only be realized if the vaccine candidates under development prove to be safe and effective and can be consistently produced to define quality standards. Whilst the responsibility for delivering a safe and effective product rests with the vaccine producer, a vaccine requires a license to allow it to be placed on the market. Licensure is based on an evaluation of the safety and efficacy profile of a vaccine candidate by national regulatory authorities, ideally on the basis of internationally agreed, science-based specifications and procedures. For vaccines, these international specifications are developed by the World Health Organization (WHO). The scientific basis for the regulatory evaluation of the safety and efficacy of HPV vaccines is described in this paper. Once a vaccine is licensed, a second set of criteria are evaluated by a different group of experts to provide advice to national health policy decision makers as to whether the vaccine should be introduced into national immunization programmes. Factors, such as evidence of high disease burden and high cost-effectiveness are taken into account in this second decision-making process.
In January 2005, WHO convened a meeting of leading experts in plant-derived vaccines and experts from regulatory authorities for an informal discussion on the state-of-the-art and to analyse whether specific guidance might be needed for plant-derived vaccines that is not yet provided by regulatory authorities. After a series of individual presentations, a general discussion was held to obtain a consensus on the need for further guidance. Both the presentations and the conclusions are presented. The meeting concluded that existing guidelines for the development, evaluation, and use of vaccines made by traditional methods can be applied to plant-derived vaccines. For plant-derived vaccines some specific issues will have to be addressed. These include, but are not restricted to, containment of the plants including disposal of waste materials. It was noted that plant-derived vaccines have been produced and clinically tested under US investigational new drug application, and all applicable regulatory and good manufacturing practice requirements are in place for this type of product. An innovator wishing to bring a plant-derived vaccine to market should consult closely with regulatory authorities to ensure that all appropriate studies are undertaken.
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Analyzing skeletal kinematics with radiostereometric analysis (RSA) following corrective orthopedic surgery allows the quantitative comparison of different implant designs. The purpose of this study was to validate a technique for dynamically estimating the relative position and orientation of skeletal segments using RSA and single plane X-ray fluoroscopy. Two micrometer-based in vitro phantom models of the skeletal segments in the hip and knee joints were used. The spatial positions of tantalum markers that were implanted into each skeletal segment were reconstructed using RSA. The position and orientation of each segment were determined in fluoroscopy images by minimizing the difference between the markers measured and projected in the image plane. Accuracy was determined in terms of bias and precision by analyzing the deviation between the applied displacement protocol and measured pose estimates. Measured translational accuracy was less than 100 microm parallel to the image plane and less than 700 microm in the direction orthogonal to the image plane. The measured rotational error was less than 1 degrees . Measured translational and rotational bias was not statistically significant at the 95% level of confidence. The technique allows real-time kinematic skeletal measurements to be performed on human subjects implanted with tantalum markers for quantitatively measuring the motion of normal joints and different implant designs.
UNLABELLED: Aromatase is the enzyme that catalyzes the conversion of androgen to oestrogen. Aromatase expression in extra-gonadal sites and local oestrogen synthesis play an important role in the physiological conditions and in the growth of certain neoplasms. OBJECTIVE: The purpose of this study was to investigate aromatase expression in oral keratinocytes and oral squamous cell carcinoma (SCC). DESIGN: Immunocytochemistry and RT-nested PCR were used to detect aromatase protein and mRNA expression in primary human oral epithelial cell culture and in an oral SCC cell line. Immunohistochemistry was used to detect aromatase protein expression in frozen and archival human tissue sections of normal oral epithelium and oral SCC. RESULTS: Cytoplasmic immunostaining was found in normal oral keratinocytes and SCC cells in culture. The common coding region of aromatase mRNA was detected in the oral keratinocytes derived from five different normal individuals and in the SCC cell line. However, there were variations in aromatase exon 1 expression among normal oral keratinocyte samples. Cytoplasmic staining was found in normal oral epithelium and well-differentiated oral SCC but not in poorly differentiated oral SCC by immunohistochemistry. CONCLUSION: Aromatase was expressed in normal oral keratinocytes and oral SCC both in cell culture and in tissues, indicating local oestrogen synthesis in normal and neoplastic conditions of oral epithelium.
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We describe a new technique and aim to justify its use in total hip arthroplasty. The incision is short and there is minimal soft tissue dissection: piriformis and most of quadratus femoris remain intact. A meticulous capsular repair is performed. Patients are mobilized without restrictions. One hundred total hip arthroplasties by the standard posterior approach (group 1) were compared with 100 by the less invasive approach (group 2). Minimum follow-up was 2 years. Mean blood loss in group 1 was higher (P < .0001) and inpatient stay longer (P < .0001). There was greater improvement in WOMAC scores for up to 1 year in the less invasive group (P = .027). In conclusion, the less invasive approach is safe and the functional benefits last up to 1 year.
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High-grade prostatic intraepithelial neoplasia (HGPIN) is generally regarded as a premalignant lesion that progresses toward prostate cancer. In light of the significant sequelae of prostate cancer treatment, prevention is desirable, and men with HGPIN would be suitable, high-risk subjects. There is in vitro, in vivo, epidemiologic, and human experimental evidence that selenium supplementation may protect against prostate cancer. This article introduces the rationale for, and progress to date, of a double-blind, randomized, placebo-controlled trial of selenium supplementation (200 mug/d in the form of selenomethionine), to prevent the development of prostate cancer among men with HGPIN. The trial, Southwest Oncology Group Protocol 9917, funded by a National Cancer Institute program supporting pivotal prevention trials has registered 537 patients and has randomized >380 to date. Subject accrual is expected to be completed by the fall of 2006, with trial completion in 2009.
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Fibrin sealant (FS), a biological adhesive material, has been recently recommended as an adjunct in autologous chondrocyte implantation (ACI). While FS has been shown to possess osteoinductive potential, little is known about its effects on chondrogenic cells. In this study, we assessed the bioactivity of FS (Tisseel) on the migration and proliferation of human articular chondrocytes in vitro. Using a co-culture assay to mimic matrix-induced ACI (MACI), chondrocytes were found to migrate from collagen membranes towards FS within 12 h of culture, with significant migratory activity evident by 24 h. In addition, 5-bromo-2'-deoxyuridine (BrdU) incorporation experiments revealed that thrombin, the active component of the tissue glue, stimulated chondrocyte proliferation, with maximal efficacy observed at 48 h post-stimulation (1-10 U/ml). In an effort to elucidate the molecular mechanisms underlying these thrombin-induced effects, we examined the expression and activation of protease-activated receptors (PARs), established thrombin receptors. Using a combination of RT-PCR and immunohistochemistry, all four PARs were detected in human chondrocytes, with PAR-1 being the major isoform expressed. Moreover, thrombin and a PAR-1, but not other PAR-isotype-specific peptide agonists, were found to induce rapid intracellular Ca2+ responses in human chondrocytes in calcium mobilization assays. Together, these data demonstrate that FS supports both the migration and proliferation of human chondrocytes. We propose that these effects are mediated, at least in part, via thrombin-induced PAR-1 signalling in human chondrocytes.
PURPOSE: Great variations exist in child health outcomes among states in the United States, with southern states consistently ranked among the lowest in the country. Investigation of the geographical distribution of children's health status and the regional factors contributing to these outcomes has been neglected. We attempted to identify the degree to which region of residence may be linked to health outcomes for children with the specific aim of determining whether living in the southern region of the United States is adversely associated with children's health status. METHODS: A child health index (CHI) that ranked each state in the United States was computed by using state-specific composite scores generated from outcome measures for a number of indicators of child health. Five indicators for physical health were chosen (percent low birth weight infants, infant mortality rate, child death rate, teen death rate, and teen birth rates) based on their historic and routine use to define health outcomes in children. Indicators were calculated as rates or percentages. Standard scores were calculated for each state for each health indicator by subtracting the mean of the measures for all states from the observed measure for each state. Indicators related to social and economic status were considered to be variables that impact physical health, as opposed to indicators of physical health, and therefore were not used to generate the composite child health score. These variables were subsequently examined in this study as potential confounding variables. Mapping was used to redefine regional groupings of states, and parametric tests (2-sample t test, analysis of means, and analysis-of-variance F tests) were used to compare the means of the CHI scores for the regional groupings and test for statistical significance. Multiple-regression analysis computed the relationship of region, social and economic indicators, and race to the CHI. Simple linear-regression analyses were used to assess the individual effect of each indicator. RESULTS: A geographic region of contiguous states, characterized by their poor child health outcomes relative to other states and regions of the United States, exists within the "Deep South" (Mississippi, Louisiana, Arkansas, Tennessee, Alabama, Georgia, North Carolina, South Carolina, and Florida). This Deep-South region is statistically different in CHI scores from the US Census Bureau-defined grouping of states in the South. The mean of CHI scores for the Deep-South region was >1 SD below the mean of CHI scores for all states. In contrast, the CHI score means for each of the other 3 regions were all above the overall mean of CHI scores for all states. Regression analysis showed that living in the Deep-South region is a stronger predictor of poor child health outcomes than other consistently collected and reported variables commonly used to predict children's health. CONCLUSIONS: The findings of this study indicate that region of residence in the United States is statistically related to important measures of children's health and may be among the most powerful predictors of child health outcomes and disparities. This clarification of the poorer health status of children living in the Deep South through spatial analysis is an essential first step for developing a better understanding of variations in the health of children. Similar to early epidemiology work linking geographic boundaries to disease, discovering the mechanisms/pathways/causes by which region influences health outcomes is a critical step in addressing disparities and inequities in child health and one that is an important and fertile area for future research. The reasons for these disparities may be complex and synergistically related to various economic, political, social, cultural, and perhaps even environmental (physical) factors in the region. This research will require the use and development of new approaches and applications of spatial analysis to develop insights into the societal, environmental, and historical determinants of child health that have been neglected in previous child health outcomes and policy research. The public policy implications of the findings in this study are substantial. Few, if any, policies identify these children as a high-risk group on the basis of their region of residence. A better understanding of the depth and breadth of disparities in health, education, and other social outcomes among and within regions of the United States is necessary for the generation of policies that enable policy makers to address and mitigate the factors that influence these disparities. Defining and clarifying the regional boundaries is also necessary to better inform public policy decisions related to resource allocation and the prevention and/or mitigation of the effects of region on child health. The identification of the Deep South as a clearly defined subregion of the Census Bureau's regional definition of the South suggests the need to use more culturally and socially relevant boundaries than the Census Bureau regions when analyzing regional data for policy development.
AIMS: Treatment guidelines for patients with established coronary disease emphasize the importance of smoking cessation. We aimed to study smoking behaviour in European patients, as well as trends in this behaviour over time. We further aimed to evaluate the relation between selected patient characteristics and smoking cessation. METHODS AND RESULTS: We studied patients who were enrolled in the second European Action on Secondary Prevention through Intervention to Reduce Events (EUROASPIRE) survey, which was undertaken in 15 European countries during 1999-2000. Consecutive patients, < or =70 years were identified after coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, admission for myocardial infarction, or admission for myocardial ischaemia. Patients were then interviewed, at a median of 1.5 years after the index event. During the interview, data were collected on a broad range of clinical characteristics, including smoking status, which was validated by breath carbon monoxide levels. The prevalence of smoking was compared with data from the first EUROASPIRE survey, which had a similar design, and was conducted during 1995-96. In EUROASPIRE II, 5551 patients attended the interview and 1172 (21%) were (persistent) smokers. No decrease in smoking prevalence was observed similar to the first survey (19%). The proportion of smokers was 39% in patients aged <50, 26% in patients aged 50-60, and 14% in patients aged > or =60. Men and women had similar prevalence. A verbal advice to give up smoking by a medical professional was given to 99% of the 2244 pre-event smokers, and 48% actually stopped. This proportion was relatively high in elderly patients > or =60 years (53%), patients with a university level of education (56%), and patients with a myocardial infarction as the index event (52%). The proportion of stopped smokers was low in patients <50 years (41%) and in patients with myocardial ischaemia as the index event (38%). CONCLUSION: The prevalence of smoking in European patients with established coronary disease is too high: one out of each five patients smokes, despite a personal advice to stop. Thus, still there is a need for the development of effective smoking cessation programmes.
Four, individually addressable 30 microm diameter, e-beam deposited, gold microelectrodes recessed by 6 microm were suitably spaced on a single substrate to avoid diffusional overlap between each microelectrode. The single substrate device was functionalised with thiolated alpha-, beta-, and gamma-cyclodextrin nanocavities without spacer groups to ensure close proximity of the cavities to the electrode surface. The microelectrodes were assessed in two stages. The e-beam deposited micron sized electrodes were characterized using models for recessed and inlaid microdisk electrodes. Subsequently, each individually addressable, atomically flat, micro-patterned gold electrode with thiolated CD ensembles was treated as a nanoporous electrode assembly. Theoretical and experimental results were compared using cyclic voltammetry. Atomic force microscopy was also used to characterise the modified microelectrodes. Comparisons were made with thiolated CDs deposited on macroelectrodes. This is the first report of the behaviour of immobilized CD nanocavities ensembles on atomically flat gold microelectrodes.
Rotavirus vaccines are at an advanced stage of development but there are as yet no WHO recommendations on production and quality control to provide regulatory guidance. A meeting of experts was convened by WHO and PAHO/AMRO to review the scientific basis for production and quality control of rotavirus vaccines, and to discuss specific measures to assure the safety and efficacy of rotavirus vaccines. The meeting was attended by 25 experts from 14 countries, drawn from academia, public health, national regulatory authorities and vaccine producers. It was agreed that existing guidance for other live virus vaccines provides a very good basis for product characterization, especially for source materials and control of production. The basis for attenuation of current vaccines or vaccine candidates is not known but, at least for the vaccines based on the Jennerian approach of using animal (bovine) rotaviruses, is likely to be multigenic. The risk of intussusception in humans is influenced by genetic background and age. Recent analyzes of large vaccine safety trials found that certain strains of vaccine virus were not associated with intussusception, although in these trials the first dose of vaccine was not administered to children over 3 months of age. Since age is a risk factor for intussusception, this may suggest that early delivery of the first dose of vaccine is desirable. However, maternal antibodies may mitigate against early delivery of the first vaccine dose. Factors which could affect vaccine efficacy or safety include strain diversity, malnutrition, other enteric infections, parasitic infection or immune suppression. It was concluded that data from clinical trials conducted in one part of the world would not necessarily be predictive of vaccine efficacy in other places. It was agreed that in nonclinical evaluations there was a need to use oral dosing for toxicity studies and, because rotavirus is non-neurovirulent, that there was no need for an animal neurovirulence test. For clinical evaluations there was a need for a standard definition of severe disease as the clinical endpoint, a need for studies in diverse geographical regions, and the need to control for possible interference by factors such as other oral vaccinations, intercurrent infections and breast feeding. There is no accepted correlate of protection. Secretory IgA is the most satisfactory laboratory parameter currently available and for a period after vaccination much of the specific serum IgA is of this type, so that serum IgA levels can act as measure of seroconversion. The need for standardization of the potency assay for release of vaccine was identified, as was a need to develop guidance on standardized approaches to post-marketing surveillance for rotavirus vaccines.