Biomedical subjects

A Davis

Publications and source records attributed to A Davis.

At least 55 records · Page 3Linked to original sources

PubMed2001

Oral immunization with HCV-NS3-transformed Salmonella: induction of HCV-specific CTL in a transgenic mouse model.

BACKGROUND & AIMS: The ability to induce cytotoxic T cells is considered an important feature of a candidate hepatitis C virus (HCV) vaccine. We used an oral immunization strategy with attenuated HCV-NS3-transformed Salmonella typhimurium to deliver DNA directly to the gut-associated lymphoid tissue. METHODS: HLA-A2.1 transgenic mice were immunized once with transformed attenuated Salmonella. HCV-specific CD8+ T cells were analyzed in vitro as well as in vivo by challenge of mice with recombinant HCV-NS3 vaccinia virus. RESULTS: Salmonella (10(8) colony-forming units; 20 microg plasmid DNA) induced cytotoxic and IFN-gamma-producing CD8+ T cells specific for the immunodominant epitope NS3-1073 in 26 of 30 mice (86%) that persisted for at least 10 months. A second epitope (NS3-1169) was also recognized by cytotoxic and IFN-gamma-producing T cells, whereas a third one (NS3-1406) stimulated IFN-gamma production without cytotoxicity. The minimal amount of plasmid DNA required to induce CTLs was 2 ng. Upon challenge with recombinant HCV-NS3-expressing vaccinia virus, vaccinia titers were significantly lower in mice immunized with Salmonella-NS3 than in mice immunized with control Salmonella, demonstrating the in vivo function of CTLs. CONCLUSIONS: Oral immunization with attenuated Salmonella typhimurium as a carrier for HCV DNA induces long-lasting T-cell responses.

Administration, Oral↗

PubMed2001

Systematic review of the clinical and cost effectiveness of digital hearing aids.

The aim of the present study was to systematically review the clinical and cost effectiveness of hearing aids which use digital signal processing relative to other forms of hearing aid technology, in particular analogue-based aids. A comprehensive search for randomized controlled trials, randomized crossover trials and economic studies was undertaken. Trial quality assessment and data extraction were undertaken by two independent reviewers. Eight trials comparing digital to non-digital devices were identified--one randomized controlled trial and seven randomized crossover trials. The majority of these studies were of small sample size and of poor methodological quality. In the majority of cases (nine out of 13), there was no evidence of a significant difference in either laboratory scores (nine out of 13 outcomes assessed) or user function/quality of life scores (six out of nine outcomes assessed) between digital and non-digital devices. In addition, there was no significant difference in patient preference for digital compared to control aids (relative risk 1.93; 95% CI 0.70-5.35) when pooled across studies. No cost-effectiveness studies directly comparing digital to non-digital devices were identified. In conclusion, the evidence identified by this review provides no significant evidence of the clinical benefit of digital devices compared to analogue-based aids. However, these results are difficult to generalize to current UK practice as the analogue aids and types of fitting in the trials are not those typically used in the NHS.

Acoustic Stimulation↗

PubMed2001

Assessing service quality in paediatric audiology and early deaf education.

Quality monitoring and assurance is a key aspect of evidence-based service provision in health and education. Part I of the present paper summarizes the results from a survey in which performance of health-based paediatric audiology services in the UK was assessed against existing good practice guidelines (NDCS, 1994, 1996). The results of the survey indicated varied levels of provision, with guidelines commonly not followed. Part II of the paper reports the detailed development of two short questionnaires designed to provide scores (out of 100) reflecting aspects of service quality in paediatric audiology services and in early deaf education services. The results from the use of the two indices (the Paediatric Audiology Service Index (PASI) and the Deaf Education Early Service Index (DEESI)) are presented along with data from some component questions. Although some services are functioning close to guideline levels of service, the overall distribution of scores is such as to raise serious concerns about the variability of quality and the consequent inequity of provision for children with permanent hearing loss and their families in both health and education services.

Age Factors↗

PubMed2001

Hearing impairment among adults--extent of the problem and scientific evidence on the outcome of hearing aid rehabilitation.

Scientific surveys on current and estimated prevalence of hearing impairment (HI) in adult populations (> or = 18 years of age) in Denmark, Finland, Norway, Sweden and the United Kingdom, and scientific reports on the outcome of hearing aid (HA) rehabilitation worldwide were reviewed. Only a few of the studies meet strict scientific criteria, and many locally clinically relevant studies cannot be generalized to larger populations. Population-based studies indicate an increase in prevalence of HI with age, but because of differences in study populations and available national population statistics, the studies do not allow reliable comparisons between countries or estimation of future prevalence of HI. Studies on HA prescription or outcomes do not provide uniform data in favour of non-linear amplification, but they do show some subject preference for the newer technology. No conclusions can be drawn regarding the degree of HI and the effects of amplification. The literature review alone gives only limited information regarding the extent of the problem of HI in adult populations in the target countries. Similarly, only a few studies on HA outcome meet strict scientific criteria and even fewer studies correlate rehabilitation outcome with the degree of HI, disability or handicap.

Adult↗

PubMed2001

Provision of hearing aid services: a comparison between the Nordic countries and the United Kingdom.

About one in five adults has some form of hearing impairment. This paper reports on a survey which found significant variation in the provision of hearing aid services across Denmark, Finland, Norway, Sweden and the United Kingdom. Per capita expenditure levels were estimated to vary from under 3 euros in the UK to nearly 10 in Denmark and Norway. Annual figures for the number of people receiving at least one aid varied from around eight per 1,000 in the UK and Denmark to 2.2 in Finland. Over 50% of hearing aid users in Norway and Denmark are estimated to have bilateral aids, compared to under 15% in the UK. Estimates of the number of people who have a hearing aid in these countries are considerably lower than the number who have a hearing impairment. More research is needed to verify the true extent of these differences and their cause.

Adult↗

PubMed2001

Performance of neonatal and infant hearing screens: sensitivity and specificity.

The terms 'sensitivity' and 'specificity' are defined and some of the factors that determine their values are discussed in the context of screening for permanent childhood hearing loss. There is a need to distinguish between the values observed in 'simple experiments' and those that may be obtained under more realistic 'field' conditions. It is not feasible to give a meta-analytic overview of published data because of the variety of methods and objectives used in those studies published in the literature. However, a qualitative synthesis of the data is possible. This suggests that most proposed neonatal hearing screening tests, when implemented in accordance with a programme of quality assurance, can be reasonably accurate at a modest cost. However, the optimal combination of tests and test parameters for given populations has not yet been fully researched. The infant distraction test screen has a lower sensitivity than neonatal hearing screening tests, particularly for moderate impairments, accompanied by a fairly low specificity.

Child Health Services↗

PubMed2001

The Interdisciplinary Generalist Curriculum (IGC) project: an overview of its experience and outcomes.

The Interdisciplinary Generalist Curriculum (IGC) Project was a competitive, seven-year demonstration project funded by the Health Resources and Services Administration (HRSA). It was established to determine whether specific interdisciplinary innovations in preclinical medical school curricula could affect students' selection of careers in family medicine, general internal medicine, or general pediatrics. Through collaboration among the three generalist disciplines, the IGC innovation exposed all preclinical students in ten demonstration schools to a new or significantly enhanced preclinical curriculum that included a direct supervised clinical experience with a generalist physician preceptor. The project was managed by an interdisciplinary executive committee that was codirected by one representative each from family medicine, general internal medicine, and general pediatrics. A national advisory committee with representation from the academic and professional organizations of family medicine, internal medicine, pediatrics, and osteopathy provided input to the executive committee in guiding the project. The project was externally evaluated. Major outcomes of the IGC Project include sustained curricular changes in ten institutions, prompted by relatively few dollars and demonstration of models for collaboration at institutional and national levels. This supplement describes the IGC Project's experience and outcomes so that others may draw pertinent information to apply to their own efforts in medical education.

Curriculum↗

PubMed2001

How did we make the Interdisciplinary Generalist Curriculum Project work? National efforts to facilitate success.

The Interdisciplinary Generalist Curriculum (IGC) Project created curricular changes at the participating schools with very little direct financial support. A reconsideration of the process of this national effort reveals many intangible elements that were as critical to the project's successes as were the direct dollars. Those factors included careful attention to the criteria for school selection, specific project requirements that allowed institutional flexibility in project evolution, national assistance in program implementation, early and ongoing national recognition for project schools, and a highly organized, involved, and goal-oriented national organization. This national initiative provides a successful model for future funding of projects in this era of dwindling financial support for medical education innovation.

Curriculum↗

PubMed2001

How did we make the Interdisciplinary Generalist Curriculum Project work? School-level efforts to facilitate success.

This article examines how the schools funded by the Interdisciplinary Generalist Curriculum (IGC) Project handled the process of planning and implementing their proposals; incorporated the IGC requirements as templates for changes in educational programs and organizational infrastructures; and identified key educational and management issues that emerged over time. How collaboration flourished at each IGC school was the central functional ingredient for successful implementation. Shared power and support from the dean were essential for success. The need for excellent channels of communication among all constituencies in the process of curricular change cannot be overemphasized. The most common approach was the addition of the new interdisciplinary clinical curriculum to the existing, usually discipline-based, curriculum, with attempts to establish integrative horizontal connections among concurrent courses in years one and two. The integration, sequencing, and correlating of basic science and clinical material occupied much of the IGC course directors' time in the early stages. Several approaches were used to help ensure a beneficial initial clinical experience for medical students, while accepting that a uniform experience for all students was not attainable or necessary. Encouraging active learning on the part of students was a goal of IGC schools' planning in and of itself. The splash of establishing interdisciplinary communication structures and greater melding of disciplinary cultures that occurred at and among the IGC schools appeared to lead to ripple effects that were recognized within the first year of planning and early implementation.

Communication↗

PubMed2001

Curricular change: recommendations from a national perspective.

Recommendations on future directions, funding, and organizational and curricular issues have emerged from the complexity of the Interdisciplinary Generalist Curriculum (IGC) Project. For example, future demonstration projects aimed at innovations in medical education that are funded through the contracting mechanism are recommended, and funding intended to serve as institutional leverage for demonstrating desired curricular innovations in medical education is encouraged. Funding provided to entities that can maximize influence within the institutions is recommended. Also, the period of time over which funds are provided needs to take into consideration the breadth of the impact of the funded program on the larger curriculum and the length of time needed to measure desired outcomes. Organizational findings are that multi-site projects with administrative oversight bodies should be governed by representatives of concerned disciplines who have stakes in the demonstration of the innovations in medical education, and roles of the executive and advisory committees involved in the effort need to be made explicit at the onset and revisited over time. Similarly, the role of the funder needs to be explicit. Curricular recommendations are that medical schools are encouraged to develop longitudinal generalist preceptorship experiences early in medical education for all students, regardless of their eventual career choices. Schools should anticipate that curricular innovations in the preclinical years may require modifications of the educational process in the clinical years.

Curriculum↗

PubMed2001

Systemic IFN-beta gene therapy results in long-term survival in mice with established colorectal liver metastases.

Most patients succumbing to colorectal cancer fail with liver-predominant metastases. To make a clinical impact in this disease, a systemic or whole-liver therapy may be required, whereas most cancer gene therapy approaches are limited in their ability to treat beyond local disease. As a preclinical model for cancer gene therapy, recombinant adenovirus containing the human IFN-beta (hIFN-beta) cDNA was delivered systemically in nude mouse xenograft models of human colorectal cancer liver metastases. The vector targeted hepatocytes that produced high levels of hIFN-beta in the liver, resulting in a profound apoptotic response in the tumors and significant tumor regression. hIFN-beta gene therapy not only resulted in improved survival and long-term cure in a micrometastatic model, but provided similar benefits in a clinically relevant gross disease model. A similar recombinant adenovirus containing the murine IFN-beta (mIFN-beta) cDNA also resulted in a therapeutic response and improved survival in syngeneic mouse models of colorectal cancer liver metastases. Depletion studies demonstrate a contribution of natural killer cells to this therapeutic response. The toxicity of an adenoviral vector expressing murine IFN-beta in a syngeneic model is also presented. These encouraging results warrant further investigation of the use of cancer gene therapy for targeting metastatic disease.

Adenocarcinoma↗

PubMed2001

Tongue-base hamartoma in tuberous sclerosis.

This paper describes the case of a 41-year-old female with tuberous sclerosis who presented with a large tongue-base hamartoma. The surgical management of the patient was complicated by the presence of a large thyroid goitre. Awake fibre-optic intubation, thyroidectomy then tracheostomy were necessary before the tongue-base hamartoma could be safely resected. To the best of our knowledge, this is the first reported case of a tongue-base hamartoma in a patient with tuberous sclerosis.

Adult↗

PubMed2001

Protein kinase CK2 signal in neoplasia.

Protein kinase CK2 (previously known as casein kinase II) is a protein serine/threonine kinase that has been implicated in cell growth and proliferation. The focus of this review is on the apparent role of CK2 in cancer. Studies from several laboratories have shown a dysregulated expression of the kinase in tumors. Nuclear matrix and chromatin appear to be key sites for signaling of the CK2 activity in relation to cell growth. Several types of growth stimuli produce a common downstream response in CK2 by enhancing its nuclear shuttling. The neoplastic change is also associated with changes in intracellular localization of the kinase so that a higher nuclear localization is observed in tumor cells compared with normal cells. Experimental studies suggest that dysregulated expression of the alpha subunit of CK2 imparts an oncogenic potential in the cells such that in cooperation with certain oncogenes it produces a profound enhancement of the tumor phenotype. Recent studies have provided evidence that overexpression of CK2 in tumor cells is not simply a reflection of tumor cell proliferation alone but additionally may reflect the pathobiological characteristics of the tumor. Of considerable interest is the possibility that CK2 dysregulation in tumors may influence the apoptotic activity in those cells. Approaches to interfering with the CK2 signal may provide a useful means for inducing tumor cell death.

Adenocarcinoma↗

PubMed2001

Pharmacogenetics research network and knowledge base: 1st annual scientific meeting.

The National Institute of General Medical Sciences of the National Institutes of Health recently established a collaborative group of scientists, called the Pharmacogenetics Research Network. Central to the network is a shared, state-of-the-art data repository, the Pharmacogenetics Knowledge Base (PharmGKB), which is housed at Stanford University. Network investigators deposit pharmacogenetic data into PharmGKB, after all individually identifying information has been removed. Contents of PharmGKB will be freely accessible to the scientific community, with the goal of forging new links between gene variation and drug response. An open scientific meeting was held recently to introduce the research community to the network and to invite academic and industry-based researchers to deposit data into PharmGKB. Featured at the meeting were summaries of research progress to date, as well as discussions of issues intimately related to pharmacogenetics research, namely ethics and relations with the biotechnology and pharmaceutical industries.

Animals↗

PubMed2001

Reliability and intraoperative validity of preoperative assessment of standardized plain radiographs in predicting bone loss at revision hip surgery.

BACKGROUND: The most challenging aspect of revision hip surgery is the management of bone loss. A reliable and valid measure of bone loss is important since it will aid in future studies of hip revisions and in preoperative planning. We developed a measure of femoral and acetabular bone loss associated with failed total hip arthroplasty. The purpose of the present study was to measure the reliability and the intraoperative validity of this measure and to determine how it may be useful in preoperative planning. METHODS: From July 1997 to December 1998, forty-five consecutive patients with a failed hip prosthesis in need of revision surgery were prospectively followed. Three general orthopaedic surgeons were taught the radiographic classification system, and two of them classified standardized preoperative anteroposterior and lateral hip radiographs with use of the system. Interobserver testing was carried out in a blinded fashion. These results were then compared with the intraoperative findings of the third surgeon, who was blinded to the preoperative ratings. Kappa statistics (unweighted and weighted) were used to assess correlation. Interobserver reliability was assessed by examining the agreement between the two preoperative raters. Prognostic validity was assessed by examining the agreement between the assessment by either Rater 1 or Rater 2 and the intraoperative assessment (reference standard). RESULTS: With regard to the assessments of both the femur and the acetabulum, there was significant agreement (p < 0.0001) between the preoperative raters (reliability), with weighted kappa values of >0.75. There was also significant agreement (p < 0.0001) between each rater's assessment and the intraoperative assessment (validity) of both the femur and the acetabulum, with weighted kappa values of >0.75. CONCLUSIONS: With use of the newly developed classification system, preoperative radiographs are reliable and valid for assessment of the severity of bone loss that will be found intraoperatively.

Acetabulum↗

PubMed2001

Response of cancer cells to molecular interruption of the CK2 signal.

Protein kinase CK2 is one of the key cellular signals for cell survival, growth, and proliferation. It is has been observed to be elevated in various cancers that have been examined. Various observations suggest that moderate dysregulation of CK2 may profoundly influence the cell response. We have examined the effects of interfering with the CK2 signal in various cancer cell lines by employing antisense oligodeoxynucleotides (ODN) against the alpha and beta subunits of CK2. Our results demonstrate that antisense CK2-alpha and antisense CK2-beta ODNs markedly influence cell viability of these cancer cells in a dose and time-dependent manner. Antisense CK2-alpha was slightly more effective than antisense CK2-beta in most of the cells tested. The efficacy of the antisense ODN seemed to vary with the cell type; however, in all cases potent induction of apoptosis was observed. Significantly, the effects of the antisense ODN on the CK2 activity in the nuclear matrix were relatively small compared to the much stronger induction of apoptosis in cells. This suggests that modest downregulation of CK2 can evoke a much greater apoptotic response in cancer cells.

Apoptosis↗

PubMed2001

Consequences of CK2 signaling to the nuclear matrix.

Protein kinase CK2 is recognized as one of the key cellular signals for cell growth and proliferation. Its nuclear targeting appears to be critical to its role in these functions. In the nucleus, nuclear matrix (NM) which plays a major role in growth-related activities is a primary locus for CK2 signaling. A variety of growth stimuli evoke a rapid translocation of the CK2 to the NM whereas removal of these factors has the opposite effect. These studies, employing various experimental models of cell growth (involving different growth-stimulatory factors), have suggested that rapid shuttling of CK2 to the NM is a key feature of early growth control. By contrast, removal of growth-stimulatory factors leading to the loss of cell viability is associated with early loss of CK2 from the NM (and chromatin). This indicates that absence of CK2 from the nuclear compartment is contributory to induction of cell death via apoptosis, implying a protective role for CK2 against cell death. Here, we review the evidence that suggests that CK2 signaling in the NM is not only involved in cell growth but also in cell survival.

Active Transport, Cell Nucleus↗

PubMed2000

Energetic and functional contribution of residues in the core binding factor beta (CBFbeta ) subunit to heterodimerization with CBFalpha.

Core-binding factors (CBFs) are a small family of heterodimeric transcription factors that play critical roles in several developmental pathways, including hematopoiesis and bone development. Mutations in CBF genes are found in leukemias and bone disorders. CBFs consist of a DNA-binding CBFalpha subunit (Runx1, Runx2, or Runx3) and a non-DNA-binding CBFbeta subunit. CBFalpha binds DNA in a sequence-specific manner, whereas CBFbeta enhances DNA binding by CBFalpha. Recent structural analyses of the DNA-binding Runt domain of CBFalpha and the CBFbeta subunit identified the heterodimerization surfaces on each subunit. Here we identify amino acids in CBFbeta that mediate binding to CBFalpha. We determine the energy contributed by each of these amino acids to heterodimerization and the importance of these residues for in vivo function. These data refine the structural analyses and further support the hypothesis that CBFbeta enhances DNA binding by inducing a conformational change in the Runt domain.

Amino Acids↗