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Biomedical subjects

J Stuart

Publications and source records attributed to J Stuart.

At least 19 recordsLinked to original sources

Structural analysis of BAG1 cochaperone and its interactions with Hsc70 heat shock protein.

BAG-family proteins share a conserved protein interaction region, called the 'BAG domain', which binds and regulates Hsp70/Hsc70 molecular chaperones. This family of cochaperones functionally regulates signal transducing proteins and transcription factors important for cell stress responses, apoptosis, proliferation, cell migration and hormone action. Aberrant overexpression of the founding member of this family, BAG1, occurs in human cancers. In this study, a structure-based approach was used to identify interacting residues in a BAG1--Hsc70 complex. An Hsc70-binding fragment of BAG1 was shown by multidimensional NMR methods to consist of an antiparallel three-helix bundle. NMR chemical shift experiments marked surface residues on the second (alpha 2) and third (alpha 3) helices in the BAG domain that are involved in chaperone binding. Structural predictions were confirmed by site-directed mutagenesis of these residues, resulting in loss of binding of BAG1 to Hsc70 in vitro and in cells. Molecular docking of BAG1 to Hsc70 and mutagenesis of Hsc70 marked the molecular surface of the ATPase domain necessary for interaction with BAG1. The results provide a structural basis for understanding the mechanism by which BAG proteins link molecular chaperones and cell signaling pathways.

Adenosine Triphosphatases↗

The Penn Psychoanalytic Treatment Collection: a set of complete and recorded psychoanalyses as a research resource.

From a set of seventeen complete and tape-recorded psychoanalyses, a sample of findings is presented: (a) the level of agreement of two clinical judges on the psychological health of these patients is adequate for the late sessions, but not for the early sessions; (b) the amount of change during psychoanalysis appears to be similar to that in the Menninger Foundation Psychotherapy Research Project; (c) psychiatric severity measures from the early sessions can yield a significant level of prediction of the later benefits from psychoanalysis. Finally, further research uses of this collection of psychoanalyses are suggested.

Adult↗

Improving preventive service delivery through office systems.

OBJECTIVE: Rates of childhood immunizations and other preventive services are lower in many practices than national goals and providers' own estimates. Office systems have been used in adult settings to improve the delivery of preventive care, but their effectiveness in pediatric practices is unknown. This study was designed to determine whether a group of primary care practices in 1 community could implement office-based quality improvement systems that would significantly improve their delivery of childhood preventive services. The study was part of a larger community-wide intervention study reported in a preceding study. METHODS: All the major providers of primary care to children in 1 community were recruited and agreed to participate (N = 8 practices). Project staff worked on-site with improvement teams in each practice to develop tailored systems to assess and improve the delivery of immunizations and screening for anemia, tuberculosis, and lead exposure. Office-based quality improvement systems typically involved some combination of chart prescreening, risk assessment forms, Post-it prompts, flow-sheets, reminder/recall systems, and patient education materials. Office systems also often involved redistributing responsibilities among office staff. RESULTS: All 8 participating practices created improvement teams. Project staff met with the practices 10 to 15 times over 12 months. After the period of office assistance, the overall rates for all preventive services except tuberculosis screening increased by amounts that were both clinically and statistically significant. Absolute percent improvements included: complete immunizations at 12 months, 7%; complete immunizations at 24 months, 12%; anemia screening, 30%; lead screening, 36%. The amount of improvement achieved varied considerably between practices. CONCLUSIONS: Office systems and the principles of quality improvement that underlie them seem to be effective in improving the delivery of childhood preventive services. Important predisposing factors may exist within practices that affect the likelihood that an individual practice will make significant improvements. prevention, immunizations, improvement, office systems, primary care.

Child↗

From concept to application: the impact of a community-wide intervention to improve the delivery of preventive services to children.

OBJECTIVE: To improve health outcomes of children, the US Maternal and Child Health Bureau has recommended more effective organization of preventive services within primary care practices and more coordination between practices and community-based agencies. However, applying these recommendations in communities is challenging because they require both more complex systems of care delivery within organizations and more complex interactions between them. To improve the way that preventive health care services are organized and delivered in 1 community, we designed, implemented, and assessed the impact of a health care system-level approach, which involved addressing multiple care delivery processes, at multiple levels in the community, the practice, and the family. Our objective was to improve the processes of preventive services delivery to all children in a defined geographic community, with particular attention to health outcomes for low-income mothers and infants. DESIGN: Observational intervention study in 1 North Carolina county (population 182 000) involving low- income pregnant mothers and their infants, primary care practices, and departments of health and mental health. An interrupted time-series design was used to assess rates of preventive services in office practices before and after the intervention, and a historical cohort design was used to compare maternal and child health outcomes for women enrolled in an intensive home visiting program with women who sought prenatal care during the 9 months before the program's initiation. Outcomes were assessed when the infants reached 12 months of age. INTERVENTIONS: Our primary objective was to achieve changes in the process of care delivery at the level of the clinical interaction between care providers and patients that would lead to improved health and developmental outcomes for families. We selected interventions that were directed toward major risk factors (eg, poverty, ineffective care systems for preventive care in office practices) and for which there was existing evidence of efficacy. The interventions involved community-, practice-, and family-level strategies to improve processes of care delivery to families and children. The objectives of the community-level intervention were: 1) to achieve policy level changes that would result in changes in resources available at the level of clinical care, 2) to engage multiple practice organizations in the intervention to achieve an effect on most, if not all, families in the community, and 3) to enhance communication between, among, and within public and private practice organizations to improve coordination and avoid duplication of services. The objective of the practice-level interventions was to overcome specific barriers in the process of care delivery so that preventive services could be effectively delivered. To assist the health department in implementing the family-level intervention, we provided assistance in hiring and training staff and ongoing consultation on staff supervision, including the use of structured protocols for care delivery, and regular feedback data about implementation of the program. Interventions with primary care practices focused on the design of the delivery system within the office and the use of teamwork and data in an "office systems" approach to improving clinical preventive care. All practices (N = 8) that enrolled at least 5 infants/month received help in assessing performance and developing systems (eg, preventive services flow sheets) for preventive services delivery. Family-level interventions addressed the process of care delivery to high-risk pregnant women (<100% poverty) and their infants. Mothers were recruited for the home visiting intervention when they first sought prenatal care at the community health center, the county's largest provider of prenatal care to underserved women. The home visiting intervention involved teams of nurses and educators and involved 2 to 4 visits per month through the infant's first year of life to provide parental education on fetal and infant health and development, enhance parents' informal support systems, and link parents with needed health and human services. We included training in injury prevention and discipline, and home visitors assisted mothers in obtaining care from one of the primary care offices. RESULTS: There were high levels of participation, changes in the organization of the delivery system, and improvements in preventive health outcomes. Agencies cooperated in joint contracting, staff training, and defining program eligibility. All 8 eligible practices agreed to participate and 7/8 implemented at least 1 new office system element. Of eligible women, 89% agreed to participate, and outcome data were available on 80% (180/225). After adjusting for differences in baseline characteristics, intervention group women were significantly more likely than comparison group women to use contraceptives (69% vs 47%), not smoke tobacco (27% vs 54%) and have a safe and stimulating home environment for their children. Intervention group children were more likely to have had an appropriate number of well-child care visits (57% vs 37%) and less likely to be injured (2% vs 7%). Intervention mothers also received Aid to Families with Dependent Children for fewer months after the birth of their child (7.7 months vs 11.3 months). CONCLUSIONS: We observed a number of positive effects at all 3 levels of intervention. Policy-level changes at the state and community led to lasting changes in the organization and financing of care, which enabled changes in clinical services to take place. These changes have now been expanded beyond this community to other communities in the state. We were also able to engage multiple practice organizations, reduce duplication, and improve the coordination of care. Changes in the process of preventive services delivery were noted in participating practices. Finally, the outcomes of the family-level intervention were comparable in direction and magnitude to the outcomes of previous randomized trials of the intervention. All the changes were achieved over a relatively brief 3-year study period, and many have been sustained since the project was completed. Tiered, interrelated interventions directed at an entire population of mothers and children hold promise to improve the effectiveness and outcomes of health care for families and children.

Adult↗

Cluster of meningococcal disease in rugby match spectators.

Four adults among three unconnected groups of spectators at a rugby match developed invasive meningococcal disease four to five days after the match. Two died. All four cases were caused by serogroup C serotype 2a strains, genotype P1.5, P1.2. Although the route of transmission remains uncertain, the most likely explanation is that an asymptomatic carrier disseminated meningococci to at least four others in the course of an afternoon. Clusters among spectators at an event without other links between cases are very unusual.

Aged↗

Risk of secondary meningococcal disease in health-care workers.

Guidelines on chemoprophylaxis vary between countries and reflect uncertainty about the risk of meningococcal disease in healthcare workers. In a retrospective survey of risk in healthcare workers in England and Wales, three pairs of primary cases and health-care workers with secondary infections were identified between 1982 and 1996. Secondary infections were probably caused by exposure to primary cases' respiratory droplets around the time of admission. We estimated an attack rate of 0.8 per 100000 health-care workers at risk, a risk 25 times that in the general population (p=0.0003). The excess risk is small and inappropriate use of prophylactic antibiotics should be avoided.

Adult↗

A secondary school outbreak of mumps following the childhood immunization programme in England and Wales.

Since the introduction of routine measles, mumps and rubella immunization for children in England and Wales in 1988, the incidence of mumps has declined steadily. We describe an outbreak of mumps in 1996 attacking 34 of a cohort of 98 schoolchildren born in 1982 and 1983. This is the largest outbreak in the UK since the introduction of the vaccine into the childhood immunization schedule. Salivary IgM assay was used as a simple, minimally invasive test to confirm the diagnosis. The occurrence of the outbreak demonstrates that British children who were just too old to receive mumps immunization in 1988 continue to be at risk of this disease as a result of diminished natural exposure. Further cases and outbreaks in this cohort are to be expected. Cohorts born before 1982 appear to be at less risk, presumably because of naturally acquired infection before the introduction of immunization.

Adolescent↗

Invasive Haemophilus influenzae disease in adults.

We reviewed retrospectively all invasive Haemophilus influenzae (Hi) infections in adults ascertained from reference laboratory records and notifications from five NHS regions over the 5 years from 1 October 1990, a period encompassing the introduction of routine Hib childhood immunization (October 1992). A total of 446 cases were identified, a rate of 0.73 infections per 10(5) adults per annum. Though numbers of Hib infections in adults fell after the introduction of Hib vaccines for children (P = 0.035), and there was no increase in infections caused by other capsulated Hi serotypes, total numbers of invasive Hi infections increased due to a large rise in infections caused by non-capsulated Hi (ncHi) strains (P = 0.0067). There was an unexpectedly low rate of infections in those aged 75 years or more (P < 0.0001). The commonest clinical presentations were pneumonia with bacteraemia (227/350, 65%) and bacteraemia alone (62/350, 18%) and the highest rates of disease were in the 65-74 years age group (P < 0.0001). Clinical presentation was not influenced by the capsulation status of the invading Hi strain. 103/350 cases (29%) died within 1 month, and 207/350 (59%) within 6 months of their Hi infection. Case fatality rates were high in all age groups. Pre-existing diseases were noted in 220/350 cases and were associated with a higher case fatality rate (82% vs. 21%, P < 0.0001). After the introduction of Hib immunization in children, invasive Hib infections in unimmunized adults also declined, but the overall rate of invasive Hi disease in adults increased, with most infections now caused by non-capsulated strains. Physicians and microbiologists should be aware of the changing epidemiology, the high associated mortality and high risk of underlying disease. Invasive haemophilus infections in adults should be investigated and treated aggressively.

Adult↗

Mathematical modelling of infection and disease due to Neisseria meningitidis and Neisseria lactamica.

BACKGROUND: Invasive meningococcal disease, due to Neisseria meningitidis, is an important cause of morbidity and mortality in young children and adolescents. Nasopharyngeal carriage of meningococci (MC), is most prevalent in young adults whereas carriage of Neisseria lactamica (LC), a related non-pathogenic organism, is most prevalent in young children. The objective of this study was to use modelling techniques to test hypotheses on the processes that govern the incidence of meningococcal disease (MD). METHODS: Deterministic compartmental models were fitted to age structured data sets of MC, LC and MD. RESULTS: The model most consistent with the available data sets is one where LC inhibits MC, an inhibition that lasts for a mean of 4.7 years. The hypothesis that LC also acts as a natural immunogen against MD was consistent with this model. The second peak of MD observed among adolescents could be due to the peak in the acquisition of MC in this age group. CONCLUSIONS: The role of LC as a natural immunogen against asymptomatic and symptomatic meningococcal infection was consistent with available field data. If the introduction of novel meningococcal vaccines into a population changes the prevalence of MC or LC, this could have a substantial impact on the effectiveness of immunization programmes. This paper demonstrates the potential utility of modelling to estimate these effects.

Adolescent↗

Evaluation of a drama-in-education programme to increase AIDS awareness in South African high schools: a randomized community intervention trial.

A community intervention trial was undertaken in KwaZulu Natal, South Africa to evaluate the effectiveness of a high school drama-in-education programme. Seven pairs of secondary schools were randomized to receive either written information about HIV/AIDS or the drama programme. Questionnaire surveys of knowledge, attitude and behaviour were compared before and 6 months after the interventions. One thousand and eighty students participated in the first survey and 699 in the second. Improvements in knowledge (P=0.0002) and attitudes (P < 0.00001) about HIV/AIDS were demonstrated in pupils at schools receiving the drama programme when compared to pupils receiving written information alone. These changes were independent of age, gender, school or previous sexual experience. In schools receiving the drama programme, sexually active pupils reported an increase in condom use (P < 0.01). It is important to provide resources to sustain such programmes and to obtain stronger evidence of effect on behaviour by measuring changes in HIV incidence.

Acquired Immunodeficiency Syndrome↗

Measuring the process of preventive service delivery in primary care practices for children.

BACKGROUND: Children may fall behind on preventive services because they do not receive needed services at the time of an office visit (a missed opportunity). However, methods are needed to measure problems in the care delivery process that lead to missed opportunities. We developed a method to examine the key steps in the preventive service delivery process and identify problems; we assessed the feasibility and validity of the method in primary care practices for children. METHODS: Using 3 data collection methods, we measured key steps in the process of preventive service delivery in primary care offices: a chart audit was used to measure each child's preventive service status before and after an office visit, a brief parent exit interview was used to assess preventive service delivery not documented in the chart, and a staff checklist was used to assess the role of nursing and other office staff. The feasibility of using this combination of measures to identify problems in the care delivery process was evaluated in 3 representative primary care practices (2 pediatric, 1 family practice) among children 5 years and younger. RESULTS: The measurement method was implemented in all 3 practices. The validity of the method was supported by its ability to detect differences among practices in the proportion of children eligible for immunizations and screening tests and in the proportion of children undergoing key steps in the process of preventive service delivery. The practice with the lowest proportion of children whose charts were screened for preventive services needs had the lowest performance of preventive services. CONCLUSIONS: It is possible to assess specific elements in the process of preventive service delivery in primary care practices. Use of this approach may help practices design and monitor interventions to improve the quality of preventive care delivery.

Algorithms↗

Mycophenolate mofetil and tacrolimus as primary maintenance immunosuppression in simultaneous pancreas-kidney transplantation: initial experience in 50 consecutive cases.

BACKGROUND: The current study examines the use of mycophenolate mofetil (MMF) and tacrolimus as primary immunosuppression in simultaneous pancreas-kidney (SPK) transplantation. In addition, analyses of the rates of conversion from one immunosuppressive agent to another, and its subsequent consequences with respect to outcomes were determined. Quality of graft function, infections, and effect on preexisting essential hypertension are also described. METHODS: Immunosuppression consisted of quadruple therapy with antithymocyte globulin induction, tacrolimus, MMF, and prednisone. Patient and graft survival and rejection rates in 50 consecutive SPK recipients, followed for a minimum of 3 months and a mean of 14 months (range: 3-34 months), are described. RESULTS: Thirty-nine of 50 (78%) patients tolerated the MMF/tacrolimus combination long-term (mean duration of follow-up: 14+/-7 months). Nine of 50 patients (18%) were converted to Neoral, and 4 patients were converted to azathioprine as a substitute for MMF. The 2-year actuarial patient, kidney, and pancreas survival rates were 97.7%, 93.3%, and 90.0%, respectively. At 6 months after transplant, the overall incidence of acute rejection was 16%. There was a statistically significant (P< or =0.04, Cox-Mantel test) difference in the rate of rejection associated with conversion to Neoral. The incidence of rejection 6 months after transplant in the group maintained on MMF/tacrolimus was 10.2% vs. 44.4% in the group converted to Neoral (P< or =0.04, Cox-Mantel test). Overall, the 1-year actuarial cumulative incidence of tissue-invasive cytomegalovirus disease was 6.6%. There were no cases of fungal infections or post-transplant lymphoproliferative disorders. One patient developed Kaposi's sarcoma 10 months after transplant. With respect to hypertensive disease, 60% (12/20) of the patients who required pharmacologic control of blood pressure before transplant were off all antihypertensive medications at 1 year after transplant. An additional 20% (4/20) of patients had a reduction in the number of medications required to control blood pressure at 1 year after transplant. CONCLUSIONS: We conclude that the combination of MMF and tacrolimus as primary immunosuppression for SPK transplantation results in excellent patient and graft survival rates, a very low rate of acute rejection, and low rates of infection and malignancy.

Adolescent↗

Outbreak of Escherichia coli O157 infection associated with a music festival.

Seven persons who attended the Glastonbury Music Festival were infected with Vero cytotoxin-producing Escherichia coli O157 and an eighth person had serological evidence of infection. Cases were reported from different parts of England. Patients were interviewed by telephone about clinical symptoms, festival attendance, camping details, food history, water exposure, and contact with mud and animals. The interviews identified no common food source, differing use of water sources and widely dispersed camping sites. Escherichia coli O157 strains from seven persons and from a cow belonging to a herd that had previously grazed the site all belonged to phage type 2 and possessed genes for Vero cytotoxin 2. Drug resistance and DNA-based tests showed that six patients were infected with strains indistinguishable from each other and from the bovine isolate. The most likely vehicle of infection was mud contaminated with Escherichia coli O157 from infected cattle.

Adult↗

Invasive meningococcal disease among university undergraduates: association with universities providing relatively large amounts of catered hall accommodation.

The incidence of invasive meningococcal disease (IMD) among UK university students and non-students of similar age was investigated. In addition, we sought to identify structural risk factors associated with high rates of IMD in individual universities. Cases were ascertained via Consultants in Communicable Disease Control (or equivalent officers) between September 1994 and March 1997. Data on individual universities were obtained from university accommodation officers. University students had an increased annual rate of invasive meningococcal disease (13.2/10(5), 95% CI 11.2-15.2) compared with non-students of similar age in the same health districts (5.5/10(5), CI 4.7-6.4) and in those health districts without universities (3.7/10(5), CI 2.9-4.4). This trend was highly significant. Regression analysis demonstrated catered hall accommodation to be the main structural risk factor. Higher rates of disease were observed at universities providing catered hall places for > 10% of their student population (15.3/10(5), CI 11.8-18;8) compared with those providing places for < 10% of students (5.9/10(5), CI 4.1-7.7). The majority of IMD amongst students was caused by serogroup B organisms. University students in the UK are at increased risk of IMD compared with non-students of a similar age. The incidence of IMD tends to be greatest at universities with a high provision of catered hall accommodation.

Adolescent↗

Inter observer variability of the transcranial Doppler ultrasound technique: impact of lack of practice on the accuracy of measurement.

OBJECTIVE: Published data on the observer variability with the transcranial doppler (TCD) ultrasound are limited by the use of the product moment correlation coefficient. This study was designed to quantify the intra and inter observer variability with the TCD in terms of the intra class correlation coefficient (ICC) and to assess the impact of lack of practice on the observer variability and the accuracy of data generated. METHODS: The study was performed in two phases. In phase I, three observers insonated the middle cerebral artery in 10 healthy volunteers and measured peak systolic and end diastolic cerebral blood flow velocities. In phase II, the same observers repeated the experiment on five healthy volunteers after an eight week break during which none of the observers were allowed to use the TCD system. The observers were blinded to the measurements obtained. RESULTS: The ICC for peak velocity measurement was 0.9 (0.81-0.99) in phase I and 0.85 (0.66-1.00) in phase II (p < 0.05). The ICCs for end diastolic velocity measurements for phase I and II were 0.8 (0.64-0.96) and 0.67 (0.33-1.00) respectively (p < 0.01). CONCLUSIONS: A high level of observer agreement is possible with the TCD for measurement of cerebral blood flow velocities. Lack of regular practice with the system reduces the accuracy of measurements and impacts on both measured and calculated indices.

Adult↗

Receptor-mediated endocytosis of albumin by kidney proximal tubule cells is regulated by phosphatidylinositide 3-kinase.

Receptor-mediated endocytosis of albumin is an important function of the kidney proximal tubule epithelium. We have measured endocytosis of [125I]-albumin in opossum kidney cells and examined the regulation of this process by phosphatidylinositide 3-kinase (PI 3-kinase). Albumin endocytosis was inhibited by both wortmannin (IC50 6.9 nM) and LY294002 (IC50 6.5 microM) at concentrations that suggested the involvement of PI 3-kinase in its regulation. Recycling rates were unaffected. We transfected OK cells with either a wild-type p85 subunit of PI 3-kinase, or a dominant negative form of the p85 subunit (Deltap85) using the LacSwitch expression system. Transfects were screened by immunoblotting with anti-PI 3-kinase antibodies. Under basal conditions, transfects demonstrated no expression of p85 or Deltap85, but expression was briskly induced by treatment of the cells with IPTG (EC50 13.7 microM). Inhibition of PI 3-kinase activity by Deltap85 was confirmed by in vitro kinase assay of anti-phosphotyrosine immunoprecipitates from transfected cells stimulated with insulin. Expression of Deltap85 resulted in marked inhibition of albumin endocytosis, predominantly as a result of reduction of the Vmax of the transport process. Expression of p85 had no significant effect on albumin uptake. The results demonstrate that PI 3-kinase regulates an early step in the receptor-mediated endocytosis of albumin by kidney proximal tubular cells.

Androstadienes↗