Perspectives. SCHIP premium subsidy plans stymied by HCFA's rigid stance.
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Centers for Medicare and Medicaid Services, U.S.↗
Biomedical subjects
S Williams
Publications and source records attributed to S Williams.
Topiramate therapy of epilepsy associated with Angelman's syndrome.
Angelman's syndrome, a genetic disorder involving a defect in the DNA coding for subunits of the gamma-aminobutyric acid (GABA) type A receptor, often is associated with intractable epilepsy. Topiramate is a novel anticonvulsant that enhances GABAergic neurotransmission. Five children with Angelman's syndrome and epilepsy were treated with topiramate for clinical indications. The drug was effective and well tolerated, possibly because of its GABAergic properties. Further studies are necessary to confirm and elucidate this observation.
Angelman Syndrome↗
Cytoskeletal protein tyrosine phosphatase PTPH1 reduces T cell antigen receptor signaling.
The subgroup of protein tyrosine phosphatases that contain an N-terminal ezrin-, radixin- and moesin homology (ERM) domain and a C-terminal catalytic domain is represented by three enzymes in Jurkat T cells, PTPH1, PTP-MEG1 and PTP36. These enzymes are located at the cytoplasmic face of the plasma membrane and may be involved in regulation of the membrane cytoskeleton, signal transduction, or both. Here we report that expression of PTPH1 in Jurkat T cells reduced the TCR-induced activation of reporter genes encompassing parts of the IL-2 gene promoter and driven by nuclear factor of activated T cells plus activator protein-1. PTP-MEG1 had a weaker inhibitory effect, while PTP36 had none. The catalytically inactive mutants PTPH1-CS and PTP-MEG1-CS lacked effects on gene transcription. Expression of active PTPH1 also reduced receptor-induced activation of Erk2 MAP kinase, its upstream activator, Mek, and the Jnk kinases. The effect of PTPH1 was reduced by deletion of its N-terminal ERM domain. We suggest that PTPH1 inhibits T cell activation by dephosphorylating membrane-associated targets involved in TCR signaling.
Cytoskeleton↗
Subcellular localization of intracellular protein tyrosine phosphatases in T cells.
A high protein tyrosine phosphatase (PTPase) activity is required to maintain circulating T lymphocytes in a resting phenotype, and to limit the initiation of T cell activation. We report that 15 of the currently known 24 intracellular PTPases are expressed in T cells, namely HePTP, TCPTP, SHP1, SHP2, PEP, PTP-PEST, PTP-MEG2, PTEN, PTPH1, PTP-MEG1, PTP36, PTP-BAS, LMPTP, PRL-1 and OV-1. Most were found in the cytosol and many were enriched at the plasma membrane. Only TCPTP and PTP-MEG2 had subcellular localizations that essentially excludes them from a direct role in early T cell antigen receptor signaling events. Overexpression of 6 of the PTPases reduced IL-2 gene activation, 3 of them thereby identified as novel candidates for negative regulators of TCR signaling. Our findings expand the repertoire of PTPases that should be considered for a regulatory role in T cell activation.
Cell Membrane↗
Does low self-esteem predict health compromising behaviours among adolescents?
It is often believed that low self-esteem is associated with such health-compromising behaviours in adolescence as substance use, early sexual activity, eating problems and suicidal ideation. Surprisingly, there is little longitudinal research addressing this issue. This longitudinal study examines the predictive association between both global and academic self-esteem from ages 9 to 13 years, and a variety of health compromising behaviours at age 15, in a large sample of young New Zealanders. Levels of global self-esteem significantly predicted adolescent report of problem eating, suicidal ideation, and multiple health compromising behaviours. Earlier levels of self-esteem were unrelated to later substance use and early sexual activity. The findings are discussed in terms of their implications for efforts to raise self-esteem among young people.
Adolescent↗
How good is good enough in path analysis of fMRI data?
This paper is concerned with the problem of evaluating goodness-of-fit of a path analytic model to an interregional correlation matrix derived from functional magnetic resonance imaging (fMRI) data. We argue that model evaluation based on testing the null hypothesis that the correlation matrix predicted by the model equals the population correlation matrix is problematic because P values are conditional on asymptotic distributional results (which may not be valid for fMRI data acquired in less than 10 min), as well as arbitrary specification of residual variances and effective degrees of freedom in each regional fMRI time series. We introduce an alternative approach based on an algorithm for automatic identification of the best fitting model that can be found to account for the data. The algorithm starts from the null model, in which all path coefficients are zero, and iteratively unconstrains the coefficient which has the largest Lagrangian multiplier at each step until a model is identified which has maximum goodness by a parsimonious fit index. Repeating this process after bootstrapping the data generates a confidence interval for goodness-of-fit of the best model. If the goodness of the theoretically preferred model is within this confidence interval we can empirically say that the theoretical model could be the best model. This relativistic and data-based strategy for model evaluation is illustrated by analysis of functional MR images acquired from 20 normal volunteers during periodic performance (for 5 min) of a task demanding semantic decision and subvocal rehearsal. A model including unidirectional connections from frontal to parietal cortex, designed to represent sequential engagement of rehearsal and monitoring components of the articulatory loop, is found to be irrefutable by hypothesis-testing and within confidence limits for the best model that could be fitted to the data.
Adult↗
Effect of asthma on the quality of life among children and their caregivers in the Atlanta Empowerment Zone.
BACKGROUND AND OBJECTIVE: Asthma is the most common chronic pediatric disease and exacts a toll on the health-related quality of life of affected children and their primary caregivers. This investigation describes the relationship between the clinical severity of asthma among inner-city children and their quality of life and that of their primary adult caregivers. METHODS: Telephone interview data were collected from individual adult caregivers of 5-12-year-old children with asthma. Questions addressed the history, diagnosis, and management of the child's asthma, the child's family and social background, the family's socioeconomic status, the caregiver's knowledge and attitude about asthma, and the health-related quality of life of both the child and the caregiver. An asthma severity score was calculated from the caregiver's responses to questions about their child's wheezing frequency, nocturnal and early morning symptoms, and speaking during an asthma attack, as well as the impact of the disease on their child's physical activity and breathing during the prior 4-month period. A clinical asthma triage score was determined from information collected at the emergency department about the child's oxygen saturation, alertness, use of accessory respiratory muscles, extent of breathlessness, and peak expiratory flow. Spearman correlation coefficients were used to identify association between quality of life and disease severity, caretaker's asthma knowledge, and functional impact of asthma symptoms. RESULTS: Data from 240 of 755 eligible children were analyzed. Most children were younger than 11 years, male, black, and non-Hispanic. The children's median duration of asthma diagnosis was 86% of their life (range less than 1 to 11.3 years, median 5.0 years). Of the primary caregivers, 69% had at least completed high school, and 90% reported a total monthly household income of $1,600 or less. The maximum possible quality-of-life score and the median for caregivers were 91 and 70, respectively; for children, the same scores were 69 and 58, respectively. In addition, there was significant negative correlation of the quality-of-life scores of both the caregivers and children with the number of schooldays the children missed (r = -0.24 and r = -0.26, respectively, P < .001 for both) and the caregivers' and children's asthma severity scores (r = -0.39 and r = -0.47, respectively, P < .001 for both). The quality-of-life scores of the children and caregivers did not correlate significantly with the asthma triage scores. CONCLUSIONS: The questionnaires captured baseline quality-of-life information about this urban population and will facilitate longitudinal monitoring. The fact that the quality-of-life scores of children with asthma correlated with those of their adult caregivers, but not with their clinical triage scores, highlights the impact of asthma on families and the importance of having a long-term comprehensive management plan that is not based on exacerbations, but that includes both the children and their primary caregivers.
Asthma↗
CT, MRI and MRS of Epstein-Barr virus infection: case report.
We report MRI and proton MR spectroscopy (MRS) findings in a 12-month-old girl with Epstein-Barr virus encephalitis. CT and MRI showed focal lesions in the basal ganglia. MRS of the lesions showed decreased N-acetyl aspartate and elevation of some amino acids, indicating an infectious rather than ischemic etiology. This case illustrates the use of MRS to narrow differential diagnosis.
Encephalitis, Viral↗
Limb salvage surgery for pathological fractures in osteosarcoma.
The local treatment of pathological fracture in patients with a primary osteosarcoma remains controversial. In this paper we report the oncological outcome of the treatment of pathological fractures in 18 patients suffering from this disease. There were ten male and eight female patients, and the average age at diagnosis was 17 years. All patients received adjuvant chemotherapy. Wide resections were performed in 17, but in one there was 'contamination' of the margins of the excision. Skeletal reconstruction was performed with a locally designed and manufactured custom 'mega' prosthesis. The average follow-up was 33 months (range: 12-93 months), and 14 patients were alive on completion of the study. Local recurrence appeared in two patients, while three developed pulmonary metastases.
Adolescent↗
Limb salvage in distal tibial osteosarcoma using a custom mega prosthesis.
We have assessed the oncological and functional results of limb salvage surgery using a custom-made endoprosthetic replacement in six patients (mean age 17 years) with distal tibial osteosarcoma (stage IIB). A wide margin excision was possible in three, marginal in two and contaminated in one. Skeletal reconstruction was performed using a locally designed and manufactured custom-made distal tibial and ankle replacement prosthesis. Two patients developed local recurrence and one necrosis of the flap and deep infection. In three in whom the prosthesis remained in place the mean functional score according to the rating system of the Musculoskeletal Tumour Society was 24.3/30. In carefully selected patients limb salvage with prosthetic replacement is possible for distal tibial osteosarcomas.
Adolescent↗
Variants in the cholesterol ester transfer protein and lipoprotein lipase genes are predictors of plasma cholesterol response to dietary change.
There are no definitive explanations as to why individuals with hypercholesterolemia, a major cardiovascular risk factor, respond differently to dietary change. Fifty five free-living individuals completed a double crossover trial with two dietary regimens, a high saturated fat diet (providing 21% energy from saturated fat and 3% energy from polyunsaturated fat) and a high polyunsaturated fat diet (providing 11% energy as saturated fat and 10% energy as polyunsaturated fat), each phase continuing for 4 weeks. Extensive genotyping and several measures of dietary compliance have provided further insights regarding the determinants of extent of cholesterol response to changes in the nature of dietary fat. Individuals with the CETP B1B1 genotype and the LPL X447+ allele showed an average 0. 44 (95% CI: 0.22, 0.66) and 0.45 (95% CI: 0.18, 0.72) mmol/l greater change in total cholesterol, respectively, than those with one or more CETP B2 allele or homozygous for the LPL S447 allele when comparing diets high and low in saturated fat. Indices of dietary compliance including changes in reported saturated and polyunsaturated fat intake and change in triglyceride linoleate were not significantly different between the CETP genotypes. Change in reported saturated (r=0.36, P=0.04) and polyunsaturated (r=0.22, P=0. 05) fat intake and change in triglyceride linoleate (reflecting polyunsaturated fat intake) (r=0.21, P=0.07), also predicted total cholesterol response to dietary fat changes. In multivariate analyses, variation in the cholesterol ester transfer protein and lipoprotein lipase genes predicted response independent of measures of dietary compliance, suggesting that these two genes are important determinants of variation in cholesterol response to dietary change in free-living individuals.
Adult↗
Potential of interventional ventilation in organ transplantation.
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Adult↗
In pursuit of ceruminolytic agents: a study of earwax composition.
OBJECTIVE: To assess the protein and simple sugar content of earwax in pursuit of better ceruminolytic agents. STUDY DESIGN: Collected earwax specimens were tested in several media for dissolution before being analyzed for amino acid and carbohydrate content. PATIENTS: The samples were obtained from eight random patients requiring ear plug removal. RESULTS: The amino acid composition differs considerably from hair and stratum corneum of glabrous skin. Sugar analysis revealed high levels of galactosamine and galactose. CONCLUSIONS: This analysis of proteins and carbohydrates further characterizes earwax. Future ceruminolytic agents must dissolve lipid, keratin, and a monolayer of lipid covalently bound to the epidermal cells, which encourages cellular aggregation.
Amino Acids↗
Cereal crops as viable production and storage systems for pharmaceutical scFv antibodies.
This report describes the stable expression of a medically important antibody in the staple cereal crops rice and wheat. We successfully expressed a single-chain Fv antibody (ScFvT84.66) against carcinoembryonic antigen (CEA), a well characterized tumor-associated marker antigen. scFv constructs were engineered for recombinant antibody targeting to the plant cell apoplast and ER. Up to 30 microg/g of functional recombinant antibody was detected in the leaves and seeds of wheat and rice. We confirmed that transgenic dry seeds could be stored for at least five months at room temperature, without significant loss of the amount or activity of scFvT84.66. Our results represent the first transition from model plant expression systems, such as tobacco and Arabidopsis, to widely cultivated cereal crops, such as rice and wheat, for expression of an antibody molecule that has already shown efficacy in clinical applications. Thus, we have established that molecular pharming in cereals can be a viable production system for such high-value pharmaceutical macromolecules. Our findings provide a strong foundation for exploiting alternative uses of cereal crops both in industrialized and developing countries.
Animals↗
Surveillance of primary dentition caries in Germiston, South Africa, 1981-97.
OBJECTIVE: This 17-year-long study examined trends of dental caries rates in the primary dentition of 6843 preschool children in a South African city. METHODS: Calibrated dentists did repeated cross-sectional epidemiological surveys of dental caries in 2- to 5-year-old nursery school children using WHO diagnostic criteria between 1981 and 1997. RESULTS: Both the percentage of children with dmft>0 and mean dmft increased between 1981 and 1989 and have slowly declined ever since in the absence of organised prevention to produce a secular trend of decreasing caries rates. The dt/dmft percentage ranged between 60% and 100% except in 1991 when it dropped to 40% and the ft/dmft percentage component rose proportionally, probably due to an economic effect. CONCLUSIONS: The percentage of children with dmft>0 and mean dmft decreased over the study period at all ages, the reason for which is unknown but is speculated to be due to a change in mutans streptococci strains.
Black or African American↗
Transplantation of CD34+ peripheral blood cells selected using a fully automated immunomagnetic system in patients with high-risk breast cancer: results of a prospective randomized multicenter clinical trial.
Tumor contamination of autologous peripheral blood stem/progenitor cell grafts occurs in a substantial proportion of high-risk breast cancer patients, and the possibility that such contamination may contribute to relapse has focused attention on methods for removal of the contaminating cells prior to transplantation. One such approach is positive selection of CD34+ cells. A fully automated immunomagnetic cell selection system has recently been introduced to facilitate the positive selection process. A multicenter randomized clinical trial was designed to evaluate the capacity of CD34+ cells isolated using the fully automated system to support prompt hematopoietic reconstitution following high-dose chemotherapy in high-risk breast cancer patients, as well as to assess the safety and tolerability of the CD34+ cell transplants. In recipients of isolated CD34+ cells, the median time to an absolute neutrophil count > or =500/microl was 10 days, a value identical to that observed in patients receiving unfractionated apheresis collections. In the isolated CD34+ cell recipients median time to a platelet count > or =20 000/microl was 12 days, compared with 10 days in the unfractionated cell group. There were no statistically significant differences between the groups in median time to neutrophil or platelet engraftment. Infusion of autologous cells was well tolerated by the study groups. There were no inter-group differences in the incidence of infections, need for platelet transfusions, or duration of hospitalization. Isolated CD34+ cells were high in purity and sufficient in number for use in autologous transplantation. The fully automated immunomagnetic cell selection system affords an efficient and time-saving option for isolation of CD34+cells to be used as autologous grafts in high-risk breast cancer patients, and the isolated CD34+ cells support undelayed hematopoietic reconstitution.
Adult↗
Use of PEG-rHuMGDF in platelet engraftment after autologous stem cell transplantation.
This paper summarizes a pilot, sequential dose-escalation study of PEG-rHuMGDF in patients with advanced malignancies who had delayed platelet recovery after autologous stem cell transplantation (ASCT). Patients were randomized to receive either placebo (n = 11) or PEG-rHuMGDF at 5 (n = 9), 10 (n = 6), or 25 (n = 7) microg/kg/day by subcutaneous injection for 14 days and were monitored for 5 weeks. Across all treatment groups, eight patients had platelet recovery to > or = 20 x 10(9)/l by day 21. The proportion of patients achieving platelet recovery, the median number of days and units of platelet transfusions were similar for the placebo and the PEG-rHuMGDF groups. PEG-rHuMGDF was well tolerated at all dosages. The incidence rates of adverse events in all groups were similar. No deaths on study, no drug-related serious adverse events, and no development of neutralizing antibodies to MGDF occurred.
Adult↗
A longitudinal study of cannabis use and mental health from adolescence to early adulthood.
AIMS: To examine the longitudinal association between cannabis use and mental health. DESIGN: Information concerning cannabis use and mental health from 15 to 21 years was available for a large sample of individuals as part of a longitudinal study from childhood to adulthood. PARTICIPANTS: Participants were enrolled in the Dunedin Multidisciplinary Health and Development Study, a research programme on the health, development and behaviour of a large group of New Zealanders born between 1 April 1972 and 31 March 1973. MEASUREMENTS: Cannabis use and identification of mental disorder was based upon self-report as part of a general assessment of mental health using a standard diagnostic interview. Daily smoking and alcohol use at age 15 were assessed by self-report. Indices of family socio-economic status, family climate and parent-child interaction were formed using information gathered from parent report and behavioural observations over early childhood. Childhood behaviour problems were assessed by parent and teacher report. Attachment to parents was assessed in adolescence. FINDINGS: Cross-sectional associations between cannabis use and mental disorder were significant at all three ages. Both outcome variables shared similar pathways of low socio-economic status and history of behaviour problems in childhood, and low parental attachment in adolescence. Mental disorder at age 15 led to a small but significantly elevated risk of cannabis use at age 18; by contrast, cannabis use at age 18 elevated the risk of mental disorder at age 21. The latter association reflected the extent to which cannabis dependence and other externalizing disorders at age 21 were predicted by earlier level of involvement with cannabis. CONCLUSIONS: The findings suggest that the primary causal direction leads from mental disorder to cannabis use among adolescents and the reverse in early adulthood. Both alcohol use and cigarette smoking had independent associations with later mental health disorder.
Adolescent↗