Immunogenicity & reactogenicity of a recombinant HPV6 fusion protein vaccine adjuvanted with monophosphoryl lipid A.
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Adjuvants, Immunologic↗
Biomedical subjects
S Thompson
Publications and source records attributed to S Thompson.
Alterations in dopamine clearance and catechol-O-methyltransferase activity by dopamine infusions in children.
OBJECTIVE: To determine the role of catechol-O-methyltransferase (COMT) in the biodisposition of pharmacologic concentrations of dopamine. DESIGN: The study was an open-label dose escalation trial in which dopamine was employed as the sole exogenous catecholamine. The dosage was adjusted to achieve improvements in cardiac output or to augment renal function. SETTING: A 16-bed pediatric intensive care unit serving both medical and surgical patients. PATIENTS: The study was performed using 14 dopamine-treated and five untreated control patients. Children ranged in age from 16 days to 12 yrs; five of the treated patients and two of the untreated controls were female. All but one of the study patients were enrolled within 24 hrs of palliative or corrective surgery for congenital heart disease. Control patients had noncardiac surgical procedures. Both treated and control groups were similar with respect to severity of illness, as judged by Therapeutic Intervention Scoring System score. INTERVENTIONS: All treated patients received dopamine as a continuous intravenous infusion. Infusion rates were determined by caregivers and ranged from 3.0 to 20 micrograms/kg/min. MEASUREMENTS AND MAIN RESULTS: Serial, timed blood samples were obtained from patients and control subjects for the determination of plasma dopamine concentrations and for the determination of mononuclear cell COMT activity. Measured rates of dopamine infusion (3.0 to 18.3 micrograms/kg/min) were consistently less than the nominal rates (3.0 to 20.0 micrograms/kg/min) of infusion (p < .0001) due in part to calculations based on the hydrochloride salt rather than dopamine base. At similar steady-state infusion rates, plasma dopamine concentrations varied over a four-fold range, with steady-state concentrations at even the lowest infusion rate exceeding endogenous concentrations by at least ten-fold. Variations in steady-state plasma dopamine concentration reflected large age-associated variations in dopamine clearance, which was found to be saturable at concentrations of > 200 ng/mL. Mononuclear cell COMT activity was assessed simultaneously in these patients. Baseline COMT activity varied over a six-fold range and was unrelated to dopamine clearance or patient age. COMT activity increased two- to six-fold in dopamine-treated patients with plasma steady-state dopamine concentrations of > 100 ng/mL. CONCLUSIONS: These data demonstrate marked age and concentration-dependent differences in dopamine clearance that account for large interindividual differences in the steady-state plasma dopamine concentrations in patients receiving similar infusion rates. While concomitant variability in COMT activity is observed, the lack of correlation between dopamine clearance and COMT activity suggests that COMT is not rate-limiting for the clearance of exogenously administered dopamine.
Catechol O-Methyltransferase↗
Acute neurologic dysfunction associated with high-dose chemotherapy and autologous bone marrow rescue for primary malignant brain tumors.
UNLABELLED: Acute neurologic complications occurred 103 times in 50 (54%) of 92 patients (primarily children) treated with high-dose chemotherapy and autologous bone marrow rescue for primary central nervous tumors. Different types of neurologic compromise occurred during the chemotherapy infusion as compared to the first 100 days after the chemotherapy and the greater-than-100-day time period. The causes of the neurologic compromise were also time sensitive. BACKGROUND: Results of treatment for children with primary brain tumors using high-dose chemotherapy with autologous marrow rescue (ABMR) have been encouraging. However, the neurotoxicity associated with this technique remains a major concern. We reviewed the records of 92 patients who underwent ABMR for malignant brain tumors between 1986 and 1992 for the occurrence and timing of acute neurologic dysfunction (AND). METHODS: Individual investigators at the participating institutions retrospectively completed standardized forms on each patient. The manner in which the distribution of AND versus time of treatment emerged led to the establishment of distinct time periods for data analysis and discussion. The pre-ABMR period included those events that occurred during the chemotherapy infusion, the early posttreatment period included the first 100 days following bone marrow rescue, and the late posttreatment period was greater than 100 days following bone marrow rescue. RESULTS: Fifty patients (54%) had 103 episodes of AND. AND included encephalopathies with or without hallucinations or coma (32), seizures (23), headaches (9), ataxia-tremor-dysarthria syndrome (7), anorexia and nausea syndrome (7) and others (25). During the chemotherapy infusion, encephalopathies and seizures were most common. Hallucinations occurred primarily related to drug infusion, while encephalopathies without hallucinations were usually due to demonstrable dysmetabolic states. In the 100 days following ABMR, dysmetabolic states and iatrogenic factors caused 45% and progressive disease caused 33% of AND. Greater than 100 days from ABMR, progressive disease caused 55% of AND; 7 patients were noted to develop chronic anorexia and nausea of unclear etiology. The occurrence of neurologic compromise was not related to the chemotherapy regimens, tumor histology, tumor location, patient age, prior treatment, or the amount of tumor at time of treatment. Dexamethasone use was the only clinical factor associated with AND (p < 0.004). CONCLUSIONS: The cause of AND was definable for 95% of instances that occurred within 100 days of ABMR. Early AND was often iatrogenic and reversible. The greater the time from ABMR the more likely AND was due to progressive disease. Clinical factors could not predict the occurrence of AND as only the concurrent use of dexamethasone at the time of treatment proved significant. Although frequent, AND should not be considered a limiting toxicity of this approach or preclude the use of this technique.
Acute Disease↗
Predictors of achieving stable housing in a mentally ill homeless population.
Relationships among demographic characteristics, diagnostic groups, presenting problems, and service use were examined in two groups of mentally ill persons: a group of 60 formerly homeless persons who had been housed for at least 24 months and a group of 60 persons who remained homeless. Use of eight types of services over a 26-month period was examined. Women were significantly more likely to be housed than men. Individuals whose primary presenting problem was subsistence needs were more likely to be housed than those whose primary problem was mental, illness or substance abuse. Those with a diagnosis of personality disorder used fewer services. Housed individuals were more likely to use services than those who were homeless.
Adult↗
Review of literature on heart transplant recipients' return to work: predictors and outcomes.
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Employment↗
Peptide aldehyde inhibitors of cathepsin K inhibit bone resorption both in vitro and in vivo.
We have shown previously that cathepsin K, a recently identified member of the papain superfamily of cysteine proteases, is expressed selectively in osteoclasts and is the predominant cysteine protease in these cells. Based upon its abundant cell type-selective expression, potent endoprotease activity at low pH and cellular localization at the bone interface, cathepsin K has been proposed to play a specialized role in osteoclast-mediated bone resorption. In this study, we evaluated a series of peptide aldehydes and demonstrated that they are potent cathepsin K inhibitors. These compounds inhibited osteoclast-mediated bone resorption in fetal rat long bone (FRLB) organ cultures in vitro in a concentration-dependent manner. Selected compounds were also shown to inhibit bone resorption in a human osteoclast-mediated assay in vitro. Chz-Leu-Leu-Leu-H (in vitro enzyme inhibition Ki,app = 1.4 nM) inhibited parathyroid hormone (PTH)-stimulated resorption in the FRLB assay with an IC-50 of 20 nM and inhibited resorption by isolated human osteoclasts cultured on bovine cortical bone slices with an IC-50 of 100 nM. In the adjuvant-arthritic (AA) rat model, in situ hybridization studies demonstrated high levels of cathepsin K expression in osteoclasts at sites of extensive bone loss in the distal tibia. Cbz-Leu-Leu-Leu-H (30 mg/kg, intraperitoneally) significantly reduced this bone loss, as well as the associated hind paw edema. In the thyroparathyriodectomized rat model, Cbz-Leu-Leu-Leu-H inhibited the increase in blood ionized calcium induced by a 6 h infusion of PTH. These data indicate that inhibitors of cathepsin K are effective at reducing osteoclast-mediated bone resorption and may have therapeutic potential in diseases of excessive bone resorption such as rheumatoid arthritis or osteoporosis.
Aldehydes↗
Disparity in glycemic control and adherence between African-American and Caucasian youths with diabetes. Family and community contexts.
OBJECTIVE: To describe sociodemographic, family, and community factors that contribute to the glycemic control of African-American and Caucasian youths with diabetes, we investigated two questions: 1) Is there a disparity in glycemic control between African-American and Caucasian youths with diabetes, and if so, what sociodemographic, family, and community factors explain the disparity? and 2) Is there a difference in the adherence to treatment between African-American and Caucasian youths with diabetes, and if so, what sociodemographic, family, and community factors explain the difference? RESEARCH DESIGN AND METHODS: This cross-sectional study included 146 youths with diabetes (95 Caucasians and 51 African-Americans) and their mothers. The youths were invited to participate if they had been diagnosed with diabetes at least 1 year before the study, did not have another chronic illness, and were < 18 years of age. RESULTS: The findings indicate that African-American youths with diabetes are in significantly poorer metabolic control than their Caucasian counterparts (1.5% difference in HbA1c levels). Single-parent household status and lower levels of adherence partially account for the poorer glycemic control. Examination of the adherence subscales indicates that African-Americans report significantly lower adherence to diet and glucose testing than Caucasian youths. CONCLUSIONS: This study suggests that African-American youths with diabetes may be at greater risk for poor glycemic control due to the higher prevalence of single parenting and lower levels of adherence found in this population.
Adolescent↗
Correlation for Eysenck's measure of Psychoticism and the Environmental Deprivation Scale.
The purpose of the present study was to evaluate the relatedness of the Psychoticism scale of Eysenck's Personality Questionnaire-Revised and the Environmental Deprivation Scale using college students as subjects. Each measure provides different information through varied techniques. Scores on both have been associated with antisocial behavior. The r of .61 is discussed in terms of the assessment of antisocial behavior.
Adolescent↗
Psychosocial issues in heart transplantation: a review for transplant coordinators.
The latest advances in medicine and technology are used to care for transplant recipients, yet many patients have psychosocial difficulties that technology alone cannot resolve. Although most healthcare professionals acknowledge the importance of the staff's role in working with patients to resolve psychosocial problems, little research has examined the nature of staff-patient relationships and the proven ability of good relationships to improve outcomes. The purposes of this paper are to profile psychosocial risk and its relationship to outcomes after heart transplantation, explore staff-patient interactions in dealing with psychosocial problems, and present a growth and development model that can be used as a theoretical base to establish a more therapeutic alliance with patients.
Adaptation, Psychological↗
The adequacy of reimbursement for HIV under Section 1115 Medicaid waivers.
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Budgets↗
Two-step tuberculin skin testing of injection drug users recruited from community-based settings.
SETTING: Cross-sectional study of drug users recruited from street-based settings in four US cities: Denver, Portland, Oakland and San Francisco. OBJECTIVE: To evaluate responses to two-step tuberculin skin testing among HIV-positive and HIV-negative injection drug users. DESIGN: Subjects were recruited from existing studies of HIV and risk behaviors for tuberculin skin testing. Those with a negative initial tuberculin test were referred for a second skin test 1-3 weeks later. A positive tuberculin test was defined as > or = 10 mm, or > or = 5 mm if the subject was HIV-positive. RESULTS: Of 997 persons receiving an initial tuberculin test, 13% had a positive response. Of 644 persons receiving a second tuberculin test, 8% had a positive response, with rates as high as 14% among those from Oakland and 12% among African Americans. HIV-positive subjects were less likely to have skin test responses > or = 10 mm on the initial test (P = 0.03), or increases between the initial and second test of > or = 10 mm (P = 0.06). CONCLUSION: Boosting occurred in both HIV-positive and HIV-negative injection drug users. Two-step testing should be considered for this population, particularly those on whom repeat tuberculin testing will be performed.
Adult↗
Effect of 13-cis-retinoic acid and alpha-interferon on transforming growth factor beta1 in patients with rising prostate-specific antigen.
The objective of this study was to test the hypothesis that 13-cis-retinoic acid (CRA) and alpha-interferon (IFN-alpha) have antitumor activity in patients with early recurrence of prostate cancer measured by rising prostate-specific antigen (PSA) after local therapy, and that this activity is associated with the increase of plasma transforming growth factor beta1 (TGF-beta1). Thirty patients with a PSA > 7 ng/ml that increased >0.4 ng/ml/month after initial radiation therapy or a PSA > 2.0 ng/ml after prostatectomy were treated with 1 mg/kg/day of CRA and 3 million units of IFN-alpha administered three times per week. Patients were followed clinically with serum measurements of PSA and assessment of toxicity. Biological activity of CRA and IFN-alpha was assessed by the measurement of plasma TGF-beta1. Twenty-six percent of patients had a partial (50% decrease maintained for 1 month) or minimal (<50% decrease maintained for 1 month) biochemical response of PSA, with a median decrease of 23% (11-55%) at 3 months. Plasma TGF-beta1 levels increased with CRA and IFN-alpha therapy and correlated with a decrease in PSA; patients with a decrease in PSA had a 151% increase in TGF-beta1 compared to 27% in patients without a decrease in PSA (P = 0.04). CRA and IFN-alpha can produce transient reduction or stabilization of PSA. The measurement of plasma TGF-beta1 at 1 month of therapy correlates with changes in PSA and may represent a useful marker for the biological effect of these agents; further analysis in larger numbers of patients and methods to optimize these effects should be explored.
Aged↗
A model of collaboration. Interview by Charlotte Alderman.
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Humans↗
Gender differences in smoking and risk for oral cancer.
Based on studies that show gender differences in cigarette smoking and lung cancer risk, we hypothesized that sex differences also exist in the risk for cancer of the oral cavity and pharynx. A hospital-based study of 1009 patients with oral neoplasia and 923 age-matched controls was conducted from 1981-1990. All subjects were interviewed directly with an extensive questionnaire containing items on tobacco smoking, alcohol consumption, and occupational exposures. Using a cumulative lifetime measure of exposure to cigarette tar, the adjusted odds ratio for men, according to increasing quartile of tar consumption and relative to never smokers, was 1.0 [95% confidence interval (CI), 0.6-1.6) for the lowest category, 0.9 (95% CI, 0.6-1.6) for the second category, 1.6 (95% CI, 1.0-2.5) for the third category, and 2.1 (95p5 CI, 1.4-3.2) for the highest category. Among women, the corresponding odds ratios were 1.8 (95% CI, 1.1-3.0), 2.8 (95% CI, 1.6-4.9), 3.2 (95% CI, 1.9-5.6), and 4.6 (95% CI, 2.5-8.7). The linear increase in risk was significantly higher for women than for men. Among nonsmoking cases, there was a significantly higher proportion of women than men over the age of 50 years. This was consistent for all subsites within the oral cavity. These findings support the hypothesis that there are gender differences in the smoking-related risks for oral cancer and in the risk for nonsmoking-related oral cancer as well. The role of nutrition in relation to these findings is discussed.
Adult↗
Randomised controlled trial of treatment of chronic suppurative otitis media in Kenyan schoolchildren.
BACKGROUND: The outcomes of treatment of chronic suppurative otitis media (CSOM) are disappointing and uncertain, especially in developing countries. Because CSOM is the commonest cause of hearing impairment in children in these countries, an effective method of management that can be implemented on a wide scale is needed. We report a randomised, controlled trial of treatment of CSOM among children in Kenya; unaffected schoolchildren were taught to administer the interventions. METHODS: We enrolled 524 children with CSOM, aged 5-15 years, from 145 primary schools in Kiambu district of Kenya. The schools were randomly assigned treatments in clusters of five in a ratio of two to dry mopping alone (201 children), two to dry mopping with topical and systemic antibiotics and topical steroids (221 children), and one to no specific treatment (102 children). Schools were matched on factors thought to be related to their socioeconomic status. The primary outcome measures were resolution of otorrhoea and healing of tympanic membranes on otoscopy by 8, 12, and 16 weeks after induction. Absence of perforation was confirmed by tympanometry, and hearing levels were assessed by audiometry. 29 children were withdrawn from the trial because they took non-trial antibiotics. There was no evidence of differences in timing of withdrawals between the groups. FINDINGS: By the 16-week follow-up visit, otorrhoea had resolved in a weighted mean proportion of 51% (95% CI 42-59) of children who received dry mopping with antibiotics, compared with 22% (14-31) of those who received dry mopping alone and 22% (9-35) of controls. Similar differences were recorded by the 8-week and 12-week visits. The weighted mean proportions of children with healing of the tympanic membranes by 16 weeks were 15% (10-21) in the dry-mopping plus antibiotics group, 13% (5-20) in the dry-mopping alone group, and 13% (3-23) in the control group. The proportion with resolution in the dry-mopping alone group did not differ significantly from that in the control group at any time. Hearing thresholds were significantly better for children with no otorrhoea at 16 weeks than for those who had otorrhoea, and were also significantly better for those whose ears had healed than for those with otorrhoea at all times. INTERPRETATION: Our finding that dry mopping plus topical and systemic antibiotics is superior to dry mopping alone contrasts with that of the only previous community-based trial in a developing country, though it accords with findings of most other trials in developed countries. The potential role of antibiotics needs further investigation. Further, similar trials are needed to identify the most cost-effective and appropriate treatment regimen for CSOM in children in developing countries.
Administration, Topical↗
Costs and cost effectiveness of cardiovascular screening and intervention: the British family heart study.
OBJECTIVE: To measure costs and cost effectiveness of the British family heart study cardiovascular screening and intervention programme. DESIGN: Cost effectiveness analysis of randomised controlled trial. Clinical and resource use data taken from trial and unit cost data from external estimates. SETTING: 13 general practices across Britain. SUBJECTS: 4185 men aged 40-59 and their 2827 partners. INTERVENTION: Nurse led programme using a family centered approach, with follow up according to degree of risk. MAIN OUTCOME MEASURES: Cost of the programme it self; overall short term cost to NHS; cost per 1% reduction in coronary risk at one year. RESULTS: Estimated cost of putting the programme into practice for one year was 63 pounds per person (95% confidence interval 60 pounds to 65 pounds). The overall short term cost to the health service was 77 pounds per man (29 pounds to 124 pounds) but only 13 pounds per woman (-48 pounds to 74 pounds), owing to differences in utilisation of other health service resources. The cost per 1% reduction in risk was 5.08 pounds per man (5.92 pounds including broader health service costs) and 5.78 pounds per woman (1.28 pounds taking into account wider health service savings). CONCLUSIONS: The direct cost of the programme to a four partner practice of 7500 patients would be approximately 58,000 pounds. Annually, 8300 pounds would currently be paid to a practice of this size working to the maximum target on the health promotion bands, plus any additional reimbursement of practice staff salaries for which the practice qualified. The broader short term costs to the NHS may augment these costs for men but offset them considerably for women.
Adult↗
Anterograde but not retrograde memory loss following combined mammillary body and medial thalamic lesions.
We report the first human case of combined mammillary body and medial thalamic lesions due to focal pathology. A patient presented with a multi-lobular lesion that affected the mammillary bodies, the medial thalamus and the brain stem. On neuropsychological testing, he showed significant anterograde memory impairment, with marked impairment on delayed story recall, but normal or only mildly impaired performance on retrograde memory tasks. Our findings corroborate the results of recent non-human lesion studies and indicate that some of the well-established features of the amnesic syndrome, such as severe retrograde amnesia, may not be due to primary diencephalic pathology. Significant retrograde amnesia may result from cortical pathology or from an interaction between cortical and subcortical pathology.
Adult↗
Light activatable antibodies: models for remotely activatable proteins.
The ability to activate biological macromolecules remotely, at specific locations and times, will allow the manipulation of a wide range of cellular activities and give rise to many practical applications. Interest has been shown in the theoretical possibility of accomplishing this by means of photochemical approaches. Photochemical changes of the guest-binding cavity of cyclodextrins has been suggested; however, these changes require organic solvent. What is needed is a widely and readily applicable method allowing activation under physiological conditions. We have developed such a method. This is based on our demonstration that relatively large amounts of the a-methyl substituted 2-nitrobenzyl alcohol, namely, 1-(2-nitrophenyl)ethanol (NPE) can be coupled to proteins using diphosgene. Previous work involved "caging" of small molecules such as ATP (ref. 5-9) and blocking amino acids in peptide synthesis with 2-nitrobenzyl compounds. For large molecules, site-specific reversible inactivation of T4-lysozyme has been reported following introduction of an aspartyl beta-nibenzyl ester into its active site by mutagenesis. In contrast, the present simple procedure allows an existing protein to be deactivated and then, when and where required, reactivated by exposure to ultraviolet-A (UV-A) light. We have employed antibodies as models for both receptors and ligands and have successfully modulated: antibody binding sites for antigen; antigen binding sites for antibody, and antibody Fc binding sites for Protein A.
Antibodies↗