Derivation of HLA-B*0702 transgenic mice: functional CTL repertoire and recognition of human B*0702-restricted CTL epitopes

Transgenic mice expressing chimeric human leukocyte antigen (HLA)-B*0702 and murine H-2K(b) class I molecules were evaluated as a model system to study the immunogenicity of human cytotoxic T lymphocyte epitopes. Immunization of these mice with six known HLA-B*0702-restricted cytotoxic T lymphocyte epitopes emulsified in incomplete Freund's adjuvant induced significant immune responses specific for all six epitopes. A comparison of the immune responses between HLA-B*0702/K(b) and HLA-A*0201/K(b) transgenic mice demonstrated that the HLA-B*0702/K(b) mice possess a T-cell receptor repertoire capable of recognizing human B*0702 epitopes. However, the magnitude of B*0702-specific responses induced in B*0702/K(b) mice were approximately tenfold lower than A*0201-specific responses induced in HLA-A*0201/K(b) transgenic mice. A panel of 24 B*0702 motif-bearing peptides was used to examine the relationship between immunogenicity and HLA-B*0702 binding capacity. All seven peptides with high binding affinities of 50% inhibitory concentration < or =50 NM (IC(50) 50 nM or less) were immunogenic. Similarly, 75% (9 of 12) of the intermediate binders (IC(50) nM of 50-500) were also immunogenic. Finally, only two of five peptides with binding capacity > 500 nM were found to have marginal immunogenicity, whereas the other three were completely negative. HLA-B*0702/K(b) transgenic mice were found to induce B*0702-specific responses after immunization with whole DNA genes or minigenes, suggesting that, at least to some degree, B*0702 epitopes were generated as a result of natural in vivo processing and presentation.     

Stage-specific protein synthesis by asexual blood stage parasites of Plasmodium knowlesi

P. knowlesi parasites with a maximum age distribution of 3 h were metabolically labelled with [³⁵S]methionine during 9 sequential non-overlapping intervals, from young rings to mature segmented schizonts. The proteins synthesised at the different stages were compared using sodium dodecyl sulphate-polyacrylamide gel electrophoresis; more than 40 polypeptides (M_r 20 000 to over 200 000) were identified in the different parasite preparations. The major polypeptides synthesised by rings and trophozoites of different ages were similar, but differences in minor polypeptides could always be recognised. At the onset of schizogony ring and trophozoite specific proteins ceased to be synthesised and proteins specific to schizogony emerged. In general, schizont-specific proteins were of higher molecular weight than ring stage proteins. Details of the morphological changes which occurred during the metabolic labelling episode permits correlation between parasite structure and synthesis of particular polypeptides. Comparison of parasite components metabolically labelled with [³H]glucosamine during defined periods of development also revealed stage-specific synthesis of glycoproteins. The extent to which proteins are altered after synthesis has been investigated by pulse-chase experiments.     

Association of total and central adiposity measures with fasting insulin in a biracial population of young adults with normal glucose tolerance: the CARDIA study.

OBJECTIVE: To determine the association of computed tomography (CT)-measured visceral adipose tissue (AT) and other measures of adiposity with fasting insulin in a biracial (African American and Caucasian) study population of young adults. RESEARCH METHODS AND PROCEDURES: The study population consisted of 251 young adults with normal glucose tolerance (NGT), ages 28-40 years, who were volunteers from the Birmingham, Alabama, and Oakland, California centers of the Coronary Artery Risk Development in Young Adults (CARDIA) study. RESULTS: In regression models with total adiposity measures (body mass index or dual-energy X-ray absorptiometry-measured percent fat), visceral AT (measured as a cross-sectional area in cm2) was generally a stronger predictor of insulin than overall adiposity in all race/gender groups (partial correlation coefficients ranging from 0.31 to 0.47) except for black men, in whom the associations were nonsignificant. Partial correlation coefficients between waist circumference and insulin, controlling for percent fat, were nearly identical to those between visceral AT and insulin in women and in white men. Analyses performed on 2060 NGT CARDIA subjects who were not in this study of visceral AT showed significant correlations of waist circumference with insulin in all race/gender groups, including black men, and that black men in the visceral AT study group were significantly leaner than other black male CARDIA subjects. DISCUSSION: We conclude that visceral AT was associated with fasting insulin in NGT participants in three of the four race/gender groups (black men excepted) and that waist circumference was a good surrogate for visceral AT in examining associations of central adiposity with fasting insulin.     

Public involvement in health care priority setting: an economic perspective

Background  Public involvement in health care decision making and priority setting in the UK is being promoted by recent policy initiatives. In 1993, the British Medical Association called for public consultation where rationing of services was to be undertaken. The approach to priority setting advocated by many health economists is the maximization of quality adjusted life years (QALYs). Typically, for a particular health care programme, the QALY calculation takes account of four features: (1) the number of patients receiving the programme, (2) the survival gain, (3) the gain in quality of life and, (4) the probability of treatment success. Only one feature, that relating to quality of life, is based upon public preferences. If the QALY is to be used as a tool for health care resource allocation at a societal level then it should incorporate broader societal preferences.
Methods  This study used an interview-based survey of 91 members of the general public to explore whether the traditional QALY maximization model is a good predictor of public responses to health care priority setting choices.
Results and conclusions  Many respondents did not choose consistently in line with a QALY maximization objective and were most influenced by quality of life concerns. There was little support for health care programmes that provided a prognostic improvement but left patients in relatively poor states of health. The level of respondent engagement in the survey exercise was not sensitive to the provision of supporting clinical information.     

Proctocolectomy for ulcerative colitis

The majority of patients with ulcerative colitis can be managed satisfactorily throughout their lives by medical treatment, but a minority require colectomy. In severe attacks, emergency surgery is often required to save the patient's life. In chronic disease not responding well to medical treatment, elective colectomy will restore the patient to good health. Colectomy is also necessary for certain local complications, such as cancer, severe fistulas, and strictures. Prophylactic colectomy is indicated in patients with long-standing disease in whom there are factors associated with a high risk of developing cancer of the large bowel. For all these indications, it is our opinion that single-stage proctocolectomy is the operation of choice in the great majority of patients. Finally, we consider that the best results are obtained when the physician and the surgeon work together in the closest possible cooperation.     

A method for estimating within-individual variability in clearance and in volume of distribution from standard bioavailability studies

Bioavailability studies are commonly undertaken, and most, because they involve subjects taking repeated doses of a drug, contain information on intraindividual variability in pharmacokinetics. However, because in such studies bioavailability itself is unknown, it is difficult to resolve which pharmacokinetic parameters vary within individuals. A mathematical model is presented which permits estimation of variability in clearance and in volume of distribution. When applied to pooled data arising from five theophylline bioavailability studies, this model has given statistical evidence that clearance of theophylline is inherently more variable within individuals (coefficient of variation, 13%) than volume of distribution (8%). As a result, use of the measurement AUC · rather than AUCas a more precise index of bioavailability is justified in studies where is measured with reasonable precision. The model could be applied to estimation of withinbatch within-person variability in bioavailability.Deceased, April 4th, 1981.     

RSR13 plus cranial radiation therapy in patients with brain metastases: comparison with the Radiation Therapy Oncology Group Recursive Partitioning Analysis Brain Metastases Database.

PURPOSE: This phase II, open-label, multicenter study assessed the efficacy and safety of the potential radiation enhancer RSR13 plus cranial radiation therapy (RT) in patients with brain metastases. The primary end point was patient survival in comparison with the Radiation Therapy Oncology Group Recursive Partitioning Analysis Brain Metastases Database (RTOG RPA BMD). PATIENTS AND METHODS: Eligibility criteria were age > or = 18 years, Karnofsky performance score > or = 70, and brain metastases with solid tumor histology. Patients received cranial RT, 30 Gy in 10 fractions of 3 Gy each, preceded by RSR13, 50 to 100 mg/kg intravenously over 30 minutes. Univariate and multivariate comparisons of survival and cause of death were made between class II study patients and RTOG BMD patients. RESULTS: Fifty-seven RPA class II patients were enrolled. With a minimum follow-up of 24 months, the median survival time and 1- and 2-year survival rates were 6.4 months, 23%, and 11% for the RSR13-treated patients compared with 4.1 months, 15%, and 3% for the RTOG BMD patients (P =.0174). In an exact-matched case analysis (n = 38), median survival time for RSR13 patients was 7.3 months versus 3.4 months for the RTOG BMD patients (P =.006). There was a 54% reduction in the risk of death for RSR13 patients (P =.0267). RSR13-related adverse events of greater than or equal to grade 3 toxicity that occurred in more than one patient included hypoxia, headache, anemia, fatigue, hypertension, and intracranial hypertension. CONCLUSION: RSR13 plus cranial RT resulted in a significant improvement in survival, as well as a reduction in death due to brain metastases, compared with class II patients in the RTOG BMD.     

Hospitalization for suicide attempt and completed suicide: epidemiological features in a managed care population

BACKGROUND: Understanding factors that contribute to high suicide risk holds important implications for prevention. We aimed to examine the sociodemographic and medical predictors of attempted suicide (severe enough to require hospitalization) and of completed suicide in a large population-based sample from a health maintenance organization (HMO) in northern California, USA. METHOD: We designed a cohort study, including 87,257 women and 70,570 men aged 15 through 89 years old at baseline (in 1977-1985) with follow-up for hospitalizations and mortality through the end of 1993. RESULTS: After a median of 10 years, 169 first hospitalizations for attempted suicide (111 among women, 58 among men) and 319 completed suicides (101 among women, 218 among men) were identified. There was a greater incidence of hospitalization for suicide attempt in women than in men and, conversely, a greater incidence of completed suicide in men than in women. The predominant methods of attempted and completed suicides were ingestion of psychotropic agents and use of firearms, respectively. In gender-specific multivariate analysis of hospitalization for suicide attempt, statistically significant associations were seen for age 15-24 years (women), 65-89 years (men), white race (women), 12th grade or less education (both genders), technical/business school education (men), never being married (men), history of emotional problems (both genders), history of family problems (women), history of job problems (men) and presence of one or more comorbidities (men). The independent predictors of completed suicide were: age 15-24 years (both genders), Asian race (women), Caucasian race (both genders), never being married (both genders), being separated/divorced (women), prior inpatient hospitalization for suicide attempt (both genders) and history of emotional problems (both genders). CONCLUSION: These findings could help health professionals be more effective in the prevention of suicide morbidity and mortality.     

Long-term follow-up of patients with giant cell tumor of the sacrum treated with selective arterial embolization

BACKGROUND: Giant cell tumors of the bone can behave as aggressive and sometimes lethal tumors. In the sacrum, the tumor can be extremely difficult to manage. Standard treatments, including surgery and radiation, are associated with significant complications and recurrence rates. The goal of this study is to evaluate the long-term outcome of selective arterial embolization as an alternative treatment modality. METHODS: From 1975 to 2001, 18 patients were treated with selective intraarterial embolization. The embolization method was a combination of Gelfoam particles and coils for peripheral and central occlusions, respectively. The number of embolizations was based on clinical symptoms, radiographic response, and the vascularity of the tumor. Nine patients received intraarterial cisplatin as part of their treatment. The median follow-up was 105 months. RESULTS: Of 18 patients, 14 responded favorably to embolization with improvement in pain and neurologic symptoms. Computed tomographic and magnetic resonance imaging scans showed reossification and stabilization of tumor size. Arteriograms showed diminished vascularity. With long-term follow-up, three patients developed late disease recurrences within the sacrum. Kaplan-Meier analysis showed that the risk of local recurrence is 31% at 10 years and 43% at 15 and 20 years. The long-term outcome was not affected by intraarterial cisplatin. There was one death that occurred 1 day after embolization. CONCLUSIONS: Most patients demonstrate an objective early radiographic response to embolization. Long-term follow-up shows that the response is durable in approximately one half of the patients. Given the potential morbidity of other treatments, embolization should be included in the armamentarium of treatment for this difficult disease. Embolization may be used alone or in conjunction with other therapy. Long-term follow-up is recommended for all patients because late disease recurrence or sarcomatous change can occur.