Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial.

BACKGROUND: STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. METHODS: We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. RESULTS: Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69-0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57-0.76, P < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59-0.81, P < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P > 0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). CONCLUSIONS: The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden.

Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.

Background: Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC + AAP versus SOC + DocP. Method: Recruitment to SOC + DocP and SOC + AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly×6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC + AAP, and HR > 1 favours SOC + DocP. Results: A total of 566 consenting patients were contemporaneously randomised: 189 SOC + DocP and 377 SOC + AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1.16 (95% CI 0.82-1.65); failure-free survival HR = 0.51 (95% CI 0.39-0.67); progression-free survival HR = 0.65 (95% CI 0.48-0.88); metastasis-free survival HR = 0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR = 1.02 (0.70-1.49); and symptomatic skeletal events HR = 0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC + DocP, and 40%, 7% and 1% SOC + AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm. Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs. Trial registration: Clinicaltrials.gov: NCT00268476.

POSEIDON study: a pilot, safety and feasibility trial of high-dose omega3 fatty acids and high-dose cholecalciferol supplementation in type 1 diabetes.

The anti-inflammatory and immunomodulatory properties of high-dose omega-3 fatty acids and Vitamin D, and the initial encouraging results from case reports on the use of this supplementation in new-onset Type 1 Diabetes (T1D), support further testing of this combination strategy. This intervention appears to be well tolerated, affordable, and sufficiently safe to be further tested in randomized prospective trials to determine whether this combination therapy may be of assistance to halt progression of autoimmunity and/or preserve residual beta-cell function in subjects with new onset and established T1D of up to 10 years duration. In addition, the 1st PreDiRe T1D conference (Preventing Disease and its Recurrence in Type 1 Diabetes - see Editorial in this issue) was organized to discuss initial results and possible alternative/complementary strategies, for collaborative international expansion of these trials, to include strategies for disease prevention. Our POSEIDON clinical trial will test the use of high dose vitamin D3 and highly purified Omega-3 fatty acids in new onset and established T1D. The draft of the study protocol, in addition to the informed consent and assent, is now shared open access to facilitate its international implementation by interested physicians and centers that would like to further test this approach through clinical trials.

Use of self-collected capillary blood samples for islet autoantibody screening in relatives: a feasibility and acceptability study.

AIMS: To evaluate the feasibility of using self-collected capillary blood samples for islet autoantibody testing to identify risk in relatives of people with Type 1 diabetes. METHODS: Participants were recruited via the observational TrialNet Pathway to Prevention study, which screens and monitors relatives of people with Type 1 diabetes for islet autoantibodies. Relatives were sent kits for capillary blood collection, with written instructions, an online instructional video link and a questionnaire. Sera from capillary blood samples were tested for autoantibodies to glutamic acid decarboxylase, islet antigen-2, insulin and zinc transporter 8. 'Successful' sample collection was defined as obtaining sufficient volume and quality to provide definitive autoantibody results, including confirmation of positive results by repeat assay. RESULTS: In 240 relatives who returned samples, the median (range) age was 15.5 (1-49) years and 51% were male. Of these samples, 98% were sufficient for glutamic acid decarboxylase, islet antigen-2 and zinc transporter 8 autoantibody testing and 84% for insulin autoantibody testing and complete autoantibody screen. The upper 90% confidence bound for unsuccessful collection was 4.4% for glutamic acid decarboxylase, islet antigen-2 and/or zinc transporter 8 autoantibody assays, and 19.3% for insulin autoantibodies. Despite 43% of 220 questionnaire respondents finding capillary blood collection uncomfortable or painful, 82% preferred home self-collection of capillary blood samples compared with outpatient venepuncture (90% of those aged <8 years, 83% of those aged 9-18 years and 73% of those aged >18 years). The perceived difficulty of collecting capillary blood samples did not affect success rate. CONCLUSIONS: Self-collected capillary blood sampling offers a feasible alternative to venous sampling, with the potential to facilitate autoantibody screening for Type 1 diabetes risk.

Reporting of treatment fidelity in behavioural paediatric obesity intervention trials: a systematic review.

Behavioural interventions for paediatric obesity are promising, but detailed information on treatment fidelity (i.e. design, training, delivery, receipt and enactment) is needed to optimize the implementation of more effective interventions. Little is known about current practices for reporting treatment fidelity in paediatric obesity studies. This systematic review, in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, describes the methods used to report treatment fidelity in randomized controlled trials. Treatment fidelity was double-coded using the National Institutes of Health Fidelity Framework checklist. Three hundred articles (N = 193 studies) were included. Mean inter-coder reliability across items was 0.83 (SD = 0.09). Reporting of treatment design elements within the field was high (e.g. 77% of studies reported designed length of treatment session), but reporting of other domains was low (e.g. only 7% of studies reported length of treatment sessions delivered). Few reported gold standard methods to evaluate treatment fidelity (e.g. coding treatment content delivered). General study quality was associated with reporting of treatment fidelity (p < 0.01) as was the number of articles published for a given study (p < 0.01). The frequency of reporting treatment fidelity components has not improved over time (p = 0.26). Specific recommendations are made to support paediatric obesity researchers in leading health behaviour disciplines towards more rigorous measurement and reporting of treatment fidelity.

Visual illusions and plate design: the effects of plate rim widths and rim coloring on perceived food portion size.

OBJECTIVE: The Delboeuf Illusion affects perceptions of the relative sizes of concentric shapes. This study was designed to extend research on the application of the Delboeuf illusion to food on a plate by testing whether a plate's rim width and coloring influence perceptual bias to affect perceived food portion size. DESIGN AND METHODS: Within-subjects experimental design. Experiment 1 tested the effect of rim width on perceived food portion size. Experiment 2 tested the effect of rim coloring on perceived food portion size. In both experiments, participants observed a series of photographic images of paired, side-by-side plates varying in designs and amounts of food. From each pair, participants were asked to select the plate that contained more food. Multilevel logistic regression examined the effects of rim width and coloring on perceived food portion size. RESULTS: Experiment 1: participants overestimated the diameter of food portions by 5% and the visual area of food portions by 10% on plates with wider rims compared with plates with very thin rims (P<0.0001). The effect of rim width was greater with larger food portion sizes. Experiment 2: participants overestimated the diameter of food portions by 1.5% and the visual area of food portions by 3% on plates with rim coloring compared with plates with no coloring (P=0.01). The effect of rim coloring was greater with smaller food portion sizes. CONCLUSION: The Delboeuf illusion applies to food on a plate. Participants overestimated food portion size on plates with wider and colored rims. These findings may help design plates to influence perceptions of food portion sizes.

Innate and adaptive immune gene expression profiles as biomarkers in human type 1 diabetes.

The mRNA levels of a set of immune-related genes were analysed with peripheral blood samples from at-risk, new-onset and long-term type 1 diabetes (T1D) patients, in comparison to those from healthy controls. The selected set includes T lymphocyte genes [CD3G and cytotoxic T lymphocyte-associated antigen 4 (CTLA4)], B lymphocyte genes (CD19 and CD20) and myeloid cell-related genes [CD11b, Toll-like receptor (TLR)-9, arginase (ARG1)]. Also included is a subset of the S100 family members that has been documented recently as regulatory elements of innate immunity. Samples from patients with long-term T1D had a reduced level of mRNA for most of selected innate and adaptive immune genes. No such reduction was detected in samples collected from at-risk or new-onset T1D patients. Analyses of regulatory gene expression ratios revealed a dynamic disproportion of CTLA4 versus CD3G expression in samples from at-risk, new-onset and long-term T1D patients. These changes could serve as immunological biomarkers for the status of the immune system during T1D progression and therapeutic interventions.

How well prepared are medical students for their first year as doctors? The views of consultants and specialist registrars in two teaching hospitals.

OBJECTIVE: To evaluate (1) the extent to which first year doctors (foundation year 1 doctors, F1s) in two teaching hospitals in the Trent Deanery were rated by specialist registrars (SpRs) and consultants as being well prepared for practice; (2) the importance ascribed by SpRs and consultants to the various items of core knowledge, skills and attitudes outlined in the publication of the General Medical Council, Tomorrow's Doctors. METHOD: SpRs and consultants were asked to rate: how well prepared F1s were in a range of items of core knowledge, skills and attitudes that a new medical graduate must possess as outlined in Tomorrow's Doctors; the importance for a new doctor of each item of core knowledge, skills and attitudes; and how well the medical school had prepared F1s in respect of key generic issues related to their practice. RESULTS: In most of the items of core knowledge, skills and attitudes covering 8 of the 11 topic areas of Tomorrow's Doctors, F1s were seen as not prepared for starting work, especially in regard to clinical and practical skills and the more challenging communication skills. They were best prepared in asking for help and in basic communication skills. CONCLUSIONS: Overall, F1s in the study were not well prepared either to perform the tasks that await them or in terms of most of the specific background knowledge and skills necessary for the successful execution of those tasks. The level of preparedness raises important issues about medical training and transition from medical graduate to first year doctor. Further research is needed to determine whether this situation exists in other regions of the UK.

SPIRAL-SPRITE: a rapid single point MRI technique for application to porous media.

This study presents the application of a new, rapid, single point MRI technique which samples k space with spiral trajectories. The general principles of the technique are outlined along with application to porous concrete samples, solid pharmaceutical tablets and gas phase imaging. Each sample was chosen to highlight specific features of the method.

Is parental control over children's eating associated with childhood obesity? Results from a population-based sample of third graders.

OBJECTIVE: Identifying parental behaviors that influence childhood obesity is critical for the development of effective prevention and treatment programs. Findings from a prior laboratory study suggest that parents who impose control over their children's eating may interfere with their children's ability to regulate intake, potentially resulting in overweight. These findings have been widely endorsed; however, the direct relationship between parental control of children's intake and their children's degree of overweight has not been shown in a generalized sample. RESEARCH METHODS AND PROCEDURES: This study surveyed 792 third-grade children with diverse ethnic and socioeconomic backgrounds from 13 public elementary schools. Parental control over children's intake was assessed through telephone interviews using a state-of-the-art instrument, and children were measured for height, weight, and triceps skinfold thickness. RESULTS: Counter to the hypothesis, parental control over children's intake was inversely associated with overweight in girls, as measured by body mass index, r = -0.12, p < 0.05, and triceps skinfolds, r = -0.11, p < 0.05. This weak relationship became only marginally significant when controlling for parents' perceptions of their own weight, level of household education, and children's age. No relationship between parental control of children's intake and their children's degree of overweight was found in boys. DISCUSSION: Previous observations of the influence of parental control over children's intake in middle-class white families did not generalize to 8- to 9-year-olds in families with diverse socioeconomic and ethnic backgrounds. The present findings reveal a more complex relationship between parental behaviors and children's weight status.

Ecologic study of children's use of a computer nutrition education program.

The purpose of this research was to describe the context created by students as they worked in groups on a nutrition computer-assisted instruction (CAI) program. Students worked on the program in groups of three. Observational methods were used to collect data from students in two sixth-grade classrooms that were part of an experimental program designed to restructure the educational process. Thirty-two students, from 12 groups, were observed as they completed the program. The groups were assigned by the teachers according to standard principles of cooperative learning. Students completed "Ship to Shore," a program designed specifically for this research. The program required three to five 50-minute classroom periods to complete. The objectives of the program were to change children's knowledge structure of basic nutrition concepts and to increase children's critical thinking skills related to nutrition concepts. We collected observational data focused on three domains: (1) student-computer interaction, (2) student-student interaction, and (3) students' thinking and learning skills. Grounded theory methods were used to analyze the data. Specifically, the constant-comparative method was used to develop open coding categories, defined by properties and described by dimensions. The open coding categories were in turn used in axial coding to differentiate students' learning styles. Five styles of student interaction were defined. These included (1) dominant directors (n = 6; 19%), (2) passive actors (n = 5; 16%), (3) action-oriented students (n = 7; 22%), (4) content-oriented students (n = 8; 25%), and (5) problem solvers (n = 5; 16%). The "student style" groups were somewhat gender specific. The dominant directors and passive actors were girls and the action-oriented and content-oriented students were boys. The problem solvers group was mixed gender. Children's responses to computer-based nutrition education are highly variable. Based on the results of this research, nutrition educators may recommend that nutrition CAI programs be implemented in mixed gender groups.

Content analysis of the use of fantasy, challenge, and curiosity in school-based nutrition education programs.

The objective of this research was to document the extent to which elements of fantasy, curiosity, and challenge are used in existing nutrition education materials. A content analysis of 30 nutrition education curricula designed for elementary and middle-school grades was conducted. Print curricula, computer software, videotapes, and puppet shows were included in the sample. The use of challenge, curiosity, and fantasy, as defined in the Theory of Intrinsically Motivating Instruction (TIMI), was assessed in each curriculum. Approximately half of the curricula included elements of challenge, curiosity, or fantasy. All of the nonprint curricula and 30% of the print curricula incorporated these characteristics. Curiosity was most frequently used in these curricula, followed by fantasy and then challenge. The TIMI provided a useful theory to examine the instructional approaches frequently used in school-based nutrition education programs. Nutritionists may apply concepts from the TIMI to the design of future curricula so that these programs are interesting and entertaining for their target audience.

Older adults' multiple stereotypes of young adults.

Although the nature of younger adults' attitudes toward older adults has been researched extensively, there are long-neglected questions regarding older adults' views of young adults. In the first phase of this three phase study, community dwelling seniors generated traits they believed characterized young people. In the second phase, a subsample of the original participants sorted the traits into groups that could be found in one and the same young person. Fifteen stereotypes appeared when these results were submitted to hierarchical cluster analysis. In the final phase, a subsample of the original older adult participants rated how typical each of the stereotypes was of younger people. As well, each of the stereotypes were rated using an abbreviated version of Kogan and Wallach's (1961) semantic differential scale. Results indicate that the stereotypes older people hold of younger people are generally more positive than negative. Further, the positive stereotypes are viewed as more typical of younger adults than are the negative stereotypes.

A 2-year comparison study of Crl:CD BR and Hsd:Sprague-Dawley SD rats.

In this 2-year study, the suitability of the Hsd:Sprague-Dawley SD (SD) as a replacement for the Crl:CD BR (CD) rat was assessed by comparing survival rates, palpable mass incidence, body weights, food consumption, clinical laboratory parameters, and necropsy and histopathology observations. At week 104, survival rates in the CD and SD males were 29 and 49%, respectively. Corresponding survival rates in females were 44 and 63%. The total numbers of animals with palpable masses and animals with neoplasms were similar in the CD and SD rats; however, the total numbers of palpable masses and neoplasms were higher in the CD rats. The incidence of corneal lesions was higher in the SD rats, whereas the incidence of lenticular opacities was higher in the CD rats. Body weights, food and water consumption, and organ weights were significantly lower in the SD rats. In contrast, food intake per kilogram of body weight was slightly higher in the SD rats. Numerous differences in clinical laboratory parameters between the CD and SD rats were observed. Some of these were consistent with the increased prevalence of kidney disease and secondary sequelae in the SD rats. Taken together, the better survival, smaller size, and lower food consumption of the SD rat may make it a better model for chronic bioassays. However, the increased propensity for spontaneous renal disease may limit the utility of the SD rat for studying nephrotoxic compounds.

Production of factors with B-cell growth and differentiation activities by peripheral blood mononuclear cells from patients with hypogammaglobulinemia.

BACKGROUND: The maturation of normal B lymphocytes proceeds through a growth phase and a differentiation phase. These two phases appear to be under the influence of mediators released by immune cells, B-cell growth factor(s), which induce proliferation of B cells; and B-cell differentiation factor(s), which induce B-cell differentiation. METHODS: We analyzed the ability of peripheral blood mononuclear cells from patients with hypogammaglobulinemia to produce B-cell growth factor and B-cell differentiation factor activity in comparison with normal peripheral blood mononuclear cells. RESULTS: Of 27 patients tested, 26 had normal production of B-cell growth factor activity. A quantitative but not absolute defect in B-cell growth factor production was demonstrable in one boy with hypogammaglobulinemia. Interleukin-2 and interleukin-4 levels, as determined antigenically in these supernatants, had a similar distribution pattern from patients' or from control peripheral blood mononuclear cells; that is, undetectable levels of interleukin-2 were produced by cells from 4 of 16 patients tested and from 4 of 13 control subjects, and undetectable levels of interleukin-4 produced by cells from 6 of 16 patients and 4 of 13 control subjects. B-cell differentiation factor activity was absent in only one child tested but present in all other patients. Two patients had quantitatively low secretion of B-cell differentiation factor, but all others were within normal range. The two patients with quantitatively depressed B-cell differentiation factor activity had normal levels of B-cell growth factor activity, interleukin-2, and interleukin-4 produced from their cells. CONCLUSION: Peripheral blood mononuclear cells from the majority of patients with hypogammaglobulinemia appear to have the capacity to produce B-cell growth factors and B-cell differentiation factor activity in vitro.

Assessing the utilization of in-patient facilities in a Canadian pediatric hospital.

STUDY OBJECTIVE: To validate the pediatric appropriateness evaluation protocol (P-AEP) for use in the Canadian health care system and then to use it to assess the extent of inappropriate utilization in a Canadian tertiary care pediatric facility. METHOD: The P-AEP was applied to a 10% random sample of all general pediatric admissions during 1990 and to a sample of 547 subsequent days of care. The reliability of the P-AEP was assessed using a subsample of 72 admissions and 72 days of care. Validity was tested by comparing the P-AEP judgment on a sample of 50 admissions and 50 days of care with the subjective opinion of panels of three pediatric staff physicians. RESULTS: In the reliability test, there was a high level of agreement between the two independent observers applying the P-AEP. In validity testing, the physicians found a slightly lower rate of inappropriateness relative to the P-AEP, but the validity was good overall. In the main study, 136 of 477 admissions (29%) were found to be inappropriate. Factors associated with inappropriate admission included nonurgent or emergent admission, surgical (versus medical) cases, residence outside the Greater Vancouver area, and admission on Sundays or Mondays. Fifty-five percent of inappropriate admissions were judged necessary but premature, whereas 45% were judged medically unnecessary. Of 547 subsequent days of care, 121 (22%) were found to be medically inappropriate. Inappropriate days of care were associated with girls, Mondays, and patients older than 14 years of age. CONCLUSIONS: The P-AEP seems to be a valid and useful instrument for assessing the utilization of pediatric beds in a Canadian health care setting. Using the P-AEP made it possible to identify several service and policy developments which would help improve the efficiency of utilization at the hospital.

Intravenous immunoglobulin induces interferon-gamma and interleukin-6 in vivo.

Immunoglobulin is known to be an immunomodulator. It can induce protein mediators from mononuclear cells, particularly monocytes in vitro. Intravenous immunoglobulin (IVIg) has been used as a therapy in several clinical situations. In this study, the influence of IVIg infusion on the plasma levels of two protein mediators, interferon-gamma (IFN-gamma) and interleukin-6 (IL-6), was assessed in patients with secondary generalized epilepsy. Compared to preinfusion levels, plasma interferon-gamma was increased in 18 of 18 patients 20 min after the 6- to 8-hr infusion of IVIg. Plasma interferon-gamma levels reached their peak at various times from 20 min to 3 days post IVIg infusion, dependent upon the individual patient. Plasma IL-6 levels also increased after IVIg infusion. Generally, IL-6 reached its peak level after IFN-gamma. No activated T cells or B cells were observed as determined by the expression of surface CD25, CD23, and HLA-DR 20 min following the infusion when the IFN-gamma and IL-6 levels were assessed. The expression of the high-affinity receptor for IgG, CD64, on monocytes was significantly enhanced after IVIg infusion, while the low-affinity receptor for IgG, CD32, was only slightly increased. Cytoplasmic staining of PBMC indicates that both CD16-positive and CD16-negative cells may contribute to the increase seen in plasma IFN-gamma. These data raise the possibility that the therapeutic effects of intravenous immunoglobulin may be related, at least in part, to the immunomodulatory activity as demonstrated by the changes in plasma levels of IFN-gamma and IL-6.

The influence of recombinant mediators on in vitro IgG subclass secretion by peripheral blood mononuclear cells from patients with hypogammaglobulinemia and from normal donors.

Patients with hypogammaglobulinemia have recurrent infections and fail to produce protective antibodies. In order for B cells to mature into antibody producing cells, several other cell types such as macrophages and helper T lymphocytes must be involved. They secrete several mediators such as interleukin-1 (IL-1), IL-4, IL-5, IL-6 and interferon-gamma (IFN-gamma). These factors, as recombinant mediators, were tested to assess their ability to correct the immunoglobulin production defect in vitro from pokeweed mitogen (PWM) stimulated cultures of peripheral blood mononuclear cells (PBMC) from 11 patients with hypogammaglobulinemia, and from 10 normals as controls. In general, PBMC from hypogammaglobulinemic patients secreted very little Ig in cultures, and no mediator induced a statistically significant increase in the secretion of any IgG subclass. When assessed on an individual basis, one patient demonstrated a variable pattern of increase in total IgG, IgG1, and IgG3, secretion induced by various mediators, to within one standard deviation of the average secretion of normal PBMC cultured in PWM. In the case of the normal cells, IL-4, IL-6 and IL-1 plus IL-4 were able to increase IgG2 secretion in culture with PWM. No increase in secretion of IgG1, IgG3 and IgG4 or total IgG was demonstrable however. Hence, although there is variability in responsiveness amongst the patients, there does not appear to be any one of these recombinant mediators which will correct the defect.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of Fc-induced IL-6 from human peripheral blood mononuclear cells.

Previous experiments demonstrated that aggregated immunoglobulin and the Fc fragment of human IgG can induce interleukin-6 (IL-6) secretion from peripheral blood monocytes. The data herein indicate that Fc-induced IL-6 is modulated by IL-1, IL-4 and interferon (IFN-gamma). When added with Fc fragments, IL-1 and IFN-gamma increased IL-6 production. IL-4 added with Fc fragment did not influence IL-6 production although IL-4 added with LPS was inhibitory to IL-6 production. However, when PBMC were pre-treated with IL-4, IL-4 downregulated Fc-induced IL-6 secretion. The inhibitory effect of IL-4 in the pre-treatment phase could be overcome with a high concentration of IFN-gamma added with the IL-4. Both IL-4 and IFN-gamma acted in a dose- and time-dependent manner. By dot blot analysis, IL-6 mRNA production appeared to be decreased in amount and duration by IL-4 whereas IFN-gamma increased the amount of IL-6 mRNA production. Hence, IL-4 and IFN-gamma appear to have opposing effects and may play a balancing role in the regulation of IL-6 production secondary to Fc exposure.