Lung Clearance Index and HRCT are complementary markers of lung abnormalities in young children with CF.

RATIONALE: High resolution computed tomography (HRCT) is a more sensitive tool for detecting early cystic fibrosis (CF) lung disease than either spirometry or plain radiography, but its relationship to other measures of lung function has not been established in young children. OBJECTIVES: (1) To assess whether the lung clearance index (LCI) derived from multiple breath inert-gas washout (MBW) is as effective as HRCT in identifying pulmonary abnormalities; and (2) explore the relationships between abnormalities detected by HRCT and by spirometry, plethysmography and MBW (collectively, LFTs) in young children with CF. METHODS: Children with CF underwent LFTs and volumetric HRCT on the same day. Healthy age-matched controls underwent identical LFTs without HRCT. Scans were anonymised, and scored using the Brody-II CT scoring system, to assess for presence and extent of bronchiectasis, airway wall thickening, mucus plugging, and parenchymal opacities. RESULTS: Assessments were undertaken in 60 children with CF (mean (SD) 7.8 (1.3 years) and 54 healthy controls (7.9 (1.2) y). Among children with CF, 84% (47/56) had abnormal LCI, 58% (27/47) abnormal plethysmographic lung volumes (FRC(pleth) or RV), 35% (21/60) abnormal sRaw and 47% (28/60) abnormal spirometry (FEV1 or FEF(25-75)); whereas HRCT scans were abnormal in 85% (51/60): median total Brody-II score: 9.5% (range 0-51%). Total CT score correlated more strongly with LCI (Spearman correlation = 0.77) than with spirometry (R = -0.43) or any other marker of lung function. Of the nine children with normal LCI, five had abnormalities on HRCT, whereas five children with normal HRCT had raised LCI. CONCLUSIONS: These results suggest that while LCI and HRCT have similar sensitivity to detect CF lung disease, complimentary information may be gained in individual patients.

Influence of secular trends and sample size on reference equations for lung function tests.

The aim of our study was to determine the contribution of secular trends and sample size to lung function reference equations, and establish the number of local subjects required to validate published reference values. 30 spirometry datasets collected between 1978 and 2009 provided data on healthy, white subjects: 19,291 males and 23,741 females aged 2.5-95 yrs. The best fit for forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC) and FEV(1)/FVC as functions of age, height and sex were derived from the entire dataset using GAMLSS. Mean z-scores were calculated for individual datasets to determine inter-centre differences. This was repeated by subdividing one large dataset (3,683 males and 4,759 females) into 36 smaller subsets (comprising 18-227 individuals) to preclude differences due to population/technique. No secular trends were observed and differences between datasets comprising >1,000 subjects were small (maximum difference in FEV(1) and FVC from overall mean: 0.30- -0.22 z-scores). Subdividing one large dataset into smaller subsets reproduced the above sample size-related differences and revealed that at least 150 males and 150 females would be necessary to validate reference values to avoid spurious differences due to sampling error. Use of local controls to validate reference equations will rarely be practical due to the numbers required. Reference equations derived from large or collated datasets are recommended.

Meta-epidemiological study of publication integrity, and quality of conduct and reporting of randomized trials included in a systematic review of low back pain.

OBJECTIVE: To comprehensively describe the quality of conduct, reporting, and publication integrity characteristics for all trials included in a large Cochrane review, comparing those published by presumed predatory publishers with those published by nonpredatory publishers. DESIGN: Cross-sectional meta-epidemiological study. STUDY SELECTION: Two hundred seventy-nine studies (25,704 participants) eligible for the recent update of the "Exercise therapy for chronic low back pain" Cochrane review were included. DATA EXTRACTION: Study and manuscript characteristics, including predatory publication status and other quality and integrity characteristics were extracted along with treatment effect. RESULTS: Nine percent of trials included were in presumed predatory publications; 12% in the period since 2010. We found frequency of other concerning characteristics to range from low (eg, plagiarism, 5%) to common (eg, lack of evidence of trial registration or protocol publication [75%]; insufficient sample size [84%]) in included studies. Studies published by presumed predatory publishers consistently had inferior conduct, reporting and publication integrity characteristics. Presumed predatory publication was associated with missing conflict of interest statement (OR 7.6, 95% CI 3.0-19.1), inadequate follow-up duration (OR 11.2, 95% CI 3.7-33.7), incomplete study methods (OR 12.1, 95% CI 2.8-52.2) and baseline reporting (OR 4.3, 95% CI 1.6-11.7), and high risk of bias (OR 2.7, 95% CI 1.2-6.3). All (100%) presumed predatory publications were missing trial registrations (vs. 72%) and had inadequate sample sizes (vs. 82%). Trials published in presumed predatory journals did not appear to have inflated effect sizes. CONCLUSIONS: Predatory publishers pose a distinct challenge to the consumption and synthesis of randomized controlled trials. More work is needed in other clinical areas to understand the potential impact of randomized controlled trials published in predatory publications, and as a result, the potential impact on evidence from systematic reviews that include these studies.

Reference values for lung function: past, present and future.

Reliable interpretation of pulmonary function results relies on the availability of appropriate reference data to help distinguish between health and disease and to assess the severity and nature of any functional impairment. The overwhelming number of published reference equations, with at least 15 published for spirometry alone in the past 3 yrs, complicates the selection of an appropriate reference. The use of inappropriate reference equations and misinterpretation, even when potentially appropriate equations are used, can lead to serious errors in both under and over diagnosis, with its associated burden in terms of financial and human costs. Further misdiagnosis occurs when fixed cut-offs, such as 80% predicted forced expiratory volume in 1 s (FEV(1)) or 0.70 FEV(1)/forced vital capacity, are used; particularly in young children and elderly adults. While per cent predicted has historically been used to interpret lung function results, z-scores are more appropriate as they take into account the predicted value, as well as the between-subject variability of measurements. We aim to highlight some of the main issues in selecting and using reference equations and discuss how recent developments may improve interpretation of pulmonary function results.

Reference ranges for interrupter resistance technique: the Asthma UK Initiative.

Measuring interrupter resistance (R(int)) is an increasingly popular lung function technique and especially suitable for preschool children because it is simple, quick and requires only passive cooperation. A European Respiratory Society (ERS)/American Thoracic Society (ATS) Task Force recently published empirical recommendations related to procedures, limitations and interpretation of the technique. However, for valid interpretation, high-quality reference equations are required and these have been lacking. The aim of the present study was to collate R(int) data from healthy children in order to produce more robust reference equations. A further aim was to examine the influence of methodological differences on predicted R(int) values. R(int) data from healthy children were collected from published and unpublished sources. Reference equations for expiratory and inspiratory R(int) were developed using the LMS (lambda, mu, sigma) method. Data from 1,090 children (51% males) aged 3-13 yrs were collated to construct sex-specific reference equations for expiratory R(int) and data from 629 children (51% males) were collated for inspiratory R(int). Height was the best independent predictor of both expiratory and inspiratory R(int). Differences between centres were clinically irrelevant, and differences between ethnic groups could not be examined. The availability of a large and generalisable sample and the use of modern statistical techniques enabled the development of more appropriate reference equations for R(int) in young children.

Reference equations for specific airway resistance in children: the Asthma UK initiative.

Plethysmographic specific airway resistance (sR(aw)) is a useful research method for discriminating lung disease in young children. Its use in clinical management has, however, been limited by lack of consensus regarding equipment, methodology and reference data. The aim of our study was to collate reference data from healthy children (3-10 yrs), document methodological differences, explore the impact of these differences and construct reference equations from the collated dataset. Centres were approached to contribute sR(aw) data as part of the Asthma UK initiative. A random selection of pressure-flow plots were assessed for quality and site visits elucidated data collection and analysis protocols. Five centres contributed 2,872 measurements. Marked variation in methodology and analysis excluded two centres. sR(aw) over-read sheets were developed for quality control. Reference equations and recommendations for recording and reporting both specific effective and total airway resistance (sR(eff) and sR(tot), respectively) were developed for White European children from 1,908 measurements made under similar conditions. Reference sR(aw) data collected from a single centre may be misleading, as methodological differences exist between centres. These preliminary reference equations can only be applied under similar measurement conditions. Given the potential clinical usefulness of sR(aw), particularly with respect to sR(eff), methodological guidelines need to be established and used in prospective data collection.

Changes in the FEV1/FVC ratio during childhood and adolescence: an intercontinental study.

In children, the ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) is reportedly constant or falls linearly with age, whereas the ratio of residual volume (RV) to total lung capacity (TLC) remains constant. This seems counter-intuitive given the changes in airway properties, body proportions, thoracic shape and respiratory muscle function that occur during growth. The age dependence of lung volumes, FEV1/FVC and RV/TLC were studied in children worldwide. Spirometric data were available for 22,412 healthy youths (51.4% male) aged 4-20 yrs from 15 centres, and RV and TLC data for 2,253 youths (56.7% male) from four centres; three sets included sitting height (SH). Data were fitted as a function of age, height and SH. In childhood, FVC outgrows TLC and FEV1, leading to falls in FEV1/FVC and RV/TLC; these trends are reversed in adolescence. Taking into account SH materially reduces differences in pulmonary function within and between ethnic groups. The highest FEV1/FVC ratios occur in those shortest for their age. When interpreting lung function test results, the changing pattern in FEV1/FVC and RV/TLC should be considered. Prediction equations for children and adolescents should take into account sex, height, age, ethnic group, and, ideally, also SH.

Non-cystic fibrosis bronchiectasis in childhood: longitudinal growth and lung function.

BACKGROUND: Non-cystic fibrosis (non-CF) bronchiectasis often starts in childhood with a significant impact on adult morbidity. Little is known about disease progression through childhood and the effect on growth and spirometry. This study reviews longitudinal lung function and growth in children with non-CF bronchiectasis. METHODS: The case notes of patients with non-CF bronchiectasis were reviewed retrospectively. Patients were included if at least three calendar years of lung function data were available. Anthropometric measurements and annual spirometry were analysed over both two and four consecutive years. Changes over time were assessed using Generalised Estimating Equations. RESULTS: Fifty-nine patients (31 boys) were identified. At baseline the median age was 8.2 years (range 4.8-15.8), the mean (SD) for height, weight and body mass index (BMI) for age z-scores were -0.68 (1.31), -0.19 (1.34) and 0.19 (1.38), respectively. At baseline, the mean (SD) z-score for forced expiratory volume in 1 s (FEV(1)) was -2.61 (1.82). Over 2 years (n = 59), mean FEV(1) and forced vital capacity (FVC) improved by 0.17 (95% CI 0.01 to 0.34, p = 0.039) and 0.21 (95% CI 0.04 to 0.39, p = 0.016) z-scores per annum, respectively. Over 4 years there was improvement in height-for-age z-scores (slope 0.05, 95% CI 0.01 to 0.095, p = 0.01) but no improvement in other anthropometric variables. There was no change in spirometry (FEV(1) slope 0.00, 95% CI -0.09 to 0.09, p = 0.999 and FVC slope 0.09, 95% CI -0.09 to 0.1, p = 0.859). CONCLUSIONS: Children with non-CF bronchiectasis show adequate growth over time. Lung function stabilises but does not normalise with treatment, underscoring the need for early detection and institution of appropriate therapy.

An urgent need for African spirometry reference equations: the Paediatric and Adult African Spirometry study.

BACKGROUND: The GLI2012 (Global Lung Initiative 2012) has provided the largest data set to date for multi-ethnic spirometry reference equations; however, data on African populations are limited. In pulmonary function testing, diagnosis of lung disorder is based on comparing the individual's lung function to a reference appropriate for sex and ethnicity.METHODS: We conducted a systematic review of studies reporting spirometry results in healthy children and adults in Africa. Data from these studies were collated for Z-scores of forced expiratory volume in 1 sec (zFEV1), forced vital capacity (zFVC) and zFEV1/FVC compared to GLI reference equations.RESULTS: Nine studies, covering a total of 4750 individuals from North, South, East, West and Central Africa (52% were female), were reviewed. Marked differences were noted between individuals from North Africa and sub-Saharan Africa. The Southern zFEV1 (-0.12 ± 0.98), zFVC (-0.15 ± 0.98) and zFEV1/FVC (0.05 ± 0.89), Central zFEV1 (-0.16 ± 0.79), zFVC (-0.09 ± 0.83) and zFEV1/FVC (-0.17 ± 0.71) and East African zFEV1 (0.10 ± 0.88), zFVC (0.16 ± 0.85) and zFEV1/FVC (-0.10 ± 0.95) cohorts had an excellent fit with the GLI-African American. The West African showed a poor fit to all reference equations. The North African group showed the best fit for the GLI Caucasian zFEV1 (-0.12 ± 1.37), zFVC (-0.26 ± 1.36) and zFEV1/FVC (0.25 ± 1.11). The zFEV1/FVC ratios were stable across all the populations.CONCLUSION: Current evidence seems to support the use of GLI2012 reference values in North African and sub-Saharan African populations after taking into account ethnic correction factors.

Role of routine computed tomography in paediatric pleural empyema.

BACKGROUND: The incidence of empyema in children is increasing worldwide. While there are emerging data for the best treatment options, there is little evidence to support the imaging modalities used to guide treatment, particularly with regard to the role of routine CT scanning. The aims of this study were to develop a radiological scoring system for paediatric empyema and to assess the utility of routine CT scanning in this disease. METHODS: Children with empyema were prospectively enrolled over a 3-year period into a randomised clinical trial of video-assisted thoracoscopic surgery versus percutaneous chest drain insertion and urokinase. All children received a preoperative chest radiograph (CXR), pleural ultrasound scan (USS) and chest CT scan. In the urokinase arm the clinician inserted the drain with USS evidence only and did not have access to the CT scan at the time of insertion to reflect clinical practice. A scoring system was developed for each individual radiological modality and used to compare imaging characteristics of the pleural fluid collection and underlying parenchyma and to assess the utility of USS and CT to predict length of stay after the intervention. RESULTS: Of the 60 subjects recruited, 46 had USS images available for review, 36 had a CT scan which met the inclusion criteria and 31 had all three radiological measurements (CT, USS and CXR) available for analysis. There was substantial interobserver agreement for USS grades (kappa = 0.709) and moderate agreement for total CT scores (kappa = 0.520). There were weak correlations between USS grade and total CT score as well as CT loculation and density scores. Of the 25 CXRs showing simple opacification of the underlying parenchyma only, CT demonstrated simple consolidation (n = 14), necrotising pneumonia (n = 7), cavitary necrosis (n = 3) and pneumatoceles (n = 1). No abnormality was detected on CT scanning which directly altered clinical management. Neither the USS score nor the CT score, nor a combination of the two, were able to predict length of hospital stay. CONCLUSIONS: CT scanning detects more parenchymal abnormalities than chest radiography. However, the additional information does not alter management and is unable to predict clinical outcome. This suggests that there is no role for the routine use of CT scanning in children if treated with urokinase and percutaneous chest drain. The omission of routine CT scanning in empyema will reduce the exposure of children to unnecessary radiation and reduce costs. TRIAL REGISTRATION NUMBER: The trial is fully registered with clinicaltrials.gov (ID: NCT00144950).

Beta-adrenoceptor blockade ameliorates the clinical course of experimental allergic encephalomyelitis and diminishes its aggravation in adrenalectomized rats.

As glucocorticoids influence both catecholamine synthesis and adrenoceptor expression by immune cells, the current study was undertaken to distinguish their direct effects on the development of experimental allergic encephalomyelitis from those induced by alteration of catecholamine signaling. We examined the influence of 16-day-long beta-adrenoceptor blockade with propranolol (0.40 mg/100 g body weight/day, s.c.) beginning 3 days before immunization on the development of experimental allergic encephalomyelitis in adrenalectomized (7 days before immunization) and in non-operated male Dark Agouti rats. Adrenalectomy aggravated the clinical course of experimental allergic encephalomyelitis. In contrast, propranolol attenuated both the clinical signs of the disease and decreased the number of lesions in the spinal cord. Furthermore, propranolol prevented adrenalectomy-induced aggravation of the disease course without affecting mortality. We also found that the percentage of CD4(+)CD25(+) T lymphocytes (recently activated or regulatory cells) was increased in peripheral blood of experimental allergic encephalomyelitis rats over that in the corresponding non-immunized and bovine serum albumin immunized rats. However, the percentage of these cells was reduced in adrenalectomized and/or propranolol-treated experimental allergic encephalomyelitis rats compared to control experimental allergic encephalomyelitis rats. Our findings, coupled with the clinical course of the disease and the underlying pathomorphological changes, clearly suggest that differential mechanisms were responsible for the changes in the percentage of CD4(+)CD25(+) T lymphocytes in propranolol-treated adrenalectomized rats and only propranolol-treated rats with experimental allergic encephalomyelitis. Our results, when viewed globally, indicate that: i) beta-adrenoceptor-dependent mechanisms are involved in the immunopathogenesis of experimental allergic encephalomyelitis, ii) experimental allergic encephalomyelitis has a more severe course in adrenalectomized rats and iii) beta-adrenoceptor-mediated mechanisms operate in adrenalectomy-induced aggravation of the disease.

Oral non-steroidal anti-inflammatory drug therapy for cystic fibrosis.

BACKGROUND: Progressive lung damage causes the majority of deaths in cystic fibrosis (CF). Non-steroidal anti-inflammatory drugs may prevent progressive pulmonary deterioration and morbidity in CF. OBJECTIVES: To assess the effectiveness of treatment with non-steroidal anti-inflammatory agents in CF. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, hand searches of relevant journals and abstract books of conference proceedings. We also contacted pharmaceutical companies manufacturing non-steroidal anti-inflammatory drugs. Most recent search of the Group's Trials Register: October 2006. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials, published and unpublished, comparing oral non-steroidal anti-inflammatory drugs, at any dose for at least two months, to placebo in people with CF. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for the review. MAIN RESULTS: The searches identified six trials, of which four, including 287 participants aged five to 39 years with a maximum follow up of four years, were eligible for inclusion in the review. Two trials reporting effectiveness of ibuprofen in people with mild lung disease were from the same center and included some of the same participants. A third assessed piroxicam in participants with more severe impairment of respiratory function and the Trans-Canada trial compared ibuprofen to placebo for a period of two years. Three of the trials in this review were deemed to have good or adequate methodological quality, but variation in outcomes reported and their summary measures precluded calculation of pooled treatment estimates. Authors considered objective measures of lung function, nutritional status, radiological assessment of pulmonary involvement, intravenous antibiotic usage, hospital admissions, survival, frequency of all adverse effects and compliance with therapy. The addition of data from the Canadian trial showed evidence of a moderate absolute annual decline in per cent predicted forced expiratory volume in one second and forced vital capacity in the placebo group than in the ibuprofen group. In one trial, long-term use of high-dose ibuprofen was associated with reduced intravenous antibiotic usage, improved nutritional and radiological pulmonary status. No major adverse effects were reported, but the power of the trials to identify clinically important differences in the incidence of adverse effects was low. AUTHORS' CONCLUSIONS: High-dose ibuprofen can slow the progression of lung disease in people with CF, especially in children, and this suggests that strategies to modulate lung inflammation can be beneficial for people with CF.

Rituximab mediates in vitro antileukemic activity in pediatric patients after allogeneic transplantation.

Relapse is a major problem after allogeneic transplantation in children with acute B-lineage lymphoblastic leukemias (ALL) and lymphomas and additional therapeutic strategies are needed to increase graft versus leukemia effects without inducing graft versus host disease (GvHD). Several studies have shown the efficacy of a humanized CD20 antibody (rituximab) for treatment of CD20+ malignancies together with conventional chemotherapy but less is known about its post transplant usefulness. We studied the ability of rituximab to mediate antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) with effector cells and complement from patients who were transplanted with T-cell-depleted grafts from unrelated or mismatched related donors. Highest lytic activity (ADCC) was observed against leukemia-derived MHH4 cells and Burkitt's lymphoma-derived Raji cells in the first months after transplantation, corresponding to the high percentage of regenerating CD56+ CD16+ cells. Moreover, primary cryopreserved ALL-blasts from a pediatric patient were also efficiently lysed. Increased lysis was obtained after stimulation with interleukin-2. Combination of ADCC and CDC had additive effects. These findings encourage clinical trials on the use of rituximab for improving minimal residual disease control and relapse prevention after allogeneic high-risk transplantation in the small group of pediatric patients with CD20+ leukemias/lymphomas.

Modulation of humoral immune response by central administration of leucine-enkephalin: effects of mu, delta and kappa opioid receptor antagonists.

The effect of leucine-enkephalin (Leu-Enk) on primary humoral immune response was investigated following intracerebroventricular (i.c.v.) administration of the peptide in the rat. Leu-Enk stimulated plaque-forming cell (PFC) response in rats i.c.v. injected with 0.1 and 1 micrograms/kg, whereas does of 20 and 50 micrograms/kg exerted immunosuppressive effects. I.c.v. treatment of rats with delta opioid receptor antagonist ICI 174,864 and kappa opioid receptor antagonist nor-binaltorphimine (nor-BNI) blocked stimulation and suppression of PFC response induced by Leu-Enk, respectively. The mu opioid receptor antagonist beta-funaltrexamine (beta-FNA) reversed both immunomodulatory effects produced by Leu-Enk. Since beta-FNA alone had no effect on PFC response (unlike ICI 174,864 and nor-BNI), these data showed that central effects of Leu-Enk on PFC response were mediated by brain mu opioid receptors, and suggested a possible involvement of delta and kappa opioid receptors.

Clinical scale isolation of T cell-depleted CD56+ donor lymphocytes in children.

We present a clinical scale method for immunomagnetic separation of CD56+ donor natural killer cells for adoptive immunotherapy of pediatric leukemias after allogeneic transplantation. This time-saving and partially automated procedure employed CD56+ selection followed by CD3+ depletion, resulting in a median purity of 98.6% NK cells and a four-log depletion of T cells. The enriched NK cells demonstrated high cytotoxic activity against K562 target cells and fresh leukemic blasts with low HLA class I expression, which could be further enhanced by IL-2 stimulation. Lysis of NK-insensitive leukemic cells with high HLA class I expression could also be demonstrated via ADCC. Due to the high degree of T cell depletion, alloreactive proliferation in mixed lymphocyte cultures and response to T cell-specific mitogen stimulation was profoundly decreased. Our results suggest that, even in the case of mismatched donors, infusions of donor NK cells with extremely low T cell content may be a promising treatment option for leukemic minimal residual disease after allogeneic transplantation without risk of inducing severe GVHD.

Effect of Met-enkephalin and opioid antagonists on rat macrophages.

Effects of Met-enkephalin (Met-ENK) and opioid antagonists on H2O2 release by peritoneal macrophages from DA and AO rats were investigated. Met-ENK increased and decreased H2O2 production by macrophages of DA and AO rats, respectively. These effects were antagonized by low, but not high, concentrations of naloxone and ICI 174864. High concentrations of both antagonists directly modulated H2O2 release and retained the strain-related differences seen with Met-ENK. The results showed direct, strain- and dose-dependent, effects of Met-ENK, naloxone, and ICI 174864 on rat macrophage function.

Age- and size-related reference ranges: a case study of spirometry through childhood and adulthood.

Age-related reference ranges are useful for assessing growth in children. The LMS method is a popular technique for constructing growth charts that model the age-changing distribution of the measurement in terms of the median, coefficient of variation and skewness. Here the methodology is extended to references that depend on body size as well as age, by exploiting the flexibility of the generalised additive models for location, scale and shape (GAMLSS) technique. GAMLSS offers general linear predictors for each moment parameter and a choice of error distributions, which can handle kurtosis as well as skewness. A key question with such references is the nature of the age-size adjustment, additive or multiplicative, which is explored by comparing the identity link and log link for the median predictor.There are several measurements whose reference ranges depend on both body size and age. As an example, models are developed here for the first four moments of the lung function variables forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC) and FEV(1)/FVC in terms of height and age, in a data set of 3598 children and adults aged 4 to 80 years. The results show a strong multiplicative association between spirometry, height and age, with a large and nonlinear age effect across the age range. Variability also depends nonlinearly on age and to a lesser extent on height. FEV(1) and FVC are close to normally distributed, while FEV(1)/FVC is appreciably skew to the left. GAMLSS is a powerful technique for the construction of such references, which should be useful in clinical medicine.

Strain differences and the role for HSP47 and HSP70 in adjuvant arthritis in rats.

Because of high sequence homology between microbial and endogenous heat shock proteins (HSP), immunological cross-reactivity to microbial HSP has been suggested as a possible cause of the development of autoimmune diseases, such as rheumatoid arthritis. The present study aimed to determine a potential role of HSP47, a molecular chaperone involved in the synthesis and assembly of collagen molecules, and microbial HSP71 (mHSP71) in adjuvant arthritis (AA) in two rat strains: Dark Agouti (DA), susceptible to AA induction and Albino Oxford (AO), which is resistant to AA induction. Immunization with complete Freund's adjuvant (CFA) induced an increased expression of HSP47 in joints of DA rats, which exhibited severe clinical signs of AA at the time of disease peak, while this protein was not detectable in joints of AO rats. In contrast, no strain differences in HSP72 (rat analogue of mHSP71) expressions in joints were observed. The increased levels of anti-HSP47 antibodies were detected in sera of DA rats during the AA peak, while the immunization with CFA increased levels of anti-mHSP71 antibodies in sera of AO rats. HSP47 and mHSP71 reduced proliferation of draining inguinal lymph node cells (LNC) in resistant AO rat strain, leading to a hypothesis that both HSP participated in AA control. Finally, mHSP71 potentiated the apoptotic response of LNC in susceptible DA rat strain. In conclusion, our findings indicate involvement of HSP47 in the development of AA in the rat, and point out to the regulatory role for both HSP47 and mHSP71.

Communication skills Assessed at OSCE are not Affected by Participation in the Adolescent Healthy Sexuality Program.

PURPOSE: We proposed that first year medical students who voluntarily participated in the Healthy Sexuality adolescent program would perform better than their peers on an adolescent counseling station at the year-end OSCE (Objective Structured Clinical Examination). In addition we compared medical students? communication skills at the time of the program as assessed by self, peers and participating adolescents. METHODS: Nineteen first year medical students voluntarily participated in the ongoing Healthy Sexuality program. Adolescent participants, medical student peer participants and medical students assessed communication comp onents on a 7-point Likert scale at the end of the program. At the year-end OSCE, all first year medical students at the University of Western Ontario were assessed at an adolescent counseling station by a standardized patient (SP) and a physician exa miner. Statistical analysis examined differences between the two groups. RESULTS: Students who participated in the Healthy Sexuality program did not perform better than their colleagues on the year-end OSCE. A statistically significant correlation between physician examiner and SP evaluations was found (r = 0.62). Adolescent participants communication skills assessments in the Healthy Sexuality Program demonstrated no significant correlation with medical student assessments (self or peer). CONCLUSIONS: Voluntary intervention with adolescents did not result in improved communication skills at the structured year-end examination. Further investigation will be directed towards delineating differences between SP and physician examiner assessments.

Modulation of humoral immune responses in the rat by centrally applied Met-Enk and opioid receptor antagonists: functional interactions of brain OP1, OP2 and OP3 receptors.

We have previously demonstrated that central application of leucine-enkephalin (Leu-Enk) elicits potentiation and suppression of humoral immune responses through OP(1) (delta) and OP(2) (kappa) receptors, respectively. Interestingly, both effects were found to be additionally dependent on OP(3) (mu) receptor function. In the present study, we have further investigated whether opioid receptor interactions underlie the immunomodulatory effects of endogenous opioids as well as exogenously applied methionine-enkephalin (Met-Enk). For that purpose, the plaque-forming cell (PFC) response was determined in rats injected intracerebroventricularly (i.c.v.) with opioid receptor-selective antagonists and Met-Enk. Application of the OP(1) antagonist ICI 174864, but not naltrindole, resulted in suppression of the PFC response. In contrast, i.c.v. injection of the OP(2) selective antagonist nor-binaltorphimine (nor-BNI) significantly potentiated the PFC response. Both effects, presumably mediated by endogenous opioid peptides, were antagonized by the OP(3) receptor antagonist beta-funaltrexamine (beta-FNA) at a dose that was devoid of immunomodulatory activity. The immunopotentiation of the PFC response induced by Met-Enk was reversed by OP(1) receptor antagonists, naltrindole and ICI 174864, but not by beta-FNA or nor-BNI. On the basis of these and previous findings, it may be concluded that central OP(3) receptors are permissive for the central immunomodulatory action of endogenous opioid peptides and Leu-Enk. In contrast, the central immunoenhancing effect of Met-Enk appears to be mediated through OP(3)-independent OP(1) receptors.