Anti-IL-5/5Ra biologics improve work productivity and activity in severe asthma: a RAPSODI registry-based cohort study.

INTRODUCTION: Severe asthma is associated with a serious disease burden, partially caused by limitations in activity and work impairment. AIMS AND OBJECTIVES: This study aims to relate treatment with biologics targeting IL-5/5Ra to work productivity and activity in the long term in a real-world context. MATERIAL AND METHODS: This is a registry-based multi-center cohort study evaluating data from adults with severe eosinophilic asthma included in the Dutch Register of Adult Patients with Severe Asthma for Optimal DIsease management (RAPSODI). Patients that started with anti-IL-5/5Ra biologics and completed the work productivity and activity improvement questionnaire, were included. Study and patient characteristics were compared between the employed and unemployed patients. Work productivity and activity impairment are related to accompanying improvements in clinical outcomes. RESULTS: At baseline, 91 of 137 patients (66%) were employed which remained stable throughout the follow-up period. Patients in the working age category were younger and had significantly better asthma control (p = 0.02). Mean overall work impairment due to health decreased significantly from 25.5% (SD2.6) to 17.6% (SD 2.8) during 12 months anti-IL-5/5Ra biologics treatment (P = 0.010). There was a significant association between ACQ6 and overall work improvement after targeted therapy (ß = 8.7, CI 2.1-15.4, P = 0.01). The improvement of asthma control of 0.5 points on the asthma Control Questionnaire was associated with an overall work impairment of -9%. CONCLUSIONS: Work productivity and activity in severe eosinophilic asthma improved after starting anti-IL-5/5Ra biologics. Clinically relevant improvement in asthma control was associated with an overall work impairment score of -9% in this study.

Cellular Radiosensitivity of Soft Tissue Sarcoma.

Currently, all soft tissue sarcomas (STS) are irradiated by the same regimen, disregarding possible subtype-specific radiosensitivities. To gain further insight, cellular radiosensitivity was investigated in a panel of sarcoma cell lines. Fourteen sarcoma cell lines, derived from synovial sarcoma, leiomyosarcoma, fibrosarcoma and liposarcoma origin, were submitted to clonogenic survival assays. Cells were irradiated with single doses from 1-8 Gy and surviving fraction (SF) was calculated from the resulting response data. Alpha/beta (α/ß) ratios were inferred from radiation-response curves using the linear-quadratic (LQ)-model. Cellular radiosensitivities varied largely in this panel, indicating a considerable degree of heterogeneity. Surviving fraction after 2 Gy (SF2) ranged from 0.27 to 0.76 with evidence of a particular radiosensitive phenotype in only few cell lines. D37% on the mean data was 3.4 Gy and the median SF2 was 0.52. The median α/ß was 4.9 Gy and in six cell lines the α/ß was below 4 Gy. A fairly homogeneous radiation response was observed in myxoid liposarcoma cell lines with SF2 between 0.64 and 0.67. Further comparing sarcomas of different origin, synovial sarcomas, as a group, showed the lowest SF2 values (mean 0.35) and was significantly more radiosensitive than myxoid liposarcomas and leiomyosarcomas (P = 0.0084 and 0.024, respectively). This study demonstrates a broad spectrum of radiosensitivities across STS cell lines and reveals subtype-specific radiation responses. The particular cellular radiosensitivity of synovial sarcoma cells supports consideration of the different sarcoma entities in clinical studies that aim to optimize sarcoma radiotherapy.

Females with cystic fibrosis have a larger decrease in sweat chloride in response to lumacaftor/ivacaftor compared to males.

AIM: To explore which patient-related factors influence sweat test response to CFTR modulators, as well as examining the correlation between the sweat chloride response and ppFEV1 or BMI response, using systematically collected real-life clinical data. METHODS: 160 CF patients were identified who had used lumacaftor/ivacaftor for at least six months. Of these patients, age, sweat chloride levels, ppFEV1 weight and BMI at the start of treatment and after 6 months were collected retrospectively. Pearson and Spearman tests were performed to assess correlations. RESULTS: Females compared to males in this group showed a larger response in sweat chloride (mean difference 10.6 mmol/l, 95% CI: 5.7-15.4) and BMI (mean difference 0.27 kg/m2, 95% CI: 0.01-0.54). A modest but significant correlation was found between patient weight and sweat chloride response (Pearson R = 0.244, p = 0.001), which diminished upon correction for the other factors. The correlation between sex and sweat chloride response remained; R = 0.253, p = 0.001. Sweat chloride response did not correlate with ppFEV1 change or BMI change at 6 months after start of therapy. CONCLUSION: Sweat chloride response is larger in females compared to males, which also explains the negative correlation of weight with the response in sweat chloride concentration after start of lumacaftor/ivacaftor. Sweat chloride response does not correlate with the responses in ppFEV1 and BMI. This information may help the interpretation of sweat test results acquired for the follow up and evaluation of CFTR modulating treatments, and warrants further investigation into the underlying mechanisms of sex differences in response to CFTR modulators.

Clinical effect of lumacaftor/ivacaftor in F508del homozygous CF patients with FEV1 ≥ 90% predicted at baseline.

OBJECTIVE: The first available CFTR modulator combination for homozygous F508del patients, lumacaftor/ivacaftor, has not been tested in patients with percentage predicted (pp)FEV1 > 90 in the phase III trials. The objective of this study is to share real life experience about treatment results in this group. METHODS: In this retrospective observational study, patients aged 6 years or older starting on lumacaftor/ivacaftor in standard care were in strict follow up. For these patients, data were obtained about FEV1, BMI, CFQ-R and sweat chloride before start and after 6 months of treatment, and data about FEV1 and BMI were recorded every 3 months. Exacerbations were recorded continuously. RESULTS: We identified 40 patients with a ppFEV1 ≥ 90 at the start of lumacaftor/ivacaftor who had been in follow up for at least 12 months. After 12 months, ppFEV1 was unchanged, whereas mean absolute change in BMI was +0.88 (p = 0.001) with a mean change in SDS for BMI of +0.26 (p = 0.014). Mean CFQ-R overall score at 6 months improved by 2.6% (p = 0.004) and mean decrease in sweat chloride was -27.3 mEq/L (p = 0.000). Exacerbation rate declined from 1.03 to 0.53/person/year (p = 0.003). One patient discontinued treatment in the first 12 months because of progression of CFRLD, two paused treatment but resumed later. CONCLUSION: Homozygous F508del patients starting lumacaftor/ivacaftor at ppFEV1 ≥ 90 improved significantly in nutritional status, sweat chloride levels and exacerbation rate, but did not respond in ppFEV1. Treatment is well tolerated in this patient group. These effects make it worth considering to treat this group of patients with lumacaftor/ivacaftor.

Variation in the time to treatment for stage III and IV non-small cell lung cancer patients for hospitals in the Netherlands.

OBJECTIVES: Increased emphasis on molecular diagnostics can lead to increased variation in time to treatment (TTT) for patients with stage III and IV non-small cell lung cancer. This article presents the variation in TTT for advanced NSCLC patients observed in Dutch hospitals before the widespread use of immunotherapy. The aim of this article was to explore the variation in TTT between patients, as well as between hospitals. MATERIAL AND METHODS: Based on the Netherlands Cancer Registry, we used patient-level data (n = 4096) from all 78 hospitals that diagnosed stage III or IV NSCLC in the Netherlands in 2016. To investigate how patient characteristics and hospital-level effects are associated with TTT (from diagnosis until start treatment), we interpreted regression model results for five common patient profiles to analyze the influence of age, gender, tumor stage, performance status, histology, and referral status as well as hospital-level characteristics on the TTT. RESULTS AND CONCLUSIONS: TTT varies substantially between and within hospitals. The median TTT was 28 days with an inter-quartile range of 22 days. The hospital-level median TTT ranges from 17 to 68 days. TTT correlates significantly with tumor stage, performance status, and histology. The hospital-level effect, unrelated to hospital volume and type, affected TTT by several weeks at most. For most patients, TTT is within range as recommended in current guidelines. Variation in TTT seems higher for patients receiving either radiotherapy or targeted therapy, or for patients referred to another hospital and we hypothesize this is related to the complexity of the diagnostic pathway. With further advances in molecular diagnostics and precision oncology we expect variation in TTT to increase and this needs to be considered in designing optimal cancer care delivery.

Micro cone beam computed tomography for sensitive assessment of radiation-induced late lung toxicity in preclinical models.

BACKGROUND AND PURPOSE: Preclinical models are much needed to assess the effect of novel radio-sensitizers or mitigators on radiation dose limiting lung toxicity. Albeit showing radiation-induced lung pathologies, current mouse models lack the sensitivity to do so. Using micro image-guided radiotherapy (µIGRT) techniques, we aimed to establish murine models which enable the sensitive detection of lung damage aggravation and characterized functional, radiological and histological responses. MATERIALS AND METHODS: Right lungs of C57Bl/6J mice were irradiated using µIGRT with doses from 15 to 27 Gy and with 21 Gy and cisplatin as a radio-sensitizer in a second study. Mice were sacrificed for histological and pathological assessment at different time-points post-IR. Lung density was determined using the integrated micro cone-beam CT (µCBCT). Lung function was measured by double-chamber-plethysmography. RESULTS: µIGRT resulted in accurate deposition of the radiation dose in the right lung only as determined by É£H2AX staining. Lung fibrosis was confirmed by pathological assessments and increased significantly at 21 Gy as determined by automated quantification of histochemical analyses. Lung function was affected in a dose-dependent manner. µCBCT-determined lung densities increased significantly over time in the irradiated lungs and showed a strong radiation dose-dependence. Importantly, the µCBCT analyses allowed the detection of additional lung damage caused by 3 Gy dose increments or by the combination with cisplatin. CONCLUSION: µCBCT after right lung µIGRT enables the sensitive detection of effects inflicted by relative small dose increments or radio-sensitizers. Our preclinical model therefore facilitates the determination of lung damage exacerbation for the safety assessment of novel RT-drug combinations.

Consolidation and prediction of long-term treatment effect of group and online mindfulness-based cognitive therapy for distressed cancer patients.

BACKGROUND: Group face-to-face and individual internet-based mindfulness-based cognitive therapy (MBCT and eMBCT) have been demonstrated to reduce psychological distress for distressed cancer patients in a randomized controlled trial (RCT). This study focused on the long-term effects of this RCT during the nine-month follow-up period, and on possible predictors, moderators and working mechanisms. METHODS: Distressed cancer patients (n = 245) were randomized to MBCT or eMBCT. Data were collected at baseline, post-treatment, three- and nine-month follow-up. Data were analyzed with linear mixed effect models and (hierarchical) linear regressions. RESULTS: Analyses revealed long-term reductions in psychological distress and rumination, and long-term increases in positive mental health and mental health-related quality of life (QoL) in both interventions over the course of the nine-month follow-up. Interestingly, patients reported less psychological distress in the follow-up period after eMBCT in comparison to MBCT. Less psychological distress, rumination and neuroticism, and more extraversion and agreeableness at baseline predicted less psychological distress at the nine-month follow-up after both interventions. Less mindful and conscientious patients at baseline benefited more from eMBCT than from MBCT. Regarding working mechanisms, changes in mindfulness skills, fear of cancer recurrence and rumination during both interventions predicted less psychological distress at follow-up. CONCLUSIONS: Our findings suggest most improvements in cancer patients' increase over time after both interventions. Furthermore, patients seemed to benefit more from eMBCT than MBCT based on psychological distress levels, especially those patients with low levels of mindfulness skills and conscientiousness.

[Joining forces for quality improvement in tuberculosis control]. / Krachten bundelen voor betere tuberculosebestrijding.

The incidence of tuberculosis (TB) in the Netherlands is declining every year. We fear there may be a loss of knowledge and awareness of detecting TB in the new generation of medical specialists. As medical specialists a great challenge lies before us in maintaining the quality of TB control in the Netherlands. Collaboration between pulmonologist, infectious disease specialist, microbiologist and the public health services is a necessity. Here we describe how, in the region of Arnhem, we work closely with these medical specialists based on structural multidisciplinary meetings. We also describe two of the quality indicators - doctor's delay and HIV testing policy - which are included in the national plan for TB control for 2016-2020. We explain how we intend to maintain and improve the quality of TB control by means of our structural meetings and collaboration.

[Acute respiratory failure caused by minocycline]. / Acuut respiratoir falen door minocycline.

BACKGROUND: In the case of pneumonia an infectious cause is always considered first. However, toxic agents and medicines can also be the cause of pneumonia. CASE DESCRIPTION: A 54-year-old woman was referred to the emergency department because of progressive dyspnoea, a non-productive cough, headache, and fever. She was admitted with the diagnosis community acquired pneumonia. Despite treatment with antibiotics and oxygen she developed hypoxic respiratory failure, which necessitated invasive mechanical ventilation. Imaging diagnostics showed extensive bilateral pulmonary consolidation, despite the absence of a causative agent in cultures. Further medical history-taking revealed that the patient had recently commenced a course of minocycline. She had used this medicine previously and had twice before developed pneumonia without the presence of a proven causative agent. Our differential diagnosis included the toxic effect of minocycline and we treated the patient with methylprednisolone. This resulted in rapid clinical improvement and full recovery of our patient. CONCLUSION: Acute respiratory failure as a side effect of medication is rare, but nonetheless potentially life-threatening. Despite repeated exposure to minocycline, the link with pneumonia was not previously made in this patient.

Factors Promoting Mental Health of Adolescents Who Have a Parent with Mental Illness: A Longitudinal Study.

BACKGROUND: Children of parents with mental illness have an elevated risk of developing a range of mental health and psychosocial problems. Yet many of these children remain mentally healthy. OBJECTIVE: The present study aimed to get insight into factors that protect these children from developing internalizing and externalizing problems. METHODS: Several possible individual, parent-child, and family protective factors were examined cross-sectionally and longitudinally in a sample of 112 adolescents. A control group of 122 adolescents whose parents have no mental illness was included to explore whether the protective factors were different between adolescents with and without a parent with mental illness. RESULTS: Cross-sectional analyses revealed that high self-esteem and low use of passive coping strategies were related to fewer internalizing and externalizing problems. Greater self-disclosure was related to fewer internalizing problems and more parental monitoring was related to fewer externalizing problems. Active coping strategies, parental support, and family factors such as cohesion were unrelated to adolescent problem behavior. Longitudinal analyses showed that active coping, parental monitoring, and self-disclosure were protective against developing internalizing problems 2 years later. We found no protective factors for externalizing problems. Moderation analyses showed that the relationships between possible protective factors and adolescent problem behavior were not different for adolescents with and without a parent with mental illness. CONCLUSIONS: The findings suggest that adolescents' active coping strategies and parent-child communication may be promising factors to focus on in interventions aimed at preventing the development of internalizing problems by adolescents who have a parent with mental illness.

Non-suicidal self-injury among Dutch and Belgian adolescents: Personality, stress and coping.

BACKGROUND: This study examines: (1) the prevalence of Non-Suicidal Self-Injury (NSSI) among Dutch and Belgian adolescents, (2) the associations between Big Five personality traits and NSSI engagement/versatility (i.e., number of NSSI methods), and (3) whether these associations are mediated by perceived stress and coping. METHODS: A total of 946 Flemish (46%) and Dutch (54%) non-institutionalized adolescents (Mean age=15.52; SD=1.34, 44% females) were surveyed. Measures included the NSSI subscale of the Self-Harm-Inventory, the Dutch Quick Big Five Personality questionnaire, the Perceived Stress Scale and the Utrecht Coping List for Adolescents. Examination of zero-order correlations was used to reveal associations, and hierarchical regression analysis was used to reveal potential mediators which were further examined within parallel mediation models by using a bootstrapping-corrected procedure. RESULTS: Lifetime prevalence of NSSI was 24.31%. Neuroticism; perceived stress; and distractive, avoidant, depressive, and emotional coping were positively associated with NSSI engagement, whereas Agreeableness, Conscientiousness; and active, social, and optimistic coping were negatively associated with NSSI engagement. Observed relationships between personality traits and NSSI engagement were consistently explained by perceived stress and depressive coping. A higher versatility of NSSI was not associated with any Big Five personality trait, but was associated with higher scores on perceived stress and depressive coping and with lower scores on active and optimistic coping. CONCLUSION: Our study suggests that a specific personality constellation is associated with NSSI engagement via high stress levels and a typical depressive reaction pattern to handle stressful life events.

Simultaneous measurement of rotational and translational diffusion of anisotropic colloids with a new integrated setup for fluorescence recovery after photobleaching.

This paper describes an integrated setup for fluorescence recovery after photobleaching (FRAP) for determining translational and rotational Brownian diffusion simultaneously, ensuring that these two quantities are measured under exactly the same conditions and at the same time in dynamic experiments. The setup is based on translational-FRAP with a fringe pattern of light for both the bleaching and monitoring of fluorescently labeled particles, and rotational-FRAP, which uses the polarization of a short bleach light pulse to create a polarization anisotropy. The fringe pattern of the probe beam is modulated in conjunction with a synchronized lock-in amplifier giving a fast, sensitive, ensemble-averaged measurement compared to microscope-image based techniques. The experimental polarization geometry we used ensures that the fluorescence emission is collected without polarization bias. Therefore, only the orientation of the absorption dipole moment of the fixed dye in the particles is measured, which simplifies interpretation of the data. The polarization is modulated rapidly between two orthogonal polarization states, giving the polarization anisotropy in one, single measurement. The rotational and translational Brownian diffusion of anisotropic colloids is measured for ellipsoids of revolution. This experiment shows that in this case the rotational correlation function matches a three-exponential decay in accordance with theoretical predictions.

A role for the DRD4 exon III VNTR in modifying the association between nicotine dependence and neuroticism.

INTRODUCTION: Neurotic psychopathology has been extensively examined as a risk factor for nicotine dependence (ND). Genetic stratification may partially explain variability in risk estimates. Genetic variants that compromise dopaminergic neurotransmission may motivate exposure to dopamine-stimulating agents, including nicotine. The 7-repeat allele of a Variable Number Tandem Repeat (VNTR) polymorphism in DRD4 (and evolutionary derivatives 5, 6, and 8 repeats; 7R+) is associated with reduced dopamine receptor function. The purpose of this study was to examine association between both smoking initiation (SI) and progression to ND by young adulthood and (a) history of neuroticism during adolescence, (b) DRD4 7R+, and (c) interaction between neuroticism and DRD4 7R+. METHODS: Participants were drawn from the Victorian Adolescent Health Cohort Study, a longitudinal study of the health and well-being of young Australians across 8 waves (14-24 years). Neuroticism was measured at Waves 3 and 6 (mean 15.9 and 17.4 years). SI was defined as any smoking at any wave. ND was measured at Wave 8 (mean 24.1 years). Genotype data for the DRD4 VNTR were available for 839 participants. RESULTS: While adolescent neuroticism was associated with SI, evidence for association with progression to ND was weak. However, there was evidence of interaction between neuroticism and DRD4 7R+: The odds of progression to ND among those with a history of neuroticism were more than 3.5-fold higher among 7R+ carriers. CONCLUSIONS: Without considering stratification by 7R+, the association between progression to ND and neuroticism would have been assumed barely significant. However, among those carrying DRD4 7R+, risk of progression was considerably intensified.

Patterns of adolescent smoking and later nicotine dependence in young adults: a 10-year prospective study.

OBJECTIVES: There is considerable variability in progression from smoking initiation to established smoking. This paper addresses the extent to which different patterns of adolescent smoking, including periods of cessation, predict smoking status in young adults. STUDY DESIGN: Ten-year, eight-wave prospective cohort study of a state-wide community sample in Victoria, Australia. METHODS: Participants were 1520 students from 44 secondary schools, initially aged 14 to 15 years. Adolescent smoking and quitting patterns were assessed during Waves 1-6 with self-reported frequency of use and a 7-day retrospective diary. The Fagerstrom Test for Nicotine Dependence (ND) was used to assess ND at the age of 24 years (Wave 8). RESULTS: The prevalence of ND in young adults was 16.9% for all adolescent smokers, with prevalence rates of 6.8% and 26.7% for adolescent non-daily and daily adolescent smokers, respectively. Maximum smoking levels, onset of daily smoking, duration of smoking, escalation time and duration of cessation during adolescence predicted later ND. Daily smokers who ceased smoking for at least two waves (> or = 12 months) had a level of risk similar to adolescents who had never smoked. CONCLUSIONS: Quitting smoking as an adolescent substantially alters the risk for later ND. For adolescents who become daily smokers, quitting for 12 months should be the aim in tobacco control and clinical interventions.

Depressive mood and smoking onset: A comparison of adolescents with and without asthma.

This prospective population-based study aimed to compare associations between depressive feelings and smoking behaviour of adolescents with and without asthma. Data were collected from a two-wave 22-24 months prospective study among 5938 adolescents who completed self-report questionnaires. Logistic regression analyses showed that depressive feelings and smoking were related both cross-sectionally and longitudinally. Smoking behaviour was similar for adolescents with and without asthma, as well as its correlation with depressive feelings. However, participants with asthma were more likely to report depressive feelings than those without asthma, implying an indirect relationship between asthma and smoking behaviour. Implications for prevention are addressed.

Rats' preferences for corn versus wood-based bedding and nesting materials.

Corn by-products can be used as bedding and nesting products. Corn-cob bedding resists ammonia build-up and corn-husk nesting material resists dampness. It is not clear whether these advantages are at the expense of animal comfort. Corn cob was compared to aspen chip bedding, and corn husk to paper strip nesting material. Data from 20 rats with differential early bedding experience suggested that they prefer aspen chip, but are also biased towards the bedding they were raised on. Data from 10 rats with no prior nesting material experience suggested that paper strip was preferred over cornhusk. Thus, corn-cob products are not recommended except in situations where air quality and/or flooding are significant problems.

Ventilatory and cerebrovascular responses in normocapnic and hypercapnic COPD patients.

This study investigated the hypothesis that hypercapnia in some chronic obstructive pulmonary disease (COPD) patients may be related to a high cerebrovascular response to carbon dioxide (CO2). The relationship between responses of ventilation and of cerebral blood volume (CBV) to acute changes in carbon dioxide tension in arterial blood (Pa,CO2) was measured in 17 chronic hypercapnic (Pa,CO2 >6.0 kPa) and 16 normocapnic (Pa,CO2 < or = 6.0 kPa) COPD patients, who were matched for degree of airway obstruction (forced expiratory volume in one second 27% predicted). Results were compared with 15 age-matched healthy subjects. CBV was measured using near infrared spectroscopy during normo- and hypercapnia and related to inspired minute ventilation (V'I) and mouth occlusion pressure (P0.1). Hypercapnia (end-tidal pressure of carbon dioxide (deltaPET,CO2) > 1 kPa) was induced by giving adequate amounts of CO2 in the inspired air. During normocapnia, CBV (mL x 100 g(-1)) was 2.41+/- 0.66 and 2.90 +/- 0.60 (mean +/- SD) in the normocapnic and chronic hypercapnic patients, respectively, which was significantly lower compared to healthy subjects (3.53 +/- 0.77). All slopes of CO2 responsiveness (deltaCBV/deltaPa,CO2, deltaV'I/deltaPa,CO2, deltaP0.1/deltaPa,CO2) were significantly lower in both COPD groups relative to healthy subjects, but were not significantly different between the COPD groups. A poor but positive correlation between ventilatory and cerebrovascular CO2 responsiveness (deltaCBV/deltaPa,CO2 and deltaV'I/deltaPa,CO2) was found in COPD patients and healthy subjects. The findings do not support the hypothesis of abnormal cerebrovascular responses to carbon dioxide in hypercapnic chronic obstructive pulmonary disease patients.

Can cerebral blood volume be measured reproducibly with an improved near infrared spectroscopy system?

In some circumstances, cerebral blood volume (CBV) can be used as a measure for cerebral blood flow. A new near infrared spectroscope was used for determining the reproducibility of CBV measurements assessed by the O2-method. Twenty-seven healthy subjects were investigated. An intrasubject coefficient of variation (CV) was calculated, based on four identical episodes of desaturation-resaturation (O2-method) procedures for CBV measurements. Two trials were performed, with (trial 1) and without (trial 2) disconnecting the equipment. A mean CV of 12.6% and 10.0% was found in trial 1 and 2, respectively. Cerebral blood volume values yield 3.60+/-0.82 mL 100 g(-1). Cerebral blood volume could be measured reproducible in adults using near infrared spectroscopy, if the arterial desaturation is limited to approximately 5% from baseline level.

Ventilatory response in metabolic acidosis and cerebral blood volume in humans.

The relationship between alterations in cerebral blood volume (CBV) and central chemosensitivity regulation was studied under neutral metabolic conditions and during metabolic acidosis. Fifteen healthy subjects (56+/-10 years) were investigated. To induce metabolic acidosis, ammonium chloride (NH(4)Cl) was given orally. CBV was measured using Near Infrared Spectroscopy during normo- and hypercapnia and related to inspired ventilation (V(i)). A mean acute metabolic acidosis of Delta pH - 0.04 was realized with a mean decreased arterialized capillary PCO(2) (P(c)CO(2)) of 0.20 kPa (1.5 mmHg) (both P<0.001). During normocapnia, CBV was 3.51+/-0.71 and 3.65+/-0.56 ml 100 g(-1) (mean+/-S.D.), measured under neutral metabolic conditions and during acute metabolic acidosis, respectively (ns). Corresponding values of V(i) were 7.6+/-1.4 and 10.0+/-2.4 l min(-1) (P<0.01), respectively. The slopes of the CO(2)-responsiveness (DeltaCBV/DeltaP(c)CO(2) and DeltaV(i)/DeltaP(c)CO(2)), were not significantly different during both metabolic conditions. A significant correlation between DeltaCBV/DeltaP(c)CO(2) and DeltaV(i)/DeltaP(c)CO(2) was found during metabolic acidosis (P<0.01), but not under neutral metabolic conditions. CBV does not contribute in a predictable way to the regulation of central chemoreceptors.

Radiolabelled interleukin-1 receptor antagonist for detection of synovitis in patients with rheumatoid arthritis.

OBJECTIVES: To investigate the distribution of radiolabelled interleukin-1 receptor antagonist (IL-1ra) in patients with rheumatoid arthritis (RA) and to assess whether this cytokine is suitable for scintigraphic visualization of synovitis. METHODS: In patients with active RA, scintigraphy was performed after a single i. v. dose of [(123)I]IL-1ra. Clearance and organ distribution of radiolabelled IL-1ra were studied. To assess whether radiolabelled IL-1ra targets the synovial IL-1 receptors, the scintigraphic images obtained with IL-1ra were compared with those obtained by the use of a non-specific control agent. In addition, autoradiography was performed in mice with antigen-induced arthritis that were injected with either radiolabelled IL-1ra or a size-matched, non-receptor-binding protein. RESULTS: Radiolabelled IL-1ra allowed clear visualization of inflamed joints. Specificity in the detection of synovitis was high, whereas a number of painful and swollen joints were not visualized by scintigraphy. The procedure was well tolerated and [(123)I]IL-1ra was rapidly cleared from the circulation (t(1/2)alpha 11 min, t(1/2)beta 612 min) and excreted mainly in the urine. The definition of synovial contours by IL-1ra scintigraphy was not better than that observed with a non-specific agent. Although radiolabelled IL-1ra retained its affinity for IL-1 receptors, no binding to synovium was observed by autoradiography. CONCLUSIONS: Radiolabelled IL-1ra allows the visualization of synovitis in patients with RA. However, neither the imaging nor the autoradiographic studies indicate that joint accumulation of radiolabelled IL-1ra is due to specific IL-1 receptor targeting. IL-1ra has proved its therapeutic value in RA, but with the dose schedule in this study it does not behave as a specific radiopharmaceutical that is suitable for scintigraphic detection of inflammation.