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.

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.

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.

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.

Domains of the TCR beta-chain required for early thymocyte development.

The T cell receptor beta (TCR beta) chain controls the developmental transition from CD4-CD8- to CD4+8+thymocytes. We show that the extracellular constant region and the transmembrane region, but not the variable domain or cytoplasmic tail of the TCR beta chain are required for this differentiation step. TCR beta mutant chains lacking the cytoplasmic tail can be found at the cell surface both in functional TCR/CD3 complexes and in a GPI-anchored monomeric form indicating that the cytoplasmic tail of the TCR beta chain functions as an ER retention signal. The concordance between cell surface expression of the mutant chains as TCR/CD3 complexes and their capacity to mediate thymocyte differentiation supports the CD3 mediated feedback model in which preTCR/CD3 complexes control the developmental transition from CD4-CD8- to CD4+CD8+thymocytes.

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.

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.

Preferential localization of systemically administered radiolabeled interleukin 1alpha in experimental inflammation in mice by binding to the type II receptor.

Previously, we have shown that systemically administered radiolabeled interleukin 1alpha (IL-1alpha) accumulates preferentially in inflammatory foci in mice. Since inflammation is characterized by influx of leukocytes, which represent IL-1 receptor (IL-1R) positive cells, radiolabeled IL-1 may specifically localize in inflammation by binding to its receptors on infiltrated leukocytes. This hypothesis was tested in a series of studies in mice with acute focal inflammations. Evidence for specific IL-1-IL-1R interaction in induced inflammation was found: microscopic autoradiography revealed that 125I-IL-1alpha localized at the site of inflammatory cells with time; 125I-myoglobin, a similar-sized protein with no known interactions in vivo, was not retained in the inflammation. Furthermore, the uptake 125I-IL-1alpha in inflammatory tissue was significantly lower in neutropenic mice than in immunocompetent mice (0.05+/-0.004 vs. 0.65+/-0.06% ID/g at 48 h after injection, P < 0.0007). Moreover, the uptake of 125I-IL-1alpha at the inflammatory site could be blocked with the anti-IL-1R type II antibody 4E2. At 48 h after injection, the uptake with and without blocking the type II IL-1R was 0.13+/-0.01 and 0. 65+/-0.05% ID/g, respectively (P < 0.0001). These in vivo studies provide evidence that systemically administered radiolabeled IL-1alpha localizes in inflammatory tissue by specific receptor binding, predominantly by binding to the type II IL-1R.

[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.

Chlorophyll a fluorescence lifetime distributions in open and closed photosystem II reaction center preparations.

We have measured the decay of chlorophyll a fluorescence at 4 degrees C under anaerobic conditions in stabilized photosystem II reaction center complex isolated from spinach, using multifrequency (2-400 MHz) cross-correlation phase fluorometry. Examination of our data shows that although the fluorescence decay of open reaction centers (i.e., when both the electron donor P-680 and the electron acceptor pheophytin are capable of engaging in charge separation) can be analyzed as a multiexponential decay, another representation of the data is obtained when the decay is analyzed using a continuous distribution of lifetimes. Our results on the open reaction center differ from the two lifetime components of 25 ps and 35 ns published by Mimuro et al. (Biochim. Biophys. Acta 933 (1988) 478-486) for the D1-D2-cytochrome b-559 complex, obtained for F682 at 4 degrees C by a time-resolved photon-counting spectrofluorometer. When the reaction centers are closed by pretreatment with sodium dithionite and methyl viologen followed by exposure to laser excitation, conditions known to result in accumulation of reduced pheophytin, a dramatic decrease in the contribution of the slow lifetime component(s) is observed. These results suggest that the slow distribution lifetime component(s) in the 5-20 ns range originate(s) in the back reaction of the charge separated state. On the other hand, the fast lifetime component(s) in the picosecond range may be only partially related to the charge separation, since no dramatic change is observed upon closure of the reaction center. Perhaps, this component is related, in part, to the excitation energy migration among the various chromophores in the reaction center preparations.

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.

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.

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.

Effect of alcohol on postmeal fat storage.

Energy expenditure and macronutrient balances were assessed in normal healthy men by whole-body indirect calorimetry after meals consumed with and without ethanol to test the theory that alcohol energy is not fully available because of futile cycling. Alcohol addition (A) or isoenergetic substitution (S) caused fat retention by significantly suppressing its oxidation when the alcohol was actively metabolized (0-6h). However, on protocol S, fat balance was later reestablished due to raised fat oxidation (6-20.5 h) secondary to a relative carbohydrate deficiency. On protocol A, fat balance remained significantly raised. The thermogenic effect of alcohol was similar to that of carbohydrate, providing no evidence for futile cycling. Short-term studies that fail to account for later readjustments of macronutrient balance can be misleading. We conclude that alcohol has a fat-sparing effect similar to that of carbohydrate and will only cause fat gain when consumed in excess of normal energy needs.

Involvement of endogenous interleukin-10 and tumor necrosis factor-alpha in renal ischemia-reperfusion injury.

BACKGROUND: Ischemia followed by reperfusion is a common clinical event associated with a pro-inflammatory response leading to organ dysfunction. The aim of the present study is to evaluate the interplay between this pro-inflammatory response and apoptosis. We investigated the role of the pro-inflammatory mediator tumor necrosis factor-alpha (TNF-alpha) and the anti-inflammatory mediator interleukin-10 (IL-10) in inflammation and apoptosis after renal ischemia reperfusion. METHODS: Male Swiss mice were subjected to 45 min of ischemia followed by reperfusion and subsequently administered neutralizing Abs against either TNF-alpha (TN3), IL-10 (JES5-2A5) or control. RESULTS: After 1 day of reperfusion, anti-TNF-alpha treatment reduced whereas anti-IL-10 treatment exacerbated postischemic renal injury, inflammation, and, to a lesser extent, apoptosis as measured by changes in blood urea nitrogen content, immunohistologically detectable renal TNF-alpha protein and neutrophils, histological integrity of renal parenchyma, and DNA ladder formation. Furthermore, anti-IL-10 treatment enhanced major histocompatibility complex class I and II expression at day 7 as measured by enzyme immunoassay and immunohistology. CONCLUSIONS: These data indicate that the extent of reperfusion-induced apoptosis is modulated by the inflammatory response, during which locally produced TNF-alpha plays a significant role in the development of tissue injury. Subsequently, this pro-inflammatory reaction is followed by endogenous production of the anti-inflammatory cytokine IL-10, which serves as a physiological counterbalance to the effects of TNF-alpha. These novel pathophysiological insights may provide new basis for the development of tools for limiting ischemia and reperfusion injury.

Dosimetry and risk estimates of radioiodine therapy for large, multinodular goiters.

UNLABELLED: In patients with a large, multinodular goiter (> 100 g), radiation absorbed doses in the thyroid, surrounding tissues and remainder of the body were estimated after therapeutic administration of 131I(3.7 MBq or 100 microCi/g of thyroid tissue retained at 24 hr). METHODS: Thermoluminescent dosimeter (TLD) measurements were performed on 23 patients (12 euthyroid and 1I hyperthyroid; thyroid weight 222 +/- 72 g; 2.1 +/- 0.9 GBq 131I) on the skin over the thyroid, over the submandibular gland and over the parotid gland. Thyroid radioactivity measurements were done daily in 6 euthyroid and 6 hyperthyroid patients (thyroid weight 204 +/- 69 g; 1.9 +/- 0.9 GBq 131I). An iodine biokinetic model and the MIRD methodology were used to estimate absorbed doses in organs. Cancer risks were calculated using ICRP Publication 60. RESULTS: Cumulated absorbed doses on the skin (TLD measurements) were 4.2 +/- 1.4 Gy (thyroid), 1.2 +/- 0.6 Gy (submandibular) and 0.4 +/- 0.2 Gy (parotid). All these values were significantly correlated with the amount of radioiodine retained in the thyroid at 24 hr (euthyroid versus hyperthyroid not significant). Absorbed doses in the thyroid of 94 +/- 25 Gy for euthyroid and 93 +/- 17 Gy for hyperthyroid patients were calculated (thyroid radioactivity measurements). Extrathyroidal absorbed doses (means of 12 patients) were 0.88 Gy in the urinary bladder, 0.57 Gy in the small intestine, 0.38 Gy in the stomach, and ranged from 0.05 to 0.30 Gy in other organs (euthyroid versus hyperthyroid not significant). A 1.6% life-time risk of development of cancer outside the thyroid gland was calculated. When applied to people of 65 yr and older the estimated risk is approximately 0.5%. CONCLUSION: These data may help in choosing the treatment regimen for individual patients with a large, multinodular goiter, who have to be treated for hyperthyroidism or compressive problems. In younger patients, surgery may be preferred. However, for elderly patients and patients with cardiopulmonary disease, the advantages of noninvasive radioiodine treatment will outweight the life-time risk of this mode of therapy.