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Introduction: Hypertension is a major cause of premature death worldwide as it is an important risk factor for coronary artery disease, myocardial infarction, heart failure and stroke. Although an estimated 1.3 billion adults suffer from hypertension, less than half of them are diagnosed correctly and therefore receive sufficient treatment. Furthermore, only one fifth of those treated reach the therapy target of normotension. This significant deficit underlines the need for new therapy concepts to improve long-term health outcomes. Several studies have shown positive effects of digital health programmes in the disease management of ambulatory, long-term hypertension treatment. More research is needed to explore the abilities of digital health programmes as an innovative pathway in ambulatory healthcare.The eXPLORE study aims to evaluate the feasibility of a clinical trial on the impact of a supplementary digital therapy programme for the treatment of primary arterial hypertension., Methods and Analyses: The eXPLORE study collects data in the setting of a prospective randomised controlled trial to evaluate methodological feasibility for larger-scaled follow-up research. The study compares a digital therapy programme using a smartphone application that is based on functions and algorithms creating tasks and recommendations based on individual health data to standard care for the treatment of primary arterial hypertension. The study period is 180 days, with a 90-day in-life phase followed by a 90-day follow-up phase. Baseline and follow-up data (3 months, 6 months follow-up) of all participants included is collected via questionnaire surveys as well as self-administered blood pressure monitoring. Patient inclusion, initial data acquisition and follow-up were carried out in an innovative remote setting. The study was initiated in November 2022 and is currently ongoing. Study outcome measures are changes in mean blood pressure, health literacy and self-sufficient health behaviour., Ethics and Dissemination: The eXPLORE study is carried out in accordance with all applicable legal regulations. Cost-effectiveness is assured by continuous evaluation and documentation over the course of the study. All health-relevant data from the eXPLORE study will be provided for analyses and publication to the investigators of LMU Hospital. The study was approved by the local ethics committee of LMU Munich (project nr.: 22-0115)., Trial Registration: NCT05580068., Protocol Version: 1.5, 28.08.2023., Competing Interests: Competing interests: PW is an employee of iATROS., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Degenerative lesions specific to the basal nuclei have not been described as a background finding in Beagle dogs. This report comprises a documentation of seven cases. In the context of a nonclinical safety studies, the authors suggest documenting the lesion descriptively as degeneration neuropil, basal nuclei, bilateral as it is characterized by (1) vacuolation, neuropil; (2) gliosis (astro- and/or microgliosis); and (3) demyelination. This novel lesion is considered a potential new background change for several reasons: (1) It occurred in animals from test item-treated and also vehicle-treated groups; (2) no dose dependency was observed; (3) in one of six affected test item-treated dogs, the given compound was shown not to penetrate the blood-brain barrier; and (4) statistical comparison between the proportions of affected dogs in the treatment and control groups did not yield a statistically significant difference. The etiology remains unknown and is subject to further investigations., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Acute altitude has a relevant impact on exercise physiology and performance. Therefore, the positive impact on the performance level is utilized as a training strategy in professional as well as recreational athletes. However, ventilatory thresholds (VTs) and lactate thresholds (LTs), as established performance measures, cannot be easily assessed at high altitudes. Therefore, a noninvasive, reliable, and cost-effective method is needed to facilitate and monitor training management at high altitudes. High Alt Med Biol . 25:94-99, 2024. Methods: In a cross-sectional setting, a total of 14 healthy recreational athletes performed a graded cycling exercise test at sea level (Munich, Germany: 512 m/949 mbar) and high altitude (Zugspitze: 2,650 m/715 mbar). Anaerobic thresholds (ATs) were assessed using a novel method based on beat-to-beat repolarization instability (dT) detected by Frank-lead electrocardiogram (ECG) monitoring. The ECG-based ATs (ATdT°) were compared to routine LTs assessed according to Dickhuth and Mader. Results: After acute altitude exposure, a decrease in AT was detected using a novel ECG-based method (ATdT°: 159.80 ± 52.21 W vs. 134.66 ± 34.91 W). AtdT° levels correlated significantly with LT Dickhuth and LT Mader , at baseline (r Dickhuth/AtdT°  = 0.979; p  < 0.001) (r Mader/AtdT°  = 0.943; p  < 0.001), and at high altitude (r Dickhuth/AtdT°  = 0.969; p  < 0.001) (r Mader/AtdT°  = 0.942; p  < 0.001). Conclusion: Assessment of ATdT is a reliable method to detect performance alterations at altitude. This novel method may facilitate the training management of athletes at high altitudes.

Background: Sports-related concussion is a relevant risk of contact sports, with several million cases per year worldwide. Prompt identification is crucial to prevent complications and late effects but may be impeded by an overlap with dehydration-associated impairment of cognitive function. Researchers have extensively studied the effects of pronounced dehydration in endurance sports, especially in the heat. However, little is known about the effects of isolated and mild dehydration., Methods: Healthy recreational athletes underwent a standardized fluid deprivation test. Hypohydration was assessed by bioelectrical impedance analysis (BIA) and laboratory testing of electrolytes and retention parameters. Participants underwent cardiopulmonary exercise testing (CPET) with a cycle ramp protocol. Each participant served as their own control undergoing CPET in a hypohydrated [HYH] and a euhydrated [EUH] state. Effects were assessed using a shortened version of Sport Concussion Assessment Tool 3 (SCAT3)., Results: Fluid deprivation caused a mild (2%) reduction in body water, resulting in a calculated body mass loss of 0.8% without alterations of electrolytes, serum-osmolality, or hematocrit. Athletes reported significantly more (1.8 ± 2.2 vs. 0.4 ± 0.7; p < 0.01) and more severe (4.4 ± 6.2 vs. 1.0 ± 1.9; p < 0.01) concussion-like symptoms in a hypohydrated state. Balance was worse in HYH by trend with a significant difference for tandem stance (1.1 ± 1.3 vs. 0.6 ± 1.1; p = 0.02). No relevant differences were presented for items of memory and concentration., Conclusions: Mild dehydration caused relevant alterations of concussion-like symptoms and balance in healthy recreational athletes in the absence of endurance exercise or heat. Further research is needed to clarify the real-life relevance of these findings and to strengthen the differential diagnosis of concussion.

Background: Heat induces a thermoregulatory strain that impairs cardiopulmonary exercise capacity. The aim of the current study is to elucidate the effect of isolated dehydration on cardiopulmonary exercise capacity in a model of preparticipating hypohydration., Methods: Healthy recreational athletes underwent a standardised fluid deprivation test. Hypohydration was assessed by bioelectrical impedance analysis (BIA) and laboratory testing of electrolytes and retention parameters in the blood and urine. The participants underwent cardiopulmonary exercise testing (CPET) with a cycle ramp protocol. Each participant served as their own control undergoing CPET in a hypohydrated [HYH] and euhydrated [EUH] state., Results: Fluid deprivation caused a mild (2%) but significant reduction of body water (38.6 [36.6; 40.7] vs. 39.4 [37.4; 41.5] %; p < 0.01) and an increase of urine osmolality (767 [694; 839] vs. 537 [445; 629] mosm/kg; p < 0.01). Hypohydration was without alterations of electrolytes, serum osmolality or hematocrit. The oxygen uptake was significantly lower after hypohydration (-4.8%; p = 0.02 at ventilatory threshold1; -2.0%; p < 0.01 at maximum power), with a corresponding decrease of minute ventilation (-4% at ventilatory threshold1; p = 0.01, -3.3% at maximum power; p < 0.01). The power output was lower in hypohydration (-6.8%; p < 0.01 at ventilatory threshold1; -2.2%; p = 0.01 at maximum power)., Conclusion: Isolated hypohydration causes impairment of workload as well as peak oxygen uptake in recreational athletes. Our findings might indicate an important role of hypohydration in the heat-induced reduction of exercise capacity.

Aims: Increased arterial stiffness, measured as arterial pulse wave velocity (PWV) is associated with an elevated cardiovascular risk. Although noninvasive PWV measurement methods have been validated by invasive measurement, there is little such data on pediatric patients. The purpose of this study was to 'fill the gap' by validating PWV obtained by Mobil-O-Graph in children, adolescents in comparison to young adults., Methods: Sixty patients (25 male, mean age 16.6 years; range 3-35 years) were included in this study. Fifty-one patients underwent cardiac catheterization after a heart transplantation (HTX) and nine for interventional atrial septal defect-closure. Specific invasive pulse wave velocities were assessed for the ascending aorta (aPWV) and entire central aorta (cPWV). These invasive PWV results were compared to simultaneously measured brachial cuff readings using Mobil-O-Graph (oPWV) stratified by age in two groups (PEDIATRICS <18 years|ADULTS ≥18 years)., Results: Correlation analysis showed a positive linear relation between both invasive PWV measurements and the oPWV in all ages (cPWV/oPWV: r  = 0.417, aPWV/oPWV: r  = 0.628; P  < 0.001). The oPWV data agreed better with the aPWV in mean-value comparisons and correlations with mean difference in PEDIATRICS was 0.41 ± 0.41 m/s (95% confidence interval 0.27-0.55). We also found the cPWV to be faster than the aPWV particularly in adults. In addition, cPWV correlated closer with age ( r  = 0.393, P  < 0.05)., Conclusion: Estimated oPWV using the Mobil-O-Graph demonstrated excellent accuracy in adults and pediatric patients. Therefore, the Mobil-O-Graph can be implemented as an ambulatory PWV measuring tool for pediatric cardiovascular risk stratification., Clinical Trial Registration: German clinical trial registration, DRKS00015066., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The COVID-19 pandemic and the implemented lockdown strongly impact on everyone's daily life. Stressful situations are known to alter eating habits and increase the risk for obesity. In our study, we aimed to investigate the effect of the lockdown measures on nutrition behavior among young adults., Methods: In this cross-sectional study, we enrolled 1964 voluntary participants from Bavarian universities. All participants were asked to complete an online questionnaire, semi-quantitatively evaluating the amount and type of food before and during pandemic lockdown. Study subjects were inquired to give information about acquisition and food procurement. The primary outcome was the change in food amount, secondary outcomes included alterations of food composition and procurement., Results: Our study cohort (mean age 23.3 ± 4.0 years, 28.5% male) had a mean body mass index of 22.1 ± 4.5 kg/m 2 . The overall food amount increased in 31.2% of participants (n = 610) during lockdown and decreased in 16.8% (n = 328). A multinominal regression model revealed that an increased food intake was less likely in male participants (OR, 0.7 [CI 0.6-0.9]) and more likely with increasing BMI (OR, 1.4 [CI 1.3-2.0]), increased sports activity (OR, 1.3 [CI 1.2-1.8]), augmented mental stress (OR 1.4 [1.1-1.7]), and an alteration of alcohol consumption (reduced alcohol amount, OR, 1.4 [CI 1.1-1.7], increased alcohol, OR, 1.9 [CI 1.4-2.5]). Increase in food intake was mainly triggered by consumption of bread (increased in 46.8%, n = 284) and confectionary (increased in 64.4%, n = 389)., Conclusion: The COVID-19 pandemic lockdown significantly affected eating habits in young adults. Further investigation to evaluate long-term effects on weight change and comorbidities are warranted., (© 2020. The Author(s).)

Background: Since the onset of the COVID-19 pandemic in December 2019, many countries around the world have imposed lockdown measures in order to reduce virus spread. Social isolation is known to have a significant psychological impact, potentially triggering alcohol misuse in adults. In our study, we aimed to investigate the effect of COVID-19 lockdown measures on alcohol consumption in adults in Bavaria., Methods: In this cross-sectional study, we enrolled 2067 participants, with 1961 young adults (mean age 23.3 ± 4.1) and 106 mature adults (mean age 66.7 ± 9.7). Participants were asked to complete a standardized questionnaire, semi-quantitatively evaluating the alcohol drinking behaviour before and during the pandemic lockdown., Results: After implementation of lockdown, the alteration of alcohol consumption was significantly different between young and mature adults (p <  0.001). Among young adults, 42% reported unchanged drinking behaviour compared to 76% in the mature adult group; 44% of young adults reported to drink less compared to only 7% of mature adults. An increase in alcohol consumption was only reported by 14% of young adults and 17% of mature adults. Interestingly, in the entire cohort, the change of alcohol intake was most pronounced among moderate drinkers (> 0 to < 5 drinks/week) in both age groups (p <  0.001). Ordinal logistic regression revealed female sex, low BMI and younger age to be associated with a decrease in number of self-reported drinks/week., Conclusion: The COVID-19 pandemic lockdown significantly affected alcohol drinking behaviour. Further studies exploring long-term effects on potential alcohol misuse and the relevance on public health are warranted., Trial Registration: The study was retrospectively registered at ClinicalTrials.gov ( NCT04361877 ) on April 24, 2020.

Due to the rapid spread of the COVID-19 pandemic, a lockdown including limitation of activity and restrictions of non-essential travel was imposed on March 21, 2020 in the State of Bavaria, Germany. The implementation of activity restrictions not only strongly affects the economy but will possibly also impact the mental and physical health status of the general population. Therefore, the present study aimed to explore psychological effects of the COVID-19 crisis on a sample of Bavarian students.In this cross-sectional study, we enrolled 1943 voluntary subjects from Bavarian universities. All subjects completed an online questionnaire asking for mental health stress, as well as potential factors, influencing the state of mental stress during pandemic lockdown. In our study cohort, 17.3% (n=336) of the students indicated that they experienced less mental stress through COVID-19 pandemic, while 39.6% (n=770) stated that they had an increased psychological burden. The bivariate analysis identified sex and the level of physical activity as potential risk factors for the level of mental stress during the COVID-19 pandemic. Further research is necessary to investigate specific symptoms of mental stress and the overall long-term impact on mental health., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Blood-brain barrier dysfunction in epilepsy contributes to seizures and resistance to antiseizure drugs. Reports show that seizures increase brain glutamate levels, leading to barrier dysfunction. One component of barrier dysfunction is overexpression of the drug efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Based on our previous studies, we hypothesized that glutamate released during seizures activates cytosolic phospholipase A2 (cPLA2), resulting in P-gp and BCRP overexpression. We exposed isolated rat brain capillaries to glutamate ex vivo and used an in vivo - ex vivo approach of isolating brain capillaries from rats after status epilepticus (SE) and in chronic epileptic (CE) rats. Glutamate increased cPLA2, P-gp, and BCRP protein and activity levels in isolated brain capillaries. We confirmed the role of cPLA2 in the signaling pathway in brain capillaries from male and female mice lacking cPLA2. We also demonstrated, in vivo , that cPLA2 inhibition prevents overexpression of P-gp and BCRP at the blood-brain barrier in rats after status epilepticus and in CE rats. Our data support the hypothesis that glutamate signals cPLA2 activation, resulting in overexpression of blood-brain barrier P-gp and BCRP.-Hartz, A. M. S., Rempe, R. G., Soldner, E. L. B., Pekcec, A., Schlichtiger, J., Kryscio, R., Bauer, B. Cytosolic phospholipase A2 is a key regulator of blood-brain barrier function in epilepsy.

The blood-brain barrier is dysfunctional in epilepsy, thereby contributing to seizure genesis and resistance to antiseizure drugs. Previously, several groups reported that seizures increase brain glutamate levels, which leads to barrier dysfunction. One critical component of barrier dysfunction is brain capillary leakage. Based on our preliminary data, we hypothesized that glutamate released during seizures mediates an increase in matrix-metalloproteinase (MMP) expression and activity levels, thereby contributing to barrier leakage. To test this hypothesis, we exposed isolated brain capillaries from male Sprague Dawley rats to glutamate ex vivo and used an in vivo / ex vivo approach of isolated brain capillaries from female Wistar rats that experienced status epilepticus as an acute seizure model. We found that exposing isolated rat brain capillaries to glutamate increased MMP-2 and MMP-9 protein and activity levels, and decreased tight junction protein levels, which resulted in barrier leakage. We confirmed these findings in vivo in rats after status epilepticus and in brain capillaries from male mice lacking cytosolic phospholipase A 2 Together, our data support the hypothesis that glutamate released during seizures signals an increase in MMP-2 and MMP-9 protein expression and activity levels, resulting in blood-brain barrier leakage. SIGNIFICANCE STATEMENT The mechanism leading to seizure-mediated blood-brain barrier dysfunction in epilepsy is poorly understood. In the present study, we focused on defining this mechanism in the brain capillary endothelium. We demonstrate that seizures trigger a pathway that involves glutamate signaling through cytosolic phospholipase A 2 , which increases MMP levels and decreases tight junction protein expression levels, resulting in barrier leakage. These findings may provide potential therapeutic avenues within the blood-brain barrier to limit barrier dysfunction in epilepsy and decrease seizure burden., (Copyright © 2018 the authors 0270-6474/18/384301-15$15.00/0.)

Background: Although several studies show that JIA-patients have significantly lower employment rates than the general population, the research on educational and occupational attainments in patients with juvenile idiopathic arthritis (JIA) remain conflicting most likely due to small sample sizes. Therefore, aim of this study is to compare the educational achievements and employment status of 3698 JIA-patients with the German general population (GGP)., Methods: "SEPIA" was a large cross-sectional study on the current status of a historic cohort of JIA-patients treated in a single center between 1952 and 2010. For the analyses of education and employment a sub-cohort was extracted, including only adult cases with a confirmed diagnosis of JIA (N = 2696). Participants were asked to fill out a standardized written questionnaire on education and employment. Outcome measures (education/unemployment) were directly standardized to the GGP using data obtained from the National Educational Panel Study 2013 (N = 11,728) and the German Unemployment Statistics 2012 of the Federal Statistical Office (N = 42,791,000)., Results: After age- and sex-standardization, 3% (95% Confidence Interval 1.9 to 4.1%) more of the JIA-patients (26%) than of the GGP (23%) had only reached primary education. In contrast, parents of JIA-patients had similar levels of education as parents in the GGP. With a standardized difference of 0.2% (95% CI: 0.16 to 0.19%), the unemployment rate in JIA-patients was slightly, but not significantly higher than in the GGP. Stratifying for disease duration and the current treatment status, differences were confirmed for persons diagnosed before 2001, whilst for patients diagnosed after 2000, differences were found only in JIA-patients with ongoing disease. Medium and high educational achievements did not differ statistically significant between JIA patients and the GPP., Conclusion: Educational achievements in German JIA-patients are significantly lower than in the GGP. Furthermore we were able to identify a slightly higher level of unemployment, especially in those with still under treatment and longer disease duration. Better treatment options as well as further development of social support programs might help to overcome this lifelong secondary effect of JIA.

A cure for epilepsy is currently not available, and seizure genesis, seizure recurrence, and resistance to antiseizure drugs remain serious clinical problems. Studies show that the blood-brain barrier is altered in animal models of epilepsy and in epileptic patients. In this regard, seizures increase expression of blood-brain barrier efflux transporters such as P-glycoprotein (P-gp), which is thought to reduce brain uptake of antiseizure drugs, and thus, contribute to antiseizure drug resistance. The goal of the current study was to assess the viability of combining in vivo and ex vivo preparations of isolated brain capillaries from animal models of seizures and epilepsy as well as from patients with epilepsy to study P-gp at the blood-brain barrier. Exposing isolated rat brain capillaries to glutamate ex vivo upregulated P-gp expression to levels that were similar to those in capillaries isolated from rats that had status epilepticus or chronic epilepsy. Moreover, the fold-increase in P-gp protein expression seen in animal models is consistent with the fold-increase in P-gp observed in human brain capillaries isolated from patients with epilepsy compared to age-matched control individuals. Overall, the in vivo/ex vivo approach presented here allows detailed analysis of the mechanisms underlying seizure-induced changes of P-gp expression and transport activity at the blood-brain barrier. This approach can be extended to other blood-brain barrier proteins that might contribute to drug-resistant epilepsy or other CNS disorders as well.

Objectives: In recent years, concern has been raised about Juvenile Idiopathic Arthritis (JIA) that it could be associated with an increased risk for malignancies. Therefore, the cancer incidence in the JIA patients was evaluated and compared to the cancer incidence in the German population., Methods: A retrospective single-center hospital-based cohort study was performed using data on the JIA patients treated between 1952 and 2010 at the German Center for Pediatric and Adolescent Rheumatology (GCPAR) (Garmisch-Partenkirchen, Germany). Self-administered standardized questionnaires were sent out in 2012. Standardized incidence ratios (SIRs) and their corresponding 95% confidence intervals (95%CIs) were calculated., Results: The study cohort consisted of 3691 JIA patients, and the response rate was 66%. Patients age ranged from 3 to 73 years of which 64% were female. Total follow-up time was 60,075 person-years; a history of malignancy was reported by 47 patients. Most common types of cancer were melanoma (n = 11), cervical cancer (n = 8) and breast cancer (n = 7). The overall SIR for women was 1.19 (95%CI: 0.77; 1.60) and for men was 0.67 (95%CI: 0.27; 1.07). The SIR for melanoma was 3.21 (95%CI: 1.60; 5.73) in women, whereas in men no melanoma cases were observed., Conclusion: Although no overall increased cancer risk was found, results suggest that the risk of melanoma might be increased in female JIA patients.

Background: Radiation-induced nephropathy is still dose limiting in radionuclide therapy of neuroendocrine tumors. We investigated the nephroprotective potential of the angiotensine converting enzyme inhibiting drug enalpril after [177Lu]-DOTATATE therapy in a murine model of radiation-induced nephropathy by renal scintigraphy. At first, the appropriate therapy activity to induce nephropathy was identified. Baseline scintigraphy (n = 12) entailed 12-min dynamic acquisitions after injection of 25 MBq [99mTc]-MAG3, which was followed by radionuclide therapy at four escalating activities of [177Lu]-DOTATATE: group (Gp) 1: 10 MBq; Gp 2: 20 MBq; Gp 3: 40 MBq; Gp 4: 65 MBq. Follow-up [99mTc]-MAG3 scintigraphy was carried out at days 9, 23, 44, and 65. The treatment activity for the intervention arm was selected on the basis of histological examination and declining renal function. In the second part, daily administration by gavage of 10 mg/kg/d enalapril or water (control group) was initiated on the day of radionuclide therapy. Follow-up scintigraphy was carried out at days 9, 23, 44, 65, and 86. We also created a non-therapy control group to detect therapy-independent changes of renal function over time. For all scintigraphies, mean renogram curves were analyzed and the "fractional uptake rate" (FUR; %I.D./min ± SEM) of the tracer by the kidneys was calculated as an index of renal clearance., Results: At day 65 of follow-up, no significant change in the FUR relative to baseline (11.0 ± 0.3) was evident in radionuclide therapy groups 1 (11.2 ± 0.5) and 2 (10.1 ± 0.6), but FUR was significantly reduced in groups 3 (8.93 ± 0.6, p < 0.05) and 4 (6.0 ± 0.8, p < 0.01); we chose 40 MBq [177Lu]-DOTATATE (Gp 3) for the intervention study. Here, at the last day of follow-up (day 86), FUR was unaltered in enalapril-treated mice (11.8 ± 0.5) relative to the baseline group (12.4 ± 0.3) and non-therapy group (11.9 ± 0.8), whereas FUR in the control group had undergone a significant decline (9.3 ± 0.5; p < 0.01). Histological examination revealed prevention of kidney damage by enalapril treatment., Conclusions: Treatment with enalapril is effective for nephroprotection during radionuclide therapy with [177Lu]-DOTATATE in mice. Although these results are only limitedly transferable to human studies, enalapril might serve as a promising drug in the mitigation of nephropathy following treatment with [177Lu]-DOTATATE.

Objective: Aims of the study were to investigate health-related quality of life (HRQOL) in adult patients with former diagnosis of Juvenile Idiopathic Arthritis (JIA), to compare their HRQOL with the general population and to identify factors related to a poor outcome., Methods: In 2012, a cross-sectional survey was performed by mailing a questionnaire to a large cohort of former and current patients of the German Centre for Rheumatology in Children and Adolescents. Only adult patients (≥18 years) with a diagnosis compatible with JIA were included (n = 2592; response 66%). The questionnaire included information about HRQOL (EQ5D), disease-related questions and socio-demographics. Prevalence and 95% confidence intervals (CI) of problems with mobility, self-care, usual activities, pain and anxiety/depression were standardized to the German general population. Factors associated with low HRQOL in JIA patients were identified using logistic regression models., Results: Sixty-two percent of the study population was female; age range was 18-73 years. In all dimensions, JIA patients reported statistically significantly more problems than the general population with largest differences in the pain dimension (JIA patients 56%; 95%CI 55-58%; general population 28%; 26-29%) and the anxiety/depression dimension (28%; 27-29% vs. 4%; 4-5%). Lower HRQOL in JIA patients was associated with female sex, older age, lower level of education, still being under rheumatic treatment and disability., Conclusions: HRQOL in adult JIA patients is considerably lower than in the general population. As this cohort includes historic patients the new therapeutic schemes available today are expected to improve HRQOL in future.

Minipigs have been used for dermal drug development studies for decades, and they are currently more frequently considered as the second nonrodent species for pivotal nonclinical studies, in lieu of the dog or nonhuman primate, for compounds delivered via standard systemic routes of administration. Little is known about the tolerability of different excipients in minipigs; sharing knowledge of excipient tolerability and compositions previously used in nonclinical studies may avoid testing of inadequate formulations, thereby contributing to reduced animal usage. This article reviews vehicles employed in the Göttingen(®)minipig based on the combined experience from a number of pharmaceutical companies and contract research organizations. The review includes vehicles tolerated for single or multiple dosing by the Göttingen minipig, some of which are not appropriate for administration to other common nonrodent species (e.g., dogs). By presenting these data for dermal, oral, subcutaneous, and intravenous routes of administration, studies to qualify these vehicles in minipigs can be minimized or avoided. Additionally, investigators may more frequently consider using the minipig in place of higher species if the tolerability of a vehicle in the minipig is known., (© The Author(s) 2015.)

Background: Several medications for treatment of Juvenile Idiopathic Arthritis (JIA) are considered to be carcinogenic. Therefore, the aim was to assess whether there is an association between therapeutic interventions and malignancies in JIA patients., Findings: A nested case-control study was carried out within a retrospective cohort study of 3698 JIA patients diagnosed between 1952 and 2010. All 48 JIA patients with a diagnosis of a malignant tumour and up to four matched controls for each received a questionnaire about their use of medication. Subsequently treatment was compared between cases and controls and analyses performed for 37 cases and 125 controls (response 88.5 %). Treatment with DMARD (84 %) was most frequently used, followed by glucocorticoids (66 %) and immunosuppressives (65 %). Twenty percent reported to have ever been taking biologics. Medication use did not differ significantly between cases and controls., Conclusions: Our results did not show an association between medications used and malignancies in JIA patients.

Unilateral inner ear damage is followed by a rapid behavioural recovery due to central vestibular compensation. In this study, we utilized serial [(18)F]Fluoro-deoxyglucose ([(18)F]FDG)-µPET imaging in the rat to visualize changes in brain glucose metabolism during behavioural recovery after surgical and chemical unilateral labyrinthectomy, to determine the extent and time-course of the involvement of different brain regions in vestibular compensation and test previously described hypotheses of underlying mechanisms. Systematic patterns of relative changes of glucose metabolism (rCGM) were observed during vestibular compensation. A significant asymmetry of rCGM appeared in the vestibular nuclei, vestibulocerebellum, thalamus, multisensory vestibular cortex, hippocampus and amygdala in the acute phase of vestibular imbalance (4 h). This was followed by early vestibular compensation over 1-2 days where rCGM re-balanced between the vestibular nuclei, thalami and temporoparietal cortices and bilateral rCGM increase appeared in the hippocampus and amygdala. Subsequently over 2-7 days, rCGM increased in the ipsilesional spinal trigeminal nucleus and later (7-9 days) rCGM increased in the vestibulocerebellum bilaterally and the hypothalamus and persisted in the hippocampus. These systematic dynamic rCGM patterns during vestibular compensation, were confirmed in a second rat model of chemical unilateral labyrinthectomy by serial [(18)F]FDG-µPET. These findings show that deafferentation-induced plasticity after unilateral labyrinthectomy involves early mechanisms of re-balancing predominantly in the brainstem vestibular nuclei but also in thalamo-cortical and limbic areas, and indicate the contribution of spinocerebellar sensory inputs and vestibulocerebellar adaptation at the later stages of behavioural recovery.

Background: Atopic diseases are a major burden of disease on a global scale. Regarding their aetiology, the early years of life are assumed to play a crucial role. In addition, there is growing evidence that elucidating the impact of cross-generational effects and epigenetic mechanisms such as DNA methylation can substantially widen the scientific knowledge of the occurrence and progression of these diseases. We are thus aiming at following the course of asthma, allergies, and potential risk factors for their occurrence across three generations by establishing a birth cohort in the offspring of an existing population-based cohort., Methods/design: 2051 young adults who have been recruited in 1995 for Phase II of the International Study of Asthma and Allergies in Childhood (ISAAC) and who have subsequently been followed-up by the Study on Occupational Allergy Risks (SOLAR) are asked bi-annually since 2009 if they conceived a child in the meantime. If parenthood is reported, parents are invited to enrol along with their children in the ACROSSOLAR cohort. Participation involves completing a questionnaire assessing general and health-related information about the course of the pregnancy and the first year of life of their children. Subsequently, the children are followed up until primary school age when asthma and allergies can be diagnosed reliably. In addition, DNA for epigenetic analysis will be collected and analysed. Longitudinal data analysis techniques will then be used to assess potential associations between early-life exposures and onset of childhood asthma and allergies taking into account epigenetics., Discussion: Birth cohorts are especially suited to elucidate the impact of genetic predisposition, epigenetics, exposures during the first years of life, and gene-environment interactions on the occurrence and progression of asthma and allergies. By building upon an existing cohort, ACROSSOLAR offers a unique and cost-effective opportunity to investigate the aetiology of atopic disease in a prospective and cross-generational way.

Purpose: The aim of this study is to non-invasively assess early, irradiation-induced normal tissue alterations via metabolic imaging with 3'-deoxy-3'-[(18) F]fluorothymidine ([(18) F]FLT)., Procedures: Twenty-nine male C57BL/6 mice were investigated by [(18) F]FLT positron emission tomography for 7 days after total body irradiation (1, 4, and 8 Gy) versus 'sham' irradiation (0 Gy). Target/background ratios were determined. The imaging results were validated by histology and immunohistochemistry (Thymidine kinase 1, Ki-67)., Results: [(18) F]FLT demonstrated a dose-dependent intestinal accumulation post irradiation. Mean target/background ratio (±standard error) 0 Gy: 1.4 (0.2), 1 Gy: 1.7 (0.1), 4 Gy: 3.1 (0.3), 8 Gy: 4.2 (0.6). Receiver operating characteristic analysis (area under the curve, p value): 0 vs. 1 Gy: 0.81, 0.049; 0 vs. 4 Gy: 1.0, 0.0016; and 0 vs. 8 Gy: 1.0, 0.0020. Immunohistochemistry confirmed the results., Conclusions: [(18) F]FLT seems to provide dose-dependent information on radiation-induced proliferation in the bowel. This opens the perspective for monitoring therapy-related side-effects as well as assessing, e.g., radiation accident victims.

Unlabelled: The progression of β-amyloid deposition in the brains of mice overexpressing Swedish mutant β-amyloid precursor protein (APP-Swe), a model of Alzheimer disease (AD), was investigated in a longitudinal PET study using the novel β-amyloid tracer (18)F-florbetaben., Methods: Groups of APP-Swe and age-matched wild-type (WT) mice (age range, 10-20 mo) were investigated. Dynamic emission recordings were acquired with a small-animal PET scanner during 90 min after the administration of (18)F-florbetaben (9 MBq, intravenously). After spatial normalization of individual PET recordings to common coordinates for mouse brain, binding potentials (BPND) and standardized uptake value ratios (SUVRs) were calculated relative to the cerebellum. Voxelwise analyses were performed using statistical parametric mapping (SPM). Histochemical analyses and ex vivo autoradiography were ultimately performed in a subset of animals as a gold standard assessment of β-amyloid plaque load., Results: SUVRs calculated from static recordings during the interval of 30-60 min after tracer injection correlated highly with estimates of BPND based on the entire dynamic emission recordings. (18)F-florbetaben binding did not significantly differ in APP-Swe mice and WT animals at 10 and 13 mo of age. At 16 mo of age, the APP-Swe mice had a significant 7.9% increase (P < 0.01) in cortical (18)F-florbetaben uptake above baseline and at 20 mo there was a 16.6% increase (P < 0.001), whereas WT mice did not show any temporal changes in tracer uptake during the interval of follow-up. Voxelwise SPM analyses revealed the first signs of increased cortical binding at 13 mo and confirmed progressive binding increases in both the frontal and the temporal cortices (P < 0.001 uncorrected) to 20 mo. The SUVR strongly correlated with percentage plaque load (R = 0.95, P < 0.001)., Conclusion: In the first longitudinal PET study in an AD mouse model using the novel β-amyloid tracer (18)F-florbetaben, the temporal and spatial progression of amyloidogenesis in the brain of APP-Swe mice were sensitively monitored. This method should afford the means for preclinical testing of novel therapeutic approaches to the treatment of AD.

Purpose: Based on experimental findings, overexpression of P-glycoprotein at the blood-brain barrier has been suggested to be a contributor to pharmacoresistance of the epileptic brain. We test a technique for evaluation of interindividual differences of elevated transporter function, through microPET analysis of the impact of the P-glycoprotein modulator tariquidar. The preclinical study is intended for eventual translation to clinical research of patients with pharmacoresistant seizure disorders., Methods: We made a microPET evaluation of the effects of tariquidar on the brain kinetics of the P-glycoprotein substrate [(18) F]MPPF in a rat model with spontaneous recurrent seizures, in which it has previously been demonstrated that phenobarbital nonresponders exhibit higher P-glycoprotein expression than do phenobarbital responders., Results: Mean baseline parametric maps of the [(18) F]MPPF unidirectional blood-brain clearance (K(1) ; ml/g per min) and the efflux rate constant (k(2) ; per min) did not differ between the nonresponder and responder group. Tariquidar pretreatment increased the magnitude of [(18) F]MPPF K(1) in hippocampus by a mean of 142% in the nonresponders, which significantly exceeded the 92% increase observed in the responder group. The same treatment decreased the mean magnitude of [(18) F]MPPF k(2) in hippocampus by 27% in nonresponders, without comparable effects in the responder group., Discussion: These results constitute a proof-of-concept for a novel imaging approach to evaluate blood-brain barrier P-glycoprotein function in animals. By extension, [(18) F]MPPF positron emission tomography (PET) with tariquidar pretreatment may be amenable for clinical applications exploring further the relevance of P-glycoprotein overexpression, and for enabling the rational design of pharmacotherapy according to individual differences in P-glycoprotein expression., (Wiley Periodicals, Inc. © 2010 International League Against Epilepsy.)

Epileptic seizures drive expression of the blood-brain barrier efflux transporter P-glycoprotein via a glutamate/cyclooxygenase-2 mediated signalling pathway. Targeting this pathway may represent an innovative approach to control P-glycoprotein expression in the epileptic brain and to enhance brain delivery of antiepileptic drugs. Therefore, we tested the effect of specific cyclooxygenase-2 inhibition on P-glycoprotein expression in two different status epilepticus models. Moreover, the impact of a cyclooxygenase-2 inhibitor on expression of the efflux transporter and on brain delivery of an antiepileptic drug was evaluated in rats with recurrent spontaneous seizures. The highly selective cyclooxygenase-2 inhibitors SC-58236 and NS-398 both counteracted the status epilepticus-associated increase in P-glycoprotein expression in the parahippocampal cortex and the ventral hippocampus. In line with our working hypothesis, a sub-chronic 2-week treatment with SC-58236 in the chronic epileptic state kept P-glycoprotein expression at control levels. As described previously, enhanced P-glycoprotein expression in chronic epileptic rats was associated with a significant reduction in the brain penetration of the antiepileptic drug phenytoin. Importantly, the brain delivery of phenytoin was significantly enhanced by sub-chronic cyclooxygenase-2 inhibition in rats with recurrent seizures. In conclusion, the data substantiate targeting of cyclooxygenase-2 in the chronic epileptic brain as a promising strategy to control the expression levels of P-glycoprotein despite recurrent seizure activity. Cyclooxygenase-2 inhibition may therefore help to increase concentrations of antiepileptic drugs at the target sites in the epileptic brain. It needs to be further evaluated whether the approach also enhances efficacy., (2009 Elsevier Ltd. All rights reserved.)

Up-regulation of the blood-brain barrier efflux transporter P-glycoprotein in central nervous system disorders results in restricted brain access and limited efficacy of therapeutic drugs. In epilepsies, seizure activity strongly triggers expression of P-glycoprotein. Here, we identified the prostaglandin E2 receptor, EP1, as a key factor in the signaling pathway that mediates seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier. In the rat pilocarpine model, status epilepticus significantly increased P-glycoprotein expression by 92 to 197% in the hippocampal hilus and granule cell layer as well as the piriform cortex. The EP1 receptor antagonist 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-(4-pyridinyl)propyl]hydrazide hydrochloride (SC-51089) abolished seizure-induced P-glycoprotein up-regulation and retained its expression at the control level. The control of P-glycoprotein expression despite prolonged seizure activity suggests that EP1 receptor antagonism will also improve antiepileptic drug efficacy. Preliminary evidence for this concept has been obtained using a massive kindling paradigm during which animals received a subchronic SC-51089 treatment. After withdrawal of the EP1 receptor antagonist, a low dose of the P-glycoprotein substrate phenobarbital resulted in an anticonvulsant effect in this pretreated group, whereas the same dosage of phenobarbital did not exert a significant effect in the respective control group. In conclusion, our data demonstrate that EP1 is a key signaling factor in the regulatory pathway that drives P-glycoprotein up-regulation during seizures. These findings suggest new intriguing possibilities to prevent and interrupt P-glycoprotein overexpression in epilepsy. Future studies are necessary to further evaluate the appropriateness of the strategy to enhance the efficacy of antiepileptic drugs.