Search

Background People with type 1 diabetes can continuously monitor their glucose levels on demand (intermittently scanned continuous glucose monitoring [isCGM]), or in real time (real-time continuous glucose monitoring [rtCGM]). However, it is unclear whether switching from isCGM to rtCGM with alert functionality offers additional benefits. Therefore, we did a trial comparing rtCGM and isCGM in adults with type 1 diabetes (ALERTT1). Methods We did a prospective, double-arm, parallel-group, multicentre, randomised controlled trial in six hospitals in Belgium. Adults with type 1 diabetes who previously used isCGM were randomly assigned (1:1) to rtCGM (intervention) or isCGM (control). Randomisation was done centrally using minimisation dependent on study centre, age, gender, glycated haemoglobin (HbA(1c)), time in range (sensor glucose 3.9-10.0 mmol/L), insulin administration method, and hypoglycaemia awareness. Participants, investigators, and study teams were not masked to group allocation. Primary endpoint was mean between-group difference in time in range after 6 months assessed in the intention-to-treat sample. This trial is registered with ClinicalTrials.gov, NCT03772600. Findings Between Jan 29 and July 30, 2019, 269 participants were recruited, of whom 254 were randomly assigned to rtCGM (n=127) or isCGM (n=127); 124 and 122 participants completed the study, respectively. After 6 months, time in range was higher with rtCGM than with isCGM (59.6% vs 51.9%; mean difference 6.85 percentage points [95% CI 4.36-9.34]; p

Background and Purpose: Lacunar syndromes correlate with a lacunar stroke on imaging in 50% to 60% of cases. Computed tomography perfusion (CTP) is becoming the preferred imaging modality for acute stroke triage. We aimed to estimate the sensitivity, specificity, and predictive values for noncontrast computed tomography and CTP in lacunar syndromes, and for cortical, subcortical, and posterior fossa regions. Methods: A retrospective analysis of confirmed ischemic stroke patients who underwent acute CTP and follow-up magnetic resonance imaging between 2010 and 2018 was performed. Brain noncontrast computed tomography and CTP were assessed independently by 2 stroke neurologists. Receiver operating characteristic curve analysis was performed to estimate sensitivity, specificity, and area under the curve (AUC) for the detection of strokes in patients with lacunar syndromes using different CTP maps. Results: We found 106 clinical lacunar syndromes, but on diffusion-weighted imaging, these consisted of 59 lacunar, 33 cortical, and 14 posterior fossa strokes. The discrimination of ischemia identification was very poor using noncontrast computed tomography in all 3 regions, but good for cortical (AUC, 0.82) and poor for subcortical and posterior regions (AUCs, 0.55 and 0.66) using automated core-penumbra maps. The addition of delay time and mean transient time maps substantially increased subcortical (AUC, 0.80) and slightly posterior stroke detection (AUC, 0.69). Conclusions: Analysis of mean transient time and delay time maps in combination with core-penumbra maps improves detection of subcortical and posterior strokes.

Background: Upper limb (UL) hemiparesis is a common, disabling and persistent problem, and a major contributor to poor well-being and quality of life in persons after stroke. Conventional U...

Background and Purpose— Poststroke fatigue affects a large proportion of stroke survivors and is associated with a poor quality of life. In a recent trial, modafinil was shown to be an effective agent in reducing poststroke fatigue; however, not all patients reported a significant decrease in fatigue with therapy. We sought to investigate clinical and radiological predictors of fatigue reduction with modafinil therapy in a stroke survivor cohort. Methods— Twenty-six participants with severe fatigue (multidimensional fatigue inventory–20 ≥60) underwent magnetic resonance imaging at baseline and during the last week of a 6-week treatment period of 200 mg modafinil taken daily. Resting-state functional magnetic resonance imaging and high-resolution structural imaging data were obtained, and functional connectivity and regional brain volumes within the fronto-striato-thalamic network were obtained. Linear regression analysis was used to identify predictors of modafinil-induced fatigue reduction. Results— Multiple regression analysis showed that baseline multidimensional fatigue inventory–20 score (β=0.576, P =0.006) and functional connectivity between the dorsolateral prefrontal cortex and the caudate nucleus (β=−0.424, P =0.008) were significant predictors of modafinil-associated decreases in poststroke fatigue (adjusted r 2 =0.52, area under the receiver operator characteristic curve=0.939). Conclusions— Fronto-striato-thalamic functional connectivity predicted modafinil response for poststroke fatigue. Fatigue in other neurological disease has been attributed to altered function of the fronto-striato-thalamic network and may indicate that poststroke fatigue has a similar mechanism to other neurological injury related fatigue. Self-reported fatigue in patients with normal fronto-striato-thalamic functional connectivity may have a different mechanism and require alternate therapeutic approaches. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: ACTRN12615000350527.

Background and Purpose: Altered executive functions and resting-state functional connectivity (rsFC) are common following a minor stroke or transient ischemic attack (TIA). However, the long-term persistence of these abnormalities is not well-studied. We investigated whether there were cognitive and rsFC differences between (a) controls and minor cerebrovascular event (CVE) patients and (b) between CVE patients with and without an imaging confirmed infarct (i.e., minor stroke and TIA, respectively) at an average of 3.8 years following their event.Methods: Structural and resting-state imaging and cognitive assessments including the Montreal Cognitive Assessment, the Trail Making Task and the National Institute of Health (NIH) Cognition Toolbox were conducted on 42 patients (minor stroke = 17, TIA = 25) and 20 healthy controls (total N = 62).Results: Controls performed better than patients on two measures of executive functioning (both p < 0.046) and had reduced rsFC between the frontoparietal and default mode networks (FPN and DMN, respectively; p = 0.035). No cognitive differences were found between minor stroke and TIA patients, however, rsFC differences were found within the FPN and the DMN (both p < 0.013). Specifically, increased connectivity within the FPN was associated with faster performance in the minor stroke group but not the TIA group (p = 0.047).Conclusions: These findings suggest that transient or relatively minor cerebrovascular events are associated with persistent disruption of functional connectivity of neural networks and cognitive performance. These findings suggest a need for novel interventions beyond secondary prevention to reduce the risk of persistent cognitive deficits.

BACKGROUND AND PURPOSE: Degeneration of gray matter and subcortical structures after ischemic stroke has been well described. However, little is known about white matter degeneration after stroke. It is unclear whether white matter degeneration occurs throughout the whole brain, or whether patterns of degeneration occur more in specific brain areas. METHODS: We prospectively collected National Institutes of Health Stroke Scale (NIHSS) scores and diffusion tensor imaging (DTI) in patients with acute ischemic stroke within the first week after onset (baseline), and at 1 and 3 months. DTI was processed to produce maps of fractional anisotropy, apparent diffusion coefficients, and axial and radial diffusivity. DTI parameters in specified regions-of-interest corresponding to items on the NIHSS were calculated and changes over time were assessed using linear mixed-effect modeling. RESULTS: Seventeen patients were included in the study. Mean age (SD) was 71 (11.7) years, and median (IQR) baseline NIHSS 9 (5-13.3). Changes over time were observed in both visual cortices, contralesional primary motor cortex, premotor cortex, and superior temporal gyrus (P < .05). Changes in the ipsilesional motor cortex and inferior parietal lobule were only seen in patients with scores on the respective NIHSS-items (P .05). CONCLUSION: White matter changes after stroke may be localized rather than a global phenomenon.

Motor function may be enhanced if aerobic exercise is paired with motor training. One potential mechanism is that aerobic exercise increases levels of brain-derived neurotrophic factor (BDNF), which is important in neuroplasticity and involved in motor learning and motor memory consolidation. This study will examine the feasibility of a parallel-group assessor-blinded randomised controlled trial investigating whether task-specific training preceded by aerobic exercise improves upper limb function more than task-specific training alone, and determine the effect size of changes in primary outcome measures. People with upper limb motor dysfunction after stroke will be allocated to either task-specific training or aerobic exercise and consecutive task-specific training. Both groups will perform 60 hours of task-specific training over 10 weeks, comprised of 3 × 1 hour sessions per week with a therapist and 3 × 1 hours of home-based self-practice per week. The combined intervention group will also perform 30 minutes of aerobic exercise (70–85%HRmax) immediately prior to the 1 hour of task-specific training with the therapist. Recruitment, adherence, retention, participant acceptability, and adverse events will be recorded. Clinical outcome measures will be performed pre-randomisation at baseline, at completion of the training program, and at 1 and 6 months follow-up. Primary clinical outcome measures will be the Action Research Arm Test (ARAT) and the Wolf Motor Function Test (WMFT). If aerobic exercise prior to task-specific training is acceptable, and a future phase 3 randomised controlled trial seems feasible, it should be pursued to determine the efficacy of this combined intervention for people after stroke. Keywords: Stroke, Motor function, Aerobic exercise, Task-specific training

Estetrol (E4) is an estrogen produced exclusively by the human fetal liver during pregnancy. In this study the pharmacodynamic effects of escalating doses of E4 in postmenopausal women were investigated.This was a partly randomized, open-label, multiple-rising-dose study in 49 postmenopausal women. Participants were randomized to receive either 2 mg E4 or 2 mg estradiol-valerate (E2 V) for 28 days. Subsequent dose-escalation groups were (non-randomized): 10, 20 and 40 mg E4. Blood samples were collected regularly for measuring endocrine and hemostasis variables, lipids and lipoproteins, fasting glucose and bone turnover markers.Estetrol treatment resulted in a decrease of follicle-stimulating hormone and luteinizing hormone and an increase of sex-hormone binding globulin. Changes in hemostasis variables were small. A lowering effect on low-density lipoprotein cholesterol was accompanied with an increase in high-density lipoprotein cholesterol and no or minimal changes in triglycerides. The considerable decrease in osteocalcin levels in the three highest E4 dose groups and the small decrease in C-telopeptide levels were comparable to the E2 V control group and suggest a preventive effect on bone loss. All changes observed were dose-dependent.In this study, estetrol treatment showed dose-dependent estrogenic effects on endocrine parameters, bone turnover markers, and lipids and lipoproteins. The effect on triglycerides was small as were the effects on hemostatic variables. These results support the further investigation of estetrol as a candidate for hormone therapy. Quantitatively, the effects of 10 mg estetrol were similar to the study comparator 2 mg estradiol valerate.

Background: The number of refugees is the highest ever worldwide. Many have experienced trauma in home countries or on their escape which has mental health sequelae. Intrusive memories comprise distressing scenes of trauma which spring to mind unbidden. Development of novel scalable psychological interventions is needed urgently. Aims: We propose that brief cognitive science-driven interventions should be developed which pinpoint a focal symptom alongside a means to monitor it using behavioural techniques. The aim of the current study was to assess the feasibility and acceptability of the methodology required to develop such an intervention. Method: In this study we recruited 22 refugees (16–25 years), predominantly from Syria and residing in Sweden. Participants were asked to monitor the frequency of intrusive memories of trauma using a daily diary; rate intrusions and concentration; and complete a 1-session behavioural intervention involving Tetris game-play via smartphone. Results: Frequency of intrusive memories was high, and associated with high levels of distress and impaired concentration. Levels of engagement with study procedures were highly promising. Conclusions: The current work opens the way for developing novel cognitive behavioural approaches for traumatized refugees that are mechanistically derived, freely available and internationally scalable.

Aim Cardiovascular disease development is highly variable between patients with familial hypercholesterolemia (FH). Since current risk prediction methods fail to estimate the risk of individual patients, all patients are treated with high-intensity lipid-lowering medication like statins and PCSK9-inhibitors. To prevent overtreatment (with its associated costs and side effects) of patients with a low risk, reliable biomarkers are urgently needed. While studying atherosclerosis development in an FH porcine model, we discovered a specific LDL profile that was directly associated with the severity of atherosclerosis development. Methods 10 adult pigs with an LDLR mutation received a high-fat diet for 12 months. Atherosclerosis development in the three main coronary arteries was monitored with intravascular ultrasound (IVUS) and optical coherence tomography at three time points. After sacrifice, tissue was harvested for detailed histological analysis of the coronary plaque composition. Size-exclusion chromatography (SEC, n=10) and LC-MSMS (n=4) were used to assess the plasma lipoprotein profile, and the sphingolipid content of LDL, relative to cholesterol. Results Imaging and histology revealed a marked difference in pigs that developed large, lumen intruding plaques (IVUS-based plaque burden 13–77%) within 9 months (n=5) and pigs (n=5) that only developed early lesions (IVUS-based plaque burden 8–34%), even after 12 months of follow-up. The plaques seen in the fast responding pigs possessed distinct characteristics of advanced disease (i.e. heavy macrophage infiltration, large lipid-rich necrotic cores, neovascularisation, micro- and macrocalcifications and intraplaque haemorrhage, see figure). In these fast responders, fibrous cap atheroma occupied 34% of the total artery. SEC revealed two distinct LDL subclasses: regular and “larger” LDL particles. Fast responding pigs with advanced atherosclerosis displayed a significantly higher ratio in cholesterol concentration of regular/'larger' LDL than slow responding pigs (1.7 (1.3–1.9) vs. 0.8 (0.6–1.2); (p=0.004), see figure). Compared to regular LDL, “larger” LDL contained relatively more sphingolipids in the fast responding than in the slow responding animals (regular LDL/'larger' LDL: S1P 0.5 (0.5–0.5) vs. 1.0 (0.8–1.2); Cer16:0 0.70 (0.67–0.73) vs. 1.04 (0.95–1.13); Cer18:0 0.60 (0.58–0.61) vs. 1.15 (1.13–1.16); Cer20:0 0.73 (0.73–0.74) vs. 0.94 (0.94–0.94)). “Larger” LDL particles and comparable sphingolipid ratios were also observed in FH patients. Cardiovascular data from our FH patient cohort, coupled to the LDL subclass distribution, will provide more insight into the potential of this novel biomarker. Conclusion A distinct difference in LDL subclasses, including a new “larger” LDL particle, was found in fast versus slow responding FH animals. This finding can potentially be used to identify FH patients at the highest risk of CVD to avoid overtreatement of low risk patients. Acknowledgement/Funding ERC- starter grant (grant agreement 310457)

The changes in the cardiovascular function (CVF) during preeclampsia are known. Whether they begin prior clinical manifestation or persist after delivery remains unclear. Objective We hypothesized that preeclampsia is preceded by early CVF changes. We evaluated the eventual difference between patients who develop preeclampsia and those who stayed normotensives. Secondly we searched for a link between CVF changes and development of preeclampsia. Methods This prospective study, included 260 normotensive primiparous women, referred for routinely control to the Cardiology section. At week 22 of gestation and 1 year after delivery were performed: Office blood pressure (OBP), blood and urine lab test. Cardiac index (CI) and systemic vascular resistance index (SVRI) through impedance cardiography. Wave pulse velocity (PWV) through pressure signals. According to the evolution during pregnancy patients were assigned to one of 3 groups: G1 preeclampsia:. G2 Gestational hypertension G3 Normotensive. Statistic tests: one-way analysis of variance and the Bonferroni post-hoc test. Results 12 patients evolved to preeclamsia, 18 to gestational hypertension and 230 remained normotensive. G1 had significantly lower value of CI in both measurements and higher values of OBP, SVRPI and WPV comparing to G3. G2 always showed intermediate values between G1 and G2. The median age of the population was 25 ≠ 4 years old. By logistic regression analysis WPV and SVRI at 22 week of gestation were predictors of preeclampsia. (p Patient Characteristics Characteristics G1 G2 G3 p Conclusion Preeclampsia showed different CVF compare with normotensive, before diagnosis and after delivery. The early endothelial dysfunction could be responsible of these changes.

Carriers of pathogenic variants in CDKN2A have a 70% life-time risk of developing melanoma and 15-20% risk of developing pancreatic cancer (PC). In the Netherlands, a 19-bp deletion in exon 2 of CDKN2A (p16-Leiden mutation) accounts for most hereditary melanoma cases. Clinical experience suggests variability in occurrence of melanoma and PC in p16-Leiden families. Thereby, the risk of developing cancer could be modified by both environmental and genetic contributors, suggesting that identification of genetic modifiers could improve patients’ surveillance. In a recent genome-wide association study (GWAS), rs36115365-C was found to significantly modify risk of PC and melanoma in the European population. This SNP is located on chr5p15.33 and has allele-specific regulatory activities on TERT expression. Herein, we investigated the modifying capacities of rs36115365-C on PC and melanoma in a cohort of 283 p16-Leiden carriers including 29 diagnosed with PC, 171 diagnosed with melanoma, 21 diagnosed with both PC and melanoma and 62 with neither PC nor melanoma. In contrast to previously reported findings, we did not find a significant association of PC risk with risk variant presence as determined by Generalized Estimating Equations (GEE) modelling. Interestingly, carrier-ship of the risk variant had a significant protective effect for melanoma (OR -0.703 [95% CI -1.201-0.205], p = 0.006); however, the observed association was no longer significant after exclusion of probands to assess possible influence of ascertainment. Collectively, genetic modifiers for the prediction of PC and melanoma risk in p16-Leiden carriers remain to be determined.

Objective This study examined the feasibility of a parallel-group assessor-blinded randomized controlled trial investigating whether task-specific training preceded by aerobic exercise (AEX + TST) improves upper limb function more than task-specific training (TST) alone. Methods People with upper limb motor dysfunction after stroke were allocated to TST or AEX + TST. Both groups were prescribed 60 hr of TST over 10 weeks (3 × 1-hr sessions with a therapist per week and 3 × 1 hr of home-based self-practice per week). The AEX + TST group performed 30 minutes of aerobic exercise immediately prior to the 1 hr of TST with the therapist. Recruitment, adherence, retention, participant acceptability, and adverse events were recorded. Clinical measures were performed prerandomization at baseline, on completion of the intervention, and at 1- and 6-month follow-up. Results Fifty-nine persons after stroke were screened, 42 met the eligibility criteria, and 20 (11 male; mean [SD] age: 55.4 [16.0] years; time since stroke: 71.7 [91.2] months) were recruited over 17 months. The mean Wolf Motor Function Test Functional Ability Score at baseline was 27.4 (max = 75) and the mean Action Research Arm Test score was 11.2 (max = 57). Nine were randomized to AEX + TST and 11 to TST. There were no adverse events, but there was one drop out. Retention at 1- and 6-month follow-up was 80% and 85%, respectively. Attendance was 93% (6) for the AEX + TST group, and 89% (9) for the TST group. AEX + TST was perceived as acceptable (100%) and beneficial (87.5%). Exertional fatigue (visual analogue scale) prior to TST was worse in the AEX + TST group (3.5 [0.7] out of 10) than the TST group (1.7 [1.4] out of 10). The TST group performed 31% more repetitions per session than the AEX + TST group. Conclusion A subsequent Phase III study is feasible, but modifications to eligibility criteria, outcome measures, and intervention delivery are recommended.

Background:The interferon (IFN) pathway is a complex system with multiple proteins and diverse downstream effects on gene and protein expression. IFNs have been implicated in multiple RMDs. Despite significant potential, IFN assays have not progressed into clinical practice.Objectives:To perform a SLR on IFN assays in RMDs and propose a consensus terminology.Methods:OvidMedline, Embase and Web of Science were searched for reports of IFN and RMDs up to October 2019. Information about the properties of assays measuring type I IFN and measures of truth were extracted and summarised. Terminology was agreed through an interactive consensus process with reference to the existing evidence.Results:10037 abstracts were identified. 275 fulfilled eligibility criteria, and were used for data extraction. Some used more than one technique to measure IFN-I pathway activation. Hence, 275 papers generated data on 393 methods. There was great heterogeneity in the methods used and presentation of results. IFN-I pathway activation was measured using: qPCR (n=121), immunoassays (n=101), microarray (n=69), reporter cell assay (n=38), DNA methylation (n=14), flow cytometry (n=14), cytopathic effect assay (n=11), RNA sequencing (n=9), Plaque reduction assay (n=8), Nanostring (n=5), bisulphite sequencing (n=3). All papers fulfilled Face Validity. Due to lack of gold standard for IFN-I pathway activation, evidence of criterion validity was variable. Concurrent validity was presented for n=150 assays. The terminology used to describe aspects of type I IFN pathway activation was not consistent, so a consensus terminology for IFN research (Table 1) was proposed by the taskforce.Table 1.Consensus terminologyTermAbbreviationDefinitionInterferonIFNProteins with anti-viral activity; IFNs are mediators of an anti-viral response. They belong to the Type I, Type II and Type III IFN families.Type I interferonIFN-IThe IFNs alpha, beta, omega, kappa, epsilon, secreted by any nucleated cell, and binding to the IFNAR, which is expressed on any nucleated cell.Type II interferonIFN-IIIFN gamma, mostly secreted by T cells, binding to the IFNGR, which is expressed on most leucocytes.Type III interferonIFN-IIIIFN lambda, which are structurally more similar to IL-10 but share downstream signalling and gene expression with IFN-I.Interferon-stimulated genesISGsGenes whose expression is known to be upregulated by any kind of IFN. Individual ISGs may not exclusively represent Type I IFN pathway activation.Type I Interferon pathway activationAny evidence for function of the components of the Type I IFN pathway. This includes: secretion of a Type I IFN protein, binding to the IFNAR, initiation of JAK/STAT signalling pathways, expression of IFN-stimulated genes, expression of IFN-stimulated proteins.Type I interferon pathway assayAn assay measuring one or more components of the Type I IFN pathway at a molecular or functional level.Interferon stimulated gene expression signatureA qualitative description of coordinated expression of a set of ISGs that is indicative of Type I IFN pathway activation.Interferon stimulated gene expression scoreA quantitative variable derived from expression of a defined set of ISGs that is indicative of Type I IFN pathway activation.Interferon stimulated protein scoreA variable derived from expression of a defined set of soluble biomarkers known to be upregulated by IFN, although not specific for Type I IFN.InterferonopathyMonogenic diseases in which there is constitutive Type I IFN pathway activation with a causal role in pathology. The clinical picture may resemble rheumatic musculoskeletal diseases. However, most diseases with IFN pathway activation are not Interferonopathies.Conclusion:Diverse methods have been reported as IFN assays and these differ in what elements of type IFN-I pathway activation they measure. The taskforce consensus terminology on type I IFN reporting should be considered for research and clinical applications.Disclosure of Interests:Agata Burska: None declared, Javier Rodriguez Carrio: None declared, Philip G Conaghan: None declared, Willem A Dik: None declared, Robert Biesen: None declared, Maija-leena Eloranta: None declared, Giulio Cavalli: None declared, Marianne Visser: None declared, Dimitrios Boumpas: None declared, George Bertsias: None declared, Marie Wahren-Herlenius: None declared, Jan Rehwinkel: None declared, Marie-Louise Frémond: None declared, Mary K. Crow Consultant of: AstraZeneca, Bristol Meyers Squibb, Lilly, Shannon Pharmaceuticals, Grant/research support from: Gilead, Lars Ronnblom Consultant of: AstraZeneca, Edward Vital Speakers bureau: GSK, Consultant of: AURINIA, SANDOZ, GSK, AstraZeneca, Roche, Modus, Grant/research support from: AstraZeneca, Marjan Versnel: None declared

Objective Estetrol (E4) is a natural fetal estrogen. The safety of increasing doses of E4 and its preliminary effects on the vagina, endometrium and menopausal vasomotor symptoms were investigated. Study design This was a partly randomized, open-label, multiple-rising-dose study in 49 postmenopausal women. Subjects with an intact uterus were randomized to receive either 2 mg E4 or 2 mg estradiol-valerate (E2V) for 28 days. Subsequent dose-escalation groups (non-randomized) were: 10 mg E4 (intact uterus and ≥35 hot flushes/week); and 20 mg and 40 mg E4 (hysterectomized subjects). Main outcome measure Adverse events (AEs) and vaginal cytology were evaluated in all treatment groups; hot flushes/sweating and endometrial proliferation were analyzed with 2 and 10 mg E4 and 2 mg E2V. Results Estetrol appeared to be safe, without serious drug-related AEs. In all the groups there was a clear shift from parabasal to superficial vaginal cells, indicating an estrogenic effect and a potential for the treatment of vulvovaginal atrophy. The endometrial thickness remained stable in the 2 mg E4 group and increased with E2V and 10 mg E4. A decrease in the mean number of hot flushes and sweating was seen with 2 and 10 mg E4 and 2 mg E2V. Conclusions Estetrol in a dose range of 2–40 mg per day improved vaginal cytology and vasomotor symptoms in postmenopausal women. Endometrial proliferation occurred with the 10 mg dose. Estetrol seems a safe and suitable candidate to develop further for hormone therapy.

Background and Purpose— This study investigated whether problem-solving therapy (PST) is an effective group intervention for improving coping strategy and health-related quality of life (HRQoL) in patients with stroke. Methods— In this multicenter randomized controlled trial, the intervention group received PST as add-on to standard outpatient rehabilitation, the control group received outpatient rehabilitation only. Measurements were performed at baseline, directly after the intervention, and 6 and 12 months later. Data were analyzed using linear-mixed models. Primary outcomes were task-oriented coping as measured by the Coping Inventory for Stressful Situations and psychosocial HRQoL as measured by the Stroke-Specific Quality of Life Scale. Secondary outcomes were the EuroQol EQ-5D-5L utility score, emotion-oriented and avoidant coping as measured by the Coping Inventory for Stressful Situations, problem-solving skills as measured by the Social Problem Solving Inventory-Revised, and depression as measured by the Center for Epidemiological Studies Depression Scale. Results— Included were 166 patients with stroke, mean age 53.06 years (SD, 10.19), 53% men, median time poststroke 7.29 months (interquartile range, 4.90–10.61 months). Six months post intervention, the PST group showed significant improvement when compared with the control group in task-oriented coping ( P =0.008), but not stroke-specific psychosocial HRQoL. Furthermore, avoidant coping ( P =0.039) and the utility value for general HRQoL ( P =0.034) improved more in the PST group than in the control after 6 months. Conclusions— PST seems to improve task-oriented coping but not disease-specific psychosocial HRQoL after stroke >6-month follow-up. Furthermore, we found indications that PST may improve generic HRQoL recovery and avoidant coping. Clinical Trial Registration— URL: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2509 . Unique identifier: CNTR2509.

Background: Nutrition studies in the intensive care unit (ICU) have shown that adequate enteral nutrition (EN) support has clinical benefits. However, the course of amino acid concentrations in plasma has never been investigated in patients admitted with shock receiving EN. We hypothesized that plasma concentrations, when deficit, increase during EN and that persistent deficiency is associated with poor outcome. Methods: In 33 septic or cardiogenic shock patients receiving EN, plasma amino acid concentrations were measured during 5 days. Changes in amino acid concentrations, correlations with clinical outcome variables, and regression analyses were studied. Results: On ICU admission, several plasma concentrations were deficient. Plasma concentrations of almost all amino acids increased. In contrast, taurine decreased by >50%, from 47.6 μmol/L on admission to 20.0 μmol/L at day 1, and remained low at day 5. Taurine (admission) correlated with time on mechanical ventilation (R = -0.42, P =.015). Taurine decrease within 24 hours correlated with Acute Physiology and Chronic Health Evaluation II predicted mortality (R = 0.43, P =.017) and Sequential Organ Failure Assessment score (R = 0.36, P =.05). Regression analyses confirmed correlations. Conclusions: Several amino acids were deficient in plasma on ICU admission but increased during EN. Taurine concentrations declined and were associated with longer periods of mechanical ventilation and ICU support. Fast taurine decline correlated with severity of organ failure. These findings support the role of taurine during ischemia, reperfusion, and inflammation. Taurine may be an essential candidate to enrich nutrition support for critically ill patients, although more research is required.

There is a growing body of evidence that links nutrition to muscle mass, strength and function in older adults, suggesting that it has an important role to play both in the prevention and management of sarcopenia. This review summarises the discussions of a working group [ESCEO working group meeting 8th September 2016] that met to review current evidence and to consider its implications for preventive and treatment strategies. The review points to the importance of 'healthier' dietary patterns that are adequate in quality in older age, to ensure sufficient intakes of protein, vitamin D, antioxidant nutrients and long-chain polyunsaturated fatty acids. In particular, there is substantial evidence to support the roles of dietary protein and physical activity as key anabolic stimuli for muscle protein synthesis. However, much of the evidence is observational and from high-income countries. Further high-quality trials, particularly from more diverse populations, are needed to enable an understanding of dose and duration effects of individual nutrients on function, to elucidate mechanistic links, and to define optimal profiles and patterns of nutrient intake for older adults. (C) 2017 The Authors. Published by Elsevier Ltd.

Estetrol (E4) is a natural fetal estrogen. In this open-label, multiple-rising-dose study, the pharmacokinetic effects of E4 in postmenopausal women were investigated as a secondary objective.In total, 49 postmenopausal women were randomized to receive either 2 mg E4 or 2 mg estradiol valerate (E2V) for 28 days, or were (non-randomized) assigned to 10, 20, or 40 mg E4. The main outcome measures were: E4 plasma concentrations at trough, and on days 1 and 28; and E4 pharmacokinetic parameters AUC, CAfter oral administration, E4 showed a very fast absorption, followed by a multiphasic elimination with an initial rapid decline, gradually continuing with a slower elimination, suggesting a long terminal half-life. Steady state was reached within 2 weeks of dosing and pharmacokinetic results were generally proportional to the dose. Estetrol concentrations on day 28 were slightly higher compared to day 1, indicating some accumulation.The pharmacokinetic profile of estetrol is characterized by a very fast absorption phase, followed by an initial rapid decline, and a slow terminal elimination phase. Based on its kinetic properties, estetrol seems suitable for use as a once-daily oral drug.

Item does not contain fulltext Aggressive behaviour is a major problem in individuals with an intellectual disability (ID) as well as in individuals with an Autism Spectrum Disorder (ASD). There are indications that suggest a link between cognitive shifting and aggression. In this study, reports of aggressive incidents of adolescents and young adults with different clinical diagnoses (ID, ID+ASD, ASD) were collected during 1 year, using the Staff Observation Aggression Scale-Revised. Whether they were diagnosed with ID, ASD or both; individuals who displayed aggression were found to face more cognitive shifting difficulties than non-aggressive individuals, while no significant differences were found on severity of ASD symptoms. Study results support the assumption that a cognition-based model for aggression may be more adequate than a diagnose-based model.

The objective of this study was to examine the validity of the diagnosis of "febrile seizureo" as reported by parents. The study was embedded in a population-based prospective cohort study. Information on paroxysmal events was obtained by screening questions at ages 1, 2, and 3 years. One of these questions was the following: "Did your child have a febrile seizure?o" If a screen-positive result was found, an additional questionnaire was sent and the medical record was consulted. Based on this information, paroxysmal events were classified by a pediatric neurologist as febrile seizure or other event. The validity of a positive reply to the screening question on febrile seizures was assessed, taking this classification as reference standard. Analyses were based on participants who reported at least one paroxysmal event (n = 610). The sensitivity of the positive reply to the question, "Did your child have a febrile seizure?o", for the diagnosis of febrile seizures was 92%, the specificity 72%, the positive predictive value 41%, and the negative predictive value 98%. In conclusion, the sensitivity of the question, "Did your child have a febrile seizure?o", is high. The positive predictive value is only 41%. Although this question may be appropriate as a screening instrument for febrile seizures, a second stage of evaluation is necessary to identify true cases.

Item does not contain fulltext Background: Clinical workplace-based learning has been the means to becoming a medical professional for many years. The importance of an adequate patient mix, as defined by the number of patients and the types of medical problems, for an optimal learning process is based on educational theory and recognised by national and international accreditation standards. The relationship between patient mix and learning in work-based curricula as yet remains unclear. Aim: To review research addressing the relationship between patient mix and learning in work-based clinical settings. Method: The search was conducted across Medline, Embase, Web of Science, ERIC and the Cochrane Library from the start date of the database to July 2011. Original quantitative studies on the relationship between patient mix and learning for learners at any level of the formal medical training/career were included. Methodological quality was assessed and two reviewers using pre-specified forms extracted results. Results: A total of 10,420 studies were screened on title and abstract. Of these, 298 articles were included for full-text analysis, which resulted in the inclusion of 22 papers. The quality of the included studies, scored with the Medical Education Research Study Quality Instrument (MERSQI), ranged from 8.0 to 14.5 (of 18 points). A positive relationship was found between patient mix and self-reported outcomes evaluating the progress in competence as experienced by the trainee, such as self-confidence and comfort level. Patient mix was also found to correlate positively with self-reported outcomes evaluating the quality of the learning period, such as self-reported learning benefit, experienced effectiveness of the rotation, or the instructional quality. Variables, such as supervision and learning style, might mediate this relationship. A relationship between patient mix and formal assessment has never been demonstrated. Conclusion: Patient mix is positively related to self-reported learning outcome, most evidently the experienced quality of the learning programme.

RNA sequencing (RNA-seq) is a powerful tool for the evaluation and quantification of transcriptomes and expression patterns in animals, tissues, or pathological conditions. The purpose of this study was to determine the physiologic expression of cytochrome P450 (CYP) mRNA transcripts in whole blood, kidney, duodenum, liver, and lung in healthy, adult male (n = 4) and female (n = 4) beagles via RNA-seq. mRNA expression was above background (transcripts per million) for 45 canine CYPs, with liver, duodenum, and lung expressing a high number of xenobiotic metabolizing CYPs, while prominent endogenous metabolizing CYP expression was present in blood and kidney. The relative expression pattern of CYP2A13, 2B11, 2C21, 2D15, 2E1, 3A12, and 27A1 in liver, lung, and duodenum was verified through qPCR. This is the first global profiling of physiologic CYP mRNA expression in multiple canine tissues, providing a platform for further studies characterizing canine CYPs and changes in gene expression in disease states.

A 36-year-old woman presented to the emergency department with black stools and syncope. Her hemoglobin was 7.0 and her red blood cells were microcytic. Upper endoscopy did not identify a clear source of bleeding, but a bulge in the third portion of the duodenum was noted. A CT scan showed a large extraintestinal mass, and follow-up esophagogastroduodenoscopy/endoscopic ultrasound with biopsy revealed a spindle cell neoplasm, consistent with gastrointestinal stromal tumor (GIST). Because of the size of the lesion and association with the superior mesenteric vein and common bile duct, she was referred to medical oncology for consideration of neoadjuvant imatinib. Neoadjuvant tyrosine kinase inhibitor therapy for GISTs is emerging as a viable treatment strategy for borderline resectable tumors, although the dose, duration, and optimal imaging modalities have not been clearly established. Recent pathologic and radiographic data have provided insight into the mechanism and kinetics of this approach. This case report presents a patient for whom surgery was facilitated using neoadjuvant imatinib.

Large population-based studies are needed to establish the magnitude and duration of the recently suggested association between arterial and venous thromboembolism. In 1997-98, all inhabitants of Groningen, the Netherlands, aged 28-75 years (n = 85 421), were invited to participate in a study that followed and monitored responding subjects (n = 40 856) for venous and arterial thromboembolism until 2009. Thromboembolism was verified with national registries of hospital discharge diagnoses and death certificates, anticoagulation clinic and medical records. During a median follow-up of 10·7 years, 549 participants developed venous thromboembolism and 3283 developed arterial thromboembolism. Annual incidence of arterial thromboembolism after venous thromboembolism was 2·03% [95% confidence interval (CI), 1·48-2·71], compared to 0·87% (95% CI, 0·84-0·90) in subjects without venous thromboembolism. The hazard ratio (HR) of arterial thromboembolism after venous thromboembolism was 1·40 (95% CI, 1·04-1·88) after adjustment for age, sex and cardiovascular risk factors. This risk was highest during the first year after venous thromboembolism [annual incidence, 3·00% (95% CI, 1·64-5·04); adjusted HR, 2·01 (95% CI, 1·19-3·40)] and after an unprovoked event [annual incidence, 2·53% (95% CI, 1·68-3·66); adjusted HR, 1·62 (95% CI, 1·11-2·34)]. This study showed that subjects with venous thromboembolism are at increased risk for arterial thromboembolism, particularly in the first year after venous thromboembolism and after an unprovoked event.

AIM General developmental outcome is known to be good in school-aged children who experienced febrile seizures. We examined cognitive and behavioural outcomes in preschool children with febrile seizures, including language and executive functioning outcomes. METHOD This work was performed in the Generation R Study, a population-based cohort study in Rotterdam from early fetal life onwards. Information about the occurrence of febrile seizures was collected by questionnaires at the ages of 1, 2, and 3 years. At the age of 3 years, behaviour and emotion were assessed using the Child Behavior Checklist. Information on expressive language development was obtained by the Language Development Survey at the age of 2 years 6 months. To assess executive functioning, parents completed the Behaviour Rating Inventory of Executive Function – Preschool Version when their children were 4 years old. Final analyses were based on 3157 children. RESULTS No associations were found between febrile seizures and the risk of behavioural problems or executive functioning. In contrast to single febrile seizures, recurrent febrile seizures were significantly associated with an increased risk of delayed vocabulary development (odds ratio 3.22, [95% confidence interval 1.30–7.94]). INTERPRETATION Febrile seizures are not associated with problem behaviour or executive functioning in preschool children, but the results suggest that children with recurrent febrile seizures might be at risk for delayed language development. Febrile seizures are common in young children, with a cumulative incidence of 2 to 5% in the first 5 years of life. The highest incidence has been reported in the first 2 years of life. The aetiology has remained unclear, although genetic and environmental mechanisms are known to be involved. 1 The behavioural and cognitive outcomes of children who had febrile seizures have been the subject of many studies. Most population-based cohort-studies did not find clear differences in developmental outcomes between children with and without febrile seizures, and suggest that febrile seizures are an essentially benign disorder with a good prognosis. 2‐5 Most of these studies assessed general intelligence, academic progress, and behavioural outcome in school-aged children. However, other aspects of cognitive function or behaviour still might be adversely affected in children with febrile seizures. Also, at a young age, differences in cognitive function or development might be apparent that disappear at a later age. Besides this, certain

Background: Estetrol (E4) is a pregnancy-specific estrogenic steroid hormone produced by the human fetal liver in both male and female fetuses. During pregnancy, E4 plasma values increase exponentially until parturition and decrease thereafter. The synthesis of E4 in the liver of a newborn ceases during the first weeks after birth. Materials and methods: Here we report the effect of E4 on the initiation and growth of mammary tumors chemically induced by 7,12 dimethylbenz(a)anthracene (DMBA) in female Sprague-Dawley rats in two different protocols. Two prevention studies to test the effect on initiation and growth of induced tumors and one intervention study to test the effect on tumor growth were performed. In the prevention studies, the effect of oral doses of E4 over a dose range of 0.5–3.0 mg/kg was investigated. In the intervention study, oral doses of 1, 3 and 10 mg/kg E4 were used. The anti-estrogen tamoxifen (TAM) and ethinylestradiol (EE) were used as reference compounds. In all studies, a group with ovariectomized animals (OVX) was included. Results: In the prevention studies, 2.5 mg and 3 mg/kg E4 showed a significant effect on the number and growth of induced tumors by DMBA, and the effects were comparable to those of TAM, whereas EE had no effect. In the intervention study, the effect of a high dose of E4 (10 mg/kg) on tumor number was similar to that of OVX and better than TAM and high-dose EE. The 3 mg/kg E4 had an effect comparable to high-dose EE. The treatment effects were largely due to complete regression of existing tumors. Conclusions: The natural fetal estrogen E4 prevents tumor initiation by DMBA and inhibits the growth of existing DMBA-induced tumors.

Purpose At present, the only approved fluorescent tracer for clinical near-infrared fluorescence-guided sentinel node (SN) detection is indocyanine green (ICG), but the use of this tracer is limited due to its poor retention in the SN resulting in the detection of higher tier nodes. We describe the development and characterization of a next-generation fluorescent tracer, nanocolloidal albumin-IRDye 800CW that has optimal properties for clinical SN detection Methods The fluorescent dye IRDye 800CW was covalently coupled to colloidal human serum albumin (HSA) particles present in the labelling kit Nanocoll in a manner compliant with current Good Manufacturing Practice. Characterization of nanocolloidal albumin-IRDye 800CW included determination of conjugation efficiency, purity, stability and particle size. Quantum yield was determined in serum and compared to that of ICG. For in vivo evaluation a lymphogenic metastatic tumour model in rabbits was used. Fluorescence imaging was performed directly after peritumoral injection of nanocolloidal albumin-IRDye 800CW or the reference ICG/HSA (i.e. ICG mixed with HSA), and was repeated after 24 h, after which fluorescent lymph nodes were excised. Results Conjugation of IRDye 800CW to nanocolloidal albumin was always about 50% efficient and resulted in a stable and pure product without affecting the particle size of the nanocolloidal albumin. The quantum yield of nanocolloidal albumin-IRDye 800CW was similar to that of ICG. In vivo evaluation revealed noninvasive detection of the SN within 5 min of injection of either nanocolloidal albumin-IRDye 800CW or ICG/HSA. No decrease in the fluorescence signal from SN was observed 24 h after injection of the nanocolloidal albumin-IRDye 800CW, while a strong decrease or complete disappearance of the fluorescence signal was seen 24 h after injection of ICG/HSA. Fluorescence-guided SN biopsy was very easy. Conclusion Nanocolloidal albumin-IRDye 800CW is a promising fluorescent tracer with optimal kinetic features for SN detection. Electronic supplementary material The online version of this article (doi:10.1007/s00259-012-2080-5) contains supplementary material, which is available to authorized users.

Background & aims: In cardiac surgical patients, undernutrition increases the risk of adverse clinical outcome. We investigated whether the bioelectrical impedance phase angle is an indicator of undernutrition and clinical outcome in cardiac surgery. Methods: In 325 cardiac surgical patients, we prospectively analyzed the associations between a preoperative low phase angle, measured by bioelectrical impedance spectroscopy, and well-established indicators of undernutrition such as body mass index (kg/m(2)), unintended weight loss, and fat free mass index (kg/m(2)), and muscle strength (handgrip strength (kg)), immune function (C-reactive protein and albumin), and adverse clinical outcomes. Results: A low phase angle (

To examine the association between the number of fever episodes and the risk of febrile seizures.This study was embedded in a population-based prospective cohort study from early foetal life onwards. Information about the occurrence of febrile seizures and fever episodes was collected by questionnaires at the ages of 12, 24 and 36 months. Analyses were based on 3033 subjects. The risk of febrile seizures was compared between children with frequent fever episodes (2 per year), and children with only 1 or 2 fever episodes per year.The frequency of fever episodes was not associated with the risk of febrile seizures in the age range of 6-12 months. In the second and third year of life, having more than 2 fever episodes was associated with an increased risk of febrile seizures (odds ratios 2.02 [95% confidence interval 1.13-3.62] and 2.29 [95% confidence interval 1.00-5.24], respectively). In the age range between 6 and 36 months, we observed a significant trend between the frequency of fever episodes (2, 3-4 or4 per year) and the risk of febrile seizures (p-value for trend 0.001). The association between the number of fever episodes and the occurrence of febrile seizures was stronger for children with recurrent febrile seizures.Frequent fever episodes are associated with an increased risk of febrile seizures in the second and third years of life. Further studies are needed to identify the mechanisms underlying this association.

Background: Memory self-efficacy (MSE) is the belief about one’s mastery of memory functioning. In healthy elderly, memory complaints are related to MSE rather than to objectively measured memory capacity. MSE has scarcely been studied in patients that suffered a stroke. The aim of this study was twofold: (1) to examine whether memory capacity and MSE can predict the presence of memory complaints in stroke patients, and (2) to study which variables are the best predictors of MSE. Methods: In a cross-sectional study, 136 stroke patients (>18 months after onset) were recruited from April 2008 to November 2009. MSE was measured using the Metamemory in Adulthood questionnaire. Depression, coping and personality were measured using validated questionnaires, and memory performance was measured using the Rivermead Behavioural Memory Test (RBMT) and the Auditory Verbal Learning Test (AVLT). Patients were divided into a ‘complaints’ and a ‘no complaints’ group. Results: A lower MSE score was an independent predictor of having memory complaints (adjusted odds ratio: 0.422; p = 0.000), adjusted for age and depression. The RBMT and AVLT scores did not predict the presence of memory complaints (p > 0.263). Presence of memory complaints and depression were the strongest predictors of MSE (B = –1.748, p = 0.000; B = –0.054, p = 0.000), followed by word fluency, not having a partner and side of stroke (B = 0.038, p = 0.012; B = –0.517, p = 0.082; B = –0.479, p = 0.088). Conclusions: Memory complaints are predicted by MSE rather than memory capacity. MSE memory training might be an effective training strategy for reducing memory complaints in selected chronic stroke patients.

AIM To examine the incidence of paroxysmal epileptic and non-epileptic disorders and the associated prenatal and perinatal factors that might predict them in the first year of life in a population-based cohort. METHOD This study was embedded in the Generation R Study, a population-based prospective cohort study from early fetal life onwards. Information about the occurrence of paroxysmal events, defined as suddenly occurring episodes with an altered consciousness, altered behaviour, involuntary movements, altered muscle tone, and/or a changed breathing pattern, was collected by questionnaires at the ages of 2, 6, and 12 months. Information on possible prenatal and perinatal determinants was obtained by measurements and questionnaires during pregnancy and after birth. RESULTS Information about paroxysmal events in the first year of life was available in 2860 participants (1410 males, 1450 females). We found an incidence of paroxysmal disorders of 8.9% (n=255) in the first year of life. Of these participants, 17 were diagnosed with febrile seizures and two with epilepsy. Non-epileptic events included physiological events, apnoeic spells, loss of consciousness by causes other than epileptic seizures or apnoeic spells, parasomnias, and other events. Preterm birth (p

BACKGROUND Aerobic exercise can improve upper limb motor function in both healthy and stroke populations. Research in animals after stroke has shown that aerobic exercise combined with forelimb motor training improved forelimb motor function more than aerobic exercise or motor training alone. There is a lack of knowledge about this combined intervention in humans after stroke. PURPOSE These 2 case reports describe the exploratory implementation of a combined aerobic exercise and task-specific training intervention to improve upper limb motor function in one person in subacute stroke recovery and one person in chronic stroke recovery. METHODS Case descriptions Subacute participant: 45-year-old female, 3 months after ischemic stroke resulting in left-sided hemiparesis affecting her non-dominant upper limb, with a baseline Action Research Arm Test (ARAT) score of 10/57 and Wolf Motor Function Test (WMFT) score of 39/75. Chronic participant: 69-year-old female, 14 years after ischemic stroke resulting in right-sided hemiparesis affecting her non-dominant upper limb, with a baseline ARAT score of 13/57 and WMFT score of 34/75. Intervention Participants performed 30 min of lower limb cycling immediately prior to 30 min of upper limb task-specific training. Sessions were undertaken 3 times a week for 8 weeks in a university rehabilitation laboratory. Results The combined intervention was feasible and perceived as acceptable and beneficial. Participants improved their upper limb motor function on the ARAT (subacute participant = 4 points; chronic participant = 2 points) and WMFT (subacute participant = 5 points; chronic participant = 3 points). Participants improved their aerobic fitness (subacute participant = +4.66 ml O2 /kg/min; chronic participant = +7.34 ml O2 /kg/min) and 6-minute walking distance (subacute participant = +50 m; chronic participant = +37 m). Discussion Combining aerobic exercise with task-specific training may be a worthwhile therapeutic approach to improve upper limb motor function suitable for persons in the subacute or chronic phase after stroke.

Purpose Immuno-PET is an emerging imaging tool for the selection of high potential antibodies (mAbs) for imaging and therapy. The positron emitter zirconium-89 (89Zr) has attractive characteristics for immuno-PET with intact mAbs. Previously, we have described a multi-step procedure for stable coupling of 89Zr to mAbs via the bifunctional chelate (BFC) tetrafluorophenol-N-succinyldesferal (TFP-N-sucDf). To enable widespread use of 89Zr-immuno-PET, we now introduce the novel BFC p-isothiocyanatobenzyl-desferrioxamine B (Df-Bz-NCS) and compare its performance in 89Zr-immuno-PET with the reference BFC TFP-N-sucDf. Methods Three mAbs were premodified with Df-Bz-NCS and labeled with 89Zr at different pHs to assess the reaction kinetics and robustness of the radiolabeling. Stability of both 89Zr-Df-Bz-NCS- and 89Zr-N-sucDf-conjugates was evaluated in different buffers and human serum. Comparative biodistribution and PET studies in tumor-bearing mice were undertaken. Results The selected conjugation conditions resulted in a chelate:mAb substitution ratio of about 1.5:1. Under optimal radiolabeling conditions (pH between 6.8–7.2), the radiochemical yield was >85% after 60 min incubation at room temperature, resulting in radioimmunoconjugates with preserved integrity and immunoreactivity. The new radioimmunoconjugate was very stable in serum for up to 7 days at 37°C, with

The human monoclonal antibody (MAb) fragment L19-SIP is directed against extra domain B (ED-B) of fibronectin, a marker of tumour angiogenesis. A clinical radioimmunotherapy (RIT) trial with (131)I-L19-SIP was recently started. In the present study, after GMP production of (124)I and efficient production of (124)I-L19-SIP, we aimed to demonstrate the suitability of (124)I-L19-SIP immuno-PET for imaging of angiogenesis at early-stage tumour development and as a scouting procedure prior to clinical (131)I-L19-SIP RIT.(124)I was produced in a GMP compliant way via (124)Te(p,n)(124)I reaction and using a TERIMO module for radioiodine separation. L19-SIP was radioiodinated by using a modified version of the IODO-GEN method. The biodistribution of coinjected (124)I- and (131)I-L19-SIP was compared in FaDu xenograft-bearing nude mice, while (124)I PET images were obtained from mice with tumours of50 to approximately 700 mm(3).(124)I was produced highly pure with an average yield of 15.4 +/- 0.5 MBq/microAh, while separation yield was approximately 90% efficient with0.5% loss of TeO(2). Overall labelling efficiency, radiochemical purity and immunoreactive fraction were for (124)I-L19-SIP: approximately 80 , 99.9 and90%, respectively. Tumour uptake was 7.3 +/- 2.1, 10.8 +/- 1.5, 7.8 +/- 1.4, 5.3 +/- 0.6 and 3.1 +/- 0.4%ID/g at 3, 6, 24, 48 and 72 h p.i., resulting in increased tumour to blood ratios ranging from 6.0 at 24 h to 45.9 at 72 h p.i.. Fully concordant labelling and biodistribution results were obtained with (124)I- and (131)I-L19-SIP. Immuno-PET with (124)I-L19-SIP using a high-resolution research tomograph PET scanner revealed clear delineation of the tumours as small as 50 mm(3) and no adverse uptake in other organs.(124)I-MAb conjugates for clinical immuno-PET can be efficiently produced. Immuno-PET with (124)I-L19-SIP appeared qualified for sensitive imaging of tumour neovasculature and for predicting (131)I-L19-SIP biodistribution.

This Appendix summarizes available data of maternal and fetal estetrol (E4) levels reported in the literature and obtained in a recent clinical study. The literature data were published mainly in t...

Stress, anxiety and depression in patients with Inflammatory Bowel Disease (IBD) and Irritable Bowel Syndrome (IBS) Stress, anxiety and depression are common in patients with Inflammatory Bowel Disease (IBD) or Irritable Bowel Syndrome (IBS), and can exacerbate symptoms. Psychosocial complaints are expected to be more severe in IBS patients as a result of their disturbed brain-gut axis. Because studies on differences in psychosocial complaints between these patients have not been performed in the Netherlands, our objective was to investigate whether stress, anxiety and depression differed between Dutch IBD and IBS patients. In this cross-sectional study, psychosocial complaints of out-clinic patients with IBD (N=452) or IBS (N=127) were measured with the Perceived Stress Scale (PSS) and the Hospital Anxiety and Depression Scale (HADS). The scores in IBD and IBS were evaluated using Cohen’s d effect sizes. Stratification was used to examine if differences in demographic and clinical characteristics between the IBD and IBS populations could (partly) be responsible for the potential differences in psychosocial complaints. IBD patients had better stress scores than IBS patients. Also, less IBD patients were classified as anxious (8.6%) or depressed (5.2%) as compared to the IBS patients (26.2 and 9.5% respectively). The difference in scores resulted in small effect sizes for stress (d = 0.40) and depression (d = 0.38), while a medium effect was seen for anxiety (d = 0.62). After stratification for actual complaints, Cohen’s d for anxiety decreased to a small effect size. It was concluded that Dutch out-clinic IBD patients have lower levels of stress, depression and especially anxiety as compared to IBS patients.

To measure the oral bioavailability of estetrol (E(4)) in rats relative to its subcutaneous administration and to test the bone-sparing effect of oral E(4) compared to that of ethinylestradiol (EE).In the bioavailability study, E(4) was administered as a single dose of 0.05, 0.5 or 5.0 mg/kg orally or subcutaneously to female rats. Plasma was analyzed using an LC-MS/MS method. The bone study was conducted in 3-month-old female rats assigned to the following seven treatment groups of ten animals each: no treatment; sham-operated + vehicle; bilaterally ovariectomized (OVX) + vehicle; OVX + E(4) 0.1, 0.5, or 2.5 mg/kg/day and OVX + EE 0.1 mg/kg/day. Once-daily treatment by oral gavage was given for 4 weeks and the following measurements were performed: serum osteocalcin, bone mineral density, bone mineral content and bone mineral area of lumbar vertebrae L3-L6, peripheral quantitative computed tomography of the left tibiae and the biomechanical properties of the distal femora.Oral bioavailability of E(4), relative to that of subcutaneous dosing, was 70% and above at the 0.05 and 0.5 mg/kg doses based on the AUC(0-t last). Subcutaneous dosing provided significantly higher E(4) levels at the 1-h time point only, and was comparable to oral dosing after 0.5, 2, 4 and 8 h. In the bone study, E(4) dose-dependently and significantly (1) inhibited the OVX-related increase in osteocalcin levels, (2) increased bone mineral density and content, and (3) increased bone strength, all attenuated by ovariectomy. In this rat model, the relative potency of the highest dose of E(4) (2.5 mg/kg/day) was comparable to the EE dose, used as positive control.Estetrol exhibits high oral bioavailability in the rat, a species considered relevant for pharmacological studies that are predictive for effects on human bone. Oral administration of E(4) conveys dose-dependent bone-sparing effects of high-quality bone in estrogen-depleted OVX rats. Based on its bone-sparing effects, its oral bioavailability and its preclinical safety and efficacy profile, E(4) may be superior to other estrogens and is a potential drug for the prevention of osteoporosis in postmenopausal women.

To evaluate the safety, tolerability, pharmacokinetics and effect on gonadotropins of a single escalating dose of estetrol (E(4)).A first-in-human study with E(4) was performed in healthy early postmenopausal women. Four single doses of 0.1, 1, 10 and 100 mg E(4) were evaluated in study groups of eight subjects each, of whom six received active treatment and two placebo treatment. Safety and tolerability were documented and several pharmacokinetic parameters were determined, as were the plasma levels of the gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH) (pharmacodynamics). The next higher-dose group was enrolled after pharmacokinetic evaluation and confirmed safety of the previous group.After oral intake, the plasma concentrations of E(4) showed a steep increase, followed by a sharp decline and a secondary increase at all dose levels. Estetrol was distributed and reabsorbed during the first 18 h after oral intake. The terminal elimination phase started at 24 h post-dose and half-life (t((1/2))) ranged in the 10 mg group between 19 and 40 h (mean 28.4 h, median 28.8 h) and in the 100 mg group between 18 and 60 h (mean 28.0 h, median 20 h), indicating a dose independency of the half-life. The pharmacokinetic parameters also demonstrated a high dose-response relationship and showed excellent consistency and low variability within the dose groups. The pharmacodynamic data showed a dose-dependent inhibition of plasma LH levels by E(4). A profound and sustained inhibition of FSH levels, lasting over 168 h, was observed in the 100 mg dose group (FSH was not measured in the other dose groups). Estetrol was well tolerated at all dose levels and no safety problems were encountered.Estetrol is orally absorbed and bioavailable with a strong dose-response relationship suggesting high oral bioavailability. Interindividual variations of plasma levels are low. The elimination half-life of 28 h suggests slow metabolism of E(4). The pharmacodynamic pattern complies with enterohepatic recirculation. Estetrol has a profound central inhibitory and dose-dependent effect on gonadotropins, confirming its biological potency.

Monoclonal antibodies (mAbs) have been approved for use as diagnostics and therapeutics in a broad range of medical indications, but especially in oncology. In addition, hundreds of new mAbs, engineered mAb fragments, and nontraditional antibody-like scaffolds directed against either validated or novel tumor targets are under development. Immuno positron emission tomography (PET), the tracking and quantification of mAbs with PET in vivo, is an exciting novel option to improve diagnostic imaging and to guide mAb-based therapy. In this review, recent technical advances leading to a jump ahead in mAb imaging are discussed. The availability of proper positron emitters, sophisticated radiochemistry, and advanced PET and PET-computed tomography scanners is crucial in these developments. Immuno-PET might play an important future role in cancer staging, in the improvement and tailoring of therapy with existing mAbs, and in the efficient development of novel mAbs. An overview of the preclinical and first clinical immuno-PET studies is provided.

Artificial disc prosthesis show fair to good short- and mid-term results. Long-term results are becoming apparent now, however, the incidence of late complications with this procedure remain poorly understood. In this report we will analyse late complications and discuss our experiences with salvage operations in patients with persistent pain after SB Charite disc prosthesis implantation. Seventy-five patients with persistent leg and back pain after insertion of an artificial disc prosthesis were enrolled in the study. In this negative selection frequently occurring late-complications were subsidence, wear, adjacent disc degeneration, facet joint degeneration and migration. In 15 patients we performed a posterior fusion without disc removal, and in 22 patients we removed 26 prostheses and performed a posterior and anterior fusion. The visual analogue scale (VAS) and Oswestry were examined before the salvage operation and after a follow-up period of at least 1 year, which is not yet available in all patients. The VAS and Oswestry decreased in the posterior group (n = 10) respectively from 8.0 (SD 0.9) to 6.3 (SD 2.1) and from 57.0 (SD 17.0) to 44.6 (SD 20.4); and in the disc removal group (n = 14) respectively from 8.0 (SD 0.9) to 5.6 (SD 2.7) and from 56.3 (SD 14.0) to 43.0 (SD 20.7). Serious late complications may occur following total disc replacement. Removal of the SB Charite artificial disc is feasible but with inherent risks. Removal of the disc prosthesis gives slightly better results than posterior fusion alone after a follow-up of at least 1 year.

The association of muscle mass and muscle strength with lower-extremity performance, as measured by timed repeated chair stands, was investigated using preliminary data from 3,075 Black and White participants (70-79 years old) in the Health, Aging, and Body Composition Study. Leg muscle mass (LM) was measured by dual-energy X-ray absorptiometry (Hologic QDR 4500). The maximal isokinetic torque of the leg extensors (LS) was measured at 60 degrees/s using a Kin-Com isokinetic dynamometer. Men were stronger, had greater LM, and better performance than women. As expected, low LS was associated with poorer performance after adjusting for race, study site, and body fat. Low LM was associated with poorer performance in men and women, with a potential threshold effect in women only. When LS and LM were modeled simultaneously, only LS remained independently associated with performance. In conclusion, muscle strength, but not muscle mass, is independently associated with lower-extremity performance.

The aim of this longitudinal study was to investigate 3-year change in serum albumin concentration as a determinant of incident cardiovascular disease (CVD) and all-cause mortality. Data were from 713 respondents of the Longitudinal Aging Study Amsterdam initially aged 55-85 years. Serum albumin was measured at baseline (1992/1993) and after 3 years. At the 6-year follow-up, incident CVD (among 456 respondents with no prevalent CVD at the 3-year follow-up) and all-cause mortality were ascertained. Overall, 18.9% developed CVD and 10.9% died. After adjustment for potential confounders, a higher level of serum albumin at the 3-year follow-up was associated with a lower risk for incident CVD (relative risk = 0.88, 95% confidence interval (CI): 0.79, 0.98). The risk of incident CVD was 0.88 (95% CI: 0.78, 0.99) per unit (g/liter) increase in change in albumin between 3-year follow-up and baseline. Chronic low serum albumin (≤43 g/liter at baseline and 3-year follow-up) was not associated with incident CVD (p = 0.22). A clinically relevant decrease in serum albumin (≥1 standard deviation (2.5 g/liter) between baseline and 3-year follow-up) tended to be associated with a twofold risk (relative risk = 2.00, 95% CI: 0.91, 4.39). For all-cause mortality, no associations were observed. These findings suggest that older persons with a decrease in serum albumin concentration, even within the normal range, might be at increased risk of incident CVD. Change in serum albumin may be used as an early marker for CVD risk. Copyright © 2006 by the Johns Hopkins Bloomberg School of Public Health. All rights reserved.

Objective: The objective of this study was to examine the types of healthcare services used by children, adolescents, and adults with Hirschsprung Disease (HD) in relation to the severity of the initial defect (mild, severe), whether additional care was needed, the provision of information, transfer to adult care, and satisfaction with the care provided.Methods: Three hundred twenty (71%) HD patients, ages 6 to 54, completed a questionnaire that assessed the use of healthcare set-vices, the need for more healthcare, the provision of information, the transfer to adult care and satisfaction with the provided care.Results: In 6 months, 45% of the children, 14% of the adolescents, and 15% of the adults consulted a medical specialist. Compared with patients with a mild form of HD in the age range of 6 to 16 years, only the more severely afflicted adult patients visited medical professionals more often (10% vs 29%) (P Conclusions: There is good access to medical healthcare services, especially for children. The only lacuna in the healthcare system we revealed was a lack of information, particularly for adult patients. Most parents and patients reported to be very satisfied with the provided care. (c) 2006 Elsevier Inc. All rights reserved.

PURPOSE: The aim of this study was to examine changes in the quality of life of adult patients with anorectal malformations or Hirschsprung's disease over a three-year interval and to identify demographic, clinical, and psychosocial variables that explain possible quality-of-life changes. Understanding the factors that affect changes in quality of life over time is particularly important to provide adequate care. METHODS: Questionnaires were administered to 261 patients ( 77 percent), with a three-year interval. Background characteristics, including demographic and clinical variables, and psychosocial variables (i.e., self-esteem, mastery, social support, disease cognition) were measured on one occasion. Generic and disease-specific quality of life were measured twice. RESULTS: On average patients indicated no change in quality-of-life level after three years. However, variance in the change scores revealed individual variation, indicating the presence of patients who improved and patients who deteriorated. Patients who were female, older, have other congenital diseases, or a stoma reported poorer quality of life over time. The psychosocial variable "disease cognition'' most strongly affected the change in quality of life of patients with anorectal malformations or Hirschsprung's disease. CONCLUSIONS: Our results could alert clinicians to patients who are at risk for quality-of-life deterioration and might therefore be in need for extra care. Our findings illustrate the importance of psychosocial functioning for enhancing the quality of life over time of these patients.