Movement disorders and nonmotor neuropsychological symptoms in children and adults with classical galactosemia

Although movement disorders (MDs) are known complications, the exact frequency and severity remains uncertain in patients with classical galactosemia, especially in children. We determined the frequency, classification and severity of MDs in a cohort of pediatric and adult galactosemia patients, and assessed the association with nonmotor neuropsychological symptoms and daily functioning. Patients from seven centers in the United Kingdom and the Netherlands with a confirmed galactosemia diagnosis were invited to participate. A videotaped neurological examination was performed and an expert panel scored the presence, classification and severity of MDs. Disease characteristics, nonmotor neuropsychological symptoms, and daily functioning were evaluated with structured interviews and validated questionnaires (Achenbach, Vineland, Health Assessment Questionnaire, SIP68). We recruited 37 patients; 19 adults (mean age 32.6 years) and 18 children (mean age 10.7 years). Subjective self-reports revealed motor symptoms in 19/37 (51.4%), similar to the objective (video) assessment, with MDs in 18/37 patients (48.6%). The objective severity scores were moderate to severe in one third (6/37). Dystonia was the overall major feature, with additional tremor in adults, and myoclonus in children. Behavioral or psychiatric problems were present in 47.2%, mostly internalizing problems, and associated with MDs. Daily functioning was significantly impaired in the majority of patients. Only one patient received symptomatic treatment for MDs. We show that MDs and nonmotor neuropsychological symptoms are frequent in both children and adults with classical galactosemia

Hepatitis B Virus Surface Antigen Activates Myeloid Dendritic Cells via a Soluble CD14-Dependent Mechanism

Hepatitis B virus (HBV) infection can cause chronic liver disease, which is associated with increased risk of liver cirrhosis, liver failure, and liver cancer. Clearance of HBV infection requires effective HBV-specific immunity; however, the immunological mechanisms that determine the development of effective HBV-specific immunity are poorly understood. Dendritic cells (DC) play a pivotal role in the regulation of antiviral immunity. Here, we investigated the interaction between HBV surface antigen (HBsAg), the main envelope glycoprotein of HBV, and BDCA1(+) myeloid dendritic cells (mDC). Exposure of peripheral blood-derived BDCA1(+) mDC to HBsAg resulted in strong DC maturation, cytokine production, and enhanced capacity to activate antigen- specific cytotoxic T cells (CTLs). By using neutralizing antibodies, crucial roles for CD14 and Toll-like receptor 4 (TLR4) in HBsAg-mediated BDCA1(+) mDC maturation were identified. Concordantly, HBsAg-mediated DC maturation required fetal calf serum (FCS) or human plasma, naturally containing soluble CD14 (sCD14). Intriguingly, HBsAg-induced DC maturation was significantly reduced in umbilical cord blood plasma, which contained less sCD14 than adult plasma, indicating that sCD14 is an important host factor for recognition of HBsAg by DC and subsequent DC activation. A direct interaction between sCD14 and HBsAg was demonstrated by using enzyme-linked immunosorbent assay (ELISA). Moreover, sCD14-HBsAg complexes were detected both in vitro and in sera of HBV-infected patients. The abundance of sCD14-HBsAg complexes varied between chronic HBV disease stages and correlated with activation of BDCA1(+) mDC in vivo. We conclude that HBsAg activates BDCA1(+) DC via an sCD14-dependent mechanism. These findings provide important novel insights into the initiation of HBV-specific immunity and facilitate development of effective immunotherapeutic interventions for HBV

Conditional deletion of TGF-βR1 using Langerin-Cre mice results in Langerhans cell deficiency and reduced contact hypersensitivity

The critical role of Langerhans cells (LC) in contact hypersensitivity (CHS) was recently questioned in studies using different LC-depletion mouse models. On one hand, inducible ablation of LC led to diminished ear swelling, suggesting functional redundancy between LC and (Langerin +) dermal dendritic cells (DC). On the other hand, constitutive or acute depletion of LC resulted in an enhanced reaction, supporting a regulatory role of LC in CHS. To address this controversy by conditional gene targeting, we generated Langerin-Cre knockin mice. Breeding these mice to a Cre-reporter strain demonstrated robust and specific DNA recombination in LC, as well as other Langerin + tissue DC. In agreement with the vital requirement of TGF-β signaling for LC development, crossing Langerin-Cre to mice homozygous for a loxP-flanked TGF-βR1 allele resulted in permanent LC deficiency, whereas the homeostasis of dermal Langerin + DC was unaffected. In the absence of LC, induction of CHS in these Langerin + DC-specific TGF-βR1-deficient mice elicited decreased ear swelling compared with controls. This novel approach provided further evidence against a regulatory function of LC in CHS. Moreover, these Langerin-Cre mice represent a unique and powerful tool to dissect the role and molecular control of Langerin + DC populations beyond LC. Copyrigh

The Successful Return-To-Work Questionnaire for Cancer Survivors (I-RTW_CS):Development, Validity and Reproducibility

Background: Cancer survivors’ perspectives on a successful return to work (RTW) may not be captured in the common measure of RTW, namely time until RTW. Objective: The purpose of this study was therefore to develop an RTW outcome measure that reflects employed cancer survivors’ perspectives, with items that could be influenced by an employer, i.e. the Successful Return-To-Work questionnaire for Cancer Survivors (I-RTW_CS), and to assess its construct validity and reproducibility. Methods: First, three focus groups with cancer survivors (n = 14) were organized to generate issues that may constitute successful RTW. Second, a two-round Delphi study among 108 cancer survivors was conducted to select the most important issues. Construct validity of the I-RTW_CS was assessed using correlations with a single-item measure of successful RTW and the Quality of Working Life Questionnaire for Cancer Survivors (QWLQ-CS; n = 57). Reproducibility (test–retest reliability) was assessed using the intraclass correlation coefficient (ICC; n = 50). Results: Forty-eight issues were generated, of which seven were included: ‘enjoyment in work’; ‘work without affecting health’; ‘confidence of employer without assumptions about work ability’; ‘open communication with employer’; ‘feeling welcome at work’; ‘good work–life balance’; and ‘joint satisfaction with the situation (employer and cancer survivor)’. Correlations with single-item successful RTW and QWLQ-CS were 0.58 and 0.85, respectively. The reproducibility showed an ICC of 0.72. Conclusions: The I-RTW_CS provides an RTW outcome measure that includes cancer survivors’ perspectives and weights its items on an individual basis, allowing a more meaningful evaluation of cancer survivors’ RTW. This study provides preliminary evidence for its construct validity and reproducibility

Interobserver reproducibility of tumor uptake quantification with 89Zr-immuno-PET: a multicenter analysis

Purpose: In-vivo quantification of tumor uptake of 89-zirconium (89Zr)-labelled monoclonal antibodies (mAbs) with PET provides a potential tool in strategies to optimize tumor targeting and therapeutic efficacy. A specific challenge for 89Zr-immuno-PET is low tumor contrast. This is expected to result in interobserver variation in tumor delineation. Therefore, the aim of this study was to determine interobserver reproducibility of tumor uptake measures by tumor delineation on 89Zr-immuno-PET scans. Methods: Data were obtained from previously published clinical studies performed with 89Zr-rituximab, 89Zr-cetuximab and 89Zr-trastuzumab. Tumor lesions on 89Zr-immuno-PET were identified as focal uptake exceeding local background by a nuclear medicine physician. Three observers independently manually delineated volumes of interest (VOI). Maximum, peak and mean standardized uptake values (SUVmax, SUVpeak and SUVmean) were used to quantify tumor uptake. Interobserver variability was expressed as the coefficient of variation (CoV). The performance of semi-automatic VOI delineation using 50% of background-corrected ACpeak was described. Results: In total, 103 VOI were delineated (3–6 days post injection (D3-D6)). Tumor uptake (median, interquartile range) was 9.2 (5.2–12.6), 6.9 (4.0–9.6) and 5.5 (3.3–7.8) for SUVmax, SUVpeak and SUVmean. Interobserver variability was 0% (0–12), 0% (0–2) and 7% (5–14), respectively (n = 103). The success rate of the semi-automatic method was 45%. Inclusion of background was the main reason for failure of semi-automatic VOI. Conclusions: This study shows that interobserver reproducibility of tumor uptake quantification on 89Zr-immuno-PET was excellent for SUVmax and SUVpeak using a standardized manual procedure for tumor segmentation. Semi-automatic delineation was not robust due to limited tumor contrast