The Dyskinesia Impairment Scale: a new instrument to measure dystonia and choreoathetosis in dyskinetic cerebral palsy

Aim The aim of this study was to examine the reliability and validity of the Dyskinesia Impairment Scale (DIS). The DIS consists of two subscales: dystonia and choreoathetosis. It measures both phenomena in dyskinetic cerebral palsy (CP). Method Twenty‐five participants with dyskinetic CP (17 males; eight females; age range 5–22y; mean age 13y 6mo; SD 5y 4mo), recruited from special schools for children with motor disorders, were included. Exclusion criteria were changes in muscle relaxant medication within the previous 3 months, orthopaedic or neurosurgical interventions within the previous year, and spinal fusion. Interrater reliability was verified by two independent raters. For interrater reliability, intraclass correlation coefficients were assessed. Standard error of measurement, the minimal detectable difference, and Cronbach’s alpha for internal consistency were determined. For concurrent validity of the DIS dystonia subscale, the Barry–Albright Dystonia Scale was administered. Results The intraclass correlation coefficient for the total DIS score and the two subscales ranged between 0.91 and 0.98 for interrater reliability. The reliability of the choreoathetosis subscale was found to be higher than that of the dystonia subscale. The standard error of the measurement and minimal detectable difference values were adequate. Cronbach’s alpha values ranged from 0.89 to 0.93. Pearson’s correlation between the dystonia subscale and Barry–Albright Dystonia Scale was 0.84 (p<0.001). Interpretation Good to excellent reliability and validity were found for the DIS. The DIS may be promising for increasing insights into the natural history of dyskinetic CP and evaluating interventions. Future research on the responsiveness of the DIS is warranted.     

Membrane-anchored uPAR regulates the proliferation, marrow pool size, engraftment, and mobilization of mouse hematopoietic stem/progenitor cells

The mechanisms of BM hematopoietic stem/progenitor cell (HSPC) adhesion, engraftment, and mobilization remain incompletely identified. Here, using WT and transgenic mice, we have shown that membrane-anchored plasminogen activator, urokinase receptor (^MuPAR) marks a subset of HSPCs and promotes the preservation of the size of this pool of cells in the BM. Loss or inhibition of ^MuPAR increased HSPC proliferation and impaired their homing, engraftment, and adhesion to the BM microenvironment. During mobilization, ^MuPAR was inactivated by plasmin via proteolytic cleavage. Cell-autonomous loss of the gene encoding ^MuPAR also impaired long-term engraftment and multilineage repopulation in primary and secondary recipient mice. These findings identify ^MuPAR and plasmin as regulators of the proliferation, marrow pool size, homing, engraftment, and mobilization of HSPCs and possibly also of HSCs.     

HRAS-related epidermal nevus syndromes: Expansion of the spectrum with first branchial arch defects

Epidermal nevus syndrome (ENS) comprises a heterogeneous group of neurocutaneous syndromes associated with the presence of epidermal nevi and variable extracutaneous manifestations. Postzygotic activating HRAS pathogenic variants were previously identified in nevus sebaceous (NS), keratinocytic epidermal nevus (KEN), and different ENS, including Schimmelpenning–Feuerstein–Mims and cutaneous-skeletal-hypophosphatasia syndrome (CSHS). Skeletal involvement in HRAS-related ENS ranges from localized bone dysplasia in association with KEN to fractures and limb deformities in CSHS. We describe the first association of HRAS-related ENS and auricular atresia, thereby expanding the disease spectrum with first branchial arch defects if affected by the mosaic variant. In addition, this report illustrates the first concurrent presence of verrucous EN, NS, and nevus comedonicus (NC), indicating the possibility of mosaic HRAS variation as an underlying cause of NC. Overall, this report extends the pleiotropy of conditions associated with mosaic pathogenic variants in HRAS affecting ectodermal and mesodermal progenitor cells.     

Role of MRP4 and MRP5 in biology and chemotherapy

Nucleotide efflux (especially cyclic nucleotides) from a variety of mammalian tissues, bacteria, and lower eukaryotes has been studied for several decades. However, the molecular identity of these nucleotide efflux transporters remained elusive, despite extensive knowledge of their kinetic properties and inhibitor profiles. Identification of the subfamily of adenosine triphosphate (ATP) binding cassette transporters, multidrug resistance protein (MRP) subfamily, permitted rapid advances because some recently identified MRP family members transport modified nucleotide analogs (ie, chemotherapeutic agents). We first identified, MRP4, based on its ability to efflux antiretroviral compounds, such as azidothymidine monophosphate (AZT-MP) and 9-(2-phosphonyl methoxyethyl) adenine (PMEA), in drug-resistant and also in transfected cell lines. MRP5, a close structural homologue of MRP4 also transported PMEA. MRP4 and MRP5 confer resistance to cytotoxic thiopurine nucleotides, and we demonstrate MRP4 expression varies among acute lymphoblastic leukemias, suggesting this as a factor in response to chemotherapy with these agents. The ability of MRP4 and MRP5 to transport 3,5-cyclic adenosine monophosphate (cAMP) and 3,5-cyclic guanosine monophosphate (cGMP) suggests they may play a biological role in cellular signaling by these nucleotides. Finally, we propose that MRP4 may also play a role in hepatic bile acid homeostasis because loss of the main bile acid efflux transporter, sister of P-glycoprotein (SPGP) aka bile-salt export pump (BSEP), leads to a strong compensatory upregulation in MRP4 expression. Cumulatively, these studies reveal that the ATP-binding cassette (ABC) transporters MRP4 and MRP5 have a unique role in biology and in chemotherapeutic response.     

Bruck syndrome: neonatal presentation and natural course in three patients

Three unrelated patients with congenital arthrogryposis and brittle bones, the main neonatal signs of Bruck syndrome, are presented. In infancy and early childhood recurrent fractures of ribs and long bones and persistent Wormian bones in the calvarium are reminiscent of osteogenesis imperfecta (OI) even with white sclerae, normal dental quality and normal hearing as important clinical negatives. The diagnosis was made before two years of age in two, and in adolescence in the third patient. The latter's radiologically documented long-term natural course reveals slow progressivity of osteopenia and growth deficiency, worsening tendon contractures and pterygia in addition to increasing spine and pelvis deformation. Mental development remains normal. Bruck syndrome is monogenic and probably due to homozygosity of an as yet unidentified gene. As no alteration in the collagens I and III is detected and molecular screening reveals no mutation in the COL1A1 and COL1A2 genes, the pathogenesis of this severe disorder of connective tissue remains largely unknown. Received/accepted: 6 May 1998     

Randomized Phase 1 Trial of Pembrolizumab with Sequential Versus Concomitant Stereotactic Body Radiotherapy in Metastatic Urothelial Carcinoma

Preclinical data indicate that radiotherapy works synergistically with pembrolizumab, but the effect and toxicity of this combination may depend on radiotherapy timing. We conducted a randomized phase 1 trial combining pembrolizumab with either sequential (A) or concomitant (B) stereotactic body radiotherapy (SBRT) in metastatic urothelial carcinoma (mUC). No dose-limiting toxicity occurred. Treatment-related adverse events (trAEs; Common Terminology Criteria for Adverse Events v4.0) of grade 1–2 occurred in six of nine and all nine patients in arms A and B, respectively. One grade 3 trAE occurred in arm B. No grade 4–5 trAEs occurred. Overall response rates of 0% and 44.4% were noted in arms A and B, respectively, as per Response Evaluation Criteria in Solid Tumors v1.1. The trial was not powered to compare efficacy between arms. Targeted sequencing of tissue DNA and circulating tumor DNA (ctDNA) revealed high genomic concordance. Treatment response was associated with ctDNA fraction decline. We conclude that sequential and concomitant SBRT can be safely combined with pembrolizumab in mUC and that the effect of SBRT timing on efficacy is worth exploring further.

Nutritional Interventions to Improve Asthma-Related Outcomes through Immunomodulation: A Systematic Review

Asthma is a chronic inflammatory disease of the airways, characterized by T-helper (Th) 2 inflammation. Current lifestyle recommendations for asthma patients are to consume a diet high in fruits and vegetables and to maintain a healthy weight. This raises the question of whether other nutritional interventions may also improve asthma-related outcomes and whether these changes occur via immunomodulation. Therefore, we systematically reviewed studies that reported both asthma-related outcomes as well as immunological parameters and searched for relations between these two domains. A systematic search identified 808 studies, of which 28 studies met the inclusion criteria. These studies were divided over six nutritional clusters: herbs, herbal mixtures and extracts (N = 6); supplements (N = 4); weight loss (N = 3); vitamin D3 (N = 5); omega-3 long-chain polyunsaturated fatty acids (LCPUFAs) (N = 5); and whole-food approaches (N = 5). Fifteen studies reported improvements in either asthma-related outcomes or immunological parameters, of which eight studies reported simultaneous improvements in both domains. Two studies reported worsening in either asthma-related outcomes or immunological parameters, of which one study reported a worsening in both domains. Promising interventions used herbs, herbal mixtures or extracts, and omega-3 LCPUFAs, although limited interventions resulted in clinically relevant results. Future studies should focus on further optimizing the beneficial effects of nutritional interventions in asthma patients, e.g., by considering the phenotypes and endotypes of asthma.     

Awareness of General Practitioners concerning cancer patients’ preferences for place of death: Evidence from four European countries

BackgroundGeneral Practitioners (GPs) are at the first level of contact in many European healthcare systems and they supposedly have a role in supporting cancer patients in achieving their desired place of death. A four-country (Belgium, the Netherlands, Italy and Spain) study was carried out exploring current practices.Patients and MethodsEURO SENTI-MELC adopted a retrospective study design and data for this study were collected in 2010 through representative GPs’ networks in four countries. In the current study all non-sudden cancer deaths were included with weekly GP registrations.ResultsThe main study sample included 930 deceased cancer patients: preference for place of death was known by GPs for only 377. GP awareness on the preferred place of death varied across countries, 27% in Italy, 36% in Spain, 45% in Belgium and 72% in the Netherlands (p < 0.01). The general level of preferences met was high, from 68% (Italy) to 92% (Spain).ConclusionsDespite the importance of being able to die in a preferred location, GPs were often unaware about patient preferences, especially in Italy and Spain. If GPs were informed, the preference was often met in all countries, indicating room for improvement in end-of-life care.