To investigate whether mammalian target of rapamycin inhibitor everolimus can improve intellectual disability, autism, and other neuropsychological deficits in children with tuberous sclerosis ...complex (TSC).
In this 12-month, randomized, double-blind, placebo-controlled trial, we attempted to enroll 60 children with TSC and IQ <80, learning disability, special schooling, or autism, aged 4-17 years, without intractable seizures to be assigned to receive everolimus or placebo. Everolimus was titrated to blood trough levels of 5-10 ng/mL. Primary outcome was full-scale IQ; secondary outcomes included autism, neuropsychological functioning, and behavioral problems.
Thirty-two children with TSC were randomized. Intention-to-treat analysis showed no benefit of everolimus on full-scale IQ (treatment effect -5.6 IQ points, 95% confidence interval -12.3 to 1.0). No effect was found on secondary outcomes, including autism and neuropsychological functioning, and questionnaires examining behavioral problems, social functioning, communication skills, executive functioning, sleep, quality of life, and sensory processing. All patients had adverse events. Two patients on everolimus and 2 patients on placebo discontinued treatment due to adverse events.
Everolimus did not improve cognitive functioning, autism, or neuropsychological deficits in children with TSC. The use of everolimus in children with TSC with the aim of improving cognitive function and behavior should not be encouraged in this age group.
NCT01730209.
This study provides Class I evidence that for children with TSC, everolimus does not improve intellectual disability, autism, behavioral problems, or other neuropsychological deficits.
Paediatric population neuroimaging is an emerging field that falls at the intersection between developmental neuroscience and epidemiology. A key feature of population neuroimaging studies involves ...largescale recruitment that is representative of the general population. One successful approach for population neuroimaging is to embed neuroimaging studies within large epidemiological cohorts. The Generation R Study is a large, prospective population-based birth-cohort in which nearly 10,000 pregnant mothers were recruited between 2002 and 2006 with repeated measurements in the children and their parents over time. Magnetic resonance imaging was included in 2009 with the scanning of 1070 6-to-9year-old children. The second neuroimaging wave was initiated in April 2013 with a total of 4245 visiting the MRI suite and 4087 9-to-11 -year-old children being scanned. The sequences included high-resolution structural MRI, 35-direction diffusion weighted imaging, and a 6 min and 2 s resting-state functional MRI scan. The goal of this paper is to provide an overview of the imaging protocol and the overlap between the neuroimaging data and metadata. We conclude by providing a brief overview of results from our first wave of neuroimaging, which highlights a diverse array of questions that can be addressed by merging the fields of developmental neuroscience and epidemiology.
Little is known about care needs of young adults with Fragile X Syndrome (FXS). Patient-driven information is needed to improve understanding and support of young adults with FXS. A qualitative study ...was performed in 5 young adult patients (aged 18–30), and 33 parents of young adults. Concerns and care needs were categorized using the International Classification of Functioning, Disability, and Health. Results indicated concerns on 14 domains for males, and 13 domains for females, including physical, psychological and socio-economical issues. In both groups parents reported high stress levels and a lack of knowledge of FXS in adult care providers. This study revealed concerns on various domains, requiring gender-specific, multidisciplinary transitional care and adult follow-up for patients with FXS.
Abstract
The physiochemical characteristics include: density, solubility, viscosity, molecular weight, degree of deacetylation and functional properties like fat and water binding capacity were ...studied for chitosan that prepared from chitin of
Agaricus bisporus
mushroom, the chitosan prepared by treatment of chitin with 47% alkaline solution at 60°C remove 4 hour
−1
. The yield of chitin extract from chitosan showed that the chitin extraction rate was 16% based on the dry weight of the fungus. Chitosan, which was produced in this study, was diagnosed by Fourier Transform Infrared Spectrophotometer (FTIR) method. The degree of deacetylation (DD%) of the chitosan produced from the fungus it was 71.5% chitosan showed viscosity of 5.5 centipoise the viscosity has been estimated when chitosan dissolved in 1% acetic acid solution. The molecular weight of the fungus chitosan was 604,610 Dalton. The chitosan was characterized by high solubility (72%) in 1% acetic acid solution and showed high water binding capacity and fat binding capacity were 674%, 257% respectively of the fungal chitosan.
Congenital diaphragmatic hernia (CDH) is a rare congenital anomaly characterised by a diaphragmatic defect, persistent pulmonary hypertension (PH) and lung hypoplasia. The relative contribution of ...these three elements can vary considerably in individual patients. Most affected children suffer primarily from the associated PH, for which the therapeutic modalities are limited and frequently not evidence based. The vascular defects associated with PH, which is characterised by increased muscularisation of arterioles and capillaries, start to develop early in gestation. Pulmonary vascular development is integrated with the development of the airway epithelium. Although our knowledge is still incomplete, the processes involved in the growth and expansion of the vasculature are beginning to be unravelled. It is clear that early disturbances of this process lead to major pulmonary growth abnormalities, resulting in serious clinical challenges and in many cases death in the newborn. Here we provide an overview of the current molecular pathways involved in pulmonary vascular development. Moreover, we describe the abnormalities associated with CDH and the potential therapeutic approaches for this severe abnormality.
Vision is initiated by the rhodopsin family of light-sensitive G protein-coupled receptors (GPCRs)
. A photon is absorbed by the 11-cis retinal chromophore of rhodopsin, which isomerizes within 200 ...femtoseconds to the all-trans conformation
, thereby initiating the cellular signal transduction processes that ultimately lead to vision. However, the intramolecular mechanism by which the photoactivated retinal induces the activation events inside rhodopsin remains experimentally unclear. Here we use ultrafast time-resolved crystallography at room temperature
to determine how an isomerized twisted all-trans retinal stores the photon energy that is required to initiate the protein conformational changes associated with the formation of the G protein-binding signalling state. The distorted retinal at a 1-ps time delay after photoactivation has pulled away from half of its numerous interactions with its binding pocket, and the excess of the photon energy is released through an anisotropic protein breathing motion in the direction of the extracellular space. Notably, the very early structural motions in the protein side chains of rhodopsin appear in regions that are involved in later stages of the conserved class A GPCR activation mechanism. Our study sheds light on the earliest stages of vision in vertebrates and points to fundamental aspects of the molecular mechanisms of agonist-mediated GPCR activation.
A new AMS system (HVEE 4103Bo-AMS) was installed at Tono Geoscience Center, Japan Atomic Energy Agency in November 2019 and AMS experiments started in 2020. The system consists of a SO-110C Cs ...sputtering ion source, a low-energy spectrometer with an ESA and an injection magnet, a 300 kV tandem accelerator, a high energy spectrometer with two analyzing magnets and an ESA, and a gas ionization chamber for rare isotope measurement. The system is designed for high-sensitivity detection of 10Be, 14C, 26Al and 129I. A comparison with our 5 MV Pelletron is also given in this paper.
Summary
This single‐centre retrospective observational study analysed the efficacy of retreatment with immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) after treatment with daratumumab ...monotherapy in patients with relapsed and/or refractory multiple myeloma (RRMM). In total 55 patients were treated with daratumumab monotherapy between 2010 and 2017. From this group 29 (53%) IMiD‐refractory patients were retreated with an IMiD after daratumumab and 6 (11%) PI‐refractory patients were retreated with a PI‐based regimen. For the IMiD‐refractory patients the overall response rate (ORR) was 52% (15/29 patients, partial response or better) upon IMiD retreatment, whereas the ORR to PI retreatment was 67% (4/6 patients) in the PI‐refractory group. The immunomodulatory effects of daratumumab may play a role in these high response rates in previously refractory patients. Due to the >6 month‐long persistence of daratumumab in the plasma the subsequent therapies can effectively be considered as combination therapy. Furthermore, the excellent tolerability of daratumumab treatment may enable patients to recover from prior lines of treatment and receive full dosing of subsequent therapies. In conclusion, a high proportion of RRMM patients benefitted from retreatment with IMiDs and PIs after daratumumab treatment. These retreatment options should therefore be explored in RRMM patients progressing on daratumumab monotherapy.
Patients with congenital diaphragmatic hernia (CDH) have structural and functional different pulmonary vessels, leading to pulmonary hypertension. They often fail to respond to standard vasodilator ...therapy targeting the major vasoactive pathways, causing a high morbidity and mortality. We analyzed whether the expression of crucial members of these vasoactive pathways could explain the lack of responsiveness to therapy in CDH patients.
The expression of direct targets of current vasodilator therapy in the endothelin and prostacyclin pathway was analyzed in human lung specimens of control and CDH patients.
CDH lungs showed increased expression of both ETA and ETB endothelin receptors and the rate-limiting Endothelin Converting Enzyme (ECE-1), and a decreased expression of the prostaglandin-I
receptor (PTGIR). These data were supported by increased expression of both endothelin receptors and ECE-1, endothelial nitric oxide synthase and PTGIR in the well-established nitrofen-CDH rodent model.
Together, these data demonstrate aberrant expression of targeted receptors in the endothelin and prostacyclin pathway in CDH already early during development. The analysis of this unique patient material may explain why a significant number of patients do not respond to vasodilator therapy. This knowledge could have important implications for the choice of drugs and the design of future clinical trials internationally.
Recent research has demonstrated that subclinical autistic traits of parents amplify the effects of deleterious mutations in the causation of autism spectrum disorder (ASD) in their offspring. Here, ...we examined the extent to which two neurodevelopmental traits that are non-specific to ASD-inattention/hyperactivity and motor coordination-might contribute to ASD recurrence in siblings of ASD probands.
Data from a quantitative trait study of 114 ASD probands and their brothers, 26% of whom also had ASD, were analyzed. Autistic trait severity was ascertained using the Social Responsiveness Scale-2, attention/hyperactivity problems using the Achenbach System of Empirically Based Assessment, and motor coordination (in a subset of participants) using the Developmental Coordination Disorder Questionnaire.
Among siblings (affected and unaffected), both categorical recurrence of ASD (Nagelkerke R
= 0.53) and quantitative ASD trait burden (R
= 0.55) were predicted by sibling ADHD and motor coordination impairment scores, even though these traits, on average, were not elevated among the unaffected siblings.
These findings in a clinical family cohort confirm observations from general population studies that inattention/hyperactivity and motor impairment-axes of behavioral development that are non-specific to ASD, and often appreciable before ASD is typically diagnosed-jointly account for over 50% of the variation in autistic impairment of siblings, whether ascertained quantitatively or categorically. This finding within a sibling design suggests that background ASD susceptibilities that are inherited but non-specific ("BASINS") may contribute to additive genetic liability in the same manner that ASD-specific susceptibilities (such as parental subclinical ASD traits and deleterious mutations) engender ASD risk.
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