Understanding caregiver descriptions of initial signs and symptoms to improve diagnosis of metachromatic leukodystrophy.

BACKGROUND: Metachromatic leukodystrophy (MLD), a relentlessly progressive and ultimately fatal condition, is a rare autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme arylsulfatase A (ARSA). Historically management has been palliative or supportive care. Hematopoietic stem cell transplantation is poorly effective in early-onset MLD and benefit in late-onset MLD remains controversial. Hematopoietic stem cell gene therapy, Libmeldy (atidarsagene autotemcel), was recently approved by the European Medicines Agency for early-onset MLD. Treatment benefit is mainly observed at an early disease stage, indicating the need for early diagnosis and intervention. This study contributes insights into the caregiver language used to describe initial MLD symptomatology, and thereby aims to improve communication between clinicians and families impacted by this condition and promote a faster path to diagnosis. RESULTS: Data was collected through a moderator-assisted online 60-min survey and 30-min semi-structured follow-up telephone interview with 31 MLD caregivers in the United States (n = 10), France (n = 10), the United Kingdom (n = 5), and Germany (n = 6). All respondents were primary caregivers of a person with late infantile (n = 20), juvenile (n = 11) or borderline late infantile/juvenile (n = 1) MLD (one caregiver reported for 2 children leading to a sample of 32 individuals with MLD). Caregivers were asked questions related to their child's initial signs and symptoms, time to diagnosis and interactions with healthcare providers. These results highlight the caregiver language used to describe the most common initial symptoms of MLD and provide added context to help elevate the index of suspicion of disease. Distinctions between caregiver descriptions of late infantile and juvenile MLD in symptom onset and disease course were also identified. CONCLUSIONS: This study captures the caregiver description of the physical, behavioral, and cognitive signs of MLD prior to diagnosis. The understanding of the caregiver language at symptom onset sheds light on a critical window of often missed opportunity for earlier diagnosis and therapeutic intervention in MLD.

Cropland trees need to be included for accurate model simulations of land-atmosphere heat fluxes, temperature, boundary layer height, and ozone.

Trees significantly impact land-atmosphere feedbacks through evapotranspiration, photosynthesis and isoprene emissions. These processes influence the local microclimate, air quality and can mitigate temperature extremes and sequester carbon dioxide. Despite such importance, currently only 5 out of 15 atmospheric chemistry climate models even partially account for the presence of cropland trees. We first show that the tree cover over intensely farmed regions in Asia, Australia and South America is significantly underestimated (e.g. only 1-3% tree cover over north-India) in the Model of Emissions of Gases and Aerosol from Nature (MEGAN) and absent in Noah land-surface module of the Weather Research and Forecasting (WRF-Chem) Model. By including the actual tree cover (~10%) over the north-west Indo Gangetic Plain in the Noah land-surface module of the WRF-Chem and the MEGAN module, during the rice growing monsoon season in August, we find that the latent heat flux alone increases by 100%-300% while sensible heat flux reduces by 50%-100%, leading to a reduction in daytime boundary layer height by 200-400 m. This greatly improves agreement between the modelled and measured temperature, boundary layer height and surface ozone, which were earlier overestimated and isoprene and its oxidation products which were earlier underestimated. Mitigating peak daytime temperatures and ozone improves rice production by 10 to 20%. Our findings from north west Indo-Gangetic Plain establish that such plantations mitigate heat stress, and have beneficial effects on crop yields while also sequestering carbon. Expanding agroforestry practices to 50% of the cropland area could result in up to 40% yield gain regionally. Implementing such strategies globally could increase crop production and sequester 0.3-30 GtC per year, and therefore future climate mitigation and food security efforts should consider stakeholder participation for increased cropland agroforestry in view of its beneficial effects.

COVID-19 stay-at-home order in Tyrol, Austria: sports and exercise behaviour in change?

OBJECTIVES: The aim of the study was to investigate differences in the frequency and types of engagement in sports before, during and after the coronavirus disease 2019 (COVID-19) stay-at-home order in Tyrol, Austria. STUDY DESIGN: A representative population survey was conducted. METHODS: A sample of Tyroleans (N = 511) was questioned by a market research institute via an online questionnaire or telephone survey. RESULTS: During the stay-at-home order, participants engaged less in sports than before and after the restrictions. However, within-group analyses revealed increasing sport participation in less active groups when comparing the pre- and post-COVID-19 period. CONCLUSIONS: Despite the restrictions during the stay-at-home order, respondents did engage in sports and promoted their health. Nevertheless, it is still necessary to investigate the long-term effects of the COVID-19 crisis on sports and exercise behaviour as well as the extent to which sports policy measures may be able increase sports participation.

Weak Polyampholytes at the Interface of Magnetic Nanocarriers: A Facile Catch-and-Release Platform for Dyes.

We present a platform of charge-invertible core-shell hybrid particles for the selective and reversible adsorption of small charged molecules as model systems. The herein employed carrier systems consist of an iron oxide core coated with different pH-responsive polyampholytes which exhibit varying surface charge depending on the surrounding pH value. The resulting materials were used for electrostatically mediated catch-and-release experiments of either cationic or anionic dyes with the perspective to allow the pH-dependent magnetically guided transport of suitable cargo. The use of three different polyampholyte coatings (poly(2-(imidazol-1-yl)acrylic acid) (PImAA), poly(dehydroalanine) (PDha), and poly(N,N-diallylglutamate) (PDAGA)) enables a deeper understanding about how the surface net charge in combination with the charge and charge density of any cargo influences such processes. The size, surface charge, and aggregation behavior of the herein described particles were investigated via dynamic light scattering (DLS), transmission electron microscopy (TEM), and pH-dependent ζ-potential measurements, whereas adsorption and release studies were investigated via UV-vis.

Functional characterization of the Hyles euphorbiae hawkmoth transcriptome reveals strong expression of phorbol ester detoxification and seasonal cold hardiness genes.

BACKGROUND: The European spurge hawkmoth, Hyles euphorbiae (Lepidoptera, Sphingidae), has been intensively studied as a model organism for insect chemical ecology, cold hardiness and evolution of species delineation. To understand species isolation mechanisms at a molecular level, this study aims at determining genetic factors underlying two adaptive ecological trait candidates, phorbol ester (TPA) detoxification and seasonal cold acclimation. METHOD: A draft transcriptome of H. euphorbiae was generated using Illumina sequencing, providing the first genomic resource for the hawkmoth subfamily Macroglossinae. RNA expression levels in tissues of experimental TPA feeding larvae and cooled pupae was compared to levels in control larvae and pupae using 26 bp RNA sequence tag libraries (DeepSuperSAGE). Differential gene expression was assessed by homology searches of the tags in the transcriptome. RESULTS: In total, 389 and 605 differentially expressed transcripts for detoxification and cold hardiness, respectively, could be identified and annotated with proteins. The majority (22 of 28) of differentially expressed detox transcripts of the four 'drug metabolism' enzyme groups (cytochrome P450 (CYP), carboxylesterases (CES), glutathione S-transferases (GST) and lipases) are up-regulated. Triacylglycerol lipase was significantly over proportionally annotated among up-regulated detox transcripts. We record several up-regulated lipases, GSTe2, two CESs, CYP9A21, CYP6BD6 and CYP9A17 as candidate genes for further H. euphorbiae TPA detoxification analyses. Differential gene expression of the cold acclimation treatment is marked by metabolic depression with enriched Gene Ontology terms among down-regulated transcripts almost exclusively comprising metabolism, aerobic respiration and dissimilative functions. Down-regulated transcripts include energy expensive respiratory proteins like NADH dehydrogenase, cytochrome oxidase and ATP synthase. Gene expression patterns show shifts in carbohydrate metabolism towards cryoprotectant production. The Glycolysis enzymes, G1Pase, A1e, Gpi and an Akr isoform are up-regulated. Glycerol, an osmolyte which lowers the body liquid supercooling point, appears to be the predominant polyol cryoprotectant in H. euphorbiae diapause pupae. Several protein candidates involved in glucose, glycerol, myo-inositol and potentially sorbitol and trehalose synthesis were identified. CONCLUSIONS: A majority of differently expressed transcripts unique for either detoxification or cold hardiness indicates highly specialized functional adaptation which may have evolved from general cell metabolism and stress response.The transcriptome and extracted candidate biomarkers provide a basis for further gene expression studies of physiological processes and adaptive traits in H. euphorbiae.

Evaluation of Parameterized Convective Transport of Trace Gases in Simulation of Storms Observed During the DC3 Field Campaign.

Deep convective transport of surface moisture and pollution from the planetary boundary layer to the upper troposphere and lower stratosphere affects the radiation budget and climate. This study uses cloud-parameterized Weather Research and Forecasting model coupled with Chemistry simulations to analyze the subgrid deep convective transport of CO at 12- and 36-km horizontal resolution in supercell and mesoscale convective systems observed during the 2012 Deep Convective Clouds and Chemistry field campaign and compares the simulation results with aircraft measurements and cloud-resolved simulations. The best Weather Research and Forecasting simulation of these storms was obtained with the use of the Grell-Freitas convective scheme. The default Weather Research and Forecasting model coupled with Chemistry subgrid convective transport scheme was replaced with a scheme to compute convective transport within the Grell-Freitas subgrid cumulus parameterization, which resulted in improved transport simulations. We examined the CO tendencies due to subgrid- and grid-scale convective transport. Results showed that the subgrid convective transport started earlier than the grid-scale convective transport. The subgrid-scale convective transport reached its maximum during the hour prior to the formation of the grid-scale constant-altitude detrainment layer. After that, both the subgrid- and grid-scale convective transport began to decrease. The subgrid-scale convective transport played a more significant role in the supercell case than the mesoscale convective system case. Subgrid contribution reached ~90% at the beginning of the storm and decreased to ~30% (17%) for the 36-km (12-km) domain 4 hr later.

Phase transformation in AFM silicon tips.

We confirmed the occurrence of phase transformations in an atomic force microscopy silicon tip during loading and unloading experiments performed on a polycrystalline Ti sample. The influence of the phase transformations on the effective mechanical and electrical properties of the tip was observed with the help of load-unload curves measured simultaneously for the tip-sample contact stiffness k * and the effective electrical resistance of the system R eff. We used the atomic force acoustic microscopy (AFAM) method to determine the values of k *. To measure the changes in R eff, we combined a high voltage source/measure unit with the existing AFAM system. The data obtained showed that the phase transformation from Si-I to Si-II is preceded by other structural changes such as formation of distorted diamond structures and formation of Si-III. This conclusion was reached after observing a small hysteretic behavior in the load-unload stiffness curve accompanied by only very small changes in the resistance of the tip-sample system occurring on the unloading. The coinciding of a sudden increase in the values of the contact stiffness with a decrease in the resistance of the system indicated that the formation of metallic Si-II occurred in the subsequent measurements. The interpretation of our results found confirmation in the results of molecular dynamics and atomistic simulations performed for silicon under nanoindentation experiments.

Using observations and source specific model tracers to characterize pollutant transport during FRAPPÉ and DISCOVER-AQ.

Transport is a key parameter in air quality research and plays a dominant role in the Colorado Northern Front Range Metropolitan Area (NFRMA), where terrain induced flows and recirculation patterns can lead to vigorous mixing of different emission sources. To assess different transport processes and their connection to air quality in the NFRMA during the FRAPPÉ and DISCOVER-AQ campaigns in summer 2014, we use the Weather Research and Forecasting Model with inert tracers. Overall, the model represents well the measured winds and the inert tracers are in good agreement with observations of comparable trace gas concentrations. The model tracers support the analysis of surface wind and ozone measurements and allow for the analysis of transport patterns and interactions of emissions. A main focus of this study is on characterizing pollution transport from the NFRMA to the mountains by mountain-valley flows and the potential for recirculating pollution back into the NFRMA. One such event on 12 August 2014 was well captured by the aircraft and is studied in more detail. The model represents the flow conditions and demonstrates that during upslope events, frequently there is a separation of air masses that are heavily influenced by oil and gas emissions to the North and dominated by urban emissions to the South. This case study provides evidence that NFRMA pollution not only can impact the nearby Foothills and mountain areas to the East of the Continental Divide, but that pollution can "spill over" into the valleys to the West of the Continental Divide.

Chronic Diarrhea in L-Amino Acid Decarboxylase (AADC) Deficiency: A Prominent Clinical Finding Among a Series of Ten French Patients.

Aromatic L-amino acid decarboxylase (AADC) deficiency is an autosomal recessive inborn error of metabolism, affecting catecholamines and serotonin biosynthesis. Cardinal signs consist in psychomotor delay, hypotonia, oculogyric crises, dystonia, and extraneurological symptoms. PATIENTS AND METHODS: We present a retrospective descriptive multicentric study concerning ten French children with a biochemical and molecular confirmed diagnosis of AADC deficiency. RESULTS: Clinical presentation of most of our patients was consistent with the previous descriptions from the literature (hypotonia (nine children), autonomic signs (nine children), sleep disorders (eight children), oculogyric crises (eight children), motor disorders like hypertonia and involuntary movements (seven children)). We described however some phenotypic particularities. Two patients exhibited normal intellectual abilities (patients already described in the literature). We also underlined the importance of digestive symptoms like diarrhea, which occurred in five among the ten patients. We report in particular two children with chronic diarrhea, complicated by severe failure to thrive. Vanillactic acid (VLA) elevation in urines of one of these two patients led to suspect the diagnosis of AADC deficiency, as in two other patients from our population. CONCLUSION: Some symptoms like chronic diarrhea were atypical and have been poorly described in the literature up to now. Diagnosis of the AADC deficiency is sometimes difficult because of the phenotypic heterogeneity of the disease and VLA elevation in urines should suggest the diagnosis.

RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes.

Pontocerebellar hypoplasias (PCH) are characterized by lack of development and/or early neurodegeneration of cerebellum and brainstem. We report five patients referred for PCH, showing atypical clinical and magnetic resonance imaging (MRI) features suggestive of defects in the Reelin pathway. We screened for mutations in RELN or VLDLR and compared the phenotype of these patients with that of previously reported patients. All patients had profound cerebellar hypoplasia on MRI with peculiar cerebellar morphology, associated with flattened pons and neocortical abnormalities. Patient 1 had profound motor and intellectual disability with moderate lissencephaly suggestive of RELN mutations and was shown to harbor a splicing homozygous RELN mutation. The four other patients had a milder phenotype consistent with CARMQ1 (cerebellar ataxia and mental retardation with or without quadrupedal locomotion). These patients showed mild simplification or thickening of cortical gyration and had VLDLR mutations. Reelin signaling regulates neuronal migration in the developing mammalian brain. VLDLR is a key component of the Reelin pathway. Our patients had a very small and dysplatic cerebellar vermis that should suggest the involvement of these genes. Moreover, differences in clinical severity, involvement of the cerebellar hemispheres, together with the severity of the neocortical defect, enables RELN-mutated patients to be distinguished from VLDLR-mutated patients.

Three dimensional image-based simulation of ultrasonic wave propagation in polycrystalline metal using phase-field modeling.

When modeling ultrasonic wave propagation in metals, it is important to introduce mesoscopic crystalline structures because the anisotropy of the crystal structure and the heterogeneity of grains disturb ultrasonic waves. In this paper, a three-dimensional (3D) polycrystalline structure generated by multiphase-field modeling was introduced to ultrasonic simulation for nondestructive testing. 3D finite-element simulations of ultrasonic waves were validated and compared with visualization results obtained from laser Doppler vibrometer measurements. The simulation results and measurements showed good agreement with respect to the velocity and front shape of the pressure wave, as well as multiple scattering due to grains. This paper discussed the applicability of a transversely isotropic approach to ultrasonic wave propagation in a polycrystalline metal with columnar structures.

In Utero Diagnosis of Niemann-Pick Type C in the Absence of Family History.

Niemann-Pick type C (NPC) disease is a recessive disorder that results in unesterified cholesterol accumulating in the lysosomal and late endosomal system. It is caused by mutations in NPC1 or NPC2 genes and leads to systemic and neurodegenerative symptoms. Few cases of prenatal presentation of NPC have been reported and only two cases in the absence of previous family history, indicating the diagnosis is particularly difficult in such a situation. We report a prenatal diagnosis of NPC in a couple without family history. An ultrasound screening at 22 weeks of gestation (WG) detected fetal ascites and hepatomegaly, which were still present at 25, 27, and 29 WG, and a splenomegaly progressively appeared. No placentomegaly or other signs of hydrops fetalis were observed. The diagnostic of NPC was prenatally confirmed by a filipin test and NPC1 sequencing and multiplex ligation-dependent probe amplification assay which revealed a maternal missense mutation (c.2608T>C; p.Ser870Pro) and a paternal deletion of exons 5 to 25. This additional prenatal case of NPC suggests that even in the absence of family history, fetal ascites associated with splenomegaly but no hydrops should nonetheless arouse suspicion concerning this disease as a possible diagnosis.

Mutation update and uncommon phenotypes in a French cohort of 96 patients with WFS1-related disorders.

WFS1 mutations are responsible for Wolfram syndrome (WS) characterized by juvenile-onset diabetes mellitus and optic atrophy, and for low-frequency sensorineural hearing loss (LFSNHL). Our aim was to analyze the French cohort of 96 patients with WFS1-related disorders in order (i) to update clinical and molecular data with 37 novel affected individuals, (ii) to describe uncommon phenotypes and, (iii) to precise the frequency of large-scale rearrangements in WFS1. We performed quantitative polymerase chain reaction (PCR) in 13 patients, carrying only one heterozygous variant, to identify large-scale rearrangements in WFS1. Among the 37 novel patients, 15 carried 15 novel deleterious putative mutations, including one large deletion of 17,444 base pairs. The analysis of the cohort revealed unexpected phenotypes including (i) late-onset symptoms in 13.8% of patients with a probable autosomal recessive transmission; (ii) two siblings with recessive optic atrophy without diabetes mellitus and, (iii) six patients from four families with dominantly-inherited deafness and optic atrophy. We highlight the expanding spectrum of WFS1-related disorders and we show that, even if large deletions are rare events, they have to be searched in patients with classical WS carrying only one WFS1 mutation after sequencing.

Blood conservation: what is current blood draw practice?

The new AABB guidelines for red blood cell transfusions narrow the threshold for transfusion. A natural outgrowth is to emphasize blood conservation strategies, including reduced blood draws. There is no universal practice for the collection of blood or strategy for blood conservation. As such, it is often assumed that frequency and amounts of blood drawn vary with patient acuity, caregiver experience, and patient length of stay. Yet, a descriptive study did not identify any significant differences in these variables. Creating a culture of low-volume blood drawing may help to reduce blood transfusions.

A prospective randomised control study: reduction of children's pain expectation using a picture book during blood withdrawal.

OBJECTIVES: Blood drawings are very painful and stressful for children. In a prospective control group study we investigated if using a picture book could reduce the children's pain expectation. In addition, the children's pain experience and the observed pain behaviour was monitored. PATIENTS/METHODS: Block-randomization were used and 120 children at the age of 6-12 years who were visiting the general pediatric and coagulation outpatient clinics were included in this study. Pain expectation and experience were assessed with the Face-Pain-Scale-Revised and the pain behavior with the Faces-Legs-Activity-Cry-Consolability Scale. Multivariate covariance analysis was used for data analysis. RESULTS: The results showed that with statistical controlling the influence of the primary pain expectation (baseline) the pain expectation before blood withdrawal was reduced significantly (p=0.001) and effectively (ES=0.56) using the picture book. Children who received no local anaesthesia reported that they felt less pain during blood drawing after reading the picture book. The few children with local anaesthesia reported no benefit from the picture book. The observed use of local anaesthesia was very heterogeneous. CONCLUSIONS: The results recommend the usage of this picture book in everyday practice, if the use of local anaesthesia could not be used in an appropriate way.

N- and C-terminal degradation of ecdysteroid receptor isoforms, when transiently expressed in mammalian CHO cells, is regulated by the proteasome and cysteine and threonine proteases.

Transcriptional activity of nuclear receptors is the result of transactivation capability and the concentration of the receptor protein. The concentration of ecdysteroid receptor (EcR) isoforms, constitutively expressed in mammalian CHO cells, is dependent on a number of factors. As shown previously, ligand binding stabilizes receptor protein concentration. In this paper, we investigate the degradation of EcR isoforms and provide evidence that N-terminal degradation is modulated by isoform-specific ubiquitination sites present in the A/B domains of EcR-A and -B1. This was demonstrated by the increase in EcR concentration by treatment with carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG132), an inhibitor of ubiquitin-mediated proteasomal degradation and by deletion of ubiquitination sites. In addition, EcR is degraded by the peptidyl-dipeptidase cathepsin B (CatB) and the endopeptidase cathepsin S (CatS) at the C-terminus in an isoform-specific manner, despite identical C-termini. Ubiquitin-proteasome-mediated degradation and the proteolytic action are modulated by heterodimerization with Ultraspiracle (USP). The complex regulation of receptor protein concentration offers an additional opportunity to regulate transcriptional activity in an isoform- and target cell-specific way and allows the temporal limitation of hormone action.

Kinetic analyses guide the therapeutic decision in a novel form of moderate aromatic Acid decarboxylase deficiency.

BACKGROUND: Aromatic amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disorder resulting in a combined dopamine and serotonin deficiency. About 50% of the cases set in the neonatal period. Here, we report an atypical clinical presentation with moderate symptoms. PATIENT: At 10months old, the patient presented paroxysmal eye movements without seizures, and feeding difficulties which were attributed to gastroesophageal reflux. She was investigated at the age of 7years, because of orofacial dyspraxia, hypomimie, axial hypotonia and focal segmental dystonia, bilateral ptosis, without evidence for cognitive impairment. RESULTS: HVA [110nM; (reference value (rv): 202-596)] and HIAA (12nM; rv: 87-366) decreased, OMD (520nM; rv: 5-60) and 5-HTP (56nM; rv: 2-16) increased in CSF. We confirmed the diagnosis of AADC deficiency because the activity in plasma was low: 4pmol/min/ml; rv: 16-137. The kinetic analysis revealed a sixfold increase in the apparent affinity for L-dopa (4.26mM; control=0.71), but the V (max) was unchanged (37.5pmol dopamine/min/ml; control=39.1), suggesting a modification in the substrate binding-site. Molecular analysis revealed two heterozygous mutations in the DDC gene: c1040G > A; pR347Q already described, and a novel mutation c478C > T, pR160W. CONCLUSION: (1) CSF neurotransmitters metabolites suggested a moderate AADC deficiency; (2) The initial velocity saturation curve for L-dopa displayed a cooperative ligand binding behavior, in keeping with the modifications of the three-dimensional structure, induced by the amino acid substitutions (3) The treatment combination of L-dopa with pyridoxine dramatically improved the quality of life, the fatigability, and the paroxysmal eye movements.

Binder phenotype in mothers affected with autoimmune disorders.

OBJECTIVE: To report four foetal cases of the Binder phenotype associated with maternal autoimmune disorders. PATIENTS AND METHODS: In three mothers with autoimmune diseases, 2D and 3D ultrasonographic measurements were made on four foetuses with the Binder profile, and were compared with postnatal phenotypes. RESULTS: The Binder phenotype can be detected in early pregnancy (14.5 WG). All foetuses had verticalized nasal bones and midfacial hypoplasia. Punctuate calcifications were found in almost all the cases. No specific maternal auto-antibody has been associated with foetal Binder phenotype. CONCLUSION: Since the Binder phenotype can be diagnosed at ultrasound examination during pregnancy, it is important to establish the underlying cause so as to assess the foetal prognosis. This study stresses the importance of systematic checks for maternal autoimmune disease in cases of prenatally diagnosed Binder phenotypes.