189 research outputs found
Self-reported neck pain is associated with migraine but not with tension-type headache in adolescents
AIM: The aim of the present analysis is to confirm or refute the association of neck pain to migraine or tension-type headache and to assess whether this association is independent of other risk factors for headache. METHODS: Secondary school students were invited to complete a questionnaire on headache and lifestyle factors in a cross-sectional study. Neck pain was assessed via (a) a screening question concerning neck pain and (b) denoting affected areas in schematic drawings of the human body. RESULTS: Absolute increment in prevalence of headache with pain in the shoulder-neck region was between 7.5 and 9.6. Gender, grade, stress and lifestyle factors were assessed as potential confounding factors. Nearly all factors were associated with shoulder-neck pain and most with headache. After adjustment for confounders, the association of neck pain with headache was almost completely confined to migraine (OR 2.39; 95 CI 1.48-3.85) and migraine + tension-type headache (OR 2.12; 95 CI 1.50-2.99), whereas the association with isolated tension-type headache was negligible (OR 1.22, 95 CI 0.87-1.69). CONCLUSION: Neck pain is associated with migraine but not with tension-type headache. A possible link between migraine and neck pain may be the cervico-trigeminal convergence of neck and meningeal sensory afferents or a disturbed descending inhibition in migraine
Self-reported neck pain is associated with migraine but not with tension-type headache in adolescents
AIM: The aim of the present analysis is to confirm or refute the association of neck pain to migraine or tension-type headache and to assess whether this association is independent of other risk factors for headache. METHODS: Secondary school students were invited to complete a questionnaire on headache and lifestyle factors in a cross-sectional study. Neck pain was assessed via (a) a screening question concerning neck pain and (b) denoting affected areas in schematic drawings of the human body. RESULTS: Absolute increment in prevalence of headache with pain in the shoulder-neck region was between 7.5 and 9.6. Gender, grade, stress and lifestyle factors were assessed as potential confounding factors. Nearly all factors were associated with shoulder-neck pain and most with headache. After adjustment for confounders, the association of neck pain with headache was almost completely confined to migraine (OR 2.39; 95 CI 1.48-3.85) and migraine + tension-type headache (OR 2.12; 95 CI 1.50-2.99), whereas the association with isolated tension-type headache was negligible (OR 1.22, 95 CI 0.87-1.69). CONCLUSION: Neck pain is associated with migraine but not with tension-type headache. A possible link between migraine and neck pain may be the cervico-trigeminal convergence of neck and meningeal sensory afferents or a disturbed descending inhibition in migraine
Metabolic network reconstruction and genome-scale model of butanol-producing strain Clostridium beijerinckii NCIMB 8052
<p>Abstract</p> <p>Background</p> <p>Solventogenic clostridia offer a sustainable alternative to petroleum-based production of butanol--an important chemical feedstock and potential fuel additive or replacement. <it>C. beijerinckii </it>is an attractive microorganism for strain design to improve butanol production because it (i) naturally produces the highest recorded butanol concentrations as a byproduct of fermentation; and (ii) can co-ferment pentose and hexose sugars (the primary products from lignocellulosic hydrolysis). Interrogating <it>C. beijerinckii </it>metabolism from a systems viewpoint using constraint-based modeling allows for simulation of the global effect of genetic modifications.</p> <p>Results</p> <p>We present the first genome-scale metabolic model (<it>i</it>CM925) for <it>C. beijerinckii</it>, containing 925 genes, 938 reactions, and 881 metabolites. To build the model we employed a semi-automated procedure that integrated genome annotation information from KEGG, BioCyc, and The SEED, and utilized computational algorithms with manual curation to improve model completeness. Interestingly, we found only a 34% overlap in reactions collected from the three databases--highlighting the importance of evaluating the predictive accuracy of the resulting genome-scale model. To validate <it>i</it>CM925, we conducted fermentation experiments using the NCIMB 8052 strain, and evaluated the ability of the model to simulate measured substrate uptake and product production rates. Experimentally observed fermentation profiles were found to lie within the solution space of the model; however, under an optimal growth objective, additional constraints were needed to reproduce the observed profiles--suggesting the existence of selective pressures other than optimal growth. Notably, a significantly enriched fraction of actively utilized reactions in simulations--constrained to reflect experimental rates--originated from the set of reactions that overlapped between all three databases (<it>P </it>= 3.52 × 10<sup>-9</sup>, Fisher's exact test). Inhibition of the hydrogenase reaction was found to have a strong effect on butanol formation--as experimentally observed.</p> <p>Conclusions</p> <p>Microbial production of butanol by <it>C. beijerinckii </it>offers a promising, sustainable, method for generation of this important chemical and potential biofuel. <it>i</it>CM925 is a predictive model that can accurately reproduce physiological behavior and provide insight into the underlying mechanisms of microbial butanol production. As such, the model will be instrumental in efforts to better understand, and metabolically engineer, this microorganism for improved butanol production.</p
Analyse der Spontanmotorik im 1. Lebensjahr: Markerlose 3-D-Bewegungserfassung zur Früherkennung von Entwicklungsstörungen
Children with motor development disorders benefit greatly from early interventions. An early diagnosis in pediatric preventive care (U2–U5) can be improved by automated screening. Current approaches to automated motion analysis, however, are expensive, require lots of technical support, and cannot be used in broad clinical application. Here we present an inexpensive, marker-free video analysis tool (KineMAT) for infants, which digitizes 3‑D movements of the entire body over time allowing automated analysis in the future.
Three-minute video sequences of spontaneously moving infants were recorded with a commercially available depth-imaging camera and aligned with a virtual infant body model (SMIL model). The virtual image generated allows any measurements to be carried out in 3‑D with high precision. We demonstrate seven infants with different diagnoses. A selection of possible movement parameters was quantified and aligned with diagnosis-specific movement characteristics.
KineMAT and the SMIL model allow reliable, three-dimensional measurements of spontaneous activity in infants with a very low error rate. Based on machine-learning algorithms, KineMAT can be trained to automatically recognize pathological spontaneous motor skills. It is inexpensive and easy to use and can be developed into a screening tool for preventive care for children.Kinder mit motorischer Entwicklungsstörung profitieren von einer frühen Entwicklungsförderung. Eine frühe Diagnosestellung in der kinderärztlichen Vorsorge (U2–U5) kann durch ein automatisiertes Screening verbessert werden. Bisherige Ansätze einer automatisierten Bewegungsanalyse sind jedoch teuer und aufwendig und nicht in der Breite anwendbar. In diesem Beitrag soll ein neues System zur Videoanalyse, das Kinematic Motion Analysis Tool (KineMAT) vorgestellt werden. Es kann bei Säuglingen angewendet werden und kommt ohne Körpermarker aus. Die Methode wird anhand von 7 Patienten mit unterschiedlichen Diagnosen demonstriert.
Mit einer kommerziell erhältlichen Tiefenbildkamera (RGB-D[Red-Green-Blue-Depth]-Kamera) werden 3‑minütige Videosequenzen von sich spontan bewegenden Säuglingen aufgenommen und mit einem virtuellen Säuglingskörpermodell (SMIL[Skinned Multi-infant Linear]-Modell) in Übereinstimmung gebracht. Das so erzeugte virtuelle Abbild erlaubt es, beliebige Messungen in 3‑D mit hoher Präzision durchzuführen. Eine Auswahl möglicher Bewegungsparameter wird mit diagnosespezifischen Bewegungsauffälligkeiten zusammengeführt.
Der KineMAT und das SMIL-Modell erlauben eine zuverlässige, dreidimensionale Messung der Spontanaktivität bei Säuglingen mit einer sehr niedrigen Fehlerrate. Basierend auf maschinellen Lernalgorithmen kann der KineMAT trainiert werden, pathologische Spontanmotorik automatisiert zu erkennen. Er ist kostengünstig und einfach anzuwenden und soll als Screeninginstrument für die kinderärztliche Vorsorge weiterentwickelt werden
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Improved Respiratory Outcomes for X-Linked Myotubular Myopathy (XLMTM) with Gene Replacement Therapy, Resamirigene Bilparvovec (ASPIRO): Preliminary Results from ASPIRO, a Phase 1/2/3 Study
Astelas Gene Therapies
Single-nucleotide resolution analysis of the transcriptome structure of Clostridium beijerinckii NCIMB 8052 using RNA-Seq
<p>Abstract</p> <p>Background</p> <p><it>Clostridium beijerinckii </it>is an important solvent producing microorganism. The genome of <it>C. beijerinckii </it>NCIMB 8052 has recently been sequenced. Although transcriptome structure is important in order to reveal the functional and regulatory architecture of the genome, the physical structure of transcriptome for this strain, such as the operon linkages and transcript boundaries are not well understood.</p> <p>Results</p> <p>In this study, we conducted a single-nucleotide resolution analysis of the <it>C. beijerinckii </it>NCIMB 8052 transcriptome using high-throughput RNA-Seq technology. We identified the transcription start sites and operon structure throughout the genome. We confirmed the structure of important gene operons involved in metabolic pathways for acid and solvent production in <it>C. beijerinckii </it>8052, including <it>pta</it>-<it>ack</it>, <it>ptb</it>-<it>buk</it>, <it>hbd</it>-<it>etfA</it>-<it>etfB</it>-<it>crt </it>(<it>bcs</it>) and <it>ald</it>-<it>ctfA</it>-<it>ctfB</it>-<it>adc </it>(<it>sol</it>) operons; we also defined important operons related to chemotaxis/motility, transcriptional regulation, stress response and fatty acids biosynthesis along with others. We discovered 20 previously non-annotated regions with significant transcriptional activities and 15 genes whose translation start codons were likely mis-annotated. As a consequence, the accuracy of existing genome annotation was significantly enhanced. Furthermore, we identified 78 putative silent genes and 177 putative housekeeping genes based on normalized transcription measurement with the sequence data. We also observed that more than 30% of pseudogenes had significant transcriptional activities during the fermentation process. Strong correlations exist between the expression values derived from RNA-Seq analysis and microarray data or qRT-PCR results.</p> <p>Conclusions</p> <p>Transcriptome structural profiling in this research provided important supplemental information on the accuracy of genome annotation, and revealed additional gene functions and regulation in <it>C. beijerinckii</it>.</p
Sea-ice dynamics in an Arctic coastal polynya during the past 6500Â years
The production of high-salinity brines during sea-ice freezing in circum-arctic coastal polynyas is thought to be part of northern deep water formation as it supplies additional dense waters to the Atlantic meridional overturning circulation system. To better predict the effect of possible future summer ice-free conditions in the Arctic Ocean on global climate, it is important to improve our understanding of how climate change has affected sea-ice and brine formation, and thus finally dense water formation during the past. Here, we show temporal coherence between sea-ice conditions in a key Arctic polynya (Storfjorden, Svalbard) and patterns of deep water convection in the neighbouring Nordic Seas over the last 6500 years. A period of frequent sea-ice melting and freezing between 6.5 and 2.8 ka BP coincided with enhanced deep water renewal in the Nordic Seas. Near-permanent sea-ice cover and low brine rejection after 2.8 ka BP likely reduced the overflow of high-salinity shelf waters, concomitant with a gradual slow down of deep water convection in the Nordic Seas, which occurred along with a regional expansion in sea-ice and surface water freshening. The Storfjorden polynya sea-ice factory restarted at ~0.5 ka BP, coincident with renewed deep water penetration to the Arctic and climate amelioration over Svalbard. The identified synergy between Arctic polynya sea-ice conditions and deep water convection during the present interglacial is an indication of the potential consequences for ocean ventilation during states with permanent sea-ice cover or future Arctic ice-free conditions
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Safety and efficacy of gene replacement therapy for X-linked myotubular myopathy (ASPIRO): a multinational, open-label, dose-escalation trial
Data sharing: Researchers may request access to anonymised participant-level data, trial-level data, and protocols from clinical trials sponsored by Astellas Gene Therapies at [email protected]. For the Astellas criteria on data sharing see https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Astellas.aspx.Supplementary Materials are available online at: https://www.sciencedirect.com/science/article/pii/S1474442223003137#sec1 .Copyright © 2023 The Author(s).. Background:
X-linked myotubular myopathy is a rare, life-threatening, congenital muscle disease observed mostly in males, which is caused by mutations in MTM1. No therapies are approved for this disease. We aimed to assess the safety and efficacy of resamirigene bilparvovec, which is an adeno-associated viral vector serotype 8 delivering human MTM1.
Methods:
ASPIRO is an open-label, dose-escalation trial at seven academic medical centres in Canada, France, Germany, and the USA. We included boys younger than 5 years with X-linked myotubular myopathy who required mechanical ventilator support. The trial was initially in two parts. Part 1 was planned as a safety and dose-escalation phase in which participants were randomly allocated (2:1) to either the first dose level (1·3 × 1014 vector genomes [vg]/kg bodyweight) of resamirigene bilparvovec or delayed treatment, then, for later participants, to either a higher dose (3·5 × 1014 vg/kg bodyweight) of resamirigene bilparvovec or delayed treatment. Part 2 was intended to confirm the dose selected in part 1. Resamirigene bilparvovec was administered as a single intravenous infusion. An untreated control group comprised boys who participated in a run-in study (INCEPTUS; NCT02704273) or those in the delayed treatment cohort who did not receive any dose. The primary efficacy outcome was the change from baseline to week 24 in hours of daily ventilator support. After three unexpected deaths, dosing at the higher dose was stopped and the two-part feature of the study design was eliminated. Because of changes to the study design during its implementation, analyses were done on an as-treated basis and are deemed exploratory. All treated and control participants were included in the safety analysis. The trial is registered with ClinicalTrials.gov, NCT03199469. Outcomes are reported as of Feb 28, 2022. ASPIRO is currently paused while deaths in dosed participants are investigated.
Findings:
Between Aug 3, 2017 and June 1, 2021, 30 participants were screened for eligibility, of whom 26 were enrolled; six were allocated to the lower dose, 13 to the higher dose, and seven to delayed treatment. Of the seven children whose treatment was delayed, four later received the higher dose (n=17 total in the higher dose cohort), one received the lower dose (n=7 total in the lower dose cohort), and two received no dose and joined the control group (n=14 total, including 12 children from INCEPTUS). Median age at dosing or enrolment was 12·1 months (IQR 10·0–30·9; range 9·5–49·7) in the lower dose cohort, 31·1 months (16·0–64·7; 6·8–72·7) in the higher dose cohort, and 18·7 months (10·1–31·5; 5·9–39·3) in the control cohort. Median follow-up was 46·1 months (IQR 41·0–49·5; range 2·1–54·7) for lower dose participants, 27·6 months (24·6–29·1; 3·4–41·0) for higher dose participants, and 28·3 months (9·7–46·9; 5·7–32·7) for control participants. At week 24, lower dose participants had an estimated 77·7 percentage point (95% CI 40·22 to 115·24) greater reduction in least squares mean hours per day of ventilator support from baseline versus controls (p=0·0002), and higher dose participants had a 22·8 percentage point (6·15 to 39·37) greater reduction from baseline versus controls (p=0·0077). One participant in the lower dose cohort and three in the higher dose cohort died; at the time of death, all children had cholestatic liver failure following gene therapy (immediate causes of death were sepsis; hepatopathy, severe immune dysfunction, and pseudomonal sepsis; gastrointestinal haemorrhage; and septic shock). Three individuals in the control group died (haemorrhage presumed related to hepatic peliosis; aspiration pneumonia; and cardiopulmonary failure).
Interpretation:
Most children with X-linked myotubular myopathy who received MTM1 gene replacement therapy had important improvements in ventilator dependence and motor function, with more than half of dosed participants achieving ventilator independence and some attaining the ability to walk independently. Investigations into the risk for underlying hepatobiliary disease in X-linked myotubular myopathy, and the need for monitoring of liver function before gene replacement therapy, are ongoing.Astellas Gene Therapies
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