1,358 research outputs found
Exclusive neuronal expression of SUCLA2 in the human brain
SUCLA2 encodes the ATP-forming subunit (A-SUCL-) of succinyl-CoA ligase, an enzyme of the citric acid cycle. Mutations in SUCLA2 lead to a mitochondrial disorder manifesting as encephalomyopathy with dystonia, deafness and lesions in the basal ganglia. Despite the distinct brain pathology associated with SUCLA2 mutations, the precise localization of SUCLA2 protein has never been investigated. Here we show that immunoreactivity of A-SUCL- in surgical human cortical tissue samples was present exclusively in neurons, identified by their morphology and visualized by double labeling with a fluorescent Nissl dye. A-SUCL- immunoreactivity co-localized >99% with that of the d subunit of the mitochondrial F0-F1 ATP synthase. Specificity of the anti-A-SUCL- antiserum was verified by the absence of labeling in fibroblasts from a patient with a complete deletion of SUCLA2. A-SUCL- immunoreactivity was absent in glial cells, identified by antibodies directed against the glial markers GFAP and S100. Furthermore, in situ hybridization histochemistry demonstrated that SUCLA2 mRNA was present in Nissl-labeled neurons but not glial cells labeled with S100. Immunoreactivity of the GTP-forming subunit (G-SUCL-) encoded by SUCLG2, or in situ hybridization histochemistry for SUCLG2 mRNA could not be demonstrated in either neurons or astrocytes. Western blotting of post mortem brain samples revealed minor G-SUCL- immunoreactivity that was however, not upregulated in samples obtained from diabetic versus non-diabetic patients, as has been described for murine brain. Our work establishes that SUCLA2 is expressed exclusively in neurons in the human cerebral cortex
Increasing galactose consumption by Saccharomyces cerevisiae through metabolic engineering of the GAL gene regulatory network
The Healthy Start project: a randomized, controlled intervention to prevent overweight among normal weight, preschool children at high risk of future overweight
BACKGROUND: Research shows that obesity prevention has to start early. Targeting interventions towards subgroups of individuals who are predisposed, but yet normal weight, may prove more effective in preventing overweight than interventions towards unselected normal weight subsets. Finally, interventions focused on other factors than diet and activity are lacking. The objectives were to perform a randomized, controlled intervention aiming at preventing overweight in children aged 2–6 years, who are yet normal weight, but have high predisposition for future overweight, and to intervene not only by improving diet and physical activity, but also reduce stress and improve sleep quality and quantity. METHODS/DESIGN: Based on information from the Danish National Birth Registry and administrative birth forms, children were selected based on having either a high birth weight, a mother who was overweight prior to pregnancy, or a familial low socioeconomic status. Selected children (n = 5,902) were randomized into three groups; an intervention group, a shadow control group followed in registers exclusively, and a control group examined at the beginning and at the end of the intervention. Approximately 21% agreed to participate. Children who presented as overweight prior to the intervention were excluded from this study (n = 92). In the intervention group, 271 children were included, and in the control group 272 were included. Information obtained from the shadow control group is on-going, but it is estimated that 394 children will be included. The intervention took place over on average 1½ year between 2009 and 2011, and consisted of optional individual guidance in optimizing diet and physical activity habits, reducing chronic stress and stressful events and improving sleep quality and quantity. The intervention also included participation in cooking classes and play arrangements. Information on dietary intake, meal habits, physical activity, sleep habits, and overall stress level was obtained by 4–7 day questionnaire diaries and objective measurements. DISCUSSION: If the Healthy Start project is effective in preventing excessive weight gain, it will provide valuable information on new determinants of obesity which should be considered in future interventions, and on new strategies to prevent development of overweight and obesity at an early age. TRIAL REGISTRATION: ClinicalTrials.gov, ID NCT01583335
The EULAR-OMERACT rheumatoid arthritis MRI reference image atlas: the wrist joint
This paper presents the wrist joint MR images of the EULAR–OMERACT rheumatoid arthritis MRI reference image atlas. Reference images for scoring synovitis, bone oedema, and bone erosions according to the OMERACT RA MRI scoring (RAMRIS) system are provided. All grades (0–3) of synovitis are illustrated in each of the three wrist joint areas defined in the scoring system—that is, the distal radioulnar joint, the radiocarpal joint, and the intercarpal-carpometacarpal joints. For reasons of feasibility, examples of bone abnormalities are limited to five selected bones: the radius, scaphoid, lunate, capitate, and a metacarpal base. In these bones, grades 0–3 of bone oedema are illustrated, and for bone erosion, grades 0–3 and examples of higher grades are presented. The presented reference images can be used to guide scoring of wrist joints according to the OMERACT RA MRI scoring system
MRI identifies plantar plate pathology in the forefoot of patients with rheumatoid arthritis
Previous cadaveric studies have suggested that forefoot deformities at the metatarsophalangeal (MTP) joints in patients with rheumatoid arthritis (RA) might result from the failure of the ligamentous system and displacement of the plantar plates. This study aimed to examine the relationship between plantar plate pathology and the rheumatoid arthritis magnetic resonance imaging score (RAMRIS) of the lesser (second to fifth) MTP joints in patients with RA using high-resolution 3 T magnetic resonance imaging (MRI). In 24 patients with RA, the forefoot was imaged using 3 T MRI. Proton density fat-suppressed, T2-weighted fat-suppressed and T1-weighted post gadolinium sequences were acquired through 96 lesser MTP joints. Images were scored for synovitis, bone marrow oedema and bone erosion using the RAMRIS system and the plantar plates were assessed for pathology. Seventeen females and 7 males with a mean age of 55.5 years (range 37–71) and disease duration of 10.6 years (range 0.6–36) took part in the study. Plantar plate pathology was most frequently demonstrated on MRI at the fifth MTP joint. An association was demonstrated between plantar plate pathology and RAMRIS-reported synovitis, bone marrow oedema and bone erosion at the fourth and fifth MTP joints. In patients with RA, 3 T MRI demonstrates that plantar plate pathology at the lesser MTP joints is associated with features of disease severity. Plantar plate pathology is more common at the fourth and fifth MTP joints in subjects with RA in contrast to the predilection for the second MTP reported previously in subjects without RA
Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome).
We report an allelic series of eight mutations in GATA2 underlying Emberger syndrome, an autosomal dominant primary lymphedema associated with a predisposition to acute myeloid leukemia. GATA2 is a transcription factor that plays an essential role in gene regulation during vascular development and hematopoietic differentiation. Our findings indicate that haploinsufficiency of GATA2 underlies primary lymphedema and predisposes to acute myeloid leukemia in this syndrome
Data-Driven Definitions for Active and Structural MRI Lesions in the Sacroiliac Joint in Spondyloarthritis and their Predictive Utility
OBJECTIVES: To determine quantitative sacroiliac joint (SIJ) MRI lesion cut-offs that optimally define a positive MRI for inflammatory and structural lesions typical of axial spondyloarthritis (axSpA) and that predict clinical diagnosis. METHODS: The ASAS MRI group assessed MRIs from the ASAS Classification Cohort in two reading exercises: A. 169 cases and 7 central readers; B. 107 cases and 8 central readers. We calculated sensitivity/specificity for the number of SIJ quadrants or slices with bone marrow edema (BME), erosion, fat lesion, where a majority of central readers had high confidence there was a definite active or structural lesion. Cut-offs with ≥95% specificity were analyzed for their predictive utility for follow-up rheumatologist diagnosis of axSpA by calculating positive/negative predictive values (PPV/NPV) and selecting cut-offs with PPV≥95%. RESULTS: Active or structural lesions typical of axSpA on MRI had PPV≥95% for clinical diagnosis of axSpA. Cut-offs that best reflect definite active lesion typical of axSpA were either ≥4 SIJ quadrants with BME at any location or at the same location in ≥ 3 consecutive slices. For definite structural lesion, the optimal cut-offs were any one of ≥ 3 SIJ quadrants with erosion or ≥ 5 with fat lesion, erosion at the same location for ≥2 consecutive slices, fat lesion at the same location for ≥3 consecutive slices, or presence of a 'deep' (>1cm) fat lesion. CONCLUSION: We propose cut-offs for definite active and structural lesions typical of axSpA that have high PPV for a long-term clinical diagnosis of axSpA for application in disease classification and clinical research
Simplifying the clinical classification of polymerase gamma (POLG) disease based on age of onset; studies using a cohort of 155 cases
Background: Variants in POLG are one of the most common causes of inherited mitochondrial disease. Phenotypic classification of POLG disease has evolved haphazardly making it complicated and difficult to implement in everyday clinical practise. The aim of our study was to simplify the classification and facilitate better clinical recognition. /
Methods: A multinational, retrospective study using data from 155 patients with POLG variants recruited from seven European countries. /
Results: We describe the spectrum of clinical features associated with POLG variants in the largest known cohort of patients. While clinical features clearly form a continuum, stratifying patients simply according to age of onset—onset prior to age 12 years; onset between 12 and 40 years and onset after the age of 40 years, permitted us to identify clear phenotypic and prognostic differences. Prior to 12 years of age, liver involvement (87%), seizures (84%), and feeding difficulties (84%) were the major features. For those with onset between 12 and 40 years, ataxia (90%), peripheral neuropathy (84%), and seizures (71%) predominated, while for those with onset over 40 years, ptosis (95%), progressive external ophthalmoplegia (89%), and ataxia (58%) were the major clinical features. The earlier the onset the worse the prognosis. Patients with epilepsy and those with compound heterozygous variants carried significantly worse prognosis. /
Conclusion: Based on our data, we propose a simplified POLG disease classification, which can be used to guide diagnostic investigations and predict disease course
The impact of gender, puberty, and pregnancy in patients with POLG disease
OBJECTIVE: To study the impact of gender, puberty, and pregnancy on the expression of POLG disease, one of the most common mitochondrial diseases known. METHODS: Clinical, laboratory, and genetic data were collected retrospectively from 155 patients with genetically confirmed POLG disease recruited from seven European countries. We used the available data to study the impact of gender, puberty, and pregnancy on disease onset and deterioration. RESULTS: We found that disease onset early in life was common in both sexes but there was also a second peak in females around the time of puberty. Further, pregnancy had a negative impact with 10 of 14 women (71%) experiencing disease onset or deterioration during pregnancy. INTERPRETATION: Gender clearly influences the expression of POLG disease. While onset very early in life was common in both males and females, puberty in females appeared associated both with disease onset and increased disease activity. Further, both disease onset and deterioration, including seizure aggravation and status epilepticus, appeared to be associated with pregnancy. Thus, whereas disease activity appears maximal early in life with no subsequent peaks in males, both menarche and pregnancy appear associated with disease onset or worsening in females. This suggests that hormonal changes may be a modulating factor
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Magnetic Resonance Lymphangiography: Establishing Normal.
BACKGROUND: Despite an increased interest in visualising the lymphatic vessels (lymphatics) with Magnetic Resonance Lymphangiography (MRL), there remains little literature describing their appearance in non-lymphoedematous individuals. To determine lymphatic abnormalities, an understanding of how healthy lymphatics appear and behave needs to be established. In this study, MRL of individuals without a history of lymphatic disease was therefore performed. METHODS: A total of 25 individuals (15 female) underwent MRL of their lower limbs using a 3.0T Philips MRI scanner. The first 9 cases were recruited to establish the concentration of Gadolinium-based contrast agent (GBCA) to administer, with the remainder imaged pre- and post-inter-digital forefoot GBCA injections at the optimised dose. Outcomes including lymphatic vessel diameter, tortuosity and the frequency of drainage via particular drainage routes were recorded. RESULTS: Healthy lymphatics following the anteromedial pathway were routinely observed in post-contrast T1 weighted images (average tortuosity = 1.09 ±0.03), with an average of 2.16 ± 0.93 lymphatic vessels, of diameter 2.47 ± 0.50 mm, crossing the anterior ankle. In six limbs, vessels following the anterolateral pathways were observed. No vessels traversing the posterior of the legs were seen. In a subset of ten vessels lymphatic signal, measured at the ankle, peaked 29:50 ± 09:29 mm:ss after GBCA administration. No lymphatic vessels were observed in T2 weighted images. CONCLUSIONS: Contrast-enhanced MRL reliably depicts the lymphatics in the legs of healthy controls. Following inter-digital contrast injection, anteromedial drainage appears dominant. Quantitative measures related to lymphatic vessel size, tortuosity and drainage rate are readily obtainable, and could be beneficial for detecting even subtle lymphatic impairment
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