390 research outputs found

    Insight Into Molecular Determinants of T3 vs T4 Recognition From Mutations in Thyroid Hormone Receptor α and β.

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    CONTEXT: The two major forms of circulating thyroid hormones (THs) are T3 and T4. T3 is regarded as the biologically active hormone because it binds to TH receptors (TRs) with greater affinity than T4. However, it is currently unclear what structural mechanisms underlie this difference in affinity. OBJECTIVE: Prompted by the identification of a novel M256T mutation in a resistance to TH (RTH)α patient, we investigated Met256 in TRα1 and the corresponding residue (Met310) in TRβ1, residues previously predicted by crystallographic studies in discrimination of T3 vs T4. METHODS: Clinical characterization of the RTHα patient and molecular studies (in silico protein modeling, radioligand binding, transactivation, and receptor-cofactor studies) were performed. RESULTS: Structural modeling of the TRα1-M256T mutant showed that distortion of the hydrophobic niche to accommodate the outer ring of ligand was more pronounced for T3 than T4, suggesting that this substitution has little impact on the affinity for T4. In agreement with the model, TRα1-M256T selectively reduced the affinity for T3. Also, unlike other naturally occurring TRα mutations, TRα1-M256T had a differential impact on T3- vs T4-dependent transcriptional activation. TRα1-M256A and TRβ1-M310T mutants exhibited similar discordance for T3 vs T4. CONCLUSIONS: Met256-TRα1/Met310-TRβ1 strongly potentiates the affinity of TRs for T3, thereby largely determining that T3 is the bioactive hormone rather than T4. These observations provide insight into the molecular basis for underlying the different affinity of TRs for T3 vs T4, delineating a fundamental principle of TH signaling

    The reliability of the patellotrochlear index on magnetic resonance imaging for measuring patellofemoral height

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    Background: The purpose of this study was to determine the inter-and intra-observer reliability of the patellotrochlear index (PTI) on magnetic resonance images (MRI) in patients with patellofemoral pain. The correlation between the PTI measured on MRI and the modified Insall-Salvati (MIS) ratio measured on radiographs was also assessed. Methods: The PTI was assessed on MRI images and the MIS ratio on radiographs of 66 knees of 62 patients. Assessment was performed by two orthopaedic surgeons, one orthopaedic surgery registrar, two radiologists and one radiology registrar. Correlation coefficients, standard errors of measurement and limits of agreement were calculated for the PTI. To assess the association between the PTI and the MIS ratio, the Pearson's correlation coefficient was calculated. Results: The PTI showed good interobserver reliability (intraclass correlation coefficient (ICC) 0.79; 95% confidence interval (CI) 0.73-0.85) and excellent intra-observer reliability (ICC 0.90; 95% CI 0.89-0.91). The standard error of measurement was 0.05 and limits of agreement with the mean +/- 0.09. A very weak and not significant correlation was found between the PTI and the MIS (r = 0.02; P = 0.77). Conclusions: The PTI showed good interobserver reliability and excellent intra-observer reliability. In order to conclude which measurement method of assessing patellar height is truly the most reliable, future studies should investigate agreement parameters (standard error of measurement, limits of agreement) besides solely correlation coefficients. We found a very weak correlation between the PTI and the MIS which suggests that at least one index has poor validity. Future validity studies on indices to assess patellar height are necessary. (c) 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

    Forearm Rotation Range of Motion and Its Velocity in Eating With Chopsticks : a Comparison Among Positions of Dish

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    The purpose of this study was to determine range of motion of forearm rotation and its velocity in eating. Six young students (age:20.5±0.5 years [range:20-21], 2 men and 4 women) participated in this study. To measure three-dimensional motions, we used an electromagnetic tracking device system. The first sensor was attached to the dorsal/distal of forearm with sprint, and the second sensor was attached to the dorsal/medial ulna with elastic belt. The subjects ate pickles with chopsticks. At a wooden desk with 70cm height they sat on a height-adjustable chair, so their olecranon was as high as the desk top. Three positions of a dish were measured; A: at the distance of length of distal to elbow, B: at the distance of length of the upper extremity, and C: at a middle position between A and B. The results revealed that forearm rotation, range of motion and its velocity were significantly different among three conditions (one-way repeated-measure ANOVA)(p<0.05). Characteristically the motion velocity of B was lower than C, and A was lower than C (p<0.05). Findings suggest that 1) limited forearm range of motion would decrease a burden of forearm by setting a dish at B or C than A, 2) the rotation (maximal pronation and supination: 11 and 49 degrees, respectively) was similar, to a fork (maximal pronation and supination: 10 and 51 degrees, respectively), 3) C may be efficiently operated, and 4) the system may be instructed as a good equipment for eating

    Expanding the genetic and phenotypic spectrum of ACTA2-related vasculopathies in a Dutch cohort

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    Purpose: Heterozygous pathogenic/likely pathogenic (P/LP) variants in the ACTA2 gene confer a high risk for thoracic aortic aneurysms and aortic dissections. This retrospective multicenter study elucidates the clinical outcome of ACTA2-related vasculopathies. Methods: Index patients and relatives with a P/LP variant in ACTA2 were included. Data were collected through retrospective review of medical records using a standardized questionnaire. Results: A total of 49 individuals from 28 families participated in our study. In total, 20 different ACTA2 variants were detected. Aortic events occurred in 65% of the cases (78.6% index patients and 47.6% relatives). Male sex and hypertension emerged as significantly associated with aortic events. Of 20 individuals, 5 had an aortic diameter of <45 mm (1.77 inches) at the time of the type A dissection. Mean age at first aortic event was 49.0 ± 12.4 years. Severe surgical complications for type A and type B dissection occurred in 25% and 16.7% of the cases and in-hospital mortality rates were 9.5% and 0%, respectively. Conclusion: P/LP ACTA2 variants are associated with an increased risk for an aortic event and age-related penetrance, which emphasizes the importance of early recognition of the disease. Caregivers should be aware of the risk for aortic dissections, even in individuals with aortic diameters within the normal range

    Patients Enrolled in Large Randomized Clinical Trials of Antiplatelet Treatment for Prevention After Transient Ischemic Attack or Ischemic Stroke Are Not Representative of Patients in Clinical Practice: the Netherlands Stroke Survey

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    Background and Purpose—Many randomized clinical trials have evaluated the benefit of long-term use of antiplatelet drugs in reducing the risk of new vascular events in patients with a recent transient ischemic attack or ischemic stroke. Evidence from these trials forms the basis for national and international guidelines for the management of nearly all such patients in clinical practice. However, abundant and strict enrollment criteria may limit the validity and the applicability of results of randomized clinical trials to clinical practice. We estimated the eligibility for participation in landmark trials of antiplatelet drugs of an unselected group of patients with stroke or transient ischemic attack from a national stroke survey. Methods—Nine hundred seventy-two patients with transient ischemic at

    Physical therapy plus general practitioners’ care versus general practitioners’ care alone for sciatica: a randomised clinical trial with a 12-month follow-up

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    A randomised clinical trial in primary care with a 12-months follow-up period. About 135 patients with acute sciatica (recruited from May 2003 to November 2004) were randomised in two groups: (1) the intervention group received physical therapy (PT) added to the general practitioners’ care, and (2) the control group with general practitioners’ care only. To assess the effectiveness of PT additional to general practitioners’ care compared to general practitioners’ care alone, in patients with acute sciatica. There is a lack of knowledge concerning the effectiveness of PT in patients with sciatica. The primary outcome was patients’ global perceived effect (GPE). Secondary outcomes were severity of leg and back pain, severity of disability, general health and absence from work. The outcomes were measured at 3, 6, 12 and 52 weeks after randomisation. At 3 months follow-up, 70% of the intervention group and 62% of the control group reported improvement (RR 1.1; 95% CI 0.9–1.5). At 12 months follow-up, 79% of the intervention group and 56% of the control group reported improvement (RR 1.4; 95% CI 1.1; 1.8). No significant differences regarding leg pain, functional status, fear of movement and health status were found at short-term or long-term follow-up. At 12 months follow-up, evidence was found that PT added to general practitioners’ care is only more effective regarding GPE, and not more cost-effective in the treatment of patients with acute sciatica than general practitioners’ care alone. There are indications that PT is especially effective regarding GPE in patients reporting severe disability at presentation

    Patch: platelet transfusion in cerebral haemorrhage: study protocol for a multicentre, randomised, controlled trial

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    <p>Abstract</p> <p>Background</p> <p>Patients suffering from intracerebral haemorrhage have a poor prognosis, especially if they are using antiplatelet therapy. Currently, no effective acute treatment option for intracerebral haemorrhage exists. Limiting the early growth of intracerebral haemorrhage volume which continues the first hours after admission seems a promising strategy. Because intracerebral haemorrhage patients who are on antiplatelet therapy have been shown to be particularly at risk of early haematoma growth, platelet transfusion may have a beneficial effect.</p> <p>Methods/Design</p> <p>The primary objective is to investigate whether platelet transfusion improves outcome in intracerebral haemorrhage patients who are on antiplatelet treatment. The PATCH study is a prospective, randomised, multi-centre study with open treatment and blind endpoint evaluation. Patients will be randomised to receive platelet transfusion within six hours or standard care. The primary endpoint is functional health after three months. The main secondary endpoints are safety of platelet transfusion and the occurrence of haematoma growth. To detect an absolute poor outcome reduction of 20%, a total of 190 patients will be included.</p> <p>Discussion</p> <p>To our knowledge this is the first randomised controlled trial of platelet transfusion for an acute haemorrhagic disease.</p> <p>Trial registration</p> <p>The Netherlands National Trial Register (NTR1303)</p
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