The Erlenmeyer flask deformity is a common skeletal modeling deformity, but current classification systems are binary and may restrict its utility as a predictor of associated skeletal conditions. A ...quantifiable 3-point system of severity classification could improve its predictive potential in disease. Ratios were derived from volumes of regions of interests drawn in 50 Gaucher’s disease patients. ROIs were drawn from the distal physis to 2 cm proximal, 2 cm to 4 cm, and 4 cm to 6 cm. Width was also measured at each of these boundaries. Two readers rated these 100 femurs using a 3-point scale of severity classification. Weighted kappa indicated reliability and one-way analysis of variance characterized ratio differences across the severity scale. Accuracy analyses allowed determination of clinical cutoffs for each ratio. Pearson’s correlations assessed the associations of volume and width with a shape-based concavity metric of the femur. The volume ratio incorporating the metaphyseal region from 0 to 2 cm and the diametaphyseal region at 4–6 cm was most accurate at distinguishing femurs on the 3-point scale. Receiver operating characteristic curves for this ratio indicated areas of 0.95 to distinguish normal and mild femurs and 0.93 to distinguish mild and severe femurs. Volume was moderately associated with the degree of femur concavity. The proposed volume ratio method is an objective, proficient method at distinguishing severities of the Erlenmeyer flask deformity with the potential for automation. This may have application across diseases associated with the deformity and deficient osteoclast-mediated modeling of growing bone.
The Gaucher Investigative Therapy Evaluation is a national clinical cohort of 250 patients aged 5-87 years with Gaucher disease in the United Kingdom-an ultra-rare genetic disorder. To inform ...clinical decision-making and improve pathophysiological understanding, we characterized the course of Gaucher disease and explored the influence of costly innovative medication and other interventions. Retrospective and prospective clinical, laboratory and radiological information including molecular analysis of the GBA1 gene and comprising > 2500 variables were collected systematically into a relational database with banking of collated biological samples in a central bioresource. Data for deep phenotyping and life-quality evaluation, including skeletal, visceral, haematological and neurological manifestations were recorded for a median of 17.3 years; the skeletal and neurological manifestations are the main focus of this study.
At baseline, 223 of the 250 patients were classified as type 1 Gaucher disease. Skeletal manifestations occurred in most patients in the cohort (131 of 201 specifically reported bone pain). Symptomatic osteonecrosis and fragility fractures occurred respectively in 76 and 37 of all 250 patients and the first osseous events occurred significantly earlier in those with neuronopathic disease. Intensive phenotyping in a subgroup of 40 patients originally considered to have only systemic features, revealed neurological involvement in 18: two had Parkinson disease and 16 had clinical signs compatible with neuronopathic Gaucher disease-indicating a greater than expected prevalence of neurological features. Analysis of longitudinal real-world data enabled Gaucher disease to be stratified with respect to advanced therapies and splenectomy. Splenectomy was associated with an increased hazard of fragility fractures, in addition to osteonecrosis and orthopaedic surgery; there were marked gender differences in fracture risk over time since splenectomy. Skeletal disease was a heavy burden of illness, especially where access to specific therapy was delayed and in patients requiring orthopaedic surgery.
Gaucher disease has been explored using real-world data obtained in an era of therapeutic transformation. Introduction of advanced therapies and repeated longitudinal measures enabled this heterogeneous condition to be stratified into obvious clinical endotypes. The study reveals diverse and changing phenotypic manifestations with systemic, skeletal and neurological disease as inter-related sources of disability.
This work is aimed at improving the understanding of cardiometabolic syndrome pathophysiology and its relationship with thrombosis by generating a multi-omic disease signature.
We combined classic ...plasma biochemistry and plasma biomarkers with the transcriptional and epigenetic characterisation of cell types involved in thrombosis, obtained from two extreme phenotype groups (morbidly obese and lipodystrophy) and lean individuals to identify the molecular mechanisms at play, highlighting patterns of abnormal activation in innate immune phagocytic cells. Our analyses showed that extreme phenotype groups could be distinguished from lean individuals, and from each other, across all data layers. The characterisation of the same obese group, 6 months after bariatric surgery, revealed the loss of the abnormal activation of innate immune cells previously observed. However, rather than reverting to the gene expression landscape of lean individuals, this occurred via the establishment of novel gene expression landscapes. NETosis and its control mechanisms emerge amongst the pathways that show an improvement after surgical intervention.
We showed that the morbidly obese and lipodystrophy groups, despite some differences, shared a common cardiometabolic syndrome signature. We also showed that this could be used to discriminate, amongst the normal population, those individuals with a higher likelihood of presenting with the disease, even when not displaying the classic features.
Important changes in acinar and ductal morphology and function, together with pronounced extracellular matrix (ECM) remodelling, are detectable in the labial salivary glands of Sjögren's syndrome ...(SS) patients. The objective of this work was to determine the effect of treatment with the anti-Ro/SSA auto-antibodies, characterizing SS, on the expression of fibulin-6, a member of the fibulins family of the ECM, in primary human salivary gland epithelial cell (SGEC) cultures established from biopsies of labial minor salivary glands obtained from healthy donors. The induction of cell detachment and anoikis in SGECs treated with anti-Ro/SSA auto-antibodies were also investigated. Changes in fibulin-6 mRNA expression were measured by semi-quantitative reverse transcriptase-PCR and real-time PCR. Fibulin-6 expression in cells treated with anti-Ro/SSA auto-antibodies was evaluated by flow cytometric analysis and confocal laser scanning microscopy. SGECs undergoing death by anoikis were identified and quantified using Calcein blue/YOPRO-1 dyes. Herein, we present the first evidence of fibulin-6 expression in SGEC that results distributed in the cytoplasm surrounding the inner side of the plasma membrane. Fibulin-6 was down-regulated in SGECs treated with anti-Ro/SSA auto-antibodies in which a marked cell detachment and a reduction of cell viability were observed. Notably, a reduction of fibulin-6 expression in SGECs treated with anti-Ro/SSA auto-antibodies corresponds to an increase of anoikis cell death. Our observations demonstrate a dysregulation of fibulin-6 in the pathological processes observed in SS and provide new evidence that disorganization of the ECM environment could damage the architecture and function of the salivary glands.
The release of the soluble form of tumor necrosis factor (TNF)-alpha from the plasma membrane occurs through the activation of the secretase tumor necrosis factor-alpha-converting enzyme (TACE). The ...current study was designed to examine whether the anti-Ro/SSA autoantibodies (Abs) are capable to regulate TACE expression in non-neoplastic human salivary gland epithelial cells (SGEC) cultures. We investigated the effect of anti-Ro/SSA Abs on the localization and abundance of cell-surface TACE and on TACE pro-domain-shedding and activation. In addition, the potential physiological consequences of TNF-alpha blockage by the biological agent Adalimumab on post-translational regulation of TACE are discussed. Anti-Ro/SSA Abs were purified from IgG fractions of patients with primary Sjögren's syndrome, using Sepharose 4B-Ro/SSA affinity columns. Flow cytometry, reverse transcription–PCR, western blot and immunohistochemistry were used to study TACE expression on SGEC and TACE regulation by Abs. Our study demonstrated a dose-dependent increase of TACE messenger RNA (mRNA) expression in anti-Ro/SSA Abs-treated SGEC, followed by internalization, pro-domain shedding and activation of TACE protein, suggesting that increased TACE activity is necessary for the release of TNF-alpha observed in anti-Ro/SSA Abs-stimulated SGEC. Adalimumab treatment brought TACE mRNA and surface TACE expression to levels than those observed in untreated SGEC. These data suggest that the effect of anti-Ro/SSA Abs on TACE expression and intracellular distribution is exerted by TNF-alpha production.
Abstract
Leber hereditary optic neuropathy (LHON) is an important example of mitochondrial blindness with the m.11778G>A mutation in the MT-ND4 gene being the most common disease-causing mtDNA ...variant worldwide.
The REFLECT phase 3 pivotal study is a randomized, double-masked, placebo-controlled trial investigating the efficacy and safety of bilateral intravitreal injection of lenadogene nolparvovec in patients with a confirmed m.11778G>A mutation, using a recombinant adeno-associated virus vector 2, serotype 2 (rAAV2/2-ND4). The first-affected eye received gene therapy; the fellow (affected/not-yet-affected) eye was randomly injected with gene therapy or placebo. The primary end point was the difference in change from baseline of best-corrected visual acuity (BCVA) in second-affected/not-yet-affected eyes treated with lenadogene nolparvovec versus placebo at 1.5 years post-treatment, expressed in logarithm of the minimal angle of resolution (LogMAR).
Forty-eight patients were treated bilaterally and 50 unilaterally. At 1.5 years, the change from baseline in BCVA was not statistically different between second-affected/not-yet-affected eyes receiving lenadogene nolparvovec and placebo (primary end point). A statistically significant improvement in BCVA was reported from baseline to 1.5 years in lenadogene nolparvovec-treated eyes: −0.23 LogMAR for the first-affected eyes of bilaterally treated patients (P < 0.01); and −0.15 LogMAR for second-affected/not-yet-affected eyes of bilaterally treated patients and the first-affected eyes of unilaterally treated patients (P < 0.05). The mean improvement in BCVA from nadir to 1.5 years was −0.38 (0.052) LogMAR and −0.33 (0.052) LogMAR in first-affected and second-affected/not-yet-affected eyes treated with lenadogene nolparvovec, respectively (bilateral treatment group). A mean improvement of −0.33 (0.051) LogMAR and −0.26 (0.051) LogMAR was observed in first-affected lenadogene nolparvovec-treated eyes and second-affected/not-yet-affected placebo-treated eyes, respectively (unilateral treatment group). The proportion of patients with one or both eyes on-chart at 1.5 years was 85.4% and 72.0% for bilaterally and unilaterally treated patients, respectively. The gene therapy was well tolerated, with no systemic issues. Intraocular inflammation, which was mostly mild and well controlled with topical corticosteroids, occurred in 70.7% of lenadogene nolparvovec-treated eyes versus 10.2% of placebo-treated eyes. Among eyes treated with lenadogene nolparvovec, there was no difference in the incidence of intraocular inflammation between bilaterally and unilaterally treated patients.
Overall, the REFLECT trial demonstrated an improvement of BCVA in LHON eyes carrying the m.11778G>A mtDNA mutation treated with lenadogene nolparvovec or placebo to a degree not reported in natural history studies and supports an improved benefit/risk profile for bilateral injections of lenadogene nolparvovec relative to unilateral injections.
Newman et al. report that bilateral injection of lenadogene nolparvovec improves vision in patients carrying the m.11778G>A MT-ND4 mutation causing Leber hereditary optic neuropathy, with a larger treatment effect in patients who received bilateral treatment and an excellent safety profile.
Abstract Objective To evaluate changes in patient’s visual performance after rehabilitation training with 2 different biofeedback training programs offered by the MP-1 microperimeter. Spontaneous ...retinal location of preferred retinal loci (PRLs) and fixation stability are not always optimal for best visual performances. MP-1 microperimeter biofeedback techniques have been suggested as modalities for training for better fixation stability and to find a better location of the new PRL in a more useful area of the retina in nonoptimal cases. The MP-1 microperimeter offers different biofeedback strategies, such as acoustic biofeedback and structured light stimulus plus acoustic biofeedback. Design Retrospective study. Participants Thirty subjects affected by age-related macular degeneration with absolute central scotoma. Methods A standard protocol of examination before and after visual rehabilitation training was performed on all study subjects. Assessment included demographics data, visual acuity, fixation stability, retinal sensitivity, and reading speed. Rehabilitation training was performed with standard and structured stimulus biofeedback. The whole sample was divided into 2 groups of 15 patients attending the 2 different stimulation training biofeedback. Results Mean reading speed was found to be significantly increased for both groups ( p < 0.05 and p < 0.01). Also, a statistically significant improvement of fixation stability was registered for both groups ( p < 0.01). Only patients trained with the flickering pattern biofeedback stimulation increased retinal sensitivity ( p < 0.01). Conclusions Both regular biofeedback and flickering pattern biofeedback training seem to improve visual functions. More benefits seem to be accrued, however, with flickering pattern biofeedback training.
Rehabilitative approach in patients with ring scotoma Amore, Filippo M., MD, PhD; Silvestri, Valeria, CO; Turco, Simona, MD, PhD ...
Canadian journal of ophthalmology,
10/2013, Letnik:
48, Številka:
5
Journal Article
Recenzirano
Abstract Objective To investigate the rehabilitative approach in patients with ring scotoma. A central scotoma is characteristic for patients with age-related macular degeneration (AMD). Sometimes ...patients with AMD maintain a residual central vision area within the scotoma (ring scotoma). Design Prospective, nonrandomized case series. Participants Twenty-four patients with AMD. Methods A formal low-vision assessment was performed for all study patients. The assessment included best corrected visual acuity (BCVA), contrast sensitivity, reading speed, and microperimetry. All patients were provided a low-vision assessment to satisfy patients’ needs. Devices were prescribed accordingly. Results The BCVA found was 0.4 logMAR (SD 0.1). All had central and stable fixation. Residual central retinal area size and sensitivity measured 2.4° (SD 0.8) and 3.1 dB (SD 0.8), respectively. Twenty patients achieved better vision with optical magnification in the eye with ring scotoma. Mean reading speed achieved was 50.2 words/min (SD 20.9). A linear correlation was found for reading speed with both central area sensitivity ( r ² = 0.5, p < 0.05) and contrast sensitivity ( r ² = 0.3, p < 0.05). Conclusions In patients with AMD with ring scotoma, moderate amounts of magnification seem to provide satisfactory rehabilitation outcomes. Central retinal spared area sensitivity may predict reading speed outcomes, whereas residual central area size is likely to be useful in determining magnification.
Background In patients with acute ischemic stroke and atrial fibrillation, early anticoagulation prevents ischemic recurrence but with the risk of hemorrhagic transformation ( HT ). The aims of this ...study were to evaluate in consecutive patients with acute stroke and atrial fibrillation (1) the incidence of early HT, (2) the time to initiation of anticoagulation in patients with HT , (3) the association of HT with ischemic recurrences, and (4) the association of HT with clinical outcome at 90 days. Methods and Results HT was diagnosed by a second brain computed tomographic scan performed 24 to 72 hours after stroke onset. The incidence of ischemic recurrences as well as mortality or disability (modified Rankin Scale scores >2) were evaluated at 90 days. Ischemic recurrences were the composite of ischemic stroke, transient ischemic attack, or systemic embolism. Among the 2183 patients included in the study, 241 (11.0%) had HT . Patients with and without HT initiated anticoagulant therapy after a mean 23.3 and 11.6 days, respectively, from index stroke. At 90 days, 4.6% (95% confidence interval, 2.3-8.0) of the patients with HT had ischemic recurrences compared with 4.9% (95% confidence interval, 4.0-6.0) of those without HT ; 53.1% of patients with HT were deceased or disabled compared with 35.8% of those without HT . On multivariable analysis, HT was associated with mortality or disability (odds ratio, 1.71; 95% confidence interval, 1.24-2.35). Conclusions In patients with HT , anticoagulation was initiated about 12 days later than patients without HT . This delay was not associated with increased detection of ischemic recurrence. HT was associated with increased mortality or disability.
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