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1
Wenger, Karl H., Ahmed R. El-Awady, Regina L. W. Messer, Mohamed M. Sharawy, Greg White, and Carol A. Lapp. "Pneumatic pressure bioreactor for cyclic hydrostatic stress application: mechanobiology effects on periodontal ligament cells." Journal of Applied Physiology 111, no. 4 (October 2011): 1072–79. http://dx.doi.org/10.1152/japplphysiol.01175.2010.
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A bioreactor system was developed to provide high-amplitude cyclic hydrostatic compressive stress (cHSC) using compressed air mixed commercially as needed to create partial pressures of oxygen and carbon dioxide appropriate for the cells under investigation. Operating pressures as high as 300 psi are achievable in this system at cyclic speeds of up to 0.2 Hz. In this study, ligamentous fibroblasts from human periodontal ligaments ( n = 6) were compressed on two consecutive days at 150 psi for 3 h each day, and the mRNA for families of extracellular matrix protein and protease isoforms was evaluated by real-time PCR array. Several integrins were significantly upregulated, most notably alpha-3 (6.4-fold), as was SPG7 (12.1-fold). Among the collagens, Col8a1 was highly upregulated at 53.5-fold, with Col6a1, Col6a2, and Col7a1 also significantly upregulated 4.4- to 8.5-fold. MMP-1 was the most affected at 122.9-fold upregulation. MMP-14 likewise increased 17.8-fold with slight reductions for the gelatinases and a significant increase of TIMP-2 at 5.8-fold. The development of this bioreactor system and its utility in characterizing periodontal ligament fibroblast mechanobiology in intermediate-term testing hold promise for better simulating the conditions of the musculoskeletal system and the large cyclic compressive stresses joints may experience in gait, exertion, and mastication.
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Chien, Tzu-I., Huey-Wen Liang, Ya-Fen Lee, Fei-Yun Liu, Chi-Kwang Hsu, Shao-Tseng Liu, Mo Siu-Mei Lee, and Pin-Fei Wei. "Evaluation of Newly Developed Easy-Open Assistive Devices for Pneumatic Tube System Carriers for the Reduction of Work-Related Musculoskeletal Disorders." BioMed Research International 2021 (January 8, 2021): 1–12. http://dx.doi.org/10.1155/2021/8853602.
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Musculoskeletal disorders may affect labor efficiency, cause disability, impair one’s work ability, and lower one’s quality of life. This consequently leads to a larger expenditure of medical resources. We aimed to design easy-to-open assistive devices for pneumatic tube systems to improve ergonomics and reduce musculoskeletal complaints of workers. We followed a design control process, including designs of motors, gears, sensors, and V-shaped connecting rods. Efficacy was evaluated by examining risks based on job strain index, user satisfaction, and musculoskeletal complaints of operators before and after the system’s implementation on a Nordic musculoskeletal questionnaire. We designed three assistive devices: two semiautomatic and one automatic. Each semiautomatic device costs about 300 US dollars and required space of 10 × 18 × 38 c m 3 . The automatic device costs about 3000 US dollars and required space of 28 × 38 × 50 c m 3 . The job strain index score decreased from 36 (very high risk) to 3 (low risk) with the semiautomatic devices and to 0 with the automatic device. Musculoskeletal complaints in the neck and upper limbs were reduced, with a significantly higher satisfaction rate for female operators. Our novel design of an automatic cap opening device for a pneumatic tube system was effective in improving ergonomics and reducing musculoskeletal complaints.
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Gadoni, Elena, Antonella Olivero, Antonella Miglietta, and Ludovica Gabriel. "Effects of 4-Hydroxynonenal on Microtubular System of Normal and Transformed Fibroblasts." Alternatives to Laboratory Animals 19, no. 1 (February 1991): 53–59. http://dx.doi.org/10.1177/026119299101900111.
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Microtubules are known to be important in cell division and proliferation; however, their role in cell transformation is controversial. Cell proliferation can be inhibited by antimicrotubular drugs, and 4-hydroxynonenal, a product of lipid peroxidation with antiproliferative characteristics, is able to interact with tubulin, the main protein of microtubules. In this study, the effects of 4-hydroxynonenal on both normal and transformed cells (3T3 and SV40 transformed 3T3 fibroblasts) were examined, in order to investigate the significance of in vivo alterations of microtubules. An immunofluorescence technique was used to examine any modifications of the microtubule network, and colchicine-binding activity was assayed to determine tubulin content. Morphological observation of the microtubule network did not reveal any significant difference between normal and transformed fibroblasts; the colchicine-binding assay detected a stronger resistance in the latter cells.
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Sunny, Sonie Sarah. "Fix That PHEX Loss." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A194—A195. http://dx.doi.org/10.1210/jendso/bvab048.395.
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Abstract Phosphorous has a critical role in multiple biological functions in the body, such as skeletal mineralization, and an imbalance of this can lead to several musculoskeletal disorders. An important regulator of renal phosphate excretion is fibroblast growth factor 23 (FGF23) which is produced by osteocytes and osteoblasts themselves thus providing a mechanism for the skeletal system to influence its own mineralization needs. PHEX is a gene that regulates FGF23 secretion therefore a loss-of-function mutation in this gene would result in elevated circulating FGF23 and phosphate depletion. This mutation has been identified as a cause for X-linked hypophosphatemia (XLH). Treatment of XLH has been limited and mainly involved phosphorous replacement in combination with 1,25(OH) vitamin D. Antiresorptive osteoporosis treatment can exacerbate the skeletal mineralization process. Here we present a patient with multiple fractures who was on denosumab treatment for presumed osteoporosis before being found to have PHEX mutation. The patient is a 64 year-old female with past medical history of bilateral hip replacement and recurrent femur fractures who was seen in clinic in 2014 due to recurrent fractures and diagnosis of osteoporosis since early 2000s. She had only tried alendronate up until that point. Due to the recurrent fractures she was switched to denosumab therapy while workup was underway for secondary causes. She was found to have low phosphorous levels and elevated FGF23 therefore genetic counseling was pursued and was recommended to check for PHEX mutation. The testing came back positive for loss-of-function mutation in PHEX, and by that point she had received 3 doses of denosumab therapy. She suffered another femoral fracture which was determined to be an atypical fracture, and therefore denosumab treatment was stopped and she was continued on phosphorous replacement as well as 1,25(OH) vitamin D replacement. Most recently her phosphorous levels have been controlled with therapy, and there is current discussion underway to try burosumab, an antibody to FGF23. During evaluation for osteoporosis, it is important to consider phosphorous roles in skeletal mineralization. If recurrent fractures are seen in a patient with low phosphorous levels, especially while they are on conventional antiresorptive osteoporosis medications, genetic testing for PHEX mutations should be considered as well as safely stopping antiresorptive medications.
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Maccaroni, Klizia, Elisa Balzano, Federica Mirimao, Simona Giunta, and Franca Pelliccia. "Impaired Replication Timing Promotes Tissue-Specific Expression of Common Fragile Sites." Genes 11, no. 3 (March 19, 2020): 326. http://dx.doi.org/10.3390/genes11030326.
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Common fragile sites (CFSs) are particularly vulnerable regions of the genome that become visible as breaks, gaps, or constrictions on metaphase chromosomes when cells are under replicative stress. Impairment in DNA replication, late replication timing, enrichment of A/T nucleotides that tend to form secondary structures, the paucity of active or inducible replication origins, the generation of R-loops, and the collision between replication and transcription machineries on particularly long genes are some of the reported characteristics of CFSs that may contribute to their tissue-specific fragility. Here, we validated the induction of two CFSs previously found in the human fetal lung fibroblast line, Medical Research Council cell strain 5 (MRC-5), in another cell line derived from the same fetal tissue, Institute for Medical Research-90 cells (IMR-90). After induction of CFSs through aphidicolin, we confirmed the expression of the CFS 1p31.1 on chromosome 1 and CFS 3q13.3 on chromosome 3 in both fetal lines. Interestingly, these sites were found to not be fragile in lymphocytes, suggesting a role for epigenetic or transcriptional programs for this tissue specificity. Both these sites contained late-replicating genes NEGR1 (neuronal growth regulator 1) at 1p31.1 and LSAMP (limbic system-associated membrane protein) at 3q13.3, which are much longer, 0.880 and 1.4 Mb, respectively, than the average gene length. Given the established connection between long genes and CFS, we compiled information from the literature on all previously identified CFSs expressed in fibroblasts and lymphocytes in response to aphidicolin, including the size of the genes contained in each fragile region. Our comprehensive analysis confirmed that the genes found within CFSs are longer than the average human gene; interestingly, the two longest genes in the human genome are found within CFSs: Contactin Associated Protein 2 gene (CNTNAP2) in a lymphocytes’ CFS, and Duchenne muscular dystrophy gene (DMD) in a CFS expressed in both lymphocytes and fibroblasts. This indicates that the presence of very long genes is a unifying feature of all CFSs. We also obtained replication profiles of the 1p31.1 and 3q13.3 sites under both perturbed and unperturbed conditions using a combination of fluorescent in situ hybridization (FISH) and immunofluorescence against bromodeoxyuridine (BrdU) on interphase nuclei. Our analysis of the replication dynamics of these CFSs showed that, compared to lymphocytes where these regions are non-fragile, fibroblasts display incomplete replication of the fragile alleles, even in the absence of exogenous replication stress. Our data point to the existence of intrinsic features, in addition to the presence of long genes, which affect DNA replication of the CFSs in fibroblasts, thus promoting chromosomal instability in a tissue-specific manner.
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Miglietta, Antonella, Elena Gadoni, Claudia Bocca, and Ludovica Gabriel. "Prooxidant Agents Induce Modifications in the Cytoskeletal Organisation of Fibroblasts." Alternatives to Laboratory Animals 24, no. 4 (August 1996): 557–65. http://dx.doi.org/10.1177/026119299602400416.
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An important modulatory role of free-radicals and related species in controlling the cell cycle has recently been revealed. The cytoskeletal system is an intracellular structure that participates in the regulatory mechanisms of the cell cycle and is involved in reactions which generate free-radicals. We studied the effects of three different prooxidant systems (ascorbate/iron II sulphate, adenosine diphosphate/iron III chloride and cumene hydroperoxide) on BALB/C 3T3 fibroblasts, in order to establish a relationship between cytoskeletal alterations and changes in cell proliferation under oxidative stress conditions. We found that prooxidant systems markedly influence cytoskeletal organisation, but only slightly modify the proliferation rate. The mechanism of cytoskeletal alteration is unclear, but does not depend on oxidative damage. The main components of the cytoskeleton appear to be involved in free-radical-generated cell reactions, even though a relationship with cell growth has yet to be identified.
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Dong, Dahai, Yu Yao, Jinlei Song, Lijiang Sun, and Guiming Zhang. "Cancer-Associated Fibroblasts Regulate Bladder Cancer Invasion and Metabolic Phenotypes through Autophagy." Disease Markers 2021 (May 25, 2021): 1–8. http://dx.doi.org/10.1155/2021/6645220.
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Recently, both cancer-associated fibroblasts (CAFs) and autophagy have been proven to play an important role in tumor development, including bladder cancer (BCa). However, the real mechanisms remain largely unclear. Here, we reconstruct a mimic tumor microenvironment to explore the interaction between CAFs and the BCa cell line T24 using a coculture system. Autophagy in CAFs was induced or inhibited by rapamycin or siRNA, respectively. After coculture with CAFs, T24 cell proliferation, invasion, and aerobic glycolysis were tested in vitro. Rapamycin induced and siAtg5 inhibited autophagy in CAFs. Enhanced autophagy in CAFs promoted cell proliferation and invasion in T24 cells in vitro, while there was no significant difference between the autophagy-inhibited group and the controls. Lactate concentration was elevated in both rapamycin-treated and siAtg5-treated groups compared with the control group. In addition, the expression levels of MCT1, MCT4, HK2, SLC2A1, and MMP-9 were all increased in T24 cells in the autophagy-enhanced group. Our results indicated that CAFs could regulate BCa invasion and metabolic phenotypes through autophagy, providing us with new alternative treatments for BCa in the future.
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Grafström, Roland C., Charlotte C. Edman, Kristina Sundqvist, Yun Liu, Sverker S. Hybbinette, Luigi Atzori, Pierluigi Nicotera, and Jeannette M. Dypbukt. "Cultured Human Bronchial Cells as a Model System in Lung Toxicology and Carcinogenesis: Implications from Studies with Acrolein." Alternatives to Laboratory Animals 16, no. 3 (March 1989): 231–43. http://dx.doi.org/10.1177/026119298901600305.
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Tissues and cells from both humans and laboratory animals can now be successfully cultured and used to examine in vitro the interspecial extrapolation of toxicity data. In particular, epithelial cells or fibroblasts from the human bronchus are systematically being used to study pathobiological effects of inhalation toxicants, e.g. acrolein, present in tobacco smoke and automobile emissions. Micromolar concentrations of acrolein are highly toxic to both bronchial epithelial cells and fibroblasts, and decrease their colony-forming efficiency, ability to exclude trypan blue dye, and content of low-molecular-weight thiols in a dose-dependent manner. Cytosolic free-calcium levels are increased at concentrations of acrolein lower than those required to decrease plasma membrane integrity (measured by exclusion of ethidium bromide dye). Acrolein also decreases growth rate and increases formation of cross-linked envelopes in bronchial epithelial cells, which are indicative of squamous differentiation. Moreover, acrolein causes several types of DNA damage, including single strand breaks, DNA-protein cross-links, interstrand cross-links and alkali-labile sites. The dose-response relationships in this study indicate that disturbance of the cellular thiol and calcium homeostasis and/or formation of DNA damage may be involved in acrolein-related toxicity and accelerated epithelial differentiation. These results also demonstrate that acrolein causes pathobiological effects associated with various phases of multi-stage carcinogenesis in human airway epithelium.
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Cornells, Marleen, Charlotte Dupont, and Jacques Wepierre. "In Vitro Cytotoxicity Tests on Cultured Human Skin Fibroblasts to Predict the Irritation Potential of Surfactants." Alternatives to Laboratory Animals 19, no. 3 (July 1991): 324–36. http://dx.doi.org/10.1177/026119299101900306.
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A comparative study of the cytotoxicity of 17 surfactants was performed in vitro on cultured human skin fibroblasts to predict their irritation potential under different experimental conditions: test media, presence of proteins, various times of exposure (2–72 hours), and evaluation methods. For cytotoxicity, the tetrazolium MTT assay after exposure for 2 hours in Hank's medium (HBSS) seemed to be more sensitive than protein and LDH leakage tests. Cytotoxicities in HBSS and in minimum Eagle's medium (MEM) were very similar. Addition of 10% fetal calf serum (FCS) to MEM decreased the cytotoxicity of surfactants; however, their order of cytotoxicity was generally the same in MEM with or without FCS. Cytotoxicity increased with incubation time, but the overall ranking remained identical. Non-ionic polyoxyethylene 20 ethers (Brij 35, 58, 78 and 99) surfactants, although considered to be non-irritant in vivo, revealed a high cytotoxic effect in our cell culture system. A good correlation with the results of in vivo Draize rabbit eye irritancy was found only when they were excluded.
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García Hernández, I., L. Fernández de la Fuente Bursón, P. Muñoz Reinoso, D. V. Mendoza Mendoza, B. Hernández-Cruz, P. González Moreno, and J. J. Pérez Venegas. "AB1159 HIGH PREVALENCE MUSCULOSKELETAL PATHOLOGY: A CHALLENGE FOR PRIMARY ATTENDING PHYSICIANS. WHAT DO WE RHEUMATOLOGISTS CONTRIBUTE TO?" Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1870.1–1870. http://dx.doi.org/10.1136/annrheumdis-2020-eular.4593.
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Background:Musculoskeletal Diseases (MSKD) represent one of the main health problems burdens worldwide. They cause a significant functional, quality of life and socioeconomic impact. Knee and lumbar osteoarthritis are the most prevalent1. MSKD can be assessed by different kind of specialists: Orthopedic and Traumatology Surgery (OTS), Rheumatology and Rehabilitation, each of them focused at one of the distinct aspects of the same disease. It is the General Practitioner (GP) consultations that usually act as a gateway to specialized care. However, this derivation is carried out in non-standardized manners that leads to an evaluation from a sometimes wrong selected specialist or sometimes overlap management between several of them2. The result is an endless waiting list in an overburden health system that cannot solve people’s health issues. In 2018, only in our area, 32.894 patients with MSKD were referred from GP to the different medical consultations: OTS (65%), Rehabilitation (25%) and Rheumatology (10%). Furthermore, there are specialized consultations called“Primary Trauma”to which GP can refer which are managed indistinctly by any of the 3 specialists mentioned before.Objectives:The following study aims to assess by collecting data in one of these consultations, how these pathologies are referred to the different specialist and the role that the rheumatologist plays in its management.Methods:From January to March 2019, 300 consecutive patients´ medical records from the HUVM area that were sent to “Primary Trauma” consultations and attended by a rheumatologist have been reviewed. The reason for consultation, tests and referrals requested, diagnoses reached and procedures and other therapeutic actions performed were collected. Descriptive statistics with percentages and mean are showed.Results:The average age of the patients was 51 years [7-88], 57% (170) women and 43% (130) men. The most frequent reasons for referral were knee pain (26), foot pathology (23%), low back pain (12%) and carpal tunnel syndrome (6%). 68% (204 patients) attended the consultation with some test already performed request in primary care, mostly radiographs (61%) and MRI scan (34%). After the first assessment during consultation, only 31% required new studies. The diagnoses that were most frequently established are showed in table 1: degenerative knee pathology (29%) was the most prevalent. 60% of the patients assessed were given exercise tables and/or postural recommendations. 14% received an infiltration on the same day of the visit. Only 78 patients (26%) needed to be reviewed later in those consultations. Of the remaining 222 (74%), 81 (27%) were referred to other specialists. 56 of them (19%) went to OTS to a surgical evaluation, most frequently of the knee (32%), hand (27%) and foot (23%). 141 (47%) were discharged and referred to GP´s for follow ups.Table 1.Diagnoses.N%Degenerative knee pathology6729Plantar support alterations3415Lumbar osteoarthritis198Deformities of the feet177Mechanical metatarsalgia125Plantar fasciitis94Carpal tunnel syndrome94Conclusion:The prevalence of MSKD found in medical consultation coincides with the national registers. Most patients did not need to be referred to surgical units. The role of the Rheumatologist is to take a comprehensive care for the patient, focusing on giving an effective evaluation and quick solution to his MSKD. In short, if the most prevalent MSKD are not subsidiary of surgical treatment (at least initially), the specialist whom patients with MSKD should be referred would be the rheumatologist.References:[1]EPISER2016: Estudio de la prevalencia de las enfermedades reumáticas en población adulta en España. Sociedad Española de Reumatología. Madrid, 2018.[2]Conill EM et al. Waiting lists in public systems: from expanding supply to timely access? Reflections on Spain’s National Health System. Cien Saude Colet. 2011;16:2783–94.Disclosure of Interests:Isabel García Hernández: None declared, Lola Fernández de la Fuente Bursón: None declared, Paloma Muñoz Reinoso: None declared, Dolores V. Mendoza Mendoza: None declared, Blanca Hernández-Cruz Speakers bureau: Abbvie, Lilly, Sanofi, BMS, STADA, Paz González Moreno: None declared, José Javier Pérez Venegas: None declared
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Rudolf, Emil, and Miroslav Červinka. "The Role of Biomembranes in Chromium (III)-induced Toxicity In Vitro." Alternatives to Laboratory Animals 33, no. 3 (June 2005): 249–59. http://dx.doi.org/10.1177/026119290503300311.
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The role of biomembranes in the chronic toxicity of environmentally occurring chromium acetate hydroxide was investigated by using primary human fibroblasts. Transport of chromium acetate hydroxide across the plasma membrane of the cell, and the effects of chromium (III) ions on the plasma membrane as well as other intracellular membranes, were determined during six weeks of continuous exposure by using atomic absorption spectrometry, observation of cell morphology, membrane integrity assays (for lactate dehydrogenase leakage and lysosomal membrane disruption), and mitochondrial assays (for mitochondrial dehydrogenase activity and mitochondrial transmembrane potential analysis). The type of cell death induced by long-term exposure was determined in terms of phosphatidylserine externalisation, caspase-3 activation, and chromatin fragmentation. Chromium acetate hydroxide, at a concentration of 100μmol/l, accumulated in exposed cells, inflicting plasma membrane damage and suppressing mitochondrial function. Antioxidant co-enzyme Q, at a concentration of 10μmol/l, partially prevented plasma membrane damage and mitochondrial dysfunction. Exposure to chromium acetate hydroxide produced apoptosis, necrosis and an intermediate type of cell death in primary human fibroblasts. These results show that the plasma membrane and mitochondrial membrane are important targets for chronic chromium acetate hydroxide toxicity, and that this in vitro system holds promise for studying the toxicity resulting from long-term exposure to metal ions.
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Ohashi, Yoshihisa, Kentaro Uchida, Kensuke Fukushima, Masashi Satoh, Tomohisa Koyama, Maho Tsuchiya, Hiroki Saito, Naonobu Takahira, Gen Inoue, and Masashi Takaso. "NGF Expression and Elevation in Hip Osteoarthritis Patients with Pain and Central Sensitization." BioMed Research International 2021 (September 18, 2021): 1–7. http://dx.doi.org/10.1155/2021/9212585.
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Osteoarthritis (OA) is a chronic degenerative musculoskeletal disease that causes articular cartilage degeneration and chronic pain. Research into OA animal models suggests that elevated NGF levels in the synovium contribute to pain and central sensitization (CS). However, it is unclear whether synovial NGF contributes to CS in patients with OA. We investigated the association between synovial NGF expression and clinical assessments of pain and CS in hip OA (hOA) patients. We also aimed to identify which cells in the synovium of hOA patients express NGF. Sixty-six patients who received total hip replacement and a diagnosis of hOA were enrolled. We measured NGF mRNA expression in synovial samples obtained from 50 patients using qPCR and analyzed the correlation of NGF expression with the CS inventory (CSI) score and Japanese Orthopaedic Association (JOA) score, a clinical scoring system for OA. To identify the synovial cells expressing NGF, we analyzed NGF mRNA expression in CD14+ and CD14- cells, which represent macrophage-rich and fibroblast-rich fractions, respectively, extracted from 8 patients. To further identify which macrophage subtypes express NGF, we examined NGF mRNA expression in CD14high and CD14low cells sorted from 8 patients. Synovial NGF mRNA expression was negatively correlated with JOA score but positively correlated with CSI score (JOA pain, r = − 0.337 , P = 0.017 ; CSI score, r = 0.358 , P = 0.011 ). Significantly greater levels of NGF were observed in CD14- cells compared to CD14+ cells ( P = 0.036 ) and in CD14high cells compared to CD14low cells ( P = 0.008 ). In conclusion, synovial NGF expression is correlated with the degree of pain and CS in hOA patients. NGF is predominantly expressed in synovial fibroblasts. Further, CD14high synovial macrophages expressed higher levels of NGF. Our results may provide a novel NGF-targeted therapeutic strategy for hOA pain.
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Mueller, A., and M. Roffler. "PARE0032 STRENGTHENING SELF-MANAGEMENT TO IMPROVE THE QUALITY OF LIFE AND HEALTH STATUS OF PATIENTS WITH INFLAMMATORY ARTHRITIS AND OSTEOPOROSIS IN SWITZERLAND." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1302.2–1302. http://dx.doi.org/10.1136/annrheumdis-2020-eular.5220.
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Background:Previous UK studies suggest that people with arthritis taking part in self-management programmes feel more confident in their ability to manage and control their symptoms. These patients may also visit the doctor less frequently and have shown improved physical and clinical outcomes (1, 2). Based on this evidence, self-management has become an essential component of care for patients with arthritis, or generally with chronic diseases. However, there is still a huge gap regarding such self-management services and support programmes in rheumatology in Switzerland.In the Swiss National Strategy “Musculoskeletal Diseases” 2017–2022, strengthening patients’ empowerment is one of the main strategic pillars. Considering that approximately 500,000 people are suffering in Switzerland from inflammatory arthritis (IA) and osteoporosis (OP) alone, there is huge potential to strengthen patients’ self-management capacity and thus improve their quality of life (3).Therefore, the SLR has developed a self-management programme for IA and OP patients. In this programme medical assistants in outpatient rheumatology clinics are trained to consult patients in self-management. This programme is part of a two-year pilot project (2019–2020) that is supported by a consortium of important stakeholders in rheumatology in Switzerland.Objectives:The ultimate objective is to increase the quality of life and the health status of people with IA and OP in Switzerland by enhancing their capacity for self-management. Furthermore, this pilot project aims at closing an important gap in the Swiss healthcare system by creating an innovative model that can potentially be replicated for other chronic diseases.Methods:To measure the quality of life, the health status as well as the change in behaviour in patients, the study design includes both qualitative and quantitative methods. Patients enrolled in the programme are asked to answer a questionnaire at three points in time; at enrolment, after the last session and two months after completing the programme. It is expected that at least 45 patients will be enrolled. For a qualitative assessment, in-depth interviews will be conducted with rheumatologists and their medical assistants as well as some of the programme participants.The training material for the medical assistants was developed by the SLR and will be evaluated by the programme participants. All patients will also evaluate the quality of the consulting provided by the medical assistant, answering a questionnaire after the last session.Results:Within the first year of implementation, ten outpatient clinics, with twenty-four rheumatologists and twelve medical assistants, were enrolled in the pilot project. Four medical assistants were trained in 2019 and eight are in the process of receiving training in spring 2020. Only after the completion of training will patients be enrolled in the self-management programme. Therefore, outcome-related results cannot be expected until the beginning of 2021.Conclusion:This pilot project provides an innovative approach to closing an important gap in the Swiss healthcare system and to providing a missing component of care for patients with IA and OP. However, it has been challenging to enrol enough clinics in the pilot project. The way the programme is embedded in the current healthcare system, it demands a cultural change within outpatient clinics, allowing medical assistants to step into a new role as consultant.References:[1]Barlow JH, Turner, Wright (2000). ‘A randomised controlled study of the arthritis self-management programme in the UK’. Health Ed Res 15(6): 665–80.[2]De Silva, D. (2011). Evidence: Helping people help themselves. A review of the evidence considering whether it is worthwhile to support self-management. The Health Foundation. London.[3]Swiss League against Rheumatism (2017). Swiss National Strategy ‘Musculoskeletal Diseases’ 2017–2022. Zurich: 10–13.Disclosure of Interests:None declared
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Jia, Yuxi, Cong Zhu, Jingcheng Du, Yang Xiang, Yong Chen, Wei Wang, and Cui Tao. "Investigating safety profiles of human papillomavirus vaccine across group differences using VAERS data and MedDRA." PeerJ 7 (August 20, 2019): e7490. http://dx.doi.org/10.7717/peerj.7490.
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Background The safety of vaccines is a critical factor in maintaining public trust in national vaccination programs. This study aimed to evaluate the safety profiles of human papillomavirus (HPV) vaccines with regard to the distribution of adverse events (AE) across gender and age, and the correlations across various AEs using the Food and Drug Administration/Centers for Disease Control and Prevention Vaccine Adverse Event Reporting System (VAERS). Methods For analyses, 27,348 patients aged between 9 and 25 years old with at least one AE reported in VAERS between the year of 2006 and 2017 were included. AEs were summarized into two levels: the lower level preferred term (PT) and higher level system organ classes (SOCs) based on the structure of Medical Dictionary for Regulatory Activities (MedDRA). A series of statistical analyses were applied on both levels of AEs. Zero-truncated Poisson regression and multivariate logistic regression models were first developed to assess the rate and risk of SOCs across age groups and genders. Pairwise Pearson correlation analyses and hierarchical clustering analyses were then conducted to explore the interrelationships and clustering pattern among AEs. Results We identified 27,337 unique HPV vaccine reports between 2006 and 2017. Disproportional reporting of AEs was observed across age and gender in 21 SOCs (p < 0.05). The correlation analyses found most SOCs demonstrate weak positive correlations except for five pairs which were negatively correlated: skin and subcutaneous tissue disorders + injury poisoning and procedural complications; skin and subcutaneous tissue disorders + nervous system disorders; Skin and subcutaneous tissue disorders + pregnancy, puerperium and perinatal conditions; nervous system disorders + pregnancy, puerperium and perinatal conditions; pregnancy, puerperium and perinatal conditions + general disorders and administration site conditions. Nervous system disorders had the most AEs which contributed to 12,448 (46%) cases. In the further analyses of correlations between PT in nervous system disorders, the three most strongly correlated AEs were psychiatric disorders (r = 0.35), gastrointestinal disorders (r = 0.215), and musculoskeletal and connective tissue disorders (r = 0.261). We observed an inter-SOCs correlation of the PTs among AE pairs by nervous system disorders/psychiatric disorders/gastrointestinal disorders/musculoskeletal and connective tissue disorders. Conclusions The analyses revealed a different distribution pattern of AEs across gender and age subgroups in 21 SOC level AEs. Correlation analyses and hierarchical clustering analyses further revealed several correlated patterns across various AEs. However, findings from this study should be interpreted with caution. Further clinical studies are needed to understand the heterogeneity of AEs reporting across subgroups and the biological pathways among the statistically correlated AEs.
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Ngoie, Leonard Banza, Eva Dybvik, Geir Hallan, Jan-Erik Gjertsen, Nyengo Mkandawire, Carlos Varela, and Sven Young. "Prevalence, causes and impact of musculoskeletal impairment in Malawi: A national cluster randomized survey." PLOS ONE 16, no. 1 (January 6, 2021): e0243536. http://dx.doi.org/10.1371/journal.pone.0243536.
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Background There is a lack of accurate information on the prevalence and causes of musculoskeletal impairment (MSI) in low income countries. The WHO prevalence estimate does not help plan services for specific national income levels or countries. The aim of this study was to find the prevalence, impact, causes and factors associated with musculoskeletal impairment in Malawi. We wished to undertake a national cluster randomized survey of musculoskeletal impairment in Malawi, one of the UN Least Developed Countries (LDC), that involved a reliable sampling methodology with a case definition and diagnostic criteria that could clearly be related to the classification system used in the WHO International Classification of Functioning, Disability and Health (ICF) Methods A sample size of 1,481 households was calculated using data from the latest national census and an expected prevalence based on similar surveys conducted in Rwanda and Cameroon. We randomly selected clusters across the whole country through probability proportional to size sampling with an urban/rural and demographic split that matched the distribution of the population. In the field, randomization of households in a cluster was based on a ground bottle spin. All household members present were screened, and all MSI cases identified were examined in more detail by medical students under supervision, using a standardized interview and examination protocol. Data collection was carried out from 1st July to 30th August 2016. Extrapolation was done based on study size compared to the population of Malawi. MSI severity was classified using the parameters for the percentage of function outlined in the WHO International Classification of Functioning (ICF). A loss of function of 5–24% was mild, 25–49% was moderate and 50–90% was severe. The Malawian version of the EQ-5D-3L questionnaire was used, and EQ-5D index scores were calculated using population values from Zimbabwe, as a population value set for Malawi is not currently available. Chi-square test was used to test categorical variables. Odds ratio (OR) was calculated with a linear regression model adjusted for age, gender, location and education. Results A total of 8,801 individuals were enumerated in 1,481 households. Of the 8,548 participants that were screened and examined (response rate of 97.1%), 810 cases of MSI were diagnosed of which 18% (108) had mild, 54% (329) had moderate and 28% (167) had severe MSI as classified by ICF. There was an overall prevalence of MSI of 9.5% (CI 8.9–10.1). The prevalence of MSI increased with age, and was similar in men (9.3%) and women (9.6%). People without formal education were more likely to have MSI [13.3% (CI 11.8–14.8)] compared to those with formal education levels [8.9% (CI 8.1–9.7), p<0.001] for primary school and [5.9% (4.6–7.2), p<0.001] for secondary school. Overall, 33.2% of MSIs were due to congenital causes, 25.6% were neurological in origin, 19.2% due to acquired non-traumatic non-infective causes, 16.8% due to trauma and 5.2% due to infection. Extrapolation of these findings indicated that there are approximately one million cases of MSI in Malawi that need further treatment. MSI had a profound impact on quality of life. Analysis of disaggregated quality of life measures using EQ-5D showed clear correlation with the ICF class. A large proportion of patients with moderate and severe MSI were confined to bed, unable to wash or undress or unable to perform usual daily activities. Conclusion This study has uncovered a high prevalence of MSI in Malawi and its profound impact on a large proportion of the population. These findings suggest that MSI places a considerable strain on social and financial structures in this low-income country. The Quality of Life of those with severe MSI is considerably affected. The huge burden of musculoskeletal impairment in Malawi is mostly unattended, revealing an urgent need to scale up surgical and rehabilitation services in the country.
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Markova, Eva, Cecilia Clemedson, and Ada Kolman. "Use of the PFGE Assay for Studies of DNA Breakage Induced by Toxic Chemicals." Alternatives to Laboratory Animals 31, no. 3 (May 2003): 283–88. http://dx.doi.org/10.1177/026119290303100311.
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The relevance of the pulsed field gel electrophoresis (PFGE) assay for the estimation of the DNA damaging effects of chemicals was studied. Four chemicals were randomly chosen from the list of 50 Multicentre Evaluation of In Vitro Cytotoxicity (MEIC) reference chemicals with known human acute systemic toxicity: acetylsalicylic acid, paracetamol, ethylene glycol and sodium chloride. Human fibroblasts (VH-10) were used as a model system. For the estimation of cytotoxic effect, cell monolayers were treated with chemicals for 24 hours. Cloning efficiency (colony-forming ability) at different concentrations of the test chemicals was estimated, and the 50% inhibitory concentration (IC50) was determined. The IC50 values obtained demonstrated a correlation with human lethal blood concentrations. The induction of DNA double-strand breaks, measured by PFGE as the fraction of activity released, was detected after treatment with paracetamol. However, the other three chemicals tested mainly induced DNA degradation.
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Dumitru, Irina Magdalena, Nicoleta Dorina Vlad, Sorin Rugina, Nicoleta Onofrei, Sabina Gherca, Marian Raduna, Aurel Trana, et al. "SARS-CoV-2 Infection and Emery-Dreifuss Syndrome in a Young Patient with a Family History of Dilated Cardiomyopathy." Genes 12, no. 7 (July 14, 2021): 1070. http://dx.doi.org/10.3390/genes12071070.
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Emery–Dreifuss muscular dystrophy (EDMD) is a rare genetic disease that affects the musculoskeletal system, including the heart, causing rhythm disorders and cardiomyopathy, sometimes requiring an implantable cardioverter-defibrillator (ICD) or heart transplantation due to severe heart damage. The case described herein concerns a 16-year-old girl, with grade II obesity, without other known pathological antecedents or cardiac pathology diagnosis given an annual history of cardiological investigations. She was admitted to the Infectious Diseases Department with SARS-CoV-2 virus infection. The anamnesis showed that the cardiological investigations performed in the past were completed due to the medical history antecedents of her sister, who had been diagnosed with dilated cardiomyopathy, having undergone the placement of an ICD and a heart transplant. Numerous investigations were performed during hospitalization, which revealed high levels of high-sensitive cardiac troponin I (hs-cTnI), creatine kinase (CK) and N-terminal pro b-type natriuretic peptide (NT-proBNP). Dynamic electrocardiographic evaluations showed ventricular extrasystoles, without clinical manifestations. The patient presented stage 2 arterial hypertension (AHT) during hospitalization. A cardiac ultrasound was also performed, which revealed suspected mild subacute viral myocarditis with cardiomyopathy, and antihypertensive medication was initiated. A heart MRI was performed, and the patient was diagnosed with dilated cardiomyopathy, refuting the suspicion of viral subacute myocarditis. After discharge, as the patient developed gait disorders with an impossible heel strike upon walking and limitation of the extension of the arms and ankles, was hospitalized in the Neurology Department. Electrocardiograms (ECGs) were dynamically performed, and because the rhythm disorders persisted, the patient was transferred to the Cardiology Department. On Holter monitoring, non-sustained ventricular tachycardia (NSVT) was detected, so antiarrhythmic treatment was initiated, and placement of an ICD was subsequently decided and was diagnosed with EDMD. Genetic tests were also performed, and a mutation of the lamin A/C gene was detected (LMNA gene exon 2, variant c448A > C (p.Thr150pro), heterozygous form, AD).
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Singh, N., I. Huang, M. Singleton, A. Bays, J. Sabo, S. Chung, G. Gardner, et al. "POS1422 CORRELATES OF TESTING POSITIVE FOR SARS-COV-2 IN PATIENTS WITH RHEUMATIC AD MUSCULOSKELETAL DISEASES." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 994.2–994. http://dx.doi.org/10.1136/annrheumdis-2021-eular.858.
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Background:Many studies on COVID-19 outcomes in patients with RMD have either restricted to COVID positive RMD patients or compared them to the general clinic population as a comparator. Given heterogeneity in behaviors and risks, clinical characteristics associated with a positive diagnosis among patients with RMD seeking testing for Sars-CoV-2 remain less well studied.Objectives:Among patients with RMD receiving a Sars-CoV-2 PCR test, we aimed to identify RMD-related factors associated with a positive test result.Methods:Among patients seen at least once in the University of Washington (UW) rheumatology clinics between March 2018 to March 2020, we reviewed electronic medical records to identify patients undergoing Sars-CoV-2 PCR testing from March 1 through October 31, 2020. Patients with RMD were categorized into two groups: those who tested positive for Sars-CoV-2 and those who tested negative. We randomly selected patients from the negative group in a 2:1 ratio for further data abstraction. Student’s t-test and Chi-squared tests were used to compare continuous and categorical variables, respectively, between the groups. To determine the correlates of testing positive for Sars-CoV-2, specifically RMD medication use and disease activity, we constructed different multivariable logistic regression models adjusted for age, sex, race/ethnicity, presence of comorbidities, body mass index, and smoking.Results:A total of 2768 RMD patients underwent SARS-CoV-2 PCR testing within the UW system, of whom 43 (1.5%) were positive at least once. Three patients with incomplete information were excluded. Patients who tested positive had higher prevalence of end stage renal disease (ESRD)/chronic kidney disease (CKD) (24% versus 11%), had higher rates of active disease (24% versus 20%), were older (>55 years) (mean age 57.3 versus 54.8 years), male (63% versus 55%), non-white race/ethnicity (32% versus 26%), and higher prevalence of multiple comorbidities (42% versus 31%) (Table 1). In the multivariable models, neither RMD medication use (versus no use, Table 1) nor high disease activity (vs low disease activity/remission) were statistically significantly associated with COVID-19 positivity. Among the 41 COVID-19 positive patients, a majority recovered without specific treatments, although approximately one third of the positive patients were hospitalized and three deaths were observed.Conclusion:In this study, patients who tested positive did not differ in many ways from those who tested negative.Table 1.Baseline characteristics of the patients prior to COVID testingVariablesAll(N=126)COVID Positive (N=41)COVID Negative(N=85)P valueAge in years – mean (SD)55.6 (15.3)57.3 (16.3)54.8 (14.9)0.40Sex0.39 Male73 (57.9)26 (63.4)47 (55.3) Female53 (42.1)15 (36.6)38 (44.7)Race0.39 White89 (71.2)26 (63.4)63 (74.1) Other race35 (28.2)13 (31.7)22 (25.9) Missing2 (1.6)2 (4.9)0 (0.0)Rheumatic disease0.64 OA/Crystal/Fibromyalgia37 (29.4)11 (26.8)26 (30.6) RA/SpA32 (25.4)9 (22.0)23 (27.1) All others57 (45.2)21 (51.2)36 (42.3)Rheumatic disease activity0.57 Active27 (21.4)10 (24.4)17 (20.0) Not active99 (78.6)31 (75.6)68 (80.0)Co-morbidities Diabetes mellitus (%)25 (19.8)9 (22.0)16 (18.8)0.68 Hypertension48 (38.1)20 (48.8)28 (32.9)0.09 Cardiovascular disease23 (18.3)9 (22.0)14 (16.5)0.46 Lung disease25 (19.8)10 (24.4)15 (17.7)0.37 Cancer10 (7.9)3 (7.3)7 (8.2)0.86 ESRD/CKD19 (15.1)10 (24.4)9 (10.6)0.04*BMI: Body mass index; SD: Standard deviation; OA: Osteoarthritis; Crystal: Crystalline diseases; RA: Rheumatoid arthritis; SpA: SpondyloarthritisAcknowledgements:The work in this study was supported by grant UL1 TR002319 to Dr Singh from the Institute of Translational Health Sciences of the University of Washington.Disclosure of Interests:None declared
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Rasmussen, Eva Selzer. "Evaluation of the Cytotoxicity of the First Ten MEIC Chemicals in 3T3 Mouse Fibroblasts with and without Microsomal Activation, Using the Neutral Red Assay." Alternatives to Laboratory Animals 21, no. 2 (April 1993): 157–63. http://dx.doi.org/10.1177/026119299302100206.
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The cytotoxicity of the first ten MEIC chemicals was evaluated by determination of neutral red uptake in BALB/C 3T3 mouse fibroblasts both with and without the addition of a microsomal activation system. The IC20 values of all the chemicals tested without microsomes were significantly correlated to in vivo data on acute systemic toxicity. The use of microsomes weakened the overall correlation with the in vivo data. Useful information regarding the activation of acetylsalicylic acid, iron sulphate, methanol and ethanol was obtained using microsomes, while misleading information was obtained regarding the metabolism of paracetamol, diazepam, digoxin and ethylene glycol. In the case of alcohol metabolism, the Aroclor 1254 induction of rat liver enzymes seems to parallel the induction of cytochrome P450 IIE1, which is known to metabolise a number of alcohols to free radicals which might exert a variety of cytotoxic effects. For this reason, the use of Aroclor 1254 induction in cytotoxicity and genotoxicity testing is questioned.
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Eberlin, Samara, Michelle Sabrina da Silva, Gustavo Facchini, Gustavo Henrique da Silva, Ana Lúcia Tabarini Alves Pinheiro, Samir Eberlin, and Adriano da Silva Pinheiro. "The Ex Vivo Skin Model as an Alternative Tool for the Efficacy and Safety Evaluation of Topical Products." Alternatives to Laboratory Animals 48, no. 1 (January 2020): 10–22. http://dx.doi.org/10.1177/0261192920914193.
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The development of alternative approaches for safety and efficacy testing that avoid the use of animals is a worldwide trend, which relies on the improvement of current models and tools so that they better reproduce human biology. Human skin from elective plastic surgery is a promising experimental model to test the effects of topically applied products. As the structure of native skin is maintained, including cell population (keratinocytes, melanocytes, Langerhans cells and fibroblasts) and dermal matrix (containing collagen, elastin, glycosaminoglycans, etc.), it most closely matches the effects of substances on in vivo human skin. In this review, we present a collection of results that our group has generated over the last years, involving the use of human skin and scalp explants, demonstrating the feasibility of this model. The development of a test system with ex vivo skin explants, of standard size and thickness, and cultured at the air–liquid interface, can provide an important tool for understanding the mechanisms involved in several cutaneous disorders.
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Honcu, Pavla, Petr Zach, Jana Mrzilkova, Dobroslava Jandova, Vladimir Musil, and Alexander Martin Celko. "Computer Kinesiology: New Diagnostic and Therapeutic Tool for Lower Back Pain Treatment (Pilot Study)." BioMed Research International 2020 (August 24, 2020): 1–10. http://dx.doi.org/10.1155/2020/2987696.
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The aim of this study was to demonstrate the effectiveness of the diagnostic and therapeutic medical information system Computer Kinesiology in physiotherapy in patients with low back pain who were not responding to conventional therapy. Computer Kinesiology is primarily intended for the diagnostics and therapy of functional disorders of the locomotor system. This pilot study population included 55 patients (Group 1) with acute and chronic back pain and 51 persons (Group 2) without back pain. The third group was a control group of 67 healthy volunteers with no evidence of musculoskeletal pathologies and no back pain. All 173 subjects were examined three times by the diagnostic part of the Computer Kinesiology method. Groups 1 and 2 were treated after every diagnostics. Group 3 was not treated. The effect was evaluated by H score. Improvements after therapy were defined by reducing the H score by at least 1 point. In Group 1, the H score decreased by at least 1 point in 87.3% (95% CI: 75.5-94.7) and in Group 2 in 78.4% (95% CI: 64.7-88.7). There was no change of distribution of H Score grade in Group 3. The improvement neither depended on gender, age, and BMI nor was it influenced by the length of the therapy. This study demonstrated a high therapeutic efficacy of the Computer Kinesiology system in patients with back pain (Group 1) and in persons without back pain (Group 2) who used the Computer Kinesiology system for primary and secondary prevention of back pain.
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Li, D., H. Lu, J. Dunphy, T. Smith, E. Vital, I. N. Bruce, and N. Mchugh. "SAT0182 THE ASSOCIATION BETWEEN AUTOANTIBODIES AND RITUXIMAB RESPONSE IN SYSTEMIC LUPUS ERYTHEMATOSUS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1032.2–1032. http://dx.doi.org/10.1136/annrheumdis-2020-eular.4284.
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Background:Systemic Lupus Erythematosus (SLE) is clinically and immunologically heterogeneous with a variable response to treatment. MASTERPLANS is an MRC-funded consortium that seeks to identify immunophenotypic subgroups of patients that predict response to therapy. Autoantibody profiles can differentiate subgroups of patients and have potential to predict response to treatment.Objectives:To determine whether known and novel autoantibodies are associated with response to rituximab (RTX), and analyse the association between these antibodies and disease involvement in various organ systems.Methods:Serum was obtained from 224 SLE patients in the BILAG Biologics Registry who received rituximab according to NHS England criteria (2). Patients were recruited if they were starting a first cycle of rituximab for active SLE (BILAG A or 2xBILAG B) despite previous cyclophosphamide or mycophenolate mofetil. Evidence of any single organ system involvement previous or current was taken as having a BILAG score of A-D but not E. Disease activity was measured using BILAG-2004. Clinical response was defined as improvement by >=1 grade in active BILAG-2004 systems with no worsening in other systems. Autoantibodies were measured by immunoprecipitation of proteins by sera from35S-labelled K562 cell lines, followed by SDS-PAGE separation and autoradiography. Autoantibodies not able to be detected by this technique (anti-Ro52, anti-dsDNA and aCL) were measured by ELISA. Autoantibody data was analysed in IBM SPSS and GraphPad Prism v8.2. Association between autoantibodies and RTX response was analysed using binary logistic interaction terms and Pearson’s Chi-Square test.Results:Of the 224 patients (201 female, 23 male, median age 40 years) the most common system involvement from the 9 BILAG domains was musculoskeletal (164 patients) and the least ophthalmic (11 patients). Patients with anti-Ro52 and anti-U1RNP/Sm had more frequent involvement of mucocutaneous (p<0.036,p<0.012) and musculoskeletal domains (p<0.015 for U1RNP) respectively.There were 136 patients with sufficient data to define as either responders (n=67) or non-responders (n=69) to RTX at 6 months. RTX responders had a higher frequency of anti-U1RNP/Sm compared to non-responders (Figure 1). Further Pearson’s Chi-Square analysis showed a significant association between presence of anti-U1RNP/Sm and better response to RTX (p<0.018).Conclusion:Our findings suggest that the presence of U1RNP/Sm autoantibodies in a cohort of patients who have received treatment with RTX is associated with more frequent musculoskeletal and mucocutaneous involvement and predicts a more favourable response to treatment.Acknowledgments :Funded by a grant from the Medical Research Council, grant number MR/M01665X/1. BILAG BR has been funded by unrestricted educational donations from Roche, GSK and LUPUS UK. Part-funded by a grant from LUPUS UK.Disclosure of Interests: :Danyang Li: None declared, Hui Lu: None declared, Juliet Dunphy: None declared, Theresa Smith: None declared, Edward Vital Grant/research support from: AstraZeneca, Roche/Genentech, and Sandoz, Consultant of: AstraZeneca, GSK, Roche/Genentech, and Sandoz, Speakers bureau: Becton Dickinson and GSK, Ian N. Bruce Grant/research support from: Genzyme Sanofi, GSK, and UCB, Consultant of: Eli Lilly, AstraZeneca, UCB, Iltoo, and Merck Serono, Speakers bureau: UCB, Neil McHugh: None declared
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Pellegrini, Graziella, Roberto Gherzi, Adriano Tito Franzi, Fiorella D'Anna, Michele De Luca, and Ranieri Cancedda. "In Vitro Reconstitution of Differentiated Human Epithelia." Alternatives to Laboratory Animals 20, no. 1 (January 1992): 95–102. http://dx.doi.org/10.1177/026119299202000113.
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Human keratinocytes obtained from skin biopsies can be serially cultured in vitro. When plated on lethally irradiated 3T3 fibroblasts, keratinocyte colonies reconstitute a stratified squamous epithelium devoid of stratum corneum. The expression of a mature cornified epidermis, expressing all the morphological and biochemical markers of the in vivo epidermis, can be obtained by the “emerged dermal equivalent” culture system. Melanocytes grown under the same culture conditions, maintain a physiological melanocyte/keratinocyte ratio, are organised in the basal layer of the cultured epidermis, and maintain differentiated functions such as dendritic arborisation, melanin synthesis and melanosome transfer. This allows the reconstitution of an epidermis physiologically populated by functionally active melanocytes. Epithelial cells from different mucosal body sites, namely palate, urethra, conjunctiva, cornea and vagina, can also be cultured and maintain the characteristics of the original donor sites. The in vitro reconstituted human epithelia, permanently transplanted onto patients presenting large epidermal or mucosal defects, retain the characteristics of the original donor site, suggesting an intrinsic site-specific differentiation programme. These three-dimensional human epithelium models could prove useful in standard cytotoxicity assays and could be used as a tool to study the effects of a variety of compounds on normal human epithelia in vitro.
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Vivekanantham, A., D. Prieto-Alhambra, and D. E. Robinson. "POS1098 PREVALENT COMORBIDITIES ASSOCIATED WITH CLINICALLY DIAGNOSED OSTEOARTHRITIS: A CASE-CONTROL ANALYSIS INCLUDING 1,936,792 PEOPLE." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 829.1–829. http://dx.doi.org/10.1136/annrheumdis-2021-eular.3202.
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Background:Osteoarthritis (OA) is the most common form of arthritis and a major cause of pain and disability worldwide. Individuals with OA have increased cardiovascular morbidity and mortality, and other comorbidities are also more common amongst them than in the general population. In this study, we examined the prevalence and timing of the diagnosis of co-morbidities prior to the clinical diagnosis of OA.Objectives:To determine the odds of comorbidities in newly diagnosed OA cases versus matched controls in the up to 10 years prior to diagnosis.Methods:Case-control study of people registered in the Information System for Research in Primary Care (SIDIAP). SIDIAP includes primary care records covering over 80% of the population of Catalonia, Spain.Participants with an incident diagnosis of OA, based on ICD-10-CM disease codes, were matched to up to 4 controls by age (within 2 years), gender and primary care practice. The first diagnosis date of OA used the index date, with matched controls using the same index date, to retrospectively review for comorbidities. Patients were required to have at least 3 years continuous registration prior to the index date. A total of 57 comorbidities were considered, based on prior knowledge and clinical consensus.Descriptive statistics were used to obtain the demographic information about cases and controls. Counts of any comorbidity were calculated, and univariable and multivariable logistic regression were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) of individual comorbidities adjusted for age, gender and socio-economic status.Results:In total, there were 455,494 OA cases and 1,481,298 matched controls. The cases and controls were similar with regards to age, gender and deprivation level.The incident diagnosis of any comorbidity at any time prior to index date was 77% (n= 350,913) in cases versus 61% (n= 909,497) in controls.The results from the multivariable analysis [Table 1] showed that OA patients had higher prevalence of many comorbidities up to 1 year prior to their diagnosis of OA compared to up to 10 years prior to diagnosis. They were most likely to be diagnosed with another musculoskeletal condition followed by neuro-psychiatric and metabolic and cardiovascular conditions. Conversely, patients with OA were less likely to be diagnosed with cancer up to 10 years prior to index date than matched controls.Table 1.Multivariable analysis at 1 year and 10 year prior to index dateCo-morbidityMultivariable analysis 1-year prior (OR, 95% CI)Multivariable analysis 10-year prior (OR, 95% CI)Musculoskeletal conditionsAnkylosing Spondylosis3.12 (2.41, 4.05)1.27 (1.12, 1.43)Fibromyalgia4.24 (3.96, 4.54)1.85 (1.80, 1.91)Rheumatoid Arthritis2.67 (2.40, 2.97)1.27 (1.20, 1.34)Back/ neck pain2.41 (2.38, 2.45)1.76 (1.75, 1.78)Neuro-psychiatricAnxiety1.69 (1.65, 1.73)1.23 (1.22, 1.24)Depression1.87 (1.81, 1.93)1.25 (1.24, 1.27)Irritable Bowel Syndrome1.90 (1.71, 2.11)1.28 (1.22, 1.34)Migraine1.81 (1.69, 1.94)1.23 (1.20, 1.27)CancerLeukaemia1.07 (0.88, 1.30)0.91 (0.82, 1.00)Lymphoma0.84 (0.68, 1.03)0.90 (0.82, 0.99)Solid malignancy0.95 (0.91, 0.99)0.95 (0.93, 0.97)Other medical conditionsStroke1.15 (1.10, 1.20)0.95 (0.93, 0.97)Hypertension1.70 (1.68, 1.74)1.26 (1.25, 1.28)Diabetes1.34 (1.30, 1.38)1.07 (1.06, 1.09)Obesity1.96 (1.92, 2.01)1.60 (1.58, 1.62)Conclusion:Patients with OA have multiple chronic conditions. Our results found that the diagnosis of these other co-morbidities (particularly musculoskeletal and neuro-psychiatric conditions) were more likely to occur in the 1-year prior to their diagnosis of OA, compared to in the 10-year prior, except for lymphoma and solid malignancy. These results help us to further understand the relationship and timing of the development of multiple co-morbidities in patients with OA.Disclosure of Interests:Arani Vivekanantham: None declared, Daniel Prieto-Alhambra: None declared, Danielle E Robinson Grant/research support from: Dr. Prieto-Alhambra reports grants and other from AMGEN, grants, non-financial support and other from UCB Biopharma, grants from Les Laboratoires Servier, outside the submitted work; and Janssen, on behalf of IMI-funded EHDEN and EMIF consortiums, and Synapse Management Partners have supported training programmes organised by DPA’s department and open for external participants.
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Desdiani, Desdiani, Hidayat Rizal, Anindita Basuki, and Fadilah Fadilah. "Case Report: Delayed treatment of tuberculosis of the elbow joint." F1000Research 10 (June 18, 2021): 486. http://dx.doi.org/10.12688/f1000research.53488.1.
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Extrapulmonary tuberculosis (TB) is known to occur in the musculoskeletal system, including the elbow joints. These cases are rarely found because the signs and symptoms are not specific to extrapulmonary TB or other diseases. We report a case of a 24-year-old male, who complained about pain in his left elbow and noticed swelling. Initially, he complained about pain all over his left arm, after several reflexology massages to alleviate his toothache. However, instead of seeking medical treatment, he visited a traditional massage therapist every week without improvement in his left arm pain for almost one year. Examination showed skin perforation with discharge. He also had fever during the first few days when the elbow became swollen. Weight loss and a decreased appetite were also noticed by the patient. The patient went to the orthopedic department and underwent surgery. Radiological examination indicated bone erosion on the left humerus and radius, while posteroanterior chest X-ray did not show any abnormality. Histopathological examinations from biopsy and fluid aspiration showed granulomas and datia Langhans cells. Mycobacterium tuberculosis was found on acid-fast bacteria smear and culture. The patient was administered multidrug tuberculosis therapy, which consisted of two months of an intensive phase and seven months of a continuation phase, in accordance with the World Health Organization’s guidelines for extrapulmonary tuberculosis treatment. He has currently undergone the continuation phase of the treatment and his condition has improved. Early detection of tuberculosis of the elbow can prevent damage to joint structure and impairment of joint function.
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Shaharir, S. S., R. Mustafar, M. S. Mohamed Said, and R. Abd Rahman. "AB0302 FACTORS ASSOCIATED WITH GESTATIONAL DIABETES MELLITUS (GDM) IN A MULTI-ETHNIC SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) COHORT." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1177.1–1177. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1044.
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Background:The risks of insulin resistance and diabetes mellitus are elevated in systemic lupus erythematosus (SLE) patients. The use of glucocorticoid and anti-double stranded DNA antibodies positive are among the factors reported to be associated with the risk of gestational diabetes mellitus (GDM) in SLE patients. However, the relationship between GDM in Asian SLE patients is still obscure.Objectives:To determine the prevalence of gestational diabetes mellitus (GDM) in a multi-ethnic SLE cohort in Malaysia and the associated risk factors.Methods:This was a retrospective study of SLE pregnant women who have completed their antenatal care in Universiti Kebangsaan Malaysia Medical Centre (UKMMC) from 2004 until 2019. Screening and diagnosis of gestational diabetes mellitus (GDM) were as recommended in the guidelines by the Ministry of Health Malaysia. Information on SLE disease activity and treatment at 6 months before pregnancy and during pregnancy were determined from the medical records. Univariate and multi-variable logistic regression analyses were performed to determine the factors associated with GDM in the SLE patients.Results:A total of 89 patients with 202 pregnancies were included in the study. Malay was the predominant ethnic in this cohort (n=82, 67.2%), followed by Chinese (n=33,27.0%) and Indian (n=7, 5.7%). The most common system involvement of SLE was musculoskeletal (n=91, 74.6%), followed by haematological (n=78, 63.9%), lupus nephritis (54.9%, n=67) and mucocutaneous (n=66, 54.1%). The prevalence of GDM was 8.9% (n=18). More patients with GDM had positive anti-cardiolipin IgG antibody (aCL IgG) and lupus anticoagulant (LA) antibody as compared to the patients with no GDM, (55.6% vs 25.8%, p=0.01) and (50.0% vs 25.4%, p=0.05) respectively. On the other hand, the use of hydroxychloroquine (HCQ) in pregnancy was significantly lower in GDM patients (11.1%) as compared to no GDM group (39.1%), p=0.02. There was no significant difference in the ethnicity, SLE system involvement, disease activity status and immunosupressant use including steroid, azathioprine and cyclosporine A at 6 months before and during pregnancy between the GDM and non-GDM group. A forward logistic regression which include aCL IgG, LA and HCQ use in pregnancy, only the HCQ use remained significantly associated with lower risk of GDM in the model with OR= 0.12, 95% C.I = 0.02-0.94, p=0.04.Conclusion:Our study demonstrates the potential benefit of hydroxychloroquine in reducing the risk of gestational diabetes mellitus in SLE patients. The prevalence of antiphospholipid antibodies particularly aCL IgG and LA was found to be higher among patients with GDM. Further prospective studies are needed to confirm this association.References:[1]Dong Y, Dai Z, Wang Z, et al. Risk of gestational diabetes mellitus in systemic lupus erythematosus pregnancy: a systematic review and meta-analysis. BMC Pregnancy and Childbirth. 2019 May;19(1):179. DOI: 10.1186/s12884-019-2329-0.Disclosure of Interests:None declared
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Holzhütter, Hermann-Georg. "A General Measure of In Vitro Phototoxicity Derived from Pairs of Dose-Response Curves and its Use for Predicting the In Vivo Phototoxicity of Chemicals." Alternatives to Laboratory Animals 25, no. 4 (July 1997): 445–62. http://dx.doi.org/10.1177/026119299702500407.
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In pharmacology, it is common to evaluate the influence of external effectors (for example, temperature, pH, and presence of a second drug) on dose-response relations by the potency factor (PF50): [Formula: see text] where ED50 (± effector) denotes the 50% effective dose in the presence and in the absence of the effector, respectively. In this paper, the external effector is ultraviolet (UV) light, and PF50 is referred to as the photoirritancy factor (PIF). There are two parameters which limit the applicability and toxicological reliability of the PIF. Firstly, the physical properties (for example, water solubility) of the chemical tested and the constraints of the biological test system may make it difficult, or even impossible, to achieve sufficiently high doses to observe 50% of the maximal response. In such cases, no numeric value of the potency factor can be computed. Secondly, the potency factor does not take into account the absolute change in response induced by UV light, i.e. depending on the shape of the ±UV dose-response curves, the absolute change in response may be small although the PIF is large, and vice versa. This paper proposes a more general measure of phototoxicity, the mean photo effect (MPE), which can be assessed from pairs of dose-response curves, even if the 50% response level is not reached in one curve or in both. The MPE is a weighted average of PIFd values across different dose levels (d being common to both dose-response curves). The absolute response changes, ΔRd, i.e. the differences between the -UV curve and the +UV curve are used as weighting factors. The numerical computation of the MPE is based on theoretical curves obtained by fitting a mathematical model to the experimental dose-response data. Plotting PIFd and ΔRd versus the corresponding doses permits differences in the shapes of the two curves to be assessed, and possible alterations in the toxic mechanisms induced by UV light to be revealed. The variance of MPE is estimated by a bootstrap procedure. The use of the MPE is illustrated by its application to dose-response data obtained with a human keratinocyte assay of fibroblasts in the EU/COLIPA international validation project on photoirritancy.
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Rodriguez-Pla, A. "AB0408 SYSTEMIC SCLERODERMA AND ENVIRONMENTAL RISK FACTORS: IDENTIFYING ASSOCIATIONS MINING THE BIOMEDICAL LITERATURE." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1232.2–1233. http://dx.doi.org/10.1136/annrheumdis-2021-eular.330.
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Background:A debate still exists concerning the role of occupational and environmental factors in the pathogenesis of systemic scleroderma (SSc).Objectives:Our aim was to explore associations between SSc and environmental factors utilizing an automatic semantic interpretation of PubMed results.Methods:The literature search string: (“systemic sclerosis” OR “scleroderma”) AND (“occupational exposure” OR “environmental” OR “risk factor”) was used to retrieve abstracts from the entire PubMed database, using Semantic MEDLINE 2, on 6/14/2020. This application represents a network of semantic predications (triples of the form subject-predicate (or relation) -object, e.g. Occupational Exposure causes Systemic Scleroderma) on a knowledge graph. Subject and object arguments of each predication are concepts from the Unified Medical Language System (UMLS) Metathesaurus and the relation is taken from the UMLS Semantic Network. The system allows for choosing the central topic (“Systemic Scleroderma”), the length of the network (3 nodes), and automatic summarization, eliminating the less informative predications.Results:The search string retrieved 864 citations and identified 6,397 predications by using 34 types of relations. Initially, we focused our attention on the ‘CAUSES’ type of relation (Figure 1), displaying a network with 59 nodes and 57 edges.The central concepts of this network, identified as having causal relationship with SSc are autoimmune diseases/autoimmunity, chemicals such as bleomycin, occupational and environmental exposure, especially silica, vinyl chloride and trichloroethylene, genes, including HLA and non-HLA genes, genetic polymorphisms, transcription factors (TFs) such as Fli1 and KLF5, and fibrosis. Eosinophilia-myalgia syndrome, toxic oil syndrome and infection were all causally linked to autoimmune diseases. Minerals were associated with occupational exposure and with autoimmune diseases. Concepts causally linked to fibrosis were rare diseases, HLA genes, other non-HLA genes, such as STAT4, IR4, IR5, TLR4, TLR7 and Rho-associated Kinase, and vinyl chloride monomer. Pathogenic factors associated with SSc were endothelial dysfunction and extracellular matrix proteins. Many of the papers in the network also suggested that hormonal factors are involved.Conclusion:Inspection on the knowledge graphs reveals concepts central to research on the etiopathogenesis of SSc. The relations in which these concepts participate, provide more specific information. The Semantic MEDLINE graph supports the kind of patterns that underpin literature-based discovery.Although the pathogenesis of SSc remains elusive, it is accepted that initial vascular damage driven by autoimmunity and environmental factors causes abnormalities in the vasculature resulting in the activation of fibroblasts in various organs. Silica and solvents such as trichloroethylene seem to be the most consistently suspected environmental agents in SSc.References:[1]Rindflesch TC,et al. Semantic MEDLINE: An advanced information management application for biomedicine. Information Services & Use 2011;31:15-21.Figure 1.Semantic Network of Casual Relationships of Systemic Scleroderma.Disclosure of Interests:None declared
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Lukina, G., P. Kulakova, N. Savenkova, E. Volnukhin, A. Kovshik, E. Alexandrova, and A. Novikov. "AB0702 THE FREQUENCY OF INFLAMMATORY BOWEL DISEASES IN PATIENTS WITH ANKYLOSING SPONDYLITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1647.2–1647. http://dx.doi.org/10.1136/annrheumdis-2020-eular.3798.
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Background:Аnkylosing Spondylitis (AS) is closely associated with inflammatory bowel disease (IBD). About 6-46% of patients with IBD have various lesions of the musculoskeletal system [1]. 5-10% of patients with spondylarthritis (SpA) eventually develop IBD, with Crohn’s disease (CD) being more common than Ulcerative colitis (UC) [2]. Determining the level of fecal calprotectin (FC) is a study that allows to diagnose IBD. The concentration of FC directly depends on the neutrophil infiltration of the intestinal mucosa and has a direct connection with the activity of the inflammatory process [3]. It is known that level of FC increases in 2/3 of patients with AS and is closely related to parameters reflecting higher disease activity [4].Objectives:The aim of this study was to evaluate the frequency of IBD in patients with AS using an assessment of FC level.Methods:In the analysis were included 40 patients with AS, fulfilling the modified New York criteria, among them man -26 (65%), woman -14 (35%), mean age of patients was 41.2 ±10.5, mean disease duration - 13±8.8 years. All patients were examined with ESR, CRP, esophagogastroduodenoscopy, colonoscopy and quantitative analysis of the fecal calprotectin levels using the method of lateral immunochromatography with the BUHLMANN Quantum Blue rapid test. Standart range: 100-1800 µg /g.Results:All patients had a high disease activity, mean BASDAI was 5.2 ± 1.7, mean ASDAS CRP 3.8 ± 1.1. 35 patients (87.5 %) had FC level more than 100 µg / g, the remaining 5 patients (12.5%) less than 100 µg /g. 12 patients (30 %) had FC level more than 1,800 µg / g, 23 (57.5 %) from 101 µg / g to 1800 µg / g. All patients with FC levels more than 100 µg / g showed an increase CRP (mean 28.4 mg / l) and ESR (mean 36.3 mm\h) levels. IBD were diagnosed in 9 cases (22.5%): 5 patients (12.5 %) with CD and 4 patients (10 %) - UC, in the remaining cases (77.5%) was no intestinal pathology.Conclusion:The results showed high frequency of IBD in patients with AS. Patients with high FC levels (more than 100 μg/g) had high disease activity (AS). In most cases, inflammatory bowel disease were diagnosed in patients with FC levels more than 100 µg/g.References:[1] Bernstein CN, Blanchard JF, Rawsthorne P, Yu N. The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study. Am J Gastroenterol. 2001 Apr;96(4):1116-22.[2] Klingberg, E., Strid, H., Stahl, A.et al. A longitudinal study of fecal calprotectin and the development of inflammatory bowel disease in ankylosing spondylitis. A longitudinal study of fecal calprotectin and the development of inflammatory bowel disease in ankylosing spondylitis. Arthritis Res Ther 2017. 19(1):21[3] Cypers H, Varkas G, Beeckman S, et al. Elevated calprotectin levels reveal bowel inflammation in spondyloarthritis. Annals of the Rheumatic Diseases. 2016. 75:1357-1362[4] Arzu Duran, Senol Kobak, Nazime Sen, et al. Fecal calprotectin is associated with disease activity in patients with ankylosing spondylitis. Bosnian Journal of Basic Medical Sciences. 2016. 16 (1):71-4Disclosure of Interests:Galina Lukina Speakers bureau: Novartis, Pfizer, UCB, Abbvie, Biocad, MSD, Roche, Polina Kulakova: None declared, Nadezhda Savenkova: None declared, Evgeniy Volnukhin: None declared, Anton Kovshik: None declared, Elena Alexandrova: None declared, Alexandr Novikov: None declared
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Qiao, J., S. X. Zhang, H. Wang, J. Q. Zhang, M. T. Qiu, M. J. Chang, R. Zhao, et al. "OP0184 PHENOTYPING OF MOLECULAR SIGNATURES IN THE SYNOVIAL TISSUE OF RHEUMATOID ARTHRITIS BY INTEGRATIVE SYSTEMS ANALYSIS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 111–12. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1970.
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Background:Rheumatoid arthritis (RA) is an aggressive immune-mediated joint disease characterized by synovial proliferation and inflammation, cartilage destruction, and joint destruction1. Despite efforts to characterize the disease subsets and to predict the differential prognosis in RA patients, disease heterogeneity is not adequately translated into the current clinical subclassification2.Objectives:To develop and validate an integrative system approach for stratifying patients with RA according to disease status and whole-genome gene expression data.Methods:An RNA sequencing dataset of synovial tissues from 124 RA patients (including 57 patients with early RA, 95 with established RA) and 15 healthy controls (HC) was imported from the Gene Expression Omnibus (GEO) database (GSE89408) by software package R (version 4.0.3). After filtrating of differentially expressed genes (DEGs) between RA and HC, non-negative matrix factorization, functional enrichment, and immune cell infiltration were applied to illustrate the landscapes of these patients for classification. Clinical features (age, gender, and auto-antibodies) were also compared to discover the signatures of these classifications.Results:A matrix of 576 DEGs from RA samples was classified into 5 subtypes (early/C1–C3, established/C4-C5) with distinct molecular and cellular signatures and two sub-groups (S1 and S2) (Figure 1A-1D). New-onset patients (early C2) and established C4 patients were named as S1, they shared similar gene signatures mainly characterized by prominent immune cells and proinflammatory signatures, and enriched in the chemokine-mediated signaling pathway, lymphocyte activation, response to bacterium and Primary immunodeficiency. S2(C1, C3 and C5) were more occupied by synovial fibroblasts of destructive phenotype. They were mainly enriched in the response to external factors and PPAR signaling pathway (Figure 1E-1H). Interestingly, combined with clinical information, S1 and S2 had no significance in age and gender (P > 0.05). But patients in S1 had a stronger association with the presence of anti-citrullinated protein antibodies (ACPA) (P < 0.05) (Figure 1I-1J).Conclusion:We successfully deconvoluted RA synovial tissues into pathobiological discrete subsets using an unsupervised machine learning method and described their distinct molecular and cellular characteristics. These results provide important insights into divergent and shared mechanistic features of RA and serve as a template for future studies to guide drug tar-get discovery by synovial molecular signatures and de-sign stratified approaches for patients with RA.References:[1]Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet 2016;388(10055):2023-38. doi: 10.1016/S0140-6736(16)30173-8 [published Online First: 2016/10/30][2]Jung SM, Park KS, Kim KJ. Deep phenotyping of synovial molecular signatures by integrative systems analysis in rheumatoid arthritis. Rheumatology (Oxford) 2020 doi: 10.1093/rheumatology/keaa751 [published Online First: 2020/11/25]Acknowledgements:This project was supported by National Science Foundation of China (82001740), Open Fund from the Key Laboratory of Cellular Physiology (Shanxi Medical University) (KLCP2019) and Innovation Plan for Postgraduate Education in Shanxi Province (2020BY078).Disclosure of Interests:None declared
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Stienstra, N., M. Lane, J. Horton, A. Kumthekar, N. Sathe, C. Sunny, V. Yadav, and A. Deodhar. "AB0323 DEMYELINATING DISEASE AFTER EXPOSURE TO TUMOR NECROSIS FACTOR ALPHA INHIBITORS (TNFI): LONG-TERM OUTCOMES FROM A SINGLE CENTER." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1460–61. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1631.
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Background:TNFi are effective treatments for multiple immune-mediated inflammatory diseases. There are five TNFi’s approved for clinical use. Despite their acceptable safety/efficacy profile, serious side effects have been reported, including central and peripheral nervous system demyelinating diseases (DD).ͥ Causation remains controversial and there is a paucity of data on the long-term outcomes in these patients.Objectives:To assess long term outcomes in patients with DD related to TNFi use.Methods:We conducted a database search and then retrospective chart review to identify patients with potential TNFi related neurologic events at a university medical center between 2006 and 2016. 15 total patients (13 living, 2 deceased) were ultimately identified. Six were able to be contacted by phone to assess their current status. Four of these patients were able to attend a one time-visit to complete a neurologic assessment and musculoskeletal examination. Interviews over the phone or in person were used to complete multiple assessments for disability.Results:15 patients with DD were identified from among 4600 patients on TNFi’s for various indications (0.3%). Mean duration of follow-up was 6.8 years. Neurologic symptoms occurred >12 months after starting a TNFi in 8/15 (53%) patients. 47% of patients had been exposed to two or more TNFi’s. 40% received some form of treatment for their DD, including MS disease modifying therapies, IVIG and immunosuppression. No patients experienced worsening DD after stopping their TNFi except for one patient with MS who experienced a repeat flare. Two of three patients diagnosed with MS after TNFi had a first degree relative with MS. 3/15 (20%) experienced complete resolution of their symptoms. Two patients were deceased; cause of death was thought not directly related to DD on chart review.Conclusion:Prevalence of DD after TNFi exposure was low at our center, consistent with previously published data. Presentations included both central and peripheral demyelinating events. With the exception of one patient who developed MS, withdrawal of TNFi’s appeared to halt further progression or development of new neurologic symptoms. It is unclear if treatment for DD is beneficial after diagnosis and TNFi withdrawal.Patient Data:Table.Baseline characteristics and 6-month outcome of patients who have switched from originator to ABP 501AgeSexIndicationTNFi at time of eventNeurologic Presentation/DiagnosisDuration of follow-up, yearsDD status at last follow-up32FJIAEAtaxia, paresthesias, dysarthria, nystagmus, tetraparesis11Persistent despite tx58MPsAGParesthesias9Improved no tx38FASANumbness and weakness5Resolved, no tx54MPsAEParesthesias, cognitive impairment10Persistent, no tx51FASAIncontinence, paresthesias10Persistent, no tx26FCrohn’sAOptic neuritis11Resolved, no tx49MPsAAMultifocal motor neuropathy3Resolved after tx37MPsAAWeakness, spasticity, paresthesias, optic neuritis9Persistent, on tx33FPsAAOptic neuritis, transverse myelitis (MS)5Flared, no tx59FPsAETransverse myelitis (MS)9Deceased45FASITransverse myelitis7Deceased70MRAACIDP1Received treatment but lost to follow-up34FCrohn’sASmall fiber neuropathy11Persistent, no tx62FRAEOptic neuritis<1Lost to follow-up after initial visit42MUveitis, retinal vasculitisAParesthesias (MS)1Persistent, on txJuvenile idiopathic arthritis (JIA), Psoriatic arthritis (PsA), Ankylosing spondylitis (AS), Rheumatoid Arthritis (RA)Adalimumab (A), Etanercept (E), Golimumab (G), Infliximab (I)Treatment (tx)References:[1]ͥKemanetzoglou E, Andreadou E. CNS Demyelination with TNF-α Blockers.Curr Neurol Neurosci Rep. 2017;17(4):36. doi:10.1007/s11910-017-0742-1Disclosure of Interests:Nicholas Stienstra: None declared, Michael Lane: None declared, Joel Horton: None declared, Anand Kumthekar: None declared, Nishad Sathe: None declared, Christy Sunny: None declared, Vijayshree Yadav Consultant of: Alexion (one time consulting fee), Atul Deodhar Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB
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Marx, D., L. Diekmann, K. Klika, H. M. Lorenz, K. Benesova, and M. Souto-Carneiro. "POS0472 COMPARATIVE METABOLOMIC ANALYSIS OF SERUM SAMPLES FROM PATIENTS WITH COINCIDENTAL RHEUMATOLOGICAL AND MALIGNANT DISEASES." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 467.2–468. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2484.
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Background:Rheumatic and musculoskeletal diseases (RMDs) and malignancies are both caused by a dysfunctional immune system and the probability of their coincidence in one individual is rising due to advances in cancer treatment and demographic changes. However, the lack of understanding of the complex interrelationship of both conditions often leads to undertreatment and high level of suffering in affected patients. Herein, the MalheuR project breaks new ground by systematic analysis of concomitant malignant and rheumatic diseases and closes the knowledge gaps on the clinical and molecular level.Objectives:To enable early diagnosis of concomitant malignancy and/or identification of patients at risk in the future, changes in serum metabolome were explored in order to create a diagnostic classification model.Methods:Serum samples from patients with concomitant RMD and cancer or obligate precancerous lesions (n=78, breast cancer (23), melanoma (14), MGUS (12), prostate cancer (8) and others (21)) were collected as a pilot study within the MalheuR project, a registry-based study initiated in 2018 at the university hospital Heidelberg, Germany. The following groups were defined by the underlying RMD: rheumatoid arthritis (n=42), psoriasis arthritis (n=23), spondylarthritis (n=9) and systemic lupus erythematosus (n=4). RMD patients without any malignancies were used as controls (n=280: 122 RA, 81 PsA, 46 SpA, 31 SLE).Samples were analyzed by 1H NMR spectroscopy. For all samples, regular 1H acquisition with presaturation and Carr-Purcell-Meiboom-Gill (CPMG) spectra were acquired using a 600 MHz Bruker NMR spectrometer. Spectra were processed with TopSpin using 0.2 Hz of line broadening and manual phasing. Molar concentrations of 26 metabolites were acquired by integration of NMR spectra. With GraphPad Prism, univariate and ANOVA statistical analysis was performed to find significant differences between each malignant group and their control group as well as between all four malignant groups.Results:Mean disease duration was 11.8 ±10.5 years for cancer and 12.8±10.8 years for RMDs since diagnosis. 1.4% received cancer treatment (6.4% of malignancy group), 69.3% csDMARDs, 42.3% b/tsDMARDs and 46.4% glucocorticoids at the time of sample collection.Most metabolites tested were significantly lower in the malignancy groups versus associated controls: Concentrations of amino acids V and L were significantly reduced in all malignancy samples. Additionally, T, D, N, Q, E, A, I were altered in RA, SpA and PsA, changes in G were seen in RA, PsA and SLE and P was altered in RA and PsA only. Furthermore, lower concentrations of short chain fatty acids and tricarboxylic acid cycle intermediates were present in the malignancy groups. In no case was a metabolite concentration significantly higher in the malignancy group than in the associated control. When comparing the metabolome within the four malignancy groups, only the concentrations of creatine, threonine and isoleucine were found higher in RA patients with malignancy.Conclusion:Significant differences between the metabolomic fingerprints of RMD patients with and without malignancies could be observed. These changes might be characteristic for cancer burden, as in most cases the underlying RMD was not relevant when comparing the concentrations between the malignancy groups. Our results may promote understanding of the interrelationships of both disease entities as well as prove useful as biomarkers for diagnostic and therapeutic purposes.Acknowledgements:Grant/research support from medical faculty (Olympia Morata Programme) and foundations commission (Herbert Daus estate) of University of HeidelbergDisclosure of Interests:None declared
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Sheikh, S., M. Scheinberg, J. C. C. Wei, D. Tegzová, W. Stohl, T. Mucenic, R. Punwaney, et al. "AB0288 SAFETY OF BELIMUMAB IN PATIENTS WITH ACTIVE SYSTEMIC LUPUS ERYTHEMATOSUS: YEAR 2 FOLLOW-UP OF A LARGE PHASE 4, RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1170–71. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2552.
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Background:Belimumab (BEL), a recombinant human monoclonal antibody that inhibits B-lymphocyte stimulator (BLyS), is approved for the treatment of systemic lupus erythematosus (SLE). Clinical studies have yielded varying incidence rates of mortality and adverse events of special interest, such as malignancies, thereby necessitating large-scale, long-term assessment following BEL exposure.Objectives:To assess all-cause mortality and new primary malignancies during post-treatment Year 2 follow-up in adult patients with active, autoantibody-positive SLE who received intravenous (IV) BEL or placebo (PBO), plus standard therapy in the 52-week double-blind treatment period of the ongoing BASE trial.1Methods:This was a post-treatment follow-up of the Phase 4, double-blind study (BASE1; GSK Study BEL115467; NCT01705977), which randomised 4019 adults with active SLE and receiving standard therapy to BEL (10 mg/kg IV) or PBO on Days 0, 14, 28, and monthly thereafter until Week 48. All patients (including those who discontinued BEL before the end-of-treatment phase) were contacted by phone annually (+/-30-day time window). Rates of mortality and new primary malignancy are summarised for Year 2 follow-up, presented by the treatment received during the 52-week double-blind treatment period (Year 1).Results:Baseline patient characteristics and disease activity collected at the start of the study, evaluated in patients with Year 2 follow-up were similar to the overall Year 1 study population. Cumulatively by Year 2 follow-up, 10.7% and 9.5% of patients had been exposed to commercial BEL in the BEL and PBO groups, respectively. Cumulative follow-up adjusted mortality and malignancy rates (per 100 patient years) were lower in the BEL vs PBO Year 1 treatment group (Table 1).Conclusion:Year 2 follow-up results of BASE, the largest clinical trial of SLE to date,1 provide continued support for the BEL safety profile. No new BEL safety concerns were identified in patients with active, autoantibody-positive SLE receiving standard therapy.Funding: GSKReferences:[1]Sheikh SZ, et al. Lancet Rheum. 2020 (ePub ahead of print) doi.org/10.1016/S2665-9913(20)30355-6Table 1.Year 2 post-treatment* follow-up mortality and new primary malignancy rates by study treatment during Year 1BELPBOTotalYear 1 as-treated populationN=2002N=2001N=4003Year 1 deaths, n (%)13 (0.65)22 (1.10)35 (0.87)Year 1 new primary malignancies, n (%)9 (0.45)10 (0.50)19 (0.47)Year 2 (as-treated in Year 1) populationN=1681N=1666N=3347Year 2 deaths by MedDRA SOC, n (%)9 (0.54)21 (1.26)30 (0.90)Cardiac disorders2 (0.12)6 (0.36)8 (0.24)Infections and infestations4 (0.24)2 (0.12)6 (0.18)Uncoded1 (0.06)3 (0.18)4 (0.12)General disorders/administration site conditions1 (0.06)2 (0.12)3 (0.09)Gastrointestinal disorders1 (0.06)1 (0.06)2 (0.06)Neoplasms02 (0.12)2 (0.06)Other05 (0.30)†5 (0.15)Cumulative deaths by Year 2 follow-up, n (%)22 (1.10)43 (2.15)65 (1.62)Incidence rate per 100 patient years0.601.180.89Year 2 new primary malignancies by MedDRA SOC, n (%)3 (0.18)4 (0.24)7 (0.21)Neoplasms2 (0.12)4 (0.24)6 (0.18)Hepatobiliary disorders1 (0.06)01 (0.03)Cumulative malignancies by Year 2 follow-up, n (%)12 (0.60)14 (0.70)26 (0.65)Patient incidence rate per 100 patient years0.340.400.37*Patients in the post-treatment follow-up period are no longer receiving study treatment; †1 event/patient: blood/lymphatic system, musculoskeletal/connective tissue, nervous system, psychiatric, and renal/urinary disorders.MedDRA, Medical Dictionary for Regulatory Activities; SOC, system organ class.Acknowledgements:Medical writing assistance was provided by Katalin Bartus, PhD, Fishawack Indicia Ltd., UK, part of Fishawack Health, and was funded by GSK.Disclosure of Interests:Saira Sheikh Grant/research support from: Pfizer, Morton Scheinberg Consultant of: GSK, Pfizer, Alnylam, AbbVie, PTC Therapeutics, James Cheng-Chung Wei Consultant of: TSH Biopharm, AbbVie, BMS, Celgene, Chugai, Eisai, Janssen, Novartis, Pfizer, Sanofi-Aventis and UCB pharma, Grant/research support from: AbbVie, Amgen, Astellas, BMS, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer Sun and UCB, Dana Tegzová: None declared, William Stohl Consultant of: GSK, Grant/research support from: GSK, Pfizer, Gilead, Tamara Mucenic Speakers bureau: Novartis, Janssen, BMS, AbbVie, Pfizer, Roche, Grant/research support from: GSK, Janssen, Roche, Eli Lilly, Gilead, UCB, Raj Punwaney Shareholder of: GSK, Employee of: GSK, Regina Kurrasch Shareholder of: GSK, Employee of: GSK, Julia Harris Shareholder of: GSK, Employee of: GSK, Saima Muzaffar Shareholder of: GSK, Employee of: GSK, Sofia Fernandes Shareholder of: GSK, Employee of: GSK, Norma Lynn Fox Shareholder of: GSK, Employee of: GSK, Andrew Liu Shareholder of: GSK, Employee of: GSK, Holly Quasny Shareholder of: GSK, Employee of: GSK, David Roth Shareholder of: GSK, Employee of: GSK
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Shaharir, S. S., M. S. Mohamed Said, S. Rajalingham, H. Mahadzir, R. Mustafar, and A. Abdul Wahab. "THU0283 DISTINCT CLINICAL FEATURES OF LATE–ONSET SYSTEMIC LUPUS ERYTHEMATOSUS AMONG MALAYSIAN MULTI-ETHNIC COHORT." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 368.2–369. http://dx.doi.org/10.1136/annrheumdis-2020-eular.272.
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Background:Systemic Lupus Erythematosus (SLE) commonly affects young women in their reproductive age group. However, there is an increase prevalence of late-onset SLE, parallel to the higher life expectancies among general populations worldwide. It has been reported that up to 25% SLE populations have a later onset of disease and their disease expression and course may be different.Objectives:To determine the clinical features and outcomes of late-onset SLE patients in a multi-ethnic Malaysian cohort.Methods:Medical records of SLE patients who attended regular follow-up clinics in Universiti Kebangsaan Malaysia Medical Centre (UKMMC) from 2011 until June 2019 were reviewed. Late-onset SLE was defined as the onset of SLE symptoms or diagnosis after the age of 50 years old. Information on their socio-demographics and disease characteristics were obtained from the clinical records. Disease damage was assessed using the SLICC/ACR (Systemic Lupus International Collaborating Clinics/American College of Rheumatology) Damage Index (SDI) scores. The disease characteristics and autoantibody profiles were compared between late-onset and younger onset patients. Damage accrual at disease onset and at 5 years was obtained and compared between the two groups.Results:A total of 429 patients were included and majority of them were Malays (n= 225, 52.4%) followed by Chinese (n=180, 42), Indian (n=21, 4.9%) and others (n=3,0.7%). This multi-ethnic SLE cohort was consisted of predominantyly female patients (n=372,86.7%) with disease duration of 9.9 years ± 6.8 years. A total of 13.8% (n=59) had late onset SLE with mean onset of disease at 58.1 ± 6.3 years while younger group was 27.2 ± 9.4 years. The commonest system involvement among the late-onset group was haematological manifestation (69.5%).Compared to the younger-onset SLE, late-onset SLE occurred significantly higher among the Chinese (66.1%) as compared to Malay (32.3%), Indians and other ethnics (1.7%), p<0.01. Patients with late-onset SLE also had significantly less musculoskeletal (37.3% vs 62.4%) and renal (23.7% vs 71.1%), p<0.001 and tend to have less muco-cutanoues manifestations (28.8 vs 42.4%, p=0.06). Meanwhile, pulmonary involvement was more common among the late onset SLE patients (11.9% vs 0.8%, p<0.001). Extractable nuclear antigen (ENA) results were available in 197 patients and patients with late-onset SLE had significantly higher rate of anti-RO positive (63% vs 3.9%), p=0.01. Otherwise, no significant difference in the other autoantibodies expressions including anti-La, anti-Sm, anti-RNP, anti-ribosomal P and anti-phospholipid antibodies. Patients with late-onset SLE tend to have more damage accrual at 5 years as compared to the younger age group (p=0.07). The mortality in the late onset group was 13.6% (n=8) as compared to 2.7% (n=10) in the younger age group, p=0.01. Majority of the cause of death in the later onset SLE was infection (87.5%) while in the younger age group was infection and active disease (90%).Conclusion:Late onset SLE occurs more commonly among Chinese ethnics in Malaysia and Malaysian SLE patients with late onset of the disease have distinct clinical manifestations. Damage accrual at 5 years tend to be higher in the late-onset group and the mortality is significantly higher with the major cause of death is infection. The different disease expression and outcome in late onset SLE suggest different factors in influencing the disease course and hence further studies including their genetic profiles are warranted.References:[1]Paula I. Burgos; Graciela S. Alarcón. Late-onset Lupus: Facts and Fiction. Future Rheumatol. 2008;3(4):351-356.[2]S Stefanidou, C Gerodimos, A Benos et al. Clinical expression and course in patients with late onset systemic lupus erythematosus. Hippokratia. 2013; 17(2): 153–156.Acknowledgments:This research was supported by the “Fundamental Research Grant Scheme (FRGS/1/2018/SKK02/UKM/03/1)” by Ministry of Education MalaysiaDisclosure of Interests:Syahrul Sazliyana Shaharir: None declared, Mohd Shahrir Mohamed Said: None declared, Sakthiswary Rajalingham Speakers bureau: Pfizer (500USD), Hazlina Mahadzir: None declared, Ruslinda Mustafar: None declared, Asrul Abdul Wahab: None declared
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Gordon, Max J., Andy Kaempf, Andrea Sitlinger, Tareq Salous, Hamood Alqahtani, Michael C. Churnetski, Paul Wisniewski, et al. "The Chronic Lymphocytic Leukemia Comorbidity Index (CLL-CI): A Novel Comorbidity Score Derived from a Large Multicenter Retrospective Cohort Study of Patients Treated with Ibrutinib and/or Chemo-Immunotherapy (CIT)." Blood 134, Supplement_1 (November 13, 2019): 4286. http://dx.doi.org/10.1182/blood-2019-124631.
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Introduction: Outcomes in CLL are highly variable and influenced by both biologic and clinical factors. The Cumulative Illness Rating Scale (CIRS) is frequently used to assess comorbidities in CLL. Our group has demonstrated that CIRS correlates with survival in patients treated with either CIT or ibrutinib. Yet, CIRS has not become part of common clinical practice due to complexities in scoring since 14 systems need to be evaluated. Furthermore, the relative contribution of individual comorbidities to patient outcomes is unknown. Here we report the impact of specific comorbidities in a large cohort of CLL patients and propose a simplified CLL-comorbidity index (CLL-CI). Methods: We conducted a retrospective analysis of patients with CLL treated with either CIT or kinase inhibitors at 10 US academic medical centers between 2000-2018. CIRS score was calculated as in Salvi et al, 2008. Patients were randomly divided into a training-set (n=381) and validation-set (n=189). Random survival forests (RSF) were constructed on the training-set to select variables for Cox regression models. Discrimination of models was tested in the validation-set. CIRS score in each organ system, relapse/refractory (R/R) disease, treatment type, age, and del(17p) were included as features for RSF modeling of event-free survival (EFS), defined as time from treatment to death, disease progression or next therapy. For each RSF, features were scored and ranked according to variable importance (VI; the decrease in prediction accuracy when the specific variable is randomly permuted) and minimal depth (MD; the minimum distance between the root node of a tree and the first node that splits on the specific variable). After 200 RSF's, VI and MD ranks were averaged. Organ system variables whose average rank for both predictive measures was ≤10 were chosen for Cox regression modeling of EFS and OS. Three sets of Cox models were fit on the training data and applied to the validation-set to compute c-statistics depicting each model's ability to predict EFS. Cox models assessed the addition of either CIRS or CLL-CI to known prognostic factors. Results: The data set contained 614 patients; 570 (93%) with complete data were included in our analysis. Median age was 67 years (range 30-91). Median CIRS was 7 (range, 0-29) with CIRS≥7 in 302 patients (53%). Median follow up was 31 months. Del(17p) and/or TP53 mutation was present in 113 patients (20%) and 299 (52%) were assessed in the R/R setting. Ibrutinib was the most common treatment (n=338, 59%), followed by fludarabine (n=163) and bendamustine (n=116). In the training-set, four organ system variables ("musculoskeletal", "renal", "endocrine" and "upper GI"), were selected based on RFS average predictive measure ranks and summed to derive the CLL-CI score. Median CLL-CI was 2 (range, 0-11) in the training cohort with a value of 3 identified as the optimal cut-point for association with EFS; 236 (41%) had a high CLL-CI score (≥3). Cox models that included either CLL-CI or CIRS (alongside age, disease status, type of treatment, and del(17p)/TP53 mutation) yielded c-statistics of 0.68 (95% CI: 0.65-0.69) and 0.68 (95% CI: 0.65-0.70), respectively. These discrimination estimates were modestly superior to the model without a comorbidity variable (c-statistic, 0.64). In the complete data set, R/R disease and age were associated with decreased EFS (HR=2.14, p<0.001 and HR=1.15, p<0.001, respectively) and OS (HR=2.25, p=0.001 and HR=1.29, p<0.001, respectively). Treatment with ibrutinib was associated with superior EFS (HR=0.52, p<0.001), but did not significantly impact OS (p=0.51). Del(17p)/TP53 mutation demonstrated a trend towards shortened EFS (HR=1.27, p=0.125) and significantly shorter OS (HR=1.88, p=0.008). CLL-CI≥3 and CIRS≥7 showed similar independent associations with worse EFS and OS (Table). Median EFS and OS were shorter in patients with high CLL-CI score (Fig). Results were consistent in patients treated with either ibrutinib or CIT. Conclusion: In this large data set, we utilized random forests to identify "musculoskeletal", "upper GI", "endocrine", and "renal" comorbidities as the most prognostic of EFS in patients with CLL. Using only these 4 CIRS variables, we developed and validated a simplified comorbidity score (CLL-CI) which performed similar to CIRS, but has lower complexity and therefore can be easily incorporated into clinical practice. Disclosures Patel: Sunesis: Consultancy; Pharmacyclics/Janssen: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau. Persky:Sandoz: Consultancy; Morphosys: Other: Member, Independent Data Monitoring Committee; Debiopharm: Other: Member, Independent Data Monitoring Committee; Bayer: Consultancy. Cohen:Genentech, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding. Choi:Rigel: Consultancy, Research Funding; Gilead: Consultancy, Speakers Bureau; Oncternal: Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau. Hill:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria; Amgen: Research Funding; Takeda: Research Funding; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; TG therapeutics: Research Funding. Shadman:Sunesis: Research Funding; Pharmacyclics: Consultancy, Research Funding; Celgene: Research Funding; ADC Therapeutics: Consultancy; Atara Biotherapeutics: Consultancy; Genentech: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Mustang Bio: Research Funding; Verastem: Consultancy; Astra Zeneca: Consultancy; AbbVie: Consultancy, Research Funding; BeiGene: Research Funding; TG Therapeutic: Research Funding; Sound Biologics: Consultancy; Acerta Pharma: Research Funding. Stephens:Acerta: Research Funding; Karyopharm: Research Funding; Gilead: Research Funding. Brander:Tolero: Research Funding; MEI: Research Funding; Acerta: Research Funding; Genentech: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; BeiGene: Research Funding; DTRM Biopharma: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding. Danilov:Celgene: Consultancy; Curis: Consultancy; Bayer Oncology: Consultancy, Research Funding; Seattle Genetics: Consultancy; AstraZeneca: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Aptose Biosciences: Research Funding; Bristol-Meyers Squibb: Research Funding; TG Therapeutics: Consultancy; Takeda Oncology: Research Funding; MEI: Research Funding; Abbvie: Consultancy; Genentech: Consultancy, Research Funding.
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Salas-Labadía, C., S. Gómez-Carmona, R. Cruz-Alcívar, D. Martínez-Anaya, V. Del Castillo-Ruiz, C. Durán-McKinster, V. Ulloa-Avilés, et al. "Genetic and clinical characterization of 73 Pigmentary Mosaicism patients: revealing the genetic basis of clinical manifestations." Orphanet Journal of Rare Diseases 14, no. 1 (November 15, 2019). http://dx.doi.org/10.1186/s13023-019-1208-0.
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Abstract Background Pigmentary mosaicism constitutes a heterogeneous group of skin pigmentation alterations associated with multisystem involvement. The aim of this study was to establish a complete cytogenetic and molecular characterization of PM patients, emphasizing on searching for possible low chromosomal mosaicism and on establishing an accurate genotype-phenotype correlation. Results A total of 73 patients were included (3 months to 18 years of age), 52% male and 48% female. Observed in 69 (95%) patients, the most frequent pattern of pigmentation was fine and whorled BL, which was associated with disseminated skin extent in 41 (59%) patients. Central nervous system (84%) alterations were the most frequent observed in the group of patients, followed by the musculoskeletal (53%) and ophthalmologic (27%) alterations. Considering the pattern of pigmentation, no significant differences in association with skin extent or extracutaneous manifestations were detected. Following a strict cytogenetic analysis strategy, screening metaphases from three different tissues (peripheral blood, hyperpigmented and hypopigmented skin) we found that 23/73 patients had chromosomal abnormalities classified as follows: 1) Mosaic with 2 or more different cell lines with structural alterations n = 19; 2) Polyploidy (mosaic) n = 1 and 3) Alterations in all cells in three different tissues n = 3. SNP array, array CGH and FISH were useful for the complete characterization of the chromosomal aberrations, for the detection of microdeletions in patients with normal karyotype but with strong clinical suspicious of chromosomal alteration, and for a better establishment of genotype-phenotype correlation. In 2 patients we found genes associated with some of the extracutaneous manifestations (SHH, MNX1, PPP2R2C). Conclusions This group of 73 patients finely described is the largest series of patients with pigmentary mosaicism reported worldwide. As we showed in this study, the followed analysis strategy allowed the detection of cytogenetic and molecular abnormalities, and made possible the establishment of genotype-phenotype associations in some patients. An important limitation of our study was the analysis of fibroblasts cultures instead of melanocytes and keratinocytes. In some cases the direct molecular DNA analysis of skin biopsy could be another choice.
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Yaseen, Wesal, Ortal Kraft-Sheleg, Shelly Zaffryar-Eilot, Shay Melamed, Chengyi Sun, Douglas P. Millay, and Peleg Hasson. "Fibroblast fusion to the muscle fiber regulates myotendinous junction formation." Nature Communications 12, no. 1 (June 22, 2021). http://dx.doi.org/10.1038/s41467-021-24159-9.
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AbstractVertebrate muscles and tendons are derived from distinct embryonic origins yet they must interact in order to facilitate muscle contraction and body movements. How robust muscle tendon junctions (MTJs) form to be able to withstand contraction forces is still not understood. Using techniques at a single cell resolution we reexamine the classical view of distinct identities for the tissues composing the musculoskeletal system. We identify fibroblasts that have switched on a myogenic program and demonstrate these dual identity cells fuse into the developing muscle fibers along the MTJs facilitating the introduction of fibroblast-specific transcripts into the elongating myofibers. We suggest this mechanism resulting in a hybrid muscle fiber, primarily along the fiber tips, enables a smooth transition from muscle fiber characteristics towards tendon features essential for forming robust MTJs. We propose that dual characteristics of junctional cells could be a common mechanism for generating stable interactions between tissues throughout the musculoskeletal system.
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Dalley, Arthur F. "Osteophytes for neophytes: what every medical student should know about the anatomy of the musculoskeletal system and advancing age." FASEB Journal 21, no. 5 (April 2007). http://dx.doi.org/10.1096/fasebj.21.5.a135-d.
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Peng, Ke, Keerthana Deepti Karunakaran, Robert Labadie, Miranda Veliu, Chandler Cheung, Arielle Lee, Paul B. Yu, and Jaymin Upadhyay. "Suppressed prefrontal cortex oscillations associate with clinical pain in fibrodysplasia ossificans progressiva." Orphanet Journal of Rare Diseases 16, no. 1 (January 30, 2021). http://dx.doi.org/10.1186/s13023-021-01709-4.
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AbstractBackgroundPain is a highly prevalent symptom experienced by patients across numerous rare musculoskeletal conditions. Much remains unknown regarding the central, neurobiological processes associated with clinical pain in musculoskeletal disease states. Fibrodysplasia ossificans progressiva (FOP) is an inherited condition characterized by substantial physical disability and pain. FOP arises from mutations of the bone morphogenetic protein (BMP) receptor Activin A receptor type 1 (ACVR1) causing patients to undergo painful flare-ups as well as heterotopic ossification (HO) of skeletal muscles, tendons, ligaments, and fascia. To date, the neurobiological processes that underlie pain in FOP have rarely been investigated. We examined pain and central pain mechanism in FOP as a model primary musculoskeletal condition. Central nervous system (CNS) functional properties were investigated in FOP patients (N = 17) stratified into low (0–3; 0–10 Scale) and high (≥ 4) pain cohorts using functional near-infrared spectroscopy (fNIRS). Associations among clinical pain, mental health, and physical health were also quantified using responses derived from a battery of clinical questionnaires.ResultsResting-state fNIRS revealed suppressed power of hemodynamic activity within the slow-5 frequency sub-band (0.01–0.027 Hz) in the prefrontal cortex in high pain FOP patients, where reduced power of slow-5, prefrontal cortex oscillations exhibited robust negative correlations with pain levels. Higher clinical pain intensities were also associated with higher magnitudes of depressive symptoms.ConclusionsOur findings not only demonstrate a robust coupling among prefrontal cortex functionality and clinical pain in FOP but lays the groundwork for utilizing fNIRS to objectively monitor and central pain mechanisms in FOP and other musculoskeletal disorders.
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Hentschel, Andreas, Artur Czech, Ute Münchberg, Erik Freier, Ulrike Schara-Schmidt, Albert Sickmann, Jens Reimann, and Andreas Roos. "Protein signature of human skin fibroblasts allows the study of the molecular etiology of rare neurological diseases." Orphanet Journal of Rare Diseases 16, no. 1 (February 9, 2021). http://dx.doi.org/10.1186/s13023-020-01669-1.
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Abstract Background The elucidation of pathomechanisms leading to the manifestation of rare (genetically caused) neurological diseases including neuromuscular diseases (NMD) represents an important step toward the understanding of the genesis of the respective disease and might help to define starting points for (new) therapeutic intervention concepts. However, these “discovery studies” are often limited by the availability of human biomaterial. Moreover, given that results of next-generation-sequencing approaches frequently result in the identification of ambiguous variants, testing of their pathogenicity is crucial but also depending on patient-derived material. Methods Human skin fibroblasts were used to generate a spectral library using pH8-fractionation of followed by nano LC-MS/MS. Afterwards, Allgrove-patient derived fibroblasts were subjected to a data independent acquisition approach. In addition, proteomic signature of an enriched nuclear protein fraction was studied. Proteomic findings were confirmed by immunofluorescence in a muscle biopsy derived from the same patient and cellular lipid homeostasis in the cause of Allgrove syndrome was analysed by fluorescence (BODIPY-staining) and coherent anti-Stokes Raman scattering (CARS) microscopy. Results To systematically address the question if human skin fibroblasts might serve as valuable biomaterial for (molecular) studies of NMD, we generated a protein library cataloguing 8280 proteins including a variety of such linked to genetic forms of motoneuron diseases, congenital myasthenic syndromes, neuropathies and muscle disorders. In silico-based pathway analyses revealed expression of a diversity of proteins involved in muscle contraction and such decisive for neuronal function and maintenance suggesting the suitability of human skin fibroblasts to study the etiology of NMD. Based on these findings, next we aimed to further demonstrate the suitability of this in vitro model to study NMD by a use case: the proteomic signature of fibroblasts derived from an Allgrove-patient was studied. Dysregulation of paradigmatic proteins could be confirmed in muscle biopsy of the patient and protein-functions could be linked to neurological symptoms known for this disease. Moreover, proteomic investigation of nuclear protein composition allowed the identification of protein-dysregulations according with structural perturbations observed in the muscle biopsy. BODIPY-staining on fibroblasts and CARS microscopy on muscle biopsy suggest altered lipid storage as part of the underlying disease etiology. Conclusions Our combined data reveal that human fibroblasts may serve as an in vitro system to study the molecular etiology of rare neurological diseases exemplified on Allgrove syndrome in an unbiased fashion.
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Gorini, Francesca, Alessio Coi, Lorena Mezzasalma, Silvia Baldacci, Anna Pierini, and Michele Santoro. "Survival of patients with rare diseases: a population-based study in Tuscany (Italy)." Orphanet Journal of Rare Diseases 16, no. 1 (June 14, 2021). http://dx.doi.org/10.1186/s13023-021-01907-0.
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Abstract Background Rare diseases (RDs) encompass a heterogeneous group of life-threatening or chronically debilitating conditions that individually affect a small number of subjects but overall represent a major public health issue globally. There are still limited data on RD burden due to the paucity of large population-based epidemiological studies. The aim of this research was to provide survival estimates of patients with a RD residing in Tuscany, Italy. Methods Cases collected in the Rare Diseases Registry of Tuscany with diagnosis between 1st January 2000 and 31th December 2018 were linked to the regional health databases in order to retrieve information on mortality of all subjects. Survival at 1, 5 and 10 years from diagnosis with 95% confidence intervals (CI) was estimated by sex, age class, nosological group and subgroup using the Kaplan–Meier method. The effect of sex, age and period of diagnosis (years 2000–2009 or 2010–2018) on survival was estimated using Cox proportional hazards regression. Results Survival at 1, 5 and 10 years from diagnosis was 97.3%, 88.8% and 80.8%, respectively. Respiratory diseases and peripheral and central nervous system disorders were characterized by the lowest survival at 5 and 10 years. Despite a modest higher prevalence of RDs among females (54.0% of the total), male cases had a significant increased risk of death (hazard ratio, HR 1.48, 95% CI 1.38–1.58). Cases diagnosed during 2010–2018 period had a risk of death significantly lower than those diagnosed during 2000–2009 (HR 0.81, 95% CI 0.82–0.96), especially for immune system disorders (HR 0.48, 95% CI 0.26–0.87), circulatory system diseases (HR 0.61, 95% CI 0.45–0.84) and diseases of the musculoskeletal system and connective tissue (HR 0.64, 95% CI 0.49–0.84). Conclusions An earlier diagnosis as well as the improvement in the efficacy of treatment resulted in a decreased risk of death over the years for specific RDs. The linkage between a population-based registry and other regional databases exploited in this study provides a large and accurate mass of data capable of estimating patients’ life-expectancy and increasing knowledge on the collective burden of RDs.
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Anttila, Heidi, Susanna Tallqvist, Minna Muñoz, Sanna Leppäjoki-Tiistola, Outi Mäkitie, and Sinikka Hiekkala. "Towards an ICF-based self-report questionnaire for people with skeletal dysplasia to study health, functioning, disability and accessibility." Orphanet Journal of Rare Diseases 16, no. 1 (May 22, 2021). http://dx.doi.org/10.1186/s13023-021-01857-7.
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Abstract Background Little is known about the spectrum of everyday challenges that people with skeletal dysplasia face because of their health and functioning. We aimed to identify factors related to health, functioning and disability in people with skeletal dysplasia, and their challenges with accessibility in order to form a self-reported questionnaire for national data collection. The comprehensive musculoskeletal post-acute core set of the International Classification of Functioning, Disability and Health (ICF) was used as a framework. Methods An iterative, participatory and qualitative process was used to formulate a questionnaire. Items were searched from Patient-Reported Outcomes Measurement Information System and from other self-report instruments, additional items were formulated using ICF linking rules. Expert panels from the target population assessed the face and content validity in thematic interviews. Results The questionnaire demonstrated its relevance, comprehensiveness and feasibility for people with skeletal dysplasia. The ICF linkages showed the contents’ correspondence to the construct. Expert panels added 15 categories and one on chapter level to the core set and confirmed content validity. The final survey covers 86 ICF categories and 173 ICF-linked items that were grouped to 33 questions. Conclusions The content of the questionnaire proved to be sufficiently valid for people with skeletal dysplasia. It can be used to explore their health, functioning, disability and accessibility to develop care and rehabilitation policies, to plan services and to provide information to various parties involved.
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Stengl, Roland, Bence Ágg, Miklós Pólos, Gábor Mátyás, Gábor Szabó, Béla Merkely, Tamás Radovits, Zoltán Szabolcs, and Kálmán Benke. "Potential predictors of severe cardiovascular involvement in Marfan syndrome: the emphasized role of genotype–phenotype correlations in improving risk stratification—a literature review." Orphanet Journal of Rare Diseases 16, no. 1 (May 31, 2021). http://dx.doi.org/10.1186/s13023-021-01882-6.
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Abstract Background Marfan syndrome (MFS) is a genetically determined systemic connective tissue disorder, caused by a mutation in the FBN1 gene. In MFS mainly the cardiovascular, musculoskeletal and ocular systems are affected. The most dangerous manifestation of MFS is aortic dissection, which needs to be prevented by a prophylactic aortic root replacement. Main body The indication criteria for the prophylactic procedure is currently based on aortic diameter, however aortic dissections below the threshold defined in the guidelines have been reported, highlighting the need for a more accurate risk stratification system to predict the occurrence of aortic complications. The aim of this review is to present the current knowledge on the possible predictors of severe cardiovascular manifestations in MFS patients, demonstrating the wide range of molecular and radiological differences between people with MFS and healthy individuals, and more importantly between MFS patients with and without advanced aortic manifestations. These differences originating from the underlying common molecular pathological processes can be assessed by laboratory (e.g. genetic testing) and imaging techniques to serve as biomarkers of severe aortic involvement. In this review we paid special attention to the rapidly expanding field of genotype–phenotype correlations for aortic features as by collecting and presenting the ever growing number of correlations, future perspectives for risk stratification can be outlined. Conclusions Data on promising biomarkers of severe aortic complications of MFS have been accumulating steadily. However, more unifying studies are required to further evaluate the applicability of the discussed predictors with the aim of improving the risk stratification and therefore the life expectancy and quality of life of MFS patients.
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Moisan, Lina, David Iannuzzi, Bruno Maranda, Philippe M. Campeau, and John J. Mitchell. "Clinical characteristics of patients from Quebec, Canada, with Morquio A syndrome: a longitudinal observational study." Orphanet Journal of Rare Diseases 15, no. 1 (September 29, 2020). http://dx.doi.org/10.1186/s13023-020-01545-y.
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Abstract Background Morquio A syndrome is a rare, autosomal recessive, progressively debilitating disorder, with multi-system impairments and high medical burden. Quebec, Canada has a large Morquio A population, which is considered unique due to the presence of founder pathogenic variants. The objectives of this study were to document the genetic and clinical heterogeneity of patients with Morquio A in Quebec, to better characterize the phenotype of those with the French Canadian founder pathogenic variant (NM_000512.5: c.1171A>G, p.Met391Val), and to describe the natural history of the patients treated with elosulfase alfa enzyme replacement therapy. Patients with Morquio A were genotyped for pathogenic variants in the lysosomal enzyme N-acetylgalactosamine-6-sulfatase. Clinical data were retrospectively collected from medical charts of patients and included medical history, height, physical examination, respiratory function tests, electrocardiogram, echocardiogram, endurance in the 6-min walk test (6MWT), and activities of daily living (ADL) as assessed by the Mucopolysaccharidosis Health Assessment Questionnaire (MPS-HAQ). Longitudinal data were collected retrospectively and prospectively for patients treated with elosulfase alfa. Results A total of 33 patients, aged 5–63 years, were included in the analysis. Patients with the founder pathogenic variant (n = 17) generally exhibited a non-classical form of Morquio A. As compared with patients with a non-founder pathogenic variant (n = 16), these patients were generally taller, had greater endurance and were better able to perform ADL. However, they still had significant musculoskeletal disease. Most of the 26 patients treated with elosulfase alfa, regardless of pathogenic variant, showed improvements in endurance and ADL. After 5 to 12 months of treatment, the mean improvement from baseline in the 6MWT was 23% and 10 of 14 patients improved in at least one MPS-HAQ domain. Endurance and ADL generally continued to improve or maintained stable in the long term (up to 7 years). Four out of 19 treated patients with echocardiogram data at follow-up showed progression of cardiac disease. Conclusions In Quebec, Canada, Morquio A frequently manifests as a non-classical form of the syndrome due to a founder effect. Patients treated with elosulfase alfa generally show long-term improvement or stability in endurance and function, regardless of pathogenic variant.