Academic literature on the topic 'Musculoskeletal system Medical genetics. Fibroblasts'

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.

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.

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.

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.

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.

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.

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.

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.

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.

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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