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Topic:In Vivo

In vivo studies involving horses refer to research conducted within living organisms to understand various biological processes, disease mechanisms, and therapeutic interventions in equine species. These studies provide insights into the physiological and pathological responses of horses under natural conditions. In vivo research encompasses a range of investigations, including pharmacokinetics, disease modeling, and the evaluation of treatment efficacy. It often involves the use of controlled environments to simulate real-life scenarios while observing the effects of specific variables on equine health. This page gathers peer-reviewed research articles and scholarly studies that explore the methodologies, findings, and implications of in vivo research in horses, contributing to the advancement of equine science and veterinary medicine.
The influence of temperature and age on the T1 relaxation time of the equine distal limb. Adrian AM, Koene M, Roberts S, Doughty P, Bolas N, Kinns J, Brehm W, Gerlach K.The extent of fat suppression using short tau inversion recovery (STIR) imaging is variable between horses. Our aim was to determine if patient's age and/or hoof temperature have an influence on the T(1) relaxation time of bone marrow in the equine distal limb, thereby affecting the suppression of fat signal. Magnetic resonance imaging was conducted on standing horses and cadaver samples using a low-field magnet (0.27 T). The hoof temperature was measured at the lateral side of the coronary band. A modified inversion recovery fast spin-echo (IR-FSE) sequence was used to measure the signal inte...
Sequence variations in equine candidate genes For XX and XY inherited disorders of sexual development.
Reproduction in domestic animals = Zuchthygiene    January 13, 2012   Volume 47, Issue 5 827-834 doi: 10.1111/j.1439-0531.2011.01976.x
Pujar S, Meyers-Wallen VN.Inherited disorders of sexual development (DSD) cause sterility and infertility in horses. Mutations causing such disorders have been identified in other mammals, but there is little information on the molecular causes in horses. While the equine genome sequence has made it possible to identify candidate genes, additional tools are needed to routinely screen them for causative mutations. In this study, we designed a screening panel of polymerase chain reaction primer pairs for 15 equine genes. These are the candidate genes for testicular or ovotesticular XX DSD and XY DSD, the latter of which ...
Pharmacokinetics of firocoxib and its interaction with enrofloxacin in horses.
Journal of veterinary pharmacology and therapeutics    January 11, 2012   Volume 35, Issue 6 615-617 doi: 10.1111/j.1365-2885.2011.01362.x
Cox S, Dudenbostel L, Sommardahl C, Yarbrough J, Saleh M, Doherty T.No abstract available
A test for the “physiological phagemia” hypothesis-natural intestinal coliphages do not penetrate to the blood in horses.
Folia microbiologica    January 11, 2012   Volume 57, Issue 1 81-83 doi: 10.1007/s12223-011-0096-z
Letarova M, Strelkova D, Nevolina S, Letarov A.No abstract available
Thiolated carboxymethyl-hyaluronic-Acid-based biomaterials enhance wound healing in rats, dogs, and horses.
ISRN veterinary science    January 11, 2012   Volume 2011 851593 doi: 10.5402/2011/851593
Yang G, Prestwich GD, Mann BK.The progression of wound healing is a complicated but well-known process involving many factors, yet there are few products on the market that enhance and accelerate wound healing. This is particularly problematic in veterinary medicine where multiple species must be treated and large animals heal slower, oftentimes with complicating factors such as the development of exuberant granulation tissue. In this study a crosslinked-hyaluronic-acid (HA-) based biomaterial was used to treat wounds on multiple species: rats, dogs, and horses. The base molecule, thiolated carboxymethyl HA, was first foun...
Inflammation and immune response of intra-articular serotype 2 adeno-associated virus or adenovirus vectors in a large animal model.
Arthritis    January 11, 2012   Volume 2012 735472 doi: 10.1155/2012/735472
Ishihara A, Bartlett JS, Bertone AL.Intra-articular gene therapy has potential for the treatment of osteoarthritis and rheumatoid arthritis. To quantify in vitro relative gene transduction, equine chondrocytes and synovial cells were treated with adenovirus vectors (Ad), serotype 2 adeno-associated virus vectors (rAAV2), or self-complementary (sc) AAV2 vectors carrying green fluorescent protein (GFP). Using 6 horses, bilateral metacarpophalangeal joints were injected with Ad, rAAV2, or scAAV2 vectors carrying GFP genes to assess the in vivo joint inflammation and neutralizing antibody (NAb) titer in serum and joint fluid. In vit...
Detection of small tendon lesions by sonoelastographic visualization of strain profile differences: initial experiences.
Skeletal radiology    January 5, 2012   Volume 41, Issue 9 1073-1079 doi: 10.1007/s00256-011-1349-2
Buck AR, Verstraete N, Li Y, Schweizer A, Snedeker JG, Buck FM.To assess the capability of a commercial sonoelastography system to detect small tendon lesions by quantitative analysis of elastogram profiles. Methods: Strips of equine digital flexor tendons were used to model small human tendons. Two tendons were examined. From each tendon, six unmodified tendon strips (controls) and six tendon strips with a central defect of the same tendons were compared. The tendon strips were placed under a physiological tensile strain of 5%. Sonoelastographic visualization of the strain profile was performed. Regions of interest (ROI) were defined left and right of th...
Vertical ridge augmentation using an equine bone and collagen block infused with recombinant human platelet-derived growth factor-BB: a randomized single-masked histologic study in non-human primates.
Journal of periodontology    January 5, 2012   Volume 83, Issue 7 878-884 doi: 10.1902/jop.2012.110478
Nevins M, Al Hezaimi K, Schupbach P, Karimbux N, Kim DM.This study tests the effectiveness of hydroxyapatite and collagen bone blocks of equine origin (eHAC), infused with recombinant human platelet-derived growth factor-BB (rhPDGF-BB), to augment localized posterior mandibular defects in non-human primates (Papio hamadryas). Methods: Bilateral critical-sized defects simulating severe atrophy were created at the time of the posterior teeth extraction. Test and control blocks (without growth factor) were randomly grafted into the respective sites in each non-human primate. Results: All sites exhibited vertical ridge augmentation, with physiologic ha...
Profiling of differentially expressed genes using suppression subtractive hybridization in an equine model of chronic asthma.
PloS one    January 3, 2012   Volume 7, Issue 1 e29440 doi: 10.1371/journal.pone.0029440
Lavoie JP, Lefebvre-Lavoie J, Leclere M, Lavoie-Lamoureux A, Chamberland A, Laprise C, Lussier J.Gene expression analyses are used to investigate signaling pathways involved in diseases. In asthma, they have been primarily derived from the analysis of bronchial biopsies harvested from mild to moderate asthmatic subjects and controls. Due to ethical considerations, there is currently limited information on the transcriptome profile of the peripheral lung tissues in asthma. Objective: To identify genes contributing to chronic inflammation and remodeling in the peripheral lung tissue of horses with heaves, a naturally occurring asthma-like condition. Methods: Eleven adult horses (6 heaves-af...
Characterization of the cDNA and genomic DNA sequence encoding for the platelet integrin alpha IIB and beta III in a horse with Glanzmann thrombasthenia.
Canadian journal of veterinary research = Revue canadienne de recherche veterinaire    January 3, 2012   Volume 75, Issue 3 222-227 
Macieira S, Lussier J, Bédard C.Glanzmann thrombasthenia (GT) is characterized by a defect of platelet aggregation. This autosomal recessive genetic disorder is caused by an abnormality of the platelet glycoprotein receptors alpha IIb or beta III. Recently, we identified a horse with clinical and pathological features of GT. The aim of this study was to describe this case of GT at the molecular level. A point mutation from G to C in exon 2 of ITGA2B causing a substitution of the expected amino acid arginine 72 (Arg(72)) by a proline (Pro(72)) was encountered. This amino acid change may result in abnormal structural conformat...
Comparative Analysis of the Immunomodulatory Properties of Equine Adult-Derived Mesenchymal Stem Cells().
Cell medicine    January 1, 2012   Volume 4, Issue 1 1-11 doi: 10.3727/215517912X647217
Carrade DD, Lame MW, Kent MS, Clark KC, Walker NJ, Borjesson DL.Mesenchymal stem cells (MSCs) derived from bone marrow (BM), adipose tissue (AT), umbilical cord blood (CB), and umbilical cord tissue (CT) are increasingly being used to treat equine inflammatory and degenerative lesions. MSCs modulate the immune system in part through mediator secretion. Animal species and MSC tissue of origin are both important determinants of MSC function. In spite of widespread clinical use, how equine MSCs function to heal tissues is fully unknown. In this study, MSCs derived from BM, AT, CB, and CT were compared for their ability to inhibit lymphocyte proliferation and ...
Scintigraphic evaluation of intra-arterial and intravenous regional limb perfusion of allogeneic bone marrow-derived mesenchymal stem cells in the normal equine distal limb using (99m) Tc-HMPAO.
Equine veterinary journal    December 30, 2011   Volume 44, Issue 5 594-599 doi: 10.1111/j.2042-3306.2011.00530.x
Sole A, Spriet M, Galuppo LD, Padgett KA, Borjesson DL, Wisner ER, Brosnan RJ, Vidal MA.Mesenchymal stem cells (MSCs) are commonly injected intralesionally for treatment of soft tissue injuries in the horse. Alternative routes of administration would be beneficial for treatment of lesions that cannot be accessed directly or to limit needle-induced iatrogenic damage to the surrounding tissue. Objective: The purpose of our study was to evaluate MSC distribution after intra-arterial (IA) and intravenous (IV) regional limb perfusions (RLP) using scintigraphy. We hypothesised that MSCs would persist in the distal limb after tourniquet removal and that both techniques would lead to dif...
Hindlimb laminar inflammatory response is similar to that present in forelimbs after carbohydrate overload in horses.
Equine veterinary journal    December 30, 2011   Volume 44, Issue 6 633-639 doi: 10.1111/j.2042-3306.2011.00531.x
Leise BS, Faleiros RR, Watts M, Johnson PJ, Black SJ, Belknap JK.A significant proinflammatory response is known to occur in the forelimb lamina after carbohydrate administration. As the hindlimbs are often less affected by laminitis compared with the forelimbs, we assessed hindlimb inflammatory response in the early stages of carbohydrate-induced laminitis to determine whether differences in the response existed. Objective: To determine whether a similar proinflammatory response occurs in the hindlimb laminae to that previously reported for the forelimb. Methods: Archived laminar samples from 12 horses administered 17.6 g of starch (85% corn starch, 15% wo...
Advanced glycation endproducts in horses with insulin-induced laminitis.
Veterinary immunology and immunopathology    December 26, 2011   Volume 145, Issue 1-2 395-401 doi: 10.1016/j.vetimm.2011.12.016
de Laat MA, Kyaw-Tanner MT, Sillence MN, McGowan CM, Pollitt CC.Advanced glycation endproducts (AGEs) have been implicated in the pathogenesis of cancer, inflammatory conditions and diabetic complications. An interaction of AGEs with their receptor (RAGE) results in increased release of pro-inflammatory cytokines and reactive oxygen species (ROS), causing damage to susceptible tissues. Laminitis, a debilitating foot condition of horses, occurs in association with endocrine dysfunction and the potential involvement of AGE and RAGE in the pathogenesis of the disease has not been previously investigated. Glucose transport in lamellar tissue is thought to be l...
Clarithromycin is absorbed by an intestinal uptake mechanism that is sensitive to major inhibition by rifampicin: results of a short-term drug interaction study in foals.
Drug metabolism and disposition: the biological fate of chemicals    December 14, 2011   Volume 40, Issue 3 522-528 doi: 10.1124/dmd.111.042267
Peters J, Eggers K, Oswald S, Block W, Lütjohann D, Lämmer M, Venner M, Siegmund W.Pulmonary penetration of clarithromycin (CLR) in epithelial lining fluid (ELF) and bronchoalveolar lavage cells (BALCs) can be influenced by CYP3A4, by P-glycoprotein, and, according to our hypothesis, by a member of the organic anion-transporting protein (OATP) family, for which rifampicin (RIF) is inhibiting in single doses but inducing after long-term coadministration. To assess the partial inhibitory effect, we measured absorption and pulmonary distribution of CLR after short-term (2.5-day) coadministration of RIF, after which up-regulation is not expected. The drug interaction study was p...
Comparison of cytokine mRNA expression in the bronchoalveolar lavage fluid of horses with inflammatory airway disease and bronchoalveolar lavage mastocytosis or neutrophilia using REST software analysis.
Journal of veterinary internal medicine    December 14, 2011   Volume 26, Issue 1 153-161 doi: 10.1111/j.1939-1676.2011.00847.x
Beekman L, Tohver T, Léguillette R.The pathophysiology of inflammatory airway disease (IAD) is unknown, but in some cases involves the accumulation of mast cells, neutrophils, or both in the bronchoalveolar lavage fluid (BALF). The objective of this study was to characterize cytokine gene expression in the BALF cells of horses with IAD, including a comparison of cytokine gene expression between IAD horses with increased BALF mast cells (IAD-Mast) or neutrophils (IAD-Neutro). Methods: The mRNA expression of IL-4, IFN-γ, IL-17, IL-8, IL-1β, IL-5, IL-6, IL-10, IL-12p35, and eotaxin-2 was studied by quantitative polymerase chain ...
Performance characteristics of a conformal ultra-wideband multilayer applicator (CUMLA) for hyperthermia in veterinary patients: a pilot evaluation of its use in the adjuvant treatment of non-resectable tumours.
Veterinary and comparative oncology    December 13, 2011   Volume 11, Issue 1 14-29 doi: 10.1111/j.1476-5829.2011.00297.x
Smrkovski OA, Koo Y, Kazemi R, Lembcke LM, Fathy A, Liu Q, Phillips JC.Performance and clinical characteristics of a novel hyperthermia antenna operating at 434 MHz were evaluated for the adjuvant treatment of locally advanced superficial tumours in cats, dogs and horses. Electromagnetic simulations were performed to determine electric field characteristics and compared to simulations for a flat microwave antenna with similar dimensions. Simulation results show a reduced skin surface and backfield irradiation and improved directional irradiation (at broadside) compared to a flat antenna. Radiated power and penetration is notably increased with a penetration depth...
The effect of intralesional injection of bone marrow derived mesenchymal stem cells and bone marrow supernatant on collagen fibril size in a surgical model of equine superficial digital flexor tendonitis.
Equine veterinary journal    December 11, 2011   Volume 44, Issue 5 587-593 doi: 10.1111/j.2042-3306.2011.00514.x
Caniglia CJ, Schramme MC, Smith RK.Collagen fibril size is decreased in repair tissue following tendon injury compared to normal tendon matrix in horses. Mesenchymal stem cells have been suggested to promote regeneration of tendon matrix rather than fibrotic repair following injury, although this concept remains unproven. Objective: To explore the hypothesis that implantation of autologous mesenchymal stem cells derived from bone marrow into a surgically created central core defect in the superficial digital flexor tendon (SDFT) of horses would induce the formation of a matrix with greater ultrastructural similarities to tendon...
Changes in histone H4 acetylation during in vivo versus in vitro maturation of equine oocytes.
Molecular human reproduction    December 7, 2011   Volume 18, Issue 5 243-252 doi: 10.1093/molehr/gar077
Franciosi F, Lodde V, Goudet G, Duchamp G, Deleuze S, Douet C, Tessaro I, Luciano AM.Epigenetic modifications are established during gametogenesis and preimplantation embryonic development. Any disturbance of the normal natural environment during these critical phases could cause alterations of the epigenetic signature. Histone acetylation is an important epigenetic modification involved in the regulation of chromatin organization and gene expression. The present study was aimed to determine whether the proper establishment of post-translational histone H4 acetylation at lysine 8 (AcH4K8), 12 (AcH4K12) and 16 (AcH4K16) of equine oocytes is adversely affected during in vitro ma...
Phenylbutazone and flunixin meglumine used singly or in combination in experimental lameness in horses.
Equine veterinary journal. Supplement    December 7, 2011   Issue 40 12-17 doi: 10.1111/j.2042-3306.2011.00485.x
Foreman JH, Ruemmler R.Using an adjustable heart bar shoe model of foot pain, the objective of this study was to test the hypothesis that the combined use of phenylbutazone (PBZ) and flunixin meglumine (FM) would prove more efficacious in alleviating lameness than either drug alone. Methods: One hour after induction of lameness at weekly intervals, 8 healthy adult Thoroughbred horses randomly underwent one of 4 i.v. treatments: saline (SAL) placebo (1 ml/45 kg bwt), PBZ (4.4 mg/kg bwt), FM (1.1 mg/kg bwt) or PBZ+FM (at the same dosages as given individually). Heart rate (HR) and lameness score (LS) responses were as...
The reproductive performance of Thoroughbred mares treated with intravaginal progesterone at the start of the breeding season.
Theriogenology    December 6, 2011   Volume 77, Issue 5 952-958 doi: 10.1016/j.theriogenology.2011.10.001
Hanlon DW, Firth EC.The objective of this study was to investigate the effects of intravaginal progesterone on the reproductive performance of transitional Thoroughbred mares on commercial stud farms. Two hundred twenty-seven (227) non-lactating transitional Thoroughbred mares aged between 4 and 18 y (mean 9.4 ± 3.2 y) located on three stud farms in the Waikato region of New Zealand were used in the study performed during four consecutive breeding seasons (2007-10). Mares were age-matched in pairs and either treated with an intravaginal progesterone releasing device (Cue-Mare, 1.72 g progesterone, 10% w/w) for u...
Comparison of three methods of sampling for endometrial cytology in the mare. Preliminary study.
Tierarztliche Praxis. Ausgabe G, Grosstiere/Nutztiere    December 6, 2011   Volume 39, Issue 3 171-175 
Defontis M, Vaillancourt D, Grand FX.This prospective study aims to compare three different sampling techniques for the collection of endometrial cytological specimens in the mare: the guarded culture swab, the uterine cytobrush and the low volume uterine flush. Methods: The study population consisted of six healthy Standardbred mares in dioestrus. In each mare an acute endometritis was induced by performing a low- volume uterine flush 6days after ovulation using a sterile isotonic solution (lactated Ringer's solution or ViGro™ Complete Flush Solution). Two days after initiating inflammation, samples were collected from each ma...
Localization of Bovine papillomavirus in equine sarcoids and inflammatory skin conditions of horses using laser microdissection and two forms of DNA amplification. Wobeser BK, Hill JE, Jackson ML, Kidney BA, Mayer MN, Townsend HG, Allen AL.Equine sarcoids are the most common tumor of horses. Bovine papillomavirus (BPV) has been suggested as the cause of sarcoids. Studies have shown that BPV is present in swabs or biopsies from nonsarcoid-bearing equine skin. Skin biopsies from a variety of different conditions and normal skin from horses with no reported history of sarcoids were examined by polymerase chain reaction (PCR) for the presence of BPV, which was found in all different types of skin conditions as well as normal skin. Forty-one out of 86 skin biopsies from horses without sarcoids were found to contain BPV DNA. Laser mic...
Short-term cast immobilisation is effective in reducing lesion propagation in a surgical model of equine superficial digital flexor tendon injury.
Equine veterinary journal    December 5, 2011   Volume 44, Issue 5 570-575 doi: 10.1111/j.2042-3306.2011.00513.x
David F, Cadby J, Bosch G, Brama P, van Weeren R, van Schie H.Larger superficial digital flexor tendon (SDFT) injuries have a poorer prognosis than smaller lesions. During the inflammatory phase enlargement of the initial lesion is frequently noted, with biomechanical loading being recently proposed to play an important role. Objective: To evaluate the effect of lower limb cast immobilisation on tendon lesion propagation in an equine model of surgically induced SDFT injury. Methods: Core lesions were surgically induced in both front SDFTs of 6 young mature horses. At the end of surgery, one leg was randomly placed in a lower limb cast and the other leg (...
Pharmacokinetics and preliminary safety evaluation of azithromycin in adult horses.
Journal of veterinary pharmacology and therapeutics    December 5, 2011   Volume 35, Issue 6 541-549 doi: 10.1111/j.1365-2885.2011.01351.x
Leclere M, Magdesian KG, Cole CA, Szabo NJ, Ruby RE, Rhodes DM, Edman J, Vale A, Wilson WD, Tell LA.Azithromycin is widely used in foals but has not been studied in adult horses. The goals of this study were to determine the pharmacokinetic profile and to make a preliminary assessment of the safety of azithromycin in adult horses. Azithromycin was administered intravenously (5 mg/kg) and intragastrically (10 mg/kg) to six healthy mares in a crossover design. Serial plasma samples, blood neutrophils, and pulmonary macrophages were collected for the measurement of azithromycin concentrations. Azithromycin was also administered orally (10 mg/kg) once a day for 5 days to five healthy mares for p...
Assessment of correlation between in vitro CD3+ T cell susceptibility to EAV infection and clinical outcome following experimental infection.
Veterinary microbiology    December 2, 2011   Volume 157, Issue 1-2 220-225 doi: 10.1016/j.vetmic.2011.11.031
Go YY, Cook RF, Fulgêncio JQ, Campos JR, Henney P, Timoney PJ, Horohov DW, Balasuriya UB.In a recent study, we demonstrated that the virulent Bucyrus strain (VBS) of EAV could infect in vitro a small population of CD3(+) T lymphocytes from some but not all horses. Furthermore, we have shown that a common haplotype is associated with this in vitro CD3(+) T cell susceptibility/resistance phenotype to EAV infection. In this study, we investigated whether the differences in the susceptibility or resistance of CD3(+) T cells in vitro correlate with the outcome and severity of clinical signs in vivo. Thus, horses were divided into two groups based on their CD3(+) T cell susceptible or r...
Fertilisation in the horse and paracrine signalling in the oviduct.
Reproduction, fertility, and development    December 1, 2011   Volume 23, Issue 8 941-951 doi: 10.1071/RD10285
Goudet G.The mammalian oviduct plays a crucial role in the preparation of gametes for fertilisation (transport and final maturation) and fertilisation itself. An increasing number of studies offers a comprehensive overview of the functions of the oviduct and its secretions, but this topic has had limited investigation in the horse. Limited data are available on the final oocyte maturation in the equine oviduct. However, in vitro and in vivo systems have been established to analyse the influence of equine oviduct epithelial cells (OEC) during maturation on the potential of oocytes for fertilisation and ...
Treatment of subchondral cystic lesions of the medial femoral condyle of mature horses with growth factor enhanced chondrocyte grafts: a retrospective study of 49 cases.
Equine veterinary journal    December 1, 2011   Volume 44, Issue 5 606-613 doi: 10.1111/j.2042-3306.2011.00510.x
Ortved KF, Nixon AJ, Mohammed HO, Fortier LA.To evaluate the long-term clinical outcome after allogeneic chondrocyte and insulin-like growth factor-I (IGF-I) grafting of subchondral cystic lesions (SCLs) of the femoral condyle in horses. Objective: To test the hypothesis that chondrocyte and IGF-I grafts will improve the long-term clinical outcome in arthroscopically debrided SCLs. Methods: Medical records of 49 horses with SCLs of the femoral condyle treated by debridement and implantation of chondrocytes and IGF-I were reviewed. Preoperative radiographs were obtained, and caudocranial radiographic projections were used to establish a r...
Intra-abdominal hyaluronan concentration in peritoneal fluid of horses with sudden signs of severe abdominal pain.
American journal of veterinary research    December 1, 2011   Volume 72, Issue 12 1666-1673 doi: 10.2460/ajvr.72.12.1666
Lillich JD, Ray-Miller W, Silver KS, Davis EG, Schultz BD.To determine hyaluronan concentrations in peritoneal fluid from healthy horses and horses with sudden signs of severe abdominal pain and to identify the cellular sources of hyaluronan within the peritoneal cavity. Methods: 7 client-owned horses that were evaluated for sudden signs of severe abdominal pain, 6 healthy teaching horses, and 13 euthanized horses (11 with no abdominal disease and 2 that had undergone abdominal surgery 2 weeks previously for a different study). Methods: Abdominal fluid was collected from the client-owned and teaching horses. Hyaluronan concentrations were determined ...
Comparison of the response to experimentally induced short-term inflammation in the temporomandibular and metacarpophalangeal joints of horses.
American journal of veterinary research    December 1, 2011   Volume 72, Issue 12 1586-1591 doi: 10.2460/ajvr.72.12.1586
Carmalt JL, Bell CD, Tatarniuk DM, Suri SS, Singh B, Waldner C.To investigate the relationship between inflammatory responses of the temporomandibular joint (TMJ) and the metacarpophalangeal (MCP) joint in clinically normal horses. Methods: 7 mature horses. Methods: In each horse, 1 TMJ and 1 MCP joint were injected with lipopolysaccharide (LPS; 0.0025 μg). The contralateral TMJ and MCP joint were injected with saline (0.9% NaCl) solution. Synovial fluid samples were collected from all 4 joints over 24 hours after injection. Concentrations of interleukin-6, tumor necrosis factor-α, transforming growth factor-β, and total protein were measured via immun...
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