scholarly journals Placental-expanded, mesenchymal cells improve muscle function following hip arthroplasty

2018 ◽  
Author(s):  
Tobias Winkler ◽  
Carsten Perka ◽  
Philipp von Roth ◽  
Alison N. Agres ◽  
Henning Plage ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Hip Arthroplasty ◽  
Low Dose ◽  
Gluteus Medius ◽  
High Dose ◽  
Immune Reactivity ◽  
Surgical Trauma ◽  
Muscle Injuries ◽  
Dose Treatment ◽  
Link Type

AbstractBackgroundNo regenerative approach has thus far been shown to be effective in skeletal muscle injuries, despite high frequency and associated functional deficits. We sought to address surgical trauma related muscle injuries using local intraoperative application of allogeneic placenta-derived, mesenchymal-like adherent cells (PLX-PAD), using hip arthroplasty as a standardized injury model, because of the high regenerative and immunomodulatory potency of this cell type.MethodsOur pilot phase I/IIa study was prospective, randomized, double blind and placebo-controlled. Twenty patients undergoing hip arthroplasty via a direct lateral approach were injected with 3.0×108or 1.5×108PLX-PAD or a placebo into the gluteus medius muscle.ResultsWe did not observe any relevant PLX-PAD-related adverse events at the 2-year follow-up. Improved gluteus medius strength was noted as early as week 6 in the treatment-groups. Surprisingly, until week 26 the low-dose outperformed the high-dose group and reached significantly improved strength compared to placebo, mirrored by an increase in muscle volume. Histology indicated accelerated healing after cell therapy. Biomarker studies revealed that low-dose treatment reduced the surgery-related immunological stress reaction more than high-dose. Signs of late-onset immune reactivity after high-dose treatment corresponded to reduced functional improvement.ConclusionAllogeneic PLX-PAD therapy improved strength and volume of injured skeletal muscle with a reasonable safety profile. Outcomes could be positively correlated with the modulation of early postoperative stress-related immunological reactions.Trial RegistrationClinicalTrials.gov(numberNCT01525667) and EudraCT (number 2011-003934-16)FundingThe study was funded by the Sponsor, Pluristem Therapeutics, the Israeli innovation authority and the German Federal Ministry of Education and Research.Conflict of interestT. Winkler, C. Perka and G.N. Duda are members of a clinical advisory board of Pluristem Ltd for future indications. T. Winkler, C. Perka, G.N. Duda, P. von Roth filed a patent together with Pluristem Ltd. E. Lukasiewicz Hagai, R. Ofir, L. Pinzur and E. Eyal are current or former employees of Pluristem Ltd. T. Winkler, P. Reinke and H.-D. Volk received in the past consulting fees from Pluristem Ltd. but not for this project.

scholarly journals Glycerol Monocaprylate Modulates Gut Microbiota and Increases Short-Chain Fatty Acids Production without Adverse Effects on Metabolism and Inflammation

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1427
Author(s):  
Junhui Zhang ◽  
Fengqin Feng ◽  
Minjie Zhao
Keyword(s):  
Fatty Acids ◽  
Gut Microbiota ◽  
Dose Group ◽  
Low Dose ◽  
Short Chain Fatty Acids ◽  
Normal Diet ◽  
Short Chain ◽  
High Dose ◽  
Dose Treatment ◽  
Chain Fatty Acids

Glycerol monocaprylate (GMC) is a glycerol derivative of medium-chain fatty acids (MCFAs) and is widely used as a preservative in food processing. However, GMC and its hydrolytic acid (octylic acid) have antibacterial properties that may affect the physiology and intestinal microecology of the human body. Therefore, in this study, the effects of two different dosages of GMC (150 and 1600 mg kg−1) on glucose, lipid metabolism, inflammation, and intestinal microecology of normal diet-fed C57BL/6 mice were comprehensively investigated. The obtained results showed that the level of triglycerides (TGs) in the low-dose group down-regulated significantly, and the anti-inflammatory cytokine interleukin 10 (IL-10) significantly increased, while the pro-inflammatory cytokines monocyte chemotactic protein 1 (MCP-1) and interleukin 1beta (IL-1β) in the high-dose group were significantly decreased. Importantly, GMC promoted the α-diversity of gut microbiota in normal-diet-fed mice, regardless of dosages. Additionally, it was found that the low-dose treatment of GMC significantly increased the abundance of Lactobacillus, while the high-dose treatment of GMC significantly increased the abundance of SCFA-producers such as Clostridiales, Lachnospiraceae, and Ruminococcus. Moreover, the content of short-chain fatty acids (SCFAs) was significantly increased by GMC supplementation. Thus, our research provides a novel insight into the effects of GMC on gut microbiota and physiological characteristics.

scholarly journals Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy

2020 ◽  
Vol 8 (1) ◽  
pp. e000247
Author(s):  
Brett A Schroeder ◽  
Ralph Graeme Black ◽  
Sydney Spadinger ◽  
Shihong Zhang ◽  
Karan Kohli ◽  
...  
Keyword(s):  
T Cell ◽  
Interferon Gamma ◽  
Low Dose ◽  
Cellular Therapy ◽  
Tumor Regression ◽  
High Dose ◽  
Adoptive Cellular Therapy ◽  
Link Type ◽  
T Cell Infiltration ◽  
Ifn Γ

BackgroundAdoptive cellular therapy (ACT) is a promising treatment for synovial sarcoma (SS) with reported response rates of over 50%. However, more work is needed to obtain deeper and more durable responses. SS has a ‘cold’ tumor immune microenvironment with low levels of major histocompatibility complex (MHC) expression and few T-cell infiltrates, which could represent a barrier toward successful treatment with ACT. We previously demonstrated that both MHC expression and T-cell infiltration can be increased using systemic interferon gamma (IFN-γ), which could improve the efficacy of ACT for SS.Case presentationWe launched a phase I trial incorporating four weekly doses of IFN-γ in an ACT regimen of high-dose cyclophosphamide (HD Cy), NY-ESO-1-specific T cells, and postinfusion low-dose interleukin (IL)-2. Two patients were treated. While one patient had significant tumor regression and resultant clinical benefit, the other patient suffered a fatal histiocytic myocarditis. Therefore, this cohort was terminated for safety concerns.ConclusionWe describe a new and serious toxicity of immunotherapy from IFN-γ combined with HD Cy-based lymphodepletion and low-dose IL-2. While IFN-γ should not be used concurrently with HD Cy or with low dose IL-2, IFN-γ may still be important in sensitizing SS for ACT. Future studies should avoid using IFN-γ during the immediate period before/after cell infusion.Trial registration numbersNCT04177021,NCT01957709, andNCT03063632.

scholarly journals Lycopene supplementation attenuated xanthine oxidase and myeloperoxidase activities in skeletal muscle tissues of rats after exhaustive exercise

2005 ◽  
Vol 94 (4) ◽  
pp. 595-601 ◽  
Author(s):  
Chieh-Chung Liu ◽  
Chi-Chang Huang ◽  
Wan-Teng Lin ◽  
Chin-Cheng Hsieh ◽  
Shih-Yi Huang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Xanthine Oxidase ◽  
Low Dose ◽  
Exhaustive Exercise ◽  
Strenuous Exercise ◽  
High Dose ◽  
Sedentary Control ◽  
Muscle Tissues ◽  
Significant Difference

Strenuous exercise is known to induce oxidative stress leading to the generation of free radicals. The purpose of the present study was to investigate the effects of lycopene, an antioxidant nutrient, at a relatively low dose (2·6 mg/kg per d) and a relatively high dose (7·8 mg/kg per d) on the antioxidant status of blood and skeletal muscle tissues in rats after exhaustive exercise. Rats were divided into six groups: sedentary control (C); sedentary control with low-dose lycopene (CLL); sedentary control with high-dose lycopene (CHL); exhaustive exercise (E); exhaustive exercise with low-dose lycopene (ELL); exhaustive exercise with high-dose lycopene (EHL). After 30 d, the rats in the three C groups were killed without exercise, but the rats in the three E groups were killed immediately after an exhaustive running test on a motorised treadmill. The results showed that xanthine oxidase (XO) activities of plasma and muscle, and muscular myeloperoxidase (MPO) activity in group E were significantly increased compared with group C. Compared with group E, the elevations of XO and MPO activities of muscle were significantly decreased in group EHL. The malondialdehyde concentrations of plasma and tissues in group E were significantly increased by 72 and 114 %, respectively, compared with those in group C. However, this phenomenon was prevented in rats of the ELL and EHL groups. There was no significant difference in the GSH concentrations of erythrocytes in each group; however, exhaustive exercise resulted in a significant decrease in the GSH content of muscle. In conclusion, these results suggested that lycopene protected muscle tissue from oxidative stress after exhaustive exercise.

Effect of insulin on regional vascular resistances in conscious rats

1996 ◽  
Vol 270 (2) ◽  
pp. R450-R455
Author(s):  
E. Qadir ◽  
J. P. Porter
Keyword(s):  
Skeletal Muscle ◽  
Arterial Pressure ◽  
Low Dose ◽  
Chronic Administration ◽  
High Dose ◽  
Ganglionic Blockade ◽  
Conscious Rats ◽  
Before And After ◽  
Vascular Beds ◽  
Renal Vascular

In the rat, but not in humans and other mammals, chronic administration of insulin produces hypertension. The present aim was to determine the effect of acute insulin infusion on regional vascular resistances and to determine the neurogenic contribution to the response. Conscious rats were infused with insulin (2 or 6 mU/min) before and after ganglionic blockade with chlorisondamine (5 mg/kg). The low dose of insulin produced an increase in arterial pressure and hindquarter vascular resistance; the high dose produced a gradual decrease in arterial pressure and renal resistance. After ganglionic blockade, the hindquarter vasoconstriction produced by the low dose was abolished. The high dose of insulin produced both hindquarter and renal vasodilation. Thus the low dose of insulin had a selective neurogenic vasoconstrictor effect in rat skeletal muscle vascular beds. With higher doses, direct vasodilatory effects in both skeletal muscle and renal vascular beds appeared. This greater sensitivity of the sympathoexcitatory effects of insulin in rats may explain the ability of chronic insulin infusions to increase blood pressure in this species.

Effect of insulin on dexamethasone-induced ultrastructural changes in skeletal and cardiac muscle

Biologia ◽  
2012 ◽  
Vol 67 (3) ◽  
Author(s):  
Jian Qin ◽  
Rong Du ◽  
Yaqun Yang ◽  
Hongqiang Zhang ◽  
Ying Zhou
Keyword(s):  
Skeletal Muscle ◽  
Body Weight ◽  
Cardiac Muscle ◽  
Muscle Atrophy ◽  
Low Dose ◽  
The Body ◽  
Muscle Size ◽  
Ultrastructural Changes ◽  
High Dose ◽  
High Dose Dexamethasone

AbstractGlucocorticoids help animals respond to stressors but excessive glucocorticoids cause muscle atrophy, while insulin can promote anabolism and growth. In order to compare the glucocorticoids-induced ultrastructural changes between skeletal muscle and cardiac muscle, and investigate the preventive effects of insulin on the changes, eighteen male chicks with similar initial weight were randomly divided into three groups. The two test groups were respectively treated with high-dose dexamethasone alone or together with low-dose insulin by intraperitoneal injection, and the control group was treated with an equal volume of saline solution. The experiment lasted for ten days, and then the body weight, muscle size and ultrastructure in skeletal and cardiac muscles of twelve chicks were qualitatively or quantitatively analyzed. The results showed that high-dose dexamethasone induced obvious skeletal and cardiac muscle atrophy. The differences of ultrastructural changes between skeletal muscle and cardiac muscle (such as for the former or the latter, the intermyofibrillar-and-interfilamentary spaces reducing or enlarging, the mitochondria swelling seriously or enlarging lightly, the myofibril filaments compacting or loosing) suggested that dexamethasone induced skeletal and cardiac muscle atrophy by different mechanisms. Low-dose insulin did not affect the dexamethasone-induced decreases of body weight and skeletal muscle size, but alleviated lightly the dexamethasone-induced ultrastructural changes in skeletal muscle. Different from skeletal muscle, low-dose insulin almost resisted the dexamethasone-induced ultrastructural changes in cardiac muscle.

Reoxygenation injury in isolated hepatocytes: effect of extracellular ATP on cation homeostasis

1986 ◽  
Vol 250 (4) ◽  
pp. R573-R579 ◽  
Author(s):  
H. Hayashi ◽  
I. H. Chaudry ◽  
M. G. Clemens ◽  
M. J. Hull ◽  
A. E. Baue
Keyword(s):  
Low Dose ◽  
Isolated Hepatocytes ◽  
High Dose ◽  
Dose Treatment ◽  
Beneficial Effects ◽  
Cation Homeostasis ◽  
Electrolyte Homeostasis ◽  
Reoxygenation Injury ◽  
Specific Stimulation ◽  
Stimulation Of

The aims of this study were to determine 1) the effects of anoxia and reoxygenation on electrolytes and ATP content of isolated hepatocytes and 2) whether exogenous ATP-MgCl2 has any beneficial effects on the cellular alterations that are produced during the reoxygenation period. After 90 min anoxia, intracellular Na and inorganic phosphate (Pi) increased, K and ATP decreased, whereas Ca and Mg did not change. After 60 min of reoxygenation, intracellular Mg and Na levels decreased, Ca increased, and Pi levels returned to normal, but ATP levels remained low. These results suggest that the plasma membrane is relatively impermeable to divalent ions such as Ca2+, Mg2+, and HPO2-4 during anoxia but becomes permeable to them after reoxygenation. When anoxic cells were treated with ATP-MgCl2 during reoxygenation, intracellular ATP and Mg levels increased, but accumulation of Ca and Pi was also observed. Thus enhancement of Mg transport and specific stimulation of Ca-Pi sequestration occurs with ATP-MgCl2 treatment. Na and K levels exhibited biphasic reciprocal dose-response changes to ATP-MgCl2 treatment; i.e., 0.1 mM ATP-MgCl2 (low-dose) treatment increased K and decreased Na, whereas 1 mM ATP-MgCl2 (high-dose) treatment decreased K and increased Na. These results indicate that although addition of a single high-dose ATP-MgCl2 was deleterious over a period of 60 min, low-dose ATP-MgCl2 accelerates the recovery of postanoxic cellular electrolyte homeostasis.

Administration of Particulate Oxygen Generators Improves Skeletal Muscle Contractile Function Following Ischemia-Reperfusion Injury in the Rat Hind Limb

2022 ◽  
Author(s):  
Sarah E. Dyer ◽  
J. David Remer ◽  
Kelsey E. Hannifin ◽  
Aishwarya Hombal ◽  
Joseph C. Wenke ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Functional Recovery ◽  
Hind Limb ◽  
Low Dose ◽  
Contractile Function ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
High Dose ◽  
Extremity Trauma ◽  
The Impact

Extended tourniquet application, often associated with battlefield extremity trauma, can lead to severe ischemia-reperfusion (I/R) injury in skeletal muscle. Particulate oxygen generators (POGs) can be directly injected into tissue to supply oxygen to attenuate the effects of I/R injury in muscle. The goal of this study was to investigate the efficacy of a sodium percarbonate (SPO)-based POG formulation in reducing ischemic damage in a rat hind limb during tourniquet application. Male Lewis rats were anesthetized and underwent tourniquet application for 3 hours, at a pressure of 300 mmHg. Shortly after tourniquet inflation animals received intramuscular injections of either 0.2 mg/mL SPO with catalase (n=6) or 2.0 mg/mL SPO with catalase (n=6) directly into the tibialis anterior (TA) muscle. An additional Tourniquet-Only group (n=12) received no intervention. Functional recovery was monitored using in vivo contractile testing of the hind limb at 1-, 2-, and 4-weeks post-injury. By the 4 week time point, the Low Dose POGs group continued to show improved functional recovery (85% of baseline) compared to the Tourniquet-Only (48%) and High Dose POG (56%) groups. In short, the Low Dose POGs formulation appeared, at least in part, to mitigate the impact of ischemic tissue injury, thus improving contractile function following tourniquet application. Functional improvement correlated with maintenance of larger muscle fiber cross sectional area, and the presence of fewer fibers containing centrally located nuclei. As such, POGs represent a potentially attractive therapeutic solution for addressing I/R injuries associated with extremity trauma.

scholarly journals Low-dose glucocorticoids plus rituximab versus high-dose glucocorticoids plus rituximab for remission induction in ANCA-associated vasculitis (LoVAS): protocol for a multicentre, open-label, randomised controlled trial

BMJ Open ◽  
2017 ◽  
Vol 7 (12) ◽  
pp. e018748 ◽  
Author(s):  
Shunsuke Furuta ◽  
Takao Sugiyama ◽  
Takeshi Umibe ◽  
Yuko Kaneko ◽  
Koichi Amano ◽  
...  
Keyword(s):  
Side Effects ◽  
Randomised Controlled Trial ◽  
Low Dose ◽  
Controlled Trial ◽  
University Hospital ◽  
Remission Induction ◽  
High Dose ◽  
Open Label ◽  
Link Type ◽  
Randomised Controlled

IntroductionAntineutrophil cytoplasm antibody-associated vasculitis (AAV) is a form of systemic vasculitis. The current standard induction therapy with the combination of high-dose glucocorticoids and cyclophosphamide or rituximab has high remission rates of 80%–90%. However, it is also associated with various side effects, including death due to infection or cardiovascular disease. There is an unmet medical need of a new therapy to reduce side effects.Methods and analysisThis is a phase IV multicentre, open-label, randomised controlled trial that aims to evaluate the efficacy and safety of a new remission induction regimen with the combination of low-dose glucocorticoids and rituximab. Newly diagnosed patients with AAV will be assessed for eligibility at 34 tertiary rheumatology/nephrology centres in Japan. One hundred and forty patients will be randomised (1:1) to receive low-dose prednisolone (0.5 mg/kg daily) plus rituximab (375 mg/m2weekly) or high-dose prednisolone (1 mg/kg daily) plus rituximab. The trial consists of remission induction and maintenance phases. The primary endpoint of the study is the remission rate at 6 months (induction phase). Relapse and long-term safety profile will also be assessed until 24 months (maintenance phase).Ethics and disseminationThe protocol was first approved by the Institutional Review Board of Chiba University Hospital (reference number: G25051), and then approved by each participating site. The trial was registered at the University hospital Medical Information Network (UMIN) clinical registry (UMIN000014222) and ClinicalTrials.gov registry (NCT02198248). The Low-dose Glucocorticoid Vasculitis Induction Study (LoVAS) trial is currently ongoing and is due to finish in September 2019. The findings of this trial will be disseminated to participants through peer-reviewed publications and presented at national and international conferences in accordance with the Consolidated Standards of Reporting Trials (CONSORT) Statement.Trial registration numberUMIN000014222;NCT02198248.

Low-dose Estrogen Is as Effective as High-dose Treatment in Rats With Postmenopausal Hypertension

2014 ◽  
Vol 63 (2) ◽  
pp. 144-151 ◽  
Author(s):  
Cristina Campos ◽  
Carmem L. Sartorio ◽  
Karina R. Casali ◽  
Rafael O. Fernandes ◽  
Susana Llesuy ◽  
...  
Keyword(s):  
Low Dose ◽  
High Dose ◽  
Dose Treatment ◽  
High Dose Treatment
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