Potentiation of indomethacin-induced anti-inflammatory response by pioglitazone in carrageenan-induced acute inflammation in rats: Role of PPARγ receptors

This study aimed to assess the interaction between anti-inflammatory effects of pioglitazone (peroxysome proliferator activated receptor-gamma (PPARγ) agonist, PGL), and indomethacin (cyclooxygenase (COX) inhibitor, IND) and to evaluate the possible underlying mechanisms. Paw edema induced by carrageenan was used to induce inflammation. Different doses of IND (0.3–10 mg/kg) and PGL (1–20 mg/kg) alone or in combination were administered intraperitoneally to rats. Paw tissue levels of PPARγ, COX-2, and prostaglandin E2 and serum levels of TNF-α and IL-10 were also estimated.Doses of IND and PGL showed a statistically significant anti-inflammatory effect. Combination of a non-effective dose of IND (0.3 mg/kg) with increasing doses of PGL (1–10 mg/kg) resulted in potentiated anti-inflammation and vise versa. IND, PGL and the combination were able to reduce the COX-2, PGE2 contents and TNF-α level. Moreover, all these treatments caused elevation in PPARγ levels and IL-10 levels. However, when the rats were pre-treated with GW-9662 (a selective PPARγ antagonist), all the anti-inflammation and alterations in the biochemical factors were antagonized.These results showed that PGL markedly enhanced the anti-inflammatory activity of IND and this effect mediated partly at least, through PPARγ. Possible mechanisms of the interaction were that PGL stimulates the PPARγ and inhibits COX-2 by those cytokines that trigger the PPARγ and also inhibit COX-2. This study suggests that combination therapy with pioglitazone and indomethacin may provide an alternative for the clinical control of inflammation especially in patients with diabetes.     

The effects of alendronate on the suppression of bone resorption and the promotion of cartilage formation in the human mosaicplasty donor site: A randomized,double-blind,placebo-controlled prospective study

BackgroundWe previously reported that early alendronate administration accelerated bone formation and improved the quality of repaired cartilage in the donor site in rabbits. To investigate whether alendronate administration has effects in humans similar to those observed in rabbits.MethodsThe study cohort included 35 patients over the age of 12-years old who underwent mosaicplasty without osteoporotic therapy from March 2011 to October 2012. The donor sites were medial or lateral in the patellofemoral joint. Placebo (P) or Bonalon containing 35 mg of alendronate (A) was administered orally every week for 8 weeks. The cohort comprised 15 male and 20 female, including 14 right and 21 left knees. The mean age at the time of surgery was 57.1 years. Bone formation was examined using computer tomography and lateral knee radiography, and cartilage formation was examined using magnetic resonance imaging (MRI), second-look assessment, and intraoperative acoustic evaluation. The clinical outcomes were assessed using the Japanese Orthopaedic Association knee score and visual analog scale (VAS). Bone and cartilage formation in the donor site and clinical outcomes were assessed at 3, 6, and 12 months after mosaicplasty.ResultsThe ratio of TRAP-5b in group A was significantly smaller than that in group P at 2 and 8 weeks after mosaicplasty. The extent of bone formation in the donor sites in group A was significantly greater than that in group P at 3 and 6 months after mosaicplasty. Cartilage formation did not differ significantly between the two groups as determined by MRI, macroscopic assessment, and intraoperative acoustic evaluation. Clinical outcomes did not differ significantly between the two groups, and no negative clinical outcomes were observed.ConclusionEarly alendronate administration accelerated bone formation but not cartilage formation in the mosaicplasty donor site in humans.     

Return to Sports Activities After Flexor Hallucis Longus Transfer for Neglected Achilles Tendon Rupture

Transfer of the flexor hallucis longus (FHL) is known to be effective in the treatment of neglected Achilles tendon rupture (ATR). However, evidence on the return to sports activity levels and clinical outcomes is not sufficient. The aim of this study was assessing clinical outcomes and level of sports activity after FHL tendon transfer for treatment of neglected ATR. Twenty-eight patients who underwent FHL transfer for neglected ATR were analyzed retrospectively. Sports activity status was assessed using the Tegner Activity Scale (TAS). Clinical outcomes were evaluated using the Achilles tendon total rupture score and the American Orthopedic Foot and Ankle Society Ankle-Hindfoot Scale. By the post hoc power analyses, the power level of more than 80% was identified. The preinjury median TAS score was 4 point and unchanged at the last follow-up. The mean Achilles tendon Total Rupture Scores and American Orthopedic Foot and Ankle Society Ankle-Hindfoot Scale scores at the last follow-up were 81 and 93, respectively. While the median TAS was unchanged, 9/28 patients suffered from lower activity level after the procedure. In conclusion, midterm results of FHL transfer for neglected ATR were shown to be favorable. The median TAS score was maintained. Nonetheless, 32% of patients returned to sports activities with a TAS score 1 point lower than that at preinjury and with less favorable clinical outcomes.     

The effects of hallux valgus and walking speed on dynamic balance in older adults

BackgroundHallux valgus (HV) contributes to deficits in static balance and increased fall risk in older adults. Very limited research has examined dynamic balance deficits in walking in this population. These individuals generally walk slowly, as balance challenge is lesser at slow speeds.Research questionHow does the dynamic balance of older adults with HV differ from healthy controls at controlled slow and fast walking speeds?MethodsNineteen older adults with HV and 13 healthy controls completed 5 continuous walking trials at 1.0 and 1.3 m·s⁻¹ as whole body marker position and ground reaction force data were captured. Dynamic balance was evaluated using whole body center of mass (COM) and center of pressure (COP) inclination angles (IA) and duration of double support.ResultsThere were no differences in measures of dynamic balance between older adults with and without HV at slow and fast speeds. At the faster speed, the peak sagittal plane COM-COP IA increased and the double support duration decreased, while the peak frontal plane COM-COP IA were not affected.SignificanceOlder adults with HV do not exhibit deficits in dynamic balance during continuous walking at comfortable speeds when compared to healthy older adults.     

CHOP deficiency prevents methylglyoxal-induced myocyte apoptosis and cardiac dysfunction

Epidemiological studies indicate that methylglyoxal (MGO) plasma levels are closely linked to diabetes and the exacerbation of diabetic cardiovascular complications. Recently, it was established that endoplasmic reticulum (ER) stress importantly contributes to the pathogenesis of diabetes and its cardiovascular complications. The objective of this study was to explore the mechanism by which diabetes instigates cardiomyocyte apoptosis and cardiac dysfunction via MGO-mediated myocyte apoptosis. Intriguingly, the MGO activated unfolded protein response pathway accompanying apoptotic events, such as cleavages of PARP-1 and caspase-3. In addition, Western blot analysis revealed that MGO-induced myocyte apoptosis was inhibited by depletion of CHOP with siRNA against Ddit3, the gene name for rat CHOP. To investigate the physiologic roles of CHOP in vivo, glucose tolerance and cardiac dysfunction were assessed in CHOP-deficient mice. No significant difference was observed between CHOP KO and littermate naïve controls in terms of the MGO-induced impairment of glucose tolerance. In contrast, myocyte apoptosis, inflammation, and cardiac dysfunction were significantly diminished in CHOP KO compared with littermate naïve controls. These results showed that CHOP is the key signal for myocyte apoptosis and cardiac dysfunction induced by MGO. These findings suggest a therapeutic potential of CHOP inhibition in the management of diabetic cardiovascular complications including diabetic cardiomyopathy.     

Macroporous thin membranes for cell transplant in regenerative medicine

The aim of this paper is to present a method to produce macroporous thin membranes made of poly (ethyl acrylate-co-hydroxyethyl acrylate) copolymer network with varying cross-linking density for cell transplantation and prosthesis fabrication. The manufacture process is based on template techniques and anisotropic pore collapse. Pore collapse was produced by swelling the membrane in acetone and subsequently drying and changing the solvent by water to produce 100 microns thick porous membranes. These very thin membranes are porous enough to hold cells to be transplanted to the organism or to be colonized by ingrowth from neighboring tissues in the organism, and they present sufficient tearing stress to be sutured with surgical thread. The obtained pore morphology was observed by Scanning Electron Microscope, and confocal laser microscopy. Mechanical properties were characterized by stress–strain experiments in tension and tearing strength measurements. Morphology and mechanical properties were related to the different initial thickness of the scaffold and the cross-linking density of the polymer network. Seeding efficiency and proliferation of mesenchymal stem cells inside the pore structure were determined at 2 h, 1, 7, 14 and 21 days from seeding.