Association between the levels of prostaglandin E2 in tears and severity of dry eye

AIM: To investigate the relationship between the levels of prostaglandin E2 (PGE2) in tears and dry eye disease severity based on both clinical symptoms and signs. METHODS: Tear samples were collected from 36 non-Sjögren syndrome dry eye patients (10 males and 26 females, mean age 50.11±11.17y). All participants completed the Ocular Surface Disease Index (OSDI) questionnaire and underwent a detailed ophthalmic examination including, tear film breakup time (TBUT), ocular surface fluorescein staining, Schirmer I test, and meibomian gland assessment. The level of PGE2 in tears was measured using enzyme-linked immunosorbent assay (ELISA). The independent associations between tear PGE2 levels and other variables including demographics, OSDI scores, TBUT, Schirmer scores, ocular surface staining scores, and stage of meibomian gland dysfunction (MGD) were evaluated using linear regression analysis. RESULTS: The mean PGE2 level in tears of dry eye patients was 537.85±234.02 pg/mL. The tear PGE2 levels significantly positively correlated with OSDI scores (R=0.608, P<0.001), however, they did not significantly associate with TBUT (R=0.153, P=0.373), Schirmer scores (R=-0.098, P=0.570), ocular surface staining scores (R=0.282, P=0.095), and stage of MGD (R=-0.107, P=0.535). Male sex was significantly negatively correlated with tear PGE2 levels. CONCLUSION: The levels of PGE2 in tears are positively correlated with dry eye symptoms. However, no significant association was found between tear PGE2 levels and the results of other common dry eye diagnostic tests.     

Myoblasts isolated from hypertrophy-responsive callipyge muscles show altered growth rates and increased resistance to serum deprivation-induced apoptosis

Back and hind limb muscles of sheep paternally heterozygous for the callipyge single nucleotide polymorphism undergo extensive hypertrophy shortly after birth. We have established cell cultures from foetal semitendinosus and longissimus dorsi muscles of normal and callipyge animals. Cultures were assessed for rates of proliferation, cell death, myogenicity and DLK1 expression. Myoblasts from callipyge semitendinosus, but not longissimus dorsi muscles, proliferated faster than myoblasts isolated from normal semitendinosus muscle, and cells isolated from either callipyge muscle were more resistant to serum deprivation-induced apoptosis than equivalent cells isolated from normal individuals. These observations indicate that there are intrinsic differences in the behaviour of isolated myoblasts, which are associated with their muscle and genotype of origin. As myoblasts are the cells responsible for hypertrophy of muscle fibres, the observed differences in cell growth may play a role in the hypertrophy of certain muscles in callipyge animals.     

Osteopontin is linked with AKT,FoxO1, and myostatin in skeletal muscle cells

Introduction: Osteopontin (OPN) polymorphisms are associated with muscle size and modify disease progression in Duchenne muscular dystrophy (DMD). We hypothesized that OPN may share a molecular network with myostatin (MSTN). Methods: Studies were conducted in the golden retriever (GRMD) and mdx mouse models of DMD. Follow‐up in‐vitro studies were employed in myogenic cells and the mdx mouse treated with recombinant mouse (rm) or human (Hu) OPN protein. Results: OPN was increased and MSTN was decreased and levels correlated inversely in GRMD hypertrophied muscle. RM‐OPN treatment led to induced AKT1 and FoxO1 phosphorylation, microRNA‐486 modulation, and decreased MSTN. An AKT1 inhibitor blocked these effects, whereas an RGD‐mutant OPN protein and an RGDS blocking peptide showed similar effects to the AKT inhibitor. RMOPN induced myotube hypertrophy and minimal Feret diameter in mdx muscle. Discussion: OPN may interact with AKT1/MSTN/FoxO1 to modify normal and dystrophic muscle. Muscle Nerve 56 : 1119–1127, 2017     

Clinical outcomes after minimally invasive transforaminal lumbar interbody fusion and lateral lumbar interbody fusion for treatment of degenerative lumbar disease: a systematic review and meta-analysis

The surgical procedures used for arthrodesis in the lumbar spine for degenerative lumbar diseases remain controversial. This systematic review aims to assess and compare clinical outcomes along with the complications and fusion of each technique (minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) or minimally invasive lateral lumbar interbody fusion (MIS LLIF)) for treatment of degenerative lumbar diseases. Relevant studies were identified from Medline and Scopus from inception to July 19, 2016 that reported Oswestry Disability Index (ODI), back and leg pain visual analog score (VAS), postoperative complications, and fusion of either technique. Fifty-eight studies were included for the analysis of MIS-TLIF; 40 studies were included for analysis of LLIF, and 1 randomized controlled trial (RCT) study was included for comparison of MIS-TLIF to LLIF. Overall, there were 9506 patients (5728 in the MIS-TLIF group and 3778 in the LLIF group). Indirect meta-analysis, MIS-TLIF provided better postoperative back and leg pain (VAS), disabilities (ODI), and risk of having complications when compared to LLIF technique, but the fusion rate was not significantly different between the two techniques. However, direct meta-analysis between RCT study and pooled indirect meta-analysis of MIS-TLIF have better pain, disabilities, and complication but no statistically significant difference when compared to LLIF. In LLIF, the pooled mean ODI and VAS back pain were 2.91 (95% CI 2.49, 3.33) and 23.24 (95% CI 18.96, 27.51) in MIS approach whereas 3.14 (95% CI 2.29, 4.04) and 28.29 (95% CI 21.92, 34.67) in traditional approach. In terms of complications and fusion rate, there was no difference in both groups. In lumbar interbody fusion, MIS-TLIF had better ODI, VAS pain, and complication rate when compared to LLIF with direct and indirect meta-analysis methods. However, in terms of fusion rates, there were no differences between the two techniques.     

The effects of MyD88 deficiency on disease phenotype in dysferlin‐deficient A/J mice: role of endogenous TLR ligands

An absence of dysferlin leads to activation of innate immune receptors such as Toll‐like receptors (TLRs) and skeletal muscle inflammation. Myeloid differentiation primary response gene 88 (MyD88) is a key mediator of TLR‐dependent innate immune signalling. We hypothesized that endogenous TLR ligands released from the leaking dysferlin‐deficient muscle fibres engage TLRs on muscle and immune cells and contribute to disease progression. To test this hypothesis, we generated and characterized dysferlin and MyD88 double‐deficient mice. Double‐deficient mice exhibited improved body weight, grip strength, and maximum muscle contractile force at 6–8 months of age when compared to MyD88‐sufficient, dysferlin‐deficient A/J mice. Double‐deficient mice also showed a decrease in total fibre number, which contributed to the observed increase in the number of central nuclei/fibres. These results indicate that there was less regeneration in the double‐deficient mice. We next tested the hypothesis that endogenous ligands, such as single‐stranded ribonucleic acids (ssRNAs), released from damaged muscle cells bind to TLR‐7/8 and perpetuate the disease progression. We found that injection of ssRNA into the skeletal muscle of pre‐symptomatic mice (2 months old) resulted in a significant increase in degenerative fibres, inflammation, and regenerating fibres in A/J mice. In contrast, characteristic histological features were significantly decreased in double‐deficient mice. These data point to a clear role for the TLR pathway in the pathogenesis of dysferlin deficiency and suggest that TLR‐7/8 antagonists may have therapeutic value in this disease. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Facilitation of Th1-mediated immune response by prostaglandin E receptor EP1

Prostaglandin E₂ (PGE₂) exerts its actions via four subtypes of the PGE receptor, EP1–4. We show that mice deficient in EP1 exhibited significantly attenuated Th1 response in contact hypersensitivity induced by dinitrofluorobenzene (DNFB). This phenotype was recapitulated in wild-type mice by administration of an EP1-selective antagonist during the sensitization phase, and by adoptive transfer of T cells from sensitized EP1^−/− mice. Conversely, an EP1-selective agonist facilitated Th1 differentiation of naive T cells in vitro. Finally, CD11c⁺ cells containing the inducible form of PGE synthase increased in number in the draining lymph nodes after DNFB application. These results suggest that PGE₂ produced by dendritic cells in the lymph nodes acts on EP1 in naive T cells to promote Th1 differentiation.     

Prostaglandin E2-prostaglandin E receptor subtype 4 (EP4) signaling mediates UV irradiation-induced systemic immunosuppression

UV radiation induces systemic immunosuppression. Because nonsteroidal anti-inflammatory drugs suppress UV-induced immunosuppression, prostanoids have been suspected as a crucial mediator of this UV effect. However, the identity of the prostanoid involved and its mechanism of action remain unclear. Here, we addressed this issue by subjecting mice deficient in each prostanoid receptor individually or mice treated with a subtype-specific antagonist to UV irradiation. Mice treated with an antagonist for prostaglandin E receptor subtype 4 (EP4), but not those deficient in other prostanoid receptors, show impaired UV-induced immunosuppression, whereas administration of an EP4 agonist rescues the impairment of the UV-induced immunosuppression in indomethacin-treated mice. The EP4 antagonist treatment suppresses an increase in the number of CD4(+)/forkhead box P3-positive (Foxp3(+)) regulatory T cells (Treg cells) in the peripheral lymph nodes (LNs) and dendritic cells expressing DEC205 in the LNs and the skin after UV irradiation. Furthermore, the EP4 antagonist treatment down-regulates UV-induced expression of receptor activator of NF-κB ligand (RANKL) in skin keratinocytes. Finally, administration of anti-RANKL antibody abolishes the restoration of UV-induced immunosuppression by EP4 agonism in indomethacin-treated mice. Thus, prostaglandin E(2) (PGE(2))-EP4 signaling mediates UV-induced immunosuppression by elevating the number of Treg cells through regulation of RANKL expression in the epidermis.