Exposure to gestational diabetes mellitus increases subclinical inflammation mediated in part by obesity.

Gestational diabetes mellitus (GDM) is a frequent and serious complication of pregnancy, often associated with obesity. Metabolic dysfunction and metainflammation are evident in both obesity and GDM. In this cross-sectional study, we aimed at defining the direct contribution of the immune system in GDM, across the main metabolic tissues, specifically focussing on elucidating the roles of obesity and GDM to the clinical outcome. Using immunoassays and multicolour flow cytometry, cytokine profiles and immune cell frequencies were measured in maternal circulation and central metabolic tissues [placenta and visceral adipose tissue (VAT)] in GDM-diagnosed (n = 28) and normal glucose tolerant (n = 32) women undergoing caesarean section. Participants were sub-grouped as non-obese [body mass index (BMI) < 30 kg/m2] or obese (BMI ≥ 30 kg/m2). Unsupervised data analysis was performed on the flow cytometry data set to identify functional alterations. GDM obese participants had significantly elevated circulating IL-6 and IL-17A levels. GDM non-obese participants had elevated circulating IL-12p70, elevated placental IL-17A, and VAT IFN-γ production. Unsupervised clustering of immune populations across the three biological sites simultaneously, identified different NK- and T-cell phenotypes that were altered in NGT obese and GDM non-obese participants, while a classical tissue monocyte cluster was increased in GDM obese participants. In this study, there was significant evidence of subclinical inflammation, and significant alterations in clusters of NK cells, T cells, and tissue monocyte populations in GDM. While increased adiposity assimilates with increased inflammation in the non-pregnant state, this overt relationship may not be as evident during pregnancy and warrants further examination in future longitudinal studies.

A proteomic profile of the healthy human placenta.

BACKGROUND: The placenta remains one of the least studied organs within the human body. Yet, placental dysfunction has been associated with various pregnancy complications leading to both maternal and fetal death and long-term health consequences. The aim of this study was to characterise the protein networks of healthy term placental sub-anatomical regions using label free quantification mass spectrometry. METHODS: Three healthy placentae were sampled at five sample sites and each biopsy was dissected into maternal-, middle-, and fetal- sub-anatomical regions. Quadrupole-orbitrap mass spectrometer was used in data dependant analysis mode to identify 1859 unique proteins before detailed differential expression between regions. RESULTS: Protein profiling identified 1081, 1086, and 1101 proteins in maternal, middle, and fetal sub-anatomical regions respectively. Differentially expressed proteins were identified considering the effect between sample site location and sub-anatomical region on protein expression. Of these, 374 differentially expressed proteins (Two-way ANOVA adjusted p-value < 0.05, HSD Tukey adjusted p-value 0.05) were identified between sample site locations and sub-anatomical regions. The placenta specific disease map NaviCenta ( https://www.sbi.uni-rostock.de/minerva/index.xhtml?id=NaviCenta ) was used to focus functional analysis results to the placenta specific context. Subsequently, functional analysis with a focus on senescence, and mitochondrial function were performed. Significant differences were observed between sub-anatomical regions in protein intensity and composition. A decrease in anti-senescent proteins within the maternal sub-anatomical region, and an increase in proteins associated with a switch from ATP to fatty acid consumption as a source of energy between middle and fetal sub-anatomical regions were observed. CONCLUSION: These results suggest that normal proteomic variations exist within the anatomical structure of the placenta, thus recommending serial sectioning methodology for consistent placental research.

Heterogenous Differences in Cellular Senescent Phenotypes in Pre-Eclampsia and IUGR following Quantitative Assessment of Multiple Biomarkers of Senescence.

Premature ageing of the placenta in pregnancy outcomes is associated with the persistent presence of oxidative stress and placental insufficiency reducing its functional capacity. In this study, we investigated cellular senescence phenotypes of pre-eclampsia and IUGR pregnancies by simultaneously measuring several biomarkers of senescence. Maternal plasma and placental samples were collected at term gestation from nulliparous women undergoing pre-labour elective caesarean section with pre-eclampsia without intrauterine growth restriction (PE; n = 5), pre-eclampsia associated with intrauterine growth restriction (n = 8), intrauterine growth restriction (IUGR < 10th centile; n = 6), and age-matched controls (n = 20). Placental absolute telomere length and senescence gene analysis was performed by RTqPCR. The expression of cyclin-dependent kinase inhibitors (p21 and p16) was determined by Western blot. Senescence-associated secretory phenotypes (SASPs) were evaluated in maternal plasma by multiplex ELISA assay. Placental expression of senescence-associated genes showed significant increases in CHEK1, PCNA, PTEN, CDKN2A, and CCNB-1 (p < 0.05) in pre-eclampsia, while TBX-2, PCNA, ATM, and CCNB-1 expression were evident (p < 0.05) and were significantly decreased in IUGR compared with controls. Placental p16 protein expression was significantly decreased in pre-eclampsia only compared with controls (p = 0.028). IL-6 was significantly increased in pre-eclampsia (0.54 pg/mL ± 0.271 vs. 0.3 pg/mL ± 0.102; p = 0.017) while IFN-γ was significantly increased in IUGR (4.6 pg/mL ± 2.2 vs. 2.17 pg/mL ± 0.8; p = 0.002) compared with controls. These results provide evidence of premature senescence in IUGR pregnancies, and while cell cycle checkpoint regulators are activated in pre-eclampsia, the cellular phenotype is one of cell repair and subsequent proliferation rather than progression to senescence. The heterogeneity of these cellular phenotypes highlights the complexity of characterising cellular senescence and may equally be indicative of the differing pathophysiological insults unique to each obstetric complication.

A comparative study of two immunoassays of maternal placental growth factor.

Circulating maternal levels of placental growth factor correlates well with placental function and numerous studies advocate its role to help rule-out preterm pre-eclampsia. A number of automated immunoassay platforms to quantify placental growth factors are currently available. The aim of this study was to highlight the importance of developing and validating appropriate reference ranges and clinical cut-offs for immunoassays, by comparing the results obtained from two different immunoassays of placental growth factor; the Quantikine® ELISA and the automated Triage® test. This was a secondary subgroup analysis of samples collected as part of a prospective cross-sectional study of placental growth factors in twin pregnancy. Consenting pregnant women with a twin pregnancy, across a variety of gestations, had a single blood sample taken at a one-time point only during their pregnancy. The plasma was initially biobanked and then later analysed in batches using both immunoassays. Although the placental growth factor values of the two immunoassays correlated well (r = 0.88, n = 178, p < .001), the actual results obtained were significantly different (mean difference 238.1 pg/ml). Poor concordance between the two immunoassays was also present, with the Triage® test recording 36 cases as <100 pg/ml whereas the Quantikine® ELISA identified only 4 as <100 pg/ml. Biomarker levels may vary significantly between different immunoassay platforms, highlighting the importance of developing validated clinical cut-offs for any automated immunoassay before its clinical application. These differences need to be understood to facilitate clinical utility given that placental growth factor testing is likely to be introduced into widespread clinical practice.

Gestational Diabetes Mellitus and Maternal Immune Dysregulation: What We Know So Far.

Gestational diabetes mellitus (GDM) is an obstetric complication that affects approximately 5-10% of all pregnancies worldwide. GDM is defined as any degree of glucose intolerance with onset or first recognition during pregnancy, and is characterized by exaggerated insulin resistance, a condition which is already pronounced in healthy pregnancies. Maternal hyperglycaemia ensues, instigating a 'glucose stress' response and concurrent systemic inflammation. Previous findings have proposed that both placental and visceral adipose tissue play a part in instigating and mediating this low-grade inflammatory response which involves altered infiltration, differentiation and activation of maternal innate and adaptive immune cells. The resulting maternal immune dysregulation is responsible for exacerbation of the condition and a further reduction in maternal insulin sensitivity. GDM pathology results in maternal and foetal adverse outcomes such as increased susceptibility to diabetes mellitus development and foetal neurological conditions. A clearer understanding of how these pathways originate and evolve will improve therapeutic targeting. In this review, we will explore the existing findings describing maternal immunological adaption in GDM in an attempt to highlight our current understanding of GDM-mediated immune dysregulation and identify areas where further research is required.

The biology of ergothioneine, an antioxidant nutraceutical.

Ergothioneine (ERG) is an unusual thio-histidine betaine amino acid that has potent antioxidant activities. It is synthesised by a variety of microbes, especially fungi (including in mushroom fruiting bodies) and actinobacteria, but is not synthesised by plants and animals who acquire it via the soil and their diet, respectively. Animals have evolved a highly selective transporter for it, known as solute carrier family 22, member 4 (SLC22A4) in humans, signifying its importance, and ERG may even have the status of a vitamin. ERG accumulates differentially in various tissues, according to their expression of SLC22A4, favouring those such as erythrocytes that may be subject to oxidative stress. Mushroom or ERG consumption seems to provide significant prevention against oxidative stress in a large variety of systems. ERG seems to have strong cytoprotective status, and its concentration is lowered in a number of chronic inflammatory diseases. It has been passed as safe by regulatory agencies, and may have value as a nutraceutical and antioxidant more generally.

Mitochondrial [dys]function; culprit in pre-eclampsia?

Mitochondria are extensively identified for their bioenergetic capacities; however, recently these metabolic hubs are increasingly being appreciated as critical regulators of numerous cellular signalling systems. Mitochondrial reactive oxygen species have evolved as a mode of cross-talk between mitochondrial function and physiological systems, to sustain equipoise and foster adaption to cellular stress. Redox signalling mediated by exaggerated mitochondrial-ROS (reactive oxygen species) has been incriminated in a plethora of disease pathologies. Excessive production of mitochondrial ROS is intrinsically linked to mitochondrial dysfunction. Furthermore, mitochondrial dysfunction is a key facilitator of oxidative stress, inflammation, apoptosis and metabolism. These are key pathogenic intermediaries of pre-eclampsia, hence we hypothesize that mitochondrial dysfunction is a pathogenic mediator of oxidative stress in the pathophysiology of pre-eclampsia. We hypothesize that mitochondrial-targeted antioxidants may restrain production of ROS-mediated deleterious redox signalling pathways. If our hypothesis proves correct, therapeutic strategies directly targeting mitochondrial superoxide scavenging should be actively pursued as they may alleviate maternal vascular dysfunction and dramatically improve maternal and fetal health worldwide.

IL-10 mediates the immunoregulatory response in conjugated linoleic acid-induced regression of atherosclerosis.

Conjugated linoleic acid (CLA) induces regression of preestablished atherosclerosis in the ApoE(-/-) mouse. Understanding the mechanisms involved may help in identifying novel pathways associated with the regression of human disease. Animals were administered a 1% cholesterol diet for 12 wk, with 1% CLA supplementation from wk 8 to 12. ApoE(-/-) mice fed only the 1% cholesterol diet for 12 wk were employed as controls. Transcriptomic analysis of mouse aorta showed that many of the components of the IL-10 signaling pathway were modified during CLA-induced regression. Real-time PCR and Western blot analysis showed increased IL-10 receptor expression, phosphorylation of STAT3, and downstream target gene expression in the aorta, alongside an increase in serum IL-10 (79.8 ± 22.4 vs. 41.9 ± 5.5 pg/ml, n = 10; P < 0.01). CLA -supplementation also increased IL-10 production in bone marrow-derived macrophages (143.6 ± 28.6 vs. 94 ± 5.6 pg/ml, n = 5; P < 0.05). To explore the mechanisms for altered IL-10 production, we examined the profile of monocyte/macrophage phenotype in the vessel wall, bone marrow, and spleen. CLA increased macrophage polarization toward an anti-inflammatory M2 phenotype in vivo, increasing the population of Ly6C(lo) monocytes (29 vs. 77 ± 14, n=5, P < 0.05) in the aorta. CLA had similar effects on monocytes/macrophages differentiated from marrow-derived progenitor cells and on splenocytes. The induction of IL-10 on CLA supplementation in this model may reflect a systemic alteration toward an anti-inflammatory phenotype, which, in turn promotes increased vascular infiltration by Ly6C(lo) monocytes. These cells may contribute to CLA-induced disease regression.

Isolated Extensor Hallucis Longus Compartment Syndrome: A Case Report.

We present the case of an isolated extensor hallucis longus compartment syndrome following a diaphyseal fibular fracture. Our subject underwent syndesmotic fixation and experienced ongoing pain post-procedure. This was associated with an isolated loss of power in extension of the hallux. A diagnosis of an isolated extensor hallucis longus compartment syndrome followed. Our case highlights the vulnerability of this muscle belly to ischemia and reiterates the value of complete clinical examination in the postoperative patient.

L-ergothioneine reduces mitochondrial-driven NLRP3 activation in gestational diabetes mellitus.

BACKGROUND: Maternal hyperglycaemia has a significant impact on placental metabolism and mitochondrial function. The NLRP3 inflammasome is responsive to endogenous signals of mitochondrial dysfunction. We tested our hypothesis that mitochondrial dysfunction orchestrates activation of the NLRP3 inflammasome and contributes to inflammation in gestational diabetes mellitus (GDM). METHODS: Fasting blood, omental and placental tissue were collected on the day of caesarean section from nulliparous women with normal glucose tolerant (NGT) (n = 30) and GDM (n = 27) pregnancies. Cell-free mitochondrial DNA (cf-mtDNA) copy number was quantified by real-time PCR. M1-like (CD14+CD86+CD206-) and M2-like (CD14+CD86+CD206+) macrophage populations were characterized by flow cytometry. Immunoblotting for protein expression of NLRP3, ASC and caspase-1 was performed in maternal BMI and age-matched tissue samples. IL-1ß and IL-18 were measured by multiplex ELISA. Placental explants from GDM participants were cultured for 24 h with 1 mM L-ergothioneine (antioxidant) and 1 µM MCC950 (NLRP3 inhibitor). RESULTS: Cf-mtDNA copy numbers were significantly higher in GDM compared to NGT participants (p = 0.002). Placental populations of CD14+ (p = 0.02) and CD14+CD86+CD206- (p = 0.03) macrophages produced significantly increased levels of mitochondrial superoxide in GDM compared to NGT participants. Placental production of IL-18 (p = 0.04) was significantly increased in GDM. This increase in placental IL-18 was attenuated by treatment with 1 µM MCC950 (p = 0.0005), and 1 mM L-ergothioneine (p = 0.007). CONCLUSION: Placental inflammation is significantly increased in women with GDM. Furthermore, this increase may be initiated by elevated production of mitochondrial superoxide by macrophage subpopulations and orchestrated by the NLRP3 inflammasome. The mitochondrial antioxidant, L-ergothioneine, ameliorates NLRP3-induced placental inflammation in GDM, identifying a potential therapeutic role.

Defective Visceral Adipose Tissue Adaptation in Gestational Diabetes Mellitus.

CONTEXT: Gestational diabetes mellitus (GDM) is a complex obstetric condition affecting localized glucose metabolism, resulting in systemic metabolic dysfunction. OBJECTIVE: This cross-sectional study aimed to explore visceral adipose tissue (VAT) as an integral contributor to GDM, focusing on elucidating the specific contribution of obesity and GDM pathology to maternal outcomes. METHODS: Fifty-six nulliparous pregnant women were recruited, including normal glucose tolerant (NGT) (n = 30) and GDM (n = 26) participants. Participants were subgrouped as nonobese (BMI <30 kg/m2) or obese (BMI ≥30 kg/m2). Metabolic markers in circulation, VAT, and placenta were determined. Morphological analysis of VAT and immunoblotting of the insulin signaling cascade were performed. RESULTS: GDM participants demonstrated hyperinsulinemia and elevated homeostatic model assessment for insulin resistance (HOMA-IR) scores relative to NGT participants. The GDM-obese subgroup had significant VAT adipocyte hypoplasia relative to NGT-nonobese tissue. GDM-obese VAT had significantly lower insulin receptor substrate (IRS)-2 expression, with elevated ser312 phosphorylation of IRS-1, relative to NGT-nonobese. GDM-obese participants had significantly elevated circulating leptin levels and placental adipsin secretion, while GDM-nonobese participants had elevated circulating adipsin levels with reduced placental adiponectin secretion. CONCLUSION: These findings suggest that GDM-obese pregnancy is specifically characterized by inadequate VAT remodeling and dysfunctional molecular signaling, which contribute to insulin resistance and hinder metabolic health.

An altered gut microbiome in pre-eclampsia: cause or consequence.

Hypertensive disorders of pregnancy, including pre-eclampsia, are a leading cause of serious and debilitating complications that affect both the mother and the fetus. Despite the occurrence and the health implications of these disorders there is still relatively limited evidence on the molecular underpinnings of the pathophysiology. An area that has come to the fore with regard to its influence on health and disease is the microbiome. While there are several microbiome niches on and within the body, the distal end of the gut harbors the largest of these impacting on many different systems of the body including the central nervous system, the immune system, and the reproductive system. While the role of the microbiome in hypertensive disorders, including pre-eclampsia, has not been fully elucidated some studies have indicated that several of the symptoms of these disorders are linked to an altered gut microbiome. In this review, we examine both pre-eclampsia and microbiome literature to summarize the current knowledge on whether the microbiome drives the symptoms of pre-eclampsia or if the aberrant microbiome is a consequence of this condition. Despite the paucity of studies, obvious gut microbiome changes have been noted in women with pre-eclampsia and the individual symptoms associated with the condition. Yet further research is required to fully elucidate the role of the microbiome and the significance it plays in the development of the symptoms. Regardless of this, the literature highlights the potential for a microbiome targeted intervention such as dietary changes or prebiotic and probiotics to reduce the impact of some aspects of these disorders.

sFlt-1 impairs neurite growth and neuronal differentiation in SH-SY5Y cells and human neurons.

Pre-eclampsia (PE) is a hypertensive disorder of pregnancy which is associated with increased risk of neurodevelopmental disorders in exposed offspring. The pathophysiological mechanisms mediating this relationship are currently unknown, and one potential candidate is the anti-angiogenic factor soluble Fms-like tyrosine kinase 1 (sFlt-1), which is highly elevated in PE. While sFlt-1 can impair angiogenesis via inhibition of VEGFA signalling, it is unclear whether it can directly affect neuronal development independently of its effects on the vasculature. To test this hypothesis, the current study differentiated the human neural progenitor cell (NPC) line ReNcell® VM into a mixed culture of mature neurons and glia, and exposed them to sFlt-1 during development. Outcomes measured were neurite growth, cytotoxicity, mRNA expression of nestin, MBP, GFAP, and ßIII-tubulin, and neurosphere differentiation. sFlt-1 induced a significant reduction in neurite growth and this effect was timing- and dose-dependent up to 100 ng/ml, with no effect on cytotoxicity. sFlt-1 (100 ng/ml) also reduced ßIII-tubulin mRNA and neuronal differentiation of neurospheres. Undifferentiated NPCs and mature neurons/glia expressed VEGFA and VEGFR-2, required for endogenous autocrine and paracrine VEGFA signalling, while sFlt-1 treatment prevented the neurogenic effects of exogenous VEGFA. Overall, these data provide the first experimental evidence for a direct effect of sFlt-1 on neurite growth and neuronal differentiation in human neurons through inhibition of VEGFA signalling, clarifying our understanding of the potential role of sFlt-1 as a mechanism by which PE can affect neuronal development.

Human α-synuclein overexpression upregulates SKOR1 in a rat model of simulated nigrostriatal ageing.

Parkinson's disease (PD) is characterised by progressive loss of dopaminergic (DA) neurons from the substantia nigra (SN) and α-synuclein (αSyn) accumulation. Age is the biggest risk factor for PD and may create a vulnerable pre-parkinsonian state, but the drivers of this association are unclear. It is known that ageing increases αSyn expression in DA neurons and that this may alter molecular processes that are central to maintaining nigrostriatal integrity. To model this, adult female Sprague-Dawley rats received a unilateral intranigral injection of adeno-associated viral (AAV) vector carrying wild-type human αSyn (AAV-αSyn) or control vector (AAV-Null). AAV-αSyn induced no detrimental effects on motor behaviour, but there was expression of human wild-type αSyn throughout the midbrain and ipsilateral striatum at 20 weeks post-surgery. Microarray analysis revealed that the gene most-upregulated in the ipsilateral SN of the AAV-αSyn group was the SKI Family Transcriptional Corepressor 1 (SKOR1). Bioenergetic state analysis of mitochondrial function found that SKOR1 overexpression reduced the maximum rate of cellular respiration in SH-SY5Y cells. Furthermore, experiments in SH-SY5Y cells revealed that SKOR1 overexpression impaired neurite growth to the same extent as αSyn, and inhibited BMP-SMAD-dependent transcription, a pathway that promotes DA neuronal survival and growth. Given the normal influence of ageing on DA neuron loss in human SN, the extent of αSyn-induced SKOR1 expression may influence whether an individual undergoes normal nigrostriatal ageing or reaches a threshold for prodromal PD. This provides new insight into mechanisms through which ageing-related increases in αSyn may influence molecular mechanisms important for the maintenance of neuronal integrity.

Open Reduction and Internal Fixation and Cement-In-Cement Revision for Selected Vancouver B Proximal Femur Periprosthetic Fractures.

The incidence of periprosthetic proximal femoral fractures is increasing with the increase in arthroplasty being performed as well as aging populations. We describe an open reduction and internal fixation and cement-in-cement technique utilizing a well-fixed cement mantle. The advantages of this allow for a shorter operative time, reduction in risk of iatrogenic femoral fractures, and reduction in blood loss. This was a retrospective study reviewing 20 patients that underwent this technique for periprosthetic fractures. Thirty percent (n = 6) of patients underwent subsequent surgery. We had a 95% (n = 19) union rate with 1 case refracturing through the old fracture. This technique can allow for shorter operative times and a lower physiological insult in reducible periprosthetic proximal femur fractures with a stable cement mantle.

Asymmetric Post-Traumatic Knee Arthritis Is Closely Correlated With Both Severity and Time for Lower Limb Coronal Plane Malalignment.

OBJECTIVE: Mechanical alignment of the lower limbs has been suggested to cause abnormal uneven loading across the compartments at the knee, but its contribution to the initiation and progression of arthritis remains controversial. This study aimed to establish whether malalignment of the lower limb after trauma is associated with worsened arthritis scores in the theoretically overloaded compartment, and if arthritis scores continuously correlate with the degree of malalignment and time with deformity. DESIGN: After screening 1160 X-rays, 60 patients were identified with long-leg radiographs > 2 years after fracture. Measurement of mechanical axis deviation (MAD) divided into groups of varus malalignment (n = 16, >16 mm), valgus (n = 25, <0 mm), and normal alignment (n = 19). Alignment and bilateral knee compartmental arthritis scores were recorded by three clinicians, compared via analysis of variance and assessed with linear regression against time since injury using MAD as a covariate. RESULTS: In varus and valgus malalignment, there was a greater mean arthritis score in the "overloaded" compartment compared to the contralateral side, with varus medial Osteoarthritis Research Society International (OARSI) scores 5.17 ± 2.91 vs 3.50 ± 2.72 (P = 0.006) and Kellegren-Lawrence scores 2.65 ± 1.19 vs 1.79 ± 1.24 (P ≤ 0.001). In a linear regression model, OARSI arthritis score was significantly associated with absolute MAD (0.6/10 mm MAD, P < 0.001) and time (0.7/decade, P ≤ 0.001). CONCLUSIONS: Malalignment consistently results in more advanced arthritis scores in the overloaded compartment, most likely related to abnormal loading across the knee. Severity of arthritis using OARSI grading continuously correlates with degree of malalignment and time with deformity after post-traumatic malunion.

Large head metal-on-metal bearing surface with a TMZF titanium alloy femoral stem with high rates of revision and trunnion failure.

Background: Mechanically assisted crevice corrosion at the head-neck interface puts implants at risk of trunnionosis, femoral head dissociation, implant failure and the development of metallosis. Metal-on-Metal bearings have very low wear rates, significantly lower than metal-on-polytethylene, but their wear results in cobalt and chromium ion systemic distribution. This is a study of the MITCH metal-on-metal bearing surface coupled with an Accolade TMZF stem. Methods: This was a retrospective review of 24 total hip replacements 21 patients in that underwent MITCH TRH/Accolade TMZF implantation at a minimum of 12 years post operatively. The primary outcome of this study was all-cause revision with particular attention to revision due to trunnion failure and/or cobalt and chromium ion level. Results: There was a revision rate of 66.7 % (n = 16) at a minimum of twelve years post operatively. Most notably there were six revisions for a gross trunnion failure. Two cases were revised for impending trunnion failure. There were seven cases revised for elevated serum cobalt and chromium levels and one was revised for unexplained pain. Discussion: Patients in our study that underwent TMZF alloy cementless stems coupled with large cobalt chromium alloy heads are at high risk of catastrophic trunnion failure. The high rate of trunnnionosis in this implant combination is thought to be related to a significantly different Young's modulus due to a material mismatch coupled with galvanic corrosion.

Mesenchymal stem cell inhibition of T-helper 17 cell- differentiation is triggered by cell-cell contact and mediated by prostaglandin E2 via the EP4 receptor.

Mesenchymal stem cells (MSCs) inhibit T-cell activation and proliferation but their effects on individual T-cell-effector pathways and on memory versus naïve T cells remain unclear. MSC influence on the differentiation of naïve and memory CD4(+) T cells toward the Th17 phenotype was examined. CD4(+) T cells exposed to Th17-skewing conditions exhibited reduced CD25 and IL-17A expression following MSC co-culture. Inhibition of IL-17A production persisted upon re-stimulation in the absence of MSCs. These effects were attenuated when cell-cell contact was prevented. Th17 cultures from highly purified naïve- and memory-phenotype responders were similarly inhibited. Th17 inhibition by MSCs was reversed by indomethacin and a selective COX-2 inhibitor. Media from MSC/Th17 co-cultures contained increased prostaglandin E2 (PGE2) levels and potently suppressed Th17 differentiation in fresh cultures. MSC-mediated Th17 inhibition was reversed by a selective EP4 antagonist and was mimicked by synthetic PGE2 and a selective EP4 agonist. Activation-induced IL-17A secretion by naturally occurring, effector-memory Th17 cells from a urinary obstruction model was also inhibited by MSC co-culture in a COX-dependent manner. Overall, MSCs potently inhibit Th17 differentiation from naïve and memory T-cell precursors and inhibit naturally-occurring Th17 cells derived from a site of inflammation. Suppression entails cell-contact-dependent COX-2 induction resulting in direct Th17 inhibition by PGE2 via EP4.

Effects of conjugated linoleic acid isomers on monocyte, macrophage and foam cell phenotype in atherosclerosis.

Conjugated linoleic acid (CLA) is a generic term denoting a group of naturally occurring isomers of linoleic acid (18:2, n6) that differ in the position or geometry (i.e. cis or trans) of their double bonds. The predominant isomers in ruminant fats are cis-9,trans-11 CLA (c9,t11-CLA), and trans-10,cis-12 CLA (t10,c12-CLA). The biological activities of CLA have received considerable attention because of its protective effects in cancer, immune function, obesity and atherosclerosis. Importantly, dietary administration of a blend of the two most abundant isomers of CLA, has been shown to inhibit the progression and induce the regression of pre-established atherosclerosis in the ApoE⁻/⁻ murine model. Studies investigating the mechanisms involved in CLA induced protective effects are continually emerging with results from both in vitro and in vivo models yielding confounding and often inconsistent results depending on both the isomer of CLA and the species under investigation. The purpose of this review is to comprehensively discuss the effects of CLA on monocyte/macrophage function in atherosclerosis. This review also discusses the possible mechanisms through which CLA mediates its atheroprotective effects with a particular emphasis on the migratory capacity of the monocyte and the inflammatory and cholesterol homeostasis of the macrophage.

Assessment of previous fracture and anti-osteoporotic medication prescription in hip fracture patients.

INTRODUCTION: Hip fracture prevention is an essential component in elderly patient care. History of prior fracture is a significant risk factor for subsequent hip fracture. There are variable rates of treatment for these groups of patients. The aims of this study were to make an assessment of how many hip fracture patients over a 1 year period had a previous fracture and to assess whether or not these patients were on anti-osteoporotic medication. METHODS: Assessment on whether or not patients had a prior fracture using the national radiology imaging system checking radiology reports for all previous imaging performed. Checking patients bone health status using the hip fracture database for our hospital. RESULTS: There were 225 hip fractures in 221 patients over a 1-year period. About 42.6% of females and 35.9% of males had a history of previous fracture. Vertebral fractures were the most common type of fracture. We found 7% of patients had a contralateral hip fracture. There were 81% of patients with prior fracture, and 71% of those without prior fracture were on anti-osteoporotic medication. DISCUSSION: Vertebral fractures were the most common preceding fracture in hip fracture patients. There were many patients with a history of fragility fractures that were not on preventative medication. Overall there were good prescription rates of anti-osteoporotic medication. There were significantly higher rates of prescription amongst females compared with males.