11 Beta-hydroxysteroid dehydrogenase type 1 regulates synovitis, joint destruction, and systemic bone loss in chronic polyarthritis.

OBJECTIVE: In rheumatoid arthritis, the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is highly expressed at sites of inflammation, where it converts inactive glucocorticoids (GC) to their active counterparts. In conditions of GC excess it has been shown to be a critical regulator of muscle wasting and bone loss. Here we examine the contribution of 11ß-HSD1 to the pathology of persistent chronic inflammatory disease. METHODS: To determine the contribution of 11ß-HSD1 to joint inflammation, destruction and systemic bone loss associated with persistent inflammatory arthritis, we generated mice with global and mesenchymal specific 11ß-HSD1 deletions in the TNF-transgenic (TNF-tg) model of chronic polyarthritis. Disease severity was determined by clinical scoring. Histology was assessed in formalin fixed sections and fluorescence-activated cell sorting (FACS) analysis of synovial tissue was performed. Local and systemic bone loss were measured by micro computed tomography (micro-CT). Measures of inflammation and bone metabolism were assessed in serum and in tibia mRNA. RESULTS: Global deletion of 11ß-HSD1 drove an enhanced inflammatory phenotype, characterised by florid synovitis, joint destruction and systemic bone loss. This was associated with increased pannus invasion into subchondral bone, a marked polarisation towards pro-inflammatory M1 macrophages at sites of inflammation and increased osteoclast numbers. Targeted mesenchymal deletion of 11ß-HSD1 failed to recapitulate this phenotype suggesting that 11ß-HSD1 within leukocytes mediate its protective actions in vivo. CONCLUSIONS: We demonstrate a fundamental role for 11ß-HSD1 in the suppression of synovitis, joint destruction, and systemic bone loss. Whilst a role for 11ß-HSD1 inhibitors has been proposed for metabolic complications in inflammatory diseases, our study suggests that this approach would greatly exacerbate disease severity.

Multimerin-2 is a ligand for group 14 family C-type lectins CLEC14A, CD93 and CD248 spanning the endothelial pericyte interface.

The C-type lectin domain containing group 14 family members CLEC14A and CD93 are proteins expressed by endothelium and are implicated in tumour angiogenesis. CD248 (alternatively known as endosialin or tumour endothelial marker-1) is also a member of this family and is expressed by tumour-associated fibroblasts and pericytes. Multimerin-2 (MMRN2) is a unique endothelial specific extracellular matrix protein that has been implicated in angiogenesis and tumour progression. We show that the group 14 C-type lectins CLEC14A, CD93 and CD248 directly bind to MMRN2 and only thrombomodulin of the family does not. Binding to MMRN2 is dependent on a predicted long-loop region in the C-type lectin domain and is abrogated by mutation within the domain. CLEC14A and CD93 bind to the same non-glycosylated coiled-coil region of MMRN2, but the binding of CD248 occurs on a distinct non-competing region. CLEC14A and CD248 can bind MMRN2 simultaneously and this occurs at the interface between endothelium and pericytes in human pancreatic cancer. A recombinant peptide of MMRN2 spanning the CLEC14A and CD93 binding region blocks CLEC14A extracellular domain binding to the endothelial cell surface as well as increasing adherence of human umbilical vein endothelial cells to the active peptide. This MMRN2 peptide is anti-angiogenic in vitro and reduces tumour growth in mouse models. These findings identify novel protein interactions involving CLEC14A, CD93 and CD248 with MMRN2 as targetable components of vessel formation.

The role of stromal cells in inflammatory bone loss.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation, local and systemic bone loss and a lack of compensatory bone repair. Fibroblast-like synoviocytes (FLS) are the most abundant cells of the stroma and a key population in autoimmune diseases such as RA. An increasing body of evidence suggests that these cells play not only an important role in chronic inflammation and synovial hyperplasia, but also impact bone remodelling. Under inflammatory conditions FLS release inflammatory cytokines, regulate bone destruction and formation and communicate with immune cells to control bone homeostasis. Other stromal cells, such as osteoblasts and terminally differentiated osteoblasts, termed osteocytes, are also involved in the regulation of bone homeostasis and are dysregulated during inflammation. This review highlights our current understanding of how stromal cells influence the balance between bone formation and bone destruction. Increasing our understanding of these processes is critical to enable the development of novel therapeutic strategies with which to treat bone loss in RA.

Treatment of inflammatory arthritis via targeting of tristetraprolin, a master regulator of pro-inflammatory gene expression.

OBJECTIVES: Tristetraprolin (TTP), a negative regulator of many pro-inflammatory genes, is strongly expressed in rheumatoid synovial cells. The mitogen-activated protein kinase (MAPK) p38 pathway mediates the inactivation of TTP via phosphorylation of two serine residues. We wished to test the hypothesis that these phosphorylations contribute to the development of inflammatory arthritis, and that, conversely, joint inflammation may be inhibited by promoting the dephosphorylation and activation of TTP. METHODS: The expression of TTP and its relationship with MAPK p38 activity were examined in non-inflamed and rheumatoid arthritis (RA) synovial tissue. Experimental arthritis was induced in a genetically modified mouse strain, in which endogenous TTP cannot be phosphorylated and inactivated. In vitro and in vivo experiments were performed to test anti-inflammatory effects of compounds that activate the protein phosphatase 2A (PP2A) and promote dephosphorylation of TTP. RESULTS: TTP expression was significantly higher in RA than non-inflamed synovium, detected in macrophages, vascular endothelial cells and some fibroblasts and co-localised with MAPK p38 activation. Substitution of TTP phosphorylation sites conferred dramatic protection against inflammatory arthritis in mice. Two distinct PP2A agonists also reduced inflammation and prevented bone erosion. In vitro anti-inflammatory effects of PP2A agonism were mediated by TTP activation. CONCLUSIONS: The phosphorylation state of TTP is a critical determinant of inflammatory responses, and a tractable target for novel anti-inflammatory treatments.

Using the STOP-BANG questionnaire to predict hypoxaemia in patients recovering from noncardiac surgery: a prospective cohort analysis.

BACKGROUND: The STOP-BANG questionnaire is a validated, eight-point dichotomized scale used to screen preoperative patients for obstructive sleep apnoea. Sleep apnoea causes hypoxaemia, and nocturnal oxygen desaturation is diagnostic in these patients. We tested the hypothesis that STOP-BANG score is associated with hypoxaemia after noncardiac surgery. METHODS: This analysis was a sub-study of VISION, a prospective cohort study of perioperative cardiovascular events. With institutional review board approval, we included 630 patients in the final analysis. We assessed the association between the STOP-BANG score and postoperative hypoxaemia, defined as integrated area under the curve of [Formula: see text] saturation of 90% per h using median quantile regression. Secondarily, we selected a subset of STOP-BANG questions that best predicts postoperative hypoxaemia using 'Least Absolute Shrinkage and Selection Operator' method, and then assessed the association between the new score based on the selected questions and the primary outcome using quantile regression. RESULTS: The median [q1, q3] area under [Formula: see text] of 90% per h was 0.09 [0.02, 0.39] %-h. The STOP-BANG score was not associated with hypoxaemia, with a multivariable slope coefficient of 0.002 (95% CI: -0.01, 0.01) %-h for a unit increase in the score (P=0.76). Secondarily, no association was found between the new score based on the two retained STOP-BANG questions, treatment for hypertension and neck circumference >40 cm, and the primary outcome with a multivariable slope coefficient of 0.03 (98.3% CI: -0.01, 0.06) %-h/score (P=0.07). CONCLUSIONS: The STOP-BANG score does not predict hypoxaemia in adults recovering from noncardiac surgery. CLINICAL TRIAL REGISTRATION: NCT00512109.

The role of stromal cells in the persistence of chronic inflammation.

Inflammation is an unstable state; it either resolves or persists. Inflammatory reactions often have a propensity for specific anatomical sites. Why inflammation persists with specific tissue tropism remains obscure. Increasing evidence suggests that stromal cells which define tissue architecture are the key cells involved, and therefore make attractive therapeutic targets. Research on stromal cells in general and fibroblasts in particular has so far been hampered by a lack of fibroblast-specific cell markers. This review highlights our increasing understanding of the role of fibroblasts in inflammation, and suggests that these cells provide the cellular basis for site specific chronic inflammation.

Selenium supplementation affects broiler growth performance, meat yield and feather coverage.

(1) Selenium (Se) is an essential part of numerous selenoproteins, most of which are involved in the antioxidant system of the body. It is also required by poultry for the maintenance of optimal health and meat quality. This paper reports data from a study examining the effect of dietary source and concentration of selenium on broiler performance and meat quality. (2) Increased dietary selenium content markedly reduced feed conversion ratio (FCR) as a result of significantly lower feed intakes of birds while maintaining the same weight gains. (3) Selenium supplementation increased feathering, with organic selenium (selenised yeast) being superior to inorganic selenium (sodium selenite). (4) Birds receiving organic selenium in their diets had improved eviscerated weight, breast yield and reduced drip loss. (5) There were significant concentration x source interactions on yields of breasts and marylands (thigh plus drumstick), with elevated levels of organic selenium increasing the yields, whereas the opposite was true for the inorganic selenium.

Baby-Friendly Hospital Initiative. Protecting, promoting, and supporting breastfeeding in the twenty-first century.

The BFHI is a global UNICEF/WHO-sponsored effort to promote breastfeeding by ensuring that all women are provided with sound information regarding their infant feeding choices and that those who elect to breastfeed their infants are given physiologically sound, evidence-based advice and skilled assistance prenatally and as they begin nursing their infants during their postpartum hospital or birth center stay. The initiative is based on ten policy or procedure statements, The Ten Steps, which were jointly developed and published in 1989 by the sponsoring agencies in consultation with international experts. In 1990, the Ten Steps were accepted as the central theme of the Innocenti Declaration and, later that year, endorsed at the World Summit on Children. In 1992, UNICEF and WHO launched a major international campaign to encourage all hospitals with maternity services to accept the Ten Steps as basic maternity and newborn infant care policies and procedures. These Ten Steps were reviewed briefly in this article. Official designation as Baby Friendly requires a careful assessment completed by a trained external team to confirm that the institution is truly carrying out all Ten Steps and conforming to the International Code of Marketing of Breastmilk Substitutes. During the 8 years since the initiative began, more than 15,000 hospitals in 136 countries have been designated as Baby Friendly. Twenty-seven of these officially designated institutions are in the United States, where the campaign has been active only since 1996. The BFHI is considered one of the most successful international efforts ever performed to protect, promote, and support breastfeeding. Although it does not ensure that mothers will aspire to or achieve the widely accepted goal of approximately 6 months of exclusive breastfeeding, it helps mothers to initiate exclusive nursing, an essential step in the right direction.

Lactation management education for physicians.

All health professional groups support breastfeeding as the ideal way to nourish an infant, but numerous surveys have shown that, in general, even perinatal health professionals are not prepared to provide lactation management as part of routine care. Integration of lactation topics into current medical curriculum, whether traditional or problem-based, is the ideal and is possible. Faculty are encouraged to assess the current program for signs of "curriculosclerosis," a prevalent disease characterized by Abrahamson as "hardening of the categories," to look for ways to elasticize the relevant departments, and to integrate lactation management topics at the appropriate place in the larger educational plan. Faculty leadership is crucial. Remedial work, in terms of continuing education, will be necessary for perinatal health professionals until the curriculum model has been in place in preservice and postgraduate programs sufficiently long. Breastfeeding as a primary health care strategy, with its clear health and economic benefits, must be a part of any health care reform and, as such, will be a service expected to be provided by perinatal health professionals.

A study of salicylate and caffeine excretion in the breast milk of two nursing mothers.

Salicylate excretion was studied in the breast milk of a nursing mother (Patient A) taking chronic therapeutic doses of aspirin, and caffeine excretion was monitored in the breast milk of a nursing mother (Patient B) who was a heavy coffee drinker. Salicylate concentrations were maximal in serum at 2.25 hours (10.8 mg/dL) and in milk at 3.00 hours (1.0 mg/dL) following 975 mg of aspirin in Patient A. Caffeine concentrations peaked at 5.50 hours in serum (2.14 micrograms/mL) and at 2.00 hours in milk (1.15 micrograms/mL) during a period of steady coffee drinking by Patient B. Milk:serum concentration ratios ranged up to 0.08 for patient A and up to 0.63 for Patient B, demonstrating that relatively more caffeine than salicylate was excreted into milk. Sodium, potassium, pH, and percent solute remained essentially unchanged in milk samples from both patients throughout the study periods so that changes in the state of hydration of pH of the milk could not be implicated for the observed excretion patterns. More than 25 liters of milk at its peak drug concentration would have to be consumed by the infants of Patients A and B respectively to provide the salicylate content of one aspirin tablet or the caffeine content of an average cup of coffee.