Search

Endogenous glucocorticoids and commonly used oral glucocorticoids have the property of existing in an inactive and active form in vivo. The inactive form can be converted back to the active form, or ‘recycled’ in cells and tissues that express the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme. This recycling provides an important contribution to the action of glucocorticoids. This review examines the literature relating to the importance of 11β-HSD1 activity during glucocorticoid treatment, with an emphasis on studies examining bone and joint disease and the ability of glucocorticoids to suppress inflammatory damage in models of arthritis. Animal models with global or selective deletion of 11β-HSD1 have determined the extent to which this recycling is important in normal physiology and during treatment with oral glucocorticoids. These studies demonstrate that 11β-HSD1-mediated recycling of inactive glucocorticoids has a substantial action and indeed is responsible for the majority of the effects of orally administered glucocorticoids on a range of tissues. Importantly, the anti-inflammatory actions of glucocorticoids appear largely through this mechanism such that mice that lack 11β-HSD1 are resistant to the anti-inflammatory actions of glucocorticoids. The recognition that to a large extent the circulating inactive counterpart of these glucocorticoids is more important to anti-inflammatory effects than the active glucocorticoid presents novel opportunities to more selectively target glucocorticoids to tissues or to reduce the likely side effects. [ABSTRACT FROM AUTHOR]

Prolonged exposure to excessive levels of endogenous or exogenous glucocorticoids is associated with serious clinical features including altered body composition and the development of insulin resistance, impaired glucose tolerance and diabetes. It had been assumed that these adverse effects were mediated by direct effects of glucocorticoids on tissues such as adipose or liver. Recent studies have however indicated that these effects are, at least in part, mediated through the actions of glucocorticoids on bone and specifically the osteoblast. In mice, targeted abrogation of glucocorticoid signalling in osteoblasts significantly attenuated the changes in body composition and systemic fuel metabolism seen during glucocorticoid treatment. Heterotopic expression of osteocalcin in the liver of normal mice was also able to protect against the metabolic changes induced by glucocorticoids indicating that osteocalcin was the likely factor connecting bone osteoblasts to systemic fuel metabolism. Studies are now needed in humans to determine the extent to which glucocorticoid induced changes in body composition and systemic fuel metabolism are mediated through bone. This article is part of a Special Issue entitled Bone and diabetes. [ABSTRACT FROM AUTHOR]

Objectives: Knowledge is limited regarding the adverse effects of therapeutic glucocorticoids on pediatric mental health outcomes. Glucocorticoid-induced psychosis (GIP) is a rare but severe side effect of high-dose glucocorticoid therapy in children and adolescents. This study identified reported pediatric cases of GIP, based on DSM-5 criteria, and defined its presentation, treatments, and outcomes. Methods: A systematic review was completed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, including pediatric patients with incident psychosis following glucocorticoid treatment. Patient demographics, clinical presentation, interventions, outcomes, and long-term management were extracted from individual cases. Results: Of 1131 articles screened, 28 reports were included, comprising of 31 patients. The mean age was 13 years, and 61% of patients were male. The most common medical illnesses requiring administration of high dose glucocorticoids were asthma (23%) and acute lymphoblastic leukemia (23%). The most common glucocorticoid used was prednisone (35%), and most patients (91%) received doses greater than or equal to 40 mg/day of prednisone. The range of time to symptom onset was 1 day to 7 months. Hallucinations alone (45%) were the most reported feature of GIP. Glucocorticoids were discontinued in 52% of cases, reduced in dosage in 32%, and 81% of affected patients were prescribed psychotropic medications. Long-term management plans and prophylactic psychotropic use were not mentioned in 52% of cases. Symptoms resolved in 90% of patients, and the majority (71%) had no recurrence of psychiatric symptoms. Conclusions: GIP can generally be managed by tapering the causative agent with adjunctive second-generation antipsychotics if psychotic symptoms persist. All patients in this review had complete resolution or improvement of their psychotic symptoms; however, there is likely reporting bias due to the expected underreporting of negative outcomes. Managing clinicians must take a circumspect approach when prescribing high-dose glucocorticoids to minimize the risk of serious but preventable side effects. [ABSTRACT FROM AUTHOR]

Objective Several studies suggest that bone mineral density (BMD) is reduced in chronic inflammatory diseases. Higher serum levels of C-reactive protein (CRP) have been associated with lower BMD in women and older adults. However, it is not clear whether this association holds in a representative sample of the general population. The purpose of this study was to examine the relationship between BMD and CRP level in a large representative US population-based sample from the National Health and Nutrition Examination Survey (NHANES). Methods We included participants age ≥20 years with BMD (total and subregions) measured by dual x-ray absorptiometry scans and complete information on covariates from NHANES. The association between CRP level and BMD was evaluated using multivariate linear regression models, adjusting for potential confounders and further adjusting for comorbid diseases, medications, and serum vitamin D levels. Results The study sample included 10,475 participants (53% Caucasian, 22% Mexican American, 18% African American, and 7% other races). Men had higher BMD and lower CRP concentrations than women. BMD (total body BMD as well as subtotal BMD and BMD of the extremities, ribs, and trunk subregions) was inversely associated with quintiles of CRP concentration both in men and in women in a dose-dependent manner (for total BMD, P for trend < 0.0001 for men, P for trend = 0.0005 for women). The associations were independent of medications, comorbidities, and other potential confounders. The results remained largely unchanged with further adjustment for serum vitamin D levels. Conclusion Among men and women in a large representative population-based sample, the CRP level was inversely and independently associated with total BMD in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

Therapeutic glucocorticoids are widely used to treat a variety of inflammatory conditions. However, the beneficial anti-inflammatory effects of glucocorticoids are limited by their detrimental effects on bone, including decreased bone density and increased fracture risk. Glucocorticoids adversely affect bone because they inhibit the amount of bone formed by osteoblasts. Surprisingly, through the expression of the11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme, osteoblasts can generate active glucocorticoids (cortisol and/or prednisolone) from their inactive counterparts (cortisone and/or prednisone). 11β-HSD1 activity in an individual predicts the impact of glucocorticoids on bone. 11β-HSD1 expression within bone also increases with age and inflammation. This implicates locally produced glucocorticoids in age-related and inflammation-associated osteoporosis. Glucocorticoids are also generated by synovial tissue through the expression of 11β-HSD1. Activity increases with joint inflammation and could represent a local anti-inflammatory system. The recognition that peripheral tissues generate glucocorticoids suggests that, for conditions associated with ageing or inflammation, one should consider glucocorticoid activity beyond the circulation. [ABSTRACT FROM AUTHOR]

Abstract: The adrenal gland synthesizes steroid hormones from the adrenal cortex and catecholamines from the adrenal medulla. Both cortisol and adrenal androgens can have powerful effects on bone. The overproduction of cortisol in Cushing’s disease leads to a dramatic reduction in bone density and an increase risk of fracture. Overproduction of adrenal androgens in congenital adrenal hyperplasia (CAH) leads to marked changes in bone growth and development with early growth acceleration but ultimately a significant reduction in final adult height. The role of more physiological levels of glucocorticoids and androgens on bone metabolism is less clear. Cortisol levels measured in elderly individuals show a weak correlation with measures of bone density and change in bone density over time with a high cortisol level associated with lower bone density and more rapid bone loss. Cortisol levels and the dynamics of cortisol secretion change with age which could also explain some age related changes in bone physiology. It is also now clear that adrenal steroids can be metabolized within bone tissue itself. Local synthesis of cortisol within bone from its inactive precursor cortisone has been demonstrated and the amount of cortisol produced within osteoblasts appears to increase with age. With regard to adrenal androgens there is a dramatic reduction in levels with aging and several studies have examined the impact that restoration of these levels back to those seen in younger individuals has on bone health. Most of these studies show small positive effects in women, not men, but the skeletal sites where benefits are seen varies from study to study. [ABSTRACT FROM AUTHOR]

The article presents an overview of the diagnosis and management of hypocalcemia, a potentially life threatening biochemical abnormality that carries risks for serious errors in diagnosis and treatment. A discussion of the prevalence of the disease, of the risk factors and symptoms of the disease, which include neuromuscular excitability in the form of muscle twitching, and of its causes, is presented. The two different types of hypocalcemia, persistent hypocalcemia and acutely presenting hypocalcemia, are discussed. INSET: UNANSWERED QUESTIONS.

Although this study shows that the benefits of corticosteroid therapy are independent of underlying adrenal function in patients with pneumonia, the study doesn't rule out the development of important and potentially treatable adrenal dysfunction in other groups of critically ill patients. In this population of moderate to severely ill patients, none of the diagnostic criteria proposed for conditions such as relative adrenal insufficiency or critical illness-related corticosteroid insufficiency had any value in predicting clinical response to glucocorticoids. Although only the 1mcg ACTH test was used the majority of patients had stimulated cortisol values above the thresholds conventionally used for the diagnosis of adrenal insufficiency in patients evaluated in an outpatient setting. [Extracted from the article]

Cortisone is an endogenous corticosteroid that has negligible intrinsic glucocorticoid activity but can be converted to the active corticosteroid cortisol by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). 11β-HSD1 is expressed in osteoblasts and may play a role in determining susceptibility to glucocorticoid-induced osteoporosis. In intact osteoblasts enzyme activity, and thus cortisol generation, is dependent on substrate concentration with an almost linear increase in activity across the physiological range. We have therefore attempted to measure the impact of 11β-HSD1 activity on bonein vivoby examining the association of circulating cortisone with bone markers, bone mineral density (BMD) and bone loss in a cohort of women and men.Baseline cross-sectional association study involving 135 women and 171 men aged 61–73 years from the Hertfordshire Cohort Study and a 4 year follow-up study examining changes in BMD.Serum cortisone, cortisol and osteocalcin, and urinary type I collagen cross-linked N-telopeptide (NTX) were measured at baseline. BMD at spine and hip was measured at baseline and 4 years later.In men serum cortisone levels were negatively correlated with serum osteocalcin (r =  −0·20,P = 0·01); a similar relationship was seen in women (r =  −0·16,P = 0·06). No correlation was seen between serum cortisone and urinary NTX (r = 0·03,P = 0·74 for women;r = −0·03,P = 0·72 for men). A negative correlation was observed between serum cortisone and spine BMD in women (r = −0·18,P = 0·04); a similar relationship was also seen in men (r = −0·14,P = 0·07). However, cortisone did not correlate with BMD at the femoral neck or total hip or changes in BMD at any site over time. In analyses adjusted for adiposity, osteoarthritis grade and a range of life-style variables, these relationships did not change substantially. All these relationships were independent of cortisol concentrations.The most plausible explanation for the association of circulating cortisone levels with osteocalcin is the presence of 11β-HSD1 activity within osteoblasts. The measurement of serum cortisone may independently give insights into the action of glucocorticoids on bone. [ABSTRACT FROM AUTHOR]

Using mice with targeted deletion of the glucocorticoid receptor, a new study has examined the cell types that mediate the anti-arthritic effects of therapeutic glucocorticoids. Surprisingly, in the serum transfer-induced arthritis model, glucocorticoids target stromal cells rather than immune cells. [ABSTRACT FROM AUTHOR]

Therapeutic glucocorticoids have been widely used in rheumatic diseases since they became available over 60 years ago. Despite the advent of more specific biologic therapies, a notable proportion of individuals with chronic rheumatic diseases continue to be treated with these drugs. Glucocorticoids are powerful, broad-spectrum anti-inflammatory agents, but their use is complicated by an equally broad range of adverse effects. The specific cellular mechanisms by which glucocorticoids have their therapeutic action have been difficult to identify, and attempts to develop more selective drugs on the basis of the action of glucocorticoids have proven difficult. The actions of glucocorticoids seem to be highly cell-type and context dependent. Despite emerging data on the effect of tissue-specific manipulation of glucocorticoid receptors in mouse models of inflammation, the cell types and intracellular targets of glucocorticoids in rheumatic diseases have not been fully identified. Although showing some signs of decline, the use of systemic glucocorticoids in rheumatology is likely to continue to be widespread, and careful consideration is required by rheumatologists to balance the beneficial effects and deleterious effects of these agents. [ABSTRACT FROM AUTHOR]

The article focuses on the study that examines the peripheral aspects of complex regional pain syndrome (CRPS). It contends that a role for nerve injury as an antecedent to CRPS dystonia remains controversial. It argues that the psychosomatic perspectives need to be used to understand the heterogeneous characteristics of CRPS dystonias.

The article focuses on the effect of variation in normal function of thyroid-related hormones within the euthyroid reference range on bone health that may result in fracture. It states that thyroid stimulating hormone (TSH) level is associated with age-adjusted lumbar spine bone mass density (BMD). Variations in thyroid hormone levels may indicate hyperthyroidism and hypothyroidism as explained.

BACKGROUND Hydrocortisone is widely used to treat septic shock in hospitalized patients; nonetheless, the risks and benefits remain debated. OBJECTIVE To assess the efficacy and safety of hydrocortisone therapy for septic shock in a broad spectrum of patients admitted to the intensive care unit (ICU). DESIGN AND INTERVENTION CORTICUS (Corticosteroid Therapy of Septic Shock) was a rnulticenter, double-blind, randomized, placebo-controlled trial of hydrocortisone therapy. Inclusion criteria included age ≥18years, hospitalization in the ICU, clinical signs of infection, systemic response to infection, onset of septic shock within the previous 72 h, and organ dysfunction or hypoperfusion as a result of sepsis. Septic shock was defined as a systolic blood pressure <90mmHg despite fluid replacement or the need for vasopressors for ≥1 h. Exclusion criteria included immunosuppression, life expectancy <24 h and corticosteroid use within the previous 1-6 months. Patients were randomly allocated to receive 50mg hydrocortisone or placebo administered as an intravenous bolus every 6h for 5 days. The dose was then reduced to 50mg every 12 h during days 6-8 and to 50 mg every 24 h during days 9-11. Treatment was stopped after 29 doses. A corticotropin test was performed immediately before and 60min after a 0.25mg intravenous bolus of cosyntropin. Absence of a corticotropin response was defined as an increase in cortisol levels of ≤248 nmol/I. Reversal of shock was defined as maintenance of systolic blood pressure ≥90 mmHg without vasopressor support for ≥24 h. Superinfection was defined as new infection occurring ≥48 h after initiation of the study medication. OUTCOME MEASURES The primary outcome measure was the 28-day mortality rate. Secondary outcome measures included reversal of shock and the incidence and severity of adverse events. RESULTS The study cohort comprised 499 patients, 251 of whom received hydrocortisone. A total of 233 patients did not respond to corticotropin (125 in the hydrocortisone group), whereas 254 patients were responsive (118 in the hydrocortisone group). Test results were unavailable for 12 patients. Among the 96 patients who received etomidate, 58 (60.4%) did not respond to corticotropin, whereas 175 (43.3%) of the patients who did not receive etomidate were unresponsive to corticotropin (P=0.004). No significant differences in mortality were detected between either the two treatment groups or between the corticotropin subgroups within 12 h of baseline and at 28 days. By contrast, increased mortality was observed among patients who received etomidate (P = 0.03). The proportion of patients who underwent reversal of shock was similar in all groups; however, the time to reversal of shock was reduced in the hydrocortisone group, regardless of the response to corticotropin. The hydrocortisone group experienced more episodes of superinfection and new septic shock than the placebo group. CONCLUSION Hydrocortisone therapy did not affect mortality in patients with septic shock. [ABSTRACT FROM AUTHOR]

The author reflects on the approach to osteoporosis screening and treatment. The author comments on the study by Berger and colleagues which has defined the prevalence of osteoporosis in a large number of Canadian women and men. The author suggests that changes are needed in the medical society's approach to osteoporosis screening and treatment with the regards to the developments in medical research.

Accurate measurement of circulating glucocorticoid concentrations in rodents is often hampered by the stress-related activation of the hypothalamic-pituitaryadrenal axis during animal handling. The present study aims to identify methods of blood collection associated with minimal stress and thus artificial increases in plasma glucocorticoid levels. Using two strains of mice, we evaluated common laboratory methods of non-terminal (tail blood sampling with or without restraint; retro-orbital puncture) and terminal blood collection (cardiac puncture) and their immediate and prolonged effect on plasma corticosterone levels. Compared to retro-orbital and cardiac puncture, mice from both the unrestrained and restrained tail snip collection groups displayed the lowest plasma corticosterone levels in both mouse strains. Plasma corticosterone levels in samples obtained from retro-orbital and cardiac puncture collection were up to twenty times higher than those measured in mice undergoing blood collection via tail snip. Repeat tail snip collections (every 30 min for 120 min, or once after 120 min) revealed sustained hypercortisolaemia, compared to the initial collection. We conclude that blood sampling via tail snip without restraint remains the gold-standard method of collection that is associated with minimal stress-related artefacts and hence feasible for single time point corticosterone analyses. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Reduced Cortisol Metabolism During Critical Illness," by E. Boone, H. Vervenne, P. Meersseman and colleagues in the April 18, 2013 issue.

Bone morphogenetic protein (Bmp) signaling has long been known to be important for the early development of the ventral mesoderm, including blood, vasculature and kidney cells. Although Bmp genes are continually expressed in the ventral cells throughout gastrulation and somitogenesis, previous studies in zebrafish have not addressed how the role of Bmp signaling changes over time to regulate ventral mesoderm development. Here, we describe the use of a transgenic inducible dominant-negative Bmp receptor line to examine the temporal roles of Bmp signaling in ventral mesoderm patterning. Surprisingly, we find that Bmp signaling from the mid-gastrula stage through early somitogenesis is important for excluding blood and vascular precursors from the extreme ventral mesoderm, and we show that this domain is normally required for development of the cloaca (the common gut and urogenital opening). Using a novel assay for cloacal function, we find that larvae with reduced mid-gastrula Bmp signaling cannot properly excrete waste. We show that the cloacal defects result from alterations in the morphogenesis of the cloaca and from changes in the expression of genes marking the excretory system. Finally, we show that HrT, a T-box transcription factor, is a Bmp-regulated gene that has an essential function in cloacal development. We conclude that sustained Bmp signaling plays an important role in specification of the zebrafish cloaca by maintaining the fate of extreme ventral cells during the course of gastrulation and early somitogenesis. Furthermore, our data suggest that alterations in Bmp signaling are one possible cause of anorectal malformations during human embryogenesis. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Long-term, high-dose glucocorticoids and bone mineral content in childhood glucocorticoid-sensitive nephrotic syndrome," by M. B. Leonard, H. I. Feldman, J. Shults, B. S. Zemel, B. J. Foster and V. A. Stallings.

Reviews the physiology of the corticosteroid response to acute illness, describes the clinical features of hypoadrenalism in patients with acute illness, and discusses practical issues relating to diagnosis and treatment of corticosteroid insufficiency in acutely ill patients. Idea that an increase in tissue corticosteroid levels during acute illness is an important protective response; Secretion of cortisol from the adrenal cortex in humans; Factors which can impair the normal corticosteroid response during severe illness, including destruction of adrenal tissue by tumors or infection; Clinical features of corticosteroid insufficiency during acute illness.

Objective: Individuals with primary adrenal insufficiency (PAI) or congenital adrenal hyperplasia (CAH) receive life-long glucocorticoid (GC) replacement therapy. Current daily GC doses are still higher than the reported adrenal cortisol production rate. This GC excess could result in long-term morbidities such as osteoporosis. No prospective trials have investigated the long-term effect of GC dose changes in PAI and CAH patients. Methods: This is a prospective and longitudinal study including 57 subjects with PAI (42 women) and 33 with CAH (21 women). Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry at baseline and after 2 years. Subjects were divided into three groups (similar baseline characteristics) depending on changes in daily hydrocortisone equivalent dose (group 1: unchanged 25.2±8.2 mg (mean±S.D., n=50); group 2: increased 18.7±10.3 to 25.9±12.0 mg (n=13); group 3: decreased 30.8±8.5 to 21.4±7.2 mg (n=27)). Results: Subjects in group 1 showed normal lumbar and femoral Z-scores which were unchanged over time. Group 2 subjects showed a significant decrease in femoral neck Z-scores over time (-0.15±1.1 to -0.37±1.0 (P<0.05)), whereas group 3 subjects showed a significant increase in lumbar spine and hip Z-scores (L1-L4: -0.93±1.2 to -0.65±1.5 (P<0.05); total hip: -0.40±1.0 to-0.28±1.0 (P<0.05)). No changes in BMI over time were seen within any group. Reduction in GC dose did not increase the risk of adrenal crisis. Conclusion: This study demonstrates for the first time that cautious reduction in hydrocortisone equivalent doses leads to increases in BMD, whereas dose increments reduced BMD. These data emphasize the need for the lowest possible GC replacement dose in AI patients to maintain health and avoid long-term adverse effects. [ABSTRACT FROM AUTHOR]

Therapeutic glucocorticoids (GCs) are powerful anti-inflammatory tools in the management of chronic inflammatory diseases such as rheumatoid arthritis (RA). However, their actions on bone in this context are complex. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a mediator of the anti-inflammatory actions of therapeutic glucocorticoids (GCs) in vivo. In this study we delineate the role of 11β-HSD1 in the effects of GC on bone during inflammatory polyarthritis. Its function was assessed in bone biopsies from patients with RA and osteoarthritis, and in primary osteoblasts and osteoclasts. Bone metabolism was assessed in the TNF-tg model of polyarthritis treated with oral GC (corticosterone), in animals with global (TNF-tg11βKO), mesenchymal (including osteoblast) (TNF-tg11βflx/tw2cre) and myeloid (including osteoclast) (TNF-tg11βflx/LysMcre) deletion. Bone parameters were assessed by micro-CT, static histomorphometry and serum metabolism markers. We observed a marked increase in 11β-HSD1 activity in bone in RA relative to osteoarthritis bone, whilst the pro-inflammatory cytokine TNFα upregulated 11β-HSD1 within osteoblasts and osteoclasts. In osteoclasts, 11β-HSD1 mediated the suppression of bone resorption by GCs. Whilst corticosterone prevented the inflammatory loss of trabecular bone in TNF-tg animals, counterparts with global deletion of 11β-HSD1 were resistant to these protective actions, characterised by increased osteoclastic bone resorption. Targeted deletion of 11β-HSD1 within osteoclasts and myeloid derived cells partially reproduced the GC resistant phenotype. These data reveal the critical role of 11β-HSD1 within bone and osteoclasts in mediating the suppression of inflammatory bone loss in response to therapeutic GCs in chronic inflammatory disease. [ABSTRACT FROM AUTHOR]

Wound healing is a complex process involving multiple independent and overlapping sequential physiological mechanisms. In addition to cutaneous injury, a severe burn stimulates physiological derangements that induce a systemic hypermetabolic response resulting in impaired wound healing. Topical application of the anti-androgen drug, flutamide accelerates cutaneous wound healing, whereas paradoxically systemic dihydrotestosterone (DHT) improves burn wound healing. We developed and characterized a PCL scaffold that is capable of controlled release of androgen (DHT) and anti-androgen (F) individually or together. This study aims to investigate whether local modification of androgen actions has an impact on burn injury wound healing. In a full-thickness burn wound healing, mouse model, DHT/F-scaffold showed a significantly faster wound healing compared with F-scaffold or DHT-scaffold. Histology analysis confirmed that DHT/Fscaffold exhibited higher re-epithelization, cell proliferation, angiogenesis, and collagen deposition. Dual release of DHT and F from PCL scaffolds promoted cell proliferation of human keratinocytes and alters the keratinocyte cell cycle. Lastly, no adverse effects on androgen-dependent organs, spleen and liver were observed. In conclusion, we demonstrated DHT plus F load PCL scaffolds accelerated burn wound healing when loading alone did not. These findings point to a complex role of androgens in burn wound healing and open novel therapeutic avenues for treating severe burn patients. [ABSTRACT FROM AUTHOR]

Wound healing is a complex process involving multiple independent and overlapping sequential physiological mechanisms. In addition to cutaneous injury, a severe burn stimulates physiological derangements that induce a systemic hypermetabolic response resulting in impaired wound healing. Topical application of the anti‐androgen drug, flutamide accelerates cutaneous wound healing, whereas paradoxically systemic dihydrotestosterone (DHT) improves burn wound healing. We developed and characterized a PCL scaffold that is capable of controlled release of androgen (DHT) and anti‐androgen (F) individually or together. This study aims to investigate whether local modification of androgen actions has an impact on burn injury wound healing. In a full‐thickness burn wound healing, mouse model, DHT/F‐scaffold showed a significantly faster wound healing compared with F‐scaffold or DHT‐scaffold. Histology analysis confirmed that DHT/F‐scaffold exhibited higher re‐epithelization, cell proliferation, angiogenesis, and collagen deposition. Dual release of DHT and F from PCL scaffolds promoted cell proliferation of human keratinocytes and alters the keratinocyte cell cycle. Lastly, no adverse effects on androgen‐dependent organs, spleen and liver were observed. In conclusion, we demonstrated DHT plus F load PCL scaffolds accelerated burn wound healing when loading alone did not. These findings point to a complex role of androgens in burn wound healing and open novel therapeutic avenues for treating severe burn patients. [ABSTRACT FROM AUTHOR]

Endogenous glucocorticoids are implicated in the development and resolution of inflammation. Until recently it was thought that these glucocorticoids arose primarily from the adrenal gland. However, it is now known that several cell types can generate active glucocorticoids within their cytoplasm through expression of the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme. In a more limited range of cell types, glucocorticoids can be inactivated by the related 11β-HSD2 enzyme. Both enzymes are regulated by inflammation in various settings. In rheumatoid arthritis, 11β-HSD activity is present in the inflamed synovium and appears to influence articular and extraarticular disease processes. The generation of active glucocorticoids in the synovium is strongly linked to the level of inflammation. This local production of glucocorticoids is likely to have paracrine consequences and could underpin inflammation-associated bone loss. The role of 11β-HSD enzymes in the severity and persistence of inflammatory arthritis in a clinical setting is currently being explored. [ABSTRACT FROM AUTHOR]

Endogenous glucocorticoids are implicated in the development and resolution of inflammation. Until recently it was thought that these glucocorticoids arose primarily from the adrenal gland. However, it is now known that several cell types can generate active glucocorticoids within their cytoplasm through expression of the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme. In a more limited range of cell types, glucocorticoids can be inactivated by the related 11β-HSD2 enzyme. Both enzymes are regulated by inflammation in various settings. In rheumatoid arthritis, 11β-HSD activity is present in the inflamed synovium and appears to influence articular and extraarticular disease processes. The generation of active glucocorticoids in the synovium is strongly linked to the level of inflammation. This local production of glucocorticoids is likely to have paracrine consequences and could underpin inflammation-associated bone loss. The role of 11β-HSD enzymes in the severity and persistence of inflammatory arthritis in a clinical setting is currently being explored. [ABSTRACT FROM AUTHOR]

Highlights: [•] 11β-HSD enzymes are important regulators of tissue glucocorticoid action. [•] In phase 2 studies specific 11β-HSD1 inhibitors show improvements in the metabolic syndrome. [•] Disrupting glucocorticoid action in osteoblasts attenuates inflammation in experimental arthritis. [•] Glucocorticoid excess can cause metabolic dysfunction though effects on bone. [ABSTRACT FROM AUTHOR]

Ever since the first use of cortisone, glucocorticoids have had a controversial role in the treatment of RA. There has been equally controversial research into the possible involvement of endogenous glucocorticoids, and their secretion via the hypothalamic–pituitary–adrenal (HPA) axis, in the development and persistence of inflammatory arthritis. Recently, our understanding of how glucocorticoids act has expanded substantially with the characterization of glucocorticoid-metabolizing enzymes that regulate glucocorticoid action at tissue level. These enzymes, the 11β-hydroxysteroid dehydrogenases, interconvert biologically inactive glucocorticoids such as cortisone and prednisone with their active counterparts, cortisol (hydrocortisone) and prednisolone. Without these enzymes, cortisone and prednisone would be therapeutically useless. Furthermore, in normal individuals, the activities of these enzymes influence the function of other components of the HPA axis. These enzymes are expressed in human synovial tissue and bone and have been implicated in the control of synovial inflammation, the development of periarticular bone loss and the sensitivity of bone to therapeutic glucocorticoids. This article reviews recent findings in this area that highlight the role of these enzymes in rheumatic diseases. [ABSTRACT FROM PUBLISHER]

Objectives: Observational studies suggest an association between vitamin D deficiency and adverse outcomes of critical illness and identify it as a potential risk factor for the development of lung injury. To determine whether preoperative administration of oral high-dose cholecalciferol ameliorates early acute lung injury postoperatively in adults undergoing elective esophagectomy.Design: A double-blind, randomized, placebo-controlled trial.Setting: Three large U.K. university hospitals.Patients: Seventy-nine adult patients undergoing elective esophagectomy were randomized.Interventions: A single oral preoperative (3-14 d) dose of 7.5 mg (300,000 IU; 15 mL) cholecalciferol or matched placebo.Measurements and Main Results: Primary outcome was change in extravascular lung water index at the end of esophagectomy. Secondary outcomes included PaO2:FIO2 ratio, development of lung injury, ventilator and organ-failure free days, 28 and 90 day survival, safety of cholecalciferol supplementation, plasma vitamin D status (25(OH)D, 1,25(OH)2D, and vitamin D-binding protein), pulmonary vascular permeability index, and extravascular lung water index day 1 postoperatively. An exploratory study measured biomarkers of alveolar-capillary inflammation and injury. Forty patients were randomized to cholecalciferol and 39 to placebo. There was no significant change in extravascular lung water index at the end of the operation between treatment groups (placebo median 1.0 [interquartile range, 0.4-1.8] vs cholecalciferol median 0.4 mL/kg [interquartile range, 0.4-1.2 mL/kg]; p = 0.059). Median pulmonary vascular permeability index values were significantly lower in the cholecalciferol treatment group (placebo 0.4 [interquartile range, 0-0.7] vs cholecalciferol 0.1 [interquartile range, -0.15 to -0.35]; p = 0.027). Cholecalciferol treatment effectively increased 25(OH)D concentrations, but surgery resulted in a decrease in 25(OH)D concentrations at day 3 in both arms. There was no difference in clinical outcomes.Conclusions: High-dose preoperative treatment with oral cholecalciferol was effective at increasing 25(OH)D concentrations and reduced changes in postoperative pulmonary vascular permeability index, but not extravascular lung water index. [ABSTRACT FROM AUTHOR]

Previous studies demonstrated that endogenous glucocorticoid signaling in osteoblasts promotes inflammation in murine immune arthritis. The current study determined whether disruption of endogenous glucocorticoid signaling in chondrocytes also modulates the course and severity of arthritis. Tamoxifen-inducible chondrocyte-targeted glucocorticoid receptor-knockout (chGRKO) mice were generated by breeding GRflox/flox mice with tamoxifen-inducible collagen 2a1 Cre (Col2a1-CreERT2) mice. Antigen-induced arthritis (AIA) and K/BxN serum transfer-induced arthritis (STIA) were induced in both chGRKO mice and their Cre-negative GRflox/flox littermates [wild type (WT)]. Arthritis was assessed by measurement of joint swelling and histology of joints collected at d 14. Neutrophil activity and gene expression patterns associated with cartilage damage were also evaluated. In both arthritis models clinical (joint swelling) and histologic indices of inflammatory activity were significantly greater in chGRKO than in WT mice. The STIA model was characterized by early up-regulation of CXCR2/CXCR2 ligand gene expression in ankle tissues, and significant and selective expansion of splenic CXCR2+ neutrophils in chGRKO arthritic compared to WT arthritic mice. At later stages, gene expression of enzymes involved in cartilage degradation was up-regulated in chGRKO but not WT arthritic mice. Therefore, we summarize that chondrocytes actively mitigate local joint inflammation, cartilage degradation and systemic neutrophil activity via a glucocorticoid-dependent pathway. [ABSTRACT FROM AUTHOR]

Previous studies demonstrated that endogenous glucocorticoid signaling in osteoblasts promotes inflammation in murine immune arthritis. The current study determined whether disruption of endogenous gluco‐corticoid signaling in chondrocytes also modulates the course and severity of arthritis. Tamoxifen‐inducible chondrocyte‐targeted glucocorticoid receptor‐knockout (chGRKO) mice were generated by breeding GRflox/flox mice with tamoxifen‐inducible collagen 2a1 Cre (Col2a1‐CreERT2) mice. Antigen‐induced arthritis (AIA) and K/BxN serum transfer‐induced arthritis (STIA) were induced in both chGRKO mice and their Cre‐negative GRflox/flox littermates [wild type (WT)]. Arthritis was assessed by measurement of joint swelling and histology of joints collected at d 14. Neutrophil activity and gene expression patterns associated with cartilage damage were also evaluated. In both arthritis models clinical (joint swelling) and histologic indices of inflammatory activity were significantly greater in chGRKO than in WT mice. The STIA model was characterized by early up‐regulation of CXCR2/CXCR2 ligand gene expression in ankle tissues, and significant and selective expansion of splenic CXCR2+ neutrophils in chGRKO arthritic compared to WT arthritic mice. At later stages, gene expression of enzymes involved in cartilage degradation was up‐regulated in chGRKO but not WT arthritic mice. Therefore, we summarize that chondrocytes actively mitigate local joint inflammation, cartilage degradation and systemic neutrophil activity via a glucocorticoid‐dependent pathway.—Tu, J., Stoner, S., Fromm, P. D., Wang, T., Chen, D., Tuckermann, J., Cooper, M. S., Seibel, M. J., Zhou, H. Endogenous glucocorticoid signaling in chondrocytes attenuates joint inflammation and damage. FASEB J. 32,478‐487 (2018). www.fasebj.org [ABSTRACT FROM AUTHOR]

Previous studies demonstrated that endogenous glucocorticoid signaling in osteoblasts promotes inflammation in murine immune arthritis. The current study determined whether disruption of endogenous glucocorticoid signaling in chondrocytes also modulates the course and severity of arthritis. Tamoxifen-inducible chondrocyte-targeted glucocorticoid receptor-knockout (chGRKO) mice were generated by breeding GRflox/flox mice with tamoxifen-inducible collagen 2a1 Cre (Col2a1-CreERT2) mice. Antigen-induced arthritis (AIA) and K/BxN serum transfer-induced arthritis (STIA) were induced in both chGRKO mice and their Cre-negative GRflox/flox littermates [wild type (WT)]. Arthritis was assessed by measurement of joint swelling and histology of joints collected at d 14. Neutrophil activity and gene expression patterns associated with cartilage damage were also evaluated. In both arthritis models clinical (joint swelling) and histologic indices of inflammatory activity were significantly greater in chGRKO than in WT mice. The STIA model was characterized by early up-regulation of CXCR2/CXCR2 ligand gene expression in ankle tissues, and significant and selective expansion of splenic CXCR2+ neutrophils in chGRKO arthritic compared to WT arthritic mice. At later stages, gene expression of enzymes involved in cartilage degradation was up-regulated in chGRKO but not WT arthritic mice. Therefore, we summarize that chondrocytes actively mitigate local joint inflammation, cartilage degradation and systemic neutrophil activity via a glucocorticoid-dependent pathway. [ABSTRACT FROM AUTHOR]

Objective: To update the 2008 consensus statements for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in adult and pediatric patients.Participants: A multispecialty task force of 16 international experts in critical care medicine, endocrinology, and guideline methods, all of them members of the Society of Critical Care Medicine and/or the European Society of Intensive Care Medicine.Design/methods: The recommendations were based on the summarized evidence from the 2008 document in addition to more recent findings from an updated systematic review of relevant studies from 2008 to 2017 and were formulated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The strength of each recommendation was classified as strong or conditional, and the quality of evidence was rated from high to very low based on factors including the individual study design, the risk of bias, the consistency of the results, and the directness and precision of the evidence. Recommendation approval required the agreement of at least 80% of the task force members.Results: The task force was unable to reach agreement on a single test that can reliably diagnose CIRCI, although delta cortisol (change in baseline cortisol at 60 min of < 9 μg/dL) after cosyntropin (250 μg) administration and a random plasma cortisol of < 10 μg/dL may be used by clinicians. We suggest against using plasma-free cortisol or salivary cortisol level over plasma total cortisol (conditional, very low quality of evidence). For treatment of specific conditions, we suggest using IV hydrocortisone < 400 mg/day for ≥ 3 days at full dose in patients with septic shock that is not responsive to fluid and moderate- to high-dose vasopressor therapy (conditional, low quality of evidence). We suggest not using corticosteroids in adult patients with sepsis without shock (conditional recommendation, moderate quality of evidence). We suggest the use of IV methylprednisolone 1 mg/kg/day in patients with early moderate to severe acute respiratory distress syndrome (PaO2/FiO2 < 200 and within 14 days of onset) (conditional, moderate quality of evidence). Corticosteroids are not suggested for patients with major trauma (conditional, low quality of evidence).Conclusions: Evidence-based recommendations for the use of corticosteroids in critically ill patients with sepsis and septic shock, acute respiratory distress syndrome, and major trauma have been developed by a multispecialty task force. [ABSTRACT FROM AUTHOR]

Objective: To provide a narrative review of the latest concepts and understanding of the pathophysiology of critical illness-related corticosteroid insufficiency (CIRCI).Participants: A multi-specialty task force of international experts in critical care medicine and endocrinology and members of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine.Data Sources: Medline, Database of Abstracts of Reviews of Effects (DARE), Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews.Results: Three major pathophysiologic events were considered to constitute CIRCI: dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, altered cortisol metabolism, and tissue resistance to glucocorticoids. The dysregulation of the HPA axis is complex, involving multidirectional crosstalk between the CRH/ACTH pathways, autonomic nervous system, vasopressinergic system, and immune system. Recent studies have demonstrated that plasma clearance of cortisol is markedly reduced during critical illness, explained by suppressed expression and activity of the primary cortisol-metabolizing enzymes in the liver and kidney. Despite the elevated cortisol levels during critical illness, tissue resistance to glucocorticoids is believed to occur due to insufficient glucocorticoid alpha-mediated anti-inflammatory activity.Conclusions: Novel insights into the pathophysiology of CIRCI add to the limitations of the current diagnostic tools to identify at-risk patients and may also impact how corticosteroids are used in patients with CIRCI. [ABSTRACT FROM AUTHOR]

The article discusses the use of the mechanical realignment of the jaws and temporomandibular joints (TMJs) to suppress movement disorders. It says that more than 20% of adult have TMJ internal derangement which occurs during the displacement of the cartilaginous disc on the superior surface of the condyle. It also states that magnetic resonance image of the TMJ is recommended to determine the presence of TMJ dysfunction.

Rationale: Vitamin D deficiency has been implicated as a pathogenic factor in sepsis and intensive therapy unit mortality but has not been assessed as a risk factor for acute respiratory distress syndrome (ARDS). Causality of these associations has never been demonstrated. Objectives: To determine if ARDS is associated with vitamin D deficiency in a clinical setting and to determine if vitamin D deficiency in experimental models of ARDS influences its severity. Methods: Human, murine and in vitro primary alveolar epithelial cell work were included in this study. Findings: Vitamin D deficiency (plasma 25(OH)D levels <50 nmol/L) was ubiquitous in patients with ARDS and present in the vast majority of patients at risk of developing ARDS following oesophagectomy. In a murine model of intratracheal lipopolysaccharide challenge, dietary-induced vitamin D deficiency resulted in exaggerated alveolar inflammation, epithelial damage and hypoxia. In vitro, vitamin D has trophic effects on primary human alveolar epithelial cells affecting >600 genes. In a clinical setting, pharmacological repletion of vitamin D prior to oesophagectomy reduced the observed changes of in vivo measurements of alveolar capillary damage seen in deficient patients. Conclusions: Vitamin D deficiency is common in people who develop ARDS. This deficiency of vitamin D appears to contribute to the development of the condition, and approaches to correct vitamin D deficiency in patients at risk of ARDS should be developed. [ABSTRACT FROM AUTHOR]

States of glucocorticoid excess are associated with defects in chondrocyte function. Most prominently there is a reduction in linear growth but delayed healing of fractures that require endochondral ossification to also occur. In contrast, little is known about the role of endogenous glucocorticoids in chondrocyte function. As glucocorticoids exert their cellular actions through the glucocorticoid receptor (GR), we aimed to elucidate the role of endogenous glucocorticoids in chondrocyte function in vivo through characterization of tamoxifen-inducible chondrocyte-specific GR knockout (chGRKO) mice in which the GR was deleted at various post-natal ages. Knee joint architecture, cartilage structure, growth plates, intervertebral discs, long bone length and bone micro-architecture were similar in chGRKO and control mice at all ages. Analysis of fracture healing in chGRKO and control mice demonstrated that in metaphyseal fractures, chGRKO mice formed a larger cartilaginous callus at 1 and 2 week post-surgery, as well as a smaller amount of well-mineralized bony callus at the fracture site 4 week post-surgery, when compared to control mice. In contrast, chondrocyte-specific GR knockout did not affect diaphyseal fracture healing. We conclude that endogenous GC signaling in chondrocytes plays an important role during metaphyseal fracture healing but is not essential for normal long bone growth. [ABSTRACT FROM AUTHOR]

Glucocorticoid (GC) excess adversely affects skin integrity, inducing thinning and impaired wound healing. Aged skin, particularly that which has been photo-exposed, shares a similar phenotype. Previously, we demonstrated age-induced expression of the GC-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in cultured human dermal fibroblasts (HDFs). Here, we determined 11β-HSD1 levels in human skin biopsies from young and older volunteers and examined the aged 11β-HSD1 KO mouse skin phenotype. 11β-HSD1 activity was elevated in aged human and mouse skin and in PE compared with donor-matched photo- protected human biopsies. Age-induced dermal atrophy with deranged collagen structural organization was prevented in 11β-HSD1 KO mice, which also exhibited increased collagen density. We found that treatment of HDFs with physiological concentrations of cortisol inhibited rate-limiting steps in collagen biosynthesis and processing. Furthermore, topical 11β-HSD1 inhibitor treatment accelerated healing of full-thickness mouse dorsal wounds, with improved healing also observed in aged 11β-HSD1 KO mice. These findings suggest that elevated 11β-HSD1 activity in aging skin leads to increased local GC generation, which may account for adverse changes occurring in the elderly, and 11β-HSD1 inhibitors may be useful in the treatment of age-associated impairments in dermal integrity and wound healing. [ABSTRACT FROM AUTHOR]

Objective CD248 (tumor endothelial marker 1/endosialin) is found on stromal cells and is highly expressed during malignancy and inflammation. Studies have shown a reduction in inflammatory arthritis in CD248-knockout (CD248−/−) mice. The aim of the present study was to investigate the functional effect of genetic deletion of CD248 on bone mass. Methods Western blotting, polymerase chain reaction, and immunofluorescence were used to investigate the expression of CD248 in humans and mice. Micro-computed tomography and the 3-point bending test were used to measure bone parameters and mechanical properties of the tibiae of 10-week-old wild-type (WT) or CD248−/− mice. Human and mouse primary osteoblasts were cultured in medium containing 10 m M β-glycerophosphate and 50 μg/ml ascorbic acid to induce mineralization, and then treated with platelet-derived growth factor BB (PDGF-BB). The mineral apposition rate in vivo was calculated by identifying newly formed bone via calcein labeling. Results Expression of CD248 was seen in human and mouse osteoblasts, but not osteoclasts. CD248−/− mouse tibiae had higher bone mass and superior mechanical properties (increased load required to cause fracture) compared to WT mice. Primary osteoblasts from CD248−/− mice induced increased mineralization in vitro and produced increased bone over 7 days in vivo. There was no decrease in bone mineralization and no increase in proliferation of osteoblasts in response to stimulation with PDGF-BB, which could be attributed to a defect in PDGF signal transduction in the CD248−/− mice. Conclusion There is an unmet clinical need to address rheumatoid arthritis-associated bone loss. Genetic deletion of CD248 in mice results in high bone mass due to increased osteoblast-mediated bone formation, suggesting that targeting CD248 in rheumatoid arthritis may have the effect of increasing bone mass in addition to the previously reported effect of reducing inflammation. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is a primary malignant tumour of bone occurring predominantly in children and young adults. Despite chemotherapy, relapse is common and mortality remains high. Nontransformed osteoblasts are highly sensitive to glucocorticoids, which reduce proliferation and induce apoptosis. Previously, we observed that OS cells, but not normal osteoblasts, express 11b-hydroxysteroid dehydrogenase type 2 (11&bgr;-HSD2). This enzyme inactivates cortisol (active) to cortisone (inactive) and expression of 11&bgr;-HSD2 renders OS cells resistant to glucocorticoids. By contrast, the related enzyme 11&bgr;-HSD1 converts cortisone to cortisol and reduces OS cell proliferation in vitro. Some synthetic glucocorticoids (e.g. dehydrodexamethasone (DHD), inactive counterpart of dexamethasone (DEX)) have been reported to be activated by 11&bgr;-HSD2. We therefore investigated expression and enzymatic activity of 11&bgr;-HSD isozymes in human OS tissue, determined whether 11&bgr;-HSD expression has prognostic value in the response to therapy, and evaluated the potential use of synthetic glucocorticoids to selectively target OS cells. OS samples expressed both 11&bgr;-HSD1 and 11&bgr;-HSD2. 11&bgr;-HSD1 expression in pretreatment biopsy specimens positively correlated with primary tumour size. Expression and activity of 11&bgr;-HSD1 in post-treatment biopsies were unrelated to the degree of tumour necrosis following chemotherapy. However, high 11&bgr;-HSD2 expression in post-treatment biopsies correlated with a poor response to therapy. OS cells that expressed 11&bgr;-HSD2 inactivated endogenous glucocorticoids; but these cells were also able to generate DEX from DHD. These results suggest that OS treatment response is related to 11&bgr;-HSD2 enzyme expression. Furthermore,OScells expressing this enzyme could be targeted by treatment with synthetic glucocorticoids that are selectively reactivated by the enzyme. [ABSTRACT FROM AUTHOR]

Objective Tissue glucocorticoid (GC) levels are regulated by the GC-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). This enzyme is expressed in cells and tissues arising from mesenchymal stromal cells. Proinflammatory cytokines dramatically increase expression of 11β-HSD1 in stromal cells, an effect that has been implicated in inflammatory arthritis, osteoporosis, obesity, and myopathy. Additionally, GCs act synergistically with proinflammatory cytokines to further increase enzyme expression. The present study was undertaken to investigate the mechanisms underlying this regulation. Methods Gene reporter analysis, rapid amplification of complementary DNA ends (RACE), chemical inhibition experiments, and genetic disruption of intracellular signaling pathways in mouse embryonic fibroblasts (MEFs) were used to define the molecular mechanisms underlying the regulation of 11β-HSD1 expression. Results Gene reporter, RACE, and chemical inhibitor studies demonstrated that the increase in 11β-HSD1 expression with tumor necrosis factor α (TNFα)/interleukin-1β (IL-1β) occurred via the proximal HSD11B1 gene promoter and depended on NF-κB signaling. These findings were confirmed using MEFs with targeted disruption of NF-κB signaling, in which RelA (p65) deletion prevented TNFα/IL-1β induction of 11β-HSD1. GC treatment did not prevent TNFα-induced NF-κB nuclear translocation. The synergistic enhancement of TNFα-induced 11β-HSD1 expression with GCs was reproduced by specific inhibitors of p38 MAPK. Inhibitor and gene deletion studies indicated that the effects of GCs on p38 MAPK activity occurred primarily through induction of dual-specificity phosphatase 1 expression. Conclusion The mechanism by which stromal cell expression of 11β-HSD1 is regulated is novel and distinct from that in other tissues. These findings open new opportunities for development of therapeutic interventions aimed at inhibiting or stimulating local GC levels in cells of mesenchymal stromal lineage during inflammation. [ABSTRACT FROM AUTHOR]

Glucocorticoids provide indispensable anti-inflammatory therapies. However, metabolic adverse effects including muscle wasting restrict their use. The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) modulates peripheral glucocorticoid responses through pre-receptor metabolism. This study investigates how 11β-HSD1 influences skeletal muscle responses to glucocorticoid therapy for chronic inflammation. We assessed human skeletal muscle biopsies from patients with rheumatoid arthritis and osteoarthritis for 11β-HSD1 activity ex vivo. Using the TNF-α-transgenic mouse model (TNF-tg) of chronic inflammation, we examined the effects of corticosterone treatment and 11β-HSD1 global knock-out (11βKO) on skeletal muscle, measuring anti-inflammatory gene expression, muscle weights, fiber size distribution, and catabolic pathways. Muscle 11β-HSD1 activity was elevated in patients with rheumatoid arthritis and correlated with inflammation markers. In murine skeletal muscle, glucocorticoid administration suppressed IL6 expression in TNF-tg mice but not in TNF-tg11βKO mice. TNF-tg mice exhibited reductions in muscle weight and fiber size with glucocorticoid therapy. In contrast, TNF-tg11βKO mice were protected against glucocorticoid-induced muscle atrophy. Glucocorticoid-mediated activation of catabolic mediators (FoxO1, Trim63) was also diminished in TNF-tg11βKO compared to TNF-tg mice. In summary, 11β-HSD1 knock-out prevents muscle atrophy associated with glucocorticoid therapy in a model of chronic inflammation. Targeting 11β-HSD1 may offer a strategy to refine the safety of glucocorticoids. [ABSTRACT FROM AUTHOR]

To assess the relationship between interstitial capillary density and interstitial macrophages we prospectively measured these factors in situ in 110 patients with chronic kidney disease. Macrophage numbers and urinary MCP-1/CCL2 levels significantly correlated inversely with capillary density which itself significantly correlated inversely with chronic damage and predicted disease progression. In 54 patients with less than 20% chronic damage, there was a significant correlation between the urinary albumin to creatinine ratio and MCP-1/CCL2, and MCP-1/CCL2 and macrophages but not between MCP-1/CCL2 and capillary density. Conversely, in 56 patients with over 20% chronic damage there was no correlation between MCP-1/CCL2 and macrophages but there were significant inverse correlations between capillary density and both macrophages and chronic damage. The expression of VEGF mRNA significantly correlated with macrophage infiltration, capillary density and chronic scarring. In an ischemic-hypertensive subgroup there was upregulation of the hypoxia marker carbonic anhydrase IX and with over 20% chronic damage an increased macrophage to CCR2 ratio. Our study shows that proteinuria and MCP-1/CCL2 are important for macrophage recruitment in early disease. As renal scarring evolves, alternative pathways relating to progressive tissue ischemia secondary to obliteration of the interstitial capillary bed predominate.Kidney International (2008) 74, 495–504; doi:10.1038/ki.2008.183; published online 4 June 2008 [ABSTRACT FROM AUTHOR]

Microsomal glucose-6-phosphatase-α (G6Pase-α) and glucose 6-phosphate transporter (G6PT) work together to increase blood glucose concentrations by performing the terminal step in both glycogenolysis and gluconeogenesis. Deficiency of the G6PT in liver gives rise to glycogen storage disease type 1b (GSD1b), whereas deficiency of G6Pase-α leads to GSD1a. G6Pase-α shares its substrate (glucose 6-phosphate; G6P) with hexose-6-phosphate-dehydrogenase (H6PDH), a microsomal enzyme that regenerates NADPH within the endoplasmic reticulum lumen, thereby conferring reductase activity upon 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). 11β-HSD1 interconverts hormonally active C11β-hydroxy steroids (cortisol in humans and corticosterone in rodents) to inactive C11-oxo steroids (cortisone and 11-dehydrocorticosterone, respectively). In vivo reductase activity predominates, generating active glucocorticoid. We hypothesized that substrate (G6P) availability to H6PDH in patients with GSD1b and GSD1a will decrease or increase 11β-HSD1 reductase activity, respectively. We investigated 11β-HSD1 activity in GSD1b and GSD1a mice and in two patients with GSD1b and five patients diagnosed with GSD1a. We confirmed our hypothesis by assessing 11β-HSD1 in vivo and in vitro, revealing a significant decrease in reductase activity in GSD1b animals and patients, whereas GSD1a patients showed a marked increase in activity. The cellular trafficking of G6P therefore directly regulates 11β-HSD1 reductase activity and provides a novel link between glucose metabolism and function of the hypothalamo-pituitary-adrenal axis. [ABSTRACT FROM AUTHOR]

Androgens have been known to inhibit cutaneous wound healing in men and male mice. However, in children with major burn injuries, a synthetic androgen was reported clinically to improve wound healing. The aim of this study is to investigate the role of dihydrotestosterone (DHT) as a new therapeutic approach in treating major burn injury. In the present study, mice received systemic androgen treatment post major burn injury. Wound healing rate and body weight were monitored over 21 days. The serum level of inflammatory cytokines/chemokines were measured using multiplex immunoassays. In addition, splenocyte enumeration was performed by flow cytometry. Healing phases of inflammation, re-epithelialization, cell proliferation and collagen deposition were also examined. In results, DHT treated mice lost less weight and displayed accelerated wound healing but has no impact on hypermetabolism. Mice, after burn injury, displayed acute systemic inflammatory responses over 21 days. DHT treatment shortened the systemic inflammatory response with reduced splenic weight and monocyte numbers on day 14 and 21. DHT treatment also reduced wound infiltrating macrophage numbers. In conclusion, DHT treatment facilitates local wound healing by accelerating the resolution of inflammation, but not through alterations of post-burn hypermetabolic response. [ABSTRACT FROM AUTHOR]

To update the 2008 consensus statements for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in adult and pediatric patients. [ABSTRACT FROM AUTHOR]

Background: Acute lung injury occurs in approximately 25% to 30% of subjects undergoing oesophagectomy. Experimental studies suggest that treatment with vitamin D may prevent the development of acute lung injury by decreasing inflammatory cytokine release, enhancing lung epithelial repair and protecting alveolar capillary barrier function.Methods/design: The 'Vitamin D to prevent lung injury following oesophagectomy trial' is a multi-centre, randomised, double-blind, placebo-controlled trial. The aim of the trial is to determine in patients undergoing elective transthoracic oesophagectomy, if pre-treatment with a single oral dose of vitamin D3 (300,000 IU (7.5 mg) cholecalciferol in oily solution administered seven days pre-operatively) compared to placebo affects biomarkers of early acute lung injury and other clinical outcomes. The primary outcome will be change in extravascular lung water index measured by PiCCO® transpulmonary thermodilution catheter at the end of the oesophagectomy. The trial secondary outcomes are clinical markers indicative of lung injury: PaO2:FiO2 ratio, oxygenation index; development of acute lung injury to day 28; duration of ventilation and organ failure; survival; safety and tolerability of vitamin D supplementation; plasma indices of endothelial and alveolar epithelial function/injury, plasma inflammatory response and plasma vitamin D status. The study aims to recruit 80 patients from three UK centres.Discussion: This study will ascertain whether vitamin D replacement alters biomarkers of lung damage following oesophagectomy.Trial Registration: Current Controlled Trials ISRCTN27673620. [ABSTRACT FROM AUTHOR]