11β-HSD1 suppresses cardiac fibroblast CXCL2, CXCL5 and neutrophil recruitment to the heart post MI

We have previously demonstrated that neutrophil recruitment to the heart following myocardial infarction (MI) is enhanced in mice lacking 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that regenerates active glucocorticoid within cells from intrinsically inert metabolites. The present study aimed to identify the mechanism of regulation. In a mouse model of MI, neutrophil mobilization to blood and recruitment to the heart were higher in 11β-HSD1-deficient (Hsd11b1(-)(/)(-) ) relative to wild-type (WT) mice, despite similar initial injury and circulating glucocorticoid. In bone marrow chimeric mice, neutrophil mobilization was increased when 11β-HSD1 was absent from host cells, but not when absent from donor bone marrow-derived cells. Consistent with a role for 11β-HSD1 in 'host' myocardium, gene expression of a subset of neutrophil chemoattractants, including the chemokines Cxcl2 and Cxcl5, was selectively increased in the myocardium of Hsd11b1(-)(/)(-) mice relative to WT. SM22α-Cre directed disruption of Hsd11b1 in smooth muscle and cardiomyocytes had no effect on neutrophil recruitment. Expression of Cxcl2 and Cxcl5 was elevated in fibroblast fractions isolated from hearts of Hsd11b1(-)(/)(-) mice post MI and provision of either corticosterone or of the 11β-HSD1 substrate, 11-dehydrocorticosterone, to cultured murine cardiac fibroblasts suppressed IL-1α-induced expression of Cxcl2 and Cxcl5 These data identify suppression of CXCL2 and CXCL5 chemoattractant expression by 11β-HSD1 as a novel mechanism with potential for regulation of neutrophil recruitment to the injured myocardium, and cardiac fibroblasts as a key site for intracellular glucocorticoid regeneration during acute inflammation following myocardial injury

Cardiomyocyte and vascular smooth muscle independent 11β-hydroxysteroid dehydrogenase 1 amplifies infarct expansion, hypertrophy and the development of heart failure following myocardial infarction in male mice

Global deficiency of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), an enzyme that regenerates glucocorticoids within cells, promotes angiogenesis, and reduces acute infarct expansion after myocardial infarction (MI), suggesting that 11β-HSD1 activity has an adverse influence on wound healing in the heart after MI. The present study investigated whether 11β-HSD1 deficiency could prevent the development of heart failure after MI and examined whether 11β-HSD1 deficiency in cardiomyocytes and vascular smooth muscle cells confers this protection. Male mice with global deficiency in 11β-HSD1, or with Hsd11b1 disruption in cardiac and vascular smooth muscle (via SM22α-Cre recombinase), underwent coronary artery ligation for induction of MI. Acute injury was equivalent in all groups. However, by 8 weeks after induction of MI, relative to C57Bl/6 wild type, globally 11β-HSD1-deficient mice had reduced infarct size (34.7 ± 2.1% left ventricle [LV] vs 44.0 ± 3.3% LV, P = .02), improved function (ejection fraction, 33.5 ± 2.5% vs 24.7 ± 2.5%, P = .03) and reduced ventricular dilation (LV end-diastolic volume, 0.17 ± 0.01 vs 0.21 ± 0.01 mL, P = .01). This was accompanied by a reduction in hypertrophy, pulmonary edema, and in the expression of genes encoding atrial natriuretic peptide and β-myosin heavy chain. None of these outcomes, nor promotion of periinfarct angiogenesis during infarct repair, were recapitulated when 11β-HSD1 deficiency was restricted to cardiac and vascular smooth muscle. 11β-HSD1 expressed in cells other than cardiomyocytes or vascular smooth muscle limits angiogenesis and promotes infarct expansion with adverse ventricular remodeling after MI. Early pharmacological inhibition of 11β-HSD1 may offer a new therapeutic approach to prevent heart failure associated with ischemic heart disease

The adult murine heart has a sparse, phagocytically active macrophage population that expands through monocyte recruitment and adopts an ‘M2’ phenotype in response to Th2 immunologic challenge

AbstractTissue resident macrophages have vital homeostatic roles in many tissues but their roles are less well defined in the heart. The present study aimed to identify the density, polarisation status and distribution of macrophages in the healthy murine heart and to investigate their ability to respond to immune challenge. Histological analysis of hearts from CSF-1 receptor (csf1-GFP; MacGreen) and CX3CR1 (Cx3cr1GFP/+) reporter mice revealed a sparse population of GFP positive macrophages that were evenly distributed throughout the left and right ventricular free walls and septum. F4/80+CD11b+ cardiac macrophages, sorted from myocardial homogenates, were able to phagocytose fluorescent beads in vitro and expressed markers typical of both ‘M1’ (IL-1β, TNF and CCR2) and ‘M2’ activation (Ym1, Arg 1, RELMα and IL-10), suggesting no specific polarisation in healthy myocardium. Exposure to Th2 challenge by infection of mice with helminth parasites Schistosoma mansoni, or Heligmosomoides polygyrus, resulted in an increase in cardiac macrophage density, adoption of a stellate morphology and increased expression of Ym1, RELMα and CD206 (mannose receptor), indicative of ‘M2’ polarisation. This was dependent on recruitment of Ly6ChighCCR2+ monocytes and was accompanied by an increase in collagen content.In conclusion, in the healthy heart resident macrophages are relatively sparse and have a phagocytic role. Following Th2 challenge this population expands due to monocyte recruitment and adopts an ‘M2’ phenotype associated with increased tissue fibrosis

How do physiotherapists solicit and explore patients’ concerns in back pain consultations ::a conversation analytic approach

Background: Guidelines advocate that non-specific chronic low back pain (NSCLBP) be considered within a multi-dimensional bio-psychosocial (BPS) framework. This BPS approach advocates incorporating the patient’s perspective as part of the treatment process. ‘Agenda setting’ has been introduced as the key to understanding patients’ concerns in medical encounters; however, this has received little attention in physiotherapy. This study explored how physiotherapists solicit and respond to the agenda of concerns that patients with NSCLBP bring to initial encounters. Method: The research setting was primary care. Twenty initial physiotherapy consultations were video-recorded, transcribed and analyzed using conversation analysis, a qualitative observational method. Both verbal and non-verbal features of the interaction were considered. Results: This data highlights a spectrum of communication styles ranging from more physiotherapist-focused, where the physiotherapists did not attend to patients’ concerns, to a more patient-focused style, which provided greater opportunities for patients to voice their concerns. On occasions, patients were willing to pursue their own agenda when their concern was initially overlooked. Conclusion: This study provides empirical evidence on communication patterns in physiotherapy practice. A more collaborative style of communication with a shared conversational agenda provided patients with the conversational space to describe their concerns more fully

Margin status and tumor recurrence after nephron-sparing surgery for bilateral Wilms tumor

Purpose Nephron-sparing surgery (NSS) has been advocated for patients with bilateral Wilms tumor (BWT). We sought to determine whether margin status impacted local tumor recurrence. Methods A retrospective review of patients undergoing NSS for BWT from November 1999 to March 2009 at our institution in which local recurrence rates based on margin status were compared. Results Of 21 patients, five (23.8%) had positive margins. These and 2 (9.5%) with focal anaplasia received flank XRT. Seven (33%) patients developed recurrent disease, a mean of 18.0 (range 1.3-39.9) months after NSS. Recurrence rates were similar in patients with positive and negative margins (1/5 [20%] vs 6/16 [37.5%]; p = 0.47). Hypertension occurred more frequently in patients who received XRT (57.1% vs 28.6%). At a median follow-up of 28.6 months (range 5.2-142.3), 19 patients are alive, without evidence of disease; one patient (with a positive margin at initial NSS) died of metastatic anaplastic WT and another died of a brain tumor. One patient, with multiple risk factors, developed renal failure. Conclusions In our experience, local recurrence rates after NSS were not affected by surgical margin status although all patients with positive margins received XRT. These results support the aggressive use of NSS for patients with BWT. © 2013 Elsevier Inc

Repeat nephron-sparing surgery for children with bilateral Wilms tumor

Background Renal insufficiency is a significant complication of Wilms tumor treatment in the 5% with bilateral disease. Nephron-sparing surgery (NSS) is recommended after neoadjuvant chemotherapy initially. However, the role of NSS in recurrent disease is unknown. We reviewed our experience to assess the feasibility and oncologic and functional outcomes of repeat NSS for children with recurrent disease. Methods A retrospective review was performed of all children treated at our institution for bilateral, favorable histology (FH) Wilms tumor. Patients undergoing repeat NSS for locally recurrent disease were identified. The outcomes evaluated included tumor recurrence, renal function, and patient survival. Results Since 2001, 36 children with bilateral FH Wilms tumor have been treated at our institution. Eight patients (22%) underwent repeat NSS for locally recurrent disease. Two patients had a second local recurrence and underwent a third NSS. Six patients are alive without disease (75%) with an average follow-up of 4.5 years. Two patients have died, each with blastemal-predominant histology at repeat NSS. The surviving patients have normal renal function, although two patients require medical management of hypertension. Conclusions Our experience suggests that repeat NSS for local recurrence of FH bilateral Wilms tumor is feasible and affords acceptable oncologic outcome with preservation of renal function. However, more aggressive therapy may be required for patients whose recurrence has blastemal-predominant histology, given the poor outcome for these patients in our series. © 2014 Elsevier Inc. All rights reserved

Racial biases in recruitment by accounting firms: the case of international Chinese applicants in Australia

This paper documents the difficulties in finding accounting work faced by international Chinese accounting graduates in Australia in the two years after graduation. We argue that Chinese accounting graduates remain a marginalised group within today’s Australian society. The interview results support this assertion, with even high-achieving Chinese graduates finding it difficult to obtain work with mainstream accounting firms and corporations. The main reasons appear to be their lack of Australian working experience, lack of knowledge of Australian culture, and lack of 'Australian English'. Australian accounting firms, due to a revealed preference to hire white Australian graduates, appear to be missing out on a vast reservoir of Chinese talent. Chinese accounting graduates speak two or three languages and have established business networks in China or at the very least insider knowledge of how that country’s business culture operates. Whilst their sub-cultural capital may be lower on average than white graduates on some conventional measures, it is higher in those areas of bilingual capability and cross-cultural knowledge which are becoming of increasing importance to Australian business

Physiotherapists’ approaches to patients’ concerns in back pain consultations following a psychologically informed training program

Guidelines advocate a combined physical and psychological approach to managing non-specific chronic low back pain (NSCLBP), referred to as psychologically informed practice (PIP). PIP is underpinned by patient-centered principles and skilled communication. Evidence suggests that a physiotherapist-focused style of communication prevails in physiotherapy. There is a recognized need for observational research to identify specific communication practices in physiotherapy interactions. This observational study explored the interactional negotiation of agenda setting following a PIP training intervention, by identifying and describing how physiotherapists solicit and respond to the agenda of concerns that patients with NSCLBP bring to primary care initial encounters. The research setting was primary care. Nineteen initial physiotherapy consultations were video recorded, transcribed, and analyzed using conversation analysis, a qualitative observational method. These data revealed a patient-focused style of communication where trained physiotherapists demonstrated a collaborative and responsive style of verbal and nonverbal communication to solicit, explore, and validate patients’ concerns