The Characteristics of Accepted Work-related Injuries and Diseases Claims in the Australian Coal Mining Industry.

Background: Coal mining is a hazardous industry. The purpose of the study is to identify the nature of occupational injuries and diseases among coal miners and to determine the factors that affect the rate of injury and duration of time loss from work. Methods: A retrospective cohort study was conducted using accepted workers' compensation claims data of 30,390 Australian coal miners between July 2003 and June 2017. Results: Musculoskeletal and fracture conditions accounted for approximately 60% of claims in all occupational groups. Cox regression analysis showed that older age and female gender were significant predictors of longer time off work. Injury types and occupations were associated with work time loss: mental health conditions, and machine operators and drivers had significantly longer durations of time off work. Conclusion: Future research can further address how these factors led to longer time off work so that coal industry regulators, employers, and healthcare providers can target interventions more effectively to these at-risk workers.

The Characteristics of Accepted Work-related Injuries and Diseases Claims in the Australian Coal Mining Industry

Background@#Coal mining is a hazardous industry. The purpose of the study is to identify the nature of occupational injuries and diseases among coal miners and to determine the factors that affect the rate of injury and duration of time loss from work. @*Methods@#A retrospective cohort study was conducted using accepted workers' compensation claims data of 30,390 Australian coal miners between July 2003 and June 2017. @*Results@#Musculoskeletal and fracture conditions accounted for approximately 60% of claims in all occupational groups. Cox regression analysis showed that older age and female gender were significant predictors of longer time off work. Injury types and occupations were associated with work time loss: mental health conditions, and machine operators and drivers had significantly longer durations of time off work. @*Conclusion@#Future research can further address how these factors led to longer time off work so that coal industry regulators, employers, and healthcare providers can target interventions more effectively to these at-risk workers.

Flightless I Alters the Inflammatory Response and Autoantibody Profile in an OVA-Induced Atopic Dermatitis Skin-Like Disease.

Atopic dermatitis (AD) is a chronic pruritic inflammatory skin disease characterized by excessive inflammation and disrupted skin barrier function. Although the etiology of AD is not completely understood, clinical and basic studies suggest increasing involvement of autoantibodies against intracellular proteins. An actin remodeling protein, Flightless I (Flii), has been shown to promote development of inflammatory mediated skin conditions and impairment of skin barrier development and function. Here, we sought to determine the effect of altering Flii expression on the development of AD and its contribution to autoimmune aspects of inflammatory skin conditions. Ovalbumin (OVA)-induced AD skin-like disease was induced in Flii heterozygous (Flii+/- ), wild-type (Flii+/+ ), and Flii transgenic (FliiTg/Tg ) mice by epicutaneous exposure to OVA for 3 weeks; each week was separated by 2-week resting period. Reduced Flii expression resulted in decreased disease severity and tissue inflammation as determined by histology, lymphocytic, and mast cell infiltrate and increased anti-inflammatory IL-10 cytokine levels and a marked IFN-γ Th1 response. In contrast, Flii over-expression lead to a Th2 skewed response characterized by increased pro-inflammatory TNF-α cytokine production, Th2 chemokine levels, and Th2 cell numbers. Sera from OVA-induced AD skin-like disease Flii+/- mice showed a decreased level of autoreactivity while sera from FliiTg/Tg mice counterparts showed an altered autoantibody profile with strong nuclear localization favoring development of a more severe disease. These findings demonstrate autoimmune responses in this model of OVA-induced AD-like skin disease and suggest that Flii is a novel target, whose manipulation could be a potential approach for the treatment of patients with AD.

Genomic stability of pulmonary artery endothelial colony-forming cells in culture.

Pulmonary vascular remodeling, including proliferation and migration of pulmonary artery endothelial cells (PAEC), is a pathologic hallmark of pulmonary arterial hypertension (PAH). Multiple studies have shown evidence of increased levels of DNA damage and lineage-specific genetic changes in PAH lung vascular cells, suggesting increased genomic instability. Highly proliferative endothelial colony-forming cell (ECFC) clones can be isolated from PAEC. Here we utilized ECFC to track chromosomal copy number of 20 PAH and eight control clones across serial passages using genome-wide microarrays. All PAH clones were genomically stable for at least 20-22 population doublings. At very late passages, ECFC developed a highly aneuploid karyotype, but this was generally associated with senescence and was common to both PAH and controls. We also utilized ECFC to isolate the chromosomally abnormal cells from a mixed population of PAH PAEC. Analysis of PAEC harboring two different changes affecting chromosomes 1 and X demonstrated that both abnormalities were present in the same clone, indicating they originated in a common ancestral cell. In a second case, with a partial duplication of chromosome 17, clones carrying the duplication were more frequent at later passages than chromosomally normal clones from the same PAEC culture, suggesting the rearrangement may confer a proliferative advantage. Overall, this small study suggests that endothelial cells from PAH lungs are stable in culture, but that when chromosome abnormalities do occur, they may confer a selective advantage that allows expansion of the abnormal cell population and could contribute to lung vascular remodeling in vivo.

Establishment of transplantation tolerance via minimal conditioning in aged recipients.

Mixed hematopoietic chimerism is a powerful means of generating donor-specific tolerance, allowing long-term graft acceptance without lifelong dependence on immunosuppressive drugs. To avoid the need for whole body irradiation and associated side effects, we utilized a radiation-free minimal conditioning regime to induce long-term tolerance across major histocompatibility barriers. We found that low-dose busulfan, in combination with host T cell depletion and short-term sirolimus-based immunosuppression, facilitated efficient donor engraftment. Tolerance was achieved when mice were transplanted with whole or T cell-depleted bone marrow, or purified progenitor cells. Tolerance induction was associated with an expansion in regulatory T cells and was not abrogated in the absence of a thymus, suggesting a dominant or compensatory peripheral mode of tolerance. Importantly, we were able to generate durable chimerism and tolerance to donor skin grafts in both young and aged mice, despite age-related thymic atrophy and immune senescence. Clinically, this is especially relevant as the majority of transplant recipients are older patients whose immune recovery might be dangerously slow and would benefit from radiation-free minimal conditioning regimes that allow efficient donor engraftment without fully ablating the recipient immune system.

A quantitative analysis of diabetic retinopathy screening in a regional treatment centre.

The aim of the study was to assess the current diabetic retinopathy screening infrastructure and implications on workload for a designated treatment centre following roll-out of a national screening programme. A combination of chart analysis and patient questionnaire was undertaken over a 4-week period in 2011 at Cork University Hospital (CUH). Data were collected on 97 patients and categorized. as demographic, medical, and screening-related. The majority of patients (80; 82.5%} had either no retinopathy or background retinopathy only. One (1.0%) patient was deemed to be ungradable due to dense cataract, while 6 (6.2%) patients had non-diabetic ocular pathology requiring follow-up. Only 11% were screened through retinal photography. In all, 74 (76.3%) patients were deemed suitable for community rather than hospital screening. Digital retinal photography is an underused screening resource Significant numbers of patients could be discharged from hospital-based to community screening to offset the increased workload expected from the national screening programme.

Lifting the silver flakes: the pathogenesis and management of chronic plaque psoriasis.

Psoriasis is a common chronic inflammatory skin condition in which patients suffer from mild to chronic plaque skin plaques. The disease manifests through an excessive inflammatory response in the skin due to complex interactions between different genetic and environmental factors. Psoriasis can affect the physical, emotional, and psychosocial well-being of patients, and currently there is no cure with treatments focusing primarily on the use of anti-inflammatory agents to control disease symptoms. Traditional anti-inflammatory agents can cause immunosuppression and adverse systemic effects. Further understanding of the disease has led to current areas of research aiming at the development of selective molecular targets to suppress the pathogenic immune responses.

Pro-angiogenic hematopoietic progenitor cells and endothelial colony-forming cells in pathological angiogenesis of bronchial and pulmonary circulation.

Dysregulation of angiogenesis is a common feature of many disease processes. Vascular remodeling is believed to depend on the participation of endothelial progenitor cells, but the identification of endothelial progenitors in postnatal neovascularization remains elusive. Current understanding posits a role for circulating pro-angiogenic hematopoietic cells that interact with local endothelial cells to establish an environment that favors angiogenesis in physiologic and pathophysiologic responses. In the lung, increased and dysregulated angiogenesis is a hallmark of diseases of the bronchial and pulmonary circulations, manifested by asthma and pulmonary arterial hypertension (PAH), respectively. In asthma, T(Helper)-2 immune cells produce angiogenic factors that mobilize and recruit pro-inflammatory and pro-angiogenic precursors from the bone marrow into the airway wall where they induce angiogenesis and fuel inflammation. In contrast, in PAH, upregulation of hypoxia-inducible factor (HIF) in vascular cells leads to the production of bone marrow-mobilizing factors that recruit pro-angiogenic progenitor cells to the pulmonary circulation where they contribute to angiogenic remodeling of the vessel wall. This review focuses on current knowledge of pro-angiogenic progenitor cells in the pathogenesis of asthma and PAH.

Pulmonary artery endothelium resident endothelial colony-forming cells in pulmonary arterial hypertension.

Proliferative pulmonary vascular remodeling is the pathologic hallmark of pulmonary arterial hypertension (PAH) that ultimately leads to right heart failure and death. Highly proliferative endothelial cells known as endothelial colony-forming cells (ECFC) participate in vascular homeostasis in health as well as in pathological angiogenic remodeling in disease. ECFC are distinguished by the capacity to clonally proliferate from a single cell. The presence of ECFC in the human pulmonary arteries and their role in PAH pathogenesis is largely unknown. In this study, we established a simple technique for isolating and growing ECFC from cultured pulmonary artery endothelial cells (PAEC) to test the hypothesis that ECFC reside in human pulmonary arteries and that the proliferative vasculopathy of PAH is related to greater numbers and/or more proliferative ECFC in the pulmonary vascular wall. Flow cytometric forward and side scatter properties and aggregate correction were utilized to sort unmanipulated, single PAEC to enumerate ECFC in primary PAEC cultures derived from PAH and healthy lungs. After 2 weeks, wells were assessed for ECFC formation. ECFC derived from PAH PAEC were more proliferative than control. A greater proportion of PAH ECFC formed colonies following subculturing, demonstrating the presence of more ECFC with high proliferative potential among PAH PAEC. Human androgen receptor assay showed clonality of progeny, confirming that proliferative colonies were single cell-derived. ECFC expressed CD31, von Willebrand factor, endothelial nitric oxide synthase, caveolin-1 and CD34, consistent with an endothelial cell phenotype. We established a simple flow cytometry method that allows ECFC quantification using unmanipulated cells. We conclude that ECFC reside among PAEC and that PAH PAEC contain ECFC that are more proliferative than ECFC in control cultures, which likely contributes to the proliferative angiopathic process in PAH.

2-triazole-substituted adenosines: a new class of selective A3 adenosine receptor agonists, partial agonists, and antagonists.

"Click chemistry" was explored to synthesize two series of 2-(1,2,3-triazolyl)adenosine derivatives (1-14). Binding affinity at the human A(1), A(2A), and A(3)ARs (adenosine receptors) and relative efficacy at the A(3)AR were determined. Some triazol-1-yl analogues showed A(3)AR affinity in the low nanomolar range, a high ratio of A(3)/A(2A) selectivity, and a moderate-to-high A(3)/A(1) ratio. The 1,2,3-triazol-4-yl regiomers typically showed decreased A(3)AR affinity. Sterically demanding groups at the adenine C2 position tended to reduce relative A(3)AR efficacy. Thus, several 5'-OH derivatives appeared to be selective A(3)AR antagonists, i.e., 10, with 260-fold binding selectivity in comparison to the A(1)AR and displaying a characteristic docking mode in an A(3)AR model. The corresponding 5'-ethyluronamide analogues generally showed increased A(3)AR affinity and behaved as full agonists, i.e., 17, with 910-fold A(3)/A(1) selectivity. Thus, N(6)-substituted 2-(1,2,3-triazolyl)adenosine analogues constitute a novel class of highly potent and selective nucleoside-based A(3)AR antagonists, partial agonists, and agonists.

Action of nucleosides and nucleotides at 7 transmembrane-spanning receptors.

Ribose ring-constrained nucleosides and nucleotides to act at cell-surface purine recesptors have been designed and synthesized. At the P2Y1 nucleotide receptor and the A3 adenosine receptor (AR) the North envelope conformation of ribose is highly preferred. We have applied mutagenesis and rhodopsin-based homology modeling to the study of purine receptors and used the structural insights gained to assist in the design of novel ligands. Two subgroups of P2Y receptors have been defined, containing different sets of cationic residues for coordinating the phosphate groups. Modeling/mutagenesis of adenosine receptors has focused on determinants of intrinsic efficacy in adenosine derivatives and on a conserved Trp residue (6.48) which is involved in the activation process. The clinical use of adenosine agonists as cytoprotective agents has been limited by the widespread occurrence of ARs, thus, leading to undesirable side effects of exogenously administered adenosine derivatives. In order to overcome the inherent nonselectivity of activating the native receptors, we have introduced the concept of neoceptors. By this strategy, intended for eventual use in gene therapy, the putative ligand binding site of a G protein-coupled receptor is reengineered for activation by synthetic agonists (neoligands) built to have a structural complementarity. Using a rational design process we have identified neoceptor-neoligand pairs which are pharmacologically orthogonal with respect to the native species.

Design, synthesis, and biological activity of N6-substituted-4'-thioadenosines at the human A3 adenosine receptor.

A large series of N6-substituted-4'-thioadenosines were synthesized starting from D-gulonic-gamma-lactone, and structure-activity relationships were studied at the human A3 and other subtypes of adenosine receptors (ARs). 2-Chloro-substituted and 2-H analogues were compared. 2-Chloro-N6-methyl-4'-thioadenosine 19b was a highly potent and selective agonist (Ki=0.8+/-0.1 nM in binding) at the A3AR, and displayed the same relative efficacy in receptor activation as a known full agonist, Cl-IB-MECA. Most of N6-substituted-4'-thioadenosines were less potent in binding than the corresponding N6-substituted-adenosines or N6-substituted-4'-thioadenosine-5'-uronamides. N6-(3-Iodobenzyl) derivative 19g was demonstrated to be an A3AR-selective partial agonist displaying a Ki value of 3.2 nM.

Orthogonal activation of the reengineered A3 adenosine receptor (neoceptor) using tailored nucleoside agonists.

An alternative approach to overcome the inherent lack of specificity of conventional agonist therapy can be the reengineering of the GPCRs and their agonists. A reengineered receptor (neoceptor) could be selectively activated by a modified agonist, but not by the endogenous agonist. Assisted by rhodopsin-based molecular modeling, we pinpointed mutations of the A(3) adenosine receptor (AR) for selective affinity enhancement following complementary modifications of adenosine. Ribose modifications examined included, at 3': amino, aminomethyl, azido, guanidino, ureido; and at 5': uronamido, azidodeoxy. N(6)-Variations included 3-iodobenzyl, 5-chloro-2-methyloxybenzyl, and methyl. An N(6)-3-iodobenzyl-3'-ureido adenosine derivative 10 activated phospholipase C in COS-7 cells (EC(50) = 0.18 microM) or phospholipase D in chick primary cardiomyocytes, both mediated by a mutant (H272E), but not the wild-type, A(3)AR. The affinity enhancements for 10 and the corresponding 3'-acetamidomethyl analogue 6 were >100-fold and >20-fold, respectively. 10 concentration-dependently protected cardiomyocytes transfected with the neoceptor against hypoxia. Unlike 10, adenosine activated the wild-type A(3)AR (EC(50) of 1.0 microM), but had no effect on the H272E mutant A(3)AR (100 microM). Compound 10 was inactive at human A(1), A(2A), and A(2B)ARs. The orthogonal pair comprising an engineered receptor and a modified agonist should be useful for elucidating signaling pathways and could be therapeutically applied to diseases following organ-targeted delivery of the neoceptor gene.

Structure-activity relationships of 2-chloro-N6-substituted-4'-thioadenosine-5'-uronamides as highly potent and selective agonists at the human A3 adenosine receptor.

We have established structure-activity relationships of novel 4'-thionucleoside analogues as the A(3) adenosine receptor (AR) agonists. Binding affinity, selectivity toward other AR subtypes, and efficacy in inhibition of adenylate cyclase were studied. From this study, 2-chloro-N(6)-methyl-4'-thioadenosine-5'-methyluronamide (36a) emerged as the most potent and selective agonist at the human A(3) AR. We have also revealed that, similar to 4'-oxoadenosine analogues, at least one hydrogen on the 5'-uronamide moiety was necessary for high-affinity binding at the human A(3) AR, presumably to allow this group to donate a H bond within the binding site. Furthermore, bulky substituents on the 5'-uronamide reduced binding affinity, but in some cases large 5'-uronamide substituents, such as substituted benzyl and 2-phenylethyl groups, maintained moderate affinity with reduced efficacy, leading to A(3) AR partial agonists or antagonists. In several cases for which the corresponding 4'-oxonucleosides have been studied, the 4'-thionucleosides showed higher binding affinity to the A(3) AR.

[Histology of liver lesions due to Schistosoma mekongi. About six cases with severe portal hypertension operated in Cambodia]. / Lesions histologiques hépatiques de la schistosomose due a Schistosoma mekongi. A propos de six cas avec hypertension portale sévère opérés au Cambodge.

Schistosomiasis mekongi was shown to be endemic, along the Mekong River, in northern Cambodia, affecting many patients with portal hypertension. Surgical procedures were proposed to some patients with digestive haemorrhage history to avoid fatal recurrence. The aim of our study was to evaluate the intensity of the liver fibrosis among these patients. During surgical treatment, liver biopsies were collected, fixed in Bouin or in formalin and processed at the Institut Pasteur of Cambodia. Sections were stained by H&E, Masson's trichrome, PAS, Ziehl-Neelsen's method and Congo Red. A total of six biopsies from patients aged 16-36 were analysed. There was complete disorganization of hepatic architecture with fibrous enlargement of portal tracts and some portal-portal bridging fibrosis, but there was no cirrhosis. In portal areas, there was blood vessel congestion and thrombosis with inflammation. Bile ducts were normal. In the parenchyma, congestion of sinusoidal capillaries was combined with focal mononuclear inflammatory infiltrate. There was no steatosis, no necrosis, no cholestasis, no iron accumulation and no amyloidosis. Numerous eggs of Schistosoma mekongi were observed in five cases, mostly in fibrous areas and more rarely in the parenchyma. Eggs were round or oval, measuring 60 x 40 microns with an acid-fast thin hyaline wall. Some eggs were surrounded by epithelioid and giant cell reaction. In conclusion, our findings illustrated a surprisingly high degree of fibrosis among young adults which contrasts with other schistosomiasis.

Semi-rational design of (north)-methanocarba nucleosides as dual acting A(1) and A(3) adenosine receptor agonists: novel prototypes for cardioprotection.

Ring-constrained adenosine analogues have been designed to act as dual agonists at tissue-protective A(1) and A(3) adenosine receptors (ARs). 9-Ribosides transformed into the ring-constrained (N)-methanocarba-2-chloro-5'-uronamides consistently lost affinity at A(1)/A(2A)ARs and gained at A(3)AR. Among 9-riboside derivatives, only N(6)-cyclopentyl and 7-norbornyl moieties were extrapolated for mixed A(1)/A(3) selectivity and rat/human A(3)AR equipotency. Consequently, 2 was balanced in affinity and potency at A(1)/A(3)ARs as envisioned and dramatically protected in an intact heart model of global ischemia and reperfusion.

(N)-methanocarba 2,N6-disubstituted adenine nucleosides as highly potent and selective A3 adenosine receptor agonists.

A series of ring-constrained (N)-methanocarba-5'-uronamide 2,N(6)-disubstituted adenine nucleosides have been synthesized via Mitsunobu condensation of the nucleobase precursor with a pseudosugar ring containing a 5'-ester functionality. Following appropriate functionalization of the adenine ring, the ester group was converted to the 5'-N-methylamide. The compounds, mainly 2-chloro-substituted derivatives, were tested in both binding and functional assays at human adenosine receptors (ARs), and many were found to be highly potent and selective A(3)AR agonists. Selected compounds were compared in binding to the rat A(3)AR to assess their viability for testing in rat disease models. The N(6)-(3-chlorobenzyl) and N(6)-(3-bromobenzyl) analogues displayed K(i) values at the human A(3)AR of 0.29 and 0.38 nM, respectively. Other subnanomolar affinities were observed for the following N(6) derivatives: 2,5-dichlorobenzyl, 5-iodo-2-methoxybenzyl, trans-2-phenyl-1-cyclopropyl, and 2,2-diphenylethyl. Selectivity for the human A(3)AR in comparison to the A(1)AR was the following (fold): the N(6)-(2,2-diphenylethyl) analogue 34 (1900), the N(6)-(2,5-dimethoxybenzyl) analogue 26 (1200), the N(6)-(2,5-dichlorobenzyl) and N(6)-(2-phenyl-1-cyclopropyl) analogues 20 and 33 (1000), and the N(6)-(3-substituted benzyl) analogues 17, 18, 28, and 29 (700-900). Typically, even greater selectivity ratios were obtained in comparison with the A(2A) and A(2B)ARs. The (N)-methanocarba-5'-uronamide analogues were full agonists at the A(3)AR, as indicated by the inhibition of forskolin-stimluated adenylate cyclase at a concentration of 10 microM. The N(6)-(2,2-diphenylethyl) derivative was an A(3)AR agonist in the (N)-methanocarba-5'-uronamide series, although it was an antagonist in the ribose series. Thus, many of the previously known groups that enhance A(3)AR affinity in the 9-riboside series, including those that reduce intrinsic efficacy, may be adapted to the (N)-methanocarba nucleoside series of full agonists.

A neoceptor approach to unraveling microscopic interactions between the human A2A adenosine receptor and its agonists.

Strategically mutated neoceptors, e.g., with anionic residues in TMs 3 and 7 intended for pairing with positively charged amine-modified nucleosides, were derived from the antiinflammatory A(2A) adenosine receptor (AR). Adenosine derivatives functionalized at the 5', 2, and N(6) positions were synthesized. The T88D mutation selectively enhanced the binding of the chain-length-optimized 5'-(2-aminoethyl)uronamide but not 5'-(2-hydroxyethyl)uronamide, suggesting a critical role of the positively charged amine. Combination of this modification with the N(6)-(2-methylbenzyl) group enhanced affinity at the Q89D- and N181D- but not the T88D-A(2A)AR. Amino groups placed near the 2- or N(6)-position only slightly affected the binding to mutant receptors. The 5'-hydrazide MRS3412 was 670- and 161-fold enhanced, in binding and functionally, respectively, at the Q89D-A(2A)AR compared to the wild-type. Thus, we identified and modeled pairs of A(2A)AR-derived neoceptor-neoligand, which are pharmacologically orthogonal with respect to the native species.