Despite strong evidence of the benefits of preconception interventions for improving pregnancy outcomes, the delivery and uptake of preconception care and periconceptional folate supplementation ...remain low. General practitioners play a central role in the delivery of preconception care. Understanding general practitioners' perceptions of the barriers and enablers to implementing preconception care allows for more appropriate targeting of quality improvement interventions. Consequently, the aim of this study was to examine the barriers and enablers to the delivery and uptake of preconception care guidelines from general practitioners' perspective using theoretical domains related to behaviour change.
We conducted a qualitative study using focus groups consisting of 22 general practitioners who were recruited from three regional general practice support organisations. Questions were based on the theoretical domain framework, which describes 12 domains related to behaviour change. General practitioners' responses were classified into predefined themes using a deductive process of thematic analysis.
Beliefs about capabilities, motivations and goals, environmental context and resources, and memory, attention and decision making were the key domains identified in the barrier analysis. Some of the perceived barriers identified by general practitioners were time constraints, the lack of women presenting at the preconception stage, the numerous competing preventive priorities within the general practice setting, issues relating to the cost of and access to preconception care, and the lack of resources for assisting in the delivery of preconception care guidelines. Perceived enablers identified by general practitioners included the availability of preconception care checklists and patient brochures, handouts, and waiting room posters outlining the benefits and availability of preconception care consultations.
Our study has identified some of the barriers and enablers to the delivery and uptake of preconception care guidelines, as perceived by general practitioners. Relating these barriers to a theoretical domain framework provides a clearer understanding of some of the psychological aspects that are involved in the behaviour of general practitioners towards the delivery and uptake of preconception care. Further research prioritising these barriers and the theoretical domains to which they relate to is necessary before a methodologically rigorous intervention can be designed, implemented, and evaluated.
Myeloperoxidase is a neutrophil enzyme that promotes oxidative stress in numerous inflammatory pathologies. It uses hydrogen peroxide to catalyze the production of strong oxidants including chlorine ...bleach and free radicals. A physiological defense against the inappropriate action of this enzyme has yet to be identified. We found that myeloperoxidase oxidized 75% of the ascorbate in plasma from ceruloplasmin knock-out mice, but there was no significant loss in plasma from wild type animals. When myeloperoxidase was added to human plasma it became bound to other proteins and was reversibly inhibited. Ceruloplasmin was the predominant protein associated with myeloperoxidase. When the purified proteins were mixed, they became strongly but reversibly associated. Ceruloplasmin was a potent inhibitor of purified myeloperoxidase, inhibiting production of hypochlorous acid by 50% at 25 nm. Ceruloplasmin rapidly reduced Compound I, the FeV redox intermediate of myeloperoxidase, to Compound II, which has FeIV in its heme prosthetic groups. It also prevented the fast reduction of Compound II by tyrosine. In the presence of chloride and hydrogen peroxide, ceruloplasmin converted myeloperoxidase to Compound II and slowed its conversion back to the ferric enzyme. Collectively, our results indicate that ceruloplasmin inhibits myeloperoxidase by reducing Compound I and then trapping the enzyme as inactive Compound II. We propose that ceruloplasmin should provide a protective shield against inadvertent oxidant production by myeloperoxidase during inflammation.
Background: Myeloperoxidase promotes oxidative stress during inflammation by producing hypochlorous acid.
Results: Ceruloplasmin was a potent inhibitor of myeloperoxidase and slowed its activity in plasma from wild type mice compared with ceruloplasmin knock-out animals.
Conclusion: Ceruloplasmin is a physiologically relevant inhibitor of myeloperoxidase.
Significance: Ceruloplasmin will provide a protective shield against oxidant production by myeloperoxidase during inflammation.
Charcot-Marie-Tooth disease (CMT) represents a group of neurodegenerative disorders typically characterised by demyelination (CMT1) or distal axon degeneration (CMT2) of motor and sensory neurons. ...The majority of CMT2 cases are caused by mutations in mitofusin 2 (MFN2); an essential gene encoding a protein responsible for fusion of the mitochondrial outer membrane. The mechanism of action of MFN2 mutations is still not fully resolved. To investigate a role for loss of Mfn2 function in disease we investigated an ENU-induced nonsense mutation in zebrafish MFN2 and characterised the phenotype of these fish at the whole organism, pathological, and subcellular level. We show that unlike mice, loss of MFN2 function in zebrafish leads to an adult onset, progressive phenotype with predominant symptoms of motor dysfunction similar to CMT2. Mutant zebrafish show progressive loss of swimming associated with alterations at the neuro-muscular junction. At the cellular level, we provide direct evidence that mitochondrial transport along axons is perturbed in Mfn2 mutant zebrafish, suggesting that this is a key mechanism of disease in CMT. The progressive phenotype and pathology suggest that zebrafish will be useful for further investigating the disease mechanism and potential treatment of axonal forms of CMT. Our findings support the idea that MFN2 mutation status should be investigated in patients presenting with early-onset recessively inherited axonal CMT.
Innate lymphoid cells (ILCs) are increasingly appreciated as key regulators of tissue immunity. However, their role in human tissue homeostasis and disease remains to be fully elucidated. Here we ...characterize the ILCs in human skin from healthy individuals and from the inflammatory skin disease psoriasis. We show that a substantial proportion of IL-17A and IL-22 producing cells in the skin and blood of normal individuals and psoriasis patients are CD3-negative innate lymphocytes. Deep immunophenotyping of human ILC subsets showed a statistically significant increase in the frequency of circulating NKp44+ ILC3 in the blood of psoriasis patients compared with healthy individuals or atopic dermatitis patients. More than 50% of circulating NKp44+ ILC3 expressed cutaneous lymphocyte–associated antigen, indicating their potential for skin homing. Analysis of skin tissue revealed a significantly increased frequency of total ILCs in the skin compared with blood. Moreover, the frequency of NKp44+ ILC3 was significantly increased in non-lesional psoriatic skin compared with normal skin. A detailed time course of a psoriasis patient treated with anti–tumor necrosis factor showed a close association between therapeutic response, decrease in inflammatory skin lesions, and decrease of circulating NKp44+ ILC3. Overall, data from this initial observational study suggest a potential role for NKp44+ ILC3 in psoriasis pathogenesis.
Osteoid osteoma of the foot and ankle—A systematic review Jordan, Robert W., MBChB, MRCS; Koç, Togay, MBBS MSc MRCS; Chapman, Anna W.P., MBBS MSc(Ed) FRCS (Orth) ...
Foot and ankle surgery,
12/2015, Letnik:
21, Številka:
4
Journal Article
Recenzirano
Highlights • Commonest in males under 30 years of age affecting the talus. • Clinical features include night pain and a good response to NSAIDs but diagnosis is typically delayed. • CT scan is the ...most useful radiological investigation with MRI missing the diagnosis in 34% of cases. • Thermal destruction techniques are becoming increasingly used over the last 5 years.
Clonal selection and transcriptional reprogramming (e.g., epithelial-mesenchymal transition or phenotype switching) are the predominant theories thought to underlie tumor progression. However, a ...“division of labor” leading to cooperation among tumor-cell subpopulations could be an additional catalyst of progression. Using a zebrafish-melanoma xenograft model, we found that in a heterogeneous setting, inherently invasive cells, which possess protease activity and deposit extracellular matrix (ECM), co-invade with subpopulations of poorly invasive cells, a phenomenon we term “cooperative invasion”. Whereas the poorly invasive cells benefit from heterogeneity, the invasive cells switch from protease-independent to an MT1-MMP-dependent mode of invasion. We did not observe changes in expression of the melanoma phenotype determinant MITF during cooperative invasion, thus ruling out the necessity for phenotype switching for invasion. Altogether, our data suggest that cooperation can drive melanoma progression without the need for clonal selection or phenotype switching and can account for the preservation of heterogeneity seen throughout tumor progression.
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•Inherently invasive and poorly invasive melanoma subpopulations co-invade•Leader cells are inherently invasive and provide MT1-MMP and deposit ECM•Follower cells affect the mode of invasion and thereby elicit protease dependency•Cooperative invasion bypasses phenotype switching and maintains tumor heterogeneity
Tumor heterogeneity has been viewed as the outcome of adaptive competition or differential transcriptional reprogramming (phenotype switching). Alternatively, heterogeneity may reflect a division of labor between tumor cell subpopulations with complementary acquired characteristics. Chapman et al. now show reciprocal interactions between heterogeneous melanoma cell subpopulations that lead to cooperative invasion without competition and without phenotype switching. Thus, cooperative behavior emerges as a property of heterogeneity relevant for tumor biology and worth targeting therapeutically.
Despite strong evidence of the benefits of preconception interventions to improve pregnancy outcomes, the delivery and uptake of preconception care in general and periconceptional folate ...supplementation in particular remains low. The aim of this study was to determine women's views of the barriers and enablers to the uptake of preconception care and periconceptional folate supplementation.
Focus groups were undertaken in 2007 with 17 women of reproductive age (18-45 years). To identify key issues and themes within the data, focus groups were analysed using an inductive process of thematic analysis.
Most women were unaware of the need to attend for preconception care and were surprised at the breadth of issues involved. Women also felt general practitioners (GPs) should be more proactive in promoting preconception care availability but acknowledged that they themselves had to be thinking about pregnancy or becoming pregnant to be receptive to it. Barriers to periconceptional folate supplementation included confusion about reasons for use, dose, duration, timing and efficacy of folate use. Enablers included the desire to do anything they could to ensure optimum pregnancy outcomes, and promotional material and letters of invitation from their GP to advise them of the availability and the need for preconception care.
A number of important barriers and enablers exist for women regarding the delivery and uptake of preconception care and periconceptional folate supplementation. It is essential that these patient perspectives are addressed in both the implementation of evidence based clinical practice guidelines and in the systematic design of an intervention to improve preconception care delivery.
Myeloperoxidase (MPO) is an abundant hemoprotein expressed by neutrophil granulocytes that is recognized to play an important role in the development of vascular diseases. Upon degranulation from ...circulating neutrophil granulocytes, MPO binds to the surface of endothelial cells in an electrostatic-dependent manner and undergoes transcytotic migration to the underlying extracellular matrix (ECM). However, the mechanisms governing the binding of MPO to subendothelial ECM proteins, and whether this binding modulates its enzymatic functions are not well understood.
We investigated MPO binding to ECM derived from aortic endothelial cells, aortic smooth muscle cells, and fibroblasts, and to purified ECM proteins, and the modulation of these associations by glycosaminoglycans. The oxidizing and chlorinating potential of MPO upon binding to ECM proteins was tested.
MPO binds to the ECM proteins collagen IV and fibronectin, and this association is enhanced by the pre-incubation of these proteins with glycosaminoglycans. Correspondingly, an excess of glycosaminoglycans in solution during incubation inhibits the binding of MPO to collagen IV and fibronectin. These observations were confirmed with cell-derived ECM. The oxidizing and chlorinating potential of MPO was preserved upon binding to collagen IV and fibronectin; even the potentiation of MPO activity in the presence of collagen IV and fibronectin was observed.
Collectively, the data reveal that MPO binds to ECM proteins on the basis of electrostatic interactions, and MPO chlorinating and oxidizing activity is potentiated upon association with these proteins.
Our findings provide new insights into the molecular mechanisms underlying the interaction of MPO with ECM proteins.
•Myeloperoxidase binds to extracellular matrix proteins in an electrostatic-dependent manner.•This association is enhanced by the glycosaminoglycan coating of these proteins.•An excess of glycosaminoglycans inhibits the binding of myeloperoxidase.•Myeloperoxidase activity was potentiated in the presence of collagen IV and fibronectin.
The neutrophil enzyme, myeloperoxidase, by converting hydrogen peroxide (H2O2) and chloride to hypochlorous acid (HOCl), provides important defense against ingested micro-organisms. However, there is ...debate about how efficiently HOCl is produced within the phagosome and whether its reactions with phagosomal constituents influence the killing mechanism. The phagosome is a small space surrounding the ingested organism, into which superoxide, H2O2 and high concentrations of proteins from cytoplasmic granules are released. Previous studies imply that HOCl is produced in the phagosome, but a large proportion should react with proteins before reaching the microbe. To mimic these conditions, we subjected neutrophil granule extract to sequential doses of H2O2. Myeloperoxidase in the extract converted all the H2O2 to HOCl, which reacted with the granule proteins. 3-Chlorotyrosine, protein carbonyls and large amounts of chloramines were produced. At higher doses of H2O2, the extract developed potent bactericidal activity against Staphylococcus aureus. This activity was due to ammonia monochloramine, formed as a secondary product from protein chloramines and dichloramines. Isolated myeloperoxidase and elastase also became bactericidal when modified with HOCl and antibacterial activity was seen with a range of species. Comparison of levels of protein modification in the extract and in phagosomes implies that a relatively low proportion of phagosomal H2O2 would be converted to HOCl, but there should be sufficient for substantial protein chloramine formation and some breakdown to ammonia monochloramine. It is possible that HOCl could kill ingested bacteria by an indirect mechanism involving protein oxidation and monochloramine formation.
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•MPO-dependent protein oxidation occurs in neutrophil granule extract treated with H2O2.•Chloramines are formed and the extract becomes potently bactericidal.•Bactericidal activity is due to NH2Cl, formed by decomposition of protein chloramines.•NH2Cl formed by this mechanism could contribute to neutrophil bactericidal activity.
Abstract Pathological and problem gambling refer to a class of disorders, including those meeting criteria for a psychiatric diagnosis (i.e., pathological gambling), and others comprising a spectrum ...of severity defined by significant personal and social harm (i.e., problem gambling), that may be common in substance use treatment but are frequently unrecognized. This paper presents a systematic review and meta-analysis of available evidence indicating the prevalence of such gambling disorders in substance use treatment. It provides weighted mean estimates from across studies of clinical samples of substance users, and suggests around 14% of patients that demonstrate comorbid pathological gambling. Around 23% suffer conditions along the broader spectrum of problem gambling. The review also highlights important limitations of existing evidence, including scant data on current versus lifetime comorbidity, as well as reliance on convenience samples and self-administered measures of gambling problems. Notwithstanding a concomitant need for caution when applying these results, the findings suggest a strong need to identify and manage gambling comorbidity in substance use treatment. Strategies for identification of gambling disorders, and therapies that may provide useful adjunctive interventions in substance use treatment are discussed.
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