The exact function(s) of the lagovirus non-structural protein p23 is unknown as robust cell culture systems for the
Rabbit haemorrhagic disease virus
(RHDV) and other lagoviruses have not been ...established. Instead, a range of
in vitro
and
in silico
models have been used to study p23, revealing that p23 oligomerizes, accumulates in the cytoplasm, and possesses a conserved C-terminal region with two amphipathic helices. Furthermore, the positional homologs of p23 in other caliciviruses have been shown to possess viroporin activity. Here, we report on the mechanistic details of p23 oligomerization. Site-directed mutagenesis revealed the importance of an N-terminal cysteine for dimerization. Furthermore, we identified cellular interactors of p23 using stable isotope labeling with amino acids in cell culture (SILAC)-based proteomics; heat shock proteins Hsp70 and 110 interact with p23 in transfected cells, suggesting that they ‘chaperone’ p23 proteins before their integration into cellular membranes. We investigated changes to the global transcriptome and proteome that occurred in infected rabbit liver tissue and observed changes to the misfolded protein response, calcium signaling, and the regulation of the endoplasmic reticulum (ER) network. Finally, flow cytometry studies indicate slightly elevated calcium concentrations in the cytoplasm of p23-transfected cells. Taken together, accumulating evidence suggests that p23 is a viroporin that might form calcium-conducting channels in the ER membranes.
Pancreatic ductal adenocarcinomas are characterized by a complex and robust tumor microenvironment (TME) consisting of fibrotic tissue, excessive levels of hyaluronan (HA), and immune cells. We ...utilized quantitative multi-parametric magnetic resonance imaging (mp-MRI) methods at 14 Tesla in a genetically engineered KPC (
,
,
mouse model to assess the complex TME in advanced stages of tumor development. The whole tumor, excluding cystic areas, was selected as the region of interest for data analysis and subsequent statistical analysis. Pearson correlation was used for statistical inference. There was a significant correlation between tumor volume and T2 (r = -0.66), magnetization transfer ratio (MTR) (r = 0.60), apparent diffusion coefficient (ADC) (r = 0.48), and Glycosaminoglycan-chemical exchange saturation transfer (GagCEST) (r = 0.51). A subset of mice was randomly selected for histological analysis. There were positive correlations between tumor volume and fibrosis (0.92), and HA (r = 0.76); GagCEST and HA (r = 0.81); and MTR and CD31 (r = 0.48). We found a negative correlation between ADC low-b (perfusion) and Ki67 (r = -0.82). Strong correlations between mp-MRI and histology results suggest that mp-MRI can be used as a non-invasive tool to monitor the tumor microenvironment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Objective To determine the long-term outcome of surgical repair of popliteal artery aneurysms (PAA). Methods A retrospective review of consecutive patients who underwent surgical PAA repair in two ...vascular surgery units between 1988 and 2006 was performed. Primary and secondary graft patency, limb salvage and patient survival rates were determined using Kaplan-Meier methods. Results 48 patients underwent repair of 63 PAAs (ligation and bypass = 45, interposition grafting = 18). The 5-year primary graft patency, secondary graft patency, limb salvage and patient survival rates were 75%, 95%, 98% and 81%, respectively. The 10-year primary graft patency rates were significantly lower for emergency cases (59%) compared with elective cases (66%) (p = 0.0023). Thirteen patients (16 PAAs) required a total of 20 late re-interventions. Duplex ultrasound was available in 33 of 45 PAAs treated by ligation and bypass. Five (15%) PAAs demonstrated perfusion of the aneurysm sac at median(range) follow up of 75 (1–246) months after primary repair and two of these required emergency re-operation. Conclusions These data demonstrate that surgical PAA repair is associated with excellent long-term durability and provide an important benchmark with which to compare results of endovascular PAA repair. Patients treated using the ligation and bypass technique should be enrolled in an aneurysm sac surveillance program.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Complementary and alternative medicine (CAM) is commonly used by children with juvenile idiopathic arthritis (JIA), yet no validated questionnaires assess that use. The objective of this study was to ...develop child self- and parent proxy-report questionnaires assessing CAM use and to determine the face and content validity of the "Which Health Approaches and Treatments are you using?" (WHAT) questionnaires in pediatric rheumatology.
A sequential phased mixed methods approach was used to develop the questionnaires. A Delphi Survey of 126 experts followed by an interdisciplinary consensus conference of 14 stakeholders in CAM, general pediatrics and pediatric rheumatology was held to develop consensus on the content of the questionnaires using a nominal group technique. To determine face and content validity of the questionnaires, two groups, including (a) a purposive sample of 22 children with JIA 8 to 18 years and their parents from the Children's Hospital of Eastern Ontario and the Hospital for Sick Children, and (b) 21 Canadian pediatric rheumatology experts, participated in interviews. Participants were independently asked about the goal, understandability and comprehensiveness of the WHAT questionnaires, as well as the relevance of items.
Consensus was reached on 17 items of the WHAT questionnaires. The domains found to be relevant were child's CAM use, factors associated with CAM use, perceived impact of CAM use, and communication about CAM. A total of 15 items in the parent proxy-report questionnaire and 13 items in the child report questionnaire showed adequate content validity.
Consensus was reached by experts on the content of a pediatric CAM questionnaire. Face and content validity testing and modifications made to the WHAT questionnaires have helped ensure adequate preliminary validity for use in pediatric rheumatology. This constitutes the basis for further testing of these questionnaires in pediatric rheumatology and for adaptation to other chronic diseases.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IntroductionOpioid use disorder (OUD) is characterised by the fifth Edition of the Diagnostic and Statistics Manual as a problematic pattern of opioid use (eg, fentanyl, heroin, oxycodone) that leads ...to clinically significant impairment. OUD diagnoses have risen substantially over the last decade, and treatment services have struggled to meet the demand. Evidence suggests when patients with chronic illnesses are matched with their treatment preferences and engaged in shared decision-making (SDM), health outcomes may improve. However, it is not known whether SDM could impact outcomes in specific substance use disorders such as OUD.Methods and analysisA scoping review will be conducted according to Arksey and O’Malley’s framework and by recommendations from Levac et al. The search strategy was developed to retrieve relevant publications from database inception and June 2017. MEDLINE, EMBASE, PsycINFO, Cochrane Database for Controlled Trials, Cochrane Database for Systematic Reviews and reference lists of relevant articles and Google Scholar will be searched. Included studies must be composed of adults with a diagnosis of OUD, and investigate SDM or its constituent components. Experimental, quasi-experimental, qualitative, case–control, cohort studies and cross-sectional surveys will be included. Articles will be screened for final eligibility according to title and abstract, and then by full text. Two independent reviewers will screen excluded articles at each stage. A consultation phase with expert clinicians and policy-makers will be added to set the scope of the work, refine research questions, review the search strategy and identify additional relevant literature. Results will summarise whether SDM impacts health and patient-centred outcomes in OUD.Ethics and disseminationScoping review methodology is considered secondary analysis and does not require ethics approval. The final review will be submitted to a peer-reviewed journal, disseminated at relevant academic conferences and will be shared with policy-makers, patients and clinicians.
Background
Shared decision-making encourages patients to explore treatment options/choices in collaboration with their healthcare provider, inclusive of the best available evidence and the patient's ...values/preferences. Several effective treatments exist for people with anxiety and/or depressive disorders; shared decision-making may be particularly useful in this context.
Aims
To investigate whether shared decision-making enhances clinical outcomes in adults with anxiety and/or depressive disorders.
Method
A systematic review was conducted. Five electronic health databases were searched from database inception until August 2019, in addition to reference lists of included studies. Prospective controlled studies of shared decision-making in adults (aged 18–64 years) diagnosed with an anxiety and/or depressive disorder were included. Two reviewers independently conducted each stage of the review process.
Results
Six randomised controlled trials (
N
= 1834 participants) were included. Patient satisfaction improved in four studies. Patients were more likely to receive adequate treatment for depression in three studies. Anxiety symptoms decreased in one study. Patient involvement in decision-making increased in three studies. Because of the lack of blinded interventions and outcome assessment, the included studies were at moderate risk of bias. The certainty of evidence ranged from low to moderate, per GRADE criteria.
Conclusions
Shared decision-making shows promise for enhancing quality-of-care outcomes such as patient satisfaction, without increasing consultation time, but appears unlikely to improve symptoms of depression. However, it appears to be understudied in patients with anxiety disorders. Heterogeneity regarding definition and measurement of shared decision-making posed challenges for interpreting the results. More research is recommended to advance the field.
Background Hormone replacement therapy (HRT) is recommended to post-menopausal women to control menopausal symptoms and prevent osteoporosis. The management of women with peripheral arterial disease ...(PAD) and who are taking HRT is controversial. Aim To summarise what is known about HRT and its effect on the natural progression of PAD and its subsequent treatment. Methods A MEDLINE (1966–2004) and Cochrane library search for articles relating to HRT and PAD was undertaken. Results The potential benefits of unopposed estrogen therapy on atherosclerotic progression and limb microcirculation are outweighed by the increased risk of endometrial dysplasia and thrombotic complications. Only one major study (Rotterdam) specifically assessed the impact of HRT on the clinical course of PAD. The findings suggested a decreased risk of PAD among healthy post-menopausal women taking HRT which contrasts with the sub-group analyses of other major studies (HERS/HERS II). HRT appears to reduce the primary success rates of both endovascular and open surgical revascularisation in patients with PAD. Conclusions Further studies are required to investigate the effects of HRT on the progression of PAD and its management.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The follicle-associated epithelium (FAE) is a specialized structure that samples luminal antigens and transports them into mucosa-associated lymphoid tissues (MALT). In mammals, transcytosis of ...antigens across the gut epithelium is performed by a subset of FAE cells known as M cells. Here we show that colony-stimulating factor 1 receptor (CSF1R) is expressed by a subset of cells in the avian bursa of Fabricius FAE. Expression was initially detected using a
-reporter transgene that also label subsets of bursal macrophages. Immunohistochemical detection using a specific monoclonal antibody confirmed abundant expression of CSF1R on the basolateral membrane of FAE cells.
-transgene expressing bursal FAE cells were enriched for expression of markers previously reported as putative M cell markers, including annexin A10 and CD44. They were further distinguished from a population of
-transgene negative epithelial cells within FAE by high apical F-actin expression and differential staining with the lectins jacalin, PHA-L and SNA. Bursal FAE cells that express the
-reporter transgene were responsible for the bulk of FAE transcytosis of labeled microparticles in the size range 0.02-0.1 μm. Unlike mammalian M cells, they did not readily take up larger bacterial sized microparticles (0.5 μm). Their role in uptake of bacteria was tested using
, which can enter via M cells in mammals. Labeled
serovar Typhimurium entered bursal tissue via the FAE. Entry was partially dependent upon Type III secretion system-1. However, the majority of invading bacteria were localized to
-negative FAE cells and in resident phagocytes that express the phosphatidylserine receptor TIM4.
-expressing FAE cells in infected follicles showed evidence of cell death and shedding into the bursal lumen. In mammals, CSF1R expression in the gut is restricted to macrophages which only indirectly control M cell differentiation. The novel expression of CSF1R in birds suggests that these functional equivalents to mammalian M cells may have different ontological origins and their development and function are likely to be regulated by different growth factors.
Opioid use disorder (OUD) is a leading cause of preventable mortality amongst young people worldwide. Early identification and intervention of modifiable risk factors may reduce future OUD risk. The ...aim of this study was to explore whether the onset of OUD is associated with preexisting mental health conditions such as anxiety and depressive disorders in young people.
A retrospective, population-based case-control study was conducted from 31 March 2018 until 01 January 2002. Provincial administrative health data were collected from Alberta, Canada.
Individuals 18-25 years on 01 April 2018, with a previous record of OUD.
Individuals without OUD were matched to cases, on age/sex/index date. Conditional logistic regression analysis was used to control for additional covariates (e.g., alcohol-related disorders, psychotropic medications, opioid analgesics, and social/material deprivation).
We identified N = 1848 cases and N = 7392 matched controls. After adjustment, OUD was associated with the following preexisting mental health conditions: Anxiety disorders, aOR = 2.53 (95% CI = 2.16-2.96); depressive disorders, aOR = 2.20 (95% CI = 1.80-2.70); alcohol-related disorders, aOR = 6.08 (95% CI, 4.86-7.61); anxiety and depressive disorders, aOR = 1.94 (95% CI = 1.56-2.40); anxiety and alcohol-related disorders, aOR = 5.22 (95% CI = 4.03-6.77); depressive and alcohol-related disorders, aOR = 6.47 (95% CI = 4.73-8.84); anxiety, depressive and alcohol-related disorders, aOR = 6.09 (95% CI = 4.41-8.42).
Preexisting mental health conditions such as anxiety and depressive disorders are risk factors for future OUD in young people. Preexisting alcohol-related disorders showed the strongest association with future OUD and demonstrated an additive risk when concurrent with anxiety/depression. As not all plausible risk factors could be examined, more research is still needed.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background Abdominal aortic aneurysm (AAA) is associated with a prothrombotic diathesis that may increase the risk of cardiovascular events. This diathesis is exacerbated in the short term by open ...aneurysm repair (OAR) and endovascular aneurysm repair (EVAR). However, the effect of EVAR and OAR on coagulation and fibrinolysis in the medium and long term is poorly understood. The purpose of this study was to investigate the medium-term effects of EVAR and OAR on thrombin generation, neutralization, and fibrinolysis. Methods Prothrombin fragment (PF)1 + 2, thrombin antithrombin (TAT) complex, plasminogen activator inhibitor (PAI) activity, and tissue-plasminogen activator (t-PA) antigen were measured in eight age-matched controls (AMCs), 29 patients with AAA immediately before (preoperatively) and 12 months after EVAR (post-EVAR), and in 11 patients at a mean of 16 months after OAR (post-OAR). Results Preoperatively, PF1 + 2 levels were significantly higher in patients with AAAs than in AMC. PF1 + 2 levels post-EVAR and post-OAR were significantly lower than preoperative values and similar to AMC. There was no significant difference in TAT, PAI, or t-PA between AMC, AAA preoperatively, and post-EVAR. Post-OAR, PAI activity was significantly higher than in preoperative patients. Conclusions AAA is associated with increased thrombin generation without upregulation of fibrinolysis. The prothrombotic, hypofibrinolytic diathesis observed in patients with AAA returns toward normal in the medium term after EVAR and OAR, although there is a trend toward decreased fibrinolysis post-OAR.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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