Stable amorphous georgeite as a precursor to a high-activity catalyst .

Copper and zinc form an important group of hydroxycarbonate minerals that include zincian malachite, aurichalcite, rosasite and the exceptionally rare and unstable—and hence little known and largely ignored1—georgeite. The first three of these minerals are widely used as catalyst precursors2, 3, 4 for the industrially important methanol-synthesis and low-temperature water–gas shift (LTS) reactions5, 6, 7, with the choice of precursor phase strongly influencing the activity of the final catalyst. The preferred phase2, 3, 8, 9, 10 is usually zincian malachite. This is prepared by a co-precipitation method that involves the transient formation of georgeite11; with few exceptions12 it uses sodium carbonate as the carbonate source, but this also introduces sodium ions—a potential catalyst poison. Here we show that supercritical antisolvent (SAS) precipitation using carbon dioxide (refs 13, 14), a process that exploits the high diffusion rates and solvation power of supercritical carbon dioxide to rapidly expand and supersaturate solutions, can be used to prepare copper/zinc hydroxycarbonate precursors with low sodium content. These include stable georgeite, which we find to be a precursor to highly active methanol-synthesis and superior LTS catalysts. Our findings highlight the value of advanced synthesis methods in accessing unusual mineral phases, and show that there is room for exploring improvements to established industrial catalysts

Protective Unfolded Protein Response in Human Pancreatic Beta Cells Transplanted into Mice

Background: There is great interest about the possible contribution of ER stress to the apoptosis of pancreatic beta cells in the diabetic state and with islet transplantation. Methods and Findings: Expression of genes involved in ER stress were examined in beta cell enriched tissue obtained with laser capture microdissection (LCM) from frozen sections of pancreases obtained from non-diabetic subjects at surgery and from human islets transplanted into ICR-SCID mice for 4 wk. Because mice have higher glucose levels than humans, the transplanted beta cells were exposed to mild hyperglycemia and the abnormal environment of the transplant site. RNA was extracted from the LCM specimens, amplified and then subjected to microarray analysis. The transplanted beta cells showed an unfolded protein response (UPR). There was activation of many genes of the IRE-1 pathway that provide protection against the deleterious effects of ER stress, increased expression of ER chaperones and ERAD (ER-associated protein degradation) proteins. The other two arms of ER stress, PERK and ATF-6, had many down regulated genes. Downregulation of EIF2A could protect by inhibiting protein synthesis. Two genes known to contribute to apoptosis, CHOP and JNK, were downregulated. Conclusions: Human beta cells in a transplant site had UPR changes in gene expression that protect against the proapoptotic effects of unfolded proteins

A model of access combining triage with initial management reduced waiting time for community outpatient services: a stepped wedge cluster randomised controlled trial

BACKGROUND: Long waiting times are associated with public community outpatient health services. This trial aimed to determine if a new model of care based on evidence-based strategies that improved patient flow in two small pilot trials could be used to reduce waiting time across a variety of services. The key principle of the Specific Timely Appointments for Triage (STAT) model is that patients are booked directly into protected assessment appointments and triage is combined with initial management as an alternative to a waiting list and triage system. METHODS: A stepped wedge cluster randomised controlled trial was conducted between October 2015 and March 2017, involving 3116 patients at eight sites across a major Australian metropolitan health network. RESULTS: The intervention reduced waiting time to first appointment by 33.8% (IRR = 0.663, 95% CI 0.516 to 0.852, P = 0.001). Median waiting time decreased from a median of 42 days (IQR 19 to 86) in the control period to a median of 24 days (IQR 13 to 48) in the intervention period. A substantial reduction in variability was also noted. The model did not impact on most secondary outcomes, including time to second appointment, likelihood of discharge by 12 weeks and number of appointments provided, but was associated with a small increase in the rate of missed appointments. CONCLUSIONS: Broad-scale implementation of a model of access and triage that combined triage with initial management and actively managed the relationship between supply and demand achieved substantial reductions in waiting time without adversely impacting on other aspects of care. The reductions in waiting time are likely to have been driven, primarily, by substantial reductions for those patients previously considered low priority. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12615001016527 registration date: 29/09/2015

Acute hypoxia induces apoptosis of pancreatic β-cell by activation of the unfolded protein response and upregulation of CHOP

The success of pancreatic β-cells transplantation to treat type 1 diabetes has been hindered by massive β-cell dysfunction and loss of β-cells that follows the procedure. Hypoxia-mediated cell death has been considered one of the main difficulties that must be overcome for transplantation to be regarded as a reliable therapy. Here we have investigated the mechanisms underlying β-cell death in response to hypoxia (1% O2). Our studies show that mouse insulinoma cell line 6 (Min6) cells undergo apoptosis with caspase-3 activation occurring as early as 2 h following exposure to hypoxia. Hypoxia induces endoplasmic reticulum stress in Min6 cells leading to activation of the three branches of the unfolded protein response pathway. In response to hypoxia the pro-apoptotic transcription factor C/EBP homologous protein (CHOP) is upregulated. The important role of CHOP in the apoptotic process was highlighted by the rescue of Min6 cells from hypoxia-mediated apoptosis observed in CHOP-knockdown cells. Culturing isolated pancreatic mouse islets at normoxia showed intracellular hypoxia with accumulation of hypoxia-inducible factor-1α and upregulation of CHOP, the latter one occurring as early as 4 h after isolation. Finally, we observed that pancreatic islets of type 2 db/db diabetic mice were more hypoxic than their counterpart in normoglycemic animals. This finding indicates that hypoxia-mediated apoptosis may occur in type 2 diabetes

Attitudes to colorectal cancer screening among ethnic minority groups in the UK

Background: Colorectal screening by Flexible Sigmoidoscopy (FS) is under evaluation in the UK. Evidence from existing cancer screening programmes indicates lower participation among minority ethnic groups than the white-British population. To ensure equality of access, it is important to understand attitudes towards screening in all ethnic groups so that barriers to screening acceptance can be addressed.Methods: Open- and closed-ended questions on knowledge about colorectal cancer and attitudes to FS screening were added to Ethnibus (TM) - a monthly, nationwide survey of the main ethnic minority communities living in the UK (Indian, Pakistani, Bangladeshi, Caribbean, African, and Chinese). Interviews (n = 875) were conducted, face-to-face, by multilingual field-workers, including 125 interviews with white-British adults.Results: All respondents showed a notable lack of knowledge about causes of colorectal cancer, which was more pronounced in ethnic minority than white-British adults. Interest in FS screening was uniformly high (> 60%), with more than 90% of those interested saying it would provide 'peace of mind'. The most frequently cited barrier to screening 'in your community' was embarrassment, particularly among ethnic minority groups.Conclusion: Educational materials should recognise that non-white groups may be less knowledgeable about colorectal cancer. The findings of the current study suggest that embarrassment may be a greater deterrent to participation to FS screening among ethnic minority groups, but this result requires exploration in further research

Investigation of the Role of Mitochondrial DNA in Multiple Sclerosis Susceptibility

Several lines of evidence suggest that mitochondrial genetic factors may influence susceptibility to multiple sclerosis. To explore this hypothesis further, we re-sequenced the mitochondrial genome (mtDNA) from 159 patients with multiple sclerosis and completed a haplogroup analysis including a further 835 patients and 1,506 controls. A trend towards over-representation of super-haplogroup U was the only evidence for association with mtDNA that we identified in these samples. In a parallel analysis of nuclear encoded mitochondrial genes, we also found a trend towards association with the complex I gene, NDUFS2. These results add to the evidence suggesting that variation in mtDNA and nuclear encoded mitochondrial genes may contribute to disease susceptibility in multiple sclerosis

Serum carbon and nitrogen stable isotopes as potential biomarkers of dietary intake and their relation with incident type 2 diabetes: the EPIC-Norfolk study.

BACKGROUND: Stable-isotope ratios of carbon (¹³C/¹²C, expressed as δ¹³C) and nitrogen (¹⁵N/¹⁴N, or δ¹⁵N) have been proposed as potential nutritional biomarkers to distinguish between meat, fish, and plant-based foods. OBJECTIVE: The objective was to investigate dietary correlates of δ¹³C and δ¹⁵N and examine the association of these biomarkers with incident type 2 diabetes in a prospective study. DESIGN: Serum δ¹³C and δ¹⁵N (‰) were measured by using isotope ratio mass spectrometry in a case-cohort study (n = 476 diabetes cases; n = 718 subcohort) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk population-based cohort. We examined dietary (food-frequency questionnaire) correlates of δ¹³C and δ¹⁵N in the subcohort. HRs and 95% CIs were estimated by using Prentice-weighted Cox regression. RESULTS: Mean (±SD) δ¹³C and δ¹⁵N were -22.8 ± 0.4‰ and 10.2 ± 0.4‰, respectively, and δ¹³C (r = 0.22) and δ¹⁵N (r = 0.20) were positively correlated (P < 0.001) with fish protein intake. Animal protein was not correlated with δ¹³C but was significantly correlated with δ¹⁵N (dairy protein: r = 0.11; meat protein: r = 0.09; terrestrial animal protein: r = 0.12, P ≤ 0.013). δ¹³C was inversely associated with diabetes in adjusted analyses (HR per tertile: 0.74; 95% CI: 0.65, 0.83; P-trend < 0.001], whereas δ¹⁵N was positively associated (HR: 1.23; 95% CI: 1.09, 1.38; P-trend = 0.001). CONCLUSIONS: The isotope ratios δ¹³C and δ¹⁵N may both serve as potential biomarkers of fish protein intake, whereas only δ¹⁵N may reflect broader animal-source protein intake in a European population. The inverse association of δ¹³C but a positive association of δ¹⁵N with incident diabetes should be interpreted in the light of knowledge of dietary intake and may assist in identifying dietary components that are associated with health risks and benefits.The EPIC-Norfolk study is supported by program grants from the Medical Research Council UK and Cancer Research UK. MRC Epidemiology Unit core support is acknowledged (MC_UU_12015/1 and MC_UU_12015/5). TCO and CKK were supported by the Wellcome Trust (grant no. 074229/Z/04/Z).This version is the published accepted manuscript, distributed under a Creative Commons Attribution License 2.0. It can also be found on the publisher's website at: http://ajcn.nutrition.org/content/early/2014/07/02/ajcn.113.068577.abstrac

Dietary nitrate improves vascular function in patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled study

Background: The beneficial cardiovascular effects of vegetables may be underpinned by their high inorganic nitrate content. Objective: We sought to examine the effects of a 6-wk once-daily intake of dietary nitrate (nitrate-rich beetroot juice) compared with placebo intake (nitrate-depleted beetroot juice) on vascular and platelet function in untreated hypercholesterolemics. Design: A total of 69 subjects were recruited in this randomized, double-blind, placebo-controlled parallel study. The primary endpoint was the change in vascular function determined with the use of ultrasound flow-mediated dilatation (FMD). Results: Baseline characteristics were similar between the groups, with primary outcome data available for 67 patients. Dietary nitrate resulted in an absolute increase in the FMD response of 1.1% (an ∼24% improvement from baseline) with a worsening of 0.3% in the placebo group (P 1% of this change, with the proportions of Rothia mucilaginosa trending to increase and Neisseria flavescens (P < 0.01) increased after nitrate treatment relative to after placebo treatment. Conclusions: Sustained dietary nitrate ingestion improves vascular function in hypercholesterolemic patients. These changes are associated with alterations in the oral microbiome and, in particular, nitrate-reducing genera. Our findings provide additional support for the assessment of the potential of dietary nitrate as a preventative strategy against atherogenesis in larger cohorts. This trial was registered at clinicaltrials.gov as NCT01493752

Characterization of the innate immune response to chronic aspiration in a novel rodent model

<p>Abstract</p> <p>Background</p> <p>Although chronic aspiration has been associated with several pulmonary diseases, the inflammatory response has not been characterized. A novel rodent model of chronic aspiration was therefore developed in order to investigate the resulting innate immune response in the lung.</p> <p>Methods</p> <p>Gastric fluid or normal saline was instilled into the left lung of rats (n = 48) weekly for 4, 8, 12, or 16 weeks (n = 6 each group). Thereafter, bronchoalveolar lavage specimens were collected and cellular phenotypes and cytokine concentrations of IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, GM-CSF, IFN-gamma, TNF-alpha, and TGF-beta were determined.</p> <p>Results</p> <p>Following the administration of gastric fluid but not normal saline, histologic specimens exhibited prominent evidence of giant cells, fibrosis, lymphocytic bronchiolitis, and obliterative bronchiolitis. Bronchoalveolar lavage specimens from the left (treated) lungs exhibited consistently higher macrophages and T cells with an increased CD4:CD8 T cell ratio after treatment with gastric fluid compared to normal saline. The concentrations of IL-1alpha, IL-1beta, IL-2, TNF-alpha and TGF-beta were increased in bronchoalveolar lavage specimens following gastric fluid aspiration compared to normal saline.</p> <p>Conclusion</p> <p>This represents the first description of the pulmonary inflammatory response that results from chronic aspiration. Repetitive aspiration events can initiate an inflammatory response consisting of macrophages and T cells that is associated with increased TGF-beta, TNF-alpha, IL-1alpha, IL-1beta, IL-2 and fibrosis in the lung. Combined with the observation of gastric fluid-induced lymphocyitic bronchiolitis and obliterative bronchiolitis, these findings further support an association between chronic aspiration and pulmonary diseases, such as obliterative bronchiolitis, pulmonary fibrosis, and asthma.</p

Rationale, design and protocol of a longitudinal study assessing the effect of total knee arthroplasty on habitual physical activity and sedentary behavior in adults with osteoarthritis

Background: Physical activity levels are decreased and sedentary behaviour levels are increased in patients with knee osteoarthritis (OA). However, previous studies have shown that following total knee arthroplasty (TKA), objectively measured physical activity levels do not change compared to before the surgery. Very few studies have objectively assessed sedentary behaviour following TKA. This study aims to assess patterns of objective habitual physical activity and sedentary behaviour in patients with knee OA and to determine whether these change following TKA. Methods: Patients diagnosed with knee osteoarthritis and scheduled for unilateral primary total knee arthroplasty will be recruited from the Orthopaedic Division at the Charlotte Maxeke Johannesburg Academic Hospital. Eligible participants will have assessments completed one week before the scheduled arthroplasty, six weeks, and six months post-operatively. The primary outcomes are habitual physical activity and sedentary behaviour which will be measured using accelerometry (Actigraph GTX3+ and activPal monitors) at the specific time points. The secondary outcomes will be improvements in osteoarthritis-specific quality of life measures using the following questionnaires: Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee injury and Osteoarthritis Outcome Score (KOOS), Oxford Knee Score (OKS), Knee Society Clinical Rating System (KSS), UCLA activity index; subjective pain scores, and self reported sleep quality.Discussion: The present study will contribute to the field of musculoskeletal health by providing a rich detailed description of the patterns of accumulation of physical activity and sedentary behaviour in patients with knee OA. These data will contribute to existing knowledge using an objective measurement for the assessment of functional ability after total knee arthroplasty. Although studies have used accelerometry to measure physical activity in knee OA patients, the data provided thus far have not delved into the detailed patterns of how and when physical activity is accumulated before and after TKA. Accurate assessment of physical activity is important for physical activity interventions that target special populations