Patients with chronic obstructive pulmonary disease (COPD) often have vitamin D deficiency, which is associated with increased susceptibility to upper respiratory infection-a major precipitant of ...exacerbation. Multicentre trials of vitamin D supplementation for prevention of exacerbation and upper respiratory infection in patients with COPD are lacking. We therefore investigated whether vitamin D3 (colecalciferol) supplementation would reduce the incidence of moderate or severe COPD exacerbations and upper respiratory infections.
We did a randomised, double-blind, placebo-controlled trial of vitamin D3 supplementation in adults with COPD in 60 general practices and four Acute National Health Service Trust clinics in London, UK. Patients were allocated to receive six 2-monthly oral doses of 3 mg vitamin D3 or placebo over 1 year in a 1:1 ratio using computer-generated permuted block randomisation. Participants and study staff were masked to treatment assignment. Coprimary outcomes were time to first moderate or severe exacerbation and first upper respiratory infection. Analysis was by intention to treat. A prespecified subgroup analysis was done to assess whether effects of the intervention on the coprimary outcomes were modified by baseline vitamin D status. This trial is registered with ClinicalTrials.gov, number NCT00977873.
240 patients were randomly allocated to the vitamin D3 group (n=122) and placebo group (n=118). Vitamin D3 compared with placebo did not affect time to first moderate or severe exacerbation (adjusted hazard ratio 0·86, 95% CI 0·60-1·24, p=0·42) or time to first upper respiratory infection (0·95, 0·69-1·31, p=0·75). Prespecified subgroup analysis showed that vitamin D3 was protective against moderate or severe exacerbation in participants with baseline serum 25-hydroxyvitamin D concentrations of less than 50 nmol/L (0·57, 0·35-0·92, p=0·021), but not in those with baseline 25-hydroxyvitamin D levels of at least 50 nmol/L (1·45, 0·81-2·62, p=0·21; p=0·021 for interaction between allocation and baseline serum 25-hydroxyvitamin D status). Baseline vitamin D status did not modify the effect of the intervention on risk of upper respiratory infection (pinteraction=0·41).
Vitamin D3 supplementation protected against moderate or severe exacerbation, but not upper respiratory infection, in patients with COPD with baseline 25-hydroxyvitamin D levels of less than 50 nmol/L. Our findings suggest that correction of vitamin D deficiency in patients with COPD reduces the risk of moderate or severe exacerbation.
UK National Institute for Health Research.
Vitamin D deficiency is common in children with severe acute malnutrition, in whom it is associated with severe wasting. Ready-to-use therapeutic food (the standard treatment) contains modest amounts ...of vitamin D that do not reliably correct deficiency.
The aim of this study was to determine whether high-dose oral vitamin D3 enhances weight gain and development in children with uncomplicated severe acute malnutrition.
We conducted a randomized placebo-controlled trial of high-dose vitamin D3 supplementation in children aged 6–58 mo with uncomplicated severe acute malnutrition in Pakistan. Participants were randomly assigned to receive 2 oral doses of 200,000 IU vitamin D3 or placebo at 2 and 4 wk after starting ready-to-use therapeutic food. The primary outcome was the proportion of participants gaining >15% of baseline weight at 8 wk after starting ready-to-use therapeutic food (the end of the study). Secondary outcomes were mean weight-for-height or -length z score and the proportion of participants with delayed development at the end of the study (assessed with the Denver Development Screening Tool II), adjusted for baseline values.
Of the 194 randomly assigned children who started the study, 185 completed the follow-up and were included in the analysis (93 assigned to intervention, 92 to control). High-dose vitamin D3 did not influence the proportion of children gaining >15% of baseline weight at the end of the study (RR: 1.04; 95% CI: 0.94,1.15, P = 0.47), but it did increase the weight-for-height or -length z score (adjusted mean difference: 1.07; 95% CI: 0.49,1.65, P < 0.001) and reduce the proportion of participants with delayed global development adjusted RR (aRR): 0.49; 95% CI: 0.31, 0.77, P = 0.002, delayed gross motor development (aRR: 0.29; 95% CI: 0.13, 0.64, P = 0.002), delayed fine motor development (aRR: 0.59; 95% CI: 0.38, 0.91, P = 0.018), and delayed language development (aRR: 0.57; 95% CI: 0.34, 0.96, P = 0.036).
High-dose vitamin D3 improved the mean weight-for-height or -length z score and developmental indexes in children receiving standard therapy for uncomplicated severe acute malnutrition in Pakistan. This trial was registered at clinicaltrials.gov as NCT03170479.
Asthma exacerbations are commonly precipitated by viral upper respiratory infections (URIs). Vitamin D insufficiency associates with susceptibility to URI in patients with asthma. Trials of vitamin D ...in adults with asthma with incidence of exacerbation and URI as primary outcome are lacking.
To conduct a randomised controlled trial of vitamin D3 supplementation for the prevention of asthma exacerbation and URI (coprimary outcomes).
250 adults with asthma in London, UK were allocated to receive six 2-monthly oral doses of 3 mg vitamin D3 (n=125) or placebo (n=125) over 1 year. Secondary outcomes included asthma control test and St George's Respiratory Questionnaire scores, fractional exhaled nitric oxide and concentrations of inflammatory markers in induced sputum. Subgroup analyses were performed to determine whether effects of supplementation were modified by baseline vitamin D status or genotype for 34 single nucleotide polymorphisms in 11 vitamin D pathway genes.
206/250 participants (82%) were vitamin D insufficient at baseline. Vitamin D3 did not influence time to first severe exacerbation (adjusted HR 1.02, 95% CI 0.69 to 1.53, p=0.91) or first URI (adjusted HR 0.87, 95% CI 0.64 to 1.16, p=0.34). No clinically important effect of vitamin D3 was seen on any of the secondary outcomes listed above. The influence of vitamin D3 on coprimary outcomes was not modified by baseline vitamin D status or genotype.
Bolus-dose vitamin D3 supplementation did not influence time to exacerbation or URI in a population of adults with asthma with a high prevalence of baseline vitamin D insufficiency.
NCT00978315 (ClinicalTrials.gov).
•We report that 65% of a cohort of older adults living in sheltered accommodation in London, UK, were vitamin D deficient (serum 25-hydroxyvitamin D concentrations <50nmol/L).•Sampling in ...winter/spring, non-white ethnic origin and lack of vitamin D supplement use were independently associated with lower vitamin D status.•None of a panel of 15 single nucleotide polymorphisms in DBP, DHCR7, CYP2R1, CYP27B1, CYP24A1 or VDR associated with serum 25-hydroxyvitamin D concentrations in this population.•Vigorous efforts should be made to improve uptake of vitamin D supplements among older adults in the UK in order to protect them against vitamin D deficiency.
Despite the high prevalence of vitamin D deficiency among older adults in the UK, studies investigating the determinants of vitamin D status in this group are lacking. We conducted a cross-sectional study in 222 older adults living in sheltered accommodation in London, UK, who were screened for participation in a clinical trial of vitamin D supplementation for the prevention of acute respiratory infection. Details of potential demographic and lifestyle determinants of vitamin D status were collected by questionnaire and blood samples were taken for analysis of serum 25-hydroxyvitamin D (25OHD) concentration and DNA extraction. Fifteen single nucleotide polymorphisms (SNP) in 6 genes (DBP, DHCR7, CYP2R1, CYP27B1, CYP24A1, VDR) previously reported to associate with circulating 25(OH)D concentration were typed using Taqman allelic discrimination assays. Linear regression was used to identify environmental and genetic factors independently associated with serum 25(OH)D concentration. Mean serum 25(OH)D concentration was 42.7nmol/L (SD 22.0); 144/222 (64.9%) participants had serum 25(OH)D concentrations <50nmol/L. The following factors were independently associated with lower serum 25(OH)D concentration: non-white ethnicity (−8.6nmol/L, 95% CI −14.9 to −2.3, P=0.008); lack of vitamin D supplement consumption (−17.1nmol/L, 95% CI −23.3 to −10.9, P<0.001) vs. taking a daily supplement; sampling in Q1/January–March (−12.2nmol/L, 95% CI −21.5 to −2.9, P=0.01), and sampling in Q4/October–December (−10.3nmol/L, 95% CI −20.2 to −0.4, P=0.04) vs. sampling in Q3/July–September. None of the 15 SNP investigated independently associated with serum 25(OH)D concentration after correcting for multiple comparisons. In conclusion, vitamin D deficiency was highly prevalent among the older adults in this study; non-White ethnicity, lack of vitamin D supplement consumption and sampling in winter and spring independently associated with lower vitamin D status.
The purpose of this study was to discover what perceptions secondary school students held of the information seeking process and what behaviours the students used to initiate and carry out an ...information search. The study was conducted in a secondary school in North Central British Columbia, with students from Two Grade 8 and two Grade 10 Humanities classes. Data was collected by means of student journal writings, recorded interviews with randomly selected students and by participant observation. The study revealed that students held five principal perceptions about information seeking: that it provided active involvement for them in their own education; that it was a positive experience; that it made them aware of the importance of practising self discipline; that it taught them skills they needed to locate and select information as well as analyze, record and classify information; and that an information search involved varying degrees of student frustration. The study further revealed that student behaviours during a search for information were grouped into three areas: initiating behaviours; recording, analyzing and classifying behaviours; and organizational behaviours. Two further findings were stated: the importance of previous student practice with cooperatively planned projects; as well as the significance of locating computer facilities visibly adjacent to the School Library Resource Centre in elementary and secondary schools.
Leukemia phenotypes vary with age of onset. Delineating mechanisms of age specificity in leukemia could improve disease models and uncover new therapeutic approaches. Here, we used heterochronic ...transplantation of leukemia driven by
/
translocations to investigate the contribution of the age of the hematopoietic microenvironment to age-specific leukemia phenotypes. When driven by
, leukemia cells in the adult microenvironment sustained a myeloid phenotype, whereas the neonatal microenvironment supported genesis of mixed early B cell/myeloid leukemia. In
leukemia, the neonatal microenvironment potentiated B-lymphoid differentiation compared with the adult. Ccl5 elaborated from adult marrow stroma inhibited B-lymphoid differentiation of leukemia cells, illuminating a mechanism of age-specific lineage commitment. Our study illustrates the contribution of the developmental stage of the hematopoietic microenvironment in defining the age specificity of leukemia.
LIN28 is an RNA-binding protein that regulates the maturation of the let-7 family of microRNAs by bipartite interactions with let-7 precursors through its two distinct cold shock and zinc-knuckle ...domains. Through inhibition of let-7 biogenesis, LIN28 functions as a pluripotency factor, as well as a driver of tumorigenesis. Here, we report a fluorescence polarization assay to identify small-molecule inhibitors for both domains of LIN28 involved in let-7 interactions. Of 101,017 compounds screened, six inhibit LIN28:let-7 binding and impair LIN28-mediated let-7 oligouridylation. Upon further characterization, we demonstrate that the LIN28 inhibitor TPEN destabilizes the zinc-knuckle domain of LIN28, while LI71 binds the cold shock domain to suppress LIN28’s activity against let-7 in leukemia cells and embryonic stem cells. Our results demonstrate selective pharmacologic inhibition of individual domains of LIN28 and provide a foundation for therapeutic inhibition of the let-7 biogenesis pathway in LIN28-driven diseases.
Display omitted
•A screening pipeline developed to identify inhibitors targeting both domains of LIN28•Six compounds effectively inhibit LIN28-mediated oligouridylation of let-7•TPEN destabilizes the zinc-knuckle domain, while LI71 modulates the cold shock domain•MNA represents a minimal scaffold as a LIN28 inhibitor targeting the cold shock domain
LIN28 is an oncogenic protein that promotes transformation in malignancy by suppressing the maturation of let-7 microRNAs. Wang et al. developed a high-throughput screening strategy and identified inhibitors of LIN28 that restore mature let-7 levels.
A nanobody targeting the LIN28 Yu, Chunxiao; Wang, Longfei; Rowe, R. Grant ...
Proceedings of the National Academy of Sciences - PNAS,
03/2020, Letnik:
117, Številka:
9
Journal Article
Recenzirano
Odprti dostop
The LIN28:pre-let-7:TUTase ternary complex regulates pluripotency and oncogenesis by controlling processing of the let-7 family of microRNAs. The complex oligouridylates the 3′ ends of pre-let-7 ...molecules, leading to their degradation via the DIS3L2 exonuclease. Previous studies suggest that components of this complex are potential therapeutic targets in malignancies that aberrantly express LIN28. In this study we developed a functional epitope selection approach to identify nanobody inhibitors of the LIN28:pre-let-7:TUT4 complex. We demonstrate that one of the identified nanobodies, Nb-S2A4, targets the 106-residue LIN28:let-7 interaction (LLI) fragment of TUT4. Nb-S2A4 can effectively inhibit oligouridylation andmonouridylation of pre-let-7g in vitro. Expressing Nb-S2A4 allows maturation of the let-7 species in cells expressing LIN28, highlighting the therapeutic potential of targeting the LLI fragment.
Mitochondrial dysfunction contributes to myriad monogenic and complex pathologies. To understand the underlying mechanisms, it is essential to define the full complement of proteins that modulate ...mitochondrial function. To identify such proteins, we performed a meta-analysis of publicly available gene expression data. Gene co-expression analysis of a large and heterogeneous compendium of microarray data nominated a sub-population of transcripts that whilst highly correlated with known mitochondrial protein-encoding transcripts (MPETs), are not themselves recognized as generating proteins either localized to the mitochondrion or pertinent to functions therein. To focus the analysis on a medically-important condition with a strong yet incompletely understood mitochondrial component, candidates were cross-referenced with an MPET-enriched module independently generated via genome-wide co-expression network analysis of a human heart failure gene expression dataset. The strongest uncharacterized candidate in the analysis was Leucine Rich Repeat Containing 2 (LRRC2). LRRC2 was found to be localized to the mitochondria in human cells and transcriptionally-regulated by the mitochondrial master regulator Pgc-1α. We report that Lrrc2 transcript abundance correlates with that of β-MHC, a canonical marker of cardiac hypertrophy in humans and experimentally demonstrated an elevation in Lrrc2 transcript in in vitro and in vivo rodent models of cardiac hypertrophy as well as in patients with dilated cardiomyopathy. RNAi-mediated Lrrc2 knockdown in a rat-derived cardiomyocyte cell line resulted in enhanced expression of canonical hypertrophic biomarkers as well as increased mitochondrial mass in the context of increased Pgc-1α expression. In conclusion, our meta-analysis represents a simple yet powerful springboard for the nomination of putative mitochondrially-pertinent proteins relevant to cardiac function and enabled the identification of LRRC2 as a novel mitochondrially-relevant protein and regulator of the hypertrophic response.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Access to culturally‐safe dementia assessment, diagnosis, and care in Indigenous populations worldwide is an emerging challenge. In 2018, the World Health Organization recognized ...traditional healers as stakeholders in dementia care and prevention globally. Traditional healers contribute to dementia assessment, diagnosis, and care in unique ways, and play a catalytic role in the process of culturally‐safe dementia care planning and assessment with health care providers at the community level. The purpose of this scoping review was to understand the roles and experiences of traditional healers, to evaluate strategies for integration between Indigenous traditional healing and western dementia care approaches, and to examine the policy barriers and research gaps in North America, Australia, and New Zealand.
Method
The scoping review methodology used was the Joanna Briggs Institute (JBI) approach that included six steps: protocol development based on participants, content and context framework, development of a search strategy, selection of relevant studies, charting of relevant data, synthesis, and reporting of results, and conducting stakeholder consultation.
Result
Searched English literature in select bibliographic databases, including CINAHL, EMBASE, Medline and PsycINFO. The initial search identified 516 papers published between 2000 and 2020 that met the search criteria. After 164 duplicates were removed, we screened 352 titles and s, excluding the 209 that did not meet the inclusion criteria. The second stage review of 143 full‐text studies resulted in the further exclusion of 141 studies. Only two studies from Canada met all inclusion criteria for this study and explored the potential integration of traditional healing in dementia care and the roles, perceptions, and experiences of traditional healers.
Conclusion
This study emphasizes the inclusion of traditional healers, knowledge‐holders, and Grandmother groups that can contribute to building an evidence‐based dementia care decision‐making process for Indigenous people with dementia. Integration of Indigenous traditional healing and medicine in dementia care is a path to culturally‐safe dementia care and assessment. diagnosis. The study has policy implications for health care provider education and advocacy needs to engage with traditional healers in dementia care. It recommends two community‐based models to establish culturally‐safe dementia care between traditional healers and healthcare providers in a seamless collaboration.
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