Month: September 2020

Since ACOVE was designed for a vulnerable elderly population, this can lead to a biased score. Fourth, the reason for selecting a certain number and type of QIs for the assessment of care for a specific condition was not always clearly described in the studies. Difficulty in the assessment of some of the QIs could have lead to omitting these QIs from the assessment of that condition and consequently to selection bias. This can result in an incomplete picture of the quality of care of patients for the specific condition. Poor recordkeeping can influence, positively or negatively, the pass rates of various QIs. It is plausible that correct care was performed but not documented, which can lead to lower pass rates. On the other hand, poor-record keeping for the “IF” part of a rule renders the rule as inapplicable and hence failure to provide the correct care will go undetected. Irrespective of the ability to measure QI pass rates, lack of documentation can be an indicator of poor quality because it hampers continuity of care and contributes to miscommunication. Fifth, variation in scores of quality of care could be caused by either variation in the number of QIs used per study or by the fact that QIs focused on different aspects of care for a specific condition. Moreover, variation in the study sample sizes can cause differences in the pass rates per condition. A smaller study population gives more opportunity for chance findings. We suggest that future studies should explicitly mention and discuss these factors. To our knowledge, this is the first review on assessing quality of care of elderly patients using the ACOVE criteria. Although our literature search has been systematic and extensive in order to give a complete overview of the studies using ACOVE for assessing the elderly population care, it is still plausible that some articles were missed. Conclusion and recommendation Our results showed that despite the large efforts that have been expended in improving the care for elders in the last years, quality of care for elderly patients as measured by the ACOVE criteria is still poor. This is particularly worrisome as the ACOVE criteria are meant to represent a minimal standard of care for the vulnerable elderly population, although not all of the included studies included a measure of vulnerability in their inclusion criteria. The majority of the assessed conditions and domains of care seem to merit further quality improvement effort and/or a better understanding of why some QIs have low pass rates. The ACOVE QI set provides a promising and uniquely comprehensive method for assessing the quality of care of elderly patients. However, to improve the extent to which studies can be compared, two important factors should be taken into CT99021 consideration. First, researchers should strive to assess all QIs for a domain of interest, instead of a small selection thereof. This is especially important because there may be an association between ease of measuring a QI and its score. Second, should one require the adaptation of original QIs, then one should measure the same underlying concept implied by the original QIs and explicitly report on the nature of the adaptation.

SIM2 was originally thought to contribute to Down’s syndrome. As a transcription factor, murine SIM2 mediates gene expression through CNS midline enhancer element with its dimerization partner ARNT via ARNT carboxy-terminus. The transcription AZ 960 factor c-myb regulates SIM2 transcription in glioblastoma cells, and a nuclear localization signal mediates nuclear localization of SIM2. A prior in silico bioinformatics approach using the Cancer Genome Anatomy Project database of the National Cancer Institute identified SIM2 as associated with colon, pancreas and prostate carcinomas, while absent in the corresponding normal tissues. Two different spliced isoforms of SIM2 transcript, SIM2- long and SIM2-short, have been reported while their differential function in humans are not known yet. SIM2-s was specifically expressed in early stages of colon cancer. Antisense inhibition of SIM2-s expression by antisense oligos caused growth inhibition and apoptosis in colon cancer cell line RKO and tumor growth in nude mice and also in pancreatic cancer cell line CAPAN1. Apoptosis was induced by SIM2-s inhibition in the RKO colon cancer cell line. SIM2-s was also found to have tumor suppressive activity in breast cancer. The invasion potential of glioblastoma was decreased significantly by SIM2s inhibition, consistent with a decrease in the expression of matrix metalloproteinase 2 at both mRNA and protein levels. We have previously reported SIM2 as a potential biomarker and immunotherapy target for human prostate cancer. Although SIM2-s expression has been associated with aggressive histopathology in prostate cancer, and overexpressing ectopic SIM2s enhanced survival in certain conditions in PC3AR+ cells, the functional role of SIM2 gene in prostate cancer cell is largely unknown. In this study we sought to elucidate the functional role of SIM2 in PCa using a gene silencing approach and characterization of molecular and functional changes by both gene expression profiling and metabolomic profiling. In our previous biomarker identification efforts, we have identified SIM2 as a potential biomarker for PCa. Thanks to its overexpression in prostate tumors and its highly restricted expression in humans, we proposed to use SIM2 as an immunotherapy target and were able to identify 5 HLA-A2.1, SIM2-derived immunogenic epitopes. In the present study we attempted to characterize the role of SIM2 in prostate cancer using a short hairpin RNA-induced gene silencing approach in PC3 cells as a model. We focused on profiling both the transcriptome and metabolome in SIM2low and normal PC3 cells, and evaluated the impact of SIM2 silencing on cell signaling and function. The SIM2s isoform has been reported to be expressed in colon, pancreas, and prostate tumors while absent in the corresponding benign tissues. We found that SIM2 genes are detectable in all these prostate cancer cells by real time PCR. However the expression levels in DU145 and LNCaP are relatively lower than other prostate cancer cells while PC3 cells express moderate level of SIM2 genes which are consistent with other report. The whole spectrum of regulation of gene expression by the transcription factor SIM2 is still poorly defined.

Over the past decade late gadolinium-enhanced MRI has become established as one of the most useful techniques for noninvasive measurement of myocardial viability. In recent years late gadolinium-enhanced MRI has been able to detect fibrosis in patients with hypertrophic and dilated cardiomyopathy, systemic vasculitus, arrhythmogenic right ventricular disease and DMD and Becker muscular dystrophy. Late gadolinium-enhanced MRI methods have been developed for imaging mice post myocardial infarction, but to date no studies of congenital cardiomyopathies have been reported. We detected late gadolinium enhancement in 3 out of 9 mdx mice of 6 months of age. By 12 months of age, all mdx mice displayed some late gadolinium enhancement. No late gadolinium enhancement was identified in control mice. Similar to clinical reports, the extent of late gadolinium enhancement correlated with the degree of cardiac impairment and remodeling. Histology has shown that fibrosis develops in the hearts of mdx mice from 6 months, the extent related to impairment of cardiac function. The in vivo methods presented here will be useful in assessing the efficacy of gene therapy studies in the mdx mouse. This study highlights the power of comprehensive and serial non-invasive imaging for assessment of cardiac SJN 2511 ALK inhibitor function in experimental models of human disease. The detection of abnormalities in young mice gives important information regarding the speed of disease progression and response to therapy. To our knowledge, there have been no reports of cardiac MR imaging in mice as young as one month. Many transgenic animals develop cardiac abnormalities at an early age and may not survive adolescence. The results presented here demonstrate that it is feasible to image one-month-old mice and detect early alterations in function that could be valuable in characterization of animal models of human cardiac disease. Further, we show that small animal MRI measurements are directly comparable to those made in patients, increasing the relevance of pre-clinical data and speeding translation of novel therapies. Pulmonary arterial hypertension is a progressive disease characterized by increased pulmonary vascular resistance and pulmonary arterial pressure leading to right heart failure. The pathogenesis of PAH is complex involving pulmonary vasoconstriction, remodeling of the pulmonary vascular wall, and in situ thrombosis. It is becoming increasingly recognized that immune system activation and inflammation play important roles in the pathogenesis of PAH. The complement system is a key sentry of innate immunity acting as a first line of defense against injurious stimuli and invading pathogens. It may be activated by the classical, alternative or lectin pathways. All three pathways converge at the level of C3 cleavage and activation leading to the production of opsonins, the membrane attack complex, and anaphylatoxins. The anaphylatoxins are particularly interesting as potential effectors in PAH because they recruit inflammatory cells, cause degranulation of mast cells, increase vascular permeability and stimulate pulmonary vascular smooth muscle contraction. In addition, complement components C3 and C4a have been implicated as biomarkers of idiopathic pulmonary hypertension.

To further interrogate this pathway, we used a super-repressor containing mutations at position S32 and S36 of IkBa that prevents IKKb-mediated phosphorylation. This abolished the effects of H2O2 on NF-kB activation and CTCF downregulation providing further evidence for canonical activation. The activation of NF-kB results in the induction or suppression of downstream genes depending on the presence and binding of different dimers. With low dose H2O2 exposure, we observed the induction and binding of a p65/p50 heterodimer to the CTCF promoter. The presence of a NF-kB binding site on the CTCF promoter has been previously recognized. This study with EGF induction and UV light involved both p65/p50 heterodimers, as well as p50 homodimer formation. While p65/p50 heterodimers generally activate target gene transcription, transcriptional outcomes are subject to the regulation of a dynamic balance between coactivators and corepressors. Our ChIP data indicated that the corepressor HDAC1 was BI-D1870 recruited to the CTCF gene promoter in association with p50 and p65 resulting in decreased CTCF expression. This occurred at a specific region in the CTCF promoter. Other sites failed to demonstrate significant p65/p50 binding and were used as controls. The downregulation of CTCF was mediated through NF-kB signaling, we utilized two approaches. First, we introduced an IkBa super-repressor in which mutations at IkBa phosphorylation sites render it unresponsive to canonical upstream inducers. This super-repressor robustly blocked NF-kB activity and CTCF downregulation. Secondly, we employed IkBa+/2 mice which directly induced higher basal NF-kB activity. These IkBa+/2 animals have increased activation of NF-kB in the prostate. Using a polymorphism to identify different alleles, we demonstrate that the activation of NF-kB alone leads to increased IGF2 LOI in mouse prostate and decreased CTCF expression when compared to WT. These IkBa+/2 mice also demonstrate increased prostate cancer risk with aging when utilized in genetic models. Through the use of these two approaches, the important role of the NF-kB/ CTCF pathway in controlling IGF2 imprinting was confirmed. We do not, however, discount other minor effects that H2O2 might have on IGF2 biallelic expression including altering other transcription factors. The significance of the current study lies in the elucidation of a mechanism for oxidative stress to promote altered imprinting through canonical NF-kB signaling. Inflammation plays an important role in the development of age-related cancers, but mechanistic data linking inflammation to epigenetic alterations has been lacking. It is anticipated that antagonists of inflammation that inhibit NF-kB, including the spice curcumin and diterpenes found in coffee, would modulate imprinting. Our study also suggests a pivotal role for CTCF in modulating not only imprinting, but potentially regional hypermethylation. CTCF levels have been found to decrease with aging and cancer. Finally, these observations may help explain the altered epigenetic landscape seen with aging that underlies the increased risk of cancer.

Phase III studies are continuing and, because of the low prevalence of multiple sclerosis in Asia, no investigational sites in that region have been included. Rates of alcohol consumption amongst women of reproductive age are steadily increasing, with almost half of all young women in the UK are reported to drink during the week and a fifth reported to binge drink. Chronic high alcohol intake during pregnancy is associated with fetal alcohol spectrum disorder, which encompasses a range of developmental problems, including characteristic facial features, altered neurodevelopment, cognitive and behavioural disabilities and fetal growth restriction. It is recognised that FASD is entirely preventable through alcohol abstinence but worldwide 30%, and up to 60%, of pregnant women consume alcohol during pregnancy.

Diagnosis of FASD is difficult due to phenotypic variation and it is often a diagnosis of exclusion. One of the most consistent features of FASD is FGR. Poor placental development is a major underlying pathology; placentas from pregnancies with FGR are lower in weight, have increased apoptosis and reduced cell proliferation and are characterised by a more superficial invasion of trophoblast into uterine spiral arteries. FGR is also associated with altered placental function, in particular reduced activity of amino acid transporters. Alcohol and its teratogenic metabolite acetaldehyde freely cross the placenta, and accumulate in fetal blood at concentrations similar to those found in maternal blood. Length of fetal exposure to alcohol is entirely dependent on maternal metabolism, which varies between women. Despite alcohol being the most common and widely available social drug, and its association with FGR, relatively little is understood regarding its effects on the developing placenta in human pregnancies, particularly in the earliest stages of pregnancy. In the mouse, continuous exposure to high levels of ethanol during pregnancy decreases fetal growth, affecting pup development and mortality. Even at moderate levels of exposure there is significant facial dysmorphia in mice. A reduction in fetal weight and neonatal growth is also observed in rats.

Placental development is significantly altered with increased placental weight in rats following chronic high ethanol liquid diet. This R428 cost increase is accompanied by trophoblast morphological irregularities and altered blood vessel development in the nutrient-exchanging labyrinth zone. In sheep on a high ethanol diet, placental transport of system A-dependent a-amino isobutyric acid is reduced. Significant reductions in system A transport is also seen in human term placental tissue, where the effect of alcohol is dose-dependent and towards chronic levels. Acetaldehyde, a metabolite of alcohol, has well established genotoxic effects in human and in animal models. After exposure to acetaldehyde, it is found is freely present in the placenta, amniotic fluid and fetal liver in rat and sheep.