Transgenic overexpression of miR-133a in skeletal muscle

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) are a class of non-coding regulatory RNAs of ~22 nucleotides in length. miRNAs regulate gene expression post-transcriptionally, primarily by associating with the 3' untranslated region (UTR) of their regulatory target mRNAs. Recent work has begun to reveal roles for miRNAs in a wide range of biological processes, including cell proliferation, differentiation and apoptosis. Many miRNAs are expressed in cardiac and skeletal muscle, and dysregulated miRNA expression has been correlated with muscle-related disorders. We have previously reported that the expression of muscle-specific miR-1 and miR-133 is induced during skeletal muscle differentiation and miR-1 and miR-133 play central regulatory roles in myoblast proliferation and differentiation in vitro.</p> <p>Methods</p> <p>In this study, we measured the expression of miRNAs in the skeletal muscle of mdx mice, an animal model for human muscular dystrophy. We also generated transgenic mice to overexpress miR-133a in skeletal muscle.</p> <p>Results</p> <p>We examined the expression of miRNAs in the skeletal muscle of <it>mdx </it>mice. We found that the expression of muscle miRNAs, including miR-1a, miR-133a and miR-206, was up-regulated in the skeletal muscle of <it>mdx </it>mice. In order to further investigate the function of miR-133a in skeletal muscle in vivo, we have created several independent transgenic founder lines. Surprisingly, skeletal muscle development and function appear to be unaffected in miR-133a transgenic mice.</p> <p>Conclusions</p> <p>Our results indicate that miR-133a is dispensable for the normal development and function of skeletal muscle.</p

Markers of cerebral damage during delirium in elderly patients with hip fracture

BACKGROUND: S100B protein and Neuron Specific Enolase (NSE) can increase due to brain cell damage and/or increased permeability of the blood-brain-barrier. Elevation of these proteins has been shown after various neurological diseases with cognitive dysfunction. Delirium is characterized by temporal cognitive deficits and is an important risk factor for dementia. The aim of this study was to compare the level of S100B and NSE of patients before, during and after delirium with patients without delirium and investigate the possible associations with different subtypes of delirium. METHODS: The study population were patients aged 65 years or more acutely admitted after hip fracture. Delirium was diagnosed by the Confusion Assessment Method and the subtype by Delirium Symptom interview. In maximal four serum samples per patient S100B and NSE levels were determined by electrochemiluminescence immunoassay. RESULTS: Of 120 included patients with mean age 83.9 years, 62 experienced delirium. Delirious patients had more frequently pre-existing cognitive impairment (67% vs. 18%, p<0.001). Comparing the first samples during delirium to samples of non-delirious patients, a difference was observed in S100B (median 0.16 versus 0.10 ug/L, p=<0.001), but not in NSE (median 11.7 versus 11.7 ng/L, p=0.97). Delirious state (before, during, after) (p<0.001), day of blood withdrawal (p<0.001), pre- or postoperative status (p=0.001) and type of fracture (p=0.036) were all associated with S100B level. The highest S100B levels were found 'during' delirium. S100B levels 'before' and 'after' delirium were still higher than those from 'non-delirious' patients. No significant difference in S100B (p=0.43) or NSE levels (p=0.41) was seen between the hyperactive, hypoactive and mixed subtype of delirium. CONCLUSIONS: Delirium was associated with increased level of S100B which could indicate cerebral damage either due to delirium or leading to delirium. The possible association between higher levels of S100B during delirium and the higher risk of developing dementia after delirium is an interesting field for future research. More studies are needed to elucidate the role of S100B proteins in the pathophysiological pathway leading to delirium and to investigate its possibility as biomarker for deliriu

The effects of melatonin versus placebo on delirium in hip fracture patients: study protocol of a randomised, placebo-controlled, double blind trial

<p>Abstract</p> <p>Background</p> <p>With an ageing population, older persons become a larger part of the hospital population. The incidence of delirium is high in this group, and experiencing delirium has major short- and long-term sequelae, which makes prevention crucial. During delirium, a disruption of the sleep-wake cycle is frequently observed. Melatonin plays an important role in the regulation of the sleep-wake cycle, so this raised the hypothesis that alterations in the metabolism of melatonin might play an important role in the development of delirium. The aim of this article is to describe the design of a randomised, placebo controlled double-blind trial that is currently in progress and that investigates the effects of melatonin versus placebo on delirium in older, postoperative hip fracture patients.</p> <p>Methods/Design</p> <p>Acutely hospitalised patients aged 65 years or older admitted for surgical repair of hip fracture are randomised (n = 452) into a treatment or placebo group. Prophylactic treatment consists of orally administered melatonin (3 mg) at 21:00 h on five consecutive days. The primary outcome is the occurrence of delirium, to be diagnosed according to the Confusion Assessment Method, within eight days after start of the study medication. Secondary outcomes are delirium severity, measured by the Delirium Rating Scale; duration of delirium; differences in subtypes of delirium; differences in total length of hospital stay; total dose of antipsychotics and/or benzodiazepine use during delirium; and in-hospital complications. In the twelve-month follow up visit, cognitive function is measured by a Mini-Mental state examination and the Informant Questionnaire on Cognitive Decline in the Elderly. Functional status is assessed with the Katz ADL index score (patient and family version) and grip strength measurement. The outcomes of these assessments are compared to the outcomes that were obtained during admission.</p> <p>Discussion</p> <p>The proposed study will contribute to our knowledge because studies on the prophylactic treatment of delirium with long term follow up remain scarce. The results may lead to a prophylactic treatment for frail older persons at high risk for delirium that is safe, effective, and easily implementable in daily practice.</p> <p>Trial registration</p> <p>Dutch Clinical Trial Registry: <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1576">NTR1576</a></p

Genome-Wide Interaction Analysis with DASH Diet Score Identified Novel Loci for Systolic Blood Pressure.

OBJECTIVE: We examined interactions between genotype and a Dietary Approaches to Stop Hypertension (DASH) diet score in relation to systolic blood pressure (SBP). METHODS: We analyzed up to 9,420,585 biallelic imputed single nucleotide polymorphisms (SNPs) in up to 127,282 individuals of six population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE; n=35,660) and UK Biobank (n=91,622) and performed European population-specific and cross-population meta-analyses. RESULTS: We identified three loci in European-specific analyses and an additional four loci in cross-population analyses at P for interaction < 5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency = 0.03) and the DASH diet score (P for interaction = 4e-8; P for heterogeneity = 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (P for interaction = 9.4e-7) and 0.20±0.06 mm Hg (P for interaction = 0.001) in CHARGE and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants (P = 4e-273) and cis-DNA methylation quantitative trait loci (mQTL) variants (P = 1e-300). While the closest gene for rs117878928 is MTHFS, the highest narrow sense heritability accounted by SNPs potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1. CONCLUSION: We demonstrated gene-DASH diet score interaction effects on SBP in several loci. Studies with larger diverse populations are needed to validate our findings

Risk factors for delirium in acutely admitted elderly patients: a prospective cohort study

BACKGROUND: Delirium is a neuropsychiatric syndrome frequently observed in elderly hospitalised patients and can be found in any medical condition. Due to the severe consequences, early recognition of delirium is important in order to start treatment in time. Despite the high incidence rate, the occurrence of delirium is not always identified as such. Knowledge of potential risk factors is important. The aim of the current study is to determine factors associated with the occurrence of a prevalent delirium among elderly patients acutely admitted to an internal medicine ward. METHODS: All consecutive patients of 65 years and over acutely admitted to the Department of Internal Medicine of the Academic Medical Centre, Amsterdam, a university hospital, were asked to participate. The presence of delirium was determined within 48 hrs after admission by an experienced geriatrician. RESULTS: In total, 126 patients were included, 29% had a prevalent delirium after acute admission. Compared to patients without delirium, patients with delirium were older, more often were cognitively and physically impaired, more often were admitted due to water and electrolyte disturbances, and were less often admitted due to malignancy or gastrointestinal bleeding. Independent risk factors for having a prevalent delirium after acute admission were premorbid cognitive impairment, functional impairment, an elevated urea nitrogen level, and the number of leucocytes. CONCLUSIONS: In this study, the most important independent risk factors for a prevalent delirium after acute admission were cognitive and physical impairment, and a high serum urea nitrogen concentration. These observations might contribute to an earlier identification and treatment of delirium in acutely admitted elderly patients

Results of noninvasive ventilation in very old patients

International audienceABSTRACT: BACKGROUND: Noninvasive ventilation (NIV) is frequently used for the management of acute respiratory failure (ARF) in very old patients (>80 years), often in the context of a do-not-intubate order (DNI). We aimed to determine its efficacy and long-term outcome. METHODS: Prospective cohort of all patients admitted to the medical ICU of a tertiary hospital during a 2-year period and managed using NIV. Characteristics of patients, context of NIV, and treatment intensity were compared for very old and younger patients. Six-month survival and functional status were assessed in very old patients. RESULTS: During the study period, 1,019 patients needed ventilatory support and 376 (37%) received NIV. Among them, 163 (16%) very old patients received ventilatory support with 60% of them managed using NIV compared with 32% of younger patients (p < 0.0001). Very old patients received NIV more frequently with DNI than in younger patients (40% vs. 8%). Such cases were associated with high mortality for both very old and younger patients. Hospital mortality was higher in very old than in younger patients but did not differ when NIV was used for cardiogenic pulmonary edema or acute-on-chronic respiratory failure (20% vs. 15%) and in postextubation (15% vs. 17%) out of a context of DNI. Six-month mortality was 51% in very old patients, 67% for DNI patients, and 77% in case of NIV failure and endotracheal intubation. Of the 30 hospital survivors, 22 lived at home and 13 remained independent for activities of daily living. CONCLUSIONS: Very old patients managed using NIV have an overall satisfactory 6-month survival and functional status, except for endotracheal intubation after NIV failure

Assessing Quality of Care of Elderly Patients Using the ACOVE Quality Indicator Set: A Systematic Review

Background: Care of the elderly is recognized as an increasingly important segment of health care. The Assessing Care Of Vulnerable Elderly (ACOVE) quality indicators (QIs) were developed to assess and improve the care of elderly patients. Objectives: The purpose of this review is to summarize studies that assess the quality of care using QIs from or based on ACOVE, in order to evaluate the state of quality of care for the reported conditions. Methods: We systematically searched MEDLINE, EMBASE and CINAHL for English-language studies indexed by February 2010. Articles were included if they used any ACOVE QIs, or adaptations thereof, for assessing the quality of care. Included studies were analyzed and relevant information was extracted. We summarized the results of these studies, and when possible generated an overall conclusion about the quality of care as measured by ACOVE for each condition, in various settings, and for each QI. Results: Seventeen studies were included with 278 QIs (original, adapted or newly developed). The quality scores showed large variation between and within conditions. Only a few conditions showed a stable pass rate range over multiple studies. Overall, pass rates for dementia (interquartile range (IQR): 11%-35%), depression (IQR: 27%-41%), osteoporosis (IQR: 34%-43%) and osteoarthritis (IQR: 29-41%) were notably low. Medication management and use (range: 81%-90%), hearing loss (77%-79%) and continuity of care (76%-80%) scored higher than other conditions. Out of the 278 QIs, 141 (50%) had mean pass rates below 50% and 121 QIs (44%) had pass rates above 50%. Twenty-three percent of the QIs scored above 75%, and 16% scored below 25%. Conclusions: Quality of care per condition varies markedly across studies. Although there has been much effort in improving the care for elderly patients in the last years, the reported quality of care according to the ACOVE indicators is still relatively lo

The Ups and Downs of Mutation Frequencies during Aging Can Account for the Apert Syndrome Paternal Age Effect

Apert syndrome is almost always caused by a spontaneous mutation of paternal origin in one of two nucleotides in the fibroblast growth factor receptor 2 gene (FGFR2). The incidence of this disease increases with the age of the father (paternal age effect), and this increase is greater than what would be expected based on the greater number of germ-line divisions in older men. We use a highly sensitive PCR assay to measure the frequencies of the two causal mutations in the sperm of over 300 normal donors with a wide range of ages. The mutation frequencies increase with the age of the sperm donors, and this increase is consistent with the increase in the incidence rate. In both the sperm data and the birth data, the increase is non-monotonic. Further, after normalizing for age, the two Apert syndrome mutation frequencies are correlated within individual sperm donors. We consider a mathematical model for germ-line mutation which reproduces many of the attributes of the data. This model, with other evidence, suggests that part of the increase in both the sperm data and the birth data is due to selection for mutated premeiotic cells. It is likely that a number of other genetic diseases have similar features

Using hippocampal microRNA expression differences between mouse inbred strains to characterise miRNA function

Micro-RNAs (miRNAs) are short, single-stranded, noncoding RNAs that are involved in the regulation of protein-coding genes at the level of messenger RNA (mRNA). They are involved in the regulation of numerous traits, including developmental timing, apoptosis, immune function, and neuronal development. To better understand how the expression of the miRNAs themselves is regulated, we looked for miRNA expression differences among four mouse inbred strains, A/J, BALB/cJ, C57BL/6J, and DBA/2J, in one tissue, the hippocampus. A total of 166 miRNA RT-PCR assays were used to screen RNA pools for each strain. Twenty miRNA species that were markedly different between strains were further investigated using eight individual samples per strain, and 11 miRNAs showed significant differences across strains (p < 0.05). This is the first observation of miRNA expression differences across inbred mice strains. We conducted an in silico correlation analysis of the expression of these differentially expressed miRNAs with phenotype data and mRNA expression to better characterise the effects of these miRNAs on both phenotype and the regulation of mRNA expression. This approach has allowed us to nominate miRNAs that have potential roles in anxiety, exploration, and learning and memory

Effective Rheology of Bubbles Moving in a Capillary Tube

We calculate the average volumetric flux versus pressure drop of bubbles moving in a single capillary tube with varying diameter, finding a square-root relation from mapping the flow equations onto that of a driven overdamped pendulum. The calculation is based on a derivation of the equation of motion of a bubble train from considering the capillary forces and the entropy production associated with the viscous flow. We also calculate the configurational probability of the positions of the bubbles.Comment: 4 pages, 1 figur