Meta-analysis of statins in chronic kidney disease: who benefits?

Background: Attempts to reduce the burden of vascular disease in advanced chronic kidney disease (CKD) by control of lipids have not been as successful as predicted. Aim: To determine the extent to which the effectiveness of statins varies by kidney class. Design: Meta-analysis. Methods: We selected randomized trials of statin vs. placebo that gave outcomes for CKD3 (eGFR 30–59 ml/min), CKD4 (eGFR 15–29 ml/min), CKD5 (eGFR < 15 ml/min)/5D(dialysis) and transplant patients separately. Data sources were the Cholesterol Triallists’ Treatment Collaboration and previously published meta-analyses. Main outcome measures were major cardiovascular events (MACE), cardiovascular death and all-cause mortality (ACM). Results: A total of 13 studies provided 19 386 participants with CKD3, 2565 with CKD4, 7051 with CKD5/5D and 2102 with a functioning renal transplant. Statins reduced MACE (pooled HR 0.72, 95% CI 0.67–0.78) and ACM (0.82, 0.73–0.91) in CKD3; probably reduced MACE (0.78, 0.62–0.99) in CKD4; and probably reduced cardiovascular death (0.62, 0.40–0.96) in renal transplants. There were no cardiovascular or ACM data in CKD4; there was no convincing evidence of benefit for any outcome in CKD5/5D; and no significant reduction in MACE or ACM in patients with a functioning transplant. Conclusions: Statins are indicated in CKD3, probably indicated in CKD4, not indicated in CKD5/5D and probably indicated in patients with a functioning transplant. Too few patients with CKD4 and renal transplants have been included in lipid lowering trials for confident conclusions to be drawn

The role of the Prader-Willi syndrome critical interval for epigenetic regulation, transcription and phenotype

Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder caused by loss of expression of the paternally inherited genes on chromosome 15q11.2-q13. However, the core features of PWS have been attributed to a critical interval (PWS-cr) within the 15q11.2-q13 imprinted gene cluster, containing the small nucleolar RNA (snoRNA) SNORD116 and non-coding RNA IPW (Imprinted in Prader-Willi) exons. SNORD116 affects the transcription profile of hundreds of genes, possibly via DNA methylation or post-transcriptional modification, although the exact mechanism is not completely clear. IPW on the other hand has been shown to specifically modulate histone methylation of a separate imprinted locus, the DLK1-DIO3 cluster, which itself is associated with several neurodevelopmental disorders with similarities to PWS. Here we review what is currently known of the molecular targets of SNORD116 and IPW and begin to disentangle their roles in contributing to the Prader-Willi Syndrome phenotype

The challenges of renal replacement therapy and renal palliative care in the elderly

Much of the increase in take on rate for dialysis in recent years is accounted for by older patients in whom a treatment as demanding as dialysis was previously thought to be contraindicated. The decision to dialyse the elderly often remains difficult, as recent data suggest that those with significant comorbidities are unlikely to survive more than 4-6 months longer on dialysis than they would have done if treated conservatively. It is also important to recognise that conservative treatment is not simply defined by the decision not to dialyse. Good conservative care comprises active disease management eg treatment of anaemia with erythropoietin stimulating agents and intravenous iron, and supportive care which may become increasingly complex eg pain relief with fentanyl and alfentanyl, towards the end of life. Those older patients who do decide to dialyse must contend with all the usual end of life issues facing older people, in addition to the option, denied to the rest of us, of dialysis withdrawal which effectively allows them to die at a time of their choosing

EHMT1/GLP; biochemical function and association with brain disorders

The gene EHMT1 that encodes the Euchromatic Histone Methyltransferase-1, also known as GLP (G9a-like protein), has been associated with a number of neurodevelopmental and neurodegenerative disorders. GLP is a member of the euchromatic lysine histone methyltransferase family, along with EHMT2 or G9A. As its name implies, Ehmt1/GLP is involved in the addition of methyl groups to histone H3 lysine 9, a generally repressive mark linked to classical epigenetic process such as genomic imprinting, X-inactivation, and heterochromatin formation. However, GLP also plays both a direct and indirect role in regulating DNA-methylation. Here, we discuss what is currently known about the biochemical function of Ehmt1/GLP and its association, via various genetic studies, with brain disorders

Extreme relativistic electron fluxes at geosynchronous orbit: Analysis of GOES E > 2 MeV electrons

Relativistic electrons (E > 1 MeV) cause internal charging on satellites and are an important space weather hazard. A key requirement in space weather research concerns extreme events and knowledge of the largest flux expected to be encountered over the lifetime of a satellite mission. This is interesting both from a scientific and practical point of view since satellite operators, engineers and the insurance industry need this information to better evaluate the effects of extreme events on their spacecraft. Here we conduct an extreme value analysis of daily averaged E > 2 MeV electron fluxes from the Geostationary Operational Environmental Satellites (GOES) during the 19.5 year period from 1 January 1995 to 30 June 2014. We find that the daily averaged flux measured at GOES West is typically a factor of ~2.5 higher than that measured at GOES East and we conduct independent analyses for these two locations. The 1 in 10, 1 in 50 and 1 in 100 year daily averaged E > 2 MeVelectron fluxes at GOES West are 1.84×105, 5.00×105 and 7.68×105 cm−2s−1sr−1 respectively. The corresponding fluxes at GOES East are 6.53×104, 1.98×105 and 3.25×105 cm−2s−1sr−1 respectively. The largest fluxes seen during the 19.5 year period on 29 July 2004 were particularly extreme and were seen by satellites at GOES West and GOES East. The extreme value analysis suggests that this event was a 1 in 50 year event

Perceptions of Feedback among Undergraduate and Postgraduate Students of Four Health Science Disciplines

Feedback is an important support for student learning. Yet data suggests that some students are often under-whelmed with the feedback they receive. Two factors potentially influencing this perception are entry level and type of health science program. To investigate this further, 492 undergraduate and postgraduate students from four health science disciplines (occupational therapy, physiotherapy, speech pathology and audiology) at a large Australian university were asked to complete a survey on the feedback that they had received during their studies. Students reported that they valued feedback with 93% seriously engaging with their feedback and 88% considering that feedback assisted their learning. However, different perceptions on some areas of feedback were reported by different groups. Postgraduate students had significantly (p\u3c 0.01 to 0.0005) higher satisfaction with several aspects of feedback than undergraduate students, while audiology students reported significantly (p\u3c 0.05 to 0.0001) higher satisfaction levels than the other disciplinary groups. Fifty-eight percent of the students felt that feedback would be improved if it was more timely and if there was more of it, particularly in practical classes (55%). Methods of improving the feedback provided to these students are discussed

Methods of epigenome editing for probing the function of genomic imprinting

The curious patterns of imprinted gene expression draw interest from several scientific disciplines to the functional consequences of genomic imprinting. Methods of probing the function of imprinting itself have largely been indirect and correlational, relying heavily on conventional transgenics. Recently, the burgeoning field of epigenome editing has provided new tools and suggested strategies for asking causal questions with site specificity. This perspective article aims to outline how these new methods may be applied to questions of functional imprinting and, with this aim in mind, to suggest new dimensions for the expansion of these epigenome-editing tools

Behavioural abnormalities in a novel mouse model for Silver Russell Syndrome

Silver Russell Syndrome (SRS) syndrome is an imprinting disorder involving low birth weight with complex genetics and diagnostics. Some rare SRS patients carry maternally inherited microduplications spanning the imprinted genes CDKN1C, PHLDA2, SLC22A18 and KCNQ1, suggesting that overexpression of one of more of these genes contributes to the SRS phenotype. While this molecular alteration is very rare, feeding difficulties are a very common feature of this condition. Given that SRS children also have very low body mass index, understanding the underpinning biology of the eating disorder is important, as well as potential co-occurring behavioural alterations. Here, we report that a mouse model of this microduplication exhibits a number of behavioural deficits. The mice had a blunted perception of the palatability of a given foodstuff. This perception may underpin the fussiness with food. We additionally report hypoactivity, unrelated to anxiety or motoric function, and a deficit in appropriate integration of incoming sensory information. Importantly, using a second genetic model, we were able to attribute all altered behaviours to elevated expression of a single gene, Cdkn1c. This is the first report linking elevated Cdkn1c to altered behaviour in mice. Importantly, the findings from our study may have relevance for SRS and highlight a potentially underreported aspect of this disorder

Period-doubling events in the light curve of R Cygni: evidence for chaotic behaviour

A detailed analysis of the century long visual light curve of the long-period Mira star R Cygni is presented and discussed. The data were collected from the publicly available databases of the AFOEV, the BAAVSS and the VSOLJ. The full light curve consists of 26655 individual points obtained between 1901 and 2001. The light curve and its periodicity were analysed with help of the O-C diagram, Fourier analysis and time-frequency analysis. The results demonstrate the limitations of these linear methods. The next step was to investigate the possible presence of low-dimensional chaos in the light curve. For this, a smoothed and noise-filtered signal was created from the averaged data and with help of time delay embedding, we have tried to reconstruct the attractor of the system. The main result is that R Cygni shows such period-doubling events that can be interpreted as caused by a repetitive bifurcation of the chaotic attractor between a period 2T orbit and chaos. The switch between these two states occurs in a certain compact region of the phase space, where the light curve is characterized by ~1500-days long transients. The Lyapunov spectrum was computed for various embedding parameters confirming the chaotic attractor, although the exponents suffer from quite high uncertainty because of the applied approximation. Finally, the light curve is compared with a simple one zone model generated by a third-order differential equation which exhibits well-expressed period-doubling bifurcation. The strong resemblance is another argument for chaotic behaviour. Further studies should address the problem of global flow reconstruction, including the determination of the accurate Lyapunov exponents and dimension.Comment: 13 pages, 14 figures, accepted for publication in A&A (some figures are of reduced quality