Midlife diagnosis of Refsum Disease in siblings with Retinitis Pigmentosa – the footprint is the clue: a case report

<p>Abstract</p> <p>Introduction</p> <p>Refsum disease is a potentially lethal and disabling condition associated with retinitis pigmentosa in which early treatment can prevent some of the systemic manifestations.</p> <p>Case presentation</p> <p>We present the cases of two brothers with a diagnosis of retinitis pigmentosa from childhood in whom Refsum disease was subsequently diagnosed midlife, after routine enquiry into hand and feet abnormalities. Subsequent treatment through dietary modification stabilised visual impairment and has prevented development of neurological complications to date.</p> <p>Conclusion</p> <p>It is therefore important to consider the diagnosis of Refsum disease in any patient with autosomal recessive or simplex retinitis pigmentosa, and to enquire about the presence of "unusual" feet or hands in such patients.</p

A Framework for the Specificity of Addictions

Research over the last two decades suggests that a wide range of substance and behavioral addictions may serve similar functions. Yet, co-occurrence of addictions has only been reported among a minority of addicts. “Addiction specificity” pertains to a phenomenon in which one pattern of addictive behaviors may be acquired whereas another is not. This paper presents the PACE model as a framework which might help explain addiction specificity. Pragmatics, attraction, communication, and expectation (PACE) variables are described, which may help give some direction to future research needs in this arena

mTORC1 underlies ageâ related muscle fiber damage and loss by inducing oxidative stress and catabolism

Aging leads to skeletal muscle atrophy (i.e., sarcopenia), and muscle fiber loss is a critical component of this process. The mechanisms underlying these ageâ related changes, however, remain unclear. We show here that mTORC1 signaling is activated in a subset of skeletal muscle fibers in aging mouse and human, colocalized with fiber damage. Activation of mTORC1 in TSC1 knockout mouse muscle fibers increases the content of morphologically abnormal mitochondria and causes progressive oxidative stress, fiber damage, and fiber loss over the lifespan. Transcriptomic profiling reveals that mTORC1’s activation increases the expression of growth differentiation factors (GDF3, 5, and 15), and of genes involved in mitochondrial oxidative stress and catabolism. We show that increased GDF15 is sufficient to induce oxidative stress and catabolic changes, and that mTORC1 increases the expression of GDF15 via phosphorylation of STAT3. Inhibition of mTORC1 in aging mouse decreases the expression of GDFs and STAT3’s phosphorylation in skeletal muscle, reducing oxidative stress and muscle fiber damage and loss. Thus, chronically increased mTORC1 activity contributes to ageâ related muscle atrophy, and GDF signaling is a proposed mechanism.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149208/1/acel12943-sup-0002-TableS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149208/2/acel12943.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149208/3/acel12943-sup-0001-FigS1-S14.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149208/4/acel12943_am.pd

A transmission spectrum of the sub-Earth planet L98-59~b in 1.1-1.7 μ\mum

With the increasing number of planets discovered by TESS, the atmospheric characterization of small exoplanets is accelerating. L98-59 is a M-dwarf hosting a multi-planet system, and so far, four small planets have been confirmed. The innermost planet b is $\sim15\%$ smaller and $\sim60\%$ lighter than Earth, and should thus have a predominantly rocky composition. The Hubble Space Telescope observed five primary transits of L98-59b in $1.1-1.7\ \mu$m, and here we report the data analysis and the resulting transmission spectrum of the planet. We measure the transit depths for each of the five transits and, by combination, we obtain a transmission spectrum with an overall precision of $\sim20$ ppm in for each of the 18 spectrophotometric channels. With this level of precision, the transmission spectrum does not show significant modulation, and is thus consistent with a planet without any atmosphere or a planet having an atmosphere and high-altitude clouds or haze. The scenarios involving an aerosol-free, H$_2$-dominated atmosphere with H$_2$O or CH$_4$ are inconsistent with the data. The transmission spectrum also disfavors, but does not rules out, an H$_2$O-dominated atmosphere without clouds. A spectral retrieval process suggests that an H$_2$-dominated atmosphere with HCN and clouds or haze may be the preferred solution, but this indication is non-conclusive. Future James Webb Space Telescope observations may find out the nature of the planet among the remaining viable scenarios.Comment: 17 pages, 5 figures, 7 tables, accepted for publication in A

Planetary Candidates Observed by Kepler, III: Analysis of the First 16 Months of Data

New transiting planet candidates are identified in sixteen months (May 2009 - September 2010) of data from the Kepler spacecraft. Nearly five thousand periodic transit-like signals are vetted against astrophysical and instrumental false positives yielding 1,091 viable new planet candidates, bringing the total count up to over 2,300. Improved vetting metrics are employed, contributing to higher catalog reliability. Most notable is the noise-weighted robust averaging of multi-quarter photo-center offsets derived from difference image analysis which identifies likely background eclipsing binaries. Twenty-two months of photometry are used for the purpose of characterizing each of the new candidates. Ephemerides (transit epoch, T_0, and orbital period, P) are tabulated as well as the products of light curve modeling: reduced radius (Rp/R*), reduced semi-major axis (d/R*), and impact parameter (b). The largest fractional increases are seen for the smallest planet candidates (197% for candidates smaller than 2Re compared to 52% for candidates larger than 2Re) and those at longer orbital periods (123% for candidates outside of 50-day orbits versus 85% for candidates inside of 50-day orbits). The gains are larger than expected from increasing the observing window from thirteen months (Quarter 1-- Quarter 5) to sixteen months (Quarter 1 -- Quarter 6). This demonstrates the benefit of continued development of pipeline analysis software. The fraction of all host stars with multiple candidates has grown from 17% to 20%, and the paucity of short-period giant planets in multiple systems is still evident. The progression toward smaller planets at longer orbital periods with each new catalog release suggests that Earth-size planets in the Habitable Zone are forthcoming if, indeed, such planets are abundant.Comment: Submitted to ApJS. Machine-readable tables are available at http://kepler.nasa.gov, http://archive.stsci.edu/kepler/results.html, and the NASA Exoplanet Archiv

The imprint of atmospheric evolution in the D/H of Hesperian clay minerals on Mars

The deuterium to hydrogen (D/H) ratio in strongly bound water or hydroxyl groups in ancient martian clays retains the imprint of the water of formation of these minerals. Curiosity’s Sample Analysis at Mars (SAM) experiment measured thermally evolved water and hydrogen gas released between 550°C and 950°C from samples of Hesperian era Gale crater smectite to determine this isotope ratio. The D/H value is 3.0 (±0.2) times the ratio in Standard Mean Ocean Water (SMOW). The D/H ratio in this ~3 billion year old mudstone that is half that of the present martian atmosphere but substantially higher than that expected in very early Mars indicates an extended history of hydrogen escape and desiccation of the planet

Associations between Polycyclic Aromatic Hydrocarbon–Related Exposures and p53 Mutations in Breast Tumors

Background: Previous studies have suggested that polycyclic aromatic hydrocarbons (PAHs) may be associated with breast cancer. However, the carcinogenicity of PAHs on the human breast remains unclear. Certain carcinogens may be associated with specific mutation patterns in the p53 tumor suppressor gene, thereby contributing information about disease etiology. Objectives: We hypothesized that associations of PAH-related exposures with breast cancer would differ according to tumor p53 mutation status, effect, type, and number. Methods: We examined this possibility in a population-based case–control study using polytomous logistic regression. As previously reported, 151 p53 mutations among 859 tumors were identified using Surveyor nuclease and confirmed by sequencing. Results: We found that participants with p53 mutations were less likely to be exposed to PAHs (assessed by smoking status in 859 cases and 1,556 controls, grilled/smoked meat intake in 822 cases and 1,475 controls, and PAH–DNA adducts in peripheral mononuclear cells in 487 cases and 941 controls) than participants without p53 mutations. For example, active and passive smoking was associated with p53 mutation–negative [odds ratio (OR) = 1.55; 95% confidence interval (CI), 1.11–2.15] but not p53 mutation–positive (OR = 0.77; 95% CI, 0.43–1.38) cancer (ratio of the ORs = 0.50, p < 0.05). However, frameshift mutations, mutation number, G:C→A:T transitions at CpG sites, and insertions/deletions were consistently elevated among exposed subjects. Conclusions: These findings suggest that PAHs may be associated with specific breast tumor p53 mutation subgroups rather than with overall p53 mutations and may also be related to breast cancer through mechanisms other than p53 mutation

Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease

Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer's disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini-Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer's disease, which supports its potential utility as a clinically useful biomarker

The bHLH/Per-Arnt-Sim transcription factor SIM2 regulates muscle transcript myomesin2 via a novel, non-canonical E-box sequence

Despite a growing number of descriptive studies that show Single-minded 2 (Sim2) is not only essential for murine survival, but also upregulated in colon, prostate and pancreatic tumours, there is a lack of direct target genes identified for this basic helix–loop–helix/PAS transcription factor. We have performed a set of microarray experiments aimed at identifying genes that are differentially regulated by SIM2, and successfully verified that the Myomesin2 (Myom2) gene is SIM2-responsive. Although SIM2 has been reported to be a transcription repressor, we find that SIM2 induces transcription of Myom2 and activates the Myom2 promoter sequence when co-expressed with the heterodimeric partner protein, ARNT1, in human embryonic kidney cells. Truncation and mutation of the Myom2 promoter sequence, combined with chromatin immunoprecipitation studies in cells, has lead to the delineation of a non-canonical E-box sequence 5′-AACGTG-3′ that is bound by SIM2/ARNT1 heterodimers. Interestingly, in immortalized human myoblasts knock down of Sim2 results in increased levels of Myom2 RNA, suggesting that SIM2 is acting as a repressor in these cells and so its activity is likely to be highly context dependent. This is the first report of a direct SIM2/ARNT1 target gene with accompanying analysis of a functional response element