Neuronal Transcriptome from C9orf72 Repeat Expanded Human Tissue is Associated with Loss of C9orf72 Function

A hexanucleotide G4C2 repeat expansion in C9orf72 is the most common genetic cause of familial and sporadic cases of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The mutation is associated with a reduction of C9orf72 protein and accumulation of toxic RNA and dipeptide repeat aggregates. The accumulation of toxic RNA has been proposed to sequester RNA binding proteins thereby altering RNA processing, consistent with previous transcriptome studies that have shown that the C9orf72 repeat expansion is linked to abundant splicing alterations and transcriptome changes. Here, we used a subcellular fractionation method and FACS to enrich for neuronal nuclei from C9orf72 repeat expanded post-mortem human ALS/FTD brains, and to remove neuronal nuclei with TDP-43 pathology which are observed in nearly all symptomatic C9orf72 repeat expanded cases. We show that the C9orf72 expansion is associated with relatively mild gene expression changes. Dysregulated genes were enriched for vesicle transport pathways, which is consistent with the known functions of C9orf72 protein. Further analysis suggests that the C9orf72 transcriptome is not driven by toxic RNA but is rather shaped by the depletion of pathologic TDP-43 nuclei and the loss of C9orf72 expression. These findings argue against RNA binding protein sequestration in neurons as a major contributor to C9orf72 mediated toxicity

Dynamics and Pattern Formation in Large Systems of Spatially-Coupled Oscillators with Finite Response Times

We consider systems of many spatially distributed phase oscillators that interact with their neighbors. Each oscillator is allowed to have a different natural frequency, as well as a different response time to the signals it receives from other oscillators in its neighborhood. Using the ansatz of Ott and Antonsen (Ref. \cite{OA1}) and adopting a strategy similar to that employed in the recent work of Laing (Ref. \cite{Laing2}), we reduce the microscopic dynamics of these systems to a macroscopic partial-differential-equation description. Using this macroscopic formulation, we numerically find that finite oscillator response time leads to interesting spatio-temporal dynamical behaviors including propagating fronts, spots, target patterns, chimerae, spiral waves, etc., and we study interactions and evolutionary behaviors of these spatio-temporal patterns

Advances in Multidetector CT Diagnosis of Pediatric Pulmonary Thromboembolism

Although pediatric pulmonary thromboembolism is historically believed to be rare with relatively little information available in the medical literature regarding its imaging evaluation, it is more common than previously thought. Thus, it is imperative for radiologists to be aware of the most recent advances in its imaging information, particularly multidetector computed tomography (MDCT), the imaging modality of choice in the pediatric population. The overarching goal of this article is to review the most recent updates on MDCT diagnosis of pediatric pulmonary thromboembolism

An Unusual Case of Pleuropulmonary Blastoma in a Child with Jejunal Hamartomas

We report a rare case of 9-month-old girl who presented with a choking episode and was found to have an incidental finding of a lung cyst and iron deficiency anemia leading to the diagnosis of pleuropulmonary blastoma (PPB) and a jejunal hamartoma. Our patient is the eighth that has been reported with the association of PPB with jejunal hamartoma and the first one in the radiological literature. PPB is the pulmonary analog of other dysontogenetic neoplasms in childhood. A biological sequence has been described with the three types of PPB to be interrelated as part of pathologic progression. PPB can be associated with other cysts and/or neoplasms in different organs. PPB is part of a hereditary neoplasia predisposition syndrome in up to 40% of cases. Mutations in DICER gene have been described with PPB. Hence, a pediatric patient diagnosed with PPB should be screened for associated conditions during childhood and adolescence including intestinal polyps. Obtaining family history for other neoplasms or cysts is important information that should raise the possibility of PPB in pediatric patients with cystic lung lesions. The presence of this syndrome should alert the clinician to screen and follow up patients and their relatives

Diabetes and mortality in patients with prostate cancer: a meta-analysis

Background: There are conflicting results as to the association between pre-existing diabetes and the risk of mortality in patients with prostate cancer. The purpose of this study is to estimate the influence of pre-existing diabetes on prostate cancer-specific mortality and all-cause mortality. Methods: We searched PubMed and Embase to identify studies that investigated the association between pre-existing diabetes and risk of death among men with prostate cancer. Pooled risk estimates and 95 % confidence intervals were calculated using fixed-effects models or random-effects models. Heterogeneity tests were conducted between studies. Publication bias was analyzed by using the Egger’s test, Begg’s test, and the trim and fill method. Results: Of the 733 articles identified, 17 cohort studies that had 274,677 male patients were included in this meta-analysis. Pre-existing diabetes was associated with a 29 % increase in prostate cancer-specific mortality [relative risk (RR) 1.29, 95 % CI 1.22–1.38, I2 = 66.68 %], and with a 37 % increase in all-cause mortality (RR 1.37, 95 % CI 1.29–1.45, p < 0.01, I2 = 90.26 %). Additionally, in a subgroup analysis that was a type specific analysis focusing on type 2 diabetes and was conducted only with three cohort studies, pre-existing type 2 diabetes was associated with all-cause mortality (RR 2.01, 95 % CI 1.37–2.96, I2 = 95.55 %) and no significant association with prostate cancer-specific mortality was detected (RR 1.17, 95 % CI 0.96–1.42, I2 = 75.59 %). There was significant heterogeneity between studies and no publication bias was found. Conclusions: This meta-analysis suggests diabetes may result in a worse prognosis for men with prostate cancer. Considering heterogeneity between studies, additional studies should be conducted to confirm these findings, and to allow generalization regarding the influence that each type of diabetes has on prostate cancer mortality

Reinforcement learning in ophthalmology: potential applications and challenges to implementation

Reinforcement learning is a subtype of machine learning in which a virtual agent, functioning within a set of predefined rules, aims to maximise a specified outcome or reward. This agent can consider multiple variables and many parallel actions at once to optimise its reward, thereby solving complex, sequential problems. Clinical decision making requires physicians to optimise patient outcomes within a set practice framework and, thus, presents considerable opportunity for the implementation of reinforcement learning-driven solutions. We provide an overview of reinforcement learning, and focus on potential applications within ophthalmology. We also explore the challenges associated with development and implementation of reinforcement learning solutions and discuss possible approaches to address them

IDOL regulates systemic energy balance through control of neuronal VLDLR expression.

Liver X receptors limit cellular lipid uptake by stimulating the transcription of Inducible Degrader of the LDL Receptor (IDOL), an E3 ubiquitin ligase that targets lipoprotein receptors for degradation. The function of IDOL in systemic metabolism is incompletely understood. Here we show that loss of IDOL in mice protects against the development of diet-induced obesity and metabolic dysfunction by altering food intake and thermogenesis. Unexpectedly, analysis of tissue-specific knockout mice revealed that IDOL affects energy balance, not through its actions in peripheral metabolic tissues (liver, adipose, endothelium, intestine, skeletal muscle), but by controlling lipoprotein receptor abundance in neurons. Single-cell RNA sequencing of the hypothalamus demonstrated that IDOL deletion altered gene expression linked to control of metabolism. Finally, we identify VLDLR rather than LDLR as the primary mediator of IDOL effects on energy balance. These studies identify a role for the neuronal IDOL-VLDLR pathway in metabolic homeostasis and diet-induced obesity

Pre-vaccination prevalence of anogenital and oral human papillomavirus in young HIV-infected men who have sex with men.

The aims of this study were to: 1) determine prevalence of anogenital and oral HPV, 2) determine concordance between HPV at anal, perianal, scrotal/penile, and oral sites; and 3) describe factors associated with anogenital HPV types targeted by the 9-valent vaccine. Data were collected from 2012 to 2015 among men who have sex with men 18-26 years of age enrolled in a vaccine trial (N = 145). Penile/scrotal, perianal, anal, and oral samples were tested for 61 HPV types. Logistic regression was used to identify factors associated with types in the 9-valent vaccine. Participants' mean age was 23.0 years, 55.2% were African-American, and 26.2% were Hispanic; 93% had anal, 40% penile, and 6% oral HPV. Among those with anogenital infection, 18% had HPV16. Concordance was low between anogenital and oral sites. Factors independently associated with a 9-valent vaccine-type HPV were: race (African-American vs. White, OR=2.67, 95% CI=1.11-6.42), current smoking (yes vs. no, OR=2.37, 95% CI=1.03-5.48), and number of recent receptive anal sex partners (2+ vs. 0, OR=3.47, 95% CI=1.16-10.4). Most MSM were not infected with HPV16 or HPV18, suggesting that they may still benefit from HPV vaccination, but anogenital HPV was very common, highlighting the importance of vaccinating men before sexual initiation. CLINICAL TRIAL NUMBER: NCT01209325