Integrating evolutionary and regulatory information with a multispecies approach implicates genes and pathways in obsessive-compulsive disorder

Obsessive-compulsive disorder is a severe psychiatric disorder linked to abnormalities in glutamate signaling and the cortico-striatal circuit. We sequenced coding and regulatory elements for 608 genes potentially involved in obsessive-compulsive disorder in human, dog, and mouse. Using a new method that prioritizes likely functional variants, we compared 592 cases to 560 controls and found four strongly associated genes, validated in a larger cohort. NRXN1 and HTR2A are enriched for coding variants altering postsynaptic protein-binding domains. CTTNBP2 (synapse maintenance) and REEP3 (vesicle trafficking) are enriched for regulatory variants, of which at least six (35%) alter transcription factor-DNA binding in neuroblastoma cells. NRXN1 achieves genome-wide significance (p = 6.37 x 10(-11)) when we include 33,370 population-matched controls. Our findings suggest synaptic adhesion as a key component in compulsive behaviors, and show that targeted sequencing plus functional annotation can identify potentially causative variants, even when genomic data are limited.Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder with symptoms including intrusive thoughts and time-consuming repetitive behaviors. Here Noh and colleagues identify genes enriched for functional variants associated with increased risk of OCD

Dual Therapy with Cidofovir and Mirtazapine for Progressive Multifocal Leukoencephalopathy in a Sarcoidosis Patient

Background: Progressive multifocal leukoencephalopathy (PML) is a demyelinating central nervous system disease caused by JC virus (JCV) reactivation in immunocompromised patients. The disease course of PML is often progressive, fatal and at present, there are few reports on successful treatment outcomes. Case Report: A 45-year-old man with systemic sarcoidosis presented with rapidly progressive dementia and right hemiparesis. The patient was diagnosed with PML as confirmed via brain biopsy and JCV PCR. With a combination treatment of cidofovir and mirtazapine, there was significant improvement of neurological symptoms without measurable functional deficit. Conclusion: This case suggests that dual therapy with cidofovir and mirtazapine might be an effective treatment option in PML patients with sarcoidosis

A Newly Developed Pericardial Tuberculoma During Antituberculous Therapy

Tuberculosis generally affects the respiratory tract. In developing nations, the pericardium is the most common location of extrapulmonary tuberculosis; however, tuberculous pericarditis rarely appears as a localized mass or tuberculoma. We present here a case of a 62-year-old woman with pericardial tuberculoma. She had a history of effusive tuberculous pericarditis and drainage. Because she had taken regular medication over a period of six months, the pericardial mass with an adjacent lung nodule newly detected on the chest radiogram was initially suspected of being invasive lung cancer. Prior to pathologic confirmation, precise information from imaging tests, including computed tomography, magnetic resonance imaging, and positron emission tomography-computed tomography are helpful when making decisions regarding which methods should be used for surgical approach and treatment. Through imaging, our case showed typical features of pericardial tuberculoma and a favorable clinical course after two months with a change in antituberculous therapy

Selective Regional Loss of Cortical Synapses Lacking Presynaptic Mitochondria in the 5xFAD Mouse Model

Synaptic loss in Alzheimer's disease (AD) is strongly correlated with cognitive impairment. Accumulating evidence indicates that amyloid pathology leads to synaptic degeneration and mitochondrial damage in AD. However, it remains unclear whether synapses and presynaptic mitochondria are differentially affected in various cortical regions of the AD brain at the ultrastructural level. Using serial block-face scanning electron microscopy, we assessed synaptic structures in the medial prefrontal cortex (mPFC) and primary visual cortex (V1) of the 5xFAD mouse model of AD. At 6 months of age, 5xFAD mice exhibited significantly elevated levels of amyloid deposition in layer 2/3 of the mPFC but not V1. Accordingly, three-dimensional reconstruction of synaptic connectivity revealed a significant reduction in excitatory synaptic density in layer 2 of the mPFC, but not V1, of male transgenic mice. Notably, the density of synapses lacking presynaptic mitochondria was selectively decreased in the mPFC of 5xFAD mice, with no change in the density of mitochondria-containing synapses. Further classification of spines into shape categories confirmed a preferential loss of thin spines whose presynaptic boutons were largely devoid of mitochondria in the 5xFAD mPFC. Furthermore, the number of mitochondria per bouton in spared mitochondria-containing boutons was reduced in the mPFC, but not V1, of 5xFAD mice. Collectively, these results highlight region-specific vulnerability of cortical synapses to amyloid deposition and suggest that the presence of presynaptic mitochondria may affect synaptic degeneration in AD.1

Flash Pulmonary Edema in a Patient With Unilateral Renal Artery Stenosis and Bilateral Functioning Kidneys

Flash pulmonary edema typically exhibits sudden onset and resolves rapidly. It generally is associated with bilateral renal artery stenosis or unilateral stenosis in conjunction with a single functional kidney. We describe a patient who presented with flash pulmonary edema treated by percutaneous therapy with stent implantation. Our case is unique in that the flash pulmonary edema occurred in the setting of unilateral renal artery stenosis with bilateral functioning kidneys

Comparisons of Pediatric Patients who Visited to the Pediatric Emergency Department and the General Emergency Department

Purpose In 2010 and 2011, the Korean Ministry of Health and Welfare designated 2 and 4 Pediatric Emergency Centers, respectively. This study was conducted to examine the characteristics of pediatric patients who visited the pediatric emergency department (PED) compared with the general emergency department (GED). Methods We used the National Emergency Medical Department Information System (NEDIS) data on pediatric visits (<19 years old), from July 1 to December 31, 2011. We analyzed patients' general characteristics, number, severity, and length of stay (LOS). Results A total of 709,050 children visited 132 GEDs and 6 PEDs during the study period. Male patients of PED was 57.6%, and the mean age of PED was younger than GED (4.7±5.0 yr vs. 5.7±5.5 yr). There were more numbers of patient visitations per center, number of critically ill or injured patients per center, number of admitted patients per center, and the number of operation per center in PED than GED. LOS of overall, discharged, and transferred patients was the same between PED and GED; however, LOS of admitted patients was longer in PED. Conclusion We observed that PEDs did not function as a tertiary referral center. Further research is needed to find the reason for such phenomenon and provide possible solutions

Genome-Wide Analyses for Osteosarcoma in Leonberger Dogs Reveal the CDKN2A/B Gene Locus as a Major Risk Locus

Dogs represent a unique spontaneous cancer model. Osteosarcoma (OSA) is the most common primary bone tumor in dogs (OMIA 001441-9615), and strongly resembles human forms of OSA. Several large- to giant-sized dog breeds, including the Leonberger, have a greatly increased risk of developing OSA. We performed genome-wide association analysis with high-density imputed SNP genotype data from 273 Leonberger cases with a median age of 8.1 [3.1–13.5] years and 365 controls older than eight years. This analysis revealed significant associations at the CDKN2A/B gene locus on canine chromosome 11, mirroring previous findings in other dog breeds, such as the greyhound, that also show an elevated risk for OSA. Heritability (h2SNP) was determined to be 20.6% (SE = 0.08; p-value = 5.7 × 10−4) based on a breed prevalence of 20%. The 2563 SNPs across the genome accounted for nearly all the h2SNP of OSA, with 2183 SNPs of small effect, 316 SNPs of moderate effect, and 64 SNPs of large effect. As with many other cancers it is likely that regulatory, non-coding variants underlie the increased risk for cancer development. Our findings confirm a complex genetic basis of OSA, moderate heritability, and the crucial role of the CDKN2A/B locus leading to strong cancer predisposition in dogs. It will ultimately be interesting to study and compare the known genetic loci associated with canine OSA in human OSA