Genome-wide association study of NMDA receptor coagonists in human cerebrospinal fluid and plasma.

The N-methyl-D-aspartate receptor (NMDAR) coagonists glycine, D-serine and L-proline play crucial roles in NMDAR-dependent neurotransmission and are associated with a range of neuropsychiatric disorders. We conducted the first genome-wide association study of concentrations of these coagonists and their enantiomers in plasma and cerebrospinal fluid (CSF) of human subjects from the general population (N=414). Genetic variants at chromosome 22q11.2, located in and near PRODH (proline dehydrogenase), were associated with L-proline in plasma (ß=0.29; P=6.38 × 10(-10)). The missense variant rs17279437 in the proline transporter SLC6A20 was associated with L-proline in CSF (ß=0.28; P=9.68 × 10(-9)). Suggestive evidence of association was found for the D-serine plasma-CSF ratio at the D-amino-acid oxidase (DAO) gene (ß=-0.28; P=9.08 × 10(-8)), whereas a variant in SRR (that encodes serine racemase and is associated with schizophrenia) constituted the most strongly associated locus for the L-serine to D-serine ratio in CSF. All these genes are highly expressed in rodent meninges and choroid plexus, anatomical regions relevant to CSF physiology. The enzymes and transporters they encode may be targeted to further construe the nature of NMDAR coagonist involvement in NMDAR gating. Furthermore, the highlighted genetic variants may be followed up in clinical populations, for example, schizophrenia and 22q11 deletion syndrome. Overall, this targeted metabolomics approach furthers the understanding of NMDAR coagonist concentration variability and sets the stage for non-targeted CSF metabolomics projects.

Genome-wide association study of monoamine metabolite levels in human cerebrospinal fluid.

Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotype-phenotype correlations. Metabolic traits pertinent to the central nervous system (CNS) constitute a potentially informative target for genetic studies of intermediate phenotypes as their genetic underpinnings may elucidate etiological mechanisms. We therefore conducted a genome-wide association study (GWAS) of monoamine metabolite (MM) levels in cerebrospinal fluid (CSF) of 414 human subjects from the general population. In a linear model correcting for covariates, we identified one locus associated with MMs at a genome-wide significant level (standardized ß=0.32, P=4.92 × 10(-8)), located 20 kb from SSTR1, a gene involved with brain signal transduction and glutamate receptor signaling. By subsequent whole-genome expression quantitative trait locus (eQTL) analysis, we provide evidence that this variant controls expression of PDE9A (ß=0.21; P unadjusted=5.6 × 10(-7); P corrected=0.014), a gene previously implicated in monoaminergic transmission, major depressive disorder and antidepressant response. A post hoc analysis of loci significantly associated with psychiatric disorders suggested that genetic variation at CSMD1, a schizophrenia susceptibility locus, plays a role in the ratio between dopamine and serotonin metabolites in CSF. The presented DNA and mRNA analyses yielded genome-wide and suggestive associations in biologically plausible genes, two of which encode proteins involved with glutamate receptor functionality. These findings will hopefully contribute to an exploration of the functional impact of the highlighted genes on monoaminergic transmission and neuropsychiatric phenotypes.

Implanted bone marrow-derived mesenchymal stem cells fail to metabolically stabilize or recover electromechanical function in infarcted hearts.

Mesenchymal stem cells (MSCs) have been used with success in several clinical applications for clinical treatment of ischemic hearts. However, the reported effects of MSC-based therapy on myocardial infarction (MI) are inconsistent. In particular, the preventive effects of MSC-based therapy on arrhythmic sudden death and metabolic disorders after infarction remain controversial. Here, we investigated the effects of MSCs on reverse remodeling in an infarcted myocardium, and found that MSC-therapy failed to achieve the complete regeneration of infarcted myocardium. Histological analyses showed that although infarct size and interstitial fibrosis induced by MI recovered significantly after MSC treatment, these improvements were marginal, indicating that a significant amount of damaged tissue was still present. Furthermore, transplanted MSCs had slight anti-apoptotic and anti-inflammatory effects in MSC-implanted regions and no significant improvements in cardiac function were observed, suggesting that naïve MSCs might not be the right cell type to treat myocardial infarction. Furthermore, small ion profiling using ToF-SIMS revealed that the metabolic stabilization provided by the MSCs implantation was not significant compared to the sham group. Together, these results indicate that pretreatment of MSCs is needed to enhance the benefits of MSCs, particularly when MSCs are used to treat arrhythmogenicity and metabolically stabilize infarcted myocardium.

The effects of weight load and joint immobilization on reorganization of postural tremor.

To investigate change in coordinative strategies due to wrist immobilization and index loading, postural tremors from the index, hand, and forearm were recorded during different postural holding tasks. The wrist joint was immobilized with a thermoplastic splint in the constrained condition, and a copper mass of 100 grams was applied to the index finger in the loaded condition. The structures of the postural tremors of all upper limb segments among the unloaded-unconstrained, unloaded-constrained, loaded-unconstrained, and loaded-constrained conditions were compared. Index loading exaggerated index/forearm postural tremor, while the load-induced tremor enhancement was no longer evident for wrist immobilization. In the unloaded condition, wrist immobilization resulted specifically in enhancement of carpal postural tremor, rather than in the index and forearm. Index loading induced a marked tremor peak and relative power in the range of 5-8 Hz. Wrist immobilization potentiated the carpal tremor peak of 1-4 Hz in association with enhancement of carpal-forearm mechanical coupling. In light of structural changes in postural tremor, our data suggest that (1) a wrist splint is effective to counteract load-induced enhancement of postural tremor, and (2) freezing of the wrist joint might facilitate compensatory strategies to minimize passive fluctuation transmission from the carpal to index.

Efficacy of MRI in complicated congenital heart disease with visceral heterotaxy syndrome.

PURPOSE: The authors' goal was to assess the diagnostic accuracy and clinical effect of MRI compared with echocardiography and catheterization in the evaluation of cardiac defects with situs ambiguous. METHOD: Twenty-two patients with visceral heterotaxy syndrome were included. RESULTS: Because situs determined by the relation between the pulmonary artery and bronchi showed most predominantly a tendency toward lateralization, this was regarded as the standard reference of situs determination. For the purpose of this study, patients were classified as having right isomerism (n = 13) or left isomerism groups (n = 9). MRI has several advantages compared with echocardiography or cardiac angiography for examining patients with situs ambiguous. (1) The bronchial, pulmonary arterial, and splenic situs can be readily determined, and discrepancies (n = 2) can be assessed easily. (2) Venoatrial connections are adequately imaged. In particular, all types of total and partial anomalous pulmonary venous return are delineated, regardless of whether restrictions of pulmonary blood flow or pulmonary venous obstructions are involved (n = 4). The courses of vertical veins were easily identified, and the prearterial position was revealed in only one of seven right isomerisms with total anomalous pulmonary venous return. The drain pattern of the hepatic vein can be visualized using three-dimensional spatial information and is useful for total cavopulmonary connection design. (3) Associated complicated cardiac anomalies, particularly the size or peripheral stenosis of the pulmonary arteries, may be evaluated, and this information is useful for palliative shunt operations. CONCLUSION: Because of its wide field of view and imaging, which is not restricted by associated anomalies, a thorough understanding of the cardiovascular anatomy of the situs ambiguous can be achieved using MRI, which is of considerable value in the surgical correction of this complicated anomaly. MRI can obviate or facilitate catheterization in these critically ill patients.

Magnetic resonance imaging of unroofed coronary sinus: three cases.

Unroofed coronary sinus is a rare cardiac anomaly in which communication occurs between the coronary sinus and the left atrium due to the partial or complete absence of the roof of the coronary sinus. It is usually associated with other cardiovascular anomalies, especially persistent left superior vena cava. It is often not discovered during cardiac catheterization without clinical suspicion. We report three cases of unroofed coronary sinus which were incidentally detected by magnetic resonance imaging.

Takayasu arteritis in Korean children: clinical report of seventy cases.

Seventy cases of Takayasu arteritis in Korean children are reported. There were 57 females and 13 males (male-to-female ratio; 1:4.4). The youngest patient was a 3-year-old female. Family history was positive in one patient. The most common chief complaints on admission were dyspnea, headache, palpitation, and edema which were due to hypertension and congestive heart failure. Hypertension was seen in 65 out of 70 patients (92.8%). The abdominal aorta, thoracic aorta, and renal arteries were the most commonly involved sites in these children. Two patients had nephrotic syndrome. The frequency of positive tuberculin reaction was much higher in children with Takayasu arteritis compared with the general population, and the intensity of the reaction was also stronger. The majority of the patients required immediate medical treatment to control congestive heart failure due to hypertension at initial presentation. When ESR was elevated, corticosteroid was administered. Surgical treatment showed good results in six out of ten cases. Percutaneous intraluminal angioplasty was effective for lowering the blood pressure in six out of nine cases. In three cases, restenosis occurred and angioplasty was repeated in two cases.

Tricuspid atresia or severe stenosis with partial common atrioventricular canal: anatomic data, clinical profile and surgical considerations.

The anatomic findings in 11 cases of tricuspid atresia and in two cases of severe tricuspid stenosis, both combined with partial common atrioventricular (AV) canal, are presented in detail. Twelve cases were documented by postmortem examination and the diagnosis was confirmed by echocardiography and surgical observation in the one living patient. Clinical data available in nine cases and cardiac catheterization data obtained in eight are included in this report. In three cases (23%)--two with tricuspid atresia and one with extreme tricuspid stenosis--the tricuspid valve and right ventricle exhibited characteristics seen in Ebstein's anomaly. In all 13 cases, the great arteries were normally related. The ventricular septal defect(s) in 10 (83%) of the 12 postmortem cases rapidly became smaller and this resulted in marked diminution of the pulmonary blood flow and severe hypoxia. Only three of the eight patients with available cardiac catheterization and angiocardiographic data showed the scooped-out appearance of the left ventricular septal surface characteristic of AV canal defects. By contrast, two-dimensional echocardiography, available in the three most recent cases, accurately demonstrated all the defects present and represents the diagnostic method of choice. Early surgical intervention to establish a systemic to pulmonary artery anastomosis is essential for survival. More definitive surgical treatment can be achieved later by an atriopulmonary or cavopulmonary anastomosis with or without replacement of the cleft and often regurgitant mitral valve. The one living patient exemplifies this approach. This is the largest series of this unusual type of tricuspid atresia reported to date.