Reduced Creatine Kinase B Activity in Multiple Sclerosis Normal Appearing White Matter

Background: Two studies using 31 P-magnetic resonance spectroscopy (MRS) reported enhanced phosphocreatine (PCr) levels in normal appearing white matter (NAWM) of subjects with multiple sclerosis (MS), but this finding could not be properly explained. Methodology/Principal Findings: We performed 31 P-MRS and 1 H-MRS in the NAWM in 36 subjects, including 17 with progressive MS, 9 with benign MS, and 10 healthy controls. Compared to controls, PCr/b-ATP and PCr/total 31 P ratios were significantly increased in subjects with progressive MS, but not with benign MS. There was no correlation between PCr ratios and the N-acetylaspartate/creatine ratio, suggesting that elevated PCr levels in NAWM were not secondary to axonal loss. In the central nervous system, PCr is degraded by creatine kinase B (CK-B), which in the white matter is confined to astrocytes. In homogenates of NAWM from 10 subjects with progressive MS and 10 controls without central nervous system disease, we measured CK-B levels with an ELISA, and measured its activity with an enzymatic assay kit. Compared to controls, both CK-B levels and activity were decreased in subjects with MS (22.41 versus 46.28 mg/ml; p = 0.0007, and 2.89 versus 7.76 U/l; p,0.0001). Conclusions/Significance: Our results suggest that PCr metabolism in the NAWM in MS is impaired due to decreased CK-B levels. Our findings raise the possibility that a defective PCr metabolism in astrocytes might contribute to the degeneratio

Teaching midwives homeopathy—A Belgian pilot project

Introduction Recent Belgian legislation generated the need for homeopathic training of midwives. The Centre of Classical Homeopathy (CKH) offered a 50-hours course in homeopathy as a pilot project within the Continuing Professional Development (CPD) program of Thomas More College. Methods The curriculum was designed to combine a minimum of homeopathic philosophical underpinning with appropriate clinical exercises within the limited training hours available. Eight participants followed the course. Evaluation of the course followed in the last session through a self-completed questionnaire with closed questions on course content and transfer to practice and open questions on didactics and the organisation of the course. Recommendations for the future were also queried. Results Although the learning objectives were met, participants provided useful feedback regarding content and method for the future organisation of the course. They felt more topics should be included such as, the postpartum period. They suggested supplementing the material from the current training with more practice and cases, and expanding the course to a full year’s training, allowing more time between sessions for processing the material. To use homeopathy for acute prescribing, more training on repertorisation techniques and materia medica knowledge would be required. Conclusions Training midwives in homeopathy requires considerably more time than the 50 contact hours stipulated by law and would best be offered as interactive sessions providing powerful concrete case examples, spread over the course of one full year to allow for integration of the material into practice

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Hypoperfusion of the cerebral white matter in multiple sclerosis:possible mechanisms and pathophysiological significance

Multiple sclerosis (MS) is a disease of the central nervous system characterized by patchy areas of demyelination, inflammation, axonal loss and gliosis, and a diffuse axonal degeneration throughout the so-called normal-appearing white matter (NAWM). A number of recent studies using perfusion magnetic resonance imaging in both relapsing and progressive forms of MS have shown a decreased perfusion of the NAWM, which does not appear to be secondary to axonal loss. The reduced perfusion of the NAWM in MS might be caused by a widespread astrocyte dysfunction, possibly related to a deficiency in astrocytic beta(2)-adrenergic receptors and a reduced formation of cAMP, resulting in a reduced uptake of K+ at the nodes of Ranvier and a reduced release of K+ in the perivascular spaces. Pathologic and imaging studies suggest that ischemic changes might be involved in the development of a subtype of focal demyelinating lesions (type III lesions), and there appears to exist a relationship between decreased white matter perfusion and cognitive dysfunction in patients with MS

Creatine kinase B.

<p>Box plots of (<b>A</b>) creatine kinase B levels and (<b>B</b>) creatine kinase B activity in the NAWM in the MS subjects and controls.</p

Proposed model of PCr metabolism in astrocytes.

<p>PCr generated by mitochondria diffuses in the astrocytic processes where it is degraded by CK-B to deliver ATP. Free Cr, formed by the removal of phosphate from PCr, diffuses back to the mitochondria. This local energy is required for the Na⁺/K⁺-ATPase, which removes K⁺ generated during axonal electrogenesis from the extracellular space, and establishes the Na⁺ gradient required for Na⁺-dependent glutamate uptake by astrocytes. Transcription of CK-B appears to be mediated by cAMP <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010811#pone.0010811-Kuzhikandathil1" target="_blank">[23]</a><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010811#pone.0010811-Kuzhikandathil2" target="_blank">[24]</a>.</p

³¹P Magnetic resonance spectroscopy.

<p>(<b>A</b>) Volume of interest in the centrum semiovale for ³¹P MRS. (<b>B</b>) Typical decoupled ³¹P-spectrum with the peaks for PCr, phosphorylethanolamine (PE), phosphorylcholine (PC), inorganic phosphate (Pi), glycerophosphorylethanolamine (GPE), glycerophosphorylcholine (GPC), and the three peaks for ATP.</p