Mapping of multiple muscles with transcranial magnetic stimulation: absolute and relative test–retest reliability

The spatial accuracy of transcranial magnetic stimulation (TMS) may be as small as a few millimeters. Despite such great potential, navigated TMS (nTMS) mapping is still underused for the assessment of motor plasticity, particularly in clinical settings. Here, we investigate the within‐limb somatotopy gradient as well as absolute and relative reliability of three hand muscle cortical representations (MCRs) using a comprehensive grid‐based sulcus‐informed nTMS motor mapping. We enrolled 22 young healthy male volunteers. Two nTMS mapping sessions were separated by 5–10 days. Motor evoked potentials were obtained from abductor pollicis brevis (APB), abductor digiti minimi, and extensor digitorum communis. In addition to individual MRI‐based analysis, we studied normalized MNI MCRs. For the reliability assessment, we calculated intraclass correlation and the smallest detectable change. Our results revealed a somatotopy gradient reflected by APB MCR having the most lateral location. Reliability analysis showed that the commonly used metrics of MCRs, such as areas, volumes, centers of gravity (COGs), and hotspots had a high relative and low absolute reliability for all three muscles. For within‐limb TMS somatotopy, the most common metrics such as the shifts between MCR COGs and hotspots had poor relative reliability. However, overlaps between different muscle MCRs were highly reliable. We, thus, provide novel evidence that inter‐muscle MCR interaction can be reliably traced using MCR overlaps while shifts between the COGs and hotspots of different MCRs are not suitable for this purpose. Our results have implications for the interpretation of nTMS motor mapping results in healthy subjects and patients with neurological conditions.     

CHOP‐mediated hepcidin suppression modulates hepatic iron load

The liver is the central regulator of iron metabolism and accordingly, chronic liver diseases often lead to systemic iron overload due to diminished expression of the iron‐regulatory hormone hepcidin. To study the largely unknown regulation of iron metabolism in the context of hepatic disease, we used two established models of chronic liver injury, ie repeated carbon tetrachloride (CCl₄) or thioacetamide (TAA) injections. To determine the impact of CCAAT/enhancer‐binding protein (C/EBP)‐homologous protein (CHOP) on hepcidin production, the effect of a single TAA injection was determined in wild‐type and CHOP knockout mice. Furthermore, CHOP and hepcidin expression was assessed in control subjects and patients with alcoholic liver disease. Both chronic injury models developed a distinct iron overload in macrophages. TAA‐, but not CCl₄‐ injected mice displayed additional iron accumulation in hepatocytes, resulting in a significant hepatic and systemic iron overload which was due to suppressed hepcidin levels. C/EBPα signalling, a known hepcidin inducer, was markedly inhibited in TAA mice, due to lower C/EBPα levels and overexpression of CHOP, a C/EBPα inhibitor. A single TAA injection resulted in a long‐lasting (> 6 days) suppression of hepcidin levels and CHOP knockouts (compared to wild‐types) displayed significantly attenuated hepcidin down‐regulation in response to acute TAA administration. CHOP mRNA levels increased 5‐fold in alcoholic liver disease patients versus controls (p < 0.005) and negatively correlated with hepcidin expression. Our results establish CHOP as an important regulator of hepatic hepcidin expression in chronic liver disease. The differences in iron metabolism between the two widely used fibrosis models likely reflect the differential regulation of hepcidin expression in human liver disease. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

High-Resolution Strain/Stress Measurements by Three-Axis Neutron Diffractometer

Resolution properties of the unconventional high-resolution neutron diffraction three-axis setup for strain/stress measurements of large bulk polycrystalline samples are presented. Contrary to the conventional two-axis setups, in this case, the strain measurement on a sample situated on the second axis is carried out by rocking the bent perfect crystal (BPC) analyzer situated on the third axis of the diffractometer. Thus, the so-called rocking curve provides the sample diffraction profile. The neutron signal coming from the analyzer is registered by a point detector. This new setup provides a considerably higher resolution (at least by a factor of 5), which however, requires a much longer measurement time. The high-resolution neutron diffraction setting can be effectively used, namely, for bulk gauge volumes up to several cubic centimeters, and for plastic deformation studies on the basis of the analysis of diffraction line profiles, thus providing average values of microstructure characteristics over the irradiated gauge volume.     

Repeated Baclofen treatment ameliorates motor dysfunction,suppresses reflex activity and decreases the expression of signaling proteins in reticular nuclei and lumbar motoneurons after spinal trauma in rats

The interruption of supraspinal input to the spinal cord leads to motor dysfunction and the development of spasticity. Clinical studies have shown that Baclofen (a GABA_B agonist), while effective in modulating spasticity is associated with side-effects and the development of tolerance. The aim of the present study was to assess if discontinued Baclofen treatment and its repeated application leads antispasticity effects, and whether such changes affect neuronal nitric oxide synthase (nNOS) in the brainstem, nNOS and parvalbumin (PV) in lumbar α-motoneurons and glial fibrillary acidic protein in the ventral horn of the spinal cord. Adult male Wistar rats were exposed to Th9 spinal cord transection. Baclofen (30 mg/b.w.) diluted in drinking water, was administered for 6 days, starting at week 1 after injury and then repeated till week 4 after injury. The behavior of the animals was tested (tail-flick test, BBB locomotor score) from 1 to 8 weeks. Our results clearly indicate the role of nitric oxide, produced by nNOS in the initiation and the maintenance of spasticity states 1, 6 and 8 weeks after spinal trauma. A considerable decrease of nNOS staining after Baclofen treatment correlates with improvement of motor dysfunction. The findings also show that parvalbumin and astrocytes participate in the regulation of ion concentrations in the sub-acute phase after the injury.     

Life insurance: genomic stratification and risk classification

With the development and increasing accessibility of new genomic tools such as next-generation sequencing, genome-wide association studies, and genomic stratification models, the debate on genetic discrimination in the context of life insurance became even more complex, requiring a review of current practices and the exploration of new scenarios. In this perspective, a multidisciplinary group of international experts representing different interests revisited the genetics and life insurance debate during a 2-day symposium ‘Life insurance: breast cancer research and genetic risk prediction seminar'' held in Quebec City, Canada on 24 and 25 September 2012. Having reviewed the current legal, social, and ethical issues on the use of genomic information in the context of life insurance, the Expert Group identified four main questions: (1) Have recent developments in genomics and related sciences changed the contours of the genetics and life insurance debate? (2) Are genomic results obtained in a research context relevant for life insurance underwriting? (3) Should predictive risk assessment and risk stratification models based on genomic data also be used for life insurance underwriting? (4) What positive actions could stakeholders in the debate take to alleviate concerns over the use of genomic information by life insurance underwriters? This paper presents a summary of the discussions and the specific action items recommended by the Expert Group.Access to genetic information by life insurers has been a topic of discussion for many years.¹ The possibility of using genetic data to underwrite an applicant''s insurance policy has given rise to concerns about the emergence of ‘genetic discrimination''. Genetic discrimination in the field of life insurance is not necessarily illegal in that in insurance underwriting questions about health, family history of disease, or genetic information may constitute legal exceptions to antidiscrimination legislation.^{2, 3} Nevertheless, the expression ‘genetic discrimination'' has acquired public notoriety⁴ and we will use more neutral language in this paper.Countries including Canada, the United States, Russia, and Japan⁵ have chosen not to adopt laws specifically prohibiting access to genetic data for underwriting by life insurers.⁶ In these countries, life insurance underwriters treat genetic data like other types of medical or lifestyle data. However, a growing number of countries such as Belgium, France, and Norway⁵ have chosen to adopt laws to prevent or limit insurers'' access to genetic data for life insurance underwriting. Other countries including Finland and the United Kingdom have developed voluntary arrangements with the industry (ie moratoria) with similar objectives.⁷Life insurance is a private contract between the policy-holder and the insurer. Its principal role is to provide financial security to the beneficiaries in the event of the insured''s death.⁸ Because of this important role, life insurance is often required, or strongly recommended for those seeking loans to acquire primary social goods, like housing or cars.⁹ In Europe, a consequence of the advent of the welfare state is that private insurance has increasingly played a complementary and supplementary role to social insurance by offering additional security and protection to the population. Thus, in this region, insurance is often considered as a social good that allows individuals to live a comfortable life and as a tool to promote social integration.¹⁰ In other regions of the world, this social role of life insurance is also recognized to a lesser extent. Given this social role, equitable access to life insurance is perceived as a sensitive issue and cases of denial looked upon negatively in popular media. Although documented incidents of denial or of increased premiums on the basis of genetic information have remained limited to the context of a few relatively well known, highly penetrant, familial, adult-onset, genetic conditions,¹¹ they have nevertheless generated significant public concern. Fear that insurers will have access to genetic information generated in a clinical or research setting for use in underwriting has been reported by several studies as a reason for non-participation in genetic research or recommended clinical genetic testing.^{12, 13, 14}The clinical utility of genetic testing for monogenic disorders such as Huntington disease, and hereditary forms of cancer are well established.¹⁵ However, genomic risk profiles based on the known common susceptibility variants have limited utility in risk prediction at the individual level, although they could be used for risk stratification in prevention programmes in populations.¹⁶ Today, a new era of genomic research has made it increasingly affordable to scan the entire genome of an individual. Researchers and physicians can interpret these data together with medical and lifestyle information in the form of sophisticated risk prediction models.¹⁷ Moreover, improvement in computing technologies coupled with the Internet make predictive information increasingly available, whether through direct-to-consumer marketing of genetic tests, genetic data sharing online communities, or international research database projects. Given these important technological and scientific changes, and their impact on various stakeholders. The term ‘stakeholders'' is used in this text to refer to the following groups of individuals: actuaries (person who computes insurance risk and premium rates based on statistical data), academic researchers, community representatives, ethics committees, genetic counsellors, genomic researchers, human rights experts, insurers, governmental representatives, non-governmental organisations, patient representatives, physicians, policy makers, popular media, reinsurers (company in charge of calculating the risk and premium amount for insuring a particular customer), research participants, and underwriters (company or person in charge of calculating the risk involved in providing insurance for a particular customer and to decide how much should be paid for the premium). This list is not meant to be exhaustive as relevant new groups may emerge as this topic further develops in the coming years. A multidisciplinary group of international experts representing different interests (hereinafter ‘the Expert Group'') revisited the genetics and life insurance debate. The following text presents a summary of the issues discussed and the ‘Action Items'' agreed upon by the Expert Group at the ‘Life Insurance, Risk Stratification, and Personalized Medicine Symposium''.