A meta-analysis of genome-wide association studies of multiple myeloma among men and women of African ancestry

Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs ofMMin 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P < 1 × 10-6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P < .05 in AA individuals. In 8 regions, we identified markers that better captureMMrisk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10-12). Our study shows that common genetic variation contributes to MM risk in individuals with AA

Autonomic Dysfunction and Risk Stratification Assessed from Heart Rate Pattern

The modulation of the autonomic nervous system (ANS) under physiological and pathophysiological conditions is in focus of recent research. Many patients with cardio- and cerebrovascular diseases display features of sympathovagal dysregulation. Measuring specific ANS parameters could improve risk stratification. Thus, the early diagnosis of ANS dysfunction in these patients poses a great challenge with high prognostic relevance

Cortical spreading depression induces proinflammatory cytokine gene expression in the rat brain

Cortical spreading depression (CSD) is characterized by reversible neuronal dysfunction in the absence of cell death. Preconditioning by CSD induces tolerance against subsequent lethal ischemia. In this study, we used quantitative reverse transcriptase-polymerase chain reaction and immunocytochemistry to analyze proinflammatory cytokine expression after CSD induced by topical application of potassium chloride (KCl) to the cortical surface of rat brains. Relative to control cortex, we found an increase of tumor necrosis factor-alpha (mean 62-fold, P < 0.001) and interleukin (IL)-1beta (mean 24-fold, P < 0.001) mRNA levels within 4 hours ipsilateral to the site of KCl application. At 16 hours cytokine expression was decreasing toward baseline levels. Ipsilateral cytokine induction was abolished by pretreatment with the noncompetitive N-methyl-d-aspartate antagonist, MK-801. In contrast to focal cortical infarction, cytokine induction in CSD was not accompanied by the expression of inducible nitric oxide synthase mRNA. In immunocytochemical studies, expression of IL-1beta protein was localized to ramified microglia in cortical layers I to III of the ipsilateral hemisphere. Our finding that NMDA receptor signaling without subsequent neuronal cell death is sufficient to induce inflammatory cytokine expression in the brain has basic implications for central nervous system immunoregulation. We postulate that cytokine expression in CSD forms part of a physiologic stress response that contributes to the development of ischemic tolerance in this and other preconditioning paradigms

Proliferative response of distinct hippocampal progenitor cell populations after cortical infarcts in the adult brain

Precursor cells in the adult dentate gyrus are a heterogeneous population. Astrocytic cell types with radial glia-like morphology and low proliferative activity have been distinguished from highly dividing subtypes expressing early neuronal properties. Recent evidence indicates that physiological stimuli predominantly increased proliferation of non-astrocytic cell types whereas radial glia-like precursors remained quiescent. We here analyzed the proliferative response of precursor cell subtypes under pathophysiological conditions in a model of photochemical cortical infarcts. Using transgenic pNestin-GFP mice and single intraperitoneal injections of 5-bromo-2-deoxyuridine 4 h after surgery, immunocytochemical analysis revealed a differential activation of the distinct subpopulations within 72 h after the infarct. The stimulation was most prominent in radial glia-like precursor cells but also non-astrocytic precursors with early neuronal phenotypes were activated. The present study indicates that the proliferative response of precursor cell subpopulations in the subgranular zone might differ under physiological and pathophysiological conditions

Impaired synaptic plasticity in the surround of perinatally acquired dysplasia in rat cerebral cortex

Freeze-lesion induced neocortical dysplasias in rats mimic numerous aspects of human polymicrogyria and are used as a model for the study of developmental migration disorders. Since memory tests have demonstrated learning deficits in rodents with neocortical malformations, we investigated the expression and properties of long-term potentiation (LTP) in neocortical slices from adult freeze-lesioned and control rats. Field potentials, recorded in layer II/III at a distance of 2-3 mm lateral to perinatally induced microgyri, were strongly enhanced following theta-burst stimulation in layer VI (amplitude: 174 +/- 4%) compared to controls (110 +/- 2%). In contrast, in layer IV of the freeze-lesioned cortex LTP could not reliably be induced. Histochemical analysis, performed to elucidate the cellular basis of the impaired plasticity, revealed diminished amounts of the GABAA-receptor subunit gamma2 in the paramicrogyral zone, likely representing a diminished GABA-ergic filter, which is thought to prevent LTP induced in layer VI under normal conditions. Cytochrome-oxidase staining after electrophysiological examination disclosed that LTP in layer IV of the freeze-lesioned cortex could only be elicited, when stimulation was applied within a preserved barrel cortex. Our study provides evidence that focal cryolesions during cortical development cause an impaired synaptic plasticity that may underlie learning disabilities

Aberrant neurogenesis after stroke: A retroviral cell labeling study.

Background and Purpose-Adult neurogenesis in the dentate gyrus is a unique form of brain plasticity that is strongly stimulated after stroke. We investigate the morphological properties of new granule cells, which are born and develop after the ischemic insult, and query whether these adult-born neurons properly integrate into the pre-existing hippocampal circuitries. Methods-Two well-established models were used to induce either small cortical infarcts (photothrombosis model) or large territorial infarcts (transient middle cerebral artery occlusion model). New granule cells were labeled 4 days after the initial insult by intrahippocampal injection of a retroviral vector encoding green fluorescent protein and newborn neurons were morphologically analyzed using a semiautomatic Neurolucida system and confocal laser scanning microscopy at 6 weeks. Results-Approximately 5% to 10% of newborn granule cells displayed significant morphological abnormalities comprising additional basal dendrites and, after middle cerebral artery occlusion, also ectopic cell position. The extent of morphological abnormalities was higher after large territorial infarcts and seems to depend on the severity of ischemic damage. An increased portion of mushroom spines in aberrant neurons suggests stable synaptic integration. However, poststroke generated granule cells with regular appearance also demonstrate alterations in dendritic complexity and spine morphology. Conclusions-The remarkable stimulation of dentate neurogenesis after stroke coincides with an increased rate of aberrantly integrated neurons, which may contribute to functional impairments and, hypothetically, favor pathogenesis of adjustment disorders, cognitive deficits, or epilepsy often seen in stroke patients. (Stroke. 2012;43:2468-2475.

Supplementary Material for: Clinical Presentation, Magnetic Resonance Angiography, Ultrasound Findings, and Stroke Patterns in Patients with Vertebral Artery Dissection

<i>Background/Aims:</i> Vertebral artery dissection (VAD) is an important cause of ischemic stroke. In this observational study, clinical data, magnetic resonance (MR) and ultrasound (US) imaging findings and ischemic patterns were analyzed. <i>Methods:</i>Forty-seven patients with a diagnosis of VAD underwent clinical examination, US, MR of the brain and neck and MR angiography (MRA) of the cervical arteries. Vascular abnormalities and ischemic brain lesions were noted. Data were evaluated separately and compared for spontaneous and traumatic VAD subgroups. <i>Results:</i> The most common overall clinical symptom was vertigo followed by neck pain. In the traumatic subgroup, vertigo was relatively rare (p = 0.022). Most common MRA findings were vessel irregularity and vessel occlusions. Ischemic lesions occurred significantly more frequently after spontaneous than after traumatic VAD (p = 0.009). Unilateral VAD was significantly more common in non-dominant vertebral arteries (p < 0.001). Mortality after trauma was not only due to VAD complications but also due to other trauma-related injuries. <i>Conclusion:</i> The variability of MR and US imaging findings in patients with VAD is illustrated. The algorithm of management should be based on a multimodality approach involving patient history and clinical neurological examination. Several types of vessel abnormalities and ischemic lesion in diverse locations may point to arterial dissection, and the differential diagnosis of VAD must be kept in mind

Synaptic responses in superficial layers of medial entorhinal cortex from rats with kainate-induced epilepsy.

Mesial temporal lobe epilepsy patients often display shrinkage of the entorhinal cortex, which has been attributed to neuronal loss in medial entorhinal cortex layer III (MEC-III). MEC-III neuronal loss is reproduced in chronic epileptic rats after kainate-induced (KA) status epilepticus. Here we examined, in vitro, functional changes in superficial entorhinal cortex layers. Alterations in superficial layer circuitry were suggested by showing that presubiculum, parasubiculum and deep MEC stimulation evoked 100-300 Hz field potential transients and prolonged EPSPs (superimposed on IPSPs) in superficial MEC which were partially blocked by APV (in contrast to control) and fully blocked by CNQX. Contrary to controls, bicuculline (5 and 30 muM) had minor effects on evoked field potentials in KA rats. GAD65/67 in situ hybridization revealed preserved interneurons in MEC-III. In conclusion, hyperexcitability in superficial MEC neurons is not due to loss of GABAergic interneurons and probably results from alterations in synaptic connectivity within superficial MEC

Wallerian degeneration of pyramidal tract after paramedian pons infarct

The intention of this study was the prospective analysis of Wallerian degeneration of the pyramidal tract after paramedian pons infarction.Patients with paramedian pons infarct underwent MR imaging including diffusion tensor imaging at admission and got 1-3 MR scans up to 6 months of follow-up. Clinical scores and transcranial magnetic stimulation were acquired in the acute phase and 3-6 months later. The pyramidal tracts were manually segmented in fractional anisotropy (FA) color maps after coregistration of all MR datasets of each patient. FA as well as axial and radial diffusivity were measured in the volume of lesioned and contralateral pyramidal tracts distally to the ischemic lesion.From 11 patients studied, 7 developed Wallerian degeneration detected as statistically significant decrease in FA over time in the distal pyramidal tract. Wallerian degeneration could be detected at the earliest between the first and the third days after the onset of symptoms. A continuous decrease in FA and an increase in axial and radial diffusivity in degenerating pyramidal tracts over time were demonstrated. A significant correlation between NIHSS score on admission and the slope of relative axial diffusivity and a significant correlation between motor-evoked potential amplitudes of the arm on admission and the outcome relative FA was found.The initial MR image cannot predict the following Wallerian degeneration. However, the severity of motor disturbance and the motor-evoked potential of the arm on admission could be possible parameters to predict Wallerian degeneration. For estimation of Wallerian degeneration over time, at least 2 diffusion tensor imaging measurements have to be done at different time points

Age-dependent increase of cytoskeletal components in sensory axons in human skin.

Aging is a complex process characterized by several molecular and cellular imbalances. The composition and stability of the neuronal cytoskeleton is essential for the maintenance of homeostasis, especially in long neurites. Using human skin biopsies containing sensory axons from a cohort of healthy individuals, we investigate alterations in cytoskeletal content and sensory axon caliber during aging via quantitative immunostainings. Cytoskeletal components show an increase with aging in both sexes, while elevation in axon diameter is only evident in males. Transcriptomic data from aging males illustrate various patterns in gene expression during aging. Together, the data suggest gender-specific changes during aging in peripheral sensory axons, possibly influencing cytoskeletal functionality and axonal caliber. These changes may cumulatively increase susceptibility of aged individuals to neurodegenerative diseases