Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain

Stem cell transplantation promises new hope for the treatment of stroke although significant questions remain about how the grafted cells elicit their effects. One hypothesis is that transplanted stem cells enhance endogenous repair mechanisms activated after cerebral ischaemia. Recognizing that bilateral reorganization of surviving circuits is associated with recovery after stroke, we investigated the ability of transplanted human neural progenitor cells to enhance this structural plasticity. Our results show the first evidence that human neural progenitor cell treatment can significantly increase dendritic plasticity in both the ipsi- and contralesional cortex and this coincides with stem cell-induced functional recovery. Moreover, stem cell-grafted rats demonstrated increased corticocortical, corticostriatal, corticothalamic and corticospinal axonal rewiring from the contralesional side; with the transcallosal and corticospinal axonal sprouting correlating with functional recovery. Furthermore, we demonstrate that axonal transport, which is critical for both proper axonal function and axonal sprouting, is inhibited by stroke and that this is rescued by the stem cell treatment, thus identifying another novel potential mechanism of action of transplanted cells. Finally, we established in vitro co-culture assays in which these stem cells mimicked the effects observed in vivo. Through immunodepletion studies, we identified vascular endothelial growth factor, thrombospondins 1 and 2, and slit as mediators partially responsible for stem cell-induced effects on dendritic sprouting, axonal plasticity and axonal transport in vitro. Thus, we postulate that human neural progenitor cells aid recovery after stroke through secretion of factors that enhance brain repair and plasticity.

A mouse model of Schwartz-Jampel syndrome reveals myelinating Schwann cell dysfunction with persistent axonal depolarization in vitro and distal peripheral nerve hyperexcitability when perlecan is lacking

Congenital peripheral nerve hyperexcitability (PNH) is usually associated with impaired function of voltage-gated K(+) channels (VGKCs) in neuromyotonia and demyelination in peripheral neuropathies. Schwartz-Jampel syndrome (SJS) is a form of PNH that is due to hypomorphic mutations of perlecan, the major proteoglycan of basement membranes. Schwann cell basement membrane and its cell receptors are critical for the myelination and organization of the nodes of Ranvier. We therefore studied a mouse model of SJS to determine whether a role for perlecan in these functions could account for PNH when perlecan is lacking. We revealed a role for perlecan in the longitudinal elongation and organization of myelinating Schwann cells because perlecan-deficient mice had shorter internodes, more numerous Schmidt-Lanterman incisures, and increased amounts of internodal fast VGKCs. Perlecan-deficient mice did not display demyelination events along the nerve trunk but developed dysmyelination of the preterminal segment associated with denervation processes at the neuromuscular junction. Investigating the excitability properties of the peripheral nerve suggested a persistent axonal depolarization during nerve firing in vitro, most likely due to defective K(+) homeostasis, and excluded the nerve trunk as the original site for PNH. Altogether, our data shed light on perlecan function by revealing critical roles in Schwann cell physiology and suggest that PNH in SJS originates distally from synergistic actions of peripheral nerve and neuromuscular junction changes.

Interleukin-6 is an efficacious marker of axonal transport disruption during experimental glaucoma and stimulates neuritogenesis in cultured retinal ganglion cells

It is increasingly recognised that chronically activated glia contribute to the pathology of various neurodegenerative diseases, including glaucoma. One means by which this can occur is through the release of neurotoxic, proinflammatory factors. In the current study, we therefore investigated the spatio-temporal patterns of expression of three such cytokines, IL-1β, TNFα and IL-6, in a validated rat model of experimental glaucoma. First, only weak evidence was found for increased expression of IL-1β and TNFα following induction of ocular hypertension. Second, and much more striking, was that robust evidence was uncovered showing IL-6 to be synthesised by injured retinal ganglion cells following elevation of intraocular pressure and transported in an orthograde fashion along the nerve, accumulating at sites of axonal disruption in the optic nerve head. Verification that IL-6 represents a novel marker of disrupted axonal transport in this model was obtained by performing double labelling immunofluorescence with recognised markers of fast axonal transport. The stimulus for IL-6 synthesis and axonal transport during experimental glaucoma arose from axonal injury rather than ocular hypertension, as the response was identical after optic nerve crush and bilateral occlusion of the carotid arteries, each of which is independent of elevated intraocular pressure. Moreover, the response of IL-6 was not a generalised feature of the gp130 family of cytokines, as it was not mimicked by another family member, ciliary neurotrophic factor. Finally, further study suggested that IL-6 may be an early part of the endogenous regenerative response as the cytokine colocalised with growth-associated membrane phosphoprotein-43 in some putative regenerating axons, and potently stimulated neuritogenesis in retinal ganglion cells in culture, an effect that was additive to that of ciliary neurotrophic factor. These data comprise clear evidence that IL-6 is actively involved in the attempt of injured retinal ganglion cells to regenerate their axons.

Comparison of six radiographic projections to assess femoral head/neck asphericity

Early radiographic detection of femoroacetabular impingement might prevent initiation and progression of osteoarthritis. The structural abnormality in femoral-induced femoroacetabular impingement (cam type) is frequently asphericity at the anterosuperior head/neck contour. To determine which of six radiographic projections (anteroposterior, Dunn, Dunn/45 degrees flexion, cross-table/15 degrees internal rotation, cross-table/neutral rotation, and cross-table/15 degrees external rotation) best identifies femoral head/neck asphericity, we studied 21 desiccated femurs; 11 with an aspherical femoral head/neck contour and 10 with a spherical femoral head/neck contour. To radiographically quantify femoral head asphericity, we measured the angle where the femoral head/neck leaves sphericity (angle alpha). The aspherical femoral head/neck contours had a greater maximum angle alpha (70 degrees ) compared with the spherical head/neck contours (50 degrees ). The angle alpha varied depending on the radiographic projection: it was greatest in the Dunn view with 45 degrees hip flexion (71 degrees +/- 10 degrees ) and least in the cross-table view in 15 degrees external rotation (51 degrees +/- 7 degrees ). Diagnosis of a pathologic femoral head/neck contour depends on the radiologic projection. The Dunn view in 45 degrees or 90 degrees flexion or a cross-table projection in internal rotation best show femoral head/neck asphericity, whereas anteroposterior or externally rotated cross-table views are likely to miss asphericity. Level of Evidence: Prognostic study, level II-1 (retrospective study).

Percutaneous coronary interventions in Europe: prevalence, numerical estimates, and projections based on data up to 2004

AIMS: A registry mandated by the European Society of Cardiology collects data on trends in interventional cardiology within Europe. Special interest focuses on relative increases and ratios in new techniques and their distributions across Europe. We report the data through 2004 and give an overview of the development of coronary interventions since the first data collection in 1992. METHODS AND RESULTS: Questionnaires were distributed yearly to delegates of all national societies of cardiology represented in the European Society of Cardiology. The goal was to collect the case numbers of all local institutions and operators. The overall numbers of coronary angiographies increased from 1992 to 2004 from 684 000 to 2 238 000 (from 1250 to 3930 per million inhabitants). The respective numbers for percutaneous coronary interventions (PCIs) and coronary stenting procedures increased from 184 000 to 885 000 (from 335 to 1550) and from 3000 to 770 000 (from 5 to 1350), respectively. Germany was the most active country with 712 000 angiographies (8600), 249 000 angioplasties (3000), and 200 000 stenting procedures (2400) in 2004. The indication has shifted towards acute coronary syndromes, as demonstrated by rising rates of interventions for acute myocardial infarction over the last decade. The procedures are more readily performed and perceived safer, as shown by increasing rate of "ad hoc" PCIs and decreasing need for emergency coronary artery bypass grafting (CABG). In 2004, the use of drug-eluting stents continued to rise. However, an enormous variability is reported with the highest rate in Switzerland (70%). If the rate of progression remains constant until 2010 the projected number of coronary angiographies will be over three million, and the number of PCIs about 1.5 million with a stenting rate of almost 100%. CONCLUSION: Interventional cardiology in Europe is ever expanding. New coronary revascularization procedures, alternative or complementary to balloon angioplasty, have come and gone. Only stenting has stood the test of time and matured to the default technique. Facilitated access to PCI, more complete and earlier detection of coronary artery disease promise continued growth of the procedure despite the uncontested success of prevention.

Uncrossed cortico-muscular projections in humans are abundant to facial muscles of the upper and lower face, but may differ between sexes

It is a popular concept in clinical neurology that muscles of the lower face receive predominantly crossed cortico-bulbar motor input, whereas muscles of the upper face receive additional ipsilateral, uncrossed input. To test this notion, we used focal transcranial magnetic brain stimulation to quantify crossed and uncrossed cortico-muscular projections to 6 different facial muscles (right and left Mm. frontalis, nasalis, and orbicularis oris) in 36 healthy right-handed volunteers (15 men, 21 women, mean age 25 years). Uncrossed input was present in 78% to 92% of the 6 examined muscles. The mean uncrossed: crossed response amplitude ratios were 0.74/0.65 in right/left frontalis, 0.73/0.59 in nasalis, and 0.54/0.71 in orbicularis oris; ANOVA p>0.05). Judged by the sizes of motor evoked potentials, the cortical representation of the 3 muscles was similar. The amount of uncrossed projections was different between men and women, since men had stronger left-to-left projections and women stronger right-to-right projections. We conclude that the amount of uncrossed pyramidal projections is not different for muscles of the upper from those of the lower face. The clinical observation that frontal muscles are often spared in central facial palsies must, therefore, be explained differently. Moreover, gender specific lateralization phenomena may not only be present for higher level behavioural functions, but may also affect simple systems on a lower level of motor hierarchy.