Uncoupling of neuroinflammation from axonal degeneration in mice lacking the myelin protein tetraspanin‐2

Deficiency of the major constituent of central nervous system (CNS) myelin, proteolipid protein (PLP), causes axonal pathology in spastic paraplegia type‐2 patients and in Plp1^null‐mice but is compatible with almost normal myelination. These observations led us to speculate that PLP's role in myelination may be partly compensated for by other tetraspan proteins. Here, we demonstrate that the abundance of the structurally related tetraspanin‐2 (TSPAN2) is highly increased in CNS myelin of Plp1^null‐mice. Unexpectedly, Tspan2^null‐mutant mice generated by homologous recombination in embryonic stem cells displayed low‐grade activation of astrocytes and microglia in white matter tracts while they were fully myelinated and showed no signs of axonal degeneration. To determine overlapping functions of TSPAN2 and PLP, Tspan2^null*Plp1^null double‐mutant mice were generated. Strikingly, the activation of astrocytes and microglia was strongly enhanced in Tspan2^null*Plp1^null double‐mutants compared with either single‐mutant, but the levels of dysmyelination and axonal degeneration were not increased. In this model, glial activation is thus unlikely to be caused by axonal pathology, and vice versa does not potentiate axonal degeneration. Our results support the concept that multiple myelin proteins have distinct roles in the long‐term preservation of a healthy CNS, rather than in myelination per se. GLIA 2013;61:1832–1847     

Can online benchmarking increase rates of thrombolysis? Data from the Austrian stroke unit registry

Despite its widespread availability and known safety and efficacy, a therapy with intravenous thrombolysis is still undergiven. We aimed to identify whether nationwide quality projects—like the stroke registry in Austria—as well as online benchmarking and predefined target values can increase rates of thrombolysis. Therefore, we assessed 6,394 out of 48,462 patients with ischemic stroke from the Austrian stroke registry (study period from March 2003 to December 2011) who had undergone thrombolysis treatment. We defined lower level and target values as quality parameters and evaluated whether or not these parameters could be achieved in the past years. We were able to show that rates of thrombolysis in Austria increased from 4.9 % in 2003 to 18.3 % in 2011. In a multivariate regression model, the main impact seen was the increase over the years [the OR ranges from 0.47 (95 % CI 0.32–0.68) in 2003 to 2.51 (95 % CI 2.20–2.87) in 2011). The predefined lower and target levels of thrombolysis were achieved at the majority of participating centers: in 2011 the lower value of 5 % was achieved at all stroke units, and the target value of 15 % was observed at 21 of 34 stroke units. We conclude that online benchmarking and the concept of defining target values as a tool for nationwide acute stroke care appeared to result in an increase in the rate of thrombolysis over the last few years while the variability between the stroke units has not yet been reduced.     

Fibroblast growth factor receptor 3 signaling regulates injury-related effects in the peripheral nervous system

Fibroblast growth factor receptor (FGFR) signaling is crucial for neural development and regeneration. Here we investigated the L5 spinal ganglion and the sciatic nerve of intact Fgfr3-deficient mice after nerve injury. Quantification of sensory neurons in the L5 spinal ganglion revealed no significant differences between wild-type and Fgfr3-deficient mice. Seven days after nerve lesion, the normally occurring neuron loss in wild-type mice was not found in Fgfr3-deficient animals, suggesting that FGFR3 signaling is involved in the cell death process. Morphometric analysis of the sciatic nerve showed similar numbers of myelinated axons, but the axonal and myelin diameter was significantly smaller in Fgfr3-deficient mice compared to the wild types. Evaluation of regenerating myelinated axons of the sciatic nerve revealed no differences between both mouse strains 7 days after crush injury. Our results suggest that FGFR3 signaling seems to be involved in processes of damage-induced neuron death and axonal development.     

Comparative cellular distribution of GABAA and GABAB receptors in the human basal ganglia: immunohistochemical colocalization of the alpha 1 subunit of the GABAA receptor, and the GABABR1 and GABABR2 receptor subunits

The GABA(B) receptor is a G-protein linked metabotropic receptor that is comprised of two major subunits, GABA(B)R1 and GABA(B)R2. In this study, the cellular distribution of the GABA(B)R1 and GABA(B)R2 subunits was investigated in the normal human basal ganglia using single and double immunohistochemical labeling techniques on fixed human brain tissue. The results showed that the GABA(B) receptor subunits GABA(B)R1 and GABA(B)R2 were both found on the same neurons and followed the same distribution patterns. In the striatum, these subunits were found on the five major types of interneurons based on morphology and neurochemical labeling (types 1, 2, 3, 5, 6) and showed weak labeling on the projection neurons (type 4). In the globus pallidus, intense GABA(B)R1 and GABA(B)R2 subunit labeling was found in large pallidal neurons, and in the substantia nigra, both pars compacta and pars reticulata neurons were labeled for both receptor subunits. Studies investigating the colocalization of the GABA(A) alpha(1) subunit and GABA(B) receptor subunits showed that the GABA(A) receptor alpha(1) subunit and the GABA(B)R1 subunit were found together on GABAergic striatal interneurons (type 1 parvalbumin, type 2 calretinin, and type 3 GAD neurons) and on neurons in the globus pallidus and substantia nigra pars reticulata. GABA(B)R1 and GABA(B)R2 were found on substantia nigra pars compacta neurons but the GABA(A) receptor alpha(1) subunit was absent from these neurons. The results of this study provide the morphological basis for GABAergic transmission within the human basal ganglia and provides evidence that GABA acts through both GABA(A) and GABA(B) receptors. That is, GABA acts through GABA(B) receptors, which are located on most of the cell types of the striatum, globus pallidus, and substantia nigra. GABA also acts through GABA(A) receptors containing the alpha(1) subunit on specific striatal GABAergic interneurons and on output neurons of the globus pallidus and substantia nigra pars reticulata.     

Role of cytokines and chemokines in prion infections of the central nervous system

Prion infections of the central nervous system (CNS) are characterised by a reactive gliosis and the subsequent degeneration of neuronal tissue. The activation of glial cells, which precedes neuronal death, is likely to be initially caused by the deposition of misfolded, proteinase K-resistant, isoforms (termed PrP(res)) of the prion protein (PrP) in the brain. Cytokines and chemokines released by PrP(res)-activated glia cells may contribute directly or indirectly to the disease development by enhancement and generalisation of the gliosis and via cytotoxicity for neurons. However, the actual role of prion-induced glia activation and subsequent cytokine/chemokine secretion in disease development is still far from clear. In the present work, we review our present knowledge concerning the functional biology of cytokines and chemokines in prion infections of the CNS.     

Prediction of global outcome with acute neuropsychological testing following closed-head injury.

Delaying assessment until emergence from post-traumatic amnesia increases completion rates, but this practice causes variable time delays from the date of injury to testing, which can complicate the interpretation of research findings. In the current study, the performance of 105 head injury survivors on simple tests of language comprehension and attention was used to predict global outcome. It was hypothesized that 1 month performance on these measures would aid in the prediction of Disability Rating Scale (DRS) and Glasgow Outcome Scale (GOS) scores collected at 6 months post injury. Only raw scores on the modified Test of Complex Ideational Material accounted for a significant amount of the variance in DRS scores (4.4%) above that accounted for by age, education, Glasgow Coma Scale score, and pupil response. However, testability at 1 month post injury on all four tests consistently accounted for a larger portion of the variance in DRS scores (10.1-13.2%) and significantly improved prediction of GOS scores. Galveston Orientation and Amnesia Test scores collected at 1 month post injury accounted for substantially less variance in DRS scores (7.7-8.4%). Neuropsychological data, including the testability of patients, collected uniformly at 1 month following injury can contribute to the prediction of global outcome.     

Tubulin polymerization‐promoting protein family member 3, Tppp3, is a specific marker of the differentiating tendon sheath and synovial joints

Tppp3, a member of the Tubulin polymerization‐promoting protein family, is an intrinsically unstructured protein that induces tubulin polymerization. We show that Tppp3 is a distinct marker in the developing musculoskeletal system. In tendons, Tppp3 is expressed in cells at the circumference of the developing tendons, likely the progenitors of connective tissues that surround tendons: the tendon sheath, epitenon, and paratenon. These tissues form an elastic sleeve around tendons and provide lubrication to minimize friction between tendons and surrounding tissues. Tppp3 is the first molecular marker of the tendon sheath, opening the door for direct examination of these tissues. Tppp3 is also expressed in forming synovial joints. The onset of Tppp3 expression in joints coincides with cavitation, representing a molecular marker that can be used to indicate this stage in joint transition in joint differentiation. In late embryonic stages, Tppp3 expression highlights other demarcation lines that surround differentiating tissues in the forelimb. Developmental Dynamics 238:685–692, 2009. © 2009 Wiley‐Liss, Inc.     

Diastolic Function Study with Conventional and Pulsed Tissue Doppler Echocardiography Imaging in Acromegalic Patients

Acromegaly is associated with myocardial hypertrophy and it can progress to diastolic and systolic dysfunction. Purpose: To evaluate diastolic function in acromegalic patients through conventional echocardiography (CD) and tissue Doppler imaging (TDI). Methods: Seventeen acromegalic patients were submitted to CD and TDI, and early (E) and atriogenic (A) transmitral flow were evaluated in mitral, septal, and tricuspid regions. Results: In comparison with controls the means of conventional (1.06), septal (1.01), and tricuspid (0.98) E/A ratio were significantly lower in acromegalic patients. E/A ratio <1.0 was demonstrated in 41% and 49% of acromegalics by DC and TDI, respectively, with no statistical difference among the two methods. An inverse linear correlation was shown between mitral E/A ratio and acromegalic age (r =−0.7). Conclusion: In this study, DC and TDI were equally effective in demonstrating diastolic dysfunction, a common finding in acromegalic patients.     

Sleep-associated movement disorders and heart failure

Sleep-associated movement disorders are a broad group of sleep disorders characterized by involuntary movements that may disrupt sleep. Relatively little is known about the clinical consequences of sleep-associated movement disorders on cardiovascular health. Because these disorders manifest mostly during sleep, recognizing a movement disorder can be particularly difficult. Nevertheless, patients can have frequent arousals and suffer from similar sleep deprivation, fragmentation, and autonomic disruption as occurs in sleep-disordered breathing. Subsequently, these disorders may have a serious impact on daytime function and perception of health in patients with chronic heart failure.