Patient-derived olfactory mucosa cells but not lung or skin fibroblasts mediate axonal regeneration of retinal ganglion neurons

Ether-a-go-go (ERG) K⁺ channel is a channel of potassium inward rectification. ERG channelopathy may be a cause of sudden unwanted death. The purpose of our study is to assess the effect of antiepileptic drugs on the expression of ERG K⁺ channel in the hippocampus using seizure resistant (SR) and seizure sensitive (SS) gerbils. As compared to controls, in principal neuron of hippocampus ERG immunoreactivity was significantly decreased after administration of AEDs in SS and SR gerbils. In addition, population spike in response to the second stimulus disappeared, thus population spike amplitude ratio was significantly reduced to zero. These findings indicate that AEDs reduce the expression of ERG channel in the hippocampus of the SR and SS gerbils accompanied by the enhancement of paired-pulse inhibition. In addition, the influence of AEDs on ERG expression in the brain may not be relevant to sudden unexpected death in epilepsy.     

HTLV-1/2 among high-risk groups in Argentina: molecular diagnosis and prevalence of different sexual transmitted infections

The objectives of this study were to estimate the prevalence and characterize the epidemiologic patterns of HTLV-1/2 infections and co-infections with HIV, HBV (hepatitis B), HCV (hepatitis C), and Treponema Pallidum in five different high-risk groups, including injecting drug users (IDUs), female sex workers (FSWs), men who have sex with men (MSM), patients with tuberculosis (TB), and patients attending clinics for sexually transmitted infections (STIs) in Buenos Aires, Argentina. The HTLV-1/2 prevalence was 19.1% (33/173) for IDUs, 2.0% (10/613) for FSWs, 2.1% (4/187) for TB, 1.0% (4/400) for STIs and 0.4% (3/282) for MSM, respectively. Among all groups, the higher percentages of co-infection were HTLV-1/HBV (63%, 17/27) and HTLV-1/HCV (52%, 14/27). Among IDUs, there was a high percentage of co-infection of HTLV-2 with HCV (96.3%, 26/27), HIV (92.6%, 25/27), and HBV (77.8%, 21/27), respectively. In summary, HTLV-1/2 infections appear to be widely distributed among high-risk groups in a nonendemic area of Argentina being the co-infection with HBV and HCV more frequent among IDUs.     

Rescue of neurological deficits in a mouse model for Angelman syndrome by reduction of alphaCaMKII inhibitory phosphorylation

Angelman syndrome (AS) is a severe neurological disorder characterized by mental retardation, motor dysfunction and epilepsy. We show that the molecular and cellular deficits of an AS mouse model can be rescued by introducing an additional mutation at the inhibitory phosphorylation site of alphaCaMKII. Moreover, these double mutants no longer show the behavioral deficits seen in AS mice, suggesting that these deficits are the direct result of increased inhibitory phosphorylation of alphaCaMKII.     

Immunotherapy for neurological diseases

The burden of neurological diseases in western societies has accentuated the need to develop effective therapies to stop the progression of chronic neurological diseases. Recent discoveries regarding the role of the immune system in brain damage coupled with the development of new technologies to manipulate the immune response make immunotherapies an attractive possibility to treat neurological diseases. The wide repertoire of immune responses and the possibility to engineer such responses, as well as their capacity to promote tissue repair, indicates that immunotherapy might offer benefits in the treatment of neurological diseases, similar to the benefits that are being associated with the treatment of cancer and autoimmune diseases. However, before applying such strategies to patients it is necessary to better understand the pathologies to be targeted, as well as how individual subjects may respond to immunotherapies, either in isolation or in combination. Due to the powerful effects of the immune system, one priority is to avoid tissue damage due to the activity of the immune system, particularly considering that the nervous system does not tolerate even the smallest amount of tissue damage.     

Phosphorylation of microtubule-associated protein 2 (MAP2) and its relevance for the regulation of the neuronal cytoskeleton function

Neurons, the basic information processing units of the nervous system, are characterized by a complex polar morphology which is essential for their function. To attain their precise morphology, neurons extend cytoplasmatic processes (axons and dendrites) and establish synaptic connections in a highly regulated way. Additionally, neurons are also subjected to small plastic changes at the adult stage which serve to regulate synaptic transmission. Every step of neuronal development is genetically controlled by endogenous determinants, as well as by environmental signals including intercellular contacts, extracellular matrix and diffusible signals. Cytoskeletal components are among the main protein targets modified in response to most of those extracellular signals which ultimately determine neuronal morphology. One of the major mechanisms controlling the neuronal cytoskeleton is the modification of the phosphorylation state of cytoskeletal proteins via changes in the relative activities of protein kinases and phosphatases within neurons. In particular, the microtubule-associated protein 2 (MAP2) family of proteins is an abundant group of cytoskeletal components which are predominantly expressed in neurons and serve as substrates for most of protein kinases and phosphatases present in neurons. MAP2 phosphorylation seems to control its association with the cytoskeleton and it is developmentally regulated. Moreover, MAP2 may perform many functions including the nucleation and stabilization of microtubules (and maybe microfilaments), the regulation of organelle transport within axons and dendrites, as well as the anchorage of regulatory proteins such as protein kinases which may be important for signal transduction. These putative functions of MAP2 have also been proposed to play important roles in the outgrowth of neuronal processes, synaptic plasticity and neuronal cell death. Thus, MAP2 constitutes an interesting case to understand the regulation of neuronal function by the alteration of the phosphorylation state of cytoskeletal proteins in response to different extracellular signals. Here we will review the current knowledge about the regulation of MAP2 function through phosphorylation/dephosphorylation and its relevance in the broader context of neuronal functions.     

Treatment of metastatic osteosarcoma with the somatostatin analog OncoLar: significant reduction of insulin-like growth factor-1 serum levels

BACKGROUND: Insulin-like growth factor-1 (IGF-1) has been implicated in the growth and/or metastasis of osteosarcoma (OS) and chondrosarcoma based on in vitro and experimental animal studies. STUDY PURPOSE: To determine the degree of growth hormone (GH), IGF-1 axis blockade, toxicities, and antitumor effect of OncoLar (ONC) (Novartis, East Hanover, NJ, U.S.A.) in OS. DESIGN/METHODS: A phase 1 study with ONC enrolled 21 OS patients (median age 19 y) in four cohorts: ONC 60 mg or 90 mg intramuscularly every 4 weeks with/without tamoxifen (TAM) 20 mg oral daily. RESULTS: There were no dose-limiting toxicities. Nineteen percent of patients had grade III drug-related toxicities including: 62% of patients showed progressive disease after two courses (8 wk). Nineteen percent received four courses. No clinical responses were observed. At weeks two and eight of therapy, IGF-1 serum levels dropped 46% ( < 0.0001, n = 21) and 53% ( = 0.003, n = 10). The difference of the area under the curve (AUC) minus baseline AUC (DeltaAUC) for arginine-stimulated GH serum levels at week two was lower than baseline ( < 0.01). At weeks two and eight, GH peak values were lower than baseline ( < 0.0001 and = 0.002, respectively). CONCLUSIONS: A long-acting somatostatin analog was able to lower IGF-1 levels of OS patients. IGF-BP-3 and GH were only transiently reduced. Although ONC was well tolerated, no sustained clinical responses were observed. The pathophysiology of serum versus tissue concentrations of IGF-1 as well as the interplay of IGFs, IGF-binding proteins, and other growth factors and cytokines in osteosarcoma warrants further investigation. A better understanding of these processes should lead to a more effective exploitation of these pathways for the targeted therapy of OS.