Metabolic activity in the brain of juvenile and adult rats with a neonatal ventral hippocampal lesion

Longitudinal studies on patients for schizophrenia suggest that functional brain perturbations precede the onset of symptoms. Rats with a neonatal ventral hippocampal lesion (NVHL) are considered as a heuristic neurodevelopmental model of schizophrenia. We characterized basal metabolic changes observed in NVHL rats before and after the age when known behavioral alterations have been reported. Male pups were lesioned with ibotenic acid at postnatal day 7 (PD7). We measured local cerebral metabolic rates for glucose (LCMRglc) by the quantitative autoradiographic [¹⁴C]2‐deoxyglucose technique at pre‐ (PD21) and postpubertal (PD42) ages when NVHL rats do not express abnormal dopamine related behaviors, and at adulthood (PD70). We observed a widespread increase in LCMRglcs in PD21 NVHL indicative of an ongoing intense reorganization of the brain while at PD42, increases were less extended. At PD70, changes in glucose metabolism were restricted to specific systems, such as the auditory system, the cerebellum, the serotonergic median raphe, and median septum. These data show in a heuristic animal model of schizophrenia that functional metabolic changes within the brain could precede the onset of dopamine‐related behavioral alterations and lead to a distinct ensemble of functional changes in adulthood in systems that may be relevant to schizophrenia. © 2009 Wiley‐Liss, Inc.     

Mediastinal tuberculosis in an adult patient with cystic fibrosis

Tuberculosis (TB) is rarely observed in cystic fibrosis (CF) patients. We report the first case of mediastinal TB, associated with leg pain and skin rash, in an adult patient with CF, and discuss factors suggestive of TB in the course of CF.     

Hyperbranched PEGmethacrylate linear pDMAEMA block copolymer as an efficient non-viral gene delivery vector

A unique hyperbranched polymeric system with a linear poly-2-dimethylaminoethyl methacrylate (pDMAEMA) block and a hyperbranched polyethylene glycol methyl ether methacrylate (PEGMEMA) and ethylene dimethacrylate (EGDMA) block was designed and synthesized via deactivation enhanced atom transfer radical polymerisation (DE-ATRP) for efficient gene delivery. Using this unique structure, with a linear pDMAEMA block, which efficiently binds to plasmid DNA (pDNA) and hyperbranched polyethylene glycol (PEG) based block as a protective shell, we were able to maintain high transfection levels without sacrificing cellular viability even at high doses. The transfection capability and cytotoxicity of the polymers over a range of pDNA concentration were analysed and the results were compared to commercially available transfection vectors such as polyethylene imine (branched PEI, 25 kDa), partially degraded poly(amido amine)dendrimer (dPAMAM; commercial name: SuperFect(?)) in fibroblasts and adipose tissue derived stem cells (ADSCs).     

Leg muscle vibration modulates bodily self-consciousness: integration of proprioceptive, visual, and tactile signals

Behavioral studies have used visuo-tactile conflicts between a participant's body and a visually presented fake or virtual body to investigate the importance of bodily perception for self-consciousness (bodily self-consciousness). Illusory self-identification with a fake body and changes in tactile processing--modulation of visuo-tactile cross-modal congruency effects (CCEs)--were reported in previous findings. Although proprioceptive signals are deemed important for bodily self-consciousness, their contribution to the representation of the full body has not been studied. Here we investigated whether and how self-identification and tactile processing (CCE magnitude) could be modified by altering proprioceptive signals with 80-Hz vibrations at the legs. Participants made elevation judgments of tactile cues (while ignoring nearby lights) during synchronous and asynchronous stroking of a seen fake body. We found that proprioceptive signals during vibrations altered the magnitude of self-identification and mislocalization of touch (CCE) in a synchrony-dependent fashion: we observed an increase of self-identification and CCE magnitude during asynchronous stroking. In a second control experiment we studied whether proprioceptive signals per se, or those from the lower limbs in particular, were essential for these changes. We applied vibrations at the upper limbs (which provide no information about the position of the participant's body in space) and in this case observed no modulation of bodily self-consciousness or tactile perception. These data link proprioceptive signals from the legs that are conveyed through the dorsal column-medial lemniscal pathway to bodily self-consciousness. We discuss their integration with bodily signals from vision and touch for full-body representations.     

CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype–phenotype correlation

Meckel-Gruber syndrome (MKS) is a lethal fetal disorder characterized by diffuse renal cystic dysplasia, polydactyly, a brain malformation that is usually occipital encephalocele, and/or vermian agenesis, with intrahepatic biliary duct proliferation. Joubert syndrome (JBS) is a viable neurological disorder with a characteristic “molar tooth sign” (MTS) on axial images reflecting cerebellar vermian hypoplasia/dysplasia. Both conditions are classified as ciliopathies with an autosomal recessive mode of inheritance. Allelism of MKS and JBS has been reported for TMEM67/MKS3, CEP290/MKS4, and RPGRIP1L/MKS5. Recently, one homozygous splice mutation with a founder effect was reported in the CC2D2A gene in Finnish fetuses with MKS, defining the 6th locus for MKS. Shortly thereafter, CC2D2A mutations were also reported in JBS. The analysis of the CC2D2A gene in our series of MKS fetuses, identified 14 novel truncating mutations in 11 cases. These results confirm the involvement of CC2D2A in MKS and reveal a major contribution of CC2D2A to the disease. We also identified three missense CC2D2A mutations in two JBS cases. Therefore, and in accordance with the data reported regarding RPGRIP1L, our results indicate phenotype–genotype correlations, as missense and presumably hypomorphic mutations lead to JBS while all null alleles lead to MKS. Hum Mutat 30:1–9, 2009. © 2009 Wiley-Liss, Inc.     

Novel recombinant interleukin-13 peptide-based vaccine reduces airway allergic inflammatory responses in mice

RATIONALE: Interleukin (IL)-13 plays a pivotal role in the pathogenesis of allergic asthma. Passive administration of its monoclonal antibody or soluble receptor to block overproduced IL-13 has been proven to be effective in controlling airway allergic responses in animal models, but these approaches have disadvantages of short half-lives, high costs, and possible adverse effects. OBJECTIVES: We sought to develop a novel therapeutic strategy through constructing an IL-13 peptide-based vaccine for blocking IL-13 on a persistent effect basis and to evaluate its in vivo effects using a murine model. METHODS: To break self-tolerance, truncated hepatitis B core antigen was used as a carrier. Vaccine was prepared by inserting a peptide derived from the receptor binding site of mouse IL-13 into the immunodominant epitope region of the carrier using gene recombination methods. Mice received vaccine subcutaneously three times, and then subjected to intraperitoneal sensitization and intranasal challenge with ovalbumin. Control animals received carrier or saline in place of vaccine. MEASUREMENTS AND MAIN RESULTS: The vaccine presented as virus-like particles and induced sustained and high titered IL-13-specific IgG without the use of conventional adjuvant. Vaccination significantly suppressed ovalbumin-induced inflammatory cell number, and IL-13 and IL-5 levels in bronchoalveolar lavage fluids. Serum total and ovalbumin-specific IgE were also significantly inhibited. Moreover, allergen-induced goblet cell hyperplasia, lung tissue inflammatory cell infiltration, and pulmonary hyperresponsiveness to inhaled methacholine were significantly suppressed in vaccinated mice. CONCLUSIONS: Our data indicate that IL-13 peptide-based vaccines could be an effective therapeutic approach in the treatment of asthma.     

Anti-thyroperoxidase antibodies from patients with Hashimoto's encephalopathy bind to cerebellar astrocytes

A cohort of 10 Hashimoto's encephalopathy (HE) patients, 33 patients with unrelated neurological symptoms, 12 Hashimoto's thyroiditis patients and 4 healthy adult donors was studied to explore the neurological targets of anti-thyroperoxidase (TPO) autoantibodies (aAb) in HE. High levels of anti-TPO aAb were only detected in HE group's cerebrospinal fluids. In immunofluorescence assays on monkey brain cerebellum sections, both HE patients' sera and anti-TPO monoclonal antibodies (mAb) were able to bind cerebellar cells expressing glial fibrillary acid protein. Normal human astrocytes from primary cultures also reacted with anti-TPO mAb. Specific astrocyte binding of anti-TPO aAb suggests a role of these aAb in the HE pathogenesis.     

The dynamics of effector T cells and Foxp3+ regulatory T cells in the promotion and regulation of autoimmune encephalomyelitis

The Th1/Th2 paradigm of T helper cell subsets had to be revised when IL-17 producing T cells (Th17) were identified as a distinct T helper cell lineage. Th17 cells are very efficient inducers of tissue inflammation and crucial initiators of organ-specific autoimmunity. Whereas Th17 cells promote autoimmune tissue inflammation, Foxp3+ regulatory T cells (T-reg) are necessary and sufficient to prevent autoimmunity throughout the life span of an individual. Here, we review recent findings of how responses of effector T cells and T-reg cells with a defined antigen-specificity develop in autoimmune encephalomyelitis. Moreover, Th17 cells and Foxp3+ T-reg seem to be dichotomously related in that TGF-beta induces Foxp3 in na?ve T cells, but TGF-beta and IL-6 together drive the generation of Th17 cells. Thus, we give an overview of how Th17 cells, induced Foxp3+ T-reg, as well as how naturally occurring T-reg cells might cooperate to promote and regulate autoimmune inflammation of the central nervous system (CNS). The monitoring of the population dynamics of these T cell subsets in reporter mice in vivo will enable us to revisit the pathogenic concept of autoimmune inflammation in the CNS and design rational and phase-specific therapeutic interventions.