Granulocyte-macrophage colony stimulating factor inhibits class II major histocompatibility complex expression and antigen presentation by microglia

Granulocyte-macrophage colony stimulating factor (GM-CSF) modulates various functions of monocytes/ macrophages including antigen-presenting capacity. Recently it was found that astrocytes produce GM-CSF in the central nervous system (CNS) and that GM-CSF can induce proliferation and morphological changes of microglia. Here we show that GM-CSF can down regulate the interferon-γ-mediated induction of major histocompatibility complex (MHC) class II antigens in microglia, but not in astrocytes. GM-CSF pretreatment completely prevents myelin basic protein-specific T cell proliferation induced by microglia but not astrocytes. GM-CSF did not affect the cell surface expression on microglia of either MHC class I or cell adhesion molecules. The inhibition of microglial MHC class II expression and antigen-presenting function is specific for GM-CSF, as treatment with a different CSF (interleukin-3) did not modulate microglial phenotype or functional capacity. These data suggest that GM-CSF might be involved in the regulation of immune responses within the central nervous system.     

Dravet syndrome with parkinsonian symptoms and intact dopaminergic neurons: A case report

IntroductionDravet syndrome (DS) is severe myoclonic epilepsy in infancy and associated with a heterozygous mutation of the gene for the sodium channel alpha 1 subunit (SCN1A). Recently, adult patients with DS have been reported to show parkinsonism, but no corresponding neuroimaging data are available. Here, we present neuroimaging data in 2 adult patients with DS showing parkinsonian symptoms.Case reportCase 1: A man who had intractable seizures from the age of 1 year and 2 months was diagnosed with DS at 7 with a mutation in the SCN1A gene. At 18, he had parkinsonian symptoms such as masked face and bradykinesia. At 20, he was admitted to our department. Dopamine transporter single-photon emission computed tomography (DAT SPECT) showed no decrease in striatal binding of ¹²³I–N–ω–fluoropropyl–2β–carbomethoxy–3β–(4–iodophenyl) nortropane (¹²³I-FP-CIT), and myocardial scintigraphy showed no decrease in cardiac uptake of ¹²³I-metaiodobenzylguanidine (¹²³I-MIBG). Levodopa showed no significant improvement in his symptoms. Case 2: A woman who had febrile seizures at 4 months of age and myoclonic seizures at 1 year and 5 months was diagnosed with DS at 31. She had myoclonus, resting tremor, hypertonia, antecollis, crouch gait, and bradykinesia. DAT SPECT imaging showed no decrease in striatal FP-CIT binding, and levodopa did not improve her symptoms.DiscussionThe normal DAT SPECT and ¹²³I-MIBG results suggest that dopaminergic neurons projecting onto striatal neurons were not impaired in our patients, explaining the lack of response to levodopa. Thus, dopamine imaging can help to guide treatment decisions in patients with DS and parkinsonism.     

Short-term plasticity visualized with flavoprotein autofluorescence in the somatosensory cortex of anaesthetized rats

In the present study, short-term plasticity of somatosensory neural responses was investigated using flavoprotein autofluorescence imaging in rats anaesthetized with urethane (1.5 g/kg, i.p.) Somatosensory neural activity was elicited by vibratory skin stimulation (50 Hz for 1 s) applied on the surface of the left plantar hindpaw. Changes in green autofluorescence (lambda = 500-550 nm) in blue light (lambda = 450-490 nm) were elicited in the right somatosensory cortex. The normalised maximal fluorescence responses (deltaF/F) was 2.0 +/- 0.1% (n = 40). After tetanic cortical stimulation (TS), applied at a depth of 1.5-2.0 mm from the cortical surface, the responses elicited by peripheral stimulation were significantly potentiated in both peak amplitude and size of the responsive area (both P < 0.02; Wilcoxon signed rank test). This potentiation was clearly observed in the recording session started 5 min after the cessation of TS, and returned to the control level within 30 min. However, depression of the responses was observed after TS applied at a depth of 0.5 mm. TS-induced changes in supragranular field potentials in cortical slices showed a similar dependence on the depth of the stimulated sites. When TS was applied on the ipsilateral somatosensory cortex, marked potentiation of the ipsilateral responses and slight potentiation of the contralateral responses to peripheral stimulation were observed after TS, suggesting the involvement of commissural fibers in the changes in the somatosensory brain maps. The present study clearly demonstrates that functional brain imaging using flavoprotein autofluorescence is a useful technique for investigating neural plasticity in vivo.     

Intraventricular transplantation of embryonic stem cell-derived neural stem cells in intracerebral hemorrhage rats

In the present study, we attempted to explore cell transplantation therapy for intracerebral hemorrhage (ICH) using embryonic stem (ES) cells. Collagenase-induced ICH rats were used as model animals. Mouse ES cells were differentiated into nestin-positive neural stem cells in vitro by alltrans retinoic acid (ATRA). ATRA-treated ES cells (10(5)) were transplanted into the lateral ventricle in the hemisphere contralateral to the hemorrhage 7 days after collagenase infusion. Twenty-eight days after transplantation, ES-derived neurons and astrocytes were observed around the hematoma cavities of the brain in all of the ten rats receiving grafts. Graft-derived neurons were found in the subependymal area of the lateral ventricle as cellular nodules. Although one of the ten rats receiving grafts showed uncontrolled growth of astroglia derived from the ES cells, intraventricular transplantation of ATRA-treated ES cells is an effective delivery system of neuronal lineage-committed progenitor cells toward the site of ICH.     

Receptor-like protein tyrosine phosphatase zeta/RPTP beta is expressed on tangentially aligned neurons in early mouse neocortex

Protein tyrosine phosphatase zeta (PTPzeta)/RPTPbeta is a chondroitin sulfate proteoglycan predominantly expressed in the brain. In this study, we examined immunohistochemical localisation of PTPzeta in the mouse telencephalon from embryonic day 9.5 (E9.5) to E15.5. During E10.5-E12.5, immunoreactivities for PTPzeta are specifically observed on the tangentially aligned neurons at the preplate (PP) of the neocortex, as well as on the neurons at the mantle layer (ML) of the ganglionic eminences (GEs). Likewise, neurons immunoreactive for CR50, a marker for Cajal-Retzius neurons, are aligned from the ML of the ganglionic eminences to the PP of the neocortex and co-express PTPzeta. During E13.5-E15.5, PTPzeta-positive neurons are present at the subplate (SP) as well as at the marginal zone (MZ) of the neocortex. These results indicate that PTPzeta is a useful marker for early-generated neocortical neurons in mice: Cajal-Retzius neurons as well as the subplate neurons.     

Mutations of neuronal voltage-gated Na+ channel alpha 1 subunit gene SCN1A in core severe myoclonic epilepsy in infancy (SMEI) and in borderline SMEI (SMEB)

PURPOSE: Severe myoclonic epilepsy in infancy (SMEI) is a distinct epilepsy syndrome. Patients with borderline SMEI (SMEB) are a subgroup with clinical features similar to those of core SMEI but are not necessarily consistent with the accepted diagnostic criteria for core SMEI. The aim of this study was to delineate the genetic correlation between core SMEI and SMEB and to estimate the frequency of mutations in both phenotypes. METHODS: We examined 96 healthy volunteers and 58 unrelated individuals whose clinical features were consistent with either core SMEI (n = 31) or SMEB (n = 27). We screened for genetic abnormalities within exons and their flanking introns of the genes encoding major subunits of the Na+ channels (SCN1A, SCN2A, SCN1B, and SCN2B) by using a direct sequencing method. RESULTS: In both core SMEI and SMEB, various mutations of SCN1A including nonsense and missense mutations were identified, whereas no mutations of SCN2A, SCN1B, and SCN2B were found within the regions examined. All mutations were heterozygous and not found in 192 control chromosomes. Mutations were identified in 26 (44.8%) of the 58 individuals and were more frequent (p < 0.05) in core SMEI (19 of 31) than in SMEB (seven of 27), as assessed by the continuity-adjusted chi2 test. Mutations resulting in a molecular truncation were found only in core SMEI. Among the mutations, two missense mutations were found in both core SMEI and SMEB. CONCLUSIONS: Our findings confirm that SMEB is part of the SMEI spectrum and may expand the recognition of SMEI and suggest other responsible or modifying genes.     

NO EVIDENCE FOR PATIENT‐TO‐PATIENT TRANSMISSION OF HEPATITIS C VIRUS DURING UPPER GASTROINTESTINAL ENDOSCOPY: MOLECULAR STUDIES ON THREE ACUTE HEPATITIS C PATIENTS

Background: The risk of patient‐to‐patient transmission of hepatitis C virus (HCV) during endoscopy remains controversial. Using molecular approaches, we examined the possibility of patient‐to‐patient transmission of HCV in three patients who developed acute hepatitis C 1–6 months after examination by upper gastrointestinal endoscopy (UGIE) in a hospital endoscopy unit in Japan. Methods: For the source of HCV infection, we used frozen sera obtained from potential candidates who underwent UGIE earlier than three index patients on the same days in the same unit. HCV genotype was determined by multiplex polymerase chain reaction (PCR) with genotype‐specific primers. The 1087‐nucleotide (nt) sequence of the NS5B region of the HCV genome was compared between index patients and their HCV‐viremic candidates. Results: The three index patients were exclusively infected with HCV of genotype 1b. Among a total of 60 candidate patients who underwent UGIE earlier than the index patients, 14 were positive for anti‐HCV, of whom 12 had detectable HCV‐RNA (1b, n = 9; 2a, n = 1; 2b, n = 2) on sera collected during each UGIE. Shared identity within the 1087‐nt NS5B sequence was less than 95.0% between index patients and HCV/1b‐infected candidates (n = 3, 1 and 5, respectively). None of the remaining 46 candidates who were negative for anti‐HCV at UGIE examination tested positive for HCV‐RNA, nor seroconverted to anti‐HCV on their sera, which most likely excludes the possibility of HCV viremia despite the anti‐HCV‐negative serology at UGIE examination. Conclusion: The present study suggests that patient‐to‐patient transmission of HCV during UGIE is infrequent.     

Primary cutaneous CD30+ anaplastic large-cell lymphoma with generalized skin involvement and involvement of one peripheral lymph node, successfully treated with low-dose oral etoposide

Primary cutaneous CD30+ anaplastic large-cell lymphoma (PCALCL) in adults is rare, and the prognosis is generally excellent. Multifocal PCALCL tends to relapse after multiagent chemotherapy and is generally considered more prone to progress to extracutaneous involvement than is the localized disease. We report a 43-year-old woman with PCALCL who had generalized skin involvement accompanied by involvement of one peripheral draining lymph-node region. Although the disease relapsed after multiagent chemotherapy regimens, the disease was successfully treated with low-dose etoposide. We reviewed the previously reported cases of PCALCL treated with low-dose etoposide. We suggest that oral etoposide might be a useful effective treatment for treatment of relapsed multifocal PCALCL.