Spinal cord involvement by atrophy and associations with disability are different between multiple sclerosis and neuromyelitis optica spectrum disorder.

BACKGROUND AND PURPOSE: The cervical and thoracic cross-sectional spinal cord area (CS-SCA) in multiple sclerosis (MS) correlates with disability, whilst such a correlation remains to be established in neuromyelitis optica spectrum disorder (NMOSD). Our aim was to clarify differences between MS and NMOSD in spinal cord segments where CS-SCA is associated with disability. METHODS: The CS-SCA at C2/C3, C3/C4, T8/T9 and T9/T10 vertebral disc levels was measured in 140 MS patients (111 with relapsing-remitting MS and 29 with progressive MS) and 42 NMOSD patients with anti-aquaporin-4 immunoglobulin G. Disability was evaluated by Expanded Disability Status Scale (EDSS) scores. Multivariate associations between CS-SCA and disability were assessed by stepwise forward multiple linear regression. RESULTS: Thoracic CS-SCA was significantly smaller in NMOSD patients than in MS patients even after adjusting for age, sex and disease duration (P = 0.002 at T8/T9), whilst there was no difference in cervical CS-SCA between the two diseases. Cervical and thoracic CS-SCA had a negative correlation with EDSS scores in MS patients (P < 0.0001 at C3/C4 and P = 0.0002 at T8/T9) whereas only thoracic CS-SCA correlated with EDSS scores in NMOSD patients (P = 0.0006 at T8/T9). By multiple regression analyses, predictive factors for disability in MS were smaller cervical CS-SCA, progressive course, older age and a higher number of relapses, whilst those in NMOSD were smaller thoracic CS-SCA and older age. CONCLUSIONS: Thoracic CS-SCA is a useful predictive marker for disability in patients with NMOSD whilst cervical CS-SCA is associated with disability in patients with MS.

Structural and magnetic properties of mixed Co-Ln (Ln = Nd, Sm, Eu, Gd and Ho) diethyleneglycolate complexes.

New hybrid compounds LnCoCl(deg)2 (deg = diethyleneglycolate; Ln = Nd, Sm, Eu, Gd and Ho) have been synthesized by mixing cobalt and rare earth cations in a boiling diethyleneglycol (degH2) medium. Their crystallographic structures have been ab initio solved from synchrotron powder diffraction data. They consist of edge sharing tetrameric sub-units [(Ln2Co2)(deg)4(Cl)2] forming 1D infinite chains along the c parameter of a monoclinic unit cell (SG = C2/c). The five- and seven-coordination of Co(2+) and Ln(3+) cations inferred from the crystallographic results is confirmed by UV-visible absorption and Extended X-ray Absorption Fine Structure (EXAFS) spectroscopy. In the LnCoCl(deg)2 (Ln = Nd, Sm, Eu, Gd, Ho) series, weak antiferromagnetic superexchange interactions have been evidenced, between high spin Co(2+) and Ln(3+) orbitally degenerate cations. These materials are considered as potential precursors for the simultaneous reduction of Co-Ln-glycolate species into bimetallic nanoparticles by the polyol process.

Species differences in androgen receptor expression in the medial preoptic and anterior hypothalamic areas of adult male and female rodents.

The medial preoptic and anterior hypothalamic areas (MPO/AH) are important androgen targets regulating homeostasis, neuroendocrinology and circadian rhythm as well as instinctive and sociosexual behaviors. Although species differences between rats and mice have been pointed out in terms of morphology and physiology, detailed distributions of androgen receptor (AR) have never been compared between the two rodents. In the present study, AR distribution was examined immunohistochemically in serial sections of the MPO/AH and compared for adult rats and mice. Western blotting and immunohistochemistry clearly demonstrated that AR expression in the brain was stronger in mice than in rats and was stronger in males than in females. In addition, we found (1) an "obliquely elongated calbindin-ir cell island" in mice medial preoptic nucleus (MPN) expressed AR intensely, as well as the sexually dimorphic nucleus in the MPN (SDN-MPN) in rats, strongly supporting a "putative SDN-MPN" previously proposed in mice; (2) AR expression in the suprachiasmatic nucleus (SCN) was much more prominent in mice than in rats and differed in localization between the two species; (3) a mouse-specific AR-ir cell cluster was newly identified as the "tear drop nucleus (TDN)", with male-dominant sexual dimorphism; and (4) two rat-specific AR-ir cell clusters were also newly identified as the "rostral and caudal nebular islands", with male-dominant sexual dimorphism. The present results may provide basic morphological evidence underlying species differences in androgen-modified psychological, physiological and endocrinergic responses. Above all, the findings of the mouse-specific TDN and differing AR expression in the SCN might explain not only species difference in gonadal modification of circadian rhythm, but also distinct structural bases in the context of transduction of SCN oscillation. The current study could also serve as a caution that data on androgen-sensitive functions obtained from one species should not always be directly applied to others among rodents.

Depletion of foxp3(+) T cells abrogates tolerance of skin and heart allografts in murine mixed chimeras without the loss of mixed chimerism.

The relative contribution of central and peripheral mechanisms to the generation and maintenance of allograft tolerance is of considerable interest. Here, we present new evidence that regulatory T cells (Foxp3(+) ) maintain skin and heart allograft tolerance in mixed hematopoietic chimeric mice. Transient depletion of both donor- and recipient-derived Foxp3(+) cells was necessary and sufficient to induce decisive rejection of long-accepted skin and heart allografts. In contrast, stable hematopoietic chimerism remained, and there was no detectable induction of donor-specific reactivity to hematopoietic cells. Foxp3(+) cell depletion did not result in the rejection of skin grafts of only MHC-disparate donors (B6.C-H2(d) /bByJ), indicating that MHC antigens were not the target in the graft. We conclude that two different mechanisms of tolerance are present in mixed chimeras. Hematopoietic chimerism, resistant to Foxp3(+) depletion, is probably due to deletional tolerance to MHC antigens, as supported by previous studies. In contrast, regulatory tolerance mechanisms involving Foxp3(+) cells are required to control reactivity against non-MHC antigens not present on hematopoietic lineages.

Images created in a model eye during simulated cataract surgery can be the basis for images perceived by patients during cataract surgery.

PURPOSE: To evaluate the images created in a model eye during simulated cataract surgery. PATIENTS AND METHODS: This study was conducted as a laboratory investigation and interventional case series. An artificial opaque lens, a clear intraocular lens (IOL), or an irrigation/aspiration (I/A) tip was inserted into the 'anterior chamber' of a model eye with the frosted posterior surface corresponding to the retina. Video images were recorded of the posterior surface of the model eye from the rear during simulated cataract surgery. The video clips were shown to 20 patients before cataract surgery, and the similarity of their visual perceptions to these images was evaluated postoperatively. RESULTS: The images of the moving lens fragments and I/A tip and the insertion of the IOL were seen from the rear. The image through the opaque lens and the IOL without moving objects was the light of the surgical microscope from the rear. However, when the microscope light was turned off after IOL insertion, the images of the microscope and operating room were observed by the room illumination from the rear. Seventy percent of the patients answered that the visual perceptions of moving lens fragments were similar to the video clips and 55% reported similarity with the IOL insertion. Eighty percent of the patients recommended that patients watch the video clip before their scheduled cataract surgery. CONCLUSIONS: The patients' visual perceptions during cataract surgery can be reproduced in the model eye. Watching the video images preoperatively may help relax the patients during surgery.

A snapshot of plasma metabolites in first-episode schizophrenia: a capillary electrophoresis time-of-flight mass spectrometry study.

Few biomarkers have been known that can easily measure clinical conditions in mental illnesses such as schizophrenia. Capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) is a new method that can measure ionized and low-molecular-weight metabolites. To explore global metabolomic alterations that characterize the onset of schizophrenia and identify biomarkers, we profiled the relative and absolute concentrations of the plasma metabolites from 30 patients with first-episode schizophrenia (FESZ, four drug-naïve samples), 38 healthy controls and 15 individuals with autism spectrum disorders using CE-TOFMS. Five metabolites had robust changes (increased creatine and decreased betaine, nonanoic acid, benzoic acid and perillic acid) in two independent sample sets. Altered levels of these metabolites are consistent with well-known hypotheses regarding abnormalities of the homocysteine metabolism, creatine kinase-emia and oxidative stress. Although it should be considered that most patients with FESZ received medication, these metabolites are candidate biomarkers to improve the determination of diagnosis, severity and clinical stages, especially for FESZ.

Characterization of the "sporadically lurking HAP1-immunoreactive (SLH) cells" in the hippocampus, with special reference to the expression of steroid receptors, GABA, and progenitor cell markers.

Huntingtin-associated protein 1 (HAP1) is a neural huntingtin interactor that is widely expressed as a core molecule of the stigmoid body (a neurocytoplasmic inclusion) in the limbic and hypothalamic regions and has putative protective functions against some neurodegenerative diseases (HAP1 protection hypothesis). Although HAP1 has been reported to be intimately associated with several steroid receptors, HAP1-immunoreactive (HAP1-ir) cells remain to be identified in the hippocampus, which is one of the major steroidal targets. In this study, we determined the distribution of hippocampal HAP1-ir cells in light and fluorescence microscopy and characterized their morphological relationships with steroid receptors, markers of adult neurogenesis, and the GABAergic system in adult male and female Wistar rats. HAP1-ir cells, which were sporadically distributed particularly in the subgranular zone (SGZ) of the dentate gyrus and in the interface between the stratum lacunosum-moleculare and stratum radiatum of Ammon's horn, were identified as the "sporadically lurking HAP1-ir (SLH)" cells. The SLH cells showed no clear association with neural progenitor/proliferating or migrating cell markers of adult neurogenesis, such as Ki-67, proliferating cell nuclear antigen, doublecortin, and glial fibrillary acidic protein in the SGZ, whereas all the SLH cells expressed a neuronal specific nuclear protein (NeuN). More than 90% of the SLH cells expressed nuclear estrogen receptor (ER) α but neither ERß nor the androgen receptor, whereas glucocorticoid receptor was differently stained in the SLH cells depending on the antibodies. More than 60% of them exhibited GABA immunoreactivity in the SGZ, suggestive of basket cells, but they were distinct from the ones expressing cholecystokinin or parvalbumin. We conclude that SLH cells, which should be stable against apoptosis due to putative HAP1 protectivity, might be involved in estrogen-dependent maturation, remodeling and activation of hippocampal memory and learning functions via ERα and partly through GABAergic regulation.

Serum interleukin-5 levels correlate with disease activity of Churg-Strauss syndrome in a patient treated with a leucotriene receptor antagonist, pranlukast, and inhaled corticosteroid.

This case report demonstrates that interleukin (IL)-5 levels and eosinophil cationic protein (ECP) correlated well with disease activity of Churg-Strauss syndrome (CSS) in a patient receiving treatment with leucotriene receptor antagonist and inhaled corticosteroid. In addition, ECP was localized in the inflamed tissue. IL-5 levels may thus provide a clue to therapeutic efficacy in patients with CSS using leucotriene receptor antagonists and inhaled corticosteroid.

Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice.

AIMS/HYPOTHESIS: The WFS1 gene encodes an endoplasmic reticulum (ER) membrane-embedded protein called Wolfram syndrome 1 protein, homozygous mutations of which cause selective beta cell loss in humans. The function(s) of this protein and the mechanism by which the mutations of this gene cause beta cell death are still not fully understood. We hypothesised that increased insulin demand as a result of obesity/insulin resistance causes ER stress in pancreatic beta cells, thereby promoting beta cell death. METHODS: We studied the effect of breeding Wfs1 ( -/- ) mice on a C57BL/6J background with mild obesity and insulin resistance, by introducing the agouti lethal yellow mutation (A ( y ) /a). We also treated the mice with pioglitazone. RESULTS: Wfs1 ( -/- ) mice bred on a C57BL/6J background rarely develop overt diabetes by 24 weeks of age, showing only mild beta cell loss. However, Wfs1 ( -/- ) A ( y ) /a mice developed selective beta cell loss and severe insulin-deficient diabetes as early as 8 weeks. This beta cell loss was due to apoptosis. In Wfs1 ( +/+ ) A ( y ) /a islets, levels of ER chaperone immunoglobulin-binding protein (BiP)/78 kDa glucose-regulated protein (GRP78) and phosphorylation of eukaryotic translation initiation factor 2, subunit alpha (eIF2alpha) apparently increased. Levels of both were further increased in Wfs1 ( -/- ) A ( y ) /a murine islets. Electron micrography revealed markedly dilated ERs in Wfs1 (-/-) A ( y ) /a murine beta cells. Interestingly, pioglitazone treatment protected beta cells from apoptosis and almost completely prevented diabetes development. CONCLUSIONS/INTERPRETATION: Wfs1-deficient beta cells are susceptible to ER stress. Increased insulin demand prompts apoptosis in such cells in vivo. Pioglitazone, remarkably, suppresses this process and prevents diabetes. As common WFS1 gene variants have recently been shown to confer a risk of type 2 diabetes, our findings may be relevant to the gradual but progressive loss of beta cells in type 2 diabetes.

Implications of bevacizumab on vascular endothelial growth factor and endostatin in human choroidal neovascularisation.

AIM: To evaluate the implications of intravitreal bevacizumab on proangiogenic vascular endothelial growth factor (VEGF) with regard to the endogenous angiogenesis inhibitor endostatin in human choroidal neovascularisation (CNV) secondary to age-related macular degeneration. METHODS: Retrospective review of an interventional case series of 48 patients who underwent full macular translocation surgery with removal of CNV. Twenty-five patients were treated with intravitreal bevacizumab injection 1 to 154 days prior to surgery (bevacizumab CNV). Twenty-three CNV without any kind of previous treatment were used as controls (control CNV). CNV were stained for CD34, cytokeratin18, VEGF, endostatin and E-selectin. A "predominance score of VEGF over endostatin" (PS) was defined by the difference between VEGF and endostatin staining scores. RESULTS: Bevacizumab CNV revealed a weaker VEGF expression in endothelial cells (p = 0.0245) but significantly more intense endostatin in retina pigment epithelium (RPE) (p = 0.0001) and stroma (p<0.0001). Consequently, PS was significantly lower in RPE (p = 0.02), vessels (p = 0.03) and stroma (p = 0.0004) in bevacizumab CNV. The intensity of E-selectin expression in bevacizumab CNV was comparable with that in control CNV. CONCLUSIONS: A shift within the angiogenic balance in terms of decreased VEGF predominance over endostatin is detected in human CNV treated with bevacizumab.

Effect of therapeutic immunization using Ad5/35 and MVA vectors on SIV infection of rhesus monkeys undergoing antiretroviral therapy.

Antiretroviral therapy (ART) effectively slows the progression of AIDS. However, drug resistance and/or toxicity can limit the utility of ART in many patients. In this study, we assessed whether a viral vector-based vaccine can be used as a therapeutic vaccine in simian immunodeficiency virus (SIV)-infected monkeys. The effect of vaccinating SIVmac239-infected rhesus monkeys with an SIV gag and gp120-expressing adenovirus (Ad) vector vaccine and a modified vaccinia Ankara (MVA) vaccine was explored while being treated with ART. Rhesus monkeys were intravenously infected with 10 and 1000 TCID(50) (50% tissue culture infectious dose) of SIVmac239. Two months after SIV infection, the monkeys received a 4-month treatment with ART. Some of the monkeys were immunized with adenovirus-based vaccine and MVA-based vaccine with 2 months interval during ART. Viral load, CD4 count and SIV-specific immune responses were observed for 7 months after interruption of ART. The vaccinated animals had higher (i) CD4 counts, (ii) SIV-specific cell-mediated immune responses and (iii) anti-SIV-neutralizing antibody (Ab) titers than monkeys treated with ART alone. More importantly, the vaccination significantly reduced the SIV RNA load from animals infected with a low dose of SIV (10 TCID(50)). The anti-SIV cell-mediated and humoral responses induced by the vaccination was inversely correlated with a reduction in SIV viral load and positively correlated with an increase in CD4(+) T cell counts. These results suggest that vaccination can improve antiviral cell-mediated and humoral immunity, which may contribute to controlling viral replication.

Comparison of pre- vs. postmeal administration of miglitol for 3 months in type 2 diabetic patients.

AIM: alpha-Glucosidase inhibitors (alphaGIs) primarily modify postprandial plasma glucose levels and should be taken just before meals. We previously demonstrated that a single administration of miglitol within 30 min after the start of a meal was equally effective as when administered just before a meal. We here compared pre- vs. postmeal administration of miglitol for 3 months in type 2 diabetic patients. METHODS: Thirty-one type 2 diabetic outpatients who had never been treated with insulin injections or alphaGIs were randomized to two groups: patients in group A were asked to take miglitol just before meals, while patients in group B were asked to take miglitol after meals. We measured 1,5-anhydroglucitol (1,5-AG) and HbA(1C) levels in these patients. RESULTS: The administration of miglitol after meals for a 3-month period decreased HbA(1C) and increased 1,5-AG levels to the same extent as when administered just before meals. The incidence of adverse effects seemed to be unrelated to the timing of the miglitol administration. CONCLUSIONS: Our results suggest that if patients have difficulty remembering to take miglitol just before meal, they should be instructed to take the medicine together with other medicine(s) after the meal; this instruction may improve the treatment compliance of diabetic patients.

Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS.

The authors calculated the progression rate (DeltaFS) using the total revised ALS Functional Rating Scale (ALSFRS-R) and symptom duration at diagnosis in 82 Japanese patients with ALS. Survival (death or tracheostomy) differed significantly with the DeltaFS and postdiagnostic period according to log-rank testing, but Cox proportional hazards modeling revealed no strong association between total ALSFRS-R and mortality, suggesting that the DeltaFS provides an additional predictive index beyond ALSFRS-R alone.

Complete nucleotide sequence of the new potexvirus "Alstroemeria virus X". Brief report.

A flexuous virus was isolated in Japan from an alstroemeria plant showing mosaic symptoms. The virus had a broad host range but had systemically latent infectivity in alstroemeria. The virus was assigned to the genus Potexvirus based on morphology and physical properties and on an analysis of the complete nucleotide sequence. The genomic RNA of the virus was 7,009 nucleotides in length, excluding the 3'-terminal poly (A) tail. It contained five open reading frames (ORFs), which was consistent with other members of the genus Potexvirus. Although nucleotide sequences of the ORFs differ from previously reported potexviruses, a phylogenetic analysis placed it phylogenetically close to Narcissus mosaic virus and Scallion virus X. Therefore, we propose that this virus should be designated as Alstroemeria virus X (AlsVX).

Clinical manifestations of chronic inflammatory demyelinating polyneuropathy with anti-cardiolipin antibodies.

OBJECTIVE: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune syndrome where certain autoantibodies define clinicopathologic subgroups. In the present study, serum anti-cardiolipin antibodies (aCL) were evaluated. MATERIALS AND METHODS: We investigated aCL in sera from 21 patients diagnosed with CIDP in our hospital between 1991 and 2001. The four CIDP patients with aCL (aCL+) were compared with 17 patients without aCL (aCL-). RESULTS: All aCL+ patients displayed sensory-motor polyneuropathy, with severity and distribution of weakness resembling those in aCL- patients. Anti-nuclear antibody titer of aCL+ patients were significantly higher than those in aCL- patients. None of aCL+ patients presented clinical manifestations of primary anti-phospholipid syndrome (APS), such as thromboses or recurrent abortion. Although the aCL+ patients were older and had more complications and more severe pathologic features than aCL- patients, they responded well to steroid pulse or intravenous immunoglobulin. CONCLUSION: The aCL in CIDP apparently differ from 'autoimmune' aCL in APS, instead being among the autoantibodies pathologically involved in CIDP subgroups.

Opposite morphological responses of partially denervated cortical serotonergic and noradrenergic axons to repeated stress in adult rats.

We examined plastic changes in serotonin (5-HT) axons following repeated stress in the adult rat brain, and compared stress-induced changes between 5-HT and noradrenaline (NA) axons. We locally injected the specific neurotoxin to 5-HT axons or to NA axons into the frontal cortex to cause partial denervation. The animals were mildly restrained from 1 day after the neurotoxin injection and this stress was repeated daily for 20 min during the first 2 days and for 40 min during the next 11 days. On the fourteenth day after injection, the brains were removed to visualize 5-HT and NA axons by immunohistochemistry. Repeated stress did not significantly alter the denervation area of 5-HT or NA axons, but the density of 5-HT axons was increased whereas that of NA axons was decreased in cortical regions outside the denervation site. In addition, the expression of brain-derived neurotrophic factor (BDNF) was increased in cortical regions where the 5-HT axon density was increased in response to stress. These results suggest that repeated stress causes opposite changes in the morphology of partially denervated 5-HT and NA axons in the cerebral cortex. The stress-induced increase in BDNF expression may contribute to 5-HT axon sprouting following repeated stress.

Scanning laser Doppler flowmeter study of retinal blood flow in macular area of healthy volunteers.

AIM: To compare the interocular and intraocular differences of capillary perfusion, and the intraocular regional differences of retinal blood flow in the macular area of healthy volunteers. METHODS: Tissue blood flow in the macula was examined in both eyes of 20 healthy volunteers with the Heidelberg retinal flowmeter. Blood flow measurements were made in a 10 degrees x 2.5 degrees area superior and inferior to the macula. The mean blood flow (MBF) was calculated by an automatic full field perfusion image analyser program. The MBF in the right and left eyes and in the superior and inferior macular areas of the same eye were compared. RESULTS: The ratios of the MBF in the right eye to the left eye in the macular areas were 1.00, and 1.03, respectively. The ratio of the MBF in the superior macular area to the inferior area was 1.01 for the right eyes and 1.04 for the left eyes. CONCLUSIONS: Because no significant differences were found in the MBF between the two eyes and between the superior and inferior macular areas in the same eye, interocular (for example, affected eye versus fellow eye) and intraocular (superior versus inferior macular areas) comparisons of MBF can be made to determine if changes in retinal perfusion have occurred.