A novel presenilin 1 mutation (Y154N) in a patient with early onset Alzheimer's disease with spastic paraparesis

Early onset familial Alzheimer's disease with spastic paraparesis (FAD-SP) has been associated with mutations of the presenilin 1 gene (PSEN1). We report a pedigree of FAD-SP due to a novel missense mutation of PSEN1 (Y154N). The symptoms of the proband were characterized by presenile dementia in her 40s, preceded by spastic paraparesis in her 30s, whereas the mother of the proband presented with spastic paraparesis in her 40s, followed by symptoms of dementia in her mid 60s. The mutation was found only in the proband, and not in a normal family member, normal Japanese control subjects, patients with sporadic Alzheimer's disease or patients with familial spastic paraparesis without dementia. Thus, Y154N is a novel PSEN1 mutation responsible for FAD-SP of Japanese origin.     

Differential roles of spatial frequency on reading processes for ideograms and phonograms: a high-density ERP study

The neural substrate of the dissociation between reading Japanese ideograms (Kanji) and phonograms (Kana) is currently unclear. To test whether spatial frequency (SF) information is responsible for this phenomenon, we recorded high-density event-related potentials (ERPs) with unfiltered or spatially filtered word stimuli in Japanese-speaking subjects. Kanji (early-learned, late-learned), Kana (word, non-word), and scrambled characters served as stimuli. Fourier analysis revealed that Kanji and Kana were characterized by high-SF (HSF) and low-SF (LSF) information, respectively. In ERPs with unfiltered stimuli, bilateral occipital P100, left occipitotemporal N170 and fronto-central N400 were elicited. Scrambled characters did not evoke left-lateralized N170 or clear N400. Under the LSF condition, P100 and N170 latencies for Kanji were significantly longer than those for Kana. In the HSF condition, P100 and N170 latencies for late-learned Kanji were significantly longer than those for early-learned Kanji. There was no significant difference in the N400 between Kanji and Kana in both SF conditions. These results suggest that early visual responses, but not the semantic component, are influenced by SF. This indicates a close link between Kana and LSF information, and between Kanji and HSF information. The differential effects of SF could underlie the neural basis of the differences between Kanji and Kana reading.     

Detection of specific genetic abnormalities by fluorescence in situ hybridization in soft tissue tumors

For the detection of chromosome translocations/chimeric genes and specific genetic abnormalities in soft tissue tumors, we conducted fluorescence in situ hybridization (FISH) analysis on 280 cases of soft tissue and other tumors using formalin-fixed paraffin-embedded tissue sections. The detection rate of the FISH split-signal was 84% (129/154 cases) for the translocation-associated soft tissue tumors, such as Ewing's sarcoma/primitive neuroectodermal tumor, synovial sarcoma, alveolar rhabdomyosarcoma, myxoid liposarcoma, clear cell sarcoma and so forth. Positive split-signals from EWSR1, SS18 and FOXO1A probes were detected in 3% (2/64) of various histological types of carcinoma, lymphoma, melanoma, meningioma and soft tissue tumors. In FISH using the INI1/CEP22 probe, the INI1 deletion signal was detected in 100% (9/9) of epithelioid sarcoma. In well-differentiated and dedifferentiated liposarcomas, detection of MDM2 amplification signals in FISH using the MDM2/CEP12 probe were both as high as 85% (11/13) and 100% (13/13), respectively. In other adipocytic and non-adipocytic tumors requiring differentiation from these types, detection was only 13% (5/39), and CEP12 polysomy was frequently detected. As these results demonstrate the high sensitivity and specificity of FISH, we concluded FISH to be a useful pathological diagnostic adjunct for definite and differential diagnosis of soft tissue tumors.     

Biphasic effects of orexin-A on autonomic nerve activity and lipolysis

Previously, we showed that orexin-A, a 33-aa peptide, influences renal sympathetic nerve activity. Because the autonomic nervous system plays an important role in the regulation of lipid metabolism, we investigated the in vivo effects of orexin-A on the sympathetic nerve activity innervating white adipose tissue (WAT-SNA) and lipolysis. We found that intracerebroventricular (icv) administration of orexin-A at doses of 1mug/rat and 10ng/rat elevated and suppressed WAT-SNA, respectively. The effect of the high dose of orexin-A (1mug/rat) was eliminated by pretreatment with diphenhydramine hydrochloride, a histamine H(1) receptor antagonist. In contrast, the effect of the low dose of orexin-A (10ng/rat) was suppressed by thioperamide maleate salt, a histamine H(3) receptor antagonist. Moreover, icv administration of 1mug/rat and 10ng/rat of orexin-A increased and decreased the levels of plasma free fatty acids (FFAs), respectively. The effect of 1mug/rat of orexin-A on plasma FFA was eliminated by propranolol hydrochloride, a beta-adrenergic receptor blocker, and also by diphenhydramine. The effect of orexin-A at dose of 10ng/rat disappeared by pretreatment with atropine sulfate, a muscarinic receptor blocker, and thioperamide maleate salt. Our results suggest that high doses of orexin-A may regulate the lipolytic processes in adipose tissue through facilitation of the sympathetic nervous system, which is driven by histamine neurons through the H(1) receptor, and that the beta(3)-receptor may be involved in this enhanced lipolytic response. Low doses of orexin-A, on the other hand, may lower lipolysis by suppressing sympathetic nerve activity via the H(3)-receptor, and the muscarinic receptor may be related to this response.     

Inhibitory effects of valproate on impairment of Y-maze alternation behavior induced by repeated electroconvulsive seizures and c-Fos protein levels in rat brains

We previously showed that inhibition of repeated electroconvulsive shock (ECS)-induced seizures through 7-day administration of anti-epileptic drugs suppressed the impairment of spontaneous alternation behavior in the Y-maze test in rats. To clarify the precise mechanism(s), we investigated the effect of valproate on such impairment and examined the levels of brain-derived neurotrophic factor (BDNF) and c-Fos protein in the prefrontal cortex and the hippocampus 24h after the last administration of ECS. Seven-day intraperitoneal (i.p.) administration of valproate (400mg/kg) suppressed the impairment of spontaneous alternation behavior. Repeated ECS increased the BDNF protein levels in the hippocampus and prefrontal cortex in the presence or absence of valproate, indicating that the increase in BDNF protein levels resulted from electrical stimulation. c-Fos protein levels were significantly decreased in the hippocampal dentate gyrus after repeated ECS, but valproate had no significant effect on decreased c-Fos protein levels. Valproate＋ECS significantly increased the c-Fos protein levels of the prefrontal cortex compared with the ECS group. These findings suggest that the inhibitory effect of valproate on repeated ECS-induced impairment of spontaneous alternation behavior may be linked to the prefrontal cortex.     

Novel hybrid mesh surgery combines sacrocolpopexy with transvaginal mesh placement for pelvic organ prolapse

Mesh surgeries, such as sacrocolpopexy and transvaginal mesh surgery, are commonly used to treat pelvic organ prolapse. Although mesh surgeries have a high success rate, they are unsuitable for some patients. For a patient with pelvic organ prolapse and highly calcified multiple fibroids, we performed hybrid sacrocolpopexy combined with transvaginal mesh surgery with a method modified for the patient's condition. Three months after surgery, the results were highly satisfactory. This approach is simple, secure, and versatile for patients who are not good candidates for conventional mesh surgeries. This novel hybrid mesh surgery is an option for treating various types of pelvic organ prolapse.     

Genetic association between interleukin-10 gene promoter region polymorphisms and type 1 diabetes age-at-onset

This study investigated whether interleukin-10 (IL-10) gene promoter region polymorphisms are associated with susceptibility to or clinical presentation of type 1 diabetes. The frequency of -1082G/A, -819C/T, and -592C/A polymorphisms was analyzed in 128 Japanese patients with type 1 diabetes and in 107 healthy control subjects in a case-controlled study. The allelic and haplotypic frequencies of the IL-10 gene promoter region polymorphisms were similar in patients with type 1 diabetes and in control subjects. However, the -819T and -592A allele were associated with adult-onset (>18 years) of the disease (p = 0.037). Furthermore, the frequency of ATA haplotype was increased in adult-onset patients than that in early-onset patients (< or =18 years; p = 0.037). Among the genotypes comprising ATA haplotype, the frequency of ATA/ATA was significantly higher in adult-onset patients than in early-onset patients (p = 0.004). These results suggest that the IL-10 gene promoter polymorphisms are associated with the age-at-onset in Japanese patients with type 1 diabetes.     

Solitary fibrous tumor of the thyroid gland

Solitary fibrous tumor is a spindle cell neoplasm rarely arising in the thyroid gland. We present a 78-year-old man with the diagnosis of solitary fibrous tumor of the thyroid gland resected by subtotal thyroidectomy. Fine needle aspiration cytology via ultrasound guidance demonstrated a hypocellular aspirate that revealed follicular epithelial cells with mild nuclear atypia and scattered spindle cells with bland nuclei. Histologically, the patternless proliferation of spindle cells was seen among collagenous bundles, accompanied by hemangiopericytomatous vessels, and variously dilated follicles with mild atypical cells having slightly enlarged nuclei, indicating adenomatous goiter. The neoplastic spindle cells showed diffuse immunoreactivity to CD34, bcl-2, CD99 and vimentin, but were negative for cytokeratins, calcitonin, TTF-1 and CD5. Although solitary fibrous tumor arising in thyroid gland is rare, this tumor should be included in the differential diagnosis of thyroid spindle cell tumors and also that of adenomatous.     

Enhanced wound healing by topical administration of mesenchymal stem cells transfected with stromal cell-derived factor-1

The objective of this study was to investigate the ability of mesenchymal stem cells (MSC) genetically engineered with stromal cell-derived factor-1 (SDF-1) to heal skin wounds. When transfected with SDF-1 plasmid DNA, MSC which were isolated from the bone marrow of rats, secreted SDF-1 for 7 days. In vitro cell migration assay revealed that the SDF-1-engineered MSC (SDF-MSC) enhanced the migration of MSC and dermal fibroblasts to a significantly greater extent than MSC. The SDF-MSC secreted vascular endothelial growth factor, hepatocyte growth factor, and interleukin 6 at a significantly high level. A skin defect model of rats was prepared and MSC and SDF-MSC were applied to the wound to evaluate wound healing in terms of wound size and histological examinations. The wound size decreased significantly faster with SDF-MSC treatment than with MSC and PBS treatments. The length of the neoepithelium and the number of blood vessels newly formed were significantly larger. A cell-tracing experiment with fluorescently labeled cells demonstrated that the percent survival of SDF-MSC in the tissue treated was significantly high compared with that of MSC. It was concluded that SDF-1 genetic engineering is a promising way to promote the wound healing activity of MSC for a skin defect.