Longitudinal changes in 18 F-THK5351 positron emission tomography in corticobasal syndrome.

BACKGROUND AND PURPOSE: Corticobasal syndrome (CBS) is pathologically characterized by tau deposits in neuronal and glial cells and by reactive astrogliosis. In several neurodegenerative disorders, 18 F-THK5351 has been observed to bind to reactive astrocytes expressing monoamine oxidase B. In this study, the aim was to investigate the progression of disease-related pathology in the brains of patients with CBS using positron emission tomography with 18 F-THK5351. METHODS: Baseline and 1-year follow-up imaging were acquired using magnetic resonance imaging and positron emission tomography with 18 F-THK5351 in 10 subjects: five patients with CBS and five age-matched normal controls (NCs). RESULTS: The 1-year follow-up scan images revealed that 18 F-THK5351 retention had significantly increased in the superior parietal gyrus of the patients with CBS compared with the NCs. The median increases in 18 F-THK5351 accumulation in the patients with CBS were 6.53% in the superior parietal gyrus, 4.34% in the precentral gyrus and 4.33% in the postcentral gyrus. In contrast, there was no significant increase in the regional 18 F-THK5351 retention in the NCs. CONCLUSIONS: Longitudinal increases in 18 F-THK5351 binding can be detected over a short interval in the cortical sites of patients with CBS. A monoamine oxidase B binding radiotracer could be useful in monitoring the progression of astrogliosis in CBS.

Novel biallelic mutations in the PNPT1 gene encoding a mitochondrial-RNA-import protein PNPase cause delayed myelination.

Recent studies suggest that impaired transcription or mitochondrial translation of small RNAs can cause abnormal myelination. A polynucleotide phosphorylase (PNPase) encoded by PNPT1 facilitates the import of small RNAs into mitochondria. PNPT1 mutations have been reported in patients with neurodevelopmental diseases with mitochondrial dysfunction. We report here 2 siblings with PNPT1 mutations who presented delayed myelination as well as mitochondrial dysfunction. We identified compound heterozygous mutations (c.227G>A; p.Gly76Asp and c.574C>T; p.Arg192*) in PNPT1 by quartet whole-exome sequencing. Analyses of skin fibroblasts from the patient showed that PNPase expression was markedly decreased and that import of the small RNA RNaseP into mitochondria was impaired. Exogenous expression of wild-type PNPT1, but not mutants, rescued ATP production in patient skin fibroblasts, suggesting the pathogenicity of the identified mutations. Our cases expand the phenotypic spectrum of PNPT1 mutations that can cause delayed myelination.

Arl4c expression in colorectal and lung cancers promotes tumorigenesis and may represent a novel therapeutic target.

We recently demonstrated that expression of ADP-ribosylation factor (ARF)-like 4c (Arl4c) induced by a combination of Wnt/ß-catenin and epidermal growth factor/Ras signaling in normal epithelial cells grown in three-dimensional culture promotes cellular migration and proliferation, resulting in formation of tube-like structures, suggesting the involvement of Arl4c in epithelial morphogenesis. It is conceivable that there could be a common mechanism between epithelial morphogenesis and carcinogenesis. Therefore the current study was conducted to investigate whether Arl4c might be involved in tumorigenesis. Immunohistochemical analyses of tissue specimens obtained from colorectal and lung cancer patients revealed that Arl4c was not observed in non-tumor regions but was strongly expressed at high frequencies in tumor lesions. Inhibition of Wnt/ß-catenin or Ras/mitogen-activated protein kinase signaling reduced Arl4c mRNA levels in HCT116 colorectal cancer cells and A549 lung cancer cells. Knockdown of Arl4c inhibited Rac activity and also prevented nuclear localization of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) in these cancer cells. Arl4c-depleted cancer cells consistently showed decreased migration, invasion and proliferation capabilities both in vitro and in vivo. Furthermore, direct injection of Arl4c small interfering RNA (siRNA) into HCT116 cell-derived tumors (in vivo treatment with siRNA) inhibited tumor growth in immunodeficient mice. These results suggest that Arl4c is involved in tumorigenesis and might represent a novel therapeutic target for suppressing proliferation and invasion of colorectal and lung cancer cells.

Long-term outcome of childhood aplastic anemia patients who underwent allogeneic hematopoietic SCT from an HLA-matched sibling donor in Japan.

We report long-term outcomes of 329 childhood severe aplastic anemia (SAA) patients who underwent hematopoietic SCT (HSCT) from an HLA-matched sibling donor in the Japanese Hematopoietic Cell Transplantation Registry. OS and EFS at 10 years were as high as 89.7+/-1.7% and 85.5+/-2.0%, respectively. Five cases of late malignancies (LM) were identified (malignant peripheral nerve sheath tumor, thyroid carcinoma, colon carcinoma, MDS and hepatoblastoma). Cumulative incidence of LM was 0.8% at 10 years and 2.5% at 20 years, respectively, which was lower than that in previous reports. This low incidence is in keeping with the low occurrence of skin cancer in Japanese population and of acute GVHD in our study group. Radiation-containing conditioning was not significantly associated with the incidence of LM after HSCT probably because of absolute low patient number who developed LM in our series. In terms of LM development after HSCT, low-dose TBI in HSCT for SAA to avoid graft rejection, which is commonly used in Japan, might be tolerable in the Japanese population because of its low incidence.

FcγRIIB-nt645+25A/G gene polymorphism and periodontitis in Japanese women with preeclampsia.

FcγRIIB contains a unique immunoreceptor tyrosine-based inhibition motif (ITIM) and functions as a negative feedback regulator of leucocyte activation and antibody production. We have previously reported FcγRIIB-nt645+25A/G gene polymorphism to be associated with prevalence and severity of periodontitis, FcγRIIB expression level on peripheral B lymphocytes and the serum IgG level against periodontopathic bacteria. Previous studies have reported maternal periodontal disease to be associated with an increased risk for preeclampsia. Therefore, FcγRIIB-nt645+25A/G gene polymorphism may be associated with preeclampsia by affecting immune response to periodontopathic bacteria in pregnant women. To elucidate whether FcγRIIB-nt645+25A/G gene polymorphism has associations with preeclampsia and/or periodontitis in pregnant Japanese women, a case-control study was carried out on women with preeclampsia (n = 13) and without preeclampsia (n = 106). Maternal periodontal parameters and bacterial data of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis and Prevotella intermedia in subgingival plaque were collected within 5 days of delivery. FcγR genotypes of each woman were determined using the genomic DNA isolated from peripheral blood. Serum IgG levels specific for each bacteria were determined. There was a significant association between FcγRIIB-nt645+25A/G polymorphism and preeclampsia (P = 0.013). The frequency of the FcγRIIB-nt645+25AA genotype was higher in the preeclampsia group compared with the nonpreeclampsia group (P = 0.007). The DNA level of A. actinomycetemcomitans from subgingival plaque was shown to be higher in the preeclampsia group (P = 0.017). In conclusion, maternal FcγRIIB-nt645+25A/G polymorphism and subgingival DNA level of A. actinomycetemcomitans were significantly associated with the prevalence of preeclampsia in a limited number of Japanese women independently with periodontal infection. Further investigations should be performed to confirm this association in a larger population and to determine the biological process of the association.

Validation of an analytical method for the determination of cadmium (Cd) in fish by atomic absorption spectrometry with electrothermal atomisation.

The validation of an analytical method was carried out for the determination of cadmium (Cd) in fish. The method was based on sample digestion in a microwave oven and subsequent reading using an atomic absorption spectrometer with a graphite furnace. The factorial design of experiments was applied to assess method ruggedness using the methodology of Box et al. [Box GEP, Hunter WG, Hunter JS. 1978. Statistics for experiments: an introduction to design, data analysis and model building. New York (NY): Wiley], studying the influence of sample mass, volume and concentration of acid used for sample digestion and the volume of modifier used. To study the possible matrix effect in the determination of Cd, the standard addition method was also performed. The results were treated using the OLS method. For the normality test a homoskedastic distribution was observed for the developed method and the results were adjusted to the statistical model proposed. F-tests and Student's t-tests indicated that there was no matrix effect on the calibration curve between the concentration range 1.0-10.0 µg Cd l(-1). Parameters such as selectivity, precision, decision limit, detection capability and limit of quantification were established by the method of standard addition to blank samples. The limit of quantification was 6.8 µg kg(-1). Accuracy, which was evaluated by using a certified reference material, was 107.0%. The recovery of the spiked analyte was 93.69% for the concentration of 50 µg kg(-1). Precision was defined by the coefficient of variation observed (Horrat value), estimated in terms of repeatability and reproducibility, and the values were below the limit, which is 2.0. The validation procedure confirmed the suitability of the method.

Method validation for the determination of total mercury in fish muscle by cold vapour atomic absorption spectrometry.

A method was validated for the determination of total Hg in fish muscle using continuous flow cold vapour atomic absorption (CVAAS) after microwave digestion in closed vessels. The method was validated according to European Union Regulations 333/2007 and 657/2002, considering the maximum level for the metal in fish, established by European Union regulation 1881/2006. The procedure for determining linear range, selectivity, recovery, precision, trueness, decision limit (CCα), detection capability (CCß), measurement uncertainty and robustness of the method is reported. The results of the validation process demonstrate the method fulfils the provisions of the Commission Regulation. The selectivity study indicated that there was no matrix effect on the calibration curve between the concentration range of 1.0 and 30.0 µg Hg l(-1). The mean recovery calculated at six levels of fortification was in the range of 94-104%. The limit of detection (LOD) and limit of quantification (LOQ) values were 4.90 and 15.7 µg kg(-1), while the CCα and CCß values were 0.517 and 0.533 mg kg(-1), respectively, for the maximum contaminant level of 0.500 mg kg(-1). The relative expanded measurement uncertainty of the method was 0.055 mg kg(-1). The method was not affected by slight variations of some critical factors (ruggedness minor changes) as sample mass and volume of the HNO(3) and H(2)O(2) used in the digestion step. The method allowed accurate confirmation analyses of the CRM DORM 3. In fact, the Z-scores attained in a proficiency test round were well below the reference value of 2.0, proving the excellent performance of the laboratory.

Wnt5a: its signalling, functions and implication in diseases.

Wnt5a is a representative ligand that activates the ß-catenin-independent pathways. Because the ß-catenin-independent pathway includes multiple signalling cascades in addition to the planar cell polarity and Ca(2+) pathway, Wnt5a regulates a variety of cellular functions, such as proliferation, differentiation, migration, adhesion and polarity. Consistent with the multiple functions of Wnt5a signalling, Wnt5a knockout mice show various phenotypes, including an inability to extend the embryonic anterior-posterior and proximal-distal axes in outgrowth tissues. Thus, many important roles of Wnt5a in developmental processes have been demonstrated. Moreover, recent reports suggest that the postnatal abnormalities in the Wnt5a signalling are involved in various diseases, such as cancer, inflammatory diseases and metabolic disorders. Therefore, Wnt5a and its signalling pathways could be important targets for the diagnosis and therapy for human diseases.

Progressive atrophy of the cerebrum in 2 Japanese sisters with microcephaly with simplified gyri and enlarged extraaxial space.

This is a case report that describes 2 sisters with microcephaly, simplified gyri, and enlarged extraaxial space. Clinical features of the cases include dysmorphic features, congenital microcephaly, failure of postnatal brain growth, neonatal onset of seizures, quadriplegia, and severe psychomotor delay. Neuroradiological imaging demonstrated hypoplasia of bilateral cerebral hemispheres with enlarged extraaxial spaces, simplified gyral patterns without a thickened cortex, hypoplastic corpus callosum, and enlarged lateral ventricles, with a reduction in gray and white matter volume during the prenatal and neonatal periods. Repeat MRI revealed progressive atrophy of the cerebral gray and white matter, with enlarged lateral ventricles, although the sizes of the bilateral basal ganglia, thalamus, and infratentorial structures were relatively preserved. These neuroradiological findings imply that this disease is caused by the gene involved in neuronal and glial proliferation in the ventricular zone and in tangential neuronal migration from the ganglionic eminence. The nature of the progressive degeneration of the hemispheric structures should be clarified.

Single mode emission and non-stochastic laser system based on disordered point-sized structures: toward a tuneable random laser.

As an advantage, random lasers may be elaborated from a large variety of materials and do not require any cavity oscillators that usually necessitate complicated and expensive fabrication techniques. Since the feedback process of those non-conventional laser systems is provided by light interference in a disordered medium, spectral and temporal uncertainties are usually considered as an intrinsic part of their optical proprieties. We investigated random laser action under two photon absorption experiments through an auto-organized InGaN/GaN quantum-disks ensemble. Thanks to our experimental approach, we evidence random lasing based on a gain medium constituted by point-sized structures. In such context, a stabilised and individual emission mode is observed as for conventional semiconductor lasers. By controlling the emission energy of these nanostructures, a tuneable and stable random laser may be built. Moreover, our findings suggest that disordered medium should play an important role in the conception of low cost quantum dot and up conversion laser systems.

FcγRIIB polymorphisms, periodontitis and preterm birth in Japanese pregnant women.

BACKGROUND AND OBJECTIVE: Recently, numerous studies have investigated the association of preterm birth with periodontitis. FcγRIIb is a human low-affinity receptor for immunoglobulin G (IgG). We have previously demonstrated single nucleotide polymorphisms (SNPs) of FcγRIIb to be associated with periodontitis and the serum-specific IgG level against periodontopathic bacteria. In this study, we investigated whether FcγRIIB gene polymorphisms were associated with periodontitis and/or pregnancy outcome. MATERIAL AND METHODS: We assessed the periodontal conditions of 122 Japanese pregnant women within 5 d of delivery, and polymorphisms in FcγRIIB and in other Fcγ receptors were detected from the genomic DNA. Using clinical and genomic data, we analyzed the relationship between periodontitis, preterm birth and Fcγ receptor polymorphisms. RESULTS: A significant difference was observed in the distribution of FcγRIIB-nt645+25A/G (rs2125685) between preterm and term birth groups, with a higher prevalence of nt645+25AA in the preterm birth group (p = 0.032). Additionally, the FcγRIIB-nt645+25GG carrier showed significantly higher results for the prevalence of periodontitis (p = 0.048), mean pocket depth (p = 0.021), mean clinical attachment level (p = 0.010), percentage of sites with pocket depth ≥ 4 mm (p = 0.005) and percentage of sites with clinical attachment level ≥ 3 mm (p = 0.007) than the AA carrier. An association between preterm birth and periodontitis was not observed in this study. CONCLUSION: These findings suggest that FcγRIIB-nt645+25AA carriers are more likely to experience preterm birth than FcγRIIB-nt645+25AG and GG carriers. Also, women with FcγRIIB-nt645+25G exhibited a greater tendency to have periodontitis than those with nt645+25A.

Disease stage stratified effects of cell dose in unrelated BMT for hematological malignancies: a report from Japan Marrow Donor Program.

Cell dose is one of the major factors that can be manipulated in unrelated BMT. However, regarding disease-stage-stratified effects of cell dose, data are limited. We analyzed the registry data from 3559 patients with acute leukemia, CML and myelodysplastic syndrome who received T-cell replete unrelated BMT through the Japan Marrow Donor Program. Adjusted effects of cell dose were evaluated for various outcomes separately according to disease stages and children or adults. Acute GVHD and nonrelapse mortality were not affected by cell dose. Among children, a cell dose lower than 3.0 × 10(8)/kg was associated with lower engraftment rates in advanced-stage diseases. Among adults, a cell dose of 3.4 × 10(8)/kg or higher was associated with lower relapse rates and better survival rates only in early-stage diseases, whereas cell dose below 2.3 × 10(8)/kg was associated with lower engraftment rates in advanced-stage diseases. In conclusion, effects of cell dose may differ among disease stages. A cell dose of 3.4 × 10(8)/kg or higher is recommended only for adults with early-stage diseases. With the number of patients available for analysis in this study, we could not show any significant benefits associated with 4.6 × 10(8)/kg or higher in children.

Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase.

Wnt5a is a representative ligand that activates the beta-catenin-independent pathway in Wnt signaling. Although it has been reported that abnormal activation of the Wnt/beta-catenin-dependent pathway is often observed in human prostate cancer, the involvement of the beta-catenin-independent pathway in this cancer is unclear. Abnormal expression of Wnt5a and beta-catenin was observed in 27 (28%) and 49 (50%) of 98 prostate cancer cases, respectively, by immunohistochemical analyses. Simultaneous expression of Wnt5a and beta-catenin was observed in only five cases, suggesting their exclusive expression. The positive detection of Wnt5a was correlated with high Gleason scores and biochemical relapse of prostate cancer, but that of beta-catenin was not. Knockdown and overexpression of Wnt5a in human prostate cancer cell lines reduced and stimulated, respectively, their invasion activities, and the invasion activity required Frizzled2 and Ror2 as Wnt receptors. Wnt5a activated Jun-N-terminal kinase through protein kinase D (PKD) and the inhibition of PKD suppressed Wnt5a-dependent cell migration and invasion. In addition, Wnt5a induced the expression of metalloproteinase-1 through the recruitment of JunD to its promoter region. These results suggest that Wnt5a promotes the aggressiveness of prostate cancer and that its expression is involved in relapse after prostatectomy.