Extracellular volume fraction using contrast-enhanced CT is useful in differentiating intrahepatic cholangiocellular carcinoma from hepatocellular carcinoma.

Objectives: To evaluate whether tumor extracellular volume fraction (fECV) on contrast-enhanced computed tomography (CT) aids in the differentiation between intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC). Methods: In this retrospective study, 113 patients with pathologically confirmed ICC (n = 39) or HCC (n = 74) who had undergone preoperative contrast-enhanced CT were enrolled. Enhancement values of the tumor (Etumor) and aorta (Eaorta) were obtained in the precontrast and equilibrium phase CT images. fECV was calculated using the following equation: fECV [%] = Etumor/Eaorta × (100 - hematocrit [%]). fECV values were compared between the ICC and HCC groups using Welch's t-test. The diagnostic performance of fECV for differentiating ICC and HCC was assessed using receiver-operating characteristic (ROC) analysis. fECV and the CT imaging features of tumors were evaluated by two radiologists. Multivariate logistic regression analysis was performed to identify factors predicting a diagnosis of ICC. Results: Mean fECV was significantly higher in ICCs (43.8% ± 13.2%) than that in HCCs (31.6% ± 9.0%, p < 0.001). The area under the curve for differentiating ICC from HCC was 0.763 when the cutoff value of fECV was 41.5%. The multivariate analysis identified fECV (unit OR: 1.10; 95% CI: 1.01-1.21; p < 0.05), peripheral rim enhancement during the arterial phase (OR: 17.0; 95% CI: 1.29-225; p < 0.05), and absence of washout pattern (OR: 235; 95% CI: 14.03-3933; p < 0.001) as independent CT features for differentiating between the two tumor types. Conclusions: A high value of fECV, peripheral rim enhancement during the arterial phase, and absence of washout pattern were independent factors in the differentiation of ICC from HCC.

Metabolic tumor volume of metastatic lymph nodes and survival after total laryngectomy in laryngeal and hypopharyngeal cancer.

OBJECTIVES: The prognostic value of metabolic tumor volume (MTV) in locally advanced laryngeal or hypopharyngeal cancer is established in the setting of chemoradiotherapy, while it remains unknown in the setting of upfront total laryngectomy. MATERIALS AND METHODS: We retrospectively analyzed 88 patients receiving total laryngectomy and neck dissection, using Cox regression models. RESULTS AND CONCLUSION: Variables related to metastatic lymph node were associated with overall survival, whereas those related to primary tumor were not. In multivariable models, MTV of metastatic lymph nodes (N-MTV) as a continuous variable (Akaike's information criterion (AIC), 277.5) was equivalent to pathological nodal status (AIC, 278.2; P = 0.40), and superior to pathological nodal classification as an ordinal variable (AIC, 281.4; P < 0.05) in ability of predicting death. The risk of death was increased by 1.2-fold (95% confidence interval (CI), 1.0-1.4; P = 0.03) every 10-ml increment of N-MTV, while patients with pN+ disease were at a higher risk of death by 2.9-fold (95% CI, 1.0-12.2; P < 0.05) compared with patients with pN0 disease. Using recursive partitioning analysis (RPA), we classified the patients as having a low, intermediate, or high risk of death on the basis of N-MTV and extranodal extension (ENE). This RPA classification system exhibited greater concordance with overall survival than the classification considering pathological nodal status and ENE (AIC, 275.8 versus 281.4; P = 0.02). In the setting of upfront total laryngectomy, N-MTV is a critical predictor of mortality. A staging system in which N-MTV is incorporated may better inform adjuvant treatment decisions.

Distribution of norovirus genotypes and subtypes in river water by ultra-deep sequencing-based analysis.

To determine the distribution of Norovirus (NoV) genotypes in natural river water in Thailand, we conducted a genome analysis using a next-generation sequencer. Twenty-five river water samples were collected at five different sites of the Khlong Klon River in the suburbs of Bangkok between August 2013 and December 2014. The partial genome of NoV was detected in 15 of the 25 samples (60·0%). Seven of these 15 samples (46·7%) contained multiple NoV GII genotypes: GII.4, GII.6, and GII.17. Our data showed that GII.17 had already emerged in August 2013 as a minor population, and it became a major genotype in December 2014. Our findings indicate that the virus was likely to have been circulating in the community before it appeared in the river water. SIGNIFICANCE AND IMPACT OF THE STUDY: Our study was to investigate the frequencies of multiple genogroups and genotypes of norovirus in the river water near Bangkok, Thailand, by ultra-deep sequencing-based analysis. This study revealed that the epidemic strain was likely to have been circulating in the community before it appeared in the river water. Monitoring of the Norovirus (NoV) genomes in the natural environment may contribute to an understanding of the emergence of new epidemic NoV strains in human populations.

Impact of number of [(18)F]fluorodeoxyglucose-PET-positive lymph nodes on survival of patients receiving neoadjuvant chemotherapy and surgery for oesophageal cancer.

BACKGROUND: [(18) F]fluorodeoxyglucose (FDG)-PET has been used to evaluate the response of primary tumours to neoadjuvant therapy for oesophageal cancer. The clinical significance of the number of PET-positive nodes before and after therapy has not been investigated previously. METHODS: [(18) F]FDG-PET was performed before and 2-3 weeks after completion of neoadjuvant chemotherapy to identify the number of PET-positive nodes, and these numbers were assessed in relation to metabolic changes in the primary tumour. RESULTS: Of 302 patients in total, 90 had no PET-positive nodes, 83 had one, 59 had two and 70 patients had three or more positive nodes before therapy. After treatment, the numbers were: none in 207 patients, one in 59, two in 20 and three or more in 16 patients. The number of PET-positive nodes after treatment was influenced by both the number of PET-positive nodes before therapy and the response to preoperative therapy, and correlated with the number of metastatic lymph nodes. Overall survival was longer in patients who had no PET-positive nodes after treatment than in those who had one or more. Multivariable analysis identified the numbers of PET-positive nodes before and after chemotherapy as independent prognostic factors, together with clinical response, tumour depth and lymph node involvement. CONCLUSION: The number of PET-positive nodes after treatment correlated with survival in patients with oesophageal cancer who underwent neoadjuvant chemotherapy.

Possible association of CUX1 gene polymorphisms with antidepressant response in major depressive disorder.

Association between response to antidepressant treatment and genetic polymorphisms was examined in two independent Japanese samples of patients with major depressive disorder (MDD). Genome-wide approach using the Illumina Human CNV370-quad Bead Chip was utilized in the analysis of the 92 MDD patients in the first sample. In all, 11 non-intergenic single-nucleotide polymorphisms with uncorrected allelic P-value <0.0001 were selected for the subsequent association analyses in the second sample of 136 MDD patients. Difference in allele distribution between responders and nonresponders were found in the second-stage sample for rs365836 and rs201522 of the CUX1 gene (P=0.005 and 0.004, respectively). The allelic P-values for rs365836 and rs201522 in both samples combined were 0.0000023 and 0.0000040, respectively. Our results provide the first evidence that polymorphisms of the CUX1 gene may be associated with response to antidepressant treatment in Japanese patients with MDD.

Serological survey of Encephalitozoon cuniculi infection in Japanese dogs.

Antibodies to Encephalitozoon cuniculi were examined by enzyme-linked immunosorbent assay using E. cuniculi PTP2 recombinant protein and by Western blot analysis on a total of 472 dog serum samples that had been collected in Japan. Of these samples, 21.8% (103/472) had antibodies against E. cuniculi. Each of 5 serum samples that showed high (>1.0) or low (<0.1) OD value was selected randomly and further examined by Western blot using E. cuniculi-native antigens. All samples with high OD values reacted with specific E. cuniculi proteins, including an antigen of approximately 35 kDa corresponding with PTP2; sera with low OD values did not recognize this E. cuniculi band. This study is the first to demonstrate the prevalence of E. cuniculi infection in dogs in Japan.

Pituitary adenylate cyclase-activating polypeptide is associated with schizophrenia.

Pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1: adenylate cyclase-activating polypeptide 1), a neuropeptide with neurotransmission modulating activity, is a promising schizophrenia candidate gene. Here, we provide evidence that genetic variants of the genes encoding PACAP and its receptor, PAC1, are associated with schizophrenia. We studied the effects of the associated polymorphism in the PACAP gene on neurobiological traits related to risk for schizophrenia. This allele of the PACAP gene, which is overrepresented in schizophrenia patients, was associated with reduced hippocampal volume and poorer memory performance. Abnormal behaviors in PACAP knockout mice, including elevated locomotor activity and deficits in prepulse inhibition of the startle response, were reversed by treatment with an atypical antipsychotic, risperidone. These convergent data suggest that alterations in PACAP signaling might contribute to the pathogenesis of schizophrenia.

Possible association between nonsynonymous polymorphisms of the anaplastic lymphoma kinase (ALK) gene and schizophrenia in a Japanese population.

We examined, for the first time, the possible association between schizophrenia and the anaplastic lymphoma kinase (ALK) gene which plays an important role in neurodevelopment. When two nonsynonymous polymorphisms (Arg1491Lys and Glu1529Asp) were examined, there were significant differences in genotype and allele distributions between patients and controls. Individuals homozygous for the minor allele (1491Lys-1529Asp) were more common in patients than in controls (p = 0.0064, odds ratio 2.4, 95% CI 1.3-4.6). These results suggest that genetic variations of the ALK gene might confer susceptibility to schizophrenia.

A complex polymorphic region in the brain-derived neurotrophic factor (BDNF) gene confers susceptibility to bipolar disorder and affects transcriptional activity.

Previous studies have suggested that genetic variations in the brain-derived neurotrophic factor (BDNF) gene may be associated with several neuropsychiatric diseases including bipolar disorder. The present study examined a microsatellite polymorphism located approximately 1.0 kb upstream of the translation initiation site of the BDNF gene for novel sequence variations, association with bipolar disorder, and effects on transcriptional activity. Detailed sequencing analysis revealed that this polymorphism is not a simple dinucleotide repeat, but it is highly polymorphic with a complex structure containing three types of dinucleotide repeats, insertion/deletion, and nucleotide substitutions that gives rise to a total of 23 novel allelic variants. We obtained evidence supporting the association between this polymorphic region (designated as BDNF-linked complex polymorphic region (BDNF-LCPR)) and bipolar disorder. One of the major alleles ('A1' allele) was significantly more common in patients than in controls (odds ratio 2.8, 95% confidential interval 1.5-5.3, P=0.001). Furthermore, a luciferase reporter gene assay in rat primary cultured neurons suggests that this risk allele (A1) has a lower-transcription activity, compared to the other alleles. Our results suggest that the BDNF-LCPR is a functional variation that confers susceptibility to bipolar disorder and affects transcriptional activity of the BDNF gene.

Association study of the frizzled-3 (FZD3) gene with schizophrenia and mood disorders.

Two research groups have recently reported a significant association between schizophrenia and genetic variants of Frizzled-3 (FZD3) gene. We examined a possible association in a Japanese sample of schizophrenia, bipolar disorder, unipolar depression and controls with four single nucleotide polymorphisms (SNPs), tested in previous reports. We failed to find significant association in the four SNPs or haplotype analysis. The FZD3 gene might not play a role in conferring susceptibility to major psychosis in our sample.

Radionuclide imaging metabolic activity of brown adipose tissue in a patient with pheochromocytoma.

We describe a patient with extra-adrenal pheochromocytoma and high plasma norepinephrine levels. Radionuclide images of this patient obtained using (18)F-fluorodeoxyglucose and (123)I-metaiodobenzylguanidine revealed bilateral tracer accumulation in the shoulder and lower neck. The regions of radiotracer uptake corresponded to the location of human brown adipose tissue (BAT). Excessive sympathetic stimulation by high circulating catecholamine concentrations augmented the metabolic activity and tracer uptake in the BAT. This study showed that radionuclide imaging can noninvasively visualize human BAT in terms of metabolic and functional activity.

Analysis of enhancer activity of a dinucleotide repeat polymorphism in the neurotrophin-3 gene and its association with bipolar disorder.

Growing evidence has implicated the possible involvement of neurotrophins in the pathogenesis of functional psychoses such as schizophrenia and bipolar disorder. Previous studies reported a significant association of a dinucleotide repeat polymorphism of the neurotrophin-3 (NTF3) gene with schizophrenia. The aims of the present study were to examine whether this polymorphism is associated with bipolar disorder and whether the polymorphic region has an enhancer/silencer effect on transcriptional activity in an allele-dependent manner. In an association analysis between the polymorphism and bipolar disorder in a Japanese sample of 88 patients and 98 controls matched for age, sex, and ethnicity, the distribution of alleles did not differ significantly between the two groups. pGL3-promoter luciferase reporter vectors containing the polymorphic region increased luciferase activity relative to empty pGL3-promoter vector in HeLa, IMR-32 (neuroblastoma) and Hs683 (glioma) cell lines; however, no significant difference was detected between alleles for either cell line. Our results suggest that the examined polymorphism has no major role in giving susceptibility to bipolar disorder. Although the polymorphic region may have an enhancer-like effect on transcriptional activity, we obtained no evidence for allele-dependent differential effects.

Association analysis of the -308G>A promoter polymorphism of the tumor necrosis factor alpha (TNF-alpha) gene in Japanese patients with schizophrenia.

Two research groups have thus far reported a significant association between schizophrenia and a promoter polymorphism (-308G > A) of the gene encoding tumor necrosis factor alpha (TNF-alpha), while contradictive negative results have also been reported. We examined the possible association in a Japanese sample of 297 schizophrenia cases and 458 controls. Allele frequencies of both the patients and controls were very low (1.5% and 0.8%, respectively), and the difference was not statistically significant. We conclude that the effect of the -308G > A polymorphism on the development of schizophrenia is, if any, weak and the majority of Japanese schizophrenics are unrelated to the -308G > A polymorphism of the TNF-alpha gene.

Gamma camera coincidence imaging with [18F]fluorodeoxyglucose in the pretreatment evaluation of patients with oesophageal cancer.

This study investigated the role of [18F]fluorodeoxyglucose (FDG) dual-head gamma camera coincidence imaging (GCI) in the pretreatment evaluation of patients with oesophageal cancer. Twenty-two patients (20 men; mean age, 64 years) with untreated, biopsy proven squamous cell carcinoma of the oesophagus underwent positron emission tomography (PET) and GCI 1 and 3 h after a single injection of FDG, respectively. Computed tomography (CT) was performed within 2 weeks of the FDG imaging. The sensitivity of lesion detection was compared between GCI and PET. Regional (N) and distant (M) metastases detected by GCI were evaluated with reference to PET and CT. The staging obtained by each modality was also compared with pathological staging in nine patients who underwent surgery. FDG PET detected 22 primary tumours, 34 metastatic lymph nodes and four organ metastases. Of them, GCI detected all primary tumours, 24 (71%) metastatic lymph nodes, and none of the organ metastases. Lymph nodes missed by GCI were smaller in size and the majority of them were located in the thoracic region. GCI provided N and M staging identical to CT and PET in eight patients and improved staging over CT in four patients. On the other hand, GCI missed metastases detected by both PET and CT in five patients. The addition of GCI to CT could improve detection of patients with metastasis to 82% (18/22) compared with 64% (14/22) detected by CT alone. In patients with pathological staging (n = 9), GCI could influence management changes in two patients (22%). In conclusion, FDG GCI has a role that is complementary to CT in the initial staging of patients with oesophageal cancer, and due to the additional detection of nodal metastasis, GCI can provide staging information, which may influence changes in management.

Perceptibility curves for the Digora system.

OBJECTIVES: To construct perceptibility curves (PCs) for given calibration settings in order to define psychophysical properties of the Digora storage phosphor system and to evaluate the effects of automatic exposure correction (AEC) on the PCs. METHODS: The Digora system was calibrated at two exposures, 80 microC kg(-1) (high calibration) and 40 microC kg(-1) (low calibration). Since the grey levels displayed in the radiographs are adjusted by AEC, dose-response functions at high calibration were obtained using AEC on and off modes. The dose-response function at low calibration was obtained with AEC off. The PC at each experimental setting was calculated using known physical parameters of the system and the performance of the average observer used in a previous study. In addition, PCs were also constructed using transmitted radiation flux behind the test object calculated from the attenuation coefficient in order to study observer and system performance. PCs obtained under these conditions were compared. RESULTS: The PC using calculated transmitted radiation flux behind the test object showed a wide plateau at the peak owing to AEC, while the PC obtained by a modified approach showed a higher but narrower peak. There were no differences between the two PCs using AEC on and off modes when the PCs were constructed using a modified approach. There were no differences between the two PCs obtained at high and low calibration settings or between the three PCs obtained with AEC on except for the position along the exposure axis. CONCLUSIONS: Psychophysical properties of the Digora system may be determined if we employ registered exposures from a dose-response function with AEC off under a given calibration setting. Under these circumstances the shape and height of the PCs will be unchanged irrespective of the AEC mode.

Association study of C825T polymorphism of the G-protein b3 subunit gene with schizophrenia and mood disorders.

Alterations of G proteins have been implicated in major psychiatric illnesses. A C825T polymorphism of a gene encoding the beta3 subunit of heterotrimeric G proteins (GNB3) was reported to be associated with several pathological conditions, such as hypertension and depressive disorder. We examined whether this polymorphism is associated with functional psychoses in a Japanese sample of 370 schizophrenics, 164 bipolars, 68 depressive patients, and 198 controls. We obtained no evidence for an association of the polymorphism with any diagnostic group.

Effects of iterative reconstruction on image contrast and lesion detection in gamma camera coincidence imaging in lung and breast cancers.

To investigate the effects of iterative reconstruction in 18F-fluorodeoxyglucose (FDG) gamma camera coincidence imaging (GCI), image contrast and visual detection obtained by using the iterative ordered-subsets expectation maximization (OSEM) reconstruction, in a phantom and in patients with lung cancer and breast cancer, were compared with those obtained by using the conventional filtered backprojection (FBP) reconstruction. Images of a cylindrical phantom containing hot spheres of various sizes (10-38 mm) were acquired by positron emission tomography (PET) and GCI at various sphere-to-background activity ratios. Forty-one consecutive patients with biopsy-proven cancer of lung (n = 20) and breast (n = 21) underwent PET and GCI on the same day after intravenous injection of 370 MBq of FDG. GCI images reconstructed by the OSEM and the FBP were compared. FDG PET was considered as the standard of reference. In GCI phantom images, OSEM yielded better contrast and signal-to-noise ratio (SNR) than FBP over the range of sphere sizes. Attenuation correction improved both the image measures and sphere detection obtained by the OSEM in GCI. In the study involving patients, FDG PET depicted 41 primary tumours and 25 metastatic lymph nodes. All of the tumours >2 cm in diameter (n = 25), six of the nine tumours 1.5-2.0 cm in diameter (67%), two of seven tumours <1.5 cm in diameter (29%), and 20 metastatic lymph nodes (80%) were detected in attenuation uncorrected GCI reconstructed by the OSEM as well as the FBP. The undetected lesions in GCI were identical between the OSEM and the FBP reconstructions. OSEM yielded significantly greater tumour-to-background (T/B) ratios and lower noise than FBP in GCI (T/B ratios, 4.1+/-3.2 vs 3.7+/-2.7, P = 0.02; noise, 0.09+/-0.04 vs 0.14+/-0.05, P<0.0001). In conclusion, OSEM yielded better image contrast and less noise than the FBP in GCI, but the lesion detection obtained by the OSEM and the FBP in attenuation uncorrected GCI in patients with lung cancer and breast cancer were similar. Phantom data suggest the potential of OSEM for improving lesion detection in GCI after attenuation correction.

Clinical severity of Norwalk virus and Sapporo virus gastroenteritis in children in Hokkaido, Japan.

OBJECTIVE: To clarify the clinical significance and etiologic impact of Norwalk virus (NV) and Sapporo virus (SV) in viral gastroenteritis in Japanese children. STUDY DESIGN: Two outbreaks each of NV gastroenteritis and SV gastroenteritis occurring in an infant home in Sapporo, Japan, as well as 95 hospitalized children with acute gastroenteritis were retrospectively evaluated using a 0- to 20-point clinical severity scoring system. RESULTS: The mean severity scores for NV and SV gastroenteritis outbreaks were 7.9 and 5.2, respectively, as compared with 8.4 for rotavirus A gastroenteritis that occurred in the same infant home. Among 95 hospitalized children with acute gastroenteritis, rotavirus A was detected in 47% followed by NV in 18%. SV was not found. CONCLUSION: Our data indicate that NV can cause severe gastroenteritis and is an important etiologic agent in hospitalized cases, whereas SV causes mild gastroenteritis in Japanese children.

Feasibility of a short acquisition protocol for whole-body positron emission tomography with fluorine-18 fluorodeoxyglucose.

The conventional protocol for whole-body positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose (FDG) requires a total acquisition time of 40-60 min, which is inconvenient for many oncological patients owing to fatigue and discomfort. This study examined the feasibility of a short protocol for whole-body PET. A phantom containing six "hot" spheres of gradually increasing diameter (10-38 mm) was imaged using a dedicated PET scanner for 20, 40, 60, 80, 120 and 600 s at various count rates. Thirty-four patients with various neoplasms underwent whole-body emission scans for 1 min per bed position 1 h after intravenous injection of 370 MBq of FDG (short protocol). A standard simultaneous transmission-emission acquisition for 10 min per bed position was performed thereafter. The images were reconstructed using an iterative algorithm. At a count rate of 40 kcps, which is close to the average count rate obtained in a whole-body FDG PET study, the 60-s image visualised five spheres, of which the smallest was 13 mm in size. Despite the better image quality, lesion detection was not improved in images acquired for more than 60 s (80-600 s). Only three of the six spheres could be detected in images acquired for less than 60 s. In the patient study, the standard protocol visualised 120 tumour lesions, of which 93 (78%) could be detected using the short protocol. Among the non-visualised lesions, 22 (82%) were < or =1.5 cm in size and 17 (63%) were lymph nodes. It is concluded that the proposed short protocol for whole-body FDG PET has a reasonably high detection rate and may be suitable for patients who are unable to undergo scanning for a prolonged period. It may also be useful as a pre-scan guide before a standard whole-body acquisition.

Requirement of nef for HIV-1 infectivity is biased by the expression levels of Env in the virus-producing cells and CD4 in the target cells.

The nef gene of human immunodeficiency virus type 1 (HIV-1) encodes a 27 to 34 kDa myristoylated protein, which enhances viral infectivity in a single-round infection assay. The level of Nef enhancement of HIV-1 infectivity depends on the viral strains, on the target cells, and on the cells used for propagating the viruses. In this study, we aimed at clarifying the molecular basis of these differences in the requirement for Nef. We found that the requirement for Nef was increased when we decreased the quantity of Env protein in the virus-producing cells or the quantity of CD4 in the target cells. Both the wild-type and Nef-defective HIV-1 viruses were propagated in 293T cells, which did not express any CD4; therefore, Nef-induced CD4 down-regulation did not explain this phenomenon. Moreover, we did not observe any increase in the viral entry or fusion activity of gp120env in the wild-type HIV-1 compared to that in the Nef-defective HIV-1. Thus, we propose that Env on the virion and CD4 on the target cells have inhibitory effects on the post-entry step of the HIV-1 replication cycle, and that Nef functions to counteract this negative effect.