Impact of deep learning on radiologists and radiology residents in detecting breast cancer on CT: a cross-vendor test study.

AIM: To investigate the effect of deep learning on the diagnostic performance of radiologists and radiology residents in detecting breast cancers on computed tomography (CT). MATERIALS AND METHODS: In this retrospective study, patients undergoing contrast-enhanced chest CT between January 2010 and December 2020 using equipment from two vendors were included. Patients with confirmed breast cancer were categorised as the training (n=201) and validation (n=26) group and the testing group (n=30) using processed CT images from either vendor. The trained deep-learning model was applied to test group patients with (30 females; mean age = 59.2 ± 15.8 years) and without (19 males, 21 females; mean age = 64 ± 15.9 years) breast cancer. Image-based diagnostic performance of the deep-learning model was evaluated with the area under the receiver operating characteristic curve (AUC). Two radiologists and three radiology residents were asked to detect malignant lesions by recording a four-point diagnostic confidence score before and after referring to the result from the deep-learning model, and their diagnostic performance was evaluated using jackknife alternative free-response receiver operating characteristic analysis by calculating the figure of merit (FOM). RESULTS: The AUCs of the trained deep-learning model on the validation and test data were 0.976 and 0.967, respectively. After referencing with the result of the deep learning model, the FOMs of readers significantly improved (reader 1/2/3/4/5: from 0.933/0.962/0.883/0.944/0.867 to 0.958/0.968/0.917/0.947/0.900; p=0.038). CONCLUSION: Deep learning can help radiologists and radiology residents detect breast cancer on CT.

Optimisation of Radiation Therapy in Bladder Preservation Therapy for Patients With Clinical Stage T2N0M0 Bladder Cancer.

AIMS: A novel bladder preservation therapy, the OMC (Osaka Medical College) regimen, which combines radiation therapy with balloon-occluded arterial infusion of anticancer agents, is a treatment option for patients with muscle-invasive bladder cancer (MIBC). We retrospectively analysed the effects of changes in radiation dose and irradiation field on treatment efficacy and adverse events.The purpose of this study is to use the results of this study to help determine a course of radiation therapy for bladder preservation therapy of cT2N0M0 MIBC. MATERIALS AND METHODS: We examined 352 patients with clinical stage T2N0M0 (cT2N0M0) MIBC classified into the following groups based on the irradiation method: group A, the whole pelvis (50 Gy/25 fractions) + local bladder (10 Gy/5 fractions); group B, the small pelvis (50 Gy/25 fractions) + local bladder (10 Gy/5 fractions); group C, the whole pelvis (40 Gy/20 fractions) + local bladder (10 Gy/5 fractions). RESULTS: The complete response rate, 3-year overall survival and progression-free survival rates in group A were 92.9%, 94.9% and 82.1%, respectively; in group B were 87.2%, 86.7% and 76.7%, respectively; and in group C were 95.2%, 92.6% and 71.1%, respectively. No significant differences between the groups were noted. The incidence of ≥grade 3 urinary tract and gastrointestinal toxicities were not significantly different among the groups (group A: 7.8%, 1.7%; B, 11.1%, 0%; C, 7.1%, 1.8%, respectively). The 3-year progression-free rates of the common iliac lymph node (CILN) region in patients who received whole-pelvis and small-pelvis irradiation were 99.0 and 89.0% (P < 0.01), respectively, with the latter group having significantly high lymph node recurrence in the CILN region. CONCLUSIONS: Our findings showed that the optimal radiation therapy for patients with cT2N0M0 MIBC undergoing the OMC regimen is whole-pelvis irradiation including the CILN region, with a total dose of 50 Gy/25 fractions.

Impact of blood storage duration on hematologic, blood gas, biochemical, and oxidative stress variables in sheep undergoing allogeneic blood transfusions.

BACKGROUND: Hemotherapy in ruminants is limited to whole blood transfusions, sometimes with stored blood for up to 42 days, but little attention has been given to the effect of blood storage times and recipient responses after transfusions. OBJECTIVES: We aimed to evaluate the hematologic and serum biochemical effects after allogeneic blood transfusion with either fresh or stored blood in sheep. We also sought to examine hematologic and biochemical analyte changes in the store blood. METHODS: Eighteen sheep underwent a single phlebotomy to remove 40% of their blood volume. The sheep were divided into three experimental groups, G0, G15, and G35, which included six animals, each receiving 20 mL/kg of either fresh blood or blood stored in citrate, phosphate, dextrose, and adenine (CPDA-1) bags for 15 and 35 days, respectively. Biochemical, hematologic, coagulation, blood gas, lipid peroxidation, and oxidative stress test evaluations were performed using the blood samples gathered at T0 (before transfusion), 30 minutes (T30m), 6, 12, 24, 48, 72, and 96 hours (T6h-T96h), 8 days (T8d), and 16 days (T16d) after transfusions. RESULTS: Sheep exhibited increases in packed cell volumes, red blood cell counts, and total hemoglobin concentrations at T30m (P < .05). G35 animals had greater plasma hemoglobin concentrations at T12h and decreased blood pH values at T6h, characterized by slight metabolic acidemia. Regarding oxidative stress, G35 animals had decreased catalase activities from T0 at T30m, T6h, T12h, and T24h, indicating that hemolysis had occurred, which was supported by concomitant increases in bilirubin. CONCLUSIONS: Sheep transfused with 35-day stored blood exhibited greater hematologic, blood gas, biochemical, and oxidative alterations; however, anemic animals without comorbidities effectively reversed those alterations.

CT findings in 11 patients with TAFRO syndrome: a variant of multicentric Castleman's disease.

AIM: To assess detailed computed tomography (CT) findings in patients with the recently described thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome, in order to contribute to imaging interpretation in the challenging diagnosis of this disease. MATERIALS AND METHODS: The institutional review board approved this retrospective study and waived the need for informed consent. Eleven patients (six men, five women; mean age, 52.5 years) with confirmed TAFRO syndrome were included in this study. Chest-to-pelvis CT images were analysed for the presence of anasarca, organomegaly, bone lesions, and lung lesions. RESULTS: Anasarca was present in all patients and involved multiple cavities and tissues; pleural effusion and ascites were found in 100% of patients; pericardial effusion in 64%; periportal collar in 91%; gallbladder wall oedema in 78%; subcutaneous oedema in 91%; retroperitoneal oedema in 100%; and mesenteric oedema in 100%. Organomegaly involved multiple organs: hepatomegaly in 73%, splenomegaly in 82%, lymphadenopathy in 100%, and enlarged anterior mediastinum in 64% (solitary, well-circumscribed mass, 0%; infiltrative mass, 0%; non-mass-forming infiltrative lesion, 64%). Bone lesions were present in 91% patients and all bone lesions had ground-glass density with diffuse distribution. None of the patients had any lesions in their lungs. CONCLUSION: The present study revealed that the findings of anasarca, organomegaly, and diffuse bony ground-glass appearance were observed in detail on CT in patients with TAFRO syndrome. A "matted" appearance of the enlarged anterior mediastinum is the characteristic CT finding of TAFRO syndrome, and it is possible to diagnose TAFRO syndrome from the combination of several CT findings.

Releasing Mechanism of Neurotrophic Factors via Polysialic Acid.

Neurotrophins are well-characterized neurologically active molecules in the central nervous system. The regulation of these signaling molecules, which are involved in cell growth, differentiation, and survival, is critical for normal brain function. Among the different types of neurotrophins, brain-derived neurotrophic factor (BDNF) is involved in various brain functions, including memory consolidation, synaptic plasticity, and adult neurogenesis, and is therefore a key molecule for understanding comprehensive brain function and neurodevelopmental and psychiatric diseases. The concentration of BDNF in body fluid is highly related to several neurodevelopmental and psychiatric diseases, including Alzheimer's diseases, depression, schizophrenia, and bipolar disorder. In the present review, the mechanisms by which BDNF is released from secretory vesicles are reviewed, with a particular focus on the recently described glycan-mediated release. In addition, the impact of glycan-mediated BDNF release on psychiatric disorders is also discussed.

A laser-induced pulsed water jet for layer-selective submucosal dissection of the esophagus.

Background and aims: Conventional water jet devices have been used for injecting fluid to lift up lesions during endoscopic submucosal dissection or endoscopic mucosal resection procedures. However, these devices cannot dissect the submucosal layer effectively. Here we aim to elucidate the dissection capability of a laser-induced pulsed water jet and to clarify the mechanism of dissection with layer selectivity. Materials (Subjects) and methods: Pulsed water jets were ejected from a stainless nozzle by accelerating saline using the energy of a pulsed holmium: yttrium-aluminum-garnet laser. The impact force (strength) of the jet was evaluated using a force meter. Injection of the pulsed jet into the submucosal layer was documented by high-speed imaging. The physical properties of the swine esophagus were evaluated by measuring the breaking strength. Submucosal dissection of the swine esophagus was performed and the resection bed was evaluated histologically. Results: Submucosal dissection of the esophagus was accomplished at an impact force of 1.11-1.47 N/pulse (laser energy: 1.1-1.5 J/pulse; standoff distance: 60 mm). Histological specimens showed clear dissection at the submucosal layer without thermal injury. The mean static breaking strength of the submucosa (0.11 ± 0.04 MPa) was significantly lower than that of the mucosa (1.32 ± 0.18 MPa), and propria muscle (1.45 ± 0.16 MPa). Conclusions: The pulsed water jet device showed potential for achieving selective submucosal dissection. It could achieve mucosal, submucosal, and muscle layer selectivity owing to the varied breaking strengths.

Re-evaluation of the formalin-ether sedimentation method for the improvement of parasite egg recovery efficiency.

The formalin-ether sedimentation (FES) method is considered as reliable method of fecal examination for the detection of parasites. In this study, we re-evaluated several aspects of FES such as (i) pretreatment of feces; (ii) filtration of fecal suspensions; (iii) test-tube material and (iv) substitution of ether by other organic solvents as to see an improvement in parasite egg recovery. The egg count was represented by the number of ova detected per 100 µg of sediment. Pre-treatment of feces with formalin (pH 7) increased egg detection rate remarkably compared with original FES method. Use of three layers of gauze dramatically reduced the sediment in the final product, and led to an increase in the number of ova detected. Use of polypropylene test tubes instead of glass test tubes also increased the number of egg detection. None of the organic solvents used to replace the ether produced better results. Based on these findings, we proposed a modified FES procedure. Further, we also compared the parasite positive rate and the number of ova recovered by using original FES and the modified FES procedures by examining 112 fecal samples collected from school children of parasite endemic area in Nepal. Feces collected from Nepal had many parasite ova, and these fecal samples barely displayed false-negative results even by method with low sensitivity. When the mean number of Hemenolepis nana, hookworm, T. trichiura, and A. lumbricoides ova recovered by original FES and the modified FES methods was compared, the values obtained by modified FES were superior (higher). This result suggested that the modified FES is effective and better for the recovery of parasite ova in areas of low-intensity parasitic infection.

Tooth bleaching increases dentinal protease activity.

Hydrogen peroxide is an oxidative agent commonly used for dental bleaching procedures. The structural and biochemical responses of enamel, dentin, and pulp tissues to the in vivo bleaching of human (n = 20) premolars were investigated in this study. Atomic force microscopy (AFM) was used to observe enamel nanostructure. The chemical composition of enamel and dentin was analyzed by infrared spectroscopy (FTIR). The enzymatic activities of dental cathepsin B and matrix metalloproteinases (MMPs) were monitored with fluorogenic substrates. The amount of collagen in dentin was measured by emission of collagen autofluorescence with confocal fluorescence microscopy. The presence of Reactive Oxygen Species (ROS) in the pulp was evaluated with a fluorogenic 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) probe. Vital bleaching of teeth significantly altered all tested parameters: AFM images revealed a corrosion of surface enamel nanostructure; FTIR analysis showed a loss of carbonate and proteins from enamel and dentin, along with an increase in the proteolytic activity of cathepsin-B and MMPs; and there was a reduction in the autofluorescence of collagen and an increase in both cathepsin-B activity and ROS in pulp tissues. Together, these results indicate that 35% hydrogen peroxide used in clinical bleaching protocols dramatically alters the structural and biochemical properties of dental hard and soft pulp tissue.

Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes.

AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) has various extra-pancreatic actions, in addition to its enhancement of insulin secretion from pancreatic beta cells. The GLP-1 receptor is produced in kidney tissue. However, the direct effect of GLP-1 on diabetic nephropathy remains unclear. Here we demonstrate that a GLP-1 receptor agonist, exendin-4, exerts renoprotective effects through its anti-inflammatory action via the GLP-1 receptor without lowering blood glucose. METHODS: We administered exendin-4 at 10 µg/kg body weight daily for 8 weeks to a streptozotocin-induced rat model of type 1 diabetes and evaluated their urinary albumin excretion, metabolic data, histology and morphometry. We also examined the direct effects of exendin-4 on glomerular endothelial cells and macrophages in vitro. RESULTS: Exendin-4 ameliorated albuminuria, glomerular hyperfiltration, glomerular hypertrophy and mesangial matrix expansion in the diabetic rats without changing blood pressure or body weight. Exendin-4 also prevented macrophage infiltration, and decreased protein levels of intercellular adhesion molecule-1 (ICAM-1) and type IV collagen, as well as decreasing oxidative stress and nuclear factor-κB activation in kidney tissue. In addition, we found that the GLP-1 receptor was produced on monocytes/macrophages and glomerular endothelial cells. We demonstrated that in vitro exendin-4 acted directly on the GLP-1 receptor, and attenuated release of pro-inflammatory cytokines from macrophages and ICAM-1 production on glomerular endothelial cells. CONCLUSIONS/INTERPRETATION: These results indicate that GLP-1 receptor agonists may prevent disease progression in the early stage of diabetic nephropathy through direct effects on the GLP-1 receptor in kidney tissue.

A novel double mutation in FUS gene causing sporadic ALS.

It has been shown that mutations in the Fused in Sarcoma gene (FUS) could explain up to 5% of cases with familial amyotrophic lateral sclerosis (ALS). Our mutation analysis of FUS in a Canadian ALS patient of Chinese origin revealed an unusual novel heterozygous double point mutation (R514S/E516V) confirming that exon 15 is a mutation hot-spot. The substitutions are in cis position to each other and affect highly conserved codons in the RGG-rich region of the FUS protein. The absence of clinical signs of ALS in the relatives of the affected carrier could indicate that this mutation is incompletely penetrant or de novo. The pathologic significance of the R514S/E516V mutation was confirmed by immunohistochemistry. FUS-positive cytoplasmic inclusions were noted in a moderate number in neurons and abundantly in glial cells in the motor cortex and the brainstem. Of interest, a significant number of neuronal and glial FUS-positive inclusions were found in the tegmentum of the brainstem. Importantly, some neurons with inclusions showed retention of the normal nuclear FUS immunostaining.

Stimulation of neuronal neurite outgrowth using functionalized carbon nanotubes.

Low concentrations (0.11-1.7 microg ml(-1)) of functionalized carbon nanotubes (CNTs), which are multi-walled CNTs modified by amino groups, when added with nerve growth factor (NGF), promoted outgrowth of neuronal neurites in dorsal root ganglion (DRG) neurons and rat pheochromocytoma cell line PC12h cells in culture media. The quantity of active extracellular signal-regulated kinase (ERK) was higher after the addition of both 0.85 microg ml(-1) CNTs and NGF than that with NGF alone. CNTs increased the number of cells with neurite outgrowth in DRG neurons and PC12h cells after the inhibition of the ERK signaling pathway using a mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) inhibitor. Active ERK proteins were detected in MEK inhibitor-treated neurons after the addition of CNTs to the culture medium. These results demonstrate that CNTs may stimulate neurite outgrowth by activation of the ERK signaling pathway. Thus, CNTs are biocompatible and are promising candidates for biological applications and devices.

Estimation of the absorption coefficients of two-layered media by a simple method using spatially and time-resolved reflectances.

Our newly developed method using spatially and time-resolved reflectances can easily estimate the absorption coefficients of each layer in a two-layered medium if the thickness of the upper layer and the reduced scattering coefficients of the two layers are known a priori. We experimentally validated this method using phantoms and examined its possibility of estimating the absorption coefficients of the tissues in human heads. In the case of a homogeneous plastic phantom (polyacetal block), the absorption coefficient estimated by our method agreed well with that obtained by a conventional method. Also, in the case of two-layered phantoms, our method successfully estimated the absorption coefficients of the two layers. Furthermore, the absorption coefficients of the extracerebral and cerebral tissue inside human foreheads were estimated under the assumption that the human heads were two-layered media. It was found that the absorption coefficients of the cerebral tissues were larger than those of the extracerebral tissues.

A mechanism for low penetrance in an ALS family with a novel SOD1 deletion.

BACKGROUND: About 20% of familial amyotrophic lateral sclerosis (ALS) is caused by mutations in SOD1 and is typically transmitted as an autosomal dominant trait. However, due to reduced mutation penetrance, the disease may present in a recessive or sporadic manner. OBJECTIVE: To determine the factors responsible for the low penetrance of the SOD1 mutation. METHODS: Twelve members of a Canadian ALS family of Filipino origin were recruited for the study. SOD1 was sequenced in the proband. SOD1 expression was assessed by real-time-PCR and immunoblotting. RESULTS: The proband was a homozygous carrier of a novel 6 bp deletion in exon 2 (DeltaG27/P28), the pathologic significance of which was confirmed by immunohistochemistry. Eight living family members are heterozygotes and remain unaffected at ages ranging between 48 and 85 years. Haplotype analysis showed that the deletion is a single founder mutation likely common in the Cagayan province (Philippines). The low penetrance of the mutation is explained by the fact that it enhances the naturally occurring alternative splicing of exon 2 of the SOD1 mRNA, leading to reduced transcription of the mutant allele. Indeed, Western blot analysis demonstrated the low level of SOD1 protein in carriers of the DeltaG27/P28 compared to wild-type individuals or a carrier of the A4V SOD1 mutation. CONCLUSION: The enhanced splicing of exon 2 acts as a natural knock-down of the mutant SOD1 allele in the Filipino amyotrophic lateral sclerosis (ALS) family. There is a need for careful investigation of splicing isoforms of SOD1 and other ALS genes as factors influencing the severity of disease.

Heterogeneity within a large kindred with frontotemporal dementia: a novel progranulin mutation.

BACKGROUND: Frontotemporal dementia (FTD) in several 17q21-linked families was recently explained by truncating mutations in the progranulin gene (GRN). OBJECTIVE: To determine the frequency of GRN mutations in a cohort of Caucasian patients with FTD without mutations in known FTD genes. METHODS: GRN was sequenced in a series of 78 independent FTD patients including 23 familial subjects. A different Calabrian dataset (109 normal control subjects and 96 FTD patients) was used to establish the frequency of the GRN mutation. RESULTS: A novel truncating GRN mutation (c.1145insA) was detected in a proband of an extended consanguineous Calabrian kindred. Segregation analysis of 70 family members revealed 19 heterozygous mutation carriers including 9 patients affected by FTD. The absence of homozygous carriers in a highly consanguineous kindred may indicate that the loss of both GRN alleles might lead to embryonic lethality. An extremely variable age at onset in the mutation carriers (more than five decades apart) is not explained by APOE genotypes or the H1/H2 MAPT haplotypes. Intriguingly, the mutation was excluded in four FTD patients belonging to branches with an autosomal dominant mode of inheritance of FTD, suggesting that another novel FTD gene accounts for the disease in the phenocopies. It is difficult to clinically distinguish phenocopies from GRN mutation carriers, except that language in mutation carriers was more severely compromised. CONCLUSION: The current results imply further genetic heterogeneity of frontotemporal dementia, as we detected only one GRN-linked family (about 1%). The value of discovering large kindred includes the possibility of a longitudinal study of GRN mutation carriers.

Subcutaneous administration of lactone form of simvastatin stimulates ectopic osteoinduction by rhBMP-2.

OBJECTIVE: To evaluate the effects of various 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) on ectopic osteoinduction by recombinant human bone morphogenetic protein-2 (rhBMP-2) using different administration methods. MATERIALS AND METHODS: Disks containing 5 mug of rhBMP-2 and type I collagen were implanted into the calf muscles of 6-week-old male rats (n = 64). Either the lactone form of simvastatin (SV), open hydroxy-acid form of simvastatin (SVA), cerivastatin (CVA), or vehicle (control) was then administered per orally (PO group) or subcutaneously (SC group) for 20 days. The disks were removed on day 21 after implantation, and ectopic induced bone formation was evaluated by radiographic, histologic, and biochemical analysis. RESULTS: Both the projected and radiopaque area on X-ray film, and the calcium content of the SV group in the SC group (SV-SC group) were significantly greater than those in the other SC and PO groups. Alkaline phosphatase activity and tartrate-resistant acid phosphatase activity in the SV-SC group were significantly lower than those in the other SC and PO groups. Histologic examination revealed an increase of ectopic induced bone volume in the SV-SC group. CONCLUSION: Subcutaneous administration of SV stimulates ectopic osteoinduction by rhBMP-2 through reduction of bone turnover.

Cabergoline scavenges peroxynitrite enhanced by L-DOPA therapy in patients with Parkinson's disease.

Long-term or high-dose L-DOPA therapy in patients with Parkinson's disease (PD) may accelerate degeneration of dopaminergic neurons, possibly by increasing oxidative stress. To investigate the effects of cabergoline on peroxynitrite-mediated oxidative damage caused by L-DOPA, the concentration of 3-nitrotyrosine in cerebrospinal fluid (CSF) of 18 PD patients was compared with that in 20 normal controls. The concentration of 3-nitrotyrosine in patients following L-DOPA therapy was significantly higher than in untreated PD patients and controls. On the other hand, the concentration in PD patients after cabergoline therapy was significantly lower than in PD patients after L-DOPA therapy alone. These data suggest that cabergoline scavenges peroxynitrite induced by L-DOPA in patients with PD.

LRRK2 gene in Parkinson disease: mutation analysis and case control association study.

BACKGROUND: In addition to the four well-confirmed genes linked to early-onset Parkinson disease (PD) (SNCA, PARKIN, DJ-1, and PINK1), mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have recently been identified in families with autosomal dominant late-onset PD. OBJECTIVE: To perform mutation analysis of LRRK2 in probands of families showing dominant inheritance of PD and to conduct a case control association study to test the hypothesis that common coding variations might be associated with increased susceptibility to PD. METHODS: All 51 LRRK2 coding exons were sequenced in 23 probands and the mutation frequencies were evaluated in 180 neurologically normal control subjects. For the association study the authors genotyped four coding LRRK2 polymorphisms in 250 normal control subjects and 121 patients with PD (predominantly white patients of Canadian origin), 84% of whom had age at onset before 50 years and 42% had a positive family history. RESULTS: The authors identified three probands with heterozygous LRRK2 mutations: two of them have the known G2019S substitution and one proband has a novel I1371V substitution. Mutation analysis of a large family demonstrated complete segregation of the G2019S with PD. However, there was no association between PD and any of the four polymorphisms at the allelic or genotypic levels (p > 0.17). Furthermore, the authors did not detect a modifying effect for any genotype or of APOE genotypes upon the age at onset in the PD group (p > 0.20). CONCLUSIONS: The results support the prior suggestion that LRRK2 mutations cause PD. The disease in the families reported here presents a phenotype indistinguishable from typical PD. All three families demonstrate a very variable age at onset that is not explained by APOE genotypes. The common coding variations in the LRRK2 gene neither constitute strong PD risk factors nor modify the age at onset; however, the possibility of a modest risk effect remains to be assessed in large datasets.

Characteristic sequence changes of hepatitis C virus genotype 2b associated with sustained biochemical response to IFN therapy.

In hepatitis C virus (HCV) genotype 2b infection, viral eradication (sustained viral response; sVR) is obtained in about 40% by interferon monotherapy, whereas a considerable proportion of non-sVR patients exhibit sustained biochemical response (sBR) showing normal biochemical values despite persistent viraemia. However, the mechanism of sBR has not yet been established. In this study, we analysed serial changes in full-length sequences of HCV genotype 2b before and after interferon (IFN) therapy in five patients with sBR and five with no response (NR; persistent viraemia and abnormal biochemical values after IFN therapy). The overall substitution rate of amino acids in the full-length HCV genome was higher in the sBR group than in the NR group [2.22 +/- 0.48 (10(-3) changes/site/year) vs 1.04 +/- 0.30: P = 0.002]. When the genetic changes were analysed for individual HCV proteins, the sBR group had significantly higher substitution rates of amino acid in NS4A [8.82 +/- 2.80 (10(-3) changes/site/year) vs 0: P = 0.001]. These amino acid changes in sBR were mainly located in the binding motifs of HLA class I molecules including those frequently found in the Japanese population. These results demonstrated that the greater amino acid changes of HCV arising during interferon therapy are associated with the establishment of sBR. Although functional significance of these changes awaits further investigation, the finding that amino acid changes in NS4A in sBR patients are mainly located in the HLA class I binding motifs illustrated the potential roles of the escape mutations of HCV genome from CTLs in the decreasing activities of hepatitis in sBR.

Distribution of estrogen, nonylphenol and its derivatives in the sediments of a shallow lake.

To determine the distribution of endocrine disruptors (EDs) in lake water and sediments, field investigation was conducted in Lake Teganuma, which is a shallow eutrophic lake, highly affected by human activities. Concentration profiles with sediment depths were obtained for estrogens, nonylphenol (NP), nonylphenol ethoxylates (NPnEO), and nonylphenoxy acetic acids (NPnEC). 17beta-Estradiol (E2) was rarely detected, and 17alpha-ethynylestradiol (EE2) and estriol (E3) were undetected at all depths (0-98 cm) in any of the sediment core samples. The sediment concentrations of estrone (E1) ranging from <0.05 to 3.5 microg/kg-dry wt. and NP from 11.8 microg/kg-dry wt. to 21 mg/kg-dry wt. were obtained. The maximum concentrations of NPnEO and NPnEC in the core sediments were 2.5 mg/kg-dry wt. and 1.4 mg/kg-dry wt., respectively. The EDs concentrations are higher at the inlet than at the outlet (except for NP) in the sediments near the surface. The longitudinal distributions of E1, NPnEO and NPnEC in the benthic sediments show that the concentrations are highest at the inlet, and are fairly constant at lower levels towards the downstream. The obtained results also indicate that NP tends to be adsorbed to the organic particulates produced by algae, followed by sedimentation near the outlet of the lake.