Efficacy of 1-kestose supplementation in patients with mild to moderate ulcerative colitis: A randomised, double-blind, placebo-controlled pilot study.

BACKGROUND: Ulcerative colitis involves an excessive immune response to intestinal bacteria. Whether administering prebiotic 1-kestose is effective for active ulcerative colitis remains controversial. AIMS: This randomised, double-blind, placebo-controlled pilot trial investigated the efficacy of 1-kestose against active ulcerative colitis. METHODS: Forty patients with mild to moderate active ulcerative colitis were randomly treated with 1-kestose (N = 20) or placebo (maltose, N = 20) orally for 8 weeks in addition to the standard treatment. The Lichtiger clinical activity index and Ulcerative Colitis Endoscopic Index of Severity were determined. Faecal samples were analysed to evaluate the gut microbiome and metabolites. RESULTS: The clinical activity index at week 8 was significantly lower in the 1-kestose group than in the placebo group (3.8 ± 2.7 vs. 5.6 ± 2.1, p = 0.026). Clinical remission and response rates were higher in the 1-kestose group than in the placebo group (remission: 55% vs. 20%, p = 0.048; response: 60% vs. 25%, p = 0.054). The Ulcerative Colitis Endoscopic Index of Severity at week 8 was not significantly different (2.8 ± 1.6 vs. 3.5 ± 1.6, p = 0.145). Faecal analysis showed significantly reduced alpha-diversity in the 1-kestose group, with a decreased relative abundance of several bacteria, including Ruminococcus gnavus group. The short-chain fatty acid levels were not significantly different between the groups. The incidence of adverse events was comparable between the groups. DISCUSSION: Oral 1-kestose is well tolerated and provides clinical improvement for patients with mild to moderate ulcerative colitis through modulation of the gut microbiome.

Astaxanthin Attenuates Nonalcoholic Steatohepatitis with Downregulation of Osteoprotegerin in Ovariectomized Mice Fed Choline-Deficient High-Fat Diet.

BACKGROUND: Postmenopausal estrogen decline increases the risk of developing nonalcoholic steatohepatitis (NASH), and it might accelerate progression to cirrhosis and hepatocellular carcinoma. AIMS: This study aimed to investigate a novel therapy for postmenopausal women who are diagnosed with NASH. METHODS: Seven-week-old female C57BL/6 J mice were divided into three experimental groups as follows: (1) sham operation (SHAM group), (2) ovariectomy (OVX group), and (3) ovariectomy + 0.02% astaxanthin (OVX + ASTX group). These three groups of mice were fed a choline-deficient high-fat (CDHF) diet for 8 weeks. Blood serum and liver tissues were collected to examine liver injury, histological changes, and hepatic genes associated with NASH. An in vitro study was performed with the hepatic stellate cell line LX-2. RESULTS: The administration of ASTX significantly improved pathological NASH with suppressed steatosis, inflammation, and fibrosis, in comparison with those in the OVX-induced estrogen deficiency group. As a result, liver injury was also attenuated with reduced levels of alanine aminotransferase and aspartate transaminase. In addition, our study found that ASTX supplementation decreased hepatic osteoprotegerin (OPG) in vivo, a possible factor that contributes to NASH development. In vitro, this study further confirmed that ASTX has an inhibitory effect on the secretion of OPG in LX-2 human hepatic stellate cells. CONCLUSIONS: Our findings suggest that ASTX alleviates CDHF-OVX-induced pathohistological NASH with downregulated OPG, possibly via suppression of the transforming growth factor beta pathway. ASTX could has promise for use in postmenopausal women diagnosed with NASH.

Safety and Efficacy of Glass Membrane Pumping Emulsification Device in Transarterial Chemoembolization for Hepatocellular Carcinoma: First Clinical Outcomes.

AIM: Novel glass membrane pumping emulsification devices (GMDs) enable the formation of a high-percentage water-in-oil emulsion with homogeneous and stable droplets. Although GMDs are expected to improve therapeutic effects in transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC), clinical outcomes are not yet available. PATIENTS AND METHODS: A total of 26 patients with unresectable HCC who underwent TACE using a GMD were analyzed retrospectively. Ethiodized oil was mixed with epirubicin solution using a GMD. The emulsion was injected into the tumor-feeding artery, followed by embolization. RESULTS: The median size of HCCs was 28 (range=15-60) mm, and 15 nodules were solitary. Overall treatment effects were complete response in 18 cases (90%) and partial response in two (10%). The local recurrence rate at 6 months was 24.2%. No major complication was observed except for grade 4 elevations of liver enzymes in one case. CONCLUSION: TACE using a GMD is effective and safe in clinical practice.

Transient deterioration of albumin-bilirubin scores in early post-dose period of molecular targeted therapies in advanced hepatocellular carcinoma with 50% or higher liver occupation: A STROBE-compliant retrospective observational study.

ABSTRACT: Real-world clinical cases of molecularly targeted agent (MTA) administration to patients with advanced hepatocellular carcinoma (HCC) with ≥50% liver occupation have been reported, but treatment outcomes have rarely been described. We have encountered several cases in which albumin-bilirubin (ALBI) scores deteriorated markedly and C-reactive protein (CRP) levels elevated in the early post-dose period. The present study therefore investigated early clinical changes in ALBI score and CRP levels after initiating MTA in advanced HCC patients with ≥50% liver occupation, focusing on antitumor response at 6 weeks.This retrospective study included 46 HCC patients with liver occupation ≥50% and 191 patients with <50%, Child-Pugh score ≤7, and Eastern Cooperative Oncology Group Performance Status scores of 0 or 1, who were treated with sorafenib or lenvatinib as first-line systemic therapy at our hospital between June 2011 and January 2020. We analyzed their medical records up to March 2020 and investigated the outcomes and changes in CRP and ALBI scores classified according to antitumor response at 6 weeks.Overall survival was significantly longer in patients with partial response (PR) + stable disease (SD) (13.7 months) than in patients with progressive disease (PD) (1.7 months, P < .001) in the ≥50% group. Patients with antitumor response of PR + SD at 6 weeks in the ≥50% group showed more marked deterioration of ALBI score at 2 weeks than those in the <50% group. These significant differences between groups had again disappeared at 4 and 6 weeks. Focusing on patients with PD at 6 weeks, ALBI score deteriorated over time in both groups. Regarding CRP, on 6-week PR + SD patients, a significant increase in CRP levels at 1 and 2 weeks was evident in the >50% group compared to the <50% group. These significant differences between groups had again disappeared at 4 and 6 weeks. In PD patients, no difference between groups in CRP elevation occurred at 1 and 2 weeks.In MTA treatment for patients with ≥50% liver occupation, to obtain an antitumor response of PR + SD, adequate management might be important considering transient deteriorated ALBI scores and elevated CRP levels.

Efficacy and Safety of Sorafenib in Unresectable Hepatocellular Carcinoma with Bile Duct Invasion.

INTRODUCTION: Because the frequency of bile duct invasion in hepatocellular carcinoma (HCC) patients is very rare, there is limited clinical evidence to demonstrate the outcomes of systemic therapy in HCC with bile duct invasion. OBJECTIVE: Our aim was to clarify the efficacy and safety of sorafenib treatment in patients with unresectable advanced HCC with bile duct invasion. METHODS: One hundred and seventy-five patients with advanced HCC were enrolled in this study. We retrospectively compared the outcomes of sorafenib between patients without bile duct invasion [B (-) group, n = 165] and those with bile duct invasion [B (+) group, n = 10]. RESULTS: There were no significant differences in the confirmed objective response rate (ORR) and the confirmed disease control (DC) rate between the B (-) and the B (+) groups (13.9 vs. 20.0%, p = 0.637 for ORR; 47.2 vs. 70.0%, p = 0.202 for DC rate, respectively). There were no significant differences in median overall survival (OS) and time to progression (TTP) between the B (-) group and the B (+) group (14.8 vs. 14.1 months, p = 0.780 for OS; 3.4 vs. 5.7 months, p = 0.277 for TTP, respectively). Post-treatment factors associated with good OS were changes in albumin-bilirubin score (0-6 weeks) of <0.25, and antitumor response at 6 weeks of DC. Though 5 of 10 patients (50%) in the B (+) group had bile duct complications, such as obstructive jaundice and biliary bleeding, these 5 patients were able to recover from biliary troubles by careful and vigorous management with biliary endoscopic intervention, and were able to continue sorafenib therapy safely. CONCLUSIONS: Our present results suggest that sorafenib might have potential therapeutic efficacy and safety in advanced HCC patients with bile duct invasion. In case of biliary tract troubles before and during sorafenib treatment, early biliary management may be important to continue sorafenib therapy safely. Further studies are needed to confirm the outcomes of sorafenib in advanced HCC patients with bile duct invasion.

Sorafenib vs. Lenvatinib as First-line Therapy for Advanced Hepatocellular Carcinoma With Portal Vein Tumor Thrombosis.

BACKGROUND/AIM: We aimed to compare the outcomes between sorafenib and lenvatinib as first-line therapy for advanced hepatocellular carcinoma (HCC) with major portal vein tumor thrombosis (Vp3/4). PATIENTS AND METHODS: This retrospective study enrolled 41 HCC patients with Vp3/4 and Child-Pugh A. RESULTS: The outcomes in the lenvatinib group (n=13) were significantly better than those in the sorafenib group (n=28) [best objective response rate according to the modified Response Evaluation Criteria in Solid Tumors: 53.8% vs. 14.3%; p=0.0193, best disease control rate: 92.3% vs. 35.7%; p=0.0008, median overall survival (OS): not reached vs. 187 days; p=0.0040, respectively]. Lenvatinib treatment was the only significant predictor of better OS and time to tumor progression. No patient needed to discontinue lenvatinib treatment due to drug-related adverse events. CONCLUSION: Compared with sorafenib, lenvatinib treatment for advanced HCC with Vp3/4 may lead to more favorable outcomes.

Complete response of advanced hepatocellular carcinoma achieved by sorafenib dose re-escalation after failure of long-term low-dose-sorafenib treatment combined with transcatheter arterial chemoembolization: a case report.

Few reports have described dose re-escalation after long-term low-dose sorafenib leading to good outcomes. Here, we report the case of an 80-year-old woman with advanced hepatocellular carcinoma who achieved complete response from sorafenib dose re-escalation after the failure of long-term low-dose sorafenib treatment combined with transcatheter arterial chemoembolization. Sorafenib therapy was initiated at 400 mg once daily due to old age and low platelet count. 5 months later, this dose was reduced to 200 mg once daily because of adverse events. Best radiological antitumor response by sorafenib treatment alone was judged as stable disease according to the modified Response Evaluation Criteria in Solid Tumors. 1 year later, she showed progressive disease owing to the progression of intrahepatic lesions. She received combination therapy with low-dose sorafenib (200 mg every other day) and transcatheter arterial chemoembolization, which proved relatively effective for three and a half years. Antitumor response by the fourth transcatheter arterial chemoembolization and subsequent low-dose sorafenib was clearly progressive disease. At that time, sorafenib-related adverse events were well-controlled. Sorafenib dose was re-escalated to 200 mg once daily. After this re-escalation, tumor markers declined rapidly, and adverse events remained tolerable. 4 months later, complete response was achieved.

Successful Treatment of Hepatocellular Carcinoma with Regorafenib after Sorafenib-induced Hypersensitivity.

Sorafenib and regorafenib are tyrosine kinase inhibitors that are used in the treatment of hepatocellular carcinoma and which have similar chemical structures and toxicity profiles. We herein report a case in which regorafenib treatment could be continued for 10 months and stable disease could be maintained for a long period despite the discontinuation of sorafenib due to grade 4 liver injury and grade 3 fever. The severe adverse events could be attributed to drug hypersensitivity, since a drug-induced lymphocyte stimulation test (DLST) indicated sensitivity to sorafenib. A DLST for regorafenib was negative. This is the first report showing that regorafenib could be safely administered after the discontinuation of sorafenib due to hypersensitivity.

Antifibrotic Effects of 1,25(OH)2D3 on Nonalcoholic Steatohepatitis in Female Mice.

BACKGROUND: Postmenopausal women have a higher risk of nonalcoholic steatohepatitis (NASH) along with an increase in age, and vitamin D deficiency occurs in some patients with NASH. AIM: We performed ovariectomy (OVX) surgery on female mice to mimic menopause, fed them a choline-deficient high-fat (CDHF) diet to induce NASH, and then investigated the effects of treatment with 1,25(OH)2D3. METHODS: Seven-week-old C57BL/6J female mice were separated into five experimental groups: SHAM, OVX, and OVX + intraperitoneal (i.p.) injection of 1,25(OH)2D3 (0.0008, 0.004, and 0.02 µg/kg). All groups were fed a CDHF diet for 8 weeks. Injections took place twice per week throughout the experimental period. Blood samples and liver tissue were collected for analyzing liver histological changes, serum biochemical indicators of hepatic function, and hepatic genes associated with fibrosis. RESULTS: Supplementation of 1,25(OH)2D3 in CDHF-diet mice showed decreased serum levels of ALT, AST, indicating the improvement in overall liver function, and suppressed histological NASH regarding fibrosis stage, lobular inflammation, and steatosis compared to the OVX group. Primary fibrotic markers of TGF-ß, TIMP-1, α-SMA, and COL1A1 were significantly lower in the 1,25(OH)2D3 groups than in the OVX group. Furthermore, down-regulated levels of SMAD2 and SMAD3 were also observed in 1,25(OH)2D3 groups. CONCLUSION: Supplementation of 1,25(OH)2D3 may ameliorate liver fibrosis and improve liver function in OVX mice with NASH induced by a CDHF diet, suggesting the therapeutic effects on postmenopause with NASH.

Prognostic Factors Associated with Postprogression Survival in Advanced Hepatocellular Carcinoma Patients Treated with Sorafenib Not Eligible for Second-Line Regorafenib Treatment.

OBJECTIVES: The aim of this study was to investigate the prognostic factors associated with postprogression survival (PPS) in advanced hepatocellular carcinoma (HCC) patients treated with sorafenib, who were not eligible for second-line treatment with regorafenib. METHODS: A total of 103 patients with radiological confirmation of progressive disease (PD) were enrolled. RESULTS: The median PPS (n = 67) was 6.1 months. Significant and independent prognostic factors at initial radiological PD associated with good PPS were an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score of 0, the absence of macrovascular invasion (MVI), and time to progression (TTP) ≥4 months. Upon scoring these three variables as good PPS factors, the median PPS in the good PPS score of 3 or 2 group (n = 38) was significantly longer than that in the good PPS score of 1 or 0 group (n = 29) (16.6 vs. 2.9 months; p < 0.0001, respectively). CONCLUSIONS: An ECOG-PS score of 0, the absence of MVI, and TTP ≥4 months at first radiological confirmation of PD may be useful for predicting good PPS in patients with advanced HCC who do not meet the eligibility criteria for the RESORCE trial.

Large-moment antiferromagnetic order in overdoped high-Tc superconductor 154SmFeAsO1-x D x.

In iron-based superconductors, high critical temperature (Tc) superconductivity over 50 K has only been accomplished in electron-doped hREFeAsO (hRE is heavy rare earth (RE) element). Although hREFeAsO has the highest bulk Tc (58 K), progress in understanding its physical properties has been relatively slow due to difficulties in achieving high-concentration electron doping and carrying out neutron experiments. Here, we present a systematic neutron powder diffraction study of 154SmFeAsO1-x D x , and the discovery of a long-range antiferromagnetic ordering with x ≥ 0.56 (AFM2) accompanying a structural transition from tetragonal to orthorhombic. Surprisingly, the Fe magnetic moment in AFM2 reaches a magnitude of 2.73 µB/Fe, which is the largest in all nondoped iron pnictides and chalcogenides. Theoretical calculations suggest that the AFM2 phase originates in kinetic frustration of the Fe-3dxy orbital, in which the nearest-neighbor hopping parameter becomes zero. The unique phase diagram, i.e., highest-Tc superconducting phase adjacent to the strongly correlated phase in electron-overdoped regime, yields important clues to the unconventional origins of superconductivity.

Branched-chain amino acids alleviate hepatic steatosis and liver injury in choline-deficient high-fat diet induced NASH mice.

BACKGROUND: For successful treatment for nonalcoholic steatohepatitis (NASH), it may be important to treat the individual causative factors. At present, however, there is no established treatment for this disease. Branched-chain amino acids (BCAAs) have been used to treat patients with decompensated cirrhosis. AIM: In order to elucidate the mechanisms responsible for the effects of BCAAs on hepatic steatosis and disease progression, we investigated the effects of BCAA supplementation in mice fed a choline-deficient high-fat diet (CDHF), which induces NASH. METHODS: Male mice were divided into four groups that received (1) choline-sufficient high fat (HF) diet (HF-control), (2) HF plus 2% BCAA in drinking water (HF-BCAA), (3) CDHF diet (CDHF-control), or (4) CDHF-BCAA for 8weeks. We monitored liver injury, hepatic steatosis and cholesterol, gene expression related to lipid metabolism, and hepatic fat accumulation. RESULTS: Serum alanine aminotransferase (ALT) levels and hepatic triglyceride (TG) were significantly elevated in CDHF-control relative to HF-control. Liver histopathology revealed severe steatosis, inflammation, and pericellular fibrosis in CDHF-control, confirming the NASH findings. Serum ALT levels and hepatic TG and lipid droplet areas were significantly lower in CDHF-BCAA than in CDHF-control. Gene expression and protein level of fatty acid synthase (FAS), which catalyzes the final step in fatty acid biosynthesis, was significantly decreased in CDHF-BCAA than in CDHF-control (P<0.05). Moreover, hepatic total and free cholesterol of CDHF-BCAA was significantly lower than those of CDHF-control. CONCLUSIONS: BCAA can alleviate hepatic steatosis and liver injury associated with NASH by suppressing FAS gene expression and protein levels.

Fever within 2 Weeks of Sorafenib Therapy Predicts Favorable Treatment Efficacy in Patients with Advanced Hepatocellular Carcinoma.

OBJECTIVES: The aim of this study was to investigate the relationship between fever within 2 weeks after the start of sorafenib therapy and treatment efficacy in patients with advanced hepatocellular carcinoma (HCC). METHODS: One hundred and two patients with advanced HCC were enrolled in this study. We retrospectively compared patients with fever (more than 38°C) within 2 weeks after the start of sorafenib therapy (fever group, n = 34) and patients without fever (non-fever group, n = 68) in terms of survival, best antitumor response, and change in intratumor blood on contrast-enhanced computed tomography (CE-CT) after 2 weeks of sorafenib therapy. RESULTS: Fever was the only significant and independent predictor of better outcomes (hazard ratio, 0.517; 95% confidence interval, 0.319-0.838; p = 0.0071). In the fever group, the partial response rate, the disease control rate, and the rate of disappearance of arterial tumor enhancement on CE-CT after 2 weeks of sorafenib therapy were significantly higher than those in the non-fever group (38.2 vs. 5.9%, respectively, p = 0.0001; 85.3 vs. 60.3%, respectively, p = 0.0103; 76.5 vs. 35.3%, respectively, p < 0.0001). CONCLUSIONS: Fever within 2 weeks after the start of sorafenib therapy may be a useful predictor of a favorable treatment response in patients with advanced HCC.

Early Clinical Response after 2 Weeks of Sorafenib Therapy Predicts Outcomes and Anti-Tumor Response in Patients with Advanced Hepatocellular Carcinoma.

BACKGROUND & AIMS: We evaluated the relationship between the early clinical response after 2 weeks of sorafenib therapy and the outcomes and anti-tumor response in patients with advanced hepatocellular carcinoma. METHODS: Fifty-seven patients who had intrahepatic hypervascular hepatocellular carcinoma and Child-Pugh (CP) class A disease at baseline were enrolled in this prospective, multicenter, observational, non-interventional study. As an early clinical response after 2 weeks of sorafenib therapy, changes in intra-tumor blood flow on contrast-enhanced computed tomography (CE-CT), alpha-fetoprotein (AFP) levels, and remnant liver function were investigated. RESULTS: After 2 weeks of sorafenib therapy, there were 26 patients (45.6%) without disappearance of arterial tumor enhancement on CE-CT, 15 patients (26.3%) with an AFP ratio of >1.2, and seven patients (12.3%) with two or more increments in the CP score. Multivariate analysis showed that the absence of disappearance of arterial tumor enhancement on CE-CT, AFP ratio of >1.2, and two or more increments in the CP score after 2 weeks of sorafenib therapy were significant and independent predictors of worse survival. Upon scoring these three variables as "poor prognostic factors", patients with poor prognostic score 4, 3 or 2 (n = 17) had significantly worse outcomes and a significantly higher progressive disease (PD) rate based on modified Response Evaluation Criteria in Solid Tumors at 6 weeks after sorafenib therapy than those with poor prognostic score 1 or 0 (n = 40) (median overall survival: 194 days vs. 378 days; p = 0.0010, PD rate: 70.6% vs. 20.0%; p = 0.0003, respectively). CONCLUSIONS: Changes in intra-tumor blood flow on CE-CT, AFP levels, and remnant liver function after 2 weeks of sorafenib therapy may be useful for predicting the outcomes and anti-tumor response to sorafenib in patients with advanced hepatocellular carcinoma.

Thiamine-deficient encephalopathy due to excessive intake of isotonic drink or overstrict diet therapy in Japanese children.

AIM: To report on two children with encephalopathy caused by dietary thiamine deficiency due to newly developing nutritional problems in contemporary Japan. SUBJECTS: A 1-year-old boy who had consumed 1l of isotonic drinks per day for 4 months after an episode of diarrhea, and presented with ocular movement disorder, dystonia, and unconsciousness. The other subject was an 11-month-old boy who suffered from vomiting and somnolence; he and his mother had atopic dermatitis, and he had been on a low-allergen diet that strictly restricted intake of eggs, dairy products, meat, and fish since his early infancy. RESULTS: Both patients showed decreased blood thiamine levels and magnetic resonance imaging revealed striatal and thalamic lesions. Thiamine administration yielded prompt improvement of symptoms, but cavitiform lesions in the bilateral putamen persisted in the first patient, accompanied by residual generalized dystonia. Marked elevation of blood/cerebrospinal lactate levels and severe hyponatremia were present in this patient. CONCLUSION: Thiamine-deficient encephalopathy in Japanese children due to excessive intake of sports drink or overstrict diet therapy for atopic dermatitis has been increasingly reported during the last decade, but is still not broadly recognized. These children may visit hospitals due to persistent vomiting as a symptom of thiamine deficiency, but glucose infusion without thiamine supplementation can aggravate their condition. Knowledge of these facts in medical and public settings is necessary to correct the erroneous impression that nutritional options given to ill children are necessarily beneficial for health, and promote awareness that they can be harmful when consumed in excess.

PCBs and PCDD/DFs in waste oil illegally dumped and neglected for more than 20 years.

Quantification of polychlorinated biphenyls (PCBs), polychlorinated-dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) in waste oil by high resolution gas chromatography-high resolution mass spectrometry (HRGC-HRMS), and profiling of their congeners and homologues were described. Waste oil packed in drums which were estimated to have been exposed to the weather for more than 20 years were found by the illegal dumping patrol in 2006. PCBs were detected in all of 12 waste oil samples examined, with concentrations in the range of 0.0032-22 microg/g. The main pollution sources of the waste oil samples were presumed to be KC300, KC400 and/or KC500 by principal component analysis (PCA) and a chemical mass balance (CMB) method. The concentrations of PCDDs and PCDFs (PCDD/DFs) in the illegally dumped waste oil ranged from 1.1 to 360 pg/g and 1.3 to 110 pg/g, respectively. The ratios of toxicity equivalency quantity (TEQ) of PCDDs and PCDFs to Co-PCBs were lower than those of Yusho rice oil. Consequently, it was determined that even after 20 years of exposure to the weather, no PCB denaturation occurred. However, it was confirmed that low-chlorinated biphenyls in corroded drums would have evaporated into the atmosphere.

Spatial and topologic distribution of verapamil-sensitive atrial tachycardia originating from the vicinity of the atrioventricular node.

BACKGROUND: Little information exists regarding the precise distribution of verapamil-sensitive atrial tachycardia originating from the vicinity of the atrioventricular node (V-AT). METHODS: In 12 patients with V-AT, we examined the spatial and topologic distribution of tachycardia origin relative to the His bundle (HB) site. The V-AT origin was divided into six areas: anterior (A-HB), posterior (P-HB), superior (S-HB), inferior (I-HB), lateral (L-HB), and septal (SP-HB) portion of HB catheter. Three dimensional distance between the distal pair of the electrodes of HB catheter and that of V-AT origin (DIS) was obtained by calculating the distances on the right and left anterior fluoroscopic images. Topologic distribution was expressed as the interval between the onset of the atrial electrogram of V-AT origin and that of HB catheter (INT). RESULTS: The tachycardia origin was observed at the P-HB in four, S-HB in two, I-HB in two, SP-HB in three, and L-HB in one patient. The tachycardia cycle length, DIS, and INT were 369 +/- 67 ms, 12 +/- 3 mm, and -12 +/- 8 ms, respectively. After successful ablation of initial V-AT (1st V-AT), V-AT with a different origin (2nd V-AT) was induced in five patients. The tachycardia origin, tachycardia cycle length, DIS, and INT of the 2nd V-AT (P-HB in three, S-HB in one, and SP-HB in one patient; 333 +/- 66 ms, 8 +/- 3 mm, and -11 +/- 4 ms, respectively) were not different from those of 1st V-AT. CONCLUSIONS: V-AT often shows a shift in tachycardia origin to another site where the spatial and topologic distributions are similar to those of 1st V-AT.

Mutations in carboxy-terminal part of E2 including PKR/eIF2alpha phosphorylation homology domain and interferon sensitivity determining region of nonstructural 5A of hepatitis C virus 1b: their correlation with response to interferon monotherapy and viral load.

AIM: To study the amino acid substitutions in the carboxy (C)-terminal part of E2 protein and in the interferon (IFN) sensitivity determining region (ISDR) and their correlation with response to IFN and viral load in 85 hepatitis C virus (HCV)-1b-infected patients treated with IFN. METHODS: The C-terminal part of E2 (codons 617-711) including PKR/eIF2alpha phosphorylation homology domain (PePHD) and ISDR was sequenced in 85 HCV-1b-infected patients treated by IFN monotherapy. RESULTS: The amino acid substitutions in PePHD detected only in 4 of 85 patients were not correlated either with response to IFN or with viral load. The presence of substitutions in a N-terminal variable region (codons 617-641) in the C-terminal part of E2 was significantly correlated with both small viral load (33.9% vs 13.8%, P = 0.0394) and sustained response to IFN (25.0% vs 6.9%, P = 0.0429). Four or more substitutions in ISDR were significantly correlated with both small viral load (78.6% vs 16.2%, P < 0.0001) and sustained response to IFN (85.7% vs 2.9%, P < 0.0001). In multivariate analysis, ISDR in nonstructural (NS) 5A (OR = 0.39, P < 0.0001) and N-terminal variable region (OR = 0.51, P = 0.039) was selected as the independent predictors for small viral load, and ISDR (OR = 39.0, P < 0.0001) was selected as the only independent predictor for sustained response. CONCLUSION: The N-terminal variable region in the C-terminal part of E2 correlates with both response to IFN monotherapy and viral load and is one of the factors independently associated with a small viral load.

Nerve terminals extend into the temporomandibular joint of adjuvant arthritic rats.

The innervation of the temporomandibular joint (TMJ) has attracted particular interest because of the close association with complex mandibular movement. Although the pathological changes of disk innervation may have a crucial role in the development of TMJ pain, the innervation of the TMJ disk by experimentally induced arthritis has rarely been examined in detail. Arthritic rats were induced by injection with 0.1ml solution of Complete Freund's adjuvant (CFA). We investigated three-dimensional distribution of nerve fibers in the TMJ disk using immunohistochemistry for protein gene product-9.5 (PGP-9.5) and calcitonin gene-related peptide (CGRP) in naive and arthritic rats. To clarify the possible role of nerve growth factor (NGF) and its receptor on changes in peripheral innervation of the TMJ, the expressions of trkA and p75 receptor in trigeminal ganglia were examined. Although PGP-9.5 and CGRP immunoreactive (ir) fibers were seen in the peripheral part of the TMJ disk, they were not seen in its central part. The total length and the length density of PGP-9.5 ir and CGRP ir nerve fibers increased in arthritic rats. The innervation area of fibers proliferating in the rostro-medial part merged with that of fibers in the rostro-lateral part in the arthritic rats. In addition, the ratio of trkA- and p75-positive small- and medium-sized cells increased in trigeminal ganglia. It is assumed that increasing innervation of the TMJ disk may be important for the pathophysiology of TMJ pain. NGF and its receptors are likely involved in pathological changes of the TMJ disk.