Contralaterally-controlled functional electrical stimulation-induced muscle contraction for severe lower extremity paralysis.

[Purpose] We describe a new method of functional electrical stimulation therapy for severe hemiparesis. Conventional functional electrical stimulation of the lower legs has limited applications. It is only suitable for patients who can monitor their muscle contractions, and it has complicated equipment installation procedures. [Participant and Methods] The participant was a male in his 40s with severe motor paralysis following brain surgery. We monitored the participant's healthy side using the external assist mode of an Integrated Volitional Control Electrical Stimulation (IVES® OG Giken, Okayama, Japan) system while forcibly contracting the paralyzed side. The participant received this new functional electrical stimulation therapy five times per week. [Results] Two weeks after initiation of therapy, paralysis was noticeably improved, and motor function was maintained for approximately 1 year. [Conclusion] The outcomes of this case suggest that the addition of forced contraction therapy, mirror therapy, and repetitive exercise therapy to regular physical therapy may be beneficial. This treatment method may also be useful in postoperative patients with central motor palsy and no muscle contraction ability.

Isolated bilateral hypoglossal nerve paralysis following an atlanto-occipital dislocation: A case report.

The present report highlights a case of successful treatment of an 11-year-old male patient who presented with an atlanto-occipital dislocation and multiple fractures of the forearm, pelvis, and lower leg because of a fall. The patient experienced dysarthria and paralysis of the tongue, which became completely immobile and could not be moved from side to side, impeding speech. The patient also experienced dysphagia due to the inability to propel food toward the pharynx and chewing attempts resulted in scattering of food residue throughout the oral cavity. The lack of tongue mobility led to saliva accumulation, forcing the patient to swallow frequently, which was possible as larynx movement was unaffected. The other cranial and motor sensory nerves appeared normal. Our diagnostic examinations confirmed the presence of isolated bilateral paralysis of the hypoglossal nerve secondary to traction at the base of the skull. The patient was still unable to protrude his tongue and tongue gradually atrophied two weeks after admission. Electromyography revealed denervation of the tongue and minimal active contraction of the single motor units. Immobilization therapy and rehabilitation therapy were initiated to improve tongue movement, but this was unsuccessful and one month after the accident, the patient's tongue was still atrophied. The patient was placed on a soft food diet and experienced no difficulty in swallowing either saliva or food three months after admission. Tongue mobility was deemed normal. Electromyography six months after the initial episode revealed normal motor unit potentials during contractions. We postulate that compression and stretching of the bilateral hypoglossal nerves against the greater horn of the hyoid bone was a probable cause of the hypoglossal palsy. The use of immobilization and rehabilitation therapy likely supported the recovery of functionality and resulted in a good prognosis.

Case report: Unilateral masticatory atrophy caused by pure trigeminal motor neuropathy.

Pure trigeminal motor neuropathy (PTMN) is characterized by trigeminal motor weakness without signs of trigeminal sensory dysfunction or involvement of other cranial nerves. We describe a rare case of an 83-year-old man with weakness and atrophy of the right masticatory muscle without any sensory disturbance. Brain computed tomography and magnetic resonance imaging revealed atrophy and fatty infiltration of the right masticatory muscle. Electromyography revealed abnormal spontaneous activity, chronic neurogenic motor unit potentials, and reduced interference patterns in the right temporalis and the masseter muscles. The patient was diagnosed with PTMN based on the clinical symptoms and examinations. Our case presents a rare clinical manifestation with unclear etiology.

Time-course changes in liver functional reserve after successful sofosbuvir/velpatasvir treatment in patients with decompensated cirrhosis.

AIM: Direct-acting antivirals (DAAs) are currently available even for patients with decompensated cirrhosis. Reportedly, hepatic functional reserve improved in the short term after achievement of sustained virologic response (SVR). We aimed to clarify the outcomes after achievement of SVR in patients with decompensated cirrhosis who were treated by DAAs in real-world clinical practice. METHODS: A prospective, multicenter study of 12-week sofosbuvir/velpatasvir was conducted in 86 patients with decompensated cirrhosis, who were evaluated for 48 weeks post-treatment. RESULTS: The cohort included 8 patients with Child-Pugh class A, 56 with B, and 22 with C. The proportion of Child-Pugh class A patients increased from 9.1% at baseline to 44.1% at 48 weeks post-treatment, while that of class B and C patients decreased from 66.2% to 35.1% and from 24.7% to 14.3%, respectively. Among the patients with Child-Pugh class B and C, univariate analysis identified low total bilirubin, Child-Pugh score, Child-Pugh class B, ALBI score, and high serum albumin as factors associated with improvement to Child-Pugh class A. The optimal cut-off value of the factors for predicting improvement to Child-Pugh class A were 1.4 mg/dl for total bilirubin, 2.9 g/dl for serum albumin, 8 points for Child-Pugh score, and -1.88 for ALBI score. CONCLUSION: Achievement of SVR with sofosbuvir/velpatasvir improved the liver functional reserve at 12 weeks post-treatment and maintained the stable effects until 48 weeks post-treatment in patients with decompensated cirrhosis. Specifically, the patients with less advanced conditions had the likelihood of improving to Child-Pugh class A at 48 weeks post-treatment.

Safety and efficacy of the endoscopic delivery of capsule endoscopes in adult and pediatric patients: Multicenter Japanese study (AdvanCE-J study).

BACKGROUND AND AIM: We retrospectively determined the safety and efficacy of the endoscopic delivery (ED) of capsule endoscopes. METHODS: We enrolled 10,156 patients who underwent small bowel capsule endoscopy (SBCE), 3182 who underwent patency capsule (PC), and 1367 who underwent colon capsule endoscopy (CCE), at 11 gastroenterological and nine pediatric centers. RESULTS: Small bowel capsule endoscopies, PCs, and CCEs were endoscopically delivered to 546 (5.4%), 214 (6.7%), and 14 (1.0%) patients, respectively. Only mild complications occurred for 21.6% (167/774), including uneventful mucosal damage, bleeding, and abdominal pain. Successful ED of SBCE to the duodenum or jejunum occurred in 91.8% and 90.7% of patients aged <16 years and ≥16 years, respectively (P = 0.6661), but the total enteroscopy rate was higher in the first group (91.7%) than in the second (76.2%, P < 0.0001), for whom impossible ingestion (87.3%) was significantly more common than prolonged lodging in the stomach (64.2%, P = 0.0010). Successful PC and CCE delivery to the duodenum occurred in 84.1% and 28.6%, thereafter the patency confirmation rate and total colonoscopy rate was 100% and 61.5%, respectively. The height, weight, and age cutoff points in predicting spontaneous ingestion were 132 cm, 24.8 kg, and 9 years 2 months, respectively, in patients aged <16 years. Patients aged ≥16 years could not swallow the SBCEs mainly due to dysphagia (75.0%); those who retained it in the esophagus due to cardiac disease (28.6%), etc. and in the stomach due to diabetes mellitus (15.7%), etc. CONCLUSIONS: This large-scale study supports the safety and efficacy of ED in adult and pediatric patients. UMIN000042020.

Real-World Clinical Application of 12-Week Sofosbuvir/Velpatasvir Treatment for Decompensated Cirrhotic Patients with Genotype 1 and 2: A Prospective, Multicenter Study.

INTRODUCTION: Clinical trials of direct-acting antivirals for patients with decompensated cirrhosis have been conducted, but there is limited information on the medicinal applications in clinical settings. We aimed to evaluate the safety and efficacy of sofosbuvir/velpatasvir for decompensated cirrhotic patients with genotypes 1 and 2 in real-world clinical practice. METHODS: A prospective, multicenter study of 12-week sofosbuvir/velpatasvir was conducted for patients with decompensated cirrhosis at 33 institutions. RESULTS: The cohort included 71 patients (52 genotype 1, 19 genotype 2): 7 with Child-Pugh class A, 47 with class B, and 17 with class C (median score 8; range 5-13). The albumin-bilirubin (ALBI) score ranged from - 3.01 to - 0.45 (median - 1.58). Sixty-nine patients (97.2%) completed treatment as scheduled. The overall rate of sustained virologic response at 12 weeks post-treatment (SVR12) was 94.4% (67/71). SVR12 rates in the patients with Child-Pugh classes A, B, and C were 85.7%, 97.9%, and 88.2%, respectively. Among 22 patients with a history of hepatocellular carcinoma treatment, 20 (90.9%) achieved SVR12. The Child-Pugh score and ALBI grade significantly improved after achieving SVR12 (p = 7.19 × 10-4 and 2.42 × 10-4, respectively). Notably, the use of diuretics and branched-chain amino acid preparations significantly reduced after achieving SVR12. Adverse events were observed in 19.7% of the patients, leading to treatment discontinuation in two patients with cholecystitis and esophageal varices rupture, respectively. CONCLUSION: Twelve weeks of sofosbuvir/velpatasvir in real-world clinical practice yielded high SVR rates and acceptable safety profiles in decompensated cirrhotic patients with genotypes 1 and 2. Achievement of SVR not only restored the liver functional reserve but also reduced or spared the administration of drugs for related complications. TRIAL REGISTRATION: UMIN registration no, 000038587.

The effectiveness and safety of glecaprevir/pibrentasvir in chronic hepatitis C patients with refractory factors in the real world: a comprehensive analysis of a prospective multicenter study.

BACKGROUND: Direct-acting anti-virals (DAAs) have markedly improved the effectiveness of anti-viral therapy for chronic hepatitis C (CHC) patients. In a phase III trial in Japan, treatment with the NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir (G/P) resulted in a small number of patients with refractory factors. We aimed to evaluate the effectiveness and safety of G/P, especially among patients with these refractory factors, and the influence of these factors on treatment. METHODS: In a prospective, multicenter study involving 33 medical institutions, 1439 patients were treated with G/P, and their efficacy, safety, and most frequent adverse effects (AEs) were analyzed. RESULTS: Overall SVR12 rates were 99.1% (1397/1410) in the per-protocol-analysis, and genotype sustained virologic response SVR12 rates were: genotype 1, 99.4% (707/711); genotype 2, 99.4% (670/674); genotype 3, 80.0% (16/20). DAA-naïve patients (p = 0.008) with HCV genotype except 3 (genotype 1 vs. 3, p = 2.68 × 10-5; genotype 2 vs. 3, p = 3.28 × 10-5) had significantly higher SVR12 rates. No significant difference was observed between CKD stage 1-3 (99.1% [1209/1220]) and chronic kidney disease (CKD) stage 4-5 (98.9% [188/190]) patients, or between cirrhotic (99.0% [398/402]) and non-cirrhotic (99.1% [999/1008]) patients. Multiple logistic regression analysis revealed that genotype 3 [OR 33.404, 95% CI (7.512-148.550), p value (p = 4.06 × 10-5)] and past experience of IFN-free DAAs [OR 3.977, 95% CI (1.153-13.725), p value (p = 0.029)] were both significantly independent predictors of non-SVR12. AEs were reported in 28.2% of patients, and 1.6% discontinued treatment owing to drug-related AEs. AEs were significantly higher in CKD stage 4-5 (41.6% [79/190]) than CKD stage 1-3 (26.1% [319/1220]) patients (p = 2.00 × 10-5). AEs were also significantly higher in cirrhotic (38.6% [155/402]) than in non-cirrhotic (24.1% [243/1008]) (p = 2.91 × 10-18) patients. CONCLUSIONS: G/P regimen is highly effective and safe to treat CHC patients even with refractory factors such as CKD and advanced liver fibrosis. However, patients with past experience of IFN-free DAA treatment and genotype 3, CKD stage 4 or 5, and advanced liver fibrosis should be more closely observed.

Clinical Factors Associated with Missing Colorectal Polyp on Colon Capsule Endoscopy.

BACKGROUND: There are a number of reports that demonstrate the high diagnostic accuracy of colon capsule endoscopy (CCE) for polyp detection. However, some colorectal polyps are missed on CCE, and the clinical factors influencing those missed polyps are still unknown. OBJECTIVE: The aim of this study was to elucidate the clinical factors related to missing colorectal polyp on CCE by using per-polyp analysis. METHODS: We performed a retrospective multi-center study of 53 consecutive patients who underwent both CCE and colonoscopy (CS) within 3 months from January 2014 to -December 2017. Of those patients, we analyzed 151 polyps detected on CCE, and 149 polyps detected on CS diagnosed as neoplasm according to histopathological result. RESULTS: The capsule excretion rate was 81%. One hundred three polyps were detected on both CS and CCE, 46 polyps (31%) were missed on CCE, and 48 polyps were considered false positive on CCE when CS result was considered as the gold standard. Per-polyp sensitivity and positive predictive value on CCE were 69.1 and 68%. On multiple logistic analysis, only the segmental transit time on CCE was identified as the independent factor influencing missed polyp on CCE. CONCLUSIONS: The clinical factor related to missing colorectal polyp on CCE was the segmental transit time.

The efficacy and safety of glecaprevir plus pibrentasvir in 141 patients with severe renal impairment: a prospective, multicenter study.

BACKGROUND: Patients with chronic hepatitis C are often complicated by chronic kidney disease (CKD). AIM: To evaluate the efficacy, safety and pharmacokinetics of glecaprevir/pibrentasvir in patients with severe renal impairment. METHODS: In a prospective, multicentre study involving 35 medical institutions, 832 genotype 1-3 patients were treated with glecaprevir/pibrentasvir. The efficacy and safety of glecaprevir/pibrentasvir were analysed for patients with CKD stage 4 or 5. Multivariate analysis was performed to identify the factors associated with the most frequently observed adverse event. In patients undergoing haemodialysis, a pharmacokinetic study was conducted to investigate the dialysability of the drugs: plasma samples were obtained from the arterial and venous sides of a dialyser to serially measure drug concentrations. RESULTS: The subjects comprised 141 patients (32 with CKD stage 4 and 109 with CKD stage 5), of whom 100 were undergoing haemodialysis. All but one stage 5 CKD patients undergoing haemodialysis achieved sustained virologic response (99.3%). Adverse events were observed in 39.7% of subjects: pruritus was the most frequent (30.5%), and was significantly associated with haemodialysis. In the pharmacokinetic study, no arterial-venous differences in the plasma concentrations of glecaprevir/pibrentasvir were detected during the haemodialysis sessions. CONCLUSIONS: Glecaprevir/pibrentasvir was highly effective and safe in chronic hepatitis C patients with severe renal impairment. Haemodialysis was associated with increased incidence of pruritus, which was the most frequent adverse event, but had little or no influence on the drug concentrations, which indicated that their dialysability is very low and that no dose modification is required in patients undergoing haemodialysis. (UMIN registration no. 000032073).

Multicenter feasibility study of bowel preparation with castor oil for colon capsule endoscopy.

BACKGROUND AND AIM: Extensive use of laxatives and incomplete excretion rates are problematic for colon capsule endoscopy (CCE). The aim of the present study was to determine the effectiveness of castor oil as a booster. METHODS: At four Japanese hospitals, 319 examinees undergoing CCE were enrolled retrospectively. Before and after the introduction of castor oil, other preparation reagents were unchanged. RESULTS: Of 319 examinees who underwent CCE, 152 and 167 examinees took regimens with castor oil (between November 2013 and June 2016) and without castor oil (between October 2015 and September 2017), respectively. Capsule excretion rates within its battery life in the groups with and without castor oil were 97% and 81%, respectively (P < 0.0001). Multivariate analysis showed that ages younger than 65 years (adjusted odds ratio [OR], 3.00; P = 0.0048), male gender (adjusted OR, 3.20; P = 0.0051), and use of castor oil (adjusted OR, 6.29; P = 0.0003) were predictors of capsule excretion within its battery life. Small bowel transit time was shorter and total volume of lavage and fluid intake was lower with castor oil than without (P = 0.0154 and 0.0013, respectively). Overall adequate cleansing level ratios with and without castor oil were 74% and 83%, respectively (P = 0.0713). Per-examinee sensitivity for polyps ≥6 mm with and without castor oil was 83% and 85%, respectively, with specificities of 80% and 78%, respectively. CONCLUSION: Bowel preparation with castor oil was effective for improving capsule excretion rate and reducing liquid loading.

Multicenter study of pegylated interferon α-2a monotherapy for hepatitis C virus-infected patients on hemodialysis: REACH study.

Many studies have reported poor vital prognosis in hepatitis C virus (HCV)-infected dialysis patients. The rate of HCV-infected dialysis patients in Japan is as high as 9.8%, and antiviral therapy is believed to be important for improving vital prognosis. We conducted a multicenter study to examine the administration method for pegylated interferon α-2a (PEG-IFNα-2a) monotherapy in HCV-infected dialysis. We studied 56 patients: 14 with low viral loads (HCV RNA < 5.0 log IU/mL) were treated with 90 µg PEG-IFNα-2a weekly, 42 with high viral loads (HCV RNA ≥ 5.0 log IU/mL) were treated with 135 µg PEG-IFNα-2a weekly. We examined the sustained virological response (SVR), factors affecting the SVR, and treatment safety. The overall SVR rate was 39% (22/56); that for genotype 1, genotype 2, low viral loads, and high viral loads was 29%, 67%, 93%, and 21%, respectively. From receiver operating characteristic (ROC) analysis, the HCV RNA cutoff values likely to achieve SVR for genotypes 1 and 2 were <5.7 log IU/mL (SVR rate: 64% 9/14) and <6.5 log IU/mL (SVR rate: 88% 7/8), respectively. If there was HCV RNA negativation at 4 weeks (rapid virological response), the SVR rate was 94% (16/17), whereas it was 6% (1/16) if there was HCV RNA positivity at 24 weeks. The rate of treatment discontinuation from adverse events or aggravated complications was 25% (14/56). High SVR rates can potentially be achieved with PEG-IFN monotherapy by identifying the target patients, based on virus type and viral load before initiating treatment and by modifying therapy during treatment according to responsiveness.

Usefulness of Real-Time 4D Ultrasonography during Radiofrequency Ablation in a Case of Hepatocellular Carcinoma.

We report a case of hepatocellular carcinoma (HCC) with chronic hepatitis C virus infection successfully treated with percutaneous radiofrequency ablation (RFA) under live four-dimensional (4D) echo guidance. A 65-year-old Japanese man had a HCC nodule in the liver S5 region 2.0 cm in diameter. We performed real-time 4D ultrasonography during RFA therapy with a LeVeen needle electrode. The echo guidance facilitated an accurate approach for the needle puncture. The guidance was also useful for confirming whether an adequate safety margin for the nodule had been obtained. Thus real-time 4D ultrasonography echo technique appears to provide safe guidance of RFA needles via accurate targeting of HCC nodules, thereby allowing real-time visualization when combined with echo contrast. Furthermore the position of the needle in a still image was confirmed in every area using a multiview procedure.

Usefulness of radiofrequency ablation with micro-convex probe for hepatocellular carcinoma.

BACKGROUND/AIMS: It was aimed to assess whether a micro-convex probe is superior to the present conventional probe for ultrasonography from the points of safety and efficacy during percutaneous radiofrequency ablation therapy for hepatocellular carcinoma. METHODOLOGY: Twenty-one patients with 23 hepatocellular carcinoma lesions who had one or 2 lesions, each 4 cm or less in diameter, and liver function of Child-Pugh class A or B were enrolled. All the patients except for 2 patients were seropositive for hepatitis C virus. Radiofrequency ablation was carried out under a real-time US guidance. The cooled-tip electrodes used were single and clustered. RESULTS: It was possible to perform safe and accurate percutaneous radiofrequency ablation procedure using micro-convex probes for the treatment of all hepatocellular carcinoma nodules. It was also possible to treat hepatocellular carcinoma located in the right subphrenic region without artificial pleural effusion under intercostal ultrasonography guide. Improved clustered needles were successfully applied to treat the nodules more than 3 cm in diameter with less resistance for penetration compared with the conventional needle. The findings of advanced dynamic flow image on ultrasonography to assess the therapeutic efficacy indicated the consistency with those of dynamic CT which was done 3 to 5 days later radiofrequency ablation. Major complication of radiofrequency ablation procedure was noted in none. CONCLUSIONS: These results suggest that micro-convex probe with clustered tips is superior to conventional probe for ultrasonography from the points of safety and efficacy during radiofrequency ablation for hepatocellular carcinoma nodule located in the right subphrenic region and for larger sized nodule more than 3 cm.

Inflammatory cytokines modulate chemokine production patterns of HepG2 cells toward initially inclined direction.

AIM: Human hepatocytes are known to express an array of inflammatory cytokines and chemokines. In this study, we examined the potential roles of hepatocytes in regulating immune responses in the liver, by assessing the induction of Th1- or Th2-specific chemokines in HepG2 cells after various inflammatory stimulations. METHODS: HepG2 cells were stimulated with IL-1alpha, IFN-gamma, IL-4, IL-10, and/or CCL2, harvested at several time points, and served for the analyses of cytokine/chemokine mRNA expressions by semi-quantitative RT-PCR. RESULTS: (i) IL-1alpha up-regulated mRNA levels of CXCL8, CXCL10, and CCL2. IFN-gamma increased those of CXCL9, CXCL10, and CCL5, while IL-4 or IL-10 had no effect. (ii) Addition of IL-4 to the culture of IFN-gamma-stimulated cells, down-regulated CXCL9 and CXCL10 mRNA levels. (iii) Addition of IFN-gamma to the culture of IL-1alpha-stimulated cells, further up-regulated CXCL9 and CXCL10 mRNA levels. Addition of IL-4 decreased CXCL8 and CXCL10 levels, and increased CCL2 level in IL-1alpha-stimulated cells. (iv) CCL2 induced IL-4 mRNA expression. CONCLUSIONS: IFN-gamma augmented mRNA expression of Th1-specific chemokines (CXCL9 and CXCL10) in HepG2 cells. IL-4 had no effect on those of Th2-spesific chemokines (CCL17 and CCL22); however, it was supposed to augment Th2 response indirectly through the induction of CCL2 under the inflammatory condition. The findings suggest that hepatocytes have ability to promote immune responses in the liver toward the direction, initially determined by the cytokine balances in the local inflammatory region.

Hepatocellular Carcinoma 11 and a Half Years after the Resolution of Chronic Hepatitis C Virus Infection Successfully Treated with Interferon.

A 41-year-old Japanese man had received successful interferon (IFN) therapy against chronic hepatitis C in 1994. Since then, serum hepatitis C virus (HCV) RNA had been negative, and aminotransferase levels had been continuously normal. He had abstained from alcohol. However, his serum aminotransferase levels showed slight elevation as his body weight increased gradually. He was diagnosed as having fatty liver and diabetes mellitus. In January 2006, 11 and a half years after the resolution of HCV infection, he was found to have a hepatic nodule 4.0 cm in diameter at liver S4/8 region by plain abdominal CT at an annual follow-up examination. He was diagnosed as having hepatocellular carcinoma (HCC) by angiography. The tumor was curatively resected and its histological diagnosis was moderately differentiated HCC. Noncancerous lesion of the liver revealed fibrosis of stage F2 and mild inflammation of grade A1 with mild steatosis. This case suggests that all patients with chronic HCV infection should be followed as long as possible for the potential development of HCC even after clearance of the virus.

Deficiency of forkhead box P3 and cytotoxic T-lymphocyte-associated antigen-4 gene expressions and impaired suppressor function of CD4(+)CD25(+) T cells in patients with autoimmune hepatitis.

AIM: Recently, forkhead box P3 (Foxp3), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR), and CD28 were identified as the key molecules that control the development and activation of CD4+CD25+ regulatory T cells (T-reg). We investigated the expression pattern of these molecules on T-reg, and investigated the ability of T-reg to produce cytokines in patients with autoimmune hepatitis (AIH). METHODS: Fifteen patients with AIH and nine healthy patients were included. To determine the frequency of T-reg, a two-color flow cytometry analysis was performed. T-reg were isolated using immunomagnetic beads, and the mRNA levels of Foxp3, CTLA-4, GITR, and CD28 were quantified by real-time polymerase chain reaction (PCR). The ability of T-reg to produce interferon-gamma, interleukin (IL)-10, transforming growth factor-beta, and tumor necrosis factor-alpha after stimulation by OKT3 was evaluated by measuring the levels of mRNA in T-reg by real-time PCR. RESULTS: The frequency of T-reg was increased in AIH. The mRNA levels of Foxp3 and CTLA-4 were significantly lower in AIH. The ability of T-reg to produce IL-10 was impaired in AIH. CONCLUSION: We speculate that the inferiority of the Foxp3 and CTLA-4 gene expressions on T-reg results in the impaired suppressor function of T-reg, and eventually in the breakdown of self-tolerance.

Expression of Toll-like receptors in chronic hepatitis C virus infection.

BACKGROUND: Toll-like receptors (TLRs) are involved in innate immunity. Certain viruses interact with TLRs and mediate antiviral effects as well as immune responses. The aim of this study was to investigate the effect of TLRs on pathogenesis in hepatitis C virus (HCV)-infected patients. METHODS: Peripheral blood mononuclear cells (PBMC) and CD14+ (monocytes) or CD14- cells from 25 patients with chronic liver disease and 15 healthy subjects were studied for expression of TLRs 2-9 and cytokines of extracted RNA using real-time PCR. Then TLR expression was examined in HepG2 cells transfected with entire or parts (core-NS3, NS3-NS5B) of the HCV open reading frame. TLR expression was calculated as the relative mRNA levels. RESULTS: Expression of TLRs 4, 7 and 8 in CD14+ cells of PBMC was increased in patients. Levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-12 p35 for PBMC were also increased in patients. When PBMC were incubated with HCV core protein, enhancement of TLR2 expression and suppression of TLR4 and TLR7 were noted in patients. Similar alteration of TLRs expression was observed in controls. Among HepG2 transfectants, only TLR3 expression was changed; it was suppressed in entire gene transfectant and enhanced in core-NS3 transfectant. Expression of some proteins related to the TLR signaling pathway was suppressed in the entire gene transfectant. CONCLUSIONS: The results suggest a correlation between expression levels of TLRs and cytokines, and chronic HCV infection. TLR3 recognizes double-stranded RNA and induces type 1 interferon synthesis. Collectively, suppressed expression of TLR3 in cells transfected with entire HCV may be responsible for continuous HCV infection, although a part of the HCV gene enhances its expression.

Usefulness of live 3D echocardiography during radiofrequency ablation in a case of hepatocellular carcinoma.

We report a case of hepatocellular carcinoma (HCC) with chronic hepatitis C virus (HCV) infection, which was successfully treated with percutaneous radiofrequency ablation (RFA) under live three-dimensional (3D) echocardiography guidance. Recently, it was reported that live 3D echocardiography was able to enhance the efficacy of catheter-based endomyocardial injection since the 3D images made it possible to observe the target from multiple directions so that it guided more accurately. A 63-year-old Japanese man had an HCC nodule of 3.0 cm in diameter at the S8 region of the liver. Here we applied live 3D echocardiography during RFA therapy with a LeVeen needle electrode. The echocardiography guidance allowed for easier and accurate approach for needle puncture. The guidance was also effective to confirm whether an enough safety margin for the nodule was obtained. Thus, live 3D echocardiography appears to safely guide RFA needles by accurate targeting for HCC nodule, providing real-time visualization when combined with echocardiography contrast.

Noninvasive assessment of liver disease - measurement of hepatic fibrosis using tissue strain imaging.

The development of hepatic fibrosis in patients with liver disease is associated with an increased risk of liver cancer. Assessing the degree of hepatic fibrosis is therefore one of the most important factors in treatment planning. Liver biopsy is commonly performed to assess hepatic fibrosis, but this method is associated with complications such as hemorrhage. Recently, a number of studies on the noninvasive assessment of hepatic fibrosis have appeared in the literature. The present study was conducted to determine whether an easily performed myocardial examination technique can also be applied to the assessment of hepatic fibrosis. The statistical software Minitab, which performs hypothesis testing based on the P value, was used for statistical analysis. The mean strain values were 0.26 in the normal adult group, 0.155 in the chronic hepatitis group, and 0.058 in the cirrhosis group. Statistically significant differences were observed between the groups. The results of the present study suggest that noninvasive tissue strain imaging may become the method of choice for assessing hepatic fibrosis in routine clinical practice.

Effect of vitamin K2 on the recurrence in patients with hepatocellular carcinoma.

BACKGROUND/AIMS: Vitamin K2 (VK2) appears to have a potent inhibitory activity for cell growth including HCC cells. We investigated whether VK2 could reduce incidence of tumor recurrence after treatment of HCC. Forty-five patients with cured or possibly cured HCC were randomly selected, assigning patients to treatment (n=21) or control group (n=24) with randomization list. METHODOLOGY: For the treatment group, forty-five mg of Glakay was given orally every day after therapy for HCC. No patients complained of adverse effects. Abdominal ultrasonography and dynamic CT were performed at 3-month intervals. Recurrence was confirmed by abdominal angiography. RESULTS: Recurrence of HCC occurred in 7 cases (33.3%) for the treatment group and 12 cases (50.0%) for the control group during mean observation periods of 19.5 and 16.5 months, respectively. Administration of VK2 was not an independent variable for the recurrence on univariate analysis. Cumulative incidence of HCC recurrence did not differ between the two groups, and the cumulative survival rate tended to be high in treatment group (p =0.054). Cox regression analysis revealed that serum albumin concentration alone was an independent factor affecting the recurrence. CONCLUSIONS: These findings suggest that VK2 does not appear to prevent recurrence of HCC after curative treatment. Our study is preliminary and large-scale trials are needed to determine whether VK2 is of benefit to decrease the recurrence of HCC.