The Relationship Between Cardio-Ankle Vascular Index and Left Atrial Phasic Function in Hypertensive Patients With Preserved Ejection Fraction.

Background: To investigate the relationship between arterial stiffness, reflected by cardio-ankle vascular index (CAVI) value, and left atrial (LA) phasic function in hypertensive patients with preserved left ventricular ejection fraction (LVEF). Methods: We retrospectively studied 165 consecutive patients (mean age, 66.5 ± 11.7 years) diagnosed with hypertension with preserved LVEF who had undergone CAVI measurement and echocardiography on the same day. The latter included speckle-tracking echocardiography to assess LA phasic function (reservoir, conduit, and pump strain) and left ventricular global longitudinal strain (LVGLS). Results: The results of univariate analysis showed CAVI value to be correlated with LA reservoir strain and LA conduit strain (r = -0.387 and -0.448, respectively; both P < 0.0001). The results of multiple linear regression analysis showed CAVI value to be independently related to age (ß = 0.241, P = 0.002) and LA conduit strain (ß = -0.386, P = 0.021) but not LV mass index, LA volume index, or LV systolic function (including LVGLS). Conclusion: In hypertensive patients with preserved LVEF, increased CAVI value appears to be independently associated with impaired LA phasic function (particularly LA conduit function) before LA and LV remodeling. CAVI determination to assess arterial stiffness may be useful in the early detection of interactions between cardiovascular abnormalities in hypertensive patients.

Bladder Autonomic Dysfunction after a Parietal Stroke.

We describe a case of a 57-year-old man who, immediately after a right parietal ischemic stroke, showed urodynamically determined bladder sensory decrement during filling and an underactive detrusor during voiding, both of which were ameliorated during the course of his treatment. The lower urinary tract symptom (LUTS) occurs in stroke in up to 60% of patients, when it involves the frontal and insular cortices. In addition, LUTS does occur in parietal stroke as seen in our patient, presumably by sensory deafferentiation within the brain that is relevant to the central regulation of the micturition reflex.

Successful retreatment with sofosbuvir plus ledipasvir for cirrhotic patients with hepatitis C virus genotype 1b, who discontinued the prior treatment with asunaprevir plus daclatasvir: A case series and review of the literature.

BACKGROUND: Interferon-free treatment results in higher sustained virologic response (SVR) rates, with no serious adverse events in hepatitis C virus (HCV)-infected patients. However, in some patients with treatment-failure in HCV NS5A inhibitor-including interferon-free regimens, the treatment-emergent HCV NS5A resistance-associated variants (RAVs), which are resistant to interferon-free retreatment including HCV NS5A inhibitors, are observed. In HCV-infected Japanese patients with daclatasvir and asunaprevir treatment failure, retreatment with sofosbuvir and ledipasvir could lead to only ∼70% SVR rates. CASE SUMMARY: Three HCV genotype (GT)-1b-infected cirrhotic patients who discontinued the combination of daclatasvir and asunaprevir due to adverse drug reactions within 4 weeks; retreatment with sofosbuvir and ledipasvir combination could result in SVR in these patients without RAVs. One HCV GT-1b-infected cirrhotic patient who discontinued the combination of daclatasvir and asunaprevir due to viral breakthrough at week 10; retreatment with sofosbuvir and ledipasvir combination for this patient with the treatment-emergent HCV NS5A RAV-Y93H resulted in viral relapse at week 4 after the end of the treatment. CONCLUSION: Retreatment with sofosbuvir and ledipasvir is effective for HCV GT-1b patients who discontinue the combination of daclatasvir and asunaprevir within 4 weeks. The treatment response should be related to the existence of treatment-emergent HCV NS5A RAVs, but may not be related to the short duration of treatment.

Levels of soluble LR11/SorLA are highly increased in the bile of patients with biliary tract and pancreatic cancers.

BACKGROUND: The utility of molecules derived from cancer cells as biomarkers of the pathological status in biliary tract and pancreatic cancers is still limited. Soluble LDL receptor relative with 11 ligand-binding repeats (sLR11), a molecule released from immature cells, has been shown to be a circulating biomarker for early stage hematological malignancies. METHODS: We have evaluated the pathological significance of bile sLR11 levels in 147 samples from 72 patients with biliary tract cancer (BTC), pancreatic cancer (PC), or benign diseases. RESULTS: The bile sLR11 levels in the cancer patients were significantly increased compared with those in patients without cancer, independent of cytological detection of cancer cells in bile. The average bile sLR11 levels in cancer patients were significantly higher than in those with benign diseases, while levels of bile carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) were not different. LR11 protein was found to be highly expressed in the BTC and PC cells. The LR11 transcript levels in cholangiocarcinoma and pancreatic cancer cell lines were sharply induced during proliferation and significantly increased under hypoxic conditions. CONCLUSIONS: Therefore, sLR11 levels in bile may be indicative of cancer cell conditions and may serve as potential novel biomarker in patients with BTC and PC.

Effectiveness of probiotic therapy for the prevention of relapse in patients with inactive ulcerative colitis.

AIM: To evaluate the effectiveness of probiotic therapy for suppressing relapse in patients with inactive ulcerative colitis (UC). METHODS: Bio-Three tablets, each containing 2 mg of lactomin (Streptococcus faecalis T-110), 10 mg of Clostridium butyricum TO-A, and 10 mg of Bacillus mesentericus TO-A, were used as probiotic therapy. Sixty outpatients with UC in remission were randomly assigned to receive 9 Bio-Three tablets/day (Bio-Three group) or 9 placebo tablets/day (placebo group) for 12 mo in addition to their ongoing medications. Clinical symptoms were evaluated monthly or on the exacerbation of symptoms or need for additional medication. Fecal samples were collected to analyze bacterial DNA at baseline and 3-mo intervals. Terminal restriction fragment length polymorphism and cluster analyses were done to examine bacterial components of the fecal microflora. RESULTS: Forty-six patients, 23 in each group, completed the study, and 14 were excluded. The relapse rates in the Bio-Three and placebo groups were respectively 0.0% vs 17.4% at 3 mo (P = 0.036), 8.7% vs 26.1% at 6 mo (P = 0.119), and 21.7% vs 34.8% (P = 0.326) at 9 mo. At 12 mo, the remission rate was 69.5% in the Bio-Three group and 56.6% in the placebo group (P = 0.248). On cluster analysis of fecal flora, 7 patients belonged to cluster I, 32 to cluster II, and 7 to cluster III. CONCLUSION: Probiotics may be effective for maintaining clinical remission in patients with quiescent UC, especially those who belong to cluster I on fecal bacterial analysis.

IL-28B polymorphisms and treatment response in hepatitis C virus patients with persistently normal alanine aminotransferase.

AIM: To examine the association between the interleukin 28B (IL-28B) genotype and treatment response in hepatitis C virus (HCV)-infected patients with persistently normal alanine aminotransferase (PNALT). METHODS: We compared the treatment response of HCV-infected patients with PNALT to that of patients with non-PNALT. Between February 2010 and April 2013, 278 patients infected with HCV were enrolled in this study. All of the patients were treated with peginterferon-alpha 2a or 2b plus ribavirin. In addition, 180 µg of peginterferon alpha-2a or 1.5 µg/kg peginterferon alpha-2b per week plus weight-based ribavirin (600-1000 mg/d) were typically administered for 24 wk to HCV genotype 2-infected patients or for 48-72 wk to HCV genotype 1-infected patients. In all of the patients, the IL-28B rs8099917 genotype was determined using a TaqMan single-nucleotide polymorphism assay. HCV RNA was measured using the COBAS TaqMan HCV test. RESULTS: Female patients were dominant in the PNALT group (P < 0.0001). Among 72 HCV genotype 1-infected patients with PNALT, the early virologic response (EVR) rates (P < 0.01) and the sustained virologic response (SVR) rates (P < 0.01) were higher in patients with the IL-28B TT genotype than in those with the IL-28B TG/GG genotype. In HCV genotype 1-infected patients with PNALT, multivariate logistic-regression analysis showed that SVR was independently predicted by the IL-28B rs8099917 TT type (P < 0.05) and having an EVR (P < 0.01). The IL-28B rs8099917 TT genotype strongly correlated with treatment response in HCV genotype 1-infected Asian patients with PNALT. CONCLUSION: The IL-28B genotype may be useful for selecting HCV genotype 1-infected patients with PNALT who should receive interferon-based treatment.

Platelet count and sustained virological response in hepatitis C treatment.

AIM: To examine the epidemiological data, hematological safety and treatment responses of peginterferon-alpha 2a plus ribavirin therapy for hepatitis C. METHODS: Between March 2008 and February 2011, 196 hepatitis C virus (HCV) genotype 1 infected Japanese (127 treatment-naive and 69 treatment-experienced patients) patients treated with peginterferon-alpha 2a plus ribavirin were enrolled. We examined the epidemiological data and treatment responses were retrospectively analyzed in terms of hematological safety. HCV RNA was measured by the COBAS TaqMan HCV test. RESULTS: Overall sustained virological response (SVR) rates of treatment-naive and treatment-experienced patients were 56% and 39%, respectively. Multivariate logistic regression analysis showed that SVR was attained independently of early virological response in both treatment-naive and treatment-experienced patients. SVR rates did not differ between the pretreatment hemoglobin < 13 g/dL and ≥ 13 g/dL groups. However, in treatment-naive patients, the SVR rate of the pretreatment platelet count < 130000/µL group was significantly lower than that of the pretreatment platelet count ≥ 130000/µL group. CONCLUSION: Attention should be paid to potential thrombocytopenia in the treatment of chronic hepatitis C patients.

Peginterferon Alfa-2a plus ribavirin in Japanese patients infected with hepatitis C virus genotype 2 who failed previous interferon therapy.

Some patients infected with hepatitis C virus (HCV) genotype 2 could be cured with treatment shorter than 24 weeks using peginterferon plus ribavirin, but there are still treatment-refractory patients. Direct-acting antivirals (DAAs) are not currently available for HCV genotype 2 patients, different from genotype 1 patients, in clinical practice. We investigated 29 HCV genotype 2-infected Japanese patients who had been previously treated and failed to clear HCV. We retreated them with peginterferon alfa-2a plus ribavirin and measured HCV RNA level to assess the efficacy and safety of this treatment in patients who had failed previous therapy. We found that retreatment of HCV genotype 2-infected Japanese patients with peginterferon alfa-2a plus ribavirin for 24-48 weeks led to 60 to 66.6% sustained virological response (SVR) in patients previously treated with (peg-)interferon monotherapy and to 69.9% SVR in relapsers previously treated with peginterferon plus ribavirin. Attention should be paid to certain patients with unique features. Selection of patients according to their previous treatment could lead to optimal therapy in HCV genotype 2 treatment-experienced patients.

Factors associated with the loss of response to infliximab in patients with Crohn's disease.

BACKGROUND AND AIMS: The efficacy of infliximab (IFX) has validated the role of TNF-α in the immunopathogenesis of Crohn's disease (CD). However, antibodies to IFX emerge, which impair its efficacy. This study investigated factor(s) associated with the loss of response (LOR) to IFX and how IFX non-responders may be treated. METHODS: Seventy-four patients, 36 IFX responders (GI) and 38 with LOR (GII) were included. Trough IFX level, CD activity index (CDAI) and immunological markers during IFX maintenance therapy were measured. Adsorptive granulocyte/monocyte apheresis (GMA) was applied to patients with LOR. RESULTS: The durations of CD, 9.3 ± 5.5 yr and IFX therapy, 3.4 ± 2.0 yr in GII were longer vs GI (P=0.02, P=0.01). Similarly, C-reactive protein (P<0.0001) and CDAI (P<0.0001) in GII were higher. The median trough IFX was 4.7 µg/mL in GI and 8.4 µg/mL in GII, while the dose frequency was 8 weeks in GI and 4 weeks in GII. Soluble interleukin-2 receptor (sIL-2R) was higher in GII vs GI (P<0.001). Seropositive rates of anti-nuclear antibodies (ANA) and circulating immune complexes (CIC) in GII were 50.0% and 68.4%, significantly higher vs GI (P<0.05, P<0.01). Patients with LOR duration <1.5 yr showed higher CDAI and sIL-2R (P<0.05) vs patients with LOR duration <1.5 yr. Fifteen GII patients received GMA plus IFX combination and 46.7% responded. IL-10 increased in GMA-responders (P<0.05), while CIC and ANA decreased (P=0.0237, P=0.0463). CONCLUSIONS: Patients with LOR to IFX had dysregulated immune response despite uncompromised trough IFX level. Further, inadequate T-cell differentiation by IFX was suggested. GMA appeared to benefit LOR patients by immunoregulation.

Occurrence of hepatocellular carcinoma was not a rare event during and immediately after antiviral treatment in Japanese HCV-positive patients.

Advanced chronic hepatitis C patients with sustained virolological response by antivirals remain at risk for hepatocellular carcinoma (HCC). We investigated the incidence of HCC during and immediately after peginterferon-alfa-2a and ribavirin (RBV) treatment in patients with chronic hepatitis C in Japan. HCC was detected in 8 of 238 patients during and after these treatments (mean follow-up period: 572 ± 252 days). In conclusion, occurrence of HCC is not a rare event during and immediately after peginterferon-alfa-2a plus RBV treatment. In cases with cirrhosis, higher α-fetoprotein levels, old age, or a previous history of HCC treatment, clinicians should be especially alert for the possible development of HCC during and immediately after peginterferon-alfa-2a and RBV treatment. Clinicians should regularly check for the possible development of HCC even in chronic hepatitis C patients under treatment.

Monitoring functional serum antitumor necrosis factor antibody level in Crohn's disease patients who maintained and those who lost response to anti-TNF.

BACKGROUND: Infliximab (IFX) is an antitumor necrosis factor (TNF)-α antibody used to treat Crohn's disease (CD). However, antibodies to IFX (ATI) emerge, which can impair its efficacy. A fluid-phase enzyme immunoassay (FP-EIA) was established for measuring serum functional IFX (f-IFX) in CD patients receiving maintenance IFX. METHODS: In 31 patients, 16 had maintained response (GI) and 15 had lost response to IFX despite good initial response (GII) were selected. Serum f-IFX was measured just before and immediately after IFX infusion and the values together with CD activity index (CDAI) and C-reactive protein (CRP) were compared. RESULTS: IFX therapy in GI and GII were 1.8 ± 1.2 years and 2.7 ± 1.5 years, respectively, while the median dose frequency was 56 days in GI and 29 days in GII. Our FP-EIA for f-IFX showed TNF-α binding increasing with the IFX dose, which was suppressed by antibodies to IFX. On the infusion day, CRP and CDAI in GII were significantly higher than in GI, while median trough f-IFX for GI and GII were 4.7 µg/mL and 6.3 µg/mL, respectively. The median f-IFX immediately after IFX infusion for GI and GII were 149.5 µg/mL and 126.3 µg/mL, respectively (P = 0.0488), and binary logistic regression showed conditional maximum likelihood estimate to be -0.0258 (P = 0.0395), supporting association of low postinfusion f-IFX to the loss of response. CONCLUSIONS: FP-EIA could accurately measure f-IFX. High serum ATI strongly impacted f-IFX levels immediately after an infusion. The postinfusion f-IFX level was associated with clinical response. f-IFX level should be valuable in decision-making to optimize treatment efficacy.

Clinical effectiveness of probiotics therapy (BIO-THREE) in patients with ulcerative colitis refractory to conventional therapy.

OBJECTIVE: Intestinal microflora has been implicated in the etiology of ulcerative colitis (UC). Over the past few years, the use of probiotics in UC has gained attention. The aim of this study was to evaluate the efficacy of probiotics therapy for mild to moderate distal UC refractory to conventional therapies. MATERIAL AND METHODS: Twenty patients with mild to moderate distal UC took 9 BIO-THREE tablets per day for 4 weeks. Clinical symptoms and endoscopic findings were evaluated as ulcerative colitis disease activity index (UCDAI) scores before and after administration of BIO-THREE. Fecal samples were collected from all patients before and after probiotics administration, and fecal microflora was analyzed by the terminal restriction fragment length polymorphism (T-RFLP) method. RESULTS: Remission (UCDAI score < or =2) was observed in 45% (9/20) of the patients; response (decrease in UCDAI > or = 3, but final score > or = 3) in 10% (2/20); no response in 40% (8/20); and worsening (UCDAI > 3) in 5% (1/20). T-RFLP analysis indicated that the principal alteration in microflora was an increase in bifidobacteria. CONCLUSIONS: This study showed that administration of BIO-THREE improved the clinical symptoms and endoscopic findings in patients with UC, indicating that administration of BIO-THREE is safe and efficacious for the treatment of UC.

Adacolumn selective leukocyte adsorption apheresis in patients with active ulcerative colitis: clinical efficacy, effects on plasma IL-8, and expression of Toll-like receptor 2 on granulocytes.

Adacolumn selective granulocyte and monocyte apheresis (GMA) depletes activated leukocytes in patients with ulcerative colitis (UC). However, this per se cannot fully explain the efficacy of GMA. We have investigated the effects of GMA on the expression of toll-like receptors (TLRs) and plasma interleukin-8 (IL-8). Twenty-two patients with clinical activity index (CAI) of 5-17, 15 with total colitis and 7 with left-sided colitis, were included. Each patient could receive up to 10 GMA sessions, at 1 or 2 sessions per week. GMA was added to the patients' ongoing medication following a relapse or worsening UC, but no additional medication was given. Further, at entry and pre-GMA, blood samples were taken for full blood cell count, expression of TLRs on leukocytes, and plasma IL-8. Seventy-five percent of patients achieved remission after the 10th session (CAI, < or =4; P < 0.005) and there was a marked fall in C-reactive protein (P < 0.01), plasma IL-8 (P < 0.001), and granulocytes (P < 0.05) but an increase in lymphocytes (P < 0.05). The expression of TLR2 on granulocytes was down-modulated (P < 0.05) together with suppression of inflammatory cytokines produced by peripheral blood leukocytes. In conclusion, GMA appears to be an effective adjunct therapy to induce remission in the majority of patients, who are then spared from excess drug therapy. The procedure is associated with sustained immunomodulation. Control studies should strengthen these findings.