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BACKGROUND: Gait improvement in patients with stroke has been examined in terms of use or non-use of an ankle-foot orthosis (AFO), but the effects of different kinds of AFOs remain unclear. In this study, the effect on gait of using an AFO with an oil damper (AFO-OD), which has plantarflexion stiffness without dorsiflexion resistance, was compared with a nonarticulated AFO, which has both dorsiflexion and plantarflexion stiffness, in a randomized controlled trial. METHODS: Forty-one patients (31 men, 10 women; mean age 58.4 ± 11.3 years) in the subacute phase of stroke were randomly allocated to two groups to undergo gait training for 1 h daily over 2 weeks by physiotherapists while wearing an AFO-OD or a nonarticulated AFO. A motion capture system was utilized to measure shod gait without orthosis at baseline and after training with the allocated AFO. Data analysis focused on the joint kinematics and kinetics, spatial and temporal parameters, ground reaction force, and shank-to-vertical angle. Unpaired t-test or Mann-Whitney U test was performed to clarify the difference in gait with an AFO between the two AFO groups after training, with a significance level of p = 0.05. RESULTS: Thirty-six patients completed the study (17 in the AFO-OD group and 19 in the nonarticulated AFO group). The ankle joint was more dorsiflexed in single stance (p = 0.008, effect size r = 0.46) and peak ankle power absorption was larger in stance (p = 0.007, r = 0.55) in the AFO-OD group compared with the nonarticulated AFO group. Peak power absorption varied among patients in the AFO-OD group. Increased dorsiflexion angles were also found at initial contact (p = 0.008, r = 1.51), pre-swing (p = 0.045, r = 0.91), and the swing phase (p = 0.045, r = 0.91) in the AFO-OD group. There was no difference in peak plantarflexion moment, ankle power generation, spatial or temporal parameters, ground reaction force, or shank-to-vertical angle between the two groups. CONCLUSIONS: The results of this study showed that an AFO with plantarflexion stiffness but without dorsiflexion resistance produced greater improvement in ankle joint kinematics and kinetics compared with the nonarticulated AFO, but the results of peak power absorption varied greatly among patients. Trial registration UMIN000028126, Registered 1 August 2017, https://upload.umin.ac.jp/cgi-bin/icdr/ctr_menu_form_reg.cgi?recptno=R000032197.

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We investigated mediolateral dynamic stability at first foot off and first initial contact during gait initiation according to whether the paretic or non-paretic leg was used as the leading limb. Thirty-eight individuals with stroke initiated gait with the paretic and non-paretic legs as the leading limb, and their movements were measured using a 3D motion analysis system. Margin of stability (i.e., the length between the extrapolated center of mass and lateral border of the stance foot) was used as an index of dynamic stability, with a large value indicating dynamic stability in the lateral direction. However, an excessively large margin of stability value (i.e., when the extrapolated center of mass is outside the medial border of the stance foot) indicates dynamic instability in the medial direction. Differences in the margin of stability between tasks were compared using the Wilcoxon signed-rank test. The minimum margin of stability was observed just before first foot off. When the non-paretic leg was used as the leading limb, the margin of stability tended to be excessively large at first foot off compared with when the paretic leg was used (p < 0.001). In other words, the extrapolated center of mass was outside the medial border of the paretic stance foot. In conclusion, lateral stability was achieved when using the non-paretic leading limb because the extrapolated center of mass was located outside the medial border of the stance foot. However, medial dynamic stability was lower for the non-paretic leading limb compared with the paretic leading limb.

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BACKGROUND: Sit-to-walk is an asymmetric task that is challenging for individuals with stroke, and paretic limb loading at seat-off and movement fluidity may change according to whether the non-paretic or paretic leg is used as the leading limb. This study aimed to investigate differences in paretic limb loading and fluidity depending on whether the non-paretic limb or paretic limb was used as the leading limb. METHODS: Thirty-eight individuals with stroke performed sit-to-walk with each leg as the leading limb, and their movements were measured using a 3D motion analysis system. The paired t-test or Wilcoxon signed-rank test was used to assess differences according to limb selection in paretic limb loading ratio at seat-off and fluidity (Fluidity Index: ratio of the lowest to peak forward velocity before first initial contact). FINDINGS: Twenty-two of 38 participants preferred to use the paretic limb as the leading limb. When leading with the paretic limb, the paretic limb loading ratio was significantly larger (p = 0.002), and the Fluidity Index was lower (p = 0.007). INTERPRETATION: Sit-to-walk with the paretic leading limb seems to be an adaptive movement because many participants preferred leading with the paretic limb. However, selection of the leading limb in sit-to-walk involves a biomechanical tradeoff between paretic limb loading at seat-off and movement fluidity in individuals with stroke. Use of the paretic leading limb requires loading capacity of this limb, and the non-paretic leading limb must have high balance ability to merge sit-to-stand and gait initiation.

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OBJECTIVE: To investigate the abnormal kinematic and kinetic movements in the last gait cycle before a near fall in individuals poststroke, where a near fall is defined as a physical therapist feeling the need to stabilize a patient. DESIGN: Retrospective study. SETTING: A rehabilitation center. PARTICIPANTS: Twenty-five adults (22 men, 3 women; N=25) with an average age of 66.3 years and mean duration from stroke of 4 months who required manual assistance for a sudden imbalance during routine 3-dimensional motion analysis. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: We compared the averaged usual gait cycle and the last cycle before the near-falling gait cycle (pre-near-falling gait cycle). We obtained the following spatiotemporal parameters: gait velocity, gait cycle duration, mediolateral center of mass displacement, step length, step width, joint moments, and angular displacement of the trunk in a cycle. Peak values of joint moments and trunk angle displacement were calculated. RESULTS: Etiology for near falls included toe trip, mediolateral perturbation, and knee collapse. We found the following significant differences in the pre-near-falling gait cycle compared with the usual gait cycle: decreased gait velocity, prolonged total cycle time, and excessive mediolateral center of mass displacement. CONCLUSIONS: Decreased gait velocity, prolonged cycle time, and excessive mediolateral center of mass displacement may be a sign of an impending fall in people with impaired gait after stroke.

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AIM: Protease inhibitors with pegylated interferon (PEG IFN)/ribavirin improve a sustained virological response (SVR) rate to approximately 90% in chronic hepatitis C genotype 1b patients with IL28B rs8099917 genotype TT, but yield only approximately 50% in those with the unfavorable non-TT. Among such treatment-refractory patients, serum vitamin D levels could influence the SVR rate. This randomized controlled trial was conducted to assess the effect of native vitamin D supplementation in simeprevir with PEG IFN/ribavirin for 1b patients with non-TT. METHODS: Patients were randomly assigned to receive simeprevir (100 mg/day) for 12 weeks plus PEG IFN/ribavirin for 24 weeks (control group, n = 58), or vitamin D (2000 IU/day) for 16 weeks including a lead-in phase plus PEG IFN/ribavirin for 24 weeks (vitamin D group, n = 57). The primary end-point was sustainably undetectable viremia 24 weeks after the end of treatment (SVR). RESULTS: SVR rates were 37.9% in the control group and 70.2% in the vitamin D group. In subgroup analysis, SVR rates of prior null responders were 11.8% and 54.5%, respectively. SVR rates for advanced fibrosis were 28.6% and 65.4%. SVR rates for patients with vitamin D3 deficiency at the baseline were 25.0% in the control group and 66.7% in the vitamin D group. Overall, the SVR rate was significantly higher in patients with high serum 25(OH)D3 levels at the beginning of combination therapy than in those with low serum 25(OH)D3 levels. CONCLUSION: Native vitamin D3 supplementation improved SVR rates in simeprevir with PEG IFN/ribavirin for chronic hepatitis C genotype 1b patients with refractory factors.

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PURPOSE: Generally, stroke patients can walk and stand up fluidly but fulfill the sit-to-walk (STW) task with difficulty. The purpose of this study was to investigate the relationship between movement fluidity and motor strategy in the initial contact of the STW task. METHOD: Thirty stroke patients and ten healthy subjects performed the STW task from a sitting position, and their movement was measured by a motion analysis system. The differences in data between patients and healthy subjects were analyzed using the Mann-Whitney U test. The relationship between fluidity index (FI) and other indices (kinetic and kinematic data in STW, functional independence measure [FIM], and Fugl-Meyer Assessment [FMA]) were analyzed using Spearman's rank correlation coefficient. RESULTS: The stroke patients had lower FI values than the healthy subjects and exhibited shortened step length and prolonged duration from onset to the first stance leg off. FI values correlated with trunk flexure angle at initial contact, first step length, and maximum vertical floor reaction force. The independent level of the FIM of stair climbing and walking ability and the FMA of balance also correlated with FI. CONCLUSION: There is a possibility that poor balance is one of the reasons why stroke patients are unable to start walking fluently from the sitting position. To perform the STW fluidly, patients must start walking before the trunk extension is fully completed. The relationship between FI and indices of physical ability, namely stair climbing and balance, may have therapeutic benefits for coaching the STW task to stroke patients.

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The mechanism of an NOx-assisted, nitroxide(nitroxyl radical)-catalyzed aerobic oxidation of alcohols was investigated using a set of sterically and electronically modified nitroxides (i.e., TEMPO, AZADO (1), 5-F-AZADO (2), 5,7-DiF-AZADO (3), 5-MeO-AZADO (4), 5,7-DiMeO-AZADO (5), oxa-AZADO (6), TsN-AZADO (7), and DiAZADO (8)). The motivation for the present study stemmed from our previous observation that the introduction of an F atom at a remote position from the nitroxyl radical moiety on the azaadamantane nucleus effectively enhanced the catalytic activity under typical NOx-mediated aerobic-oxidation conditions. The kinetic profiles of the azaadamantane-N-oxyl-[AZADO (1)-, 5-F-AZADO (2)-, and 5,7-DiF-AZADO (3)]-catalyzed aerobic oxidations were closely investigated, revealing that AZADO (1) showed a high initial reaction rate compared to 5-F-AZADO (2) and 5,7-DiF-AZADO (3); however, AZADO-catalyzed oxidation exhibited a marked slowdown, resulting in ∼90% conversion, whereas 5-F-AZADO-catalyzed oxidation smoothly reached completion without a marked slowdown. The reasons for the marked slowdown and the role of the fluoro group are discussed. Oxa-AZADO (6), TsN-AZADO (7), and DiAZADO (8) were designed and synthesized to confirm their comparable catalytic efficiency to that of 5-F-AZADO (2), providing supporting evidence for the electronic effect on the catalytic efficiency of the heteroatoms under NOx-assisted aerobic-oxidation conditions.

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OBJECTIVES: The addition of fluvastatin significantly improves sustained virological response (SVR) in pegylated interferon and ribavirin (peg-IFN/RBV) combination therapy for patients infected with the hepatitis C virus. However, the add-on effect on telaprevir-based triple combination therapy remains unknown. The aim of this study was to investigate the effect of fluvastatin on telaprevir-based combination therapy by conducting a prospective, open-label, randomized, controlled trial. PATIENTS AND METHODS: Among 124 genotype 1b-infected chronic hepatitis C patients recruited, 116 eligible patients were allocated randomly to two study arms; they received 12 weeks of telaprevir/peg-IFN/RBV, followed by 12 weeks of peg-IFN/RBV with or without 24 weeks of fluvastatin (fluvastatin group and control group, respectively). Treatment outcomes and adverse effects were compared between the two groups. RESULTS: There were 56 men and 60 women, median age 60 years (range, 28-71 years). Rapid virological response and end of treatment response rates were 87.9% (51/58) and 96.6% (56/58) in the control group and 75.9% (44/58) and 98.3% (57/58) in the fluvastatin group, respectively. SVR rates in the control group and the fluvastatin group were 84.5% (49/58) and 81.0% (47/58), respectively; there was no significant difference (P=0.806). Stratified analysis showed that no factors associated with the SVR rate were found between the two groups. No adverse events were associated with fluvastatin. CONCLUSION: In this trial, administration of fluvastatin with telaprevir/peg-IFN/RBV was a safe combination. However, fluvastatin had no add-on effect on 24-week telaprevir-based combination therapy for chronic hepatitis C genotype 1b-infected patients.

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Phenserine is a potentially attractive drug for Alzheimer's disease. In order to further expand SAR study for inhibitions of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), the methyl group at the 3a-position of phenserine was replaced with an alkyl or alkenyl group, and its phenylcarbamoyl moiety was substituted at the o- or p-position. The synthetic methodology for these phenserine analogues includes the efficient cascade reactions for introduction of the 3a-substituent and assembly of the quaternary carbon center followed by reductive cyclization to the key pyrroloindoline structure. The bulkiness of the substituent at 3a-position of phenserine derivatives tends to reduce the inhibitory effect on AChE activity in the following order: methyl > ethyl > vinyl > propyl ≈ allyl > reverse-prenyl groups. Among the series synthesized, the 3a-ethyl derivative demonstrated the highest AChE selectivity. In construct, the 3a-reverse-prenyl derivative indicated modest BuChE selectivity.

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5-Fluoro-2-azaadamantane N-oxyl (5-F-AZADO) realizes a simple, organocatalytic aerobic alcohol oxidation system that has a wide scope under mild conditions at ambient pressure and temperature and is weakly acidic and halogen- and transition-metal-free. The oxoammonium nitrate (5-F-AZADO(+)NO(3)(-)) works as a bifunctional catalyst of 5-F-AZADO and NO(x) that enables the catalytic aerobic oxidation of alcohols by itself (a metal-salt-free system).

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The first total synthesis of (-)-idesolide was achieved via organocatalytic, enantioselective oxidative kinetic resolution (OKR) using (1S,4S)-4-Bn-1-Bu-AZADOH- and AZADO-catalyzed dimerization of (S)-(-)-methyl 1-hydroxy-6-oxo-2-cyclohexenecarboxylate. The absolute configuration of (-)-idesolide is determined to be 2R,2'S,3aS,7aR.

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In this prospective cohort study, we evaluated the use of transjugular intrahepatic portosystemic shunt (TIPS) in 50 patients with refractory ascites and a Child-Pugh score of 9.8. The mean duration of follow-up was 592 days. Ascites improved in 96% at 1 year and in 93% at 2 years. The cumulative survival rate was 71%, 52% and 18% at 1, 2 and 5 years. The Child-Pugh score and the performance status score improved significantly after TIPS. Thirty six patients required shunt revision during follow-up, due to shunt stenosis. Hepatic encephalopathy which was able to be controlled medically occurred in 26 patients. Our results suggest that although shunt revision may be needed, TIPS can control refractory ascites in most survival cases and improve QOL. However, the 5-year survival rate is still low in our TIPS-treated patients with refractory ascites.

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Some cirrhotic patients have hepatic veno-venous communications (HVVC) and large porto-systemic collaterals. However, the relationship between wedged hepatic vein pressure (WHVP) and portal vein pressure (PVP) in such patients is not clear. The aim of this study was to determine the relationships between simultaneously measured WHVP and PVP, and occluded hepatic and splenic portal venography in 100 cirrhotic patients (40 alcoholic and 60 hepatitis C virus (HCV)-related cirrhosis). PVP and WHVP were closely related in both groups (alcoholic-cirrhosis: 27.8 +/- 4.7 and 27.5 +/- 4.8 mmHg, HCV-cirrhosis: 27.3 +/- 3.7 and 26.2 +/- 4.4 mmHg, respectively). Occluded hepatic venography revealed that 13 of the 100 patients had HVVC (alcoholic-cirrhosis: 4, HCV-cirrhosis: 9). In patients with HVVC, PVP (27.9 +/- 3.0 mmHg) was significantly higher than WHVP (21.9 +/- 3.3 mmHg, P < 0.001). Large porto-systemic collaterals did not affect the relationship. We conclude that HVVC affects the relationship between PVP and WHVP. When WHVP is measured, occluded hepatic venography should be examined to detect HVVC.

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Eighteen patients with refractory ascites (Child-Pugh score 9.9) defined by our criteria were treated with transjugular intrahepatic portosystemic shunt (TIPS). The long-term efficacy of the treatment was studied in these patients. The complete and partial response rate of refractory ascites was 73% at 6 months, 90% at 1 year and 100% at 2 years. The cumulative survival rate was 89% at 6 months, 78% at 1 year and 48% at 2 years. A statistically significant(p < 0.05) increase was observed in performance status score following TIPS: Mean performance status score prior to TIPS was 43%, as opposed to 62% at 3 months after TIPS and 85% at 2 years. Child-Pugh score and liver function tests showed no significant change. During follow-up, shunt stenosis was noted in 14 patients, requiring shunt revision. Ascites recurrence was observed in 70% of patients with shunt stenosis and shunt revision resulted in good control of ascites. Post-TIPS encephalopathy was seen in 15 patients during follow-up. In conclusion, TIPS is effective on the treatment of refractory ascites and results in an improvement in quality of life. TIPS also may improve survival of the patients with refractory ascites. However, shunt stenosis and encephalopathy are common and require careful follow-up and adequate treatment.

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The aim of this study was to compare the efficacy of transjugular intrahepatic portosystemic shunt (TIPS) with that of endoscopic sclerotherapy (ES) in the long-term management of patients with cirrhosis after variceal bleeding. Seventy-eight consecutive cirrhotic patients with recent variceal bleeding were randomly allocated to either TIPS (n=38) or ES (n=40). All patients were in good condition at randomization. The mean follow-up was 1116+/-92 days in the TIPS group and 1047+/-102 days in the ES group. Differences in rebleeding from any source (18.4% vs. 32.5%) and esophageal variceal rebleeding (15.7% vs. 27.5%) were not significantly different between the two groups (P>0.05). The mortality rates were similar in both treatment groups. Shunt dysfunction was noted in 27 patients (71%) in the TIPS group. There were more numbers of rehospitalization during follow-up in the TIPS group than in the ES group (2.6+/-0.4 vs. 1.1+/-0.2) (P<0.01). TIPS and ES are equally effective in the prevention of variceal rebleeding. However, TIPS is associated with high incidence of shunt dysfunction, which lead to more rehospitalization. Therefore, TIPS may not be a first-line treatment for the prevention of variceal rebleeding in cirrhotic patients who are in stable condition.