Effects of oral administration of timothy hay and psyllium on the growth performance and fecal microbiota of preweaning calves.

The objective of this study was to evaluate the effects of oral administration of fiber from the first week of life on the growth and hindgut environment of preweaning calves. Twenty newborn female Holstein calves were divided into 2 groups as control and treatment. Calves in both groups were reared under the same feeding program except for oral fiber administration. Timothy hay and psyllium were mixed at a 50-to-6 ratio as a treatment diet for oral fiber administration. Calves in the treatment group were orally administered 50 g of fiber daily from 3 to 7 d of age and 100 g of fiber from 8 d of age until weaning. Feed intake and occurrence of diarrhea were recorded daily, and body weight (BW) was recorded weekly for the individual calf. Fresh feces were collected from calves at 7, 21, 35, 49, and 56 d of age to analyze fermentation parameters and microbiota to characterize the hindgut environment. Higher fiber intake in the treatment group due to oral administration of timothy and psyllium did not affect the starter intake and achieved higher BW at 21 d of age. The fecal pH, total volatile fatty acid, lactate, and ammonia nitrogen concentrations were not affected by oral fiber administration; meanwhile, the molar proportion of propionate was higher in the treatment group at 7 d of age. The difference in fecal microbiota in the calves subjected to the oral administration of fiber was observed within 21 d of life; Lactobacillus spp. and Prevotella spp. showed higher abundance, whereas that of Clostridium perfringens was decreased. These higher abundances of beneficial bacteria and lower abundance of pathogenic bacteria during early life may partly explain the higher BW of calves in the treatment group at 21 d of age. Furthermore, no adverse effect was observed for the BW and health status in the treatment group throughout the preweaning period. Therefore, early fiber feeding via oral administration potentially contributes to improving the hindgut environment in newborn calves, which leads to better growth of calves during the early stage of life.

Iodoarene-catalyzed oxidative transformations using molecular oxygen.

Molecular oxygen serves as a useful oxidant for the glycol scission of 1,2-diols and the Hofmann rearrangement of primary amides using pentamethyliodobenzene as a catalyst. The use of isobutyraldehyde and Lewis basic nitriles under O2 enabled the iodine(i)/(iii) catalytic cycle, where in situ-generated peracid acts as a terminal oxidant.

Predictors of delayed wound healing after endovascular therapy of isolated infrapopliteal lesions underlying critical limb ischemia in patients with high prevalence of diabetes mellitus and hemodialysis.

OBJECTIVES: Acceptable limb salvage rates underlie the widespread use of endovascular therapy (EVT) for patients with critical limb ischemia (CLI) secondary to isolated infrapopliteal lesions; however, post-EVT delayed wound healing remains a challenge. Predictors of delayed wound healing and their use in risk stratification of EVT in patients with CLI due to isolated infrapopliteal lesions are explored. METHODS: This was a retrospective multicenter study. 871 consecutive critically ischemic limbs were studied. There was tissue loss in 734 patients (age: 71 ± 10 years old; 71% male) who had undergone EVT between April 2004 and December 2012. The wound healing rate after EVT was estimated by the Kaplan-Meier method. The association between baseline characteristics and delayed wound healing was assessed by the Cox proportional hazard model. RESULTS: Diabetes mellitus and regular dialysis were present in 75% (553/734) and 64% (476/734) of patients, respectively; 67% of limbs (585/871) had Rutherford class 5 CLI; 8% (67/871) of wounds were located in the heel only; 25% (219/871) of limbs had Rutherford 6 (involving not only the heel); and 42% (354/871) of wounds were complicated by infection. The rate of freedom from major amputation at 1 year reached 88%, whereas the wound healing rate was 67%. Median time to wound healing was 146 days. By multivariate analysis, non-ambulatory status (hazard ratio [HR], 1.58; 95% confidence interval [CI] 1.31-1.91) serum albumin <3 g/dL (HR 1.42; 95% CI 1.08-1.86), Rutherford 6 (not only heel) (HR 1.68; 95% CI 1.33-2.14), wound infection (HR 1.24; 95% CI 1.03-1.50), EVT not based on angiosome concept (HR 1.28; 95% CI 1.06-1.55), and below the ankle (BTA) 0 vessel runoff after EVT (HR 1.45; 95% CI 1.14-1.86) were independent predictors of delayed wound healing. CONCLUSIONS: Non-ambulatory status, low albumin level, Rutherford 6 (not only heel), wound infection, indirect intervention, and poor BTA runoff were independent predictors for delayed wound healing after EVT in patients with CLI secondary to infrapopliteal lesions, and their use in risk stratification allows estimation of the wound healing rate.

Complex relationship of body mass index with mortality in patients with critical limb ischemia undergoing endovascular treatment.

OBJECTIVE: To investigate the relationship between body mass index (BMI) and long-term outcomes of patients with CLI after endovascular treatment (EVT). DESIGN: Retrospective multicenter study. SUBJECTS: 1088 consecutive patients (1306 limbs, mean age 72 ± 10 years) with CLI who underwent EVT for isolated infrapopliteal artery lesions were evaluated. These subjects were identified in the J-BEAT III registry. METHODS: The patients were divided into groups based on BMI <18.5 kg/m2 (underweight, n = 188; 219 limbs), 18.5 to 24.9 kg/m2 (normal weight, n = 718; 868 limbs), and >25.0 kg/m2 (overweight/obese, n = 182; 219 limbs). The endpoints were overall survival and freedom from major adverse limb events (MALE). RESULTS: The median follow up period was 1.5 years (range: 1 month-8.7 years). The 3 year overall survival rates were 33.3%, 61.2%, and 69.8% in underweight, normal, and overweight/obese patients, respectively. The survival rate was significantly lower in underweight patients and significantly higher in overweight/obese patients compared with patients of normal weight (both p < .0001). The 3 year rates of freedom from MALE did not differ significantly among the three groups (36.4%, 45.4%, and 52.3%, respectively, p = .32). Age, BMI <18.5 kg/m2, heart failure, aortic valve stenosis, renal failure, triglyceride levels, serum albumin <3.0 g/dL, anticoagulant treatment, non-ambulatory status, and Rutherford 6 classification all were significantly associated with overall survival. CONCLUSIONS: BMI has a complex correlation with mortality in patients with CLI after EVT for isolated infrapopliteal artery lesions. Underweight patients with CLI have an extremely poor prognosis. Such patients have many other factors associated with mortality, but low BMI was identified as an independent predictor of a poor prognosis in patients with CLI. Similarly, normal weight patients had a small but significant increase in mortality compared with overweight/obese patients.

Prognostic nomogram for nonresectable pancreatic cancer treated with gemcitabine-based chemotherapy.

BACKGROUND: A nomogram is progressively being used as a useful predictive tool for cancer prognosis. A nomogram to predict survival in nonresectable pancreatic cancer treated with chemotherapy has not been reported. METHODS: Using prospectively collected data on patients with nonresectable pancreatic cancer receiving gemcitabine-based chemotherapy at five Japanese hospitals, we derived a predictive nomogram and internally validated it using a concordance index and calibration plots. RESULTS: In total, 531 patients were included between June 2001 and February 2013. The American Joint Committee on Cancer (AJCC) TNM stages were III and IV in 204 and 327 patients, respectively. The median survival time of the total cohort was 11.3 months. A nomogram was generated to predict survival probabilities at 6, 12, and 18 months and median survival time, based on the following six variables: age; sex; performance status; tumour size; regional lymph node metastasis; and distant metastasis. The concordance index of the present nomogram was higher than that of the AJCC TNM staging system at 12 months (0.686 vs 0.612). The calibration plots demonstrated good fitness of the nomogram for survival prediction. CONCLUSIONS: The present nomogram can provide valuable information for tailored decision-making early after the diagnosis of nonresectable pancreatic cancer.

Perioperative complications after aorto-iliac stenting: associated factors and impact on follow-up cardiovascular prognosis.

OBJECTIVES: To investigate factors associated with 30-day perioperative complications (POC) after aorto-iliac (AI) stenting, and to compare follow-up cardiovascular prognosis between patients with and without POC. MATERIALS AND METHODS: This was a retrospective multicenter study. We used a multicenter database of 2012 consecutive patients who successfully underwent AI stenting for peripheral arterial disease in 18 centers in Japan from January 2005 to December 2009 to analyze independent predictors of POC and impact of POC on prognosis by logistic regression and a Cox proportional hazard regression model, respectively. RESULTS: Mean age was 71 ± 9 years (median: 72 years; range: 37-98 years), and 1,636 patients (81%) were men. POC occurred in 126 patients (6.3%). In multivariate logistic regression analysis, old age (≥80 years), critical limb ischemia (CLI), and Trans Atlantic Inter-Societal Consensus (TASC) II class C/D were independently associated with POC with adjusted odds ratios and 95% confidence intervals (CI) of 1.9 (1.3-2.9), 2.3 (1.5-3.4), and 2.4 (1.6-3.4), respectively. Out of 2012 patients, 1995 were followed up for more than 30 days (mean: 2.6 ± 1.5 years; range: 2-2,393 days). In a Cox hazard regression model adjusted for baseline clinical characteristics, POC was positively and independently associated with follow-up major adverse cardiac events (adjusted hazard ratio [HR]: 1.9; 95% CI: 1.3-2.8; p = .002), but not with major adverse limb events and target lesion revascularization (adjusted HR: 1.4; 95% CI: 0.7-2.7; p = .25; and adjusted HR: 1.2; 95% CI 0.6-2.6; p = .568), respectively. CONCLUSIONS: Age >80 years, CLI, and TASC C/D lesion were positively associated with POC after AI stenting. Occurrence of POC appears to adversely affect follow-up cardiovascular, but not limb and vessel prognosis.

Worse limb prognosis for indirect versus direct endovascular revascularization only in patients with critical limb ischemia complicated with wound infection and diabetes mellitus.

OBJECTIVES: To investigate factors in patients with critical limb ischemia (CLI) and isolated infrapopliteal lesions that adversely affect outcomes of endovascular therapy (EVT) with or without angiosome-oriented revascularization. METHODS: This was a retrospective multicenter study. We used a database of 718 consecutive CLI patients (70 ± 11 years, 75% diabetics, 68% on hemodialysis, 24% Rutherford class 6) with ischemic tissue loss due to isolated infrapopliteal lesions undergoing primary EVT. Primary outcome was MALE (major adverse limb event). Association between indirect EVT (recanalization of a non-angiosome-based artery) and outcome was assessed by Cox proportional hazard regression model. RESULTS: C-reactive protein (CRP) level was >3 mg/dL in 32% of cases. Indirect EVT (in 307 CLI patients, 43%), was associated with MALE (p = .04, hazard ratio [95% confidence interval] 1.25 [1.01, 1.55]), and interacted with CRP >3 mg/dL (p < .004) but not with other baseline characteristics. Indirect EVT with CRP >3 mg/dL had higher MALE risk (HR 2.08), and interacted with diabetes mellitus (DM) presence. Indirect EVT with CRP >3 mg/dL and DM had higher MALE risk (HR 2.17). CONCLUSION: Limb prognosis was equivalent for direct and indirect endovascular revascularization except in the presence of both diabetes and wound infection, when indirect revascularization has a poorer outcome.

Minocycline selectively inhibits M1 polarization of microglia.

Minocycline is commonly used to inhibit microglial activation. It is widely accepted that activated microglia exert dual functions, that is, pro-inflammatory (M1) and anti-inflammatory (M2) functions. The in vivo status of activated microglia is probably on a continuum between these two extreme states. However, the mechanisms regulating microglial polarity remain elusive. Here, we addressed this question focusing on minocycline. We used SOD1(G93A) mice as a model, which exhibit the motor neuron-specific neurodegenerative disease, amyotrophic lateral sclerosis. Administration of minocycline attenuated the induction of the expression of M1 microglia markers during the progressive phase, whereas it did not affect the transient enhancement of expression of M2 microglia markers during the early pathogenesis phase. This selective inhibitory effect was confirmed using primary cultured microglia stimulated by lipopolysaccharide (LPS) or interleukin (IL)-4, which induced M1 or M2 polarization, respectively. Furthermore, minocycline inhibited the upregulation of NF-κB in the LPS-stimulated primary cultured microglia and in the spinal cord of SOD1(G93A) mice. On the other hand, IL-4 did not induce upregulation of NF-κB. This study indicates that minocycline selectively inhibits the microglia polarization to a proinflammatory state, and provides a basis for understanding pathogeneses of many diseases accompanied by microglial activation.

Impact of cilostazol on angiographic restenosis after balloon angioplasty for infrapopliteal artery disease in patients with critical limb ischemia.

OBJECTIVE: To investigate whether cilostazol reduces restenosis and revascularization after infrapopliteal angioplasty. DESIGN: This study was a retrospective analysis of a multicenter prospective registry. MATERIALS AND METHODS: Between February and April 2011, 63 patients (68 limbs, 101 lesions) with critical limb ischemia (CLI) were enrolled. Of these, 32 were cilostazol treated and 31 were the non-cilostazol-treated group. Outcome measures were binary restenosis by angiogram, reocclusion, target lesion revascularization (TLR), limb salvage rate and complete wound healing at 3 months. RESULT: Procedural success was obtained in all patients. The backgrounds and lesion characteristics of patients with isolated tibial artery disease and CLI did not differ significantly between the two groups. In a lesion-based analysis, binary restenosis and reocclusion were significantly lower in the cilostazol group than in the non-cilostazol group (56.8% vs. 86.0%; p = 0.015, 20.5% vs. 43.6%; p = 0.015, respectively). The TLR was also significantly lower in the cilostazol group (27.5% vs. 52.8%, p = 0.014). After adjustment for covariables, cilostazol was found to be associated with reduced angiographic restenosis, reocclusion and TLR rates in CLI patients at 3 months after infrapopliteal angioplasty. However, it remained unclear whether cilostazol was also associated with improved clinical outcomes. CONCLUSION: Cilostazol may be associated with reduced restenosis, reocclusion and clinically driven TLR at 3 months after infrapopliteal angioplasty.

Angiographic restenosis and its clinical impact after infrapopliteal angioplasty.

OBJECTIVE: To assess 3- and 12-month angiographic restenosis rates and their clinical impact after infrapopliteal angioplasty. DESIGN: Prospective multicenter study. MATERIALS AND METHODS: We analyzed 68 critical ischemic limbs (tissue loss: 58 limbs) from 63 consecutive patients due to isolated infrapopliteal lesions who underwent angioplasty alone. Primary endpoint was 3-month angiographic restenosis rate; secondary endpoints were 12-month angiographic restenosis rate, and 3- and 12-month rates of mortality, major amputation and reintervention. Three- and 12-month frequency of ambulatory status and of freedom from ischemic symptoms, and time to wound healing in the ischemic wound group, were compared between restenotic and non-restenotic groups. Angiographic restenosis predictors were assessed by multivariable analysis. RESULTS: 95% of cases had 3-month angiography; restenosis rate was 73%: 40% restenosis and 33% re-occlusion. Twelve-month follow-up angiography was conducted for the patients without 3-month angiographic restenosis, and restenosis rate at 12 months was 82%. Non-administration of cilostazol and statin, and chronic total occlusion were 3-month angiographic restenosis predictors. Three- and 12-month mortality was 5% and 12%, respectively. Despite no patients having undergone amputation, 15% had persistent ischemic symptoms, and 48% of limbs underwent reintervention within 12 months. During the same study period, ambulatory status and limbs with complete healing were more frequently observed in the non-restenosis group than in the restenosis group. In the tissue loss group, time to wound healing in the restenosis group was longer than in the non-restenosis group (127 days vs. 66 days, p = 0.02). CONCLUSION: The extremely high angiographic restenosis rate after infrapopliteal angioplasty may adversely impact clinical status improvement.

Anatomical predictors of major adverse limb events after infrapopliteal angioplasty for patients with critical limb ischaemia due to pure isolated infrapopliteal lesions.

OBJECTIVE: To identify anatomical factors associated with major adverse limb events (MALE) after angioplasty as the basis for a novel morphology-driven classification of infrapopliteal lesions. DESIGN: Retrospective-multicenter study. MATERIALS AND METHODS: Between March 2004 and October 2010, 1057 limbs from 884 patients with CLI due to isolated infrapopliteal lesions were studied. Freedom-from MALE, defined as major amputation or any reintervention, was assessed out to 2 years by the Kaplan-Meier methods. Anatomical predictors and risk stratification for MALE were analyzed by multivariate analysis. RESULTS: Freedom-from MALE was 47 ± 1% at 2 years. Lesion calcification, target vessel diameter<3.0 mm, lesion length>300 mm and no below-the-ankle (BA) run-off were positively associated with MALE by multivariate-analysis. The total number of risk factors was used to calculate the risk score for each limbs for subsequent categorization into 3 groups with 0 or 1 (low-risk), 2 (moderate-risk) and 3 or 4 (high-risk) factors. Freedom-from MALE at 2 year-rates was 59% in low-risk, 46% in moderate-risk, and 29% in high-risk, respectively. CONCLUSION: Target vessel diameter <3.0 mm, lesion calcification, lesion length > 300 mm and no-BA run-off were associated with MALE after infrapopliteal angioplasty. Risk stratification based on these predictors allows estimation of future incidence of MALE in CLI with isolated infrapopliteal lesions.

A multicentre randomised phase II trial of gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer: GEMSAP study.

BACKGROUND: This randomised phase II trial compared gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer. METHODS: Patients were randomly assigned to 4-week treatment with gemcitabine alone (1000, mg m(-2) gemcitabine by 30-min infusion on days 1, 8, and 15) or gemcitabine and S-1 combination therapy (1000, mg m(-2) gemcitabine by 30-min infusion on days 1 and 15 and 40 mg m(-2) S-1 orally twice daily on days 1-15). The primary end point was progression-free survival (PFS). RESULTS: Between July 2006 and February 2009, 106 patients were enrolled. The PFS in gemcitabine and S-1 combination arm was significantly longer than in gemcitabine arm (5.4 vs 3.6 months), with a hazard ratio of 0.64 (P=0.036). Overall survival (OS) for gemcitabine and S-1 combination was longer than that for gemcitabine monotherapy (13.5 vs 8.8 months), with a hazard ratio of 0.72 (P=0.104). Overall, grade 3 or 4 adverse events were similar in both arms. CONCLUSION: Gemcitabine and S-1 combination therapy demonstrated longer PFS in advanced pancreatic cancer. Improved OS duration of 4.7 months was found for gemcitabine and S-1 combination therapy, though this was not statistically significant.