Effects of medium-chain fatty acids and tributyrin supplementation in milk replacers on growth performance, blood metabolites, and hormone concentrations in Holstein dairy calves.

This study aimed to evaluate the effects of triglycerides containing medium-chain fatty acids (MCT) and tributyrin (TB) supplementation in a milk replacer (MR) on growth performance, plasma metabolites, and hormone concentrations in dairy calves. Sixty-three Holstein heifer calves (body weight at 8 d of age, 41.1 ± 2.91 kg; mean ± SD) were randomly assigned to 1 of 4 experimental MR (28% crude protein and 18% fat): (1) containing 3.2% C8:0 and 2.8% C10:0 (in fat basis) without TB supplementation (CONT; n = 15), (2) containing 6.7% C8:0 and 6.4% C10:0 without TB supplementation (MCT; n = 16), (3) containing 3.2% C8:0 and 2.8% C10:0 with 0.6% (dry matter basis) TB supplementation (CONT+TB; n = 16), (4) containing 6.7% C8:0 and 6.4% C10:0 with 0.6% TB supplementation (MCT+TB; n = 16). The MR were offered at 600 g/d (powder basis) from 8 to 14 d, up to 1,300 g/d from 15 to 21 d, 1,400 g/d from 22 to 49 d, down to 700 g/d from 50 to 56 d, 600 g/d from 57 to 63 d, and weaned at 64 d of age. All calves were fed calf starter, chopped hay, and water ad libitum. The data were analyzed using a 2-way ANOVA via the fit model procedure of JMP Pro 16 (SAS Institute Inc.). Medium-chain fatty acid supplementation did not affect the total dry matter intake. However, calves that were fed MCT had greater feed efficiency (gain/feed) before weaning (0.74 ± 0.098 vs. 0.71 ± 0.010 kg/kg) compared with non-MCT calves. The MCT calves also had a lower incidence of diarrhea compared with non-MCT calves during 23 to 49 d of age and the weaning period (50 to 63 d of age; 9.2% vs. 18.5% and 10.5% vs. 17.2%, respectively). Calves fed with TB had a greater total dry matter intake during postweaning (3,465 vs. 3,232 g/d). Calves fed TB also had greater body weight during the weaning (90.7 ± 0.97 vs. 87.9 ± 1.01 kg) and postweaning period (116.5 ± 1.47 vs. 112.1 ± 1.50 kg) compared with that of non-TB calves. The plasma metabolites and hormone concentrations were not affected by MCT or TB. These results suggest that MCT and TB supplementation in the MR may improve the growth performance and gut health of dairy calves.

Efficacy of protocol-based pharmacotherapy management on anticoagulation with warfarin for patients with cardiovascular surgery.

WHAT IS KNOWN AND OBJECTIVE: Anticoagulation therapy with warfarin requires periodic monitoring of prothrombin time-international normalized ratio (PT-INR) and adequate dose adjustments based on the data to minimize the risk of bleeding and thromboembolic events. In our hospital, we have developed protocol-based pharmaceutical care, which we called protocol-based pharmacotherapy management (PBPM), for warfarin therapy. The protocol requires pharmacists to manage timing of blood sampling for measuring PT-INR and warfarin dosage determination based on an algorithm. This study evaluated the efficacy of PBPM in warfarin therapy by comparing to conventional pharmaceutical care. METHODS: From October 2013 to June 2015, a total of 134 hospitalized patients who underwent cardiovascular surgeries received post-operative warfarin therapy. The early series of patients received warfarin therapy as the conventional care (control group, n=77), whereas the latter received warfarin therapy based on the PBPM (PBPM group, n=68). These patients formed the cohort of the present study and were retrospectively analysed. RESULTS: The indications for warfarin included aortic valve replacement (n=56), mitral valve replacement (n=4), mitral valve plasty (n=22) and atrial fibrillation (n=29). There were no differences in patients' characteristics between both groups. The percentage time in therapeutic range in the first 10 days was significantly higher in the PBPM group (47.1%) than that in the control group (34.4%, P<.005). The average time to reach the steady state was significantly (P<.005) shorter in the PBPM group compared to the control group (7.3 vs 8.6 days). WHAT IS NEW AND CONCLUSION: Warfarin therapy based on our novel PBPM was clinically safe and resulted in significantly better anticoagulation control compared to conventional care.

Laser frequency locking with 46 GHz offset using an electro-optic modulator for magneto-optical trapping of francium atoms.

We demonstrate frequency offset locking between two laser sources using a waveguide-type electro-optic modulator (EOM) with 10th-order sidebands for magneto-optical trapping of Fr atoms. The frequency locking error signal was successfully obtained by performing delayed self-homodyne detection of the beat signal between the repumping frequency and the 10th-order sideband component of the trapping light. Sweeping the trapping-light and repumping-light frequencies with keeping its frequency difference of 46 GHz was confirmed over 1 GHz by monitoring the Doppler absorption profile of I2. This technique enables us to search for a resonance frequency of magneto-optical trapping of Fr.

miR-9-3p plays a tumour-suppressor role by targeting TAZ (WWTR1) in hepatocellular carcinoma cells.

BACKGROUND: The inactivation of the Hippo pathway lead to TAZ (PDZ-binding motif)/YAP (yes-associated protein) overexpression, and is associated with worse prognostic outcomes in various cancers including hepatocellular carcinoma (HCC). Although there are several reports of microRNA (miR) targeting for YAP, miR targeting for TAZ remains unclear. The aim of this study is to identify the miR targeting TAZ expression in HCC. METHODS: MicroRNA expression was analysed using the Human miFinder 384HC miScript miR PCR array, and was compared between low and high TAZ expression cell lines. Then, we extracted miR-9-3p as a tumour-suppressor miR targeting TAZ. We examined the functional role of miR-9-3p using miR-9-3p mimic and inhibitor in HCC cell lines). RESULTS: In HCC cell lines and HCC clinical samples, there was the inverse correlation between miR-9-3p and TAZ expressions. TAZ expression was induced by treatment of miR-9-3p inhibitor and was downregulated by treatment of miR-9-3p mimic. Treatment of miR-9-3p mimic inhibited cell proliferative ability with downregulated phosphorylations of Erk1/2, AKT, and ß-catenin in HLF. Inversely, treatment of miR-9-3p inhibitor accelerated cell growth compared with control in HuH1. CONCLUSIONS: MicroRNA-9-3p was identified as the tumour-suppressor miR targetting TAZ expression in HCC cells.

Effect of LSKL peptide on thrombospondin 1-mediated transforming growth factor ß signal activation and liver regeneration after hepatectomy in an experimental model.

BACKGROUND: A strategy for accelerating liver regeneration after hepatectomy would offer great benefits in preventing postoperative liver failure and improving surgical outcomes. Transforming growth factor (TGF) ß is a potent inhibitor of hepatocyte proliferation. Recently, thrombospondin (TSP) 1 has been identified as a negative regulator of liver regeneration by activation of local TGF-ß signals. This study aimed to clarify whether the LSKL (leucine-serine-lysine-leucine) peptide, which inhibits TSP-1-mediated TGF-ß activation, promotes liver regeneration after hepatectomy in mice. METHODS: Mice were operated on with a 70 per cent hepatectomy or sham procedure. Operated mice received either LSKL peptide or normal saline intraperitoneally at abdominal closure and 6 h after hepatectomy. Perioperative plasma TSP-1 levels were measured by enzyme-linked immunosorbent assay in patients undergoing hepatectomy. RESULTS: Administration of LSKL peptide attenuated Smad2 phosphorylation at 6 h. S-phase entry of hepatocytes was accelerated at 24 and 48 h by LSKL peptide, which resulted in faster recovery of the residual liver and bodyweight. Haematoxylin and eosin tissue staining and blood biochemical examinations revealed no significant adverse effects following the two LSKL peptide administrations. In the clinical setting, plasma TSP-1 levels were lowest on the first day after hepatectomy. However, plasma TSP-1 levels at this stage were significantly higher in patients with subsequent liver dysfunction compared with levels in those without liver dysfunction following hepatectomy. CONCLUSION: Only two doses of LSKL peptide during the early period after hepatectomy can promote liver regeneration. The transient inhibition of TSP-1/TGF-ß signal activation using LSKL peptide soon after hepatectomy may be a promising strategy to promote subsequent liver regeneration. Surgical relevance Although the mechanisms of liver regeneration after hepatectomy have been explored intensively in vivo, no therapeutic tools are thus far available to accelerate liver regeneration after hepatectomy in the clinical setting. Recently, the matricellular protein thrombospondin (TSP) 1, a major activator of latent transforming growth factor (TGF) ß1, has been identified as a negative regulator of liver regeneration after hepatectomy. In this study, the inhibition of TSP-1-mediated TGF-ß signal activation by LSKL (leucine-serine-lysine-leucine) peptide in the early period after hepatectomy accelerated liver regeneration without any adverse effects. In addition, continuous high plasma TSP-1 levels after hepatectomy were associated with liver damage in humans. The transient inhibition of TSP-1/TGF-ß signal activation using LSKL peptide in the early period after hepatectomy could be a novel therapeutic strategy to accelerate liver regeneration after hepatectomy.

Economic evaluation of a preemptive treatment strategy for invasive fungal infection in neutropenic patients with hematological diseases.

We compared the expected medical costs of empirical and preemptive treatment strategies for invasive fungal infection in neutropenic patients with hematological diseases. Based on the results of two clinical trials with different backgrounds reported by Oshima et al. [J Antimicrob Chemother 60(2):350-355; Oshima study] and Cordonnier et al. [Clin Infect Dis 48(8):1042-1051; PREVERT study], we developed a decision tree model that represented the outcomes of empirical and preemptive treatment strategies, and estimated the expected medical costs of medications and examinations in the two strategies. We assumed that micafungin was started in the empirical group at 5 days after fever had developed, while voriconazole was started in the preemptive group only when certain criteria, such as positive test results of imaging studies and/or serum markers, were fulfilled. When we used an incidence of positive test results of 6.7 % based on the Oshima study, the expected medical costs of the empirical and preemptive groups were 288,198 and 150,280 yen, respectively. Even in the case of the PREVERT study, in which the incidence of positive test results was 32.9 %, the expected medical costs in the empirical and preemptive groups were 291,871 and 284,944 yen, respectively. A sensitivity analysis indicated that the expected medical costs in the preemptive group would exceed those in the empirical group when the incidence of positive test results in the former was over 34.4 %. These results suggest that a preemptive treatment strategy can be expected to reduce medical costs compared with empirical therapy in most clinical settings.

The influence of preceding dive cycles on the foraging decisions of Antarctic fur seals.

The foraging strategy of many animals is thought to be determined by their past experiences. However, few empirical studies have investigated whether this is true in diving animals. We recorded three-dimensional movements and mouth-opening events from three Antarctic fur seals during their foraging trips to examine how they adapt their behaviour based on past experience--continuing to search for prey in the same area or moving to search in a different place. Each dive cycle was divided into a transit phase and a feeding phase. The linear horizontal distance travelled after feeding phases in each dive was affected by the mouth-opening rate during the previous 244 s, which typically covered two to three dive cycles. The linear distance travelled tended to be shorter when the mouth-opening rate in the previous 244 s was higher, i.e. seals tended to stay in the same areas with high prey-encounter rates. These results indicate that Antarctic fur seals follow decision-making strategies based on the past foraging experience over time periods longer than the immediately preceding dive.

Risk factors for pre- and post-engraftment bloodstream infections after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Bloodstream infections (BSI) are frequently observed after allogeneic hematopoietic stem cell transplant (HSCT), and could cause morbidity and mortality. METHODS: We retrospectively evaluated the incidence, characteristics of, and risk factors for BSI at both pre- and post-engraftment in 209 adult HSCT patients at our institute between June 2006 and December 2013. The median age at transplantation was 45 years (range, 15-65). A total of 122 patients received bone marrow, 68 received peripheral blood stem cells, and 19 received umbilical cord blood. RESULTS: The cumulative incidences of pre- and post-engraftment BSI were 38.9% and 17.2%, respectively. Nine patients had both pre- and post-engraftment BSI. In the pre- and post-engraftment periods, respectively, 67.4% and 84.1% of isolates were gram-positive bacteria (GPB), 28.3% and 11.4% were gram-negative bacteria (GNB), and 4.3% and 4.5% were fungi. Coagulase-negative staphylococci were the most commonly isolated GPB, while Stenotrophomonas maltophilia and Pseudomonas aeruginosa were the most commonly isolated GNB. Pre-engraftment BSI was associated with an increased risk of death. Overall survival at day 180 for patients with or without pre-engraftment BSI was 70.0% and 82.7%, respectively (P = 0.02). CONCLUSIONS: Risk factors for BSI in the pre-engraftment period were the interval between diagnosis and transplantation (261 days or more), engraftment failure, and high-risk disease status at HSCT in a multivariate analysis. No significant risk factor for BSI in the post-engraftment period was identified by a univariate analysis. These findings may be useful for deciding upon empiric antibacterial treatment for HSCT recipients.

Allotype analysis to determine the origin of cytomegalovirus immunoglobulin-G after allogeneic stem cell transplantation.

BACKGROUND: Cytomegalovirus (CMV) reactivation still remains a major problem following allogeneic hematopoietic stem cell transplantation (HSCT). PATIENTS AND METHODS: In this study, we analyzed an immunoglobulin allotype, IgG1m(f), in CMV-seropositive HSCT recipients and their donors to distinguish donor-derived antibody from recipient-derived antibody. Eight donor-recipient pairs were informative regarding the appearance of donor-derived immunoglobulin-G (IgG), as the recipients were homozygous null for the IgG1m(f) allotype and the donors were IgG1m(f) positive. In these patients, total IgG, IgM, and allotype-specific IgG against CMV were measured by enzyme-linked immunosorbent assay. All subjects were monitored for at least 9 months after HSCT with (n = 5) or without (n = 3) CMV reactivation. RESULTS: Donor-derived CMV IgG tended to be elevated earlier in patients with CMV-seropositive donors than in those with CMV-seronegative donors. In 1 patient with a CMV-negative donor, donor-derived CMV IgG was not detected until late CMV reactivation. In 3 patients without CMV reactivation, donor-derived CMV IgG was also elevated within 1-6 months after HSCT. CONCLUSION: In conclusion, the CMV serostatus of the donor may be related to the timing of the appearance of donor-derived CMV IgG and the reconstitution of humoral immunity against CMV, regardless of the CMV antigenemia level after HSCT.

Persistence of recipient-derived as well as donor-derived clones of cytomegalovirus pp65-specific cytotoxic T cells long after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Cytomegalovirus (CMV)-specific CD8(+) cytotoxic T lymphocytes (CMV-CTLs) play a crucial role in preventing CMV disease. However, the actual in vivo dynamics of CMV-CTL clones after allogeneic hematopoietic stem cell transplantation (alloHCT) are still unclear. METHODS: Using a single-cell T-cell receptor repertoire analysis, we monitored clones and chimerism of CMV-CTLs in 3 CMV-seropositive alloHCT recipients from CMV-seronegative donors, with or without CMV reactivation. RESULTS: Nearly all of the CMV-CTLs during follow-up were CD45RA(-) CCR7(-) effector memory/CD45RA(+) CCR7(-) effector T cells, and were highly matured. In each case, the use of BV gene families was restricted, especially in BV5, 7, 28, and 29. Although no common predominant CMV-CTL clones were found, several shared motifs of complementarity-determining region-3 were identified among the 3 cases; QGA in all, TGE and TDT in Case 1 and Case 2, and RDRG in Case 2 and Case 3. In all cases, CMV-CTL clones that were detected for the first time after alloHCT persisted as the dominant clones. In Case 1, without CMV reactivation, recipient-derived CMV-CTLs exclusively persisted as a dominant clone, while all CMV-CTLs in the other 2 cases, with CMV reactivation, were donor derived. CONCLUSION: Clone monitoring and chimerism analyses should help to further clarify novel aspects of immuno-reconstitution after alloHCT.

Low-dose acyclovir prophylaxis for the prevention of herpes simplex virus disease after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Currently, acyclovir (ACV) at 1000 mg/day is widely used as prophylaxis in the early phase of hematopoietic stem cell transplant (HSCT) in Japan. However, low-dose ACV (200 mg/day) has been shown to prevent varicella zoster virus reactivation in the middle and late phases of HSCT. METHODS: Therefore, in this study, we decreased the dose of ACV to 200 mg/day in the early phase after HSCT. We analyzed 93 consecutive herpes simplex virus (HSV)-seropositive patients who underwent allogeneic HSCT for the first time in our center between June 2007 and December 2011. RESULTS: Before August 2009, 38 patients received oral ACV at 1000 mg/day (ACV1000) until day 35 after HSCT, whereas 55 patients received oral ACV at 200 mg/day (ACV200) after September 2009. We compared the cumulative incidence of HSV infection in the 2 groups. Oral ACV was changed to intravenous administration because of intolerance in 66% and 45% of the patients in the ACV1000 and ACV200 groups, respectively (P = 0.060). The probability of severe stomatitis (Bearman grade II-III) was 76% and 60% in the ACV1000 and ACV200 groups, respectively (P = 0.12). The number of patients who developed HSV disease before day 100 after HSCT was 0 in the ACV1000 group and 2 in the ACV200 group, with a cumulative incidence of 3.6% (P = 0.43). HSV disease in the latter 2 patients was limited to the lips and tongue and was successfully treated with ACV or valacyclovir at a treatment dose. CONCLUSION: ACV at 200 mg/day appeared to be effective for preventing HSV disease in the early phase after HSCT.

Varicella zoster virus meningoencephalitis after allogeneic hematopoietic stem cell transplantation.

Although the reactivation of varicella zoster virus (VZV) is a common complication after allogeneic hematopoietic stem cell transplantation (HSCT), VZV meningoencephalitis is a rare life-threatening infectious disease after HSCT. We describe here a patient who developed VZV meningoencephalitis 2 years after human leukocyte antigen-matched unrelated HSCT for acute myeloblastic leukemia. She developed chronic graft-versus-host disease, and cyclosporine (CSA) was continued until 17 months after HSCT. Low-dose acyclovir (ACV) at 200 mg/day was administered to prevent the reactivation of VZV from day -7 to the termination of CSA. At 22 months, she suddenly developed fever, loss of consciousness, and seizure, with generalized skin rash. A high level of VZV DNA was detected in her cerebrospinal fluid (CSF). She was diagnosed to have VZV meningoencephalitis. Intravenous ACV at 30 mg/kg/day was given for 2 months. Although loss of consciousness was quickly resolved, some neurologic symptoms persisted. She did not have any known risk factors for VZV reactivation. Therefore, we should keep in mind that any HSCT recipient may develop VZV meningoencephalitis, and examination of CSF for VZV infection with an empiric administration of ACV may be recommended for HSCT recipients with central nervous system symptoms, even in the absence of skin manifestations.

L-index as a novel index to evaluate both the intensity and duration of lymphopenia after allogeneic hematopoietic stem cell transplantation.

We retrospectively investigated L-index, which evaluates both the intensity and duration of lymphopenia after allogeneic hematopoietic stem cell transplantation (HSCT) (n = 50). L-index was defined as the area over the lymphocyte curve during lymphopenia (absolute lymphocyte count < 700/µL). We calculated the L-index from the start of conditioning to day 30 - L-index(30) - and to day 100 - L-index(100) - after HSCT. Multivariate analysis revealed that human leukocyte antigen mismatched donor, female gender, and non-lymphoid disease were significantly associated with high L-index(30). Grade III-IV acute graft-versus-host disease, alemtuzumab-containing regimen, and non-lymphoid disease were identified as independent significant factors for high L-index(100). Cytomegalovirus (CMV) antigenemia was detected > 3 cells/2 slides by C10/11 method in 30 patients (CMV-AG ≥ 3 group) and was not detected in 20 patients (CMV-AG < 3 group). Although no significant difference was seen in absolute lymphocyte count on day 30 between the 2 groups, the L-index(30) was significantly higher in the CMV-AG ≥ 3 group than in the CMV-AG < 3 group (P = 0.050). L-index(30) was identified as an independent factor on CMV reactivation in multivariate analysis, when it was treated as a dichotomous variable with a cut-off value of 22,318, determined by receiver operating characteristic curve analysis. In conclusion, both the intensity and duration of lymphopenia in early phase after HSCT evaluated on the basis of L-index(30) showed significant association with CMV reactivation.

Living donor liver transplantation from an asymptomatic mother who was a carrier for ornithine transcarbamylase deficiency.

Liver transplantation (LT) has been adopted as a radical treatment for ornithine transcarbamylase deficiency (OTCD), yielding favorable outcomes. Despite the fact that it is an inheritable disease, a blood relative who is heterozygous for the disorder must sometimes be used as a liver donor for living donor LT. There is ongoing discussion regarding the use of heterozygous donors, however, to our knowledge, no cases where donation was determined based on the Ornithine transcarbamylase (OTC) activity before LT have been reported. Between May 2001 and April 2011, 17 patients were indicated for living donor LT because of OTCD at our facility. There were three cases with heterozygous donor candidate (17.6%). All heterozygous candidates underwent a liver biopsy to measure their OTC activity before LT and made efforts to secure the safety of the both donor and recipient. Two of 3 candidates had headaches sometimes, and their activity was less than 40%, and thus they were not employed as the donor. One candidate with 104.4% activity was employed, yielding favorable outcomes. Our current experience supported the effectiveness of our donation criteria, however it is necessary to collect sufficient data on a large number of patients to confirm the safety of the procedure.

The pathology of Mycobacterium tuberculosis infection.

Mycobacterium tuberculosis is an old enemy of the human race, with evidence of infection observed as early as 5000 years ago. Although more host-restricted than Mycobacterium bovis, which can infect all warm-blooded vertebrates, M. tuberculosis can infect, and cause morbidity and mortality in, several veterinary species as well. As M. tuberculosis is one of the earliest described bacterial pathogens, the literature describing this organism is vast and overwhelming. This review strives to distill what is currently known about this bacterium and the disease it causes for the veterinary pathologist.

[Surgical management of visceral heterotaxy syndrome].

Surgical management of the heterotaxy syndrome including asplenia or polysplenia is still challenging, because they have not only congenital heart defects but also gastrointestinal abnormalities. In most cases, they are Fontan candidates, however, indications and procedures of surgical strategy toward Fontan operation are quite difficult because of cardiac complications or abdominal manifestations. We mentioned indications, surgical technique, peri- and post-operative managements of asplenia syndrome with our experiences and results.

[Intraoperative direct angiography for the diminutive central pulmonary artery in a patient with major aortopulmonary collateral arteries].

It can be difficult to judge the degree of arborization of diminutive central pulmonary arteries (cPA) in patients with major aortopulmonary collateral arteries (MAPCA). Even through preoperative cardiac catheterization may not give adequate information. We introduce intra-operative direct angiography of diminutive cPA for patients with MAPCA. This would be one of the good options to judge the degree of arborization of the diminutive cPA, and to decide an initial surgical treatment. In this case, unifocalization of MAPCA without patch augmentation of pulmonary arteries, and an aortopulmonary shunt were performed at the 1st procedure. As enough growth of the cPA was obtained, this patient did not require additional patch augmentation of the pulmonary artery at the time of complete repair.