Effects of 5-aminolevulinic acid supplementation on milk production, iron status, and immune response of dairy cows.

The objective of this study was to investigate the effect of 5-aminolevulinic acid (5-ALA) as a dietary supplement on milk yield and composition as well as iron status and immune response in lactating dairy cows. In this study 13 lactating Holstein cows were randomly assigned to either a control group or a treatment group supplemented with 10 mg of 5-ALA per kilogram of dry matter. During feeding, 5-ALA was mixed with a small amount of the total mixed ration and top-dressed. The experiments followed a crossover design with 2 periods. Each period consisted of an adaptation period of 12 d and a test period of 2 d. Dairy cows fed the diet supplemented with 5-ALA exhibited increased counts of white blood cells and granulocytes compared with the control group. The rate of phagocytosis and mitogen-induced proliferation of peripheral blood mononuclear cells in cows fed 5-ALA were higher than in cows fed a basal diet. However, 5-ALA did not affect iron status or plasma biochemical composition. Supplementation with 5-ALA improved milk protein and milk casein contents; however, it had no effect on milk production, milk fat, lactose, total solids, or solids-not-fat, compared with the control. We conclude that dietary supplementation of 5-ALA to lactating dairy cows may have a positive effect on milk protein synthesis and the immune response.

NFκB2 Gene as a Novel Candidate that Epigenetically Responds to Interval Walking Training.

Physical fitness has been reported to decrease the risk of lifestyle-related diseases. The present study evaluated genome-wide methylation under the hypothesis that interval walking training (IWT) imparted beneficial effects on health, particularly by epigenetically ameliorating susceptibility to inflammation. We screened DNA from peripheral blood samples via genome-wide microarray for genes whose methylation was affected by IWT, paying special attention to promoter regions, and identified over 40 hyper- or hypo-methylated genes following IWT that were not witnessed in controls. We next selected genes in which the degree of methylation change in the promoter region was correlated with energy consumption following IWT. In this way, we found the NFκB2 gene to have increased methylation in multiple regions of its promoter sequence following participation in an exercise regimen. Next, IWT-induced NFκB2 hyper-methylation was confirmed by a quantitative PyroSequencing assessment of methylation in samples obtained from independent subjects who also underwent IWT. The increase in NFκB2 gene promoter methylation by IWT indicates that this regimen may suppress pro-inflammatory cytokines. Thus, these results provide an additional line of evidence that IWT is advantageous in promoting health from an epigenetic perspective by ameliorating susceptibility to inflammation.

Continuing increased risk of oral/esophageal cancer after allogeneic hematopoietic stem cell transplantation in adults in association with chronic graft-versus-host disease.

BACKGROUND: The number of long-term survivors after hematopoietic stem cell transplantation (HSCT) showed steady increase in the past two decades. Second malignancies after HSCT are a devastating late complication. We analyzed the incidence of, risk compared with that in the general population, and risk factors for secondary solid cancers. PATIENTS AND METHODS: Patients were 17 545 adult recipients of a first allogeneic stem cell transplantation between 1990 and 2007 in Japan. Risks of developing secondary solid tumors were compared with general population by using standard incidence ratios (SIRs). RESULTS: Two-hundred sixty-nine secondary solid cancers were identified. The cumulative incidence was 0.7% [95% confidence interval (CI), 0.6%-0.9%] at 5 years and 1.7% (95% CI, 1.4%-1.9%) at 10 years after transplant. The risk was significantly higher than that in the general population (SIR=1.8, 95% CI, 1.5-2.0). Risk was higher for oral cancer (SIR=15.7, 95% CI, 12.1-20.1), esophageal cancer (SIR=8.5, 95% CI, 6.1-11.5), colon cancer (SIR=1.9, 95% CI, 1.2-2.7), skin cancer (SIR=7.2, 95% CI, 3.9-12.4), and brain/nervous system cancer (SIR=4.1, 95% CI, 1.6-8.4). The risk of developing oral, esophageal, or skin cancer was higher at all times after 1-year post-transplant. Extensive-type chronic graft-versus-host disease (GVHD) was a significant risk factor for the development of all solid tumors (RR=1.8, P<0.001), as well as for oral (RR=2.9, P<0.001) and esophageal (RR=5.3, P<0.001) cancers. Limited-type chronic GVHD was an independent risk factor for skin cancers (RR=5.8, P=0.016). CONCLUSION: Recipients of allogeneic HSCT had a significantly higher ∼2-fold risk of developing secondary solid cancers than the general population. Lifelong screening for high-risk organ sites, especially oral or esophageal cancers, is important for recipients with active, or a history of, chronic GVHD.

Relative incidences and outcomes of Clostridium difficile infection following transplantation of unrelated cord blood, unrelated bone marrow, and related peripheral blood in adult patients: a single institute study.

BACKGROUND: Clostridium difficile is a major cause of nosocomial diarrhea. The incidence and prognosis of C. difficile-associated diarrhea (CDAD) has not yet been assessed in adult patients after unrelated cord blood transplantation (uCBT). METHODS: The medical records of 135 adult unrelated cord blood transplant recipients were reviewed retrospectively to investigate the clinical features of CDAD after uCBT. These data were compared to medical records of 39 unrelated bone marrow transplant recipients and 27 related peripheral blood stem cell transplant recipients as controls. RESULTS: A total of 17 recipients developed CDAD, with onset occurring at a median of 22 days (range, 0-56 days) after transplantation. Among the unrelated cord blood transplant recipients, 11 (9%) developed CDAD. These results were comparable with those of CDAD after unrelated bone marrow transplantation (uBMT) (2/39, 6%) and related peripheral blood stem cell transplantation (rPBSCT) (4/27, 16%) (P=0.37). Fifteen of the infected recipients were successfully treated with oral metronidazole, vancomycin, or cessation of antibiotics. The remaining 2 recipients who developed CDAD after uCBT died of other causes. The development of CDAD did not negatively affect overall survival after uCBT. CONCLUSIONS: These data indicate that the incidence and prognosis of CDAD after uCBT are comparable with those after uBMT and rPBSCT.

Impact of a donor source on adult Philadelphia chromosome-negative acute lymphoblastic leukemia: a retrospective analysis from the Adult Acute Lymphoblastic Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation.

BACKGROUND: We aimed to clarify the impact of the donor source of allogeneic stem cell transplantation (allo-SCT) on Philadelphia chromosome-negative acute lymphoblastic leukemia [Ph(-) ALL] with focus on cord blood (CB). PATIENTS AND METHODS: We retrospectively analyzed data of 1726 patients who underwent myeloablative allo-SCT for adult Ph(-) ALL. The sources of the allo-SCT were related donors (RD; N = 684), unrelated donors (URD; N = 809), and CB (N = 233). RESULTS: Overall survival (OS) in patients after CB allo-SCT in first complete remission (CR1) was comparable with that after RD or URD allo-SCT (RD: 65%, URD: 64% and CB: 57% at 4 years, P = 0.11). CB was not a significant risk factor for relapse or non-relapse mortality as well as for OS in multivariate analyses. Similarly, the donor source was not a significant risk factor for OS in subsequent CR or non-CR (RD: 47%, URD: 39% and CB: 48% in subsequent CR, P = 0.33; RD: 15%, URD: 21% and CB: 18% in non-CR, P = 0.20 at 4 years). CONCLUSION: Allo-SCT using CB led to OS similar to those of RD or URD in any disease status. To avoid missing the appropriate timing, CB is a favorable alternative source for adult Ph(-) ALL patients without a suitable RD or URD.

A vasodilating ß1 blocker celiprolol inhibits muscular release of uric acid precursor in patients with essential hypertension.

Although nonvasodilating ß1 blockers increase the levels of uric acid in serum, it is not known whether vasodilating ß1 blockers have a similar effect. In the present study, we evaluated the effect of celiprolol on the release of hypoxanthine, a uric acid precursor, from muscles after an exercise. We used the semi-ischemic forearm test to examine the release of lactate (ΔLAC), ammonia (ΔAmm), and hypoxanthine (ΔHX) before and 4, 10, and 60 min after an exercise in 18 hypertensive patients as well as 4 normotensive subjects. Before celiprolol treatment, all the levels of ΔHX and ΔAmm, and ΔLAC were increased by semi-ischemic exercise in hypertensive patients, and the increases were remarkably larger than those in normotensive subjects. Celiprolol decreased both systolic and diastolic pressure. It also decreased the levels of ΔHX and ΔAmm without changes in ΔLAC after an exercise. These findings also were confirmed by summation of each metabolite (ΣΔMetabolites). Celiprolol caused a marginal decrease of serum uric acid, but the difference was not statistically significant. On the other hand, nonvasodilating ß1 blockers did not suppress the levels of ΔHX and ΔAmm, whereas they significantly increased ΔLAC after an exercise. Celiprolol improved energy metabolism in skeletal muscles. It suppressed HX production and consequently did not adversely affect serum uric acid levels.

A mutation in the Pax-6 gene in rat small eye is associated with impaired migration of midbrain crest cells.

The rat small eye strain (rSey) lacks eyes and nose in the homozygote, and is similar to the mouse Sey strain with mutations in the Pax-6 gene. We isolated Pax-6 cDNA clones from an rSey homozygote library, and found an internal deletion of about 600 basepairs in the serine/threonine-rich domain. At the genomic level, a single base (G) insertion in an exon generates an abnormal 5' donor splice site, thereby producing the truncated mRNA. Anterior midbrain crest cells in the homozygous rSey embryos reached the eye rudiments but did not migrate any further to the nasal rudiments, suggesting that the Pax-6 gene is involved in conducting migration of neural crest cells from the anterior midbrain.

Polybrominated diphenyl ethers (PBDES) and polychlorinated biphenyls (PCBS) in mussels and two fish species from the estuary of the Guanabara Bay, Southeastern Brazil.

The present investigation aimed to analyze PBDE and PCB contamination in mussels (Perna perna) and two commercially important fish species, croaker (Micropogonias furnieri) and mullet (Mugil liza), in the Guanabara Bay, the most important Brazilian estuary, by gas chromatography coupled to mass spectrometry, in order to further knowledge regarding these compounds in the southern hemisphere. This is also the first report of PBDE in this mussel species in the Guanabara Bay. Fish were captured in September (dry season, winter) and March (wet season, summer) 2007 and September 2008. Mussels were collected in August (dry season, winter) 2006, in February (wet season, summer) 2007, and in August 2007 (winter). The results show that all samples showed higher PCB contamination when compared to other ecosystems around the world. On the other hand, PBDEs presented lower concentrations in 41 % of the samples. Croakers presented the highest PCB and PBDE levels, with mullet showing intermediary values and mussels, the lowest.

Pre-treatment with IL-6 potentiates ß-cell death induced by pro-inflammatory cytokines.

BACKGROUND: Type I Diabetes mellitus (T1D) is characterized by a specific destruction of ß-cells by the immune system. During this process pro-inflammatory cytokines are released in the pancreatic islets and contribute for ß-cells demise. Cytokine-induced iNOS activation, via NF-κB, is implicated in induction of ß-cells death, which includes ER stress activation. Physical exercise has been used as an adjunct for better glycemic control in patients with T1D, since it is able to increase glucose uptake independent of insulin. Recently, it was observed that the release of IL-6 by skeletal muscle, during physical exercise, could prevent ß-cells death induced by pro-inflammatory cytokines. However, the molecular mechanisms involved in this beneficial effect on ß-cells are not yet completely elucidated. Our aim was to evaluate the effect of IL-6 on ß-cells exposed to pro-inflammatory cytokines. RESULTS: Pre-treatment with IL-6 sensitized INS-1E cells to cytokine-induced cell death, increasing cytokine-induced iNOS and Caspase-3 expression. Under these conditions, however, there was a decrease in cytokines-induced p-eIF2-α but not p-IRE1expression, proteins related to ER stress. To address if this prevention of adequate UPR response is involved in the increase in ß-cells death markers induced by IL-6 pre-treatment, we used a chemical chaperone (TUDCA), which improves ER folding capacity. Use of TUDCA increased cytokines-induced Caspase-3 expression and Bax/Bcl-2 ratio in the presence of IL-6 pre-treatment. However, there is no modulation of p-eIF2-α expression by TUDCA in this condition, with increase of CHOP expression. CONCLUSION: Treatment with IL-6 alone is not beneficial for ß-cells, leading to increased cell death markers and impaired UPR activation. In addition, TUDCA has not been able to restore ER homeostasis or improve ß-cells viability under this condition, suggesting that other mechanisms may be involved.

Possibility of valence-fluctuatsion-mediated superconductivity in Cd-doped CeIrIn(5) probed by In NQR.

We report on a pressure-induced evolution of exotic superconductivity and spin correlations in CeIr(In(1-x)Cd(x))(5) by means of in-nuclear-quadrupole-resonance (NQR) studies. Measurements of an NQR spectrum and nuclear-spin-lattice-relaxation rate 1/T(1) have revealed that antiferromagnetism induced by Cd doping emerges locally around Cd dopants, but superconductivity is suddenly induced at T(c)=0.7 and 0.9 K at 2.34 and 2.75 GPa, respectively. The unique superconducting characteristics with a large fraction of the residual density of state at the Fermi level which increases with T(c) differ from those for anisotropic superconductivity mediated by antiferromagnetic correlations. By incorporating the pressure dependence of the NQR frequency pointing to the valence change of Ce, we suggest that unconventional superconductivity in the CeIr(In(1-x)Cd(x))(5) system may be mediated by valence fluctuations.

Impact of surgical site infections after open and laparoscopic colon and rectal surgeries on postoperative resource consumption.

PURPOSE: To estimate the impact of surgical site infection (SSI) on postoperative resource consumption for colon and rectal open and laparoscopic surgeries after accounting for infection depth and patient characteristics, and to compare these estimates among institutions. METHODS: We collected administrative and SSI-related data from eight Japanese hospitals, and used generalized linear models to estimate excess postoperative length of stay (LOS) and charges attributable to SSI. Covariates included wound class, American Society of Anesthesiologists (ASA) score, operation time, emergency, colostomy, trauma, implant, and comorbidities. RESULTS: We examined 1,108 colon surgery (CS) and 477 rectal surgery (RS) patients. For open surgery, the postoperative LOS in non-SSI patients was 13.5 (CS) and 15.9 days (RS). Compared with non-SSI patients, the postoperative LOS increased by 4.5 (CS) and 2.8 days (RS) for superficial SSI, 6.8 (CS) and 8.5 days (RS) for deep SSI, and 7.8 and 9.5 days for space/organ SSI. For laparoscopic surgery, the postoperative LOS was 9.8 (CS) and 14.6 days (RS). SSI was significantly associated with increased postoperative LOS for superficial SSI [by 4.8 (CS) and 3.6 days (RS)], deep SSI [by 10.3 (CS) and 23.9 days (RS)], and space/organ SSI [by 8.9 days (RS)]. The postoperative LOS among hospitals was 3.8-10.4 days (CS) and 1.3-12.2 days (RS). Postoperative SSI-attributable charges ranged from $386 to $2,873, depending on organ, procedure, and infection depth. CONCLUSION: This study quantified the impact of SSIs on resource consumption and confirmed significant cost variations among hospitals. These variations could not be explained by patient characteristics or infection type.

Rapidly progressive fatal hemorrhagic pneumonia caused by Stenotrophomonas maltophilia in hematologic malignancy.

BACKGROUND: Pneumonia caused by Stenotrophomonas maltophilia is rare, but can be lethal in severely immunocompromised patients. However, its clinical course remains unclear. PATIENTS AND METHODS: Patients with pneumonia caused by S. maltophilia in Toranomon Hospital (890 beds, Tokyo, Japan) were reviewed retrospectively between April 2006 and March 2010. RESULTS: During the study period, 10 cases of S. maltophilia pneumonia were identified. Seven patients had acute myeloid leukemia, 2 had myelodysplastic syndrome, and 1 had malignant lymphoma. All patients developed symptoms after allogeneic hematopoietic stem cell transplantation (HSCT). Five patients received first cord blood transplantation (CBT), 4 patients received second CBT, and 1 patient received first peripheral blood stem cell transplantation (PBSCT). The overall incidence of S. maltophilia pneumonia among 508 patients who received HSCT during the period was 2.0%. The incidence was 0% (0/95) in patients after bone marrow transplantation, 0.8% (1/133) after PBSCT, and 3.2% (9/279) after CBT. Pneumonia developed a median of 13.5 days (range, 6-40) after transplantation. At onset, the median white blood cell count was 10/µL (range, 10-1900), and the median neutrophil count was 0/µL (range, 0-1720). In all patients, S. maltophilia bacteremia developed with bloody sputum or hemoptysis. The 28-day mortality rate was 100%; the median survival after onset of pneumonia was 2 days (range, 1-10). CONCLUSIONS: Hemorrhagic S. maltophilia pneumonia rapidly progresses and is fatal in patients with hematologic malignancy. Attention should be particularly paid to the neutropenic phase early after HSCT or prolonged neutropenia due to engraftment failure. A prompt trimethoprim-sulfamethoxazole-based multidrug combination regimen should be considered to rescue suspected cases of S. maltophilia pneumonia in these severely immunosuppressed patients.

Chronic contamination assessment integrating biomarkers' responses in transplanted mussels--a seasonal monitoring.

This study aimed to provide the first biomonitoring integrating biomarkers and bioaccumulation data in São Paulo coast, Brazil and, for this purpose, a battery of biomarkers of defense mechanisms was analyzed and linked to contaminants' body burden in a weigh-of-evidence approach. The brown mussel Perna perna was selected to be transplanted from a farming area (Caraguatatuba) to four possibly polluted sites: Engenho D'Água, DTCS (Dutos e Terminais do Centro-Oeste de São Paulo) oil terminal (Sao Sebastiao zone), Palmas Island, and Itaipu (It; Santos Bay zone). After 3 months of exposure in each season, mussels were recollected and the cytochrome P4501A (CYP1A)- and CYP3A-like activities, glutathione-S-transferase and antioxidants enzymes (catalase, glutathione peroxidase, and glutathione reductase) were analyzed in gills. The concentrations of polycyclic aromatic hydrocarbons, linear alkylbenzenes, and nonessential metals (Cr, Cd, Pb, and Hg) in whole tissue were also analyzed and data were linked to biomarkers' responses by multivariate analysis (principal component analysis-factor analysis). A representation of estimated factor scores was performed to confirm the factor descriptions and to characterize the studied stations. Biomarkers exhibited most significant alterations all year long in mussels transplanted to It, located at Santos Bay zone, where bioaccumulation of organic and inorganic compounds was detected. This integrated approach using transplanted mussels showed satisfactory results, pointing out differences between sites, seasons, and critical areas, which could be related to land-based contaminants' sources. The influence of natural factors and other contaminants (e.g., pharmaceuticals) on biomarkers' responses are also discussed.

Diffuse dermal angiomatosis.

Diffuse dermal angiomatosis (DDA) is characterized clinically by painful erythematous lesions with ulcers and histologically by a benign, diffuse, and self-limited proliferation of tiny blood vessels in the superficial layers of the reticular dermis. Here we describe a case of DDA with leg ulcer. Erythematous lesions presented around the ulcer and angiogram revealed an occlusion of the superficial femoral artery. The erythematous lesions disappeared after revascularization. Although DDA is extremely rare, early correction of the ischemia in the peripheral artery should be taken into consideration.

UV photolysis of perfluorooctanoic acid (PFOA) in dilute aqueous solution.

Perfluorooctanoic acid (PFOA) is very persistent in the environment and widely detected in the water environment. Only some advanced methods with extreme reaction conditions are shown to be capable of degrading the compound efficiently, and almost all the earlier investigations used very high PFOA concentrations. The compound is detected normally at very low concentrations in the water environment, while mild reaction conditions for its degradation are preferable. This article aimed to elucidate photodegradation of PFOA in dilute aqueous solutions by combined UV wavelengths (185 nm+254 nm) and 254 nm using a newly designed UV jacket. PFOA degradation was greatly enhanced with the combined wavelengths with almost one hundred percent PFOA removals in four-hour reaction. The removals were well described by the first-order reaction kinetic. The removal efficiencies and rate values significantly decreased with smaller initial PFOA concentrations. But defluorination was greatly enhanced with smaller PFOA concentrations possibly due to accelerated decomposition of fluorinated intermediates of PFOA. Formic acid and acetic acid were two tentatively identified intermediates of PFOA photolysis while the former was a major intermediate predominantly controlling solution pH during the oxidation. The results demonstrated that PFOA photolysis by the combined wavelengths with mild reaction conditions can be greatly enhanced by proper design of UV jacket and reactor system.

Water matrix effect on UV photodegradation of perfluorooctanoic acid.

The widespread detection of perfluorinated compounds (PFCs) in the water environment has been a concern for the last several years, while effluents from wastewater treatment facilities are the major sources of these compounds. Even advanced oxidation technologies (AOTs) are not useful for mineralization of the compounds due to their very high stability. Photochemical techniques using particularly vacuum UV (VUV) have been found to be very promising in this regard. But the use of VUV in UV-based AOTs has still not progressed much. Moreover, the impact of water quality on PFCs photomineralization is unknown. This investigation aimed to assess photomineralization potentials of perfluorooctanoic acid (PFOA) in ultrapure water (UPW), tap water (TW), surface water and treated wastewater effluent using a reactor setup enabling maximum utilization of VUV emission of low pressure lamp in laboratory batch experiments. Neya River water (NRW) and the Nakahama Wastewater Treatment Plant Effluent (NWWTPE) represented surface water and treated wastewater effluent respectively. Also, tests were carried out in 50% diluted NRW and NWWTPE. PFOA photomineralization in terms of PFOA removal, defluorination and total organic carbon (TOC) removal are discussed. The usefulness of the method for PFOA mineralization in organic-rich wastewaters, and further research needs are also highlighted.

Prevention of venous stasis in the lower limb by transcutaneous electrical nerve stimulation.

OBJECTIVES: This study aims to investigate the effects of thromboprophylactic transcutaneous electrical nerve stimulation (TpTENS) of the peroneal nerve on venous blood flow in the limbs of volunteers. TpTENS might be considered for use in preventing venous stasis during surgical treatment. METHODS: In 10 volunteers, peak venous velocity (PV) and flow volume (FV) in the popliteal vein were measured using duplex ultrasonography during calf-muscle stimulation. The effects of TpTENS of the peroneal nerve were compared with those of other mechanical methods, including electrical muscle stimulation, intermittent pneumatic compression, active ankle motion and calf squeeze, used to prevent venous stasis and achieve thromboprophylaxis. RESULTS: TpTENS had similar effects on popliteal vein blood flow in comparison with other established methods of thromboprophylaxis. The PV increased its basal flow by 3.9 times (p < 0.01) and FV by 2.7 times (p < 0.01), respectively, compared with baseline values. CONCLUSIONS: TpTENS is as effective as other electrical and mechanical methods of calf-muscle pump activation in achieving acceleration of venous flow in the lower limb.

1,5-Anhydroglucitol attenuates cytokine release and protects mice with type 2 diabetes from inflammatory reactions.

1,5-anhydroglucitol (1,5-AG) decreases in diabetic patients and is used as a marker of glycemic control. Type 2 diabetic patients are susceptibile to lipopolysaccharides (LPS), which stimulate macrophages to release large quantities of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. This study examines the effects of 1,5-AG on lung inflammation induced by LPS and consequent systemic inflammation to determine whether the decrease of 1,5-AG concentration induces susceptibility to LPS. Before the challenge with LPS (1 mg/kg in vivo and 500 ng/ml in vitro), we pretreated db/db mice and RAW264.7 cells with 1,5-AG at 38.5 mg/kg and 500 microg/ml, respectively. The levels of IL-6, TNF-alpha, macrophage chemoattractant protein (MCP)-1 and IL-1beta in the serum and in the cell supernatants were measured. We also measured macrophage recruitment and the expression of inducible nitric oxide synthase (iNOS) in pulmonary tissues. We found that 1,5-AG attenuated serum cytokine release and protected db/db mice from LPS-induced pulmonary inflammation. In addition, 1,5-AG suppressed cytokine release and iNOS expression by suppressing Akt/NF-kB activity in RAW264.7 cells. These results suggest that 1,5-AG may be a mediator in, as well as marker for diabetes, and 1,5-AG intake may confer tolerance to LPS in patients with type 2 diabetes.