Risk factors for decreased teicoplanin trough concentrations during initial dosing in critically ill patients.

Aim of the study: Here, we investigated the risk factors for decreased teicoplanin plasma trough concentrations relative to the initial dosing in critically ill patients. Patients and methods: Data obtained from 80 eligible critically ill patients who received intravenous teicoplanin were retrospectively analyzed. Risk factors for decreases in teicoplanin trough concentrations 72 h after administration of teicoplanin of more than 30% relative to predicted concentrations based on initial dosing setting were identified by logistic regression analysis. Results: Although prediction trough concentration and total dose of two days no significant differences were seen between the variation group and the non-variation group, actual trough concentration was significantly different between two groups (19.9±5.6 µg/ml vs 10.3±2.2 µg/ml, p < 0.001). In multivariate analysis, serum albumin ≤ 2.2 mg/dl (odds ratio [OR] = 3.003, 95% CI 1.072-8.408; p = 0.036) and SOFA score ≥ 9 (OR = 3.498, 95% CI 1.171-10.450; p = 0.025) were significant risk factors for decreased teicoplanin plasma trough concentrations. Conclusion: In critically ill patients, high SOFA score and low serum albumin were risk factors for decreased teicoplanin plasma trough concentration during initial dosing.

Approximate Bayesian computation analysis of EST-associated microsatellites indicates that the broadleaved evergreen tree Castanopsis sieboldii survived the Last Glacial Maximum in multiple refugia in Japan.

Climatic changes have played major roles in plants' evolutionary history. Glacial oscillations have been particularly important, but some of their effects on plants' populations are poorly understood, including the numbers and locations of refugia in Asian warm temperate zones. In the present study, we investigated the demographic history of the broadleaved evergreen tree species Castanopsis sieboldii (Fagaceae) during the last glacial period in Japan. We used approximate Bayesian computation (ABC) for model comparison and parameter estimation for the demographic modeling using 27 EST-associated microsatellites. We also performed the species distribution modeling (SDM). The results strongly support a demographic scenario that the Ryukyu Islands and the western parts in the main islands (Kyushu and western Shikoku) were derived from separate refugia and the eastern parts in the main islands and the Japan Sea groups were diverged from the western parts prior to the coldest stage of the Last Glacial Maximum (LGM). Our data indicate that multiple refugia survived at least one in the Ryukyu Islands, and the other three regions of the western and eastern parts and around the Japan Sea of the main islands of Japan during the LGM. The SDM analysis also suggests the potential habitats under LGM climate conditions were mainly located along the Pacific Ocean side of the coastal region. Our ABC-based study helps efforts resolve the demographic history of a dominant species in warm temperate broadleaved forests during and after the last glacial period, which provides a basic model for future phylogeographical studies using this approach.

A simplified chart for determining the initial loading dose of teicoplanin in critically ill patients.

AIM OF THE STUDY: A simplified chart to determine the initial loading dose of teicoplanin (TEIC chart) for achieving the target trough concentration was developed. The aim of the present study was to evaluate the usefulness of this chart in critically ill patients. PATIENTS AND METHODS: The initial loading dose and maintenance dose to achieve a target trough concentration ≥10 µg/mL on day 4 was determined using the teicoplanin TDM software and presented in a TEIC chart. The dosage of teicoplanin, including the loading dose for the first 2 days and the maintenance dose thereafter, was selected from the chart (chart method, N = 41) or calculated using TDM software (software method, N = 39). RESULTS: The performance rate of initial loading of teicoplanin increased from 83.0% to 100% after the TEIC chart was introduced (P = 0.016). The TEIC chart significantly reduced the time required for determining the initial loading dose compared with the use of software (1.9±0.6 min vs. 29.7±13.8 min, P < 0.001). No significant differences were observed in the rates of achieving a target level ≥10 µg/mL (P = 0.766). CONCLUSION: The TEIC chart enables a simple, rapid, and reliable determination of teicoplanin dosage.

Risk factors for the failure of treatment of Pseudomonas aeruginosa bacteremia in critically ill patients.

Pseudomonas aeruginosa bacteremia is associated with high morbidity and mortality in critically ill patients. In this study, we assessed risk factors for clinical failure of first definitive therapy for P. aeruginosa bacteremia in critically ill patients. All patients with P. aeruginosa bacteremia who entered the intensive care unit in Gifu University Hospital from January 2006 to December 2015 were retrospectively identified from electronic records. Risk factors associated with clinical failure of the first definitive therapy for P. aeruginosa bacteremia were analyzed by logistic regression analysis. A total of 28 patients were enrolled in the analysis. On multivariate analysis, severe burns (odds ratio [OR] = 70.9, 95% CI 2.9-1720.3; p = 0.009) and SOFA score ≥ 10 (OR = 28.5, 95% CI 1.1-754.3; p = 0.045) were significant factors in the clinical failure of first definitive therapy for P. aeruginosa bacteremia. The clinical success rate of first definitive therapy was significantly reduced in patients with these risk factors compared with those without them (p < 0.001). Severe burns and a SOFA score (≥ 10) were significant risk factors associated with the clinical failure of first definitive therapy for P. aeruginosa bacteremia in critically ill patients. We therefore recommend the use of therapeutic drug monitoring to optimize antibiotic dosing in these critically ill patients.

Picosecond rotation of a ring-shaped optical lattice by using a chirped vortex-pulse pair.

A novel method of ultrafast rotation of a ring-shaped optical lattice in the picosecond time region was proposed and demonstrated. Our ring-lattice generator was assembled by a pair of linearly chirped pulses with a time delay, a high-order birefringent retarder, and an axially symmetric polarization element. Using a mode-locked Ti:sapphire laser oscillator as a light source, stable two-, four-, and six-petaled ring-lattice rotations were demonstrated with the rotation periods of 1.6, 3.2, and 4.8 ps, respectively. Our method has the potential to open up a new technique to resonantly excite propagating quasi-particles together with their coherent enhancement.

Codominant Role of Interferon-γ- and Interleukin-17-Producing T Cells During Rejection in Full Facial Transplant Recipients.

Facial transplantation is a life-changing procedure for patients with severe composite facial defects. However, skin is the most immunogenic of all transplants, and better understanding of the immunological processes after facial transplantation is of paramount importance. Here, we describe six patients who underwent full facial transplantation at our institution, with a mean follow-up of 2.7 years. Seum, peripheral blood mononuclear cells, and skin biopsy specimens were collected prospectively, and a detailed characterization of their immune response (51 time points) was performed, defining 47 immune cell subsets, 24 serum cytokines, anti-HLA antibodies, and donor alloreactivity on each sample, producing 4269 data points. In a nonrejecting state, patients had a predominant T helper 2 cell phenotype in the blood. All patients developed at least one episode of acute cellular rejection, which was characterized by increases in interferon-γ/interleukin-17-producing cells in peripheral blood and in the allograft's skin. Serum monocyte chemotactic protein-1 level was significantly increased during rejection compared with prerejection time points. None of the patients developed de novo donor-specific antibodies, despite a fourfold expansion in T follicular helper cells at 1 year posttransplantation. In sum, facial transplantation is frequently complicated by a codominant interferon-γ/interleukin-17-mediated acute cellular rejection process. Despite that, medium-term outcomes are promising with no evidence of de novo donor-specific antibody development.

Early optimization of antimicrobial therapy improves clinical outcomes of patients administered agents targeting methicillin-resistant Staphylococcus aureus.

WHAT IS KNOWN AND OBJECTIVE: Antimicrobial stewardship is required to ensure the appropriate use of antimicrobials. However, no reports have been published on clinical outcomes of implementation of antimicrobial stewardship in patients receiving pathogen-specific antibiotics. METHOD: To evaluate the clinical outcomes of patients who received drugs, we conducted a single-centre, retrospective study of the effects of an antimicrobial stewardship programme targeting methicillin-resistant Staphylococcus aureus (MRSA). RESULTS: The time to administer effective antimicrobials was significantly (median number of days, 3 before vs. 0 after, P < 0·001) shortened, and the rate of de-escalation was significantly elevated (47·1% vs. 96·2%, P < 0·001) after implementation of daily review. The 60-day clinical failure associated with Gram-positive bacterial infection was significantly reduced (33·3% vs. 17·6%, P = 0·007) after intervention. WHAT IS NEW AND CONCLUSIONS: Daily review of administration of antimicrobials targeting MRSA was highly effective in improving clinical outcomes by optimizing early antimicrobial therapy.

Risk assessment of medically assisted reproduction and advanced maternal ages in the development of Prader-Willi syndrome due to UPD(15)mat.

Recent studies have suggested that disomic oocyte-mediated uniparental disomy 15 (UPD(15)mat) is increased in patients with Prader-Willi syndrome (PWS) born after medically assisted reproduction (MAR). However, it remains unknown whether the increase is primarily due to MAR procedure itself or advanced maternal childbearing ages as a predisposing factor for the disomic oocyte production. To examine this matter, we studied 122 naturally conceived PWS patients (PWS-NC group) and 13 MAR-conceived patients (PWS-MAR group). The relative frequency of disomic oocyte-mediated UPD(15)mat was significantly higher in PWS-MAR group than in PWS-NC group (7/13 vs 20/122, p = 0.0045), and the maternal childbearing ages were significantly higher in PWS-MAR group than in PWS-NC group [median (range), 38 (26-45) vs 30 (19-42), p = 0.0015]. However, the logistic regression analysis revealed no significant association between the occurrence of disomic oocyte-mediated UPD(15)mat and MAR, after adjusting for childbearing age (p = 0.25). Consistent with this, while the frequency of assisted reproductive technology (ART)-conceived livebirths was higher in the PWS patients than in the Japanese general population (6.4% vs 1.1%, p = 0.00018), the distribution of childbearing ages was significantly skewed to the increased ages in the PWS patients (p < 2.2 × 10(-16) ). These results argue against a positive association of MAR procedure itself with the development of UPD(15)mat.

Risk of metabolic complications in kidney transplantation after conversion to mTOR inhibitor: a systematic review and meta-analysis.

Mammalian target of rapamycin (mTOR) inhibitors have been used in transplantation with the hope of minimizing calcineurin inhibitor (CNI)-induced nephrotoxicity. However, mTOR inhibitors are also associated with a range of side effects, including metabolic complications. We aimed to determine the risks of metabolic complications after the conversion from CNI to mTOR inhibitor postkidney transplant. A systematic search in PubMed up to September 2013 identified nine relevant trials (a total of 2323 patients). The primary end points were the relative risks (RRs) of new-onset diabetes after transplant (NODAT) and hypercholesterolemia. The overall RRs of NODAT and hypercholesterolemia associated with mTOR inhibitors were 1.32 (95% confidence interval [CI] 0.92-1.87) and 2.15 (95% CI 1.35-3.41), respectively, compared with CNI-based regimen. Subgroup analyses revealed no differences in the incidence of NODAT or hypercholesterolemia between sirolimus- versus everolimus-based regimen, or between early versus late conversion. Analyses of secondary outcomes revealed a higher risk of acute rejection, proteinuria and anemia, but no difference in the risk of opportunistic infections after mTOR inhibitor conversion. In conclusion, the conversion from CNI to mTOR inhibitor in low-to-moderate risk kidney transplant recipients was associated with nonsignificant trend toward increased risk of NODAT and significant increase in hypercholesterolemia, acute rejection, proteinuria and anemia.

Radiation therapy for primary vaginal carcinoma.

Brachytherapy plays a significant role in the management of cervical cancer, but the clinical significance of brachytherapy in the management of vaginal cancer remains to be defined. Thus, a single institutional experience in the treatment of primary invasive vaginal carcinoma was reviewed to define the role of brachytherapy. We retrospectively reviewed the charts of 36 patients with primary vaginal carcinoma who received definitive radiotherapy between 1992 and 2010. The treatment modalities included high-dose-rate intracavitary brachytherapy alone (HDR-ICBT; two patients), external beam radiation therapy alone (EBRT; 14 patients), a combination of EBRT and HDR-ICBT (10 patients), or high-dose-rate interstitial brachytherapy (HDR-ISBT; 10 patients). The median follow-up was 35.2 months. The 2-year local control rate (LCR), disease-free survival (DFS), and overall survival (OS) were 68.8%, 55.3% and 73.9%, respectively. The 2-year LCR for Stage I, II, III and IV was 100%, 87.5%, 51.5% and 0%, respectively (P = 0.007). In subgroup analysis consisting only of T2-T3 disease, the use of HDR-ISBT showed marginal significance for favorable 5-year LCR (88.9% vs 46.9%, P = 0.064). One patient each developed Grade 2 proctitis, Grade 2 cystitis, and a vaginal ulcer. We conclude that brachytherapy can play a central role in radiation therapy for primary vaginal cancer. Combining EBRT and HDR-ISBT for T2-T3 disease resulted in good local control.

Outcome measurement of extensive implementation of antimicrobial stewardship in patients receiving intravenous antibiotics in a Japanese university hospital.

BACKGROUND: Antimicrobial stewardship has not always prevailed in a wide variety of medical institutions in Japan. METHODS: The infection control team was involved in the review of individual use of antibiotics in all inpatients (6348 and 6507 patients/year during the first and second annual interventions, respectively) receiving intravenous antibiotics, according to the published guidelines, consultation with physicians before prescription of antimicrobial agents and organisation of education programme on infection control for all medical staff. The outcomes of extensive implementation of antimicrobial stewardship were evaluated from the standpoint of antimicrobial use density, treatment duration, duration of hospital stay, occurrence of antimicrobial-resistant bacteria and medical expenses. RESULTS: Prolonged use of antibiotics over 2 weeks was significantly reduced after active implementation of antimicrobial stewardship (2.9% vs. 5.2%, p < 0.001). Significant reduction in the antimicrobial consumption was observed in the second-generation cephalosporins (p = 0.03), carbapenems (p = 0.003), aminoglycosides (p < 0.001), leading to a reduction in the cost of antibiotics by 11.7%. The appearance of methicillin-resistant Staphylococcus aureus and the proportion of Serratia marcescens to Gram-negative bacteria decreased significantly from 47.6% to 39.5% (p = 0.026) and from 3.7% to 2.0% (p = 0.026), respectively. Moreover, the mean hospital stay was shortened by 2.9 days after active implementation of antimicrobial stewardship. CONCLUSION: Extensive implementation of antimicrobial stewardship led to a decrease in the inappropriate use of antibiotics, saving in medical expenses, reduction in the development of antimicrobial resistance and shortening of hospital stay.

Low-molecular-weight lignin-rich fraction in the extract of cultured Lentinula edodes mycelia attenuates carbon tetrachloride-induced toxicity in primary cultures of rat hepatocytes.

The extract of cultured Lentinula edodes mycelia (LEM) is a medicinal food ingredient that has hepatoprotective effects. In this study, we fractionated the LEM extract to explore novel active compounds related to hepatoprotection by using primary cultures of rat hepatocytes exposed to carbon tetrachloride (CCl(4)). The LEM extract and the fractions markedly inhibited the release of alanine aminotransferase (ALT) from hepatocytes damaged by CCl(4) into the culture medium. The strongest hepatocyte-protective activity was seen in a fraction (Fr. 2) in which a 50% ethanol extract was further eluted with 50% methanol and separated using reverse-phase HPLC. Fr. 2 had an average molecular weight of 2753, and the main components are lignin (49%) and saccharides (36%, of which xylose comprises 41%). Therefore, Fr. 2 was presumed to be a low-molecular-weight compound consisting mainly of lignin and xylan-like polysaccharides. The hepatocyte-protective activity was observed even after digestion of xylan-like polysaccharides in Fr.2 and confirmed with low-molecular-weight lignin (LM-lignin) alone. In addition, Fr. 2, the xylan-digested Fr. 2 and LM-lignin showed higher superoxide dismutase (SOD)-like activity than the LEM extract. These results suggested that the effective fraction in the LEM extract related to hepatocyte protection consisted mainly of LM-lignin, and its antioxidant activity partially contributes to the hepatocyte-protective activity of the LEM extract.

Combined endobronchial and endoscopic ultrasound-guided fine needle aspiration for mediastinal nodal staging of lung cancer.

BACKGROUND: Recently, transesophageal endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has been evaluated for mediastinal nodal staging (N staging) of lung cancer, as this technique is less invasive than mediastinoscopy and possibly more accurate than 18F-fluorodeoxyglucose positron emission tomography with computed tomography (PET-CT). However, EUS-FNA does not provide access to pretracheal and hilar lymph nodes. More recently, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been introduced as a novel technique for accessing pretracheal and hilar lymph nodes. Although the combined endoscopic approach of EUS-FNA and EBUS-TBNA is presumably more accurate than PET-CT, only a few reports have quantitatively evaluated its diagnostic ability. Therefore, we prospectively assessed the diagnostic yield of this combined endoscopic approach for mediastinal N staging of lung cancer. METHODS: A consecutive series of 120 patients with suspected resectable lung cancer on CT findings underwent PET-CT and combined EUS-FNA/EBUS-TBNA. The accuracy and other diagnostic indices of the combined approach in mediastinal N staging were compared with those of PET-CT. RESULTS: Among the enrolled patients, a final pathological N stage was established in 110 patients. The accuracy of the combined approach using EUS-FNA and EBUS-TBNA was significantly higher than that of PET-CT (90.0 % vs. 73.6 %; P < 0.0001). The sensitivity, specificity, and positive and negative predictive values were respectively 71.8 %, 100 %, 100 %, and 86.6 % for the combined approach vs. 47.4 %, 87.5 %, 66.7 %, and 75.9 % for PET-CT. CONCLUSIONS: The combined endoscopic approach using EUS-FNA and EBUS-TBNA provided excellent diagnostic performance. Therefore, this approach is strongly recommended before surgery or mediastinoscopy to avoid futile thoracotomy and surgical intervention.

Postnatal intestinal engraftment of prospectively selected enteric neural crest stem cells in a rat model of Hirschsprung disease.

BACKGROUND: Identification of neuronal progenitor/stem cells in the postnatal gut suggests the development of transplantation approaches to enteric nervous system (ENS) diseases. Many clinical applications would require engrafting large segments of postnatal gut in vivo. We investigated the ability of unselected gut cells vs selected enteric neural crest stem cells (eNCSCs) to engraft and differentiate in the postnatal gut in the Hirschsprung disease (HD, ednrb(sl/sl)) rat. METHODS: Total intestinal cells or eNCSCs (α(4) integrin(+), p75(++)) from embryonic day (E)14.5 rats carrying a marker transgene (human placental alkaline phosphatase, hPAP) were injected intraperitoneally (i.p.) into neonatal HD rats and their healthy littermates. The entire gut was systematically analyzed 3 weeks later for hPAP(+) cells between the serosal surface and the muscularis mucosae. Engrafted cells were examined for HuC/D, S-100B, neuropeptide Y (NPY), neuronal nitric oxide synthase (nNOS), and vasoactive intestinal peptide (VIP) expression. KEY RESULTS: No rats (0/33) injected with unselected cells had hPAP(+) cells in the ENS that expressed neuronal or glial markers. 5/11 healthy and 4/5 HD rats injected with eNCSCs showed widespread but low density engraftment in the ENS with cells expressing neuronal or glial markers. Neurons expressed nNOS and VIP. There was no engraftment in the colon of either HD or wildtype rats. CONCLUSIONS & INFERENCES: Enteric neural crest stem cells will engraft diffusely throughout the postnatal gut of HD rats and differentiate into neurons and glia. Engraftment is not uniform, likely related to age-dependent changes in the gut mesenchyme. Intraperitoneal injection is easily performed in sick neonates and may be developed as a technique to supply exogenous ENS cells to the diseased postnatal gut.

Isolation and characterisation of two cDNAs encoding the neuromedin U receptor from goldfish brain.

Intracerebroventricular administration of neuromedin U (NMU) exerts an anorexigenic effect in a goldfish model. However, little is known about the NMU receptor and its signalling system in fish. In the present study, we isolated and cloned two cDNAs encoding different proteins comprising 429 and 388 amino acid residues from the goldfish brain based on the nucleotide sequences of human NMU receptor 1 (NMU-R1) and receptor 2 (NMU-R2). Hydropathy and phylogenetic analyses suggested that these two proteins were orthologues of NMU-R1 and -R2 of goldfish. We established two human embryonic kidney 293 cell lines stably expressing putative NMU-R1 and -R2, respectively, and showed that NMU induced an increase in intracellular calcium concentration ([Ca(2+)](i)) in these cells. We examined the presence of NMU-R1 and -R2 in the goldfish brain by western blotting analysis using affinity-purified antisera raised against peptide fragments derived from these receptors. NMU-R1-specific and NMU-R2-specific antisera detected a 49-kDa and 45-kDa immunopositive bands, respectively, in the brain extract. The mass of each band corresponded to that of the deduced respective primary structures. Reverse transcriptase-polymerase chain reaction analysis showed that NMU-R1 and -R2 transcripts were detected in several tissues. In particular, both mRNAs were strongly expressed in the goldfish brain. By contrast, NMU-R2 mRNA was also expressed in the gut. These results indicate for the first time that NMU-R orthologues exist in goldfish, and suggest physiological roles of NMU and its receptor system in fish.