Model-informed precision dosing in vancomycin treatment

Introduction: While vancomycin remains a widely prescribed antibiotic, it can cause ototoxicity and nephrotoxicity, both of which are concentration-associated. Overtreatment can occur when the treatment lasts for an unnecessarily long time. Using a model-informed precision dosing scheme, this study aims to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model for vancomycin to determine the optimal dosage regimen and treatment duration in order to avoid drug-induced toxicity.Methods: The data were obtained from electronic medical records of 542 patients, including 40 children, and were analyzed using NONMEM software. For PK, vancomycin concentrations were described with a two-compartment model incorporating allometry scaling.Results and discussion: This revealed that systemic clearance decreased with creatinine and blood urea nitrogen levels, history of diabetes and renal diseases, and further decreased in women. On the other hand, the central volume of distribution increased with age. For PD, C-reactive protein (CRP) plasma concentrations were described by transit compartments and were found to decrease with the presence of pneumonia. Simulations demonstrated that, given the model informed optimal doses, peak and trough concentrations as well as the area under the concentration-time curve remained within the therapeutic range, even at doses smaller than routine doses, for most patients. Additionally, CRP levels decreased more rapidly with the higher dose starting from 10 days after treatment initiation. The developed R Shiny application efficiently visualized the time courses of vancomycin and CRP concentrations, indicating its applicability in designing optimal treatment schemes simply based on visual inspection

TOLL-LIKE RECEPTOR 2 AND MUC2 EXPRESSION ON HUMAN INTESTINAL EPITHELIAL CELLS BY GYMNOPHALLOIDES SEOI ADULT ANTIGEN

Goblet cell hyperplasia and mucin hypersecretion are important for the expulsion of the intestinal trematode, Gymnophalloides seoi, from mice. However, regulatory mechanisms underlying these processes remain elusive. To better understand the effects of G. seoi antigen on the host`s intestinal epithelial cells, we determined whether G. seoi induces expression of Toll-like receptors (TLRs) and in mucin-related (MUC) genes on a human intestinal epithelial cell line (HT29 cells). We treated HT29 cells with G. senior other adult helminth antigens and measured mRNAs of TLRs and MUCs. We also performed reverse transcriptase-polymerase chain reaction (RT-PCR) and flow cytometry to determine whether TLR and MUC expression is regulated by interferon (IFN)-gamma, interleukin-4, or monoclonal antibodies (mAbs) against G. seoi 46 kDa antigen. Gymnophalloides seoi antigen significantly induced expression of TLR2 and MUC2 in HT29 cells, and IFN-gamma was found to upregulate TLR2 expression on the surface of the cells. The expression of MUC2 was increased by IFN-gamma, but was decreased significantly via the combination of mAbs-to-human TLRs and G. seal antigen. These results demonstrated that G. seoi antigen upregulates TLR2 and MUC2 expression on human intestinal epithelial cells. These effects reflect a helminth-induced. IFN-gamma dependent, and innate mucosal immune mechanism in this human intestinal cell line.Guk SM, 2009, J PARASITOL, V95, P581, DOI 10.1645/GE-1807.1Ueno K, 2008, AM J RESP CELL MOL, V38, P263, DOI 10.1165/rcmb.2007-0336RCKraft M, 2008, EUR RESPIR J, V31, P43, DOI 10.1183/09031936.00103307Andrianifahanana M, 2007, ONCOGENE, V26, P7251, DOI 10.1038/sj.onc.1210532Ikeda H, 2007, LAB INVEST, V87, P559, DOI 10.1038/labinvest.3700556Mueller T, 2006, J IMMUNOL, V176, P5805Harris G, 2006, WORLD J GASTROENTERO, V12, P2149Yamauchi J, 2006, APMIS, V114, P270, DOI 10.1111/j.1600-0463.2006.apm_353.xSchroder K, 2006, IMMUNOBIOLOGY, V211, P511, DOI 10.1016/j.imbio.2006.05.007Chen XM, 2005, J IMMUNOL, V175, P7447Ding SZ, 2005, HELICOBACTER, V10, P193Campos-Rodriguezp R, 2005, PARASITE IMMUNOL, V27, P1Akira S, 2004, NAT REV IMMUNOL, V4, P499, DOI 10.1038/nri1391Cario E, 2004, GASTROENTEROLOGY, V127, P224, DOI 10.1053/j.gastro.2004.04.015KAMMANADIMINTI SJ, 2004, FASEB J, V18, P155Seo M, 2003, J PARASITOL, V89, P1080, DOI 10.1645/GE-3182RNMoncada DM, 2003, TRENDS PARASITOL, V19, P305, DOI 10.1016/S1471-4922(03)00122-3McGuinness DH, 2003, TRENDS PARASITOL, V19, P312, DOI 10.1016/S1471-4922(03)00123-5Chai JY, 2003, TRENDS PARASITOL, V19, P109, DOI 10.1016/S1471-4922(02)00068-5Reddy PK, 2003, EUR J CANCER, V39, P397Coelho PS, 2002, J LEUKOCYTE BIOL, V71, P837Rose MC, 2001, AM J RESP CELL MOL, V25, P533Shekels LL, 2001, DIGEST DIS SCI, V46, P1757, DOI 10.1023/A:1010622125040Gouyer V, 2001, BBA-MOL CELL RES, V1539, P71DEPLANCKE B, 2001, AM J CLIN NUTR, V73, P1131CHAI JY, 2001, KOREAN J PARASITOL, V39, P23Enss ML, 2000, INFLAMM RES, V49, P162ONAH DN, 2000, KOREAN J PARASITOLOG, V38, P209Dabbagh K, 1999, J IMMUNOL, V162, P6233Cohn L, 1999, J IMMUNOL, V162, P6178LEE SH, 1994, AM J TROP MED HYG, V51, P281NAWA Y, 1994, PARASITE IMMUNOL, V16, P333LEE SH, 1993, J PARASITOL, V79, P677CHOMCZYNSKI P, 1987, ANAL BIOCHEM, V162, P159BEAVER PC, 1984, CLIN PARASITOLOGY

Structural performance experiment by moving cart to mount measurement sensors

The development of a measurement system for the purpose of structural performance evaluation has been needed. This work introduces a moving cart system on which to mount measurement sensors to measure acceleration and sound pressure in the time domain and an impact hammer for external excitation. The measurement data are utilized to evaluate the structural performance based on a mixed approach to directly and indirectly collect response data by a microphone and an accelerometer, respectively. The reliability of the measurement data is improved by the utilization of multiple sensors. The structural state is investigated by the power spectral density estimate (PSE) or proper orthogonal mode (POM) of the sound pressure and acceleration data. The applicability of the system is illustrated in a field test

Identification of HLA-A*2402-restricted HCMV immediate early-1 (IE-1) epitopes as targets for CD8+ HCMV-specific cytotoxic T lymphocytes

<p>Abstract</p> <p>Background</p> <p>To identify novel HLA-A*2402-restricted human cytomegalovirus (HCMV) immediate early-1 (IE-1) epitopes for adoptive immunotherapy, we explored 120 overlapping 15-amino acid spanning IE-1.</p> <p>Methods</p> <p>These peptides were screened by measuring the frequency of polyclonal CD8+ T cells producing intracellular interferon-γ (IFN-γ) using flow cytometry and the epitopes were validated with a HCMV-infected target Cr release cytotoxicity assay.</p> <p>Results</p> <p>Initial screening was performed with 12 mini-pools of 10 consecutive peptides made from 120 overlapping peptides15-amino acids in length that spanned IE-1. When peripheral blood mononuclear cells (PBMCs) from HLA-A*2402 HCMV-seropositive donors were sensitized with each of the 12 mini-pools, mini-pools 1 and 2 induced the highest frequency of CD8+ cytotoxic T lymphocytes (CTLs) producing IFN-γ. When PBMCs were stimulated with each of the twenty peptides belonging to mini-pools 1 and 2, peptides IE-1_1–15MESSAKRKMDPDNPD and IE-1_5–19AKRKMDPDNPDEGPS induced the greatest quantities of IFN-γ production and cytotoxicity of HLA-matched HCMV-infected fibroblasts. To determine the exact HLA-A*2402-restricted epitopes within the two IE-1 proteins, we synthesized a total of twenty-one overlapping 9- or 10 amino acid peptides spanning IE-1_1–15and IE-1_5–19. Peptide IE-1_3–12SSAKRKMDPD induced the greatest quantities of IFN-γ production and target cell killing by CD8+ CTLs.</p> <p>Conclusion</p> <p>HCMV IE-1_3–12SSAKRKMDPD is a HLA-A*2402-restricted HCMV IE-1 epitope that can serve as a common target for CD8+ HCMV-specific CTLs.</p

Serum high mobility group box-1 (HMGB1) is closely associated with the clinical and pathologic features of gastric cancer

<p>Abstract</p> <p>Background</p> <p>High mobility group box-1 (HMGB1) is a newly recognized factor regulating cancer cell tumorigenesis, expansion and invasion. We investigated the correlation between the serum HMGB1 levels and the clinical and pathologic features of gastric cancer and evaluated the validity of HMGB1 as a potential biomarker for the early diagnosis of gastric cancer.</p> <p>Methods</p> <p>A total of 227 subjects were classified into 5 disease groups according to the 'gastritis-dysplasia-carcinoma' sequence of gastric carcinogenesis and their serum levels of HMGB1 were analyzed by an enzyme-linked immunosorbent assay (ELISA) method. Clinical parameters, International Union Against Cancer (UICC) TNM stage, cancer size, differentiation or lymphatic invasion, vascular or perineural invasion and prognosis were used as analysis variables.</p> <p>Results</p> <p>The serum HMGB1 levels were significantly different among disease groups (ANOVA, <it>p < 0.05</it>) and HMGB1 levels tended to increase according to the progression of gastric carcinogenesis. Serum HMGB1 levels were significantly associated with depth of invasion, lymph node metastasis, tumor size, and poor prognosis (<it>p < 0.05</it>). However, HMGB1 levels were not associated with patient gender or age, differentiation of tumor cells, or lymphatic, vascular and perineural invasion, or the existence of distant metastasis in advanced cancer (<it>p > 0.05</it>). The sensitivity and specificity of serum HMGB1 was 71% and 67% (cut-off value of 5 ng/ml) for the diagnosis of early gastric cancer, and 70% and 64% (cut-off value of 4 ng/ml) for the diagnosis of high-risk lesions, respectively. These values were greater than those for carcinoembryonic antigen (CEA) (30–40% of sensitivity).</p> <p>Conclusion</p> <p>HMGB1 appears to be a useful serological biomarker for early diagnosis as well as evaluating the tumorigenesis, stage, and prognosis of gastric cancer.</p

Structural performance experiment by moving cart to mount measurement sensors

The development of a measurement system for the purpose of structural performance evaluation has been needed. This work introduces a moving cart system on which to mount measurement sensors to measure acceleration and sound pressure in the time domain and an impact hammer for external excitation. The measurement data are utilized to evaluate the structural performance based on a mixed approach to directly and indirectly collect response data by a microphone and an accelerometer, respectively. The reliability of the measurement data is improved by the utilization of multiple sensors. The structural state is investigated by the power spectral density estimate (PSE) or proper orthogonal mode (POM) of the sound pressure and acceleration data. The applicability of the system is illustrated in a field test

Gene silencing in HIV-1 latency by polycomb repressive group

<p>Abstract</p> <p>Background</p> <p>The persistence of latently Human immunodeficiency virus-1 (HIV-1) infected cellular reservoirs in resting CD4⁺T cells is a major obstacle to HIV-1 eradication. The detailed mechanism of HIV-1 latency remains unclear. We investigated histones and their post-translational modification associated with HIV-1 latency in novel HIV-1 latently infected cell lines established previously, NCHA cells.</p> <p>Methods</p> <p>To examine histones and their modification linked with HIV-1 latency, the expression profiles for core histone proteins and histone deacetylases (HDACs) in NCHA cells were characterized by RT-PCR, ELISA, and western blot. The levels of histone acetylation and methylation at histone H3 Lys⁹(H3K9) and Lys²⁷(H3K27) in HIV-1 latently infected cells were analyzed by western blot and chromatin immunoprecipitation-sequencing (ChIP-seq).</p> <p>Results</p> <p>The expression levels for four core histone proteins (H2A, H2B, H3 and H4) and HDACs (HDAC1-8) in NCHA cells were not significantly different from those in their parental cells. Histone H3K9 and H3K27 acetylations in NCHA cells showed no difference in parental and NCHA cells, whereas the levels of di- and tri-methylation were increased in NCHA cells. The expression of EED which is a component of polycomb repressive complex 2 (PRC2), and BMI1 and RING2 which are constituents of PRC1, were upregulated in NCHA cells. In addition, more ubiquitylation at histone H2A was detected in NCHA cells.</p> <p>Conclusions</p> <p>Our results suggest that tri-methylation of histone H3K27 and H2A ubiquitylation via polycomb group protein may play a crucial role in epigenetic silencing accounting for HIV-1 latency in NCHA cells.</p