Pharmacokinetic study of meropenem in healthy beagle dogs receiving intermittent hemodialysis

Meropenem, a second carbapenem antimicrobial agent with a broad spectrum of activity, is used to treat sepsis and resistant-bacterial infections in veterinary medicine. The objective of this study was to identify the pharmacokinetics of meropenem in dogs receiving intermittent hemodialysis (IHD) and to determine the proper dosing in renal failure patients receiving IHD. Five healthy beagle dogs were given a single i.v. dose of 24 mg/kg of meropenem and received IHD. The blood flow rate, dialysate flow, and ultrafiltration rate were maintained at 40 mL/min, 300 mL/min, and 40 mL/h, respectively. Blood samples were collected for 24 h from the jugular vein and from the extracorporeal arterial and venous line. Urine samples and dialysate were also collected. The concentrations of meropenem were assayed using HPLC/MS/MS determination. The peak plasma concentration was 116 +/- 37 mu g/mL at 15 min. The systemic clearance was 347 +/- 117 mL/h/kg, and the steady-state volume of distribution was 223 +/- 67 mL/kg. Dialysis clearance was 71.1 +/- 34.3 mL/h/kg, and the extraction ratio by hemodialysis was 0.455 +/- 0.150. The half-life (T-1/2) in dogs with IHD decreased compared with those without IHD, and the reduction in T1/2 was greater in renal failure patients than in normal patients. Sixty-nine percent and 21% of the administered drug were recovered by urine and dialysate in the unchanged form, respectively. In conclusion, additional dosing of 24 mg/kg of meropenem after dialysis could be necessary according to the residual renal function of the patient based on the simulated data.OAIID:RECH_ACHV_DSTSH_NO:T201621129RECH_ACHV_FG:RR00200001ADJUST_YN:EMP_ID:A003050CITE_RATE:1.279FILENAME:Byun_et_al-2016-Journal_of_Veterinary_Pharmacology_and_Therapeutics.pdfDEPT_NM:수의학과EMAIL:[email protected]_YN:YFILEURL:https://srnd.snu.ac.kr/eXrepEIR/fws/file/eb2b2d93-6cb2-4420-a374-90eb43215957/linkCONFIRM:

In vivo differentiation of induced pluripotent stem cells into neural stem cells by chimera formation.

Like embryonic stem cells, induced pluripotent stem cells (iPSCs) can differentiate into all three germ layers in an in vitro system. Here, we developed a new technology for obtaining neural stem cells (NSCs) from iPSCs through chimera formation, in an in vivo environment. iPSCs contributed to the neural lineage in the chimera, which could be efficiently purified and directly cultured as NSCs in vitro. The iPSC-derived, in vivo-differentiated NSCs expressed NSC markers, and their gene-expression pattern more closely resembled that of fetal brain-derived NSCs than in vitro-differentiated NSCs. This system could be applied for differentiating pluripotent stem cells into specialized cell types whose differentiation protocols are not well established

Changes in Parthenogenetic Imprinting Patterns during Reprogramming by Cell Fusion

<div><p>Differentiated somatic cells can be reprogrammed into the pluripotent state by cell-cell fusion. In the pluripotent state, reprogrammed cells may then self-renew and differentiate into all three germ layers. Fusion-induced reprogramming also epigenetically modifies the somatic cell genome through DNA demethylation, X chromosome reactivation, and histone modification. In this study, we investigated whether fusion with embryonic stem cells (ESCs) also reprograms genomic imprinting patterns in somatic cells. In particular, we examined imprinting changes in parthenogenetic neural stem cells fused with biparental ESCs, as well as in biparental neural stem cells fused with parthenogenetic ESCs. The resulting hybrid cells expressed the pluripotency markers <i>Oct4</i> and <i>Nanog</i>. In addition, methylation of several imprinted genes except <i>Peg3</i> was comparable between hybrid cells and ESCs. This finding indicates that reprogramming by cell fusion does not necessarily reverse the status of all imprinted genes to the state of pluripotent fusion partner.</p></div

Nonarteritic anterior ischemic optic neuropathy is associated with cerebral small vessel disease.

We investigated the presence of cerebral small vessel disease (SVD) in patients with nonarteritic anterior ischemic optic neuropathy (NAION) compared to control subjects without NAION to identify the association between NAION and cerebral SVD. We retrospectively reviewed the cases of 63 patients with NAION and 2749 control subjects without any neurologic and ocular diseases including NAION who underwent careful medical interviews, ophthalmic examinations, and magnetic resonance imaging (MRI) studies of the brain. We assessed and compared the degree of cerebral SVD on the MRIs. The patients with NAION presented with cerebral SVD more frequently than controls (68% versus 37%, respectively, p<0.001), which was also observed after adjusting for age, sex, comorbid conditions including hypertension, diabetes, and dyslipidemia, and smoking using the standardized mortality ratio (68% vs. 37%, p<0.001). A multivariate logistic regression analysis showed that the odds of cerebral SVD were 4.86 (95% CI, 2.10 to 11.24, p<0.001) times higher in patients with NAION than in the controls. We found that there was an association between cerebral SVD and NAION even after adjusting for age, sex, and medical histories. Clinicians should consider brain MRI scans in patients with NAION to prevent neurological impairment after cerebral SVD

Quantitative RT-PCR analysis of imprinted gene expression.

<p>The expression profiles of paternal and maternal imprinted genes were analyzed by real-time RT-PCR. All data are normalized to <i>ACTB</i> expression and calibrated on the ESCs, whose gene expression was considered 1 for all genes. Error bars represent mean values ± SEM of three independent experiments. Student’s t-test: ***, p<0.001; **, p<0.01; *, p<0.05.</p

Generation of fusion hybrid cells between parthenogenetic and biparental cells.

<p><b>(A)</b> GFP fluorescence images of fusion between biparental ESCs and parthenogenetic neural stem cells (ES-pNSC), and between pESCs and biparental neural stem cells (pES-NSC) at day 3 after fusion (200 ×). <b>(B)</b> GFP fluorescence images of ES-pNSC and pES-NSC hybrids after FACS sorting (100 ×). <b>(C)</b> Representative tetraploid karyotype of the hybrid cells.</p

Bisulfite genome sequencing analysis of imprinted genes.

<p>DNA methylation patterns of paternally (<i>H19</i> and <i>Igf2</i>), and maternally imprinted genes (<i>Peg1</i> and <i>Peg3</i>) in ESCs, pESCs, NSCs, pNSCs, ES-pNSC, and pES-NSC hybrid cells. Black and white circles represent methylated and unmethylated CpGs, respectively.</p

Characterization of hybrid cells.

<p><b>(A)</b> Both ES-pNSC and pES-NSC hybrid cells are positive for alkaline phosphatase staining (100 ×). <b>(B)</b> RT-PCR analysis of <i>Oct4</i>, <i>Nanog</i>, <i>Sox2</i>, and <i>Nestin</i> expression in fusion partner and reprogrammed hybrid cells. Pluripotency markers, <i>Oct4</i> and <i>Nanog</i>, which were not expressed in NSCs and pNSCs were expressed in GFP⁺ fusion hybrid cells. On the other hand, <i>Nestin</i>, which was expressed in NSCs and pNSCs was silenced after forming GFP⁺ fusion hybrid cells. <b>(C)</b> Immunocytochemistry analysis of Oct4 and Nanog in ES-pNSC and pES-NSC hybrid cells (100 ×). <b>(D)</b> <i>In vitro</i> differentiation of ES-pNSC and pES-NSC hybrid cells into ectoderm (Tuj1), mesoderm (SMA), and endoderm (Sox17) lineages (200 ×). <b>(E)</b> In vivo differentiation potential of ES-pNSC and pES-NSC hybrid cells through teratoma assay. These hybrid cells were contributed to secretory epithelium (ectoderm), cartilage (mesoderm) and gut epithelium (endoderm), which were stained with PAS, Asian blue, and hematoxylin eosin, respectively. Each tissue was indicated by arrow head.</p