[A case of lymphatic vessel abnormality with chylous pneumonia].

Chylous pneumonia is a rare respiratory disease. The main clinical manifestation is coughing up chylous sputum with a variety of causes which can be clarified by lymphangiography. The lack of understanding of the disease, and infrequent lymphangiography have led to a high rate of misdiagnosis and missed diagnosis. Here, we reported a case of bronchial lymphatic fistula caused by lymphatic abnormality that led to the diagnosis and treatment of chylous pneumonia, with the aim of improving clinicians' understanding of this disease.

[Clinico-pathological features of temporal lobe epilepsy with enlarged amygdala].

OBJECTIVE: To summarize the clinical, video electroencephalogram (VEEG), radiological and pathological features of 3 patients of temporal lobe epilepsy (TLE) with amygdala enlargement (AE). METHODS: Three TLE patients with AE who were hospitalized in Peking University International Hospital were collected. The above features were retrospectively analyzed, and the amygdala volume was measured as well. RESULTS: Of all the 3 patients, 2 were females and 1 male, whose seizure onset ages varied from 21 to 40 years. Two cases presented with secondarily generalized tonicclonic seizures after falling asleep during the night. One of the 2 cases had complex partial seizures (CPSs) with episodic memory and automatism after one year, and the third one had CPSs with lip smacking and tongue wagging during the night. All the patients suffered from obvious anxious disorder. Unilateral AE by MRI was demonstrated in the 3 cases, one on the right side, and the other two on the left side. The average amygdala volume of the enlarged side and the other side were (2 123.7±131.8) mm3 and (1 276.3±156.9) mm3, respectively. Unilateral interictal epileptic discharges were ipsilateral to the AE in 2 cases, while the other patient showed bilateral interictal epileptic discharges. The ictal VEEG showed that the seizure onset zone was ipsilateral to the AE and was confined to the anterior and middle temporal regions in the 3 patients. The interictal single-photon emission computed tomography (SPECT) was negative in 2 cases. The interictal positron emission tomography (PET) showed hypometabolism in the AE in one case. The histological pathology revealed focal cortical dysplasia in the amygdala and temporal lobe in the 3 cases, and one of the 3 cases was combined with hippocampal sclerosis. All the patients became seizure free after surgery in the half year following-up. VEEG revealed slow wave activity and occasional spike wave in the operated side. CONCLUSION: AE may be one subtype of TLE. It is necessary to recognize AE in TLE with MRI-negative. For those poorly responsive to antiepileptic drugs, surgical treatment could provide a better solution. Focal cortical dysplasia may be one of the most common pathological features of TLE with AE.

Determination of 23 perfluorinated alkylated substances in water and suspended particles by ultra-performance liquid chromatography/tandem mass spectrometry.

A practical multi-residue method based on ultra-performance liquid chromatography/tandem mass spectrometry was developed for the simultaneous determination of 23 perfluorinated alkylated substances (PFASs) in water and suspended particles. Suspended particle samples were extracted with 1% formic acid-acetonitrile and cleaned by matrix solid phase dispersion extraction using a C18 sorbent and graphitized carbon black. Water samples were filtered through 0.7-µm glass fiber membranes and enriched utilizing weak anion exchange cartridges. The eluent was dried under a gentle stream of N2 at 45°C and suspended in 1 mL acetonitrile-5 mM ammonium acetate (1:1, vol:vol). Gradient elution for chromatographic separation utilized acetonitrile and 5 mM ammonium acetate as mobile phases on a reverse phase C18 column. The compounds were quantified using an internal standard method in multiple reaction-monitoring mode. Limits of detection and quantitation of the 23 PFAS test compounds in water samples were 0.5-10 ng L-1 and 2-20 ng L-1, respectively. Recoveries at three fortified levels of 20, 50, and 200 ng L-1 ranged from 68.5% to 118% with relative standard deviations below 9.6%. We used this method to determine PFAS levels in real water and suspended particle samples and found high sensitivity and good reproducibility.

[Relationship between hyperuricemia and prognosis in patients with heart failure of coronary heart disease after revascularization].

Objective: To explore the effect of hyperuricemia on prognosis in patients with heart failure of coronary heart disease (CHD) after revascularization. Methods: A single-center retrospective study of all subjects who underwent percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) as revascularization for CHD at Beijing Anzhen Hospital, Capital Medical University, between January 2005 and December 2014 was performed.Patients were divided into two groups by with or without hyperuricemia.The average follow-up was 1 818 d. Results: The Logistic regression analysis revealed that hyperuricemia was independent risk factors of readmission of heart failure(P=0.018, OR=1.499, 95%CI 1.071-2.098). The Cox regression analysis revealed that hyperuricemia was independent risk factor of all-cause mortality(P=0.002, RR=1.520, 95%CI 1.166-1.982), cardiovascular (CV) mortality(P=0.001, RR=1.811, 95%CI 1.279-2.566), heart failure mortality(P=0.006, RR=2.151, 95%CI 1.247-3.711). Conclusions: There is negative correlation between level of uric acid and left ventricular ejection fraction (LVEF). The patients with heart failure of coronary heart disease complicated with hyperuricemia have high risk of readmission of heart failure, all-cause mortality, CV mortality andheart failure mortality than patients with normal uric acid level. Hyperuricemia is an independent risk factor for patients with heart failure of coronary heart disease after revascularization.

[Clinicopathologic and molecular characterizations of Sertoli cell tumor, not otherwise specified of the testis].

Objective: To investigate the histomorpholgic spectrum, immunophenotypic, and molecular genetic features of Sertoli cell tumor, not otherwise specified (SCT, NOS) of the testis. Methods: Seven cases of SCT, NOS of the testis were analyzed(4 from Peking University Third Hospital and 3 from Zhejiang Provincial People's Hospital) between 2008 and 2017. The histopathologic features were examined based on HE staining, and EnVision method was used for immunohistochemistry staining of calretinin, inhibin, ß-catenin, cyclinD1, CD10, CKpan, neuroendocrine markers, WT1, Melan A, vimentin, SALL4, GATA3, PAX8, and S-100 protein. Mutational analysis of exon 3 of the CTNNB1 gene by polymerase chain reaction (PCR)-amplified sequences and direct sequencing was performed. Results: Patients ages ranged from 22 to 65 years (mean 43 years). The clinical manifestation in all was a slowly enlarging, painless testicular mass.The maximum diameter of the tumor ranged from 1.5 cm to 3.0 cm (mean 2.1 cm). Sectioning usually disclosed a tan-gray to white mass with vague lobular cut-surface. Microscopically, the tumors were well circumscribed and non-encapsulated; the tumor cells were rearranged in multiple growth patterns from diffuse solid sheets to trabeculae and cords, ribbon and solid or hollow tubules setting in variable amount of acellular fibrous stroma. Two cases showed acellular collagenous stroma constituted >50% of the tumor confirming to the diagnosis of sclerosing SCT. One case demonstrated a prominent myxoid stromal change. The tumor cells typically had moderate amounts of pale to lightly eosinophilic cytoplasm, 2 tumors had variable cells with abundant lipid-rich cytoplasm, and 1 other tumor showed scattered aggregates of multinucleated tumor cells. The tumor cells were bland-appearing without any evidence of atypia, mitoses were noted in 2 tumors (both were 1/50 HPF), but necrosis was absent. Immunohistochemical staining results as follows: vimentin (diffuse, 7/7), CD10 (diffuse membrane, 7/7); diffuse ß-catenin nuclear and cytoplasm staining in 5 of 7 cases, and all the 5 cases showed diffuse cyclin D1 nuclear staining, ß-catenin membrane staining in 2 of 7 cases, CKpan (5/7, focal or diffuse), calretinin (focal, 5/6), inhibin (focal, 3/7), synaptophysin (focal, 2/6), CD56 (focal or diffuse, 4/5), WT1 (diffuse nuclear, 4/5), and S-100 protein (diffuse, 3/7), and chromogranin A, Melan A, PAX8, GATA3 and SALL4 all were negative. Molecular genetic studies of PCR and direct sequencing showed CTNNB1 mutations in 4 of 7 (4/7) cases, 4 of the four mutation-carrying cases showed diffuse ß-catenin nuclear and cytoplasm immunoreactivity and diffuse cyclin D1 nuclear immunoreactivity in the tumor cells. Conclusions: SCT, NOS of the testis typically shows significant heterogeneities in both morphology and immunohistochemistry, thus causing differential diagnostic confusions. Molecular analyses showed mutations of exon 3 of CTNNB1 in more than half of these tumors, and nuclear accumulation of ß-catenin and over expression of cyclin D1 can be useful for the differential diagnosis of SCT, NOS.

A case report of a patient with high ß-hCG levels after operation because of primary broad ligament pregnancy.

INTRODUCTION: A broad ligament pregnancy is an extremely rare condition and diagnosis is frequently missed and finally made during laparotomy. This is a case of a young patient with high serum beta-human chorionic gonadotropin (ß-hCG) levels after operation because of broad ligament pregnancy. CASE REPORT: A 31-year-old multipara complained of intermittent lower abdominal pain with vaginal bleeding for four months. A color ultrasonography revealed a cystic mass in the left attachment area, indicating an interstitial tubal pregnancy. However, trophoblastic disease could not be excluded. She accepted conservative treatment with methotrexate (MTX) at first, but observation showed that conservative treatment was slow and accompanied with liver function damage. Therefore, exploratory laparotomy was performed. Intraoperative situations and postoperative pathology confirmed broad ligament pregnancy. Her serum p- hCG was sustained at a high level for three months after operation. Her examinations of serum, CT, and ultrasonography could explain this situation. CONCLUSION: Primary broad ligament pregnancy refers to pregnancy where implantation of the fertilized ovum occurs directly between the two leaves of the broad ligament. The gravid substance was removed, however serum ß-hCG could not gradually re- turn to normal levels. This case should be followed-up closely to prevent adverse outcomes.

[Clinicopathologic and molecular genetic characterizations of biphenotypic sinonasal sarcoma].

Objective: To investigate the clinicopathologic characteristics, immunophenotypes, molecular genetics, and diagnostic and differential diagnostic features of biphenotypic sinonasal sarcoma (BSNS). Methods: Three cases of BSNS were retrieved, the histomorphology, immunophenotype and molecular genetics were analyzed with review of literature. Results: There were 2 male and 1 female patient aged 45, 29 and 40 years, respectively.Computed tomography and magnetic resonance imaging examinations showed a large polypoid mass occupying the sinonasal cavity in all 3 patients. Microscopically, these tumors were un-circumscribed and composed of cellular spindle-shaped cells arranged in long and interlaced fascicles. A hemangiopericytoma-like growth pattern was frequently identified. The overlying hyperplastic respiratory epithelium invaginated down into the tumor forming a cystic (2 cases), glandular (1 case) structures and inverted in a papilloma-like (1 case)pattern, and foci of eosinophilic metaplasia were also noted in 2 of the three cases. The tumor nuclei were bland-appearing, mitoses were scarce and necrosis was absent. Immunohistochemically, the tumor cells showed co-expression of neural and myogenic markers in all the 3 cases, including that 3/3 showed diffuse and strong positivity of S-100 protein, 3/3 positivity of smooth muscle actin (1 diffuse and 2 focal), 1/2 diffuse positivity of calponin, 1/3 focal positivity of desmin, and 1/1 focal positivity of MyoD1.In addition, 1 detected for ß-catenin showed focal nuclear positivity. None of the 3 showed positivity to cytokeratin, CD34 or SOX10 in the tumor cells.Ki-67 showed an index <5%, 10% and <2%, respectively. Fluorescence in situ hybridization analysis showed rearrangements of PAX3 gene in all 3 cases. In case 3, reverse transcription polymerase chain reaction, followed by Sanger sequencing, demonstrated an in-frame fusion between PAX3 and FOXO1.Follow-up information (range 3-15 months)showed no evidence of local recurrence or distant metastasis in three cases. Conclusions: BSNS is a newly described entity which can be readily confused with a variety of benign and malignant spindle cell tumors encountered in the sinonasal cavity; immunohistochemistry co-expression of neural and myogenic markers and PAX3 gene rearrangement can help distinguish this tumor from its many mimickers.

[Clinicopathologic analysis of Ewing-like BCOR-CCNB3 undifferentiated sarcoma].

Objective: To investigate the morphologic, immunohistochemical, genetic, clinical features and prognosis of Ewing-like BCOR-CCNB3 gene fusion undifferentiated sarcoma (BCOR-CCNB3 fusion sarcoma). Method: Seventeen Ewing-like sarcoma cases were screened for CCNB3 expression and BCOR-CCNB3 fusion transcripts by immunohistochemistry and RT-PCR among 260 cases of Ewing-like sarcomas collected during Jan, 2006 to Dec, 2015. Three cases of BCOR-CCNB3 fusion sarcoma were found among 17 atypical Ewing sarcomas, and follow-up were conducted. Results: The harboring of BCOR-CCNB3 fusion transcript was confirmed by RT-PCR and directly sequencing results. The three patients aged between 8 and 11 years old. Two of them were male and the other one was female. One patient achieved a complete response after chemotherapy, the other two died without chemotherapy after surgical excision in 12 months. Tumor cells in all 3 cases showed diffuse nuclear CCNB3, TLE1 and cyclin D1 positivity, while CCNB3 (0/12), TLE1 (1/12) and cyclin D1 (4/12) positivity was infrequent in the 12 cases of classical Ewing's sarcoma. The oval or plump spindle tumor cells with fine chromatin arranged in solid pattern, the nucleoli was inconspicuous. The delicate capillary networks were obvious in the tumor. Conclusion: With a detailed description of the histological spectrum, immunohistochemical features and clinical characteristic of BCOR-CCNB3 sarcoma, justify distinction from Ewing sarcoma could be possible.

[Anomalous systemic arterial supply to normal basal segments of the lower lobe: three cases reports and literature review].

Objective: To improve the clinical recognition of anomalous systemic arterial supply to normal basal segments of the lower lobe in clinical manifestations, diagnosis and treatment. Methods: Three cases were presented and related literatures were reviewed. A literature review was performed with"anomalous systemic arterial supply to normal lower lobe of the lung","anomalous systemic arterial supply to normal basal segments of the lower lobe"and"anomalous systemic arterial supply to normal basal segments of the left lower lobe of the lung"as key words in Pubmed, Embase, Ovid, Wanfang database and CNKI. Result: Our 3 cases were male, with an average age of 36 years old; all of them were admitted with hemoptysis. Left lower lobectomy was performed in 2 cases, and the other 1 case underwent endovascular embolization. 26 related articles were retrieved and our 3 cases were included in this study with a total of 57 cases. The ratio of male to female was 2∶1 (38∶19), with an average age of about 35 years old. The most common symptom was hemoptysis (26/57), followed by asymptomatic (22/57). The main treatments included left lower lobectomy (17/47) and endovascular embolization of anomalous systemic artery (13/47). Conclusions: This disease is more common in male, and the most common symptom is hemoptysis. When chest CT scan shows a nodular retrocardiac density with hemoptysis symptom, clinicians and radiologists should raise suspicion of anomalous systemic arterial supply to normal basal segments of the lower lobe. Chest contrast-enhanced CT scan is an appropriate imaging method to confirm diagnosis. The main treatments include left lower lobectomy and endovascular embolization. For asymptomatic patient, observation may be an acceptable option.

[PTPS gene analysis and prenatal diagnosis in patients with 6-pyruvoyl-tetra hydropterin synthase deficiency].

Objective: To analyze the variations of PTPS gene in patients with suspected 6-pyruvoyl-tetra hydropterin synthase deficiency (PTPSD) and to make prenatal diagnosis in high-risk families. Methods: Chemiluminescence was used for phenylalanine detection in blood or dried blood spots.Patients with phenylalanine concentration over 120 µmol/L were detected by urine pterin analysis, and the activity of dihydropteridine reductase (DHPR) was detected. tetrahydrobiopterin loading tests were performed in suspected patients with abnormal urinary pterin profiles. PTPS gene variation analysis was performed by direct Sanger sequencing based on PCR amplification. Prenatal diagnosis in 7 high-risk families was performed by chorionic villus sampling when the genotype was identified. Results: In 656 patients with hyperphenylalanine, 22 cases were diagnosed as PTPSD clinically. 16 variations were detected in the 22 PTPSD cases. The 5 variations, p.Lys77Arg, p.Ile84Phe, c.315-2A>G, c.244-2A>T, c.187-1G>T, were identified as novel variations. Two fetuses carried the same mutation with the proband and therefore were thought to be PTPSD fetuses. Three fetuses carried only one mutant allele and thus were thought to be PTPSD carriers. The other 2 fetuses carried no mutations and were presumed normal. Conclusions: PTPS gene variation analysis is necessary to confirm the diagnosis. Prenatal diagnosis could help avoiding the defect birth in PTPSD families.

Prenatal diagnosis of Chinese families with phenylketonuria.

The aim of this study is to investigate the ability to prenatally diagnose phenylketonuria (PKU) by using phenylalanine hydroxylase (PAH) gene mutation analysis combined with short tandem repeat (STR) linkage analysis in 118 fetuses from 112 Chinese families. Genomic DNA was extracted from the peripheral blood from members of 112 families and the exons and exon-intron boundaries of the PAH gene were amplified by PCR. PCR products were analyzed by bi-directional Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). The three variable number of tandem repeat (VNTR) markers PAH-1, PAH-26, PAH-32 were used in the prenatal diagnosis for the PKU families. We identified a spectrum of 63 different mutations, including 61 point mutations and indels, two large exon deletion mutations, and five novel mutations. A substantial proportion of mutant alleles were accounted for by p.R243Q (15.62%), EX6-96AG (9.82%), p.V399V (7.59%), p.Y356X (6.70%), and p.R413P (5.36%). The same mutations were identified in 31 prenatally genotyped fetuses. We identified 58 fetuses that carried only one mutant allele and 29 fetuses that carried no mutations of PAH and were presumed normal. PAH gene mutation analysis combined with STR linkage analysis can provide rapid and accurate prenatal diagnosis for PKU families.

Effect of biological behavior and clinical significance of maspin gene on cervical squamous carcinoma SiHa cell.

OBJECTIVE: This study was performed to evaluate the effect of mammary serine protease inhibitor (maspin) overexpression on human cervical squamous carcinoma (SCC) SiHa cell proliferation and apoptosis in vitro. MATERIAL AND METHODS: Recombinant plasmid pcDNA3-maspin was stably transfected into human cervical SCC SiHa cell. Maspin mRNA was determined by RT-PCR, whereas maspin protein was detected by Western blot analysis and immunocytochemistry (IHC). Cell proliferation activity was measured by MTT method. Apoptosis rate and cell cycle distribution were detected by flow cytometry to understand the changes in the cell biological characteristics. RESULTS: The strengthened expression of the maspin gene in the SiHa cell was confirmed by RT-PCR, Western blot, and immunocytochemistry (IHC) (p < 0.05). Suppressed proliferation activity and increased apoptosis rate of SiHa-m (maspin stable transfected) versus SiHa and SiHa-vector cell (SiHa-pc3) were shown by MTT and flow cytometry (p < 0.05). SiHa and SiHa-pc3-had no statistical significance (p > 0.05). CONCLUSION: The results showed that maspin gene can significantly inhibit human cervical SCC SiHa cell proliferation and effectively slow cancer growth. Maspin may be a new molecular target in the gene therapy of human cervical SCC.

A physiologically based pharmacokinetic model for quinoxaline-2-carboxylic acid in rats, extrapolation to pigs.

A multi-compartment physiologically based pharmacokinetic (PBPK) model to describe the disposition of cyadox (CYX) and its metabolite quinoxaline-2-carboxylic acid (QCA) after a single oral administration was developed in rats (200 mg/kg b.w. of CYX). Considering interspecies differences in physiology and physiochemistry, the model efficiency was validated by pharmacokinetic data set in swine. The model included six compartments that were blood, muscle, liver, kidney, adipose, and a combined compartment for the rest of tissues. The model was parameterized using rat plasma and tissue concentration data that were generated from this study. Model simulations were achieved using a commercially available software program (ACSLXL ibero version 3.0.2.1). Results supported the validity of the model with simulated tissue concentrations within the range of the observations. The correlation coefficients of the predicted and experimentally determined values for plasma, liver, kidney, adipose, and muscles in rats were 0.98, 0.98, 0.98, 0.99, and 0.95, respectively. The rat model parameters were then extrapolated to pigs to estimate QCA disposition in tissues and validated by tissue concentration of QCA in swine. The correlation coefficients between the predicted and observed values were over 0.90. This model could provide a foundation for developing more reliable pig models once more data are available.

Pharmacokinetics, bioavailability and PK/PD relationship of cefquinome for Escherichia coli in Beagle dogs.

The pharmacokinetics and bioavailability of cefquinome in Beagle dogs were determined by intravenous (IV), intramuscular (IM) or subcutaneous (SC) injection at a single dose of 2 mg/kg body weight (BW). The minimum inhibitory concentrations (MIC) of cefquinome against 217 Escherichia coli isolated from dogs were also investigated. After IV injection, the plasma concentration-time curve of cefquinome was analyzed using a two-compartmental model, and the mean values of t1/2α (h), t1/2ß (h), Vss (L/kg), ClB (L/kg/h) and AUC (µg·h/mL) were 0.12, 0.98, 0.30, 0.24 and 8.51, respectively. After IM and SC administration, the PK data were best described by a one-compartmental model with first-order absorption. The mean values of t1/2Kel , t1/2Ka , tmax (h), Cmax (µg/mL) and AUC (µg·h/mL) were corresponding 0.85, 0.14, 0.43, 4.83 and 8.24 for IM administration, 0.99, 0.29, 0.72, 3.88 and 9.13 for SC injection. The duration of time that drug levels exceed the MIC (%T > MIC) were calculated using the determined MIC90 (0.125 µg/mL) and the PK data obtained in this study. The results indicated that the dosage regimen of cefquinome at 2 mg/kg BW with 12-h intervals could achieve %T > MIC above 50% that generally produced a satisfactory bactericidal effect against E. coli isolated from dogs in this study.

Postantibiotic effect and postantibiotic sub-minimum inhibitory concentration effect of valnemulin against Staphylococcus aureus isolates from swine and chickens.

UNLABELLED: The postantibiotic effect (PAE) and postantibiotic sub-minimum inhibitory concentration (MIC) effect (PA-SME) of valnemulin against Staphylococcus aureus were investigated in vitro using a spectrophotometric technique and classic viable count method. A standard curve was constructed by regression analysis of the number of colonies and the corresponding optical density (OD) at 630 nm of the inoculum. After exposure to valnemulin at different concentrations for an hour, the antibiotic was removed by centrifuging and washing. The PA-SMEs were measured after initial exposure to valnemulin at 4 × the MIC, and then, valnemulin was added to reach corresponding desired concentrations in the resuspended culture. Samples were collected hourly until the culture became turbid. The results were calculated by converting the OD values into the counts of bacteria in accordance with the curve. The MIC of valnemulin against eight strains was identically 0.125 µg ml(-1) . The mean PAEs were 2.12 h (1 × MIC) and 5.06 h (4 × MIC), and the mean PA-SMEs were 6.85 h (0.1 × MIC), 9.12 h (0.2 × MIC) and 10.8 h (0.3 × MIC). The results showed that the strains with identical MICs exhibited different PAEs and PA-SMEs. Valnemulin produced prolonged PAE and PA-SME periods for Staph. aureus, supporting a longer dosing interval while formulating a daily administration dosage. SIGNIFICANCE AND IMPACT OF THE STUDY: In this study, valnemulin demonstrated prolonged postantibiotic effects and postantibiotic sub-MIC effects on strains of Staphylococcus aureus. The strains with identical MICs of valnemulin exhibited different PAEs and PA-SMEs. Staphylococcus aureus isolated from different species has little impact on the postantibiotic effect of valnemulin. The result suggests a longer dosing interval while formulating a daily administration dosage, and it may play a valuable role of valnemulin in treating Staph. aureus infections in animals.

Population pharmacokinetics of valnemulin in swine.

This study was carried out in 121 pigs to develop a population pharmacokinetic (PPK) model by oral (p.o.) administration of valnemulin at a single dose of 10 mg/kg. Serum biochemistry parameters of each pig were determined prior to drug administration. Three to five blood samples were collected at random time points, but uniformly distributed in the absorption, distribution, and elimination phases of drug disposition. Plasma concentrations of valnemulin were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The concentration-time data were fitted to PPK models using nonlinear mixed effect modeling (NONMEM) with G77 FORTRAN compiler. NONMEM runs were executed using Wings for NONMEM. Fixed effects of weight, age, sex as well as biochemistry parameters, which may influence the PK of valnemulin, were investigated. The drug concentration-time data were adequately described by a one-compartmental model with first-order absorption. A random effect model of valnemulin revealed a pattern of log-normal distribution, and it satisfactorily characterized the observed interindividual variability. The distribution of random residual errors, however, suggested an additive model for the initial phase (<12 h) followed by a combined model that consists of both proportional and additive features (≥ 12 h), so that the intra-individual variability could be sufficiently characterized. Covariate analysis indicated that body weight had a conspicuous effect on valnemulin clearance (CL/F). The featured population PK values of Ka , V/F and CL/F were 0.292/h, 63.0 L and 41.3 L/h, respectively.

Mycoplasma gallisepticum and Escherichia coli mixed infection model in broiler chickens for studying valnemulin pharmacokinetics.

A Mycoplasma gallisepticum-Escherichia coli mixed infection model was developed in broiler chickens, which was applied to pharmacokinetics of valnemulin in the present experiment. The velogenic M. gallisepticum standard strain S6 was rejuvenated to establish the animal model, and the wild E. coli strain O78 was injected as supplementary inoculum to induce chronic respiratory disease in chickens. The disease model was evaluated based on its clinical signs, histopathological examination, bacteriological assay, and serum plate agglutination test. The pharmacokinetics of valnemulin in infected chickens was determined by intramuscular (i.m.) injection and oral administration (per os, p.o.) of a single dose of 10 mg/kg body weight (BW). Plasma samples were analyzed by liquid chromatography-tandem mass spectrometry. The plasma concentration-time curve of valnemulin was analyzed using the noncompartmental method. After the i.m. administration, the mean values of Cmax , Tmax , AUClast , MRT, CLß /F, Vz /F, and t1/2ß , were 27.94 µg/mL, 1.57 h, 171.63 µg·h/mL, 4.51 h, 0.06 L/h/kg, 0.56 L/kg, and 6.50 h, respectively. By contrast, the corresponding values after p.o. administration were 5.93 µg/mL, 7.14 h, 47.60 µg·h/mL, 9.80 h, 0.22 L/h/kg, 3.35 L/kg, and 10.60 h. The disposition of valnemulin was retarded in infected chickens after both modes of extravascular administration as compared to the healthy controls. More attention should be given to monitoring the therapeutic efficacy and adverse effects of mixed infection because of higher required plasma drug concentration and enlarged AUC with valnemulin treatment.

Population pharmacokinetics of cefquinome in pigs.

This study was performed in 145 pigs to develop a population pharmacokinetics (PPK) model by i.m. administration of cefquinome (CEQ) at the dose of 2 mg/kg in the neck muscle. Serum physiological and biochemical parameters for each pig were determined before administration. After administration, 2-4 samples were collected at random, with the sampling point evenly distributed in the three periods (<1 h, 1-4 h and >4 h). The plasma concentration of CEQ was determined by high performance liquid chromatography with UV detector. The pharmacostatistical analyses of concentration-time data, weight, age, gender, serum physiological and biochemical parameters were performed with nonlinear mixed effect modeling (NONMEM). A one-compartmental model with first-order absorption and elimination adequately described the data from the study group. The optimal random effect model of pharmacokinetics parameters was of log-normal distribution and the residual errors assumed a mixed-type model (proportional and additive) to best explain intra-individual variability. Covariate analysis showed that body weight is positively correlated with apparent volume of distribution (V/F) and body clearance (CL/F). The typical PPK parameters of Ka , CL, and V were 0.564/h, 5.15 L/h, and 1.36 L, respectively.