Pharmacokinetics/pharmacodynamics of antipseudomonal bacteriophage therapy in rats: a proof-of-concept study.

OBJECTIVES: Pan-drug-resistant (PDR) Pseudomonas aeruginosa is one of the three top-priority pathogens identified by the WHO, and bacteriophages have been investigated as an alternative therapy. However, knowledge on the pharmacokinetics/pharmacodynamics (PK/PD) of phage therapy is sparse, limiting its clinical applications. This study aimed to evaluate the PK/PD of the antipseudomonal phage øPEV20 in vivo following intravenous administration. METHODS: Healthy Sprague-Dawley rats were given øPEV20 as a single intravenous bolus of ~6, 9 and 11-log10PFU/rat. Arterial blood was sampled over 72 h. At 72 h, the animals were killed and multiple tissues were harvested for biodistribution studies. A PK model was developed using the importance sampling algorithm and deterministic simulations with a PD model were performed. RESULTS: A three-compartment model with non-linear clearance described the exposure of øPEV20 in blood. Model evaluation indicated that the model was robust and parameter estimates were accurate. The median (standard error) values of model-predicted PK parameters for VC, VP1, VP2, Q1, Q2, Vm and Km were 111 mL/rat (8.5%), 128 mL/rat (4.97%), 180 mL/rat (4.59%), 30.4 mL/h/rat (19.2%), 538 mL/h/rat (4.97%), 4.39 × 1010 PFU/h/rat (10.2%) and 1.64 × 107 PFU/mL/rat (3.6%), respectively. The distribution of øPEV20 was not homogeneous; there was preferential accumulation in the liver and spleen. Deterministic simulations with a PD model confirmed the importance of the host immune system in facilitating phage-mediated bacterial elimination. CONCLUSIONS: We developed a robust PK model to describe the disposition of phages in healthy rats. This model may have significant potential in facilitating future preclinical and clinical PK/PD investigations.

Correlation between liver cirrhosis and risk of death from oral cancer: Taiwan cohort study.

BACKGROUND: A nationwide population-based cohort was used to examine the severity of liver cirrhosis and risk of mortality from oral cancer. METHODS: The cohort consisted of 3583 patients with oral cancer treated by surgery between 2008 and 2011 in Taiwan. They were grouped on the basis of normal liver function (n = 3471), cirrhosis without decompensation (n = 72) and cirrhosis with decompensation (n = 40). The primary endpoint was mortality. Hazard ratios of death were also determined. RESULTS: The mortality rates in the respective groups were 14.8 per cent, 20.8 per cent and 37.5 per cent at one year (p < 0.001). The adjusted hazard ratios of death at one year for each group compared to the normal group were 2.01 (p = 0.021) for cirrhotic patients without decompensation, 4.84 (p < 0.001) for those with decompensation and 2.65 (p < 0.001) for those receiving chemotherapy. CONCLUSION: Liver cirrhosis can be used to predict one-year mortality in oral cancer patients. Chemotherapy should be used with caution and underlying co-morbidities should be managed in cirrhotic patients to reduce mortality risk.

Angiotensin II type 1 receptor gene A1166C polymorphism and breast cancer susceptibility.

Numerous studies have evaluated the association between the angiotensin II type-1 receptor (AGTR1) gene A1166C polymorphism and breast cancer risk. However, the specific association is controversial. The aim of the present study was to derive a more precise estimation of the relationship. A comprehensive research was conducted of the PubMed and the Google Scholar databases through February 2015. Data were assessed using STATA version 12.0. Pooled odds ratios with 95%CIs were derived from the fixed-effect or random-effect models. A total of 911 patients with breast cancer and 1284 controls from 5 case-control studies were included in this meta-analysis. The meta-analysis results showed no significant association between the AGTR1 gene A1166C polymorphism and breast cancer risk. Similarly, in the subgroup analysis regarding ethnicity, no associations were observed. Heterogeneity and publication bias were not observed in this meta-analysis. The A1166C polymorphism in the AGTR1 gene may not be a risk factor for breast cancer. Further, large, and well-designed studies are needed to confirm this conclusion.

Randomised clinical trial: high-dose vs. standard-dose proton pump inhibitors for the prevention of recurrent haemorrhage after combined endoscopic haemostasis of bleeding peptic ulcers.

BACKGROUND: The optimal dosage of intravenous proton pump inhibitors (PPIs) for the prevention of peptic ulcer rebleeding remains unclear. AIM: To compare the rebleeding rate of high-dose and standard-dose PPI use after endoscopic haemostasis. METHODS: A total of 201 patients with bleeding ulcers undergoing endoscopic treatment with epinephrine injection and heater probe thermocoagulation were randomised to receive a high-dose regimen (80 mg bolus, followed by pantoprazole 8 mg/h infusion, n = 100) or a standard-dose regimen (pantoprazole 40 mg bolus daily, n = 101). After 72 h, all patients were given 40 mg pantoprazole daily orally for 27 days. RESULTS: There were no statistical differences in mean units of blood transfused, length of hospitalisation ≦5 days, surgical or radiological interventions and mortality within 30 days between two groups. Bleeding recurred within 30 days in six patients [6.2%, 95% confidence interval (CI) 1.3-11.1%] in the high-dose group, as compared to five patients (5.2%, 95% CI 0.6-9.7%) in the standard-dose group (P = 0.77). The stepwise Cox regression analysis showed end-stage renal disease, haematemesis, chronic obstructive pulmonary disease (hazard ratio: 37.15, 10.07, 9.12, 95% CI: 6.76-204.14, 2.07-49.01, 1.66-50.00 respectively) were independent risk factors for rebleeding and Helicobacter pylori infection was associated with lower risk of rebleeding (hazard ratio: 0.20, 95% CI: 0.04-0.94). CONCLUSIONS: Following combined endoscopic haemostasis of bleeding ulcers, co-morbidities, haematemesis and H. pylori Status, but not PPI dosage, are associated with rebleeding (http://www.Clinical Trials.gov.ID: NCT00709046).

Automatic control of mechanical forces acting on cell biomembranes using a vision-guided microrobotic system in computer microscopy.

A prototype for automatic control of mechanical forces acting on cell biomembranes is proposed in this paper. This prototype consists of vision-guided position control of the holder and micro-force sensor, automatic mechanical property characterization of cell biomembranes and automatic control of mechanical forces acting on cell biomembranes. A template-free calibration method and autofocusing of multiple objects are introduced in the vision-guided position control to minimize external biological contamination and position the cell, holder and micro-force sensor into the same focal plane, respectively. A third-order polynomial modified from biomembrane point-load model describing the relationship between the measured mechanical force and the deformations of biomembranes is proposed. This simplified model is easily identified and inversed to facilitate the automatic control of mechanical forces. Experimental results based on zebrafish embryos demonstrate the feasibility of the proposed prototype.

Self-calibration method for vision-guided cell micromanipulation systems.

A new self-calibration method for a piezoelectric actuator-based vision-guided cell micromanipulation system is proposed. This method consolidates all the system parameters' uncertainties into a matrix instead of classifying into intrinsic and extrinsic. The position difference of the micromanipulator tip in the image plane between the measured and estimated output which is based on estimations of relevant parameters is assumed to be caused by the matrix. This matrix is estimated by means of collecting several pairs of known input and the corresponding output differences. Matrix standard deviation and gray-value based matching are applied to identify the output differences. Biological contamination is reduced since a calibration template is not required. This self-calibration is particularly suitable for cell micromanipulation systems where the micromanipulator is frequently dismounted and mounted.

[Plant regeneration from Agobacterium-mediated CTV-cp gene transformation of Poncirus trifoliata Raf].

OBJECTIVE: To lay a foundation for the resistant breeding, the anti-virus CTV-cp gene was transformed into the epicotyles mediated by Agrobacterium tumefaciens in Poncirus trifoliata. METHOD: The explants used for the genetic transformation were the epicotyls from P. trifoliata. The Agrobacterum tumefaciens strain was EHA101 containing vector plasmid pGA482GG. The coat protein gene (CTV-cp gene), GUS gene and NPT II gene were introduced into the transformation plasmid. RESULTS: Ceftaxime used as antibiotics was better than carbenicillin. The concentration was 300 mg.L-1; The selection pressure for kanamycin was 50 mg.L-1; 70.0% of the resistant plants were GUS-positive; extra gene was proved to be in P. trifoliata plant by southern blot examination. CONCLUSION: An effective genetic transformation mediated by Agrobacterium tumefacines, which harbours a CTV-cp gene, has been developed in P. trifoliata. Transgenic CTV-cp plants were obtained.

Isolation of Tyrosine Decarboxylaseless Mutants of a Bacteriocin-Producing Enterococcus faecalis Strain and Their Application in Cheese.

Enterococcus faecalis INIA 4, a bacteriocin-producing strain, was exposed to the mutagenic agent ethyl methanesulfonate (EMS). A modified differential plating medium permitted the isolation of mutants INIA 4-01 to 4-09 with reduced tyrosine decarboxylase activity. All mutant strains displayed rapid growth in milk, while bacteriocin production ranged from 15 to 125% as compared to the parental strain. Enterococcus faecalis INIA 4, INIA 4-07 (less than 0.1% residual tyrosine decarboxylase activity) and INIA 4-03 (10% residual activity) were used in cheese-making experiments. In cheese made from pasteurized milk, using INIA 4-07 as adjunct starter, tyramine was not produced (< 5 mg/kg of cheese after 4 months of ripening). Suppression of Listeria innocua in raw-milk cheeses made using INIA 4-03 and INIA 4-07 was equal to that observed in the cheese made using the parental strain INIA 4. After 2 months of ripening, no free tyrosine and 195 mg/kg of tyramine were detected in the cheese with INIA 4. The tyrosine content of the cheeses made with INIA 4-03 and INIA 4-07 and of the control cheese was approximately 95 mg/kg. The cheeses with INIA 4-03 and 4-07 contained 116 and 120 mg/kg of tyramine respectively, values comparable to the level of 101 mg/kg detected in a control raw-milk cheese to which no enterococci were added. The relatively high tyramine formation in the cheeses made with INIA 4-03 and INIA 4-07 and in the control cheese was probably caused by the decarboxylating activity of the indigenous flora of the raw milk.

[Estrogen and progesterone cytosol receptor concentrations in patients with endometriosis and their changes after gossypol therapy].

UNLABELLED: Estrogen and progesterone cytosol receptor (ERc, PRc) concentrations of endometrium biopsied during different phases of menstrual cycle were measured by dextran-coated charcoal method in 27 normal fertile women and 24 patients with endometriosis. 15 out of 24 endometriotic patients were put on gossypol for 2 months thereafter. After discontinuation of the drug, ERc, PRc contents of endometrium were reexamined during the same cycle day. Serum estradiol (E2) and progesterone (P) levels were also compared before and after gossypol treatment. In addition, endometriotic tissue and intrauterine endometrium were immediately obtained from the same patient after surgery in 16 cases with endometriosis, and their ERc, PRc concentrations were also compared. RESULTS: endometrium ERc, PRc concentrations of normal controls fluctuated during the menstrual cycle, with the peak at late follicular phase. In endometriosis group, the ERc, PRc contents and cyclic changes of endometrium in situ were not significantly different from the normal controls. However, the ERc, PRc contents of endometriotic tissue were significantly lower than those of endometrium in situ (P = 0.0036 and < 0.0001 respectively) without cyclic changes during menstrual cycle. After 2 months of gossypol therapy, serum E2 and P levels tended to decrease but the differences were not significant. Glandular secretion of endometrium decreased in only 4 out of 15 cases under pathological examination. In contrast, the ERc, PRc concentrations of endometrium in situ differed significantly from the pretreatment values (P = 0.0217 and 0.01 respectively). These data indicated: (1) The response of endometriotic tissue to estrogen and progestin was lower than that of endometrium in situ.(ABSTRACT TRUNCATED AT 250 WORDS)

Detection of transmural myocardial infarction by single-photon emission computed tomography with thallium-201: comparison with planar imaging.

The ability of single-photon emission computed tomography (SPECT) with thallium-201 to detect transmural myocardial infarction was compared with that of planar imaging. Planar imaging was performed at rest after SPECT in 80 patients with the first myocardial infarction and in 20 patients without myocardial infarction. The planar and SPECT images were interpreted qualitatively. Tomography was significantly more sensitive than planar imaging in detecting inferior infarctions (43/46 or 93% vs 22/46 or 48%; p less than 0.05). In detecting anterior infarctions, the sensitivity rate was 92% (35/38) for SPECT and 79% (30/38) for planar imaging (p = NS). The overall sensitivity was 93% for tomography and 63% for planar imaging (p less than 0.05). The specificity was similar (100%) with the 2 techniques. It is concluded that SPECT significantly improves the detection of thallium-201 myocardial perfusion defects in patients with myocardial infarctions, especially those occurring on the inferior wall.

Luteal function in patients with endometriosis.

Nineteen patients with endometriosis were selected for investigation of luteal function as determined by serum progesterone (P) concentrations at different stages of the luteal phase, and by observation of basal body temperature (BBT) profiles and endometrial histological appearances. Sixteen cases were accompanied with infertility. All data were synchronized to the day of midcycle serum luteinizing hormone (LH) peak (D0) and analyzed accordingly. In the endometriosis group, mean serum P concentrations of early, mid luteal phases and the integrated P concentration of the whole luteal phase were significantly lower than in the control group. Five cases (26.3%) had low peak P values during mid-luteal phase and/or low integrated P levels. Delayed endometrial maturation was revealed in 10 of 16 cases (62.5%). Short luteal phase, as defined by BBT, was observed in 3 of 14 cases (21.4%). A total of 12 cases were screened for all three parameters, among them, ten (83.3%) had at least one abnormality and seven (58.3%) showed two aberrant results. In summary, the incidence of luteal phase defect was higher in the endometriosis group than in controls. The pathogenic mechanism of luteal phase defect and its role in infertility are discussed.