The roles and interaction of FXR and PPARs in the pathogenesis of nonalcoholic fatty liver disease

Background and study aimsTo identify the roles and interaction of farnesoid X receptor (FXR) and peroxisome proliferator activated receptors (PPARs) in Non-alcoholic fatty liver disease (NAFLD) pathogenesis.Material and Methods16 C57/BL male FXR knockout (KO) mice and sex- and age-matched C57/BL wild type mice were received either standard rodent chow or high-fat and sucrose diet (Blank control, NAFLD, FXR KO and FXR KO NAFLD) for 8 weeks. After that, all mice were sacrificed. Liver tissues and blood samples were collected for laboratory and RT-PCR examination.ResultsNAFLD, FXR KO and FXR KO NAFLD mouse models were successful established. Compared with blank control, FXR and PPAR-α mRNA expression decreased significantly (P < 0.05), PPAR-β expression increased slightly (P > 0.05), PPAR-γ expression increased significantly in NAFLD (P < 0.05). Slight increased PPAR-α mRNA expression (P > 0.05) and markedly decreased PPAR-β and PPAR-γ expression (P < 0.05) were found in FXR KO. Compared with FXR KO group, there was a slight increase in PPAR-αand PPAR-βmRNA expression (P > 0.05) and significant increase in PPAR-γ expression (P < 0.05) in FXR KO NAFLD group. Comparison with NAFLD, PPAR-α mRNA expression increased slightly (P > 0.05), PPAR-β and PPAR-γ expression decreased significantly (P < 0.05) in FXR KO NAFLD.ConclusionFXR and PPARs interaction may play important roles in NAFLD pathogenesis.     

In vitro characterization,ADME analysis,and histological and toxicological evaluation of BM1, a macrocyclic amidinourea active against azole-resistant Candida strains

BackgroundCandida species are one of the most common causes of nosocomial bloodstream infections among the opportunistic fungi. Extensive use of antifungal agents, most of which were launched on the market more than 20 years ago, led to the selection of drug-resistant or even multidrug-resistant fungi. We recently described a novel class of antifungal macrocyclic compounds with an amidinourea moiety that is highly active against azole-resistant Candida strains.ObjectiveA compound from this family, BM1, was investigated in terms of in vitro activity against various Candida species, including C. auris isolates, interaction with the ABC transporter, CDR6, and in vivo distribution and safety.MethodsIn vitro assays (CYP inhibition, microsomal stability, permeability, spot assays) were used to collect chemical and biological data; animal models (rat) paired with LC-MS analysis were utilised to evaluate in vivo toxicology, pharmacokinetics, and distribution.ResultsThe current research shows BM1 has a low in vivo toxicity profile, affinity for the renal system in rats, and good absorption, distribution, metabolism, and excretion (ADME). BM1 also has potent activity against azole-resistant fungal strains, including C. auris isolates and CDR6-overexpressing strains.ConclusionsThe results confirmed low minimum inhibitory concentrations (MICs) against several Candida species, including preliminary data vs. C. auris. BM1 has good ADME and biochemical characteristics, is suitable and safe for daily administration and is particularly indicated for renal infections. These data indicate BM1 and its derivatives form a novel, promising antifungal class.     

一测多评法同时测定补骨脂中16种化学成分的含量

目的建立补骨脂中16个化学成分的一测多评分析方法,结合化学计量学评价不同批次补骨脂药材的质量差异。方法采用高效液相色谱法,以异补骨脂素为内参物,测得待测成分的相对校正因子,在不同色谱仪和色谱柱上考察每个化学成分的相对校正因子的稳定性和耐用性;比较一测多评法和外标法测定结果的差异,以此验证一测多评法在补骨脂中应用的准确性。结果在建立的色谱条件下,补骨脂中15种化学成分相对于异补骨脂素的相对校正因子准确性较高,耐用性较好,且在不同实验条件下重现性良好;2种分析方法所得结果无显著差异。不同批次间补骨脂的化学成分群一致性较好,但不同化学成分的含量差异较大。结论新建立的同时测定补骨脂中16个化学成分的一测多评法,能为更加全面地评价不同来源补骨脂的整体质量提供参考。     

A high fraction of inspired oxygen may increase mortality in intubated trauma patients – A retrospective cohort study

BackgroundMechanical ventilation of trauma patients is common, and many will require a higher than normal fraction of inspired oxygen (FiO₂) to avoid hypoxaemia. The primary objective of this study was to assess the association between FiO₂ and all-cause, one-year mortality in intubated trauma patients.MethodsAdult trauma patients intubated in the initial phase post-trauma between 2015 and 2017 were retrospectively identified. Information on FiO₂ during the first 24 hours of hospitalisation and mortality was registered. For each patient the number of hours of the first 24 hours exposed to an FiO₂ ≥ 80%, ≥ 60%, and ≥ 40%, respectively, were determined and categorised into exposure durations. The associations of these FiO₂ exposures with mortality were evaluated using Cox regression adjusting for age, sex, body mass index (BMI), Injury Severity Score (ISS), prehospital Glasgow Coma Scale (GCS) score, and presence of thoracic injuries.ResultsWe included 218 intubated trauma patients. The median prehospital GCS score was 6 and the median ISS was 25. One-year mortality was significantly increased when patients had received an FiO₂ above 80% for 3-4 hours compared to <2 hours (hazard ratio (95% CI) 2.7 (1.3-6.0), p= 0.011). When an FiO₂ above 80% had been administered for more than 4 hours, there was a trend towards a higher mortality as well, but this was not statistically significant. There was a significant, time-dependent increase in mortality for patients who had received an FiO₂ ≥ 60%. There was no significant relationship observed between mortality and the duration of FiO₂ ≥ 40%.ConclusionA fraction of inspired oxygen above 60% for more than 2 hours during the first 24 hours of admission was associated with increased mortality in intubated trauma patients in a duration-dependent manner. However, given the limitations of this retrospective study, the findings need to be confirmed in a larger, randomized set-up.     

Genetic characterization of 19 X-STRs in Sierra Leone population from Freetown

International Journal of Legal Medicine - A total of 550 individuals (265 males and 285 females) from Sierra Leone, a west-African coastal country, were genotyped using the Microreader™ 19X...     

Gait analysis and muscle weight analysis after lower extremity fractures in a small animal model

BackgroundBesides adequate healing of bone and soft tissues, mobility represents a significant factor in functional outcome after lower extremity fractures. Although gait analysis is gaining clinical interest and importance in the rehabilitation of patients with fractures, it is rarely used in experimental fracture healing research. The aim of this study is to establish an accurate gait analysis method for fracture healing research in small animal models and to evaluate the influence of a lower extremity fracture on gait pattern and muscle atrophy in rats.Research questionHow does an intramedullary stabilized femur fracture influence the gait pattern and muscle atrophy during fracture healing in rats?MethodsAn isolated femur fracture with intramedullary stabilization was induced in 26 Sprague Dawley rats. Different gait parameters (e.g. intensity, print area, stand duration, duty cycle, and swing speed) were evaluated with the CatWalk gait analysis system during the fracture healing process. Furthermore, muscle weight analysis was performed at different time points.ResultsThe gait analyses with the CatWalk system showed a high correlation with the osteogenesis of fracture healing in this model. Muscle atrophy increased during the early fracture healing stages and then decreased in the later stages.SignificanceWe are the first to show that the CatWalk system is a useful tool to perform gait analyses after lower extremity fractures in a murine model. These results could form a basis for future gait analyses research in fracture healing studies to improve knowledge about bone regeneration and rehabilitation after lower extremity fractures.