Activity

Our HCV research program investigated novel 2′-dihalogenated nucleoside HCV polymerase inhibitors and identified compound 1, a 5′-phosphoramidate prodrug of 2′-deoxy-2′-α-bromo-β-chloro uridine. Although 1 had a favorable in vitro activity profile in HCV replicons, oral dosing in dog resulted in low levels of the active 5′-triphosphate (TP) in liver. Metabolism studies using human hepatocytes provided a simple assay for screening alternative phosphoramidate prodrug analogs. Compounds that produced high TP concentrations in hepatocytes were tested in dog liver biopsy studies. This method identified 2-aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrug 14, which provided 100-fold higher TP concentrations in dog liver in comparison to 1 (4 and 24 h after 5 mg/kg oral dose). Two new macrolide metabolites of the hygrolidin family, catenulisporidins A and B (1 and 2), together with a known compound hygrolidin (3), were isolated from the culture broth of the rare actinobacterium Catenulispora sp. selleck chemicals KCB13F192. Their structures were elucidated on the basis of HRESIMS spectrometric and NMR spectroscopic analyses. Catenulisporidins A and B are the first example of natural hygrolidin and bafilomycin derivatives featuring a modified macrolide ring, and catenulisporidin A possesses a tetrahydrofuran ring through an ether linkage between C-7 and C-10. In cell-based fluorescent imaging and immunoblot assays, the three compounds were shown to inhibit autophagic flux in HeLa cells. BACKGROUND Paraoesophageal hernia (POH) comprising type II-IV hiatal hernia often presents with pulmonary symptoms such as shortness of breath. However, impact of surgical repair on improvement in pulmonary symptoms is unclear. OBJECTIVE This systematic review and meta-analysis aimed at characterising impact of POH repair on patient reported improvement in pulmonary symptoms. METHODS This systematic review identified studies reported pulmonary symptoms in patients with undergoing surgical repair for Type II-IV POH from 1st January 2001 to 1st December 2018. Primary outcome was improvement in pulmonary symptoms. Secondary outcomes were improvement in other patient-reported outcomes such as heartburn, regurgitation, chest pain, and dysphagia and intraoperative and postoperative outcomes. RESULTS This systematic review identified 27 studies (n = 4428 patients) reporting assessment of pulmonary symptoms. However, only 21 studies (n = 2902 patients) reported preoperative and postoperative pulmonary symptoms and hence these were included in the final meta-analysis. There was significant improvement in pulmonary symptoms following POH repair (OR 8.40, CI95% 4.91-14.35, p  less then  0.001), with improvement in all types of POH. Rates of overall and major complications were 16% and 5%, respectively. Rates of conversion, 30-day mortality, reoperation and recurrence were 2%, 1% 4% and 12% respectively. CONCLUSION This review demonstrates that POH repair is associated with improvement in pulmonary symptoms with acceptable low laparoscopic conversion rates, morbidity, mortality and recurrence rates. BACKGROUND A special combined proximal tibial osteotomy (CPTO) was designed to correct varus osteoarthritis of the knee with severe intra-articular pathologies, which could not be fully corrected by opening-wedge high tibial osteotomy (OWHTO). The biomechanical strength of the CPTO bone-implant construct was evaluated and compared with those of existing osteotomy methods. METHODS Three variations of osteotomy including OWHTO, tibial condylar valgus osteotomy (TCVO), and CPTO were performed on synthetic bones with locking plate and screws. Wedge stiffness, wedge displacement, and load failure were measured by biomechanical tests. Three types of numerical tibial models were also constructed by three-dimensional model reconstruction software. The stability parameters of the three variations including wedge stiffness, wedge displacement, and stress distribution were further measured by finite-element analyses. RESULTS The biomechanical testing results revealed that the wedge stiffness, wedge displacement, and failure load of the CPTO construct were very close to those of the OWHTO construct. The numerical results of wedge stiffness and displacement showed good conformity to the previous biomechanical results. The stress distribution at the lateral hinge, the plate corner, and the holes of the CPTO construct were close to those of the OWHTO counterpart, while the stress distribution at the inter-condylar eminence of the tibia and at the middle region of the screws was close to those of the TCVO counterpart. CONCLUSIONS The CPTO construct can provide comparable strength for early mobilization and rehabilitation to that of the OWHTO construct. BACKGROUND Chronic neuropathic pain associated with peripheral neuropathies cannot be attributed solely to lesions of peripheral sensory axons and likely involves alteration in the processing of nociceptive information in the central nervous system in most patients. Few data are available regarding EEG correlates of chronic neuropathic pain. The fact is that effective cortical neuromodulation strategies to treat neuropathic pain target the precentral cortical region, i.e. a cortical area corresponding to the motor cortex. It is not known how these strategies might modulate brain rhythms in the central cortical region, but it can be speculated that sensorimotor rhythms (SMRs) are modified. Another potent way of modulating cortical rhythms is to use EEG-based neurofeedback (NFB). Rare studies previously aimed at relieving neuropathic pain using EEG-NFB training. METHODS/DESIGN The objective of this single-centre, single-blinded, randomized controlled pilot study is to assess the value of an EEG-NFB procedure totimulation. In the case of significant clinical benefit produced by the low-β(SMR)/high-β ratio increasing strategy, this work could pave the way for using EEG-NFB training within the armamentarium of neuropathic pain therapy. The objective of our study was to assess the reliability of the estimation of posttraumatic survival time (PTST) in forensic cases based on microCT and histology of putrefied/dry bone samples with comparison of initial macroscopic fracture classification performed during autopsy. Macroscopic morphological patterns of bone fracture are routinely used in forensic pathology and anthropology to distinguish between antemortem, perimortem and postmortem injuries. Based on macroscopic and microscopic analysis of six craniofacial fractures, our study results illustrate the need to complete macroscopical findings and initial fracture classification with microscopic analysis to avoid any inaccuracy. MicroCT has become a powerful technique to identify early bone healing signs but histology remains the gold standard to estimate the PTST and determine vital fracture based on hemorrhage marker. Raman microspectroscopy can identify a blood clot in the fracture line.