Structural Simplification of Bedaquiline: the Discovery of 3-(4-(N,N-dimethylaminomethyl)phenyl)quinoline Derived Antitubercular Lead Compounds

Bedaquiline (BDQ) is a novel and highly potent last-line antituberculosis drug that was approved by the US FDA in 2013. Owing to its stereo-structural complexity, chemical synthesis and compound optimization are rather difficult and expensive. This study describes the structural simplification of bedaquiline while preserving antitubercular activity. The compound's structure was split into fragments and reassembled in various combinations while replacing the two chiral carbon atoms with an achiral linkage instead. Four series of analogues were designed; these candidates retained their potent antitubercular activity at sub-microgram per mL concentrations against both sensitive and multidrug-resistant (MDR) Mycobacterium tuberculosis strains. Six out of the top nine MIC-ranked candidates were found to inhibit mycobacterial ATP synthesis activity with IC50 values between 20 and 40 μm, one had IC50>66 μm, and two showed no inhibition, despite their antitubercular activity. These results provide a basis for the development of chemically less complex, lower-cost bedaquiline derivatives and describe the identification of two derivatives with antitubercular activity against non-ATP synthase related targets

Lack of association between mutations of gene-encoding mitochondrial D310 (displacement loop) mononucleotide repeat and oxidative stress in chronic dialysis patients in Taiwan

<p>Abstract</p> <p>Background</p> <p>Mitochondria (mt) are highly susceptible to reactive oxygen species (ROS). In this study, we investigated the association between a region within the displacement loop (D-loop) in mtDNA that is highly susceptible to ROS and oxidative stress markers in chronic dialysis patients. We enrolled 184 chronic dialysis patients and 213 age-matched healthy subjects for comparison. Blood levels of oxidative stress markers, such as thiobarbituric acid reactive substances (TBARS) and free thiol, and the mtDNA copy number were determined. A mononucleotide repeat sequence (CCCC...CCCTCCCCCC) between nucleotides 303 and 316-318 (D310) was identified in mtDNA.</p> <p>Results</p> <p>Depending on alterations in the D310 mononucleotide repeat, subjects were categorized into 4 subgroups: 7-C, 8-C, 9 or 10-C, and T-to-C transition. Oxidative stress was higher in chronic dialysis patients, evidenced by higher levels of TBARS and mtDNA copy number, and a lower level of free thiol. The distribution of 7-C, 8-C, and 9-10C in dialysis and control subjects was as follows: 7-C (38% <it>vs. </it>31.5%), 8-C (35.3% <it>vs. </it>43.2%), and 9-10C (24.5% <it>vs. </it>22.1%). Although there were significant differences in levels of TBARS, free thiol, and the mtDNA copy number in the D310 repeat subgroups (except T-to-C transition) between dialysis patients and control subjects, post hoc analyses within the same study cohort revealed no significant differences.</p> <p>Conclusion</p> <p>Although oxidative stress was elevated in chronic dialysis patients and resulted in a compensatory increase in the mtDNA copy number, homopolymeric C repeats in the mtDNA region (D310), susceptible to ROS, were not associated with oxidative stress markers in these patients.</p

Luminescent Organic–Inorganic Hybrids of Functionalized Mesoporous Silica SBA-15 by Thio-Salicylidene Schiff Base

Novel organic–inorganic mesoporous luminescent hybrid material N, N′-bis(salicylidene)-thiocarbohydrazide (BSTC-SBA-15) has been obtained by co-condensation of tetraethyl orthosilicate and the organosilane in the presence of Pluronic P123 surfactant as a template. N,N′-bis(salicylidene)-thiocarbohydrazide (BSTC) grafted to the coupling agent 3-(triethoxysilyl)-propyl isocyanate (TESPIC) was used as the precursor for the preparation of mesoporous materials. In addition, for comparison, SBA-15 doped with organic ligand BSTC was also synthesized, denoted as BSTC/SBA-15. This organic–inorganic hybrid material was well-characterized by X-ray diffraction, Fourier transform infrared spectroscopy, transmission electron microscopy (HRTEM), and photoluminescence spectra, which reveals that they all have high surface area, uniformity in the mesostructure. The resulting materials (BSTC-SBA-15 and BSTC/SBA-15) exhibit regular uniform microstructures, and no phase separation happened for the organic and the inorganic compounds was covalently linked through Si–O bonds via a self-assemble process. Furthermore, the two materials have different luminescence range: BSTC/SBA-15 presents the strong dominant green luminescence, while BSTC-functionalized material BSTC-SBA-15 shows the dominant blue emission

Role of the supine lateral radiograph of the spine in vertebroplasty for osteoporotic vertebral compression fracture: a prospective study

<p>Abstract</p> <p>Background</p> <p>Severely collapsed vertebral compression fracture (VCF) is usually considered as a contraindication for vertebroplasty because of critically decreased vertebral height (less than one-third the original height). However, osteoporotic VCF can possess dynamic mobility with intravertebral cleft (IVC), which can be demonstrated on supine lateral radiographs (SuLR) and standing lateral radiographs (StLR). The purposes of this study were to: (1) evaluate the efficacy of SuLR to detect IVCs and assess the intravertebral mobility in VCFs, and (2) evaluate the short-term results of vertebroplasty in severely collapsed VCFs with IVCs.</p> <p>Methods</p> <p>We enrolled 37 patients with 40 symptomatic osteoporotic VCFs for vertebroplasty; 11 had severely collapsed VCFs with concurrent IVCs detected on the SuLR, the others had not-severely collapsed VCFs. A preoperative StLR, SuLR, magnetic resonance imaging (MRI), and postoperative StLR were taken from all patients. Radiographs were digitized to calculate vertebral body morphometrics including vertebral height ratio and Cobb's kyphotic angle. The intensity of the patient's pain was assessed by the visual analogue scale (VAS) on the day before operation and 1 day, 1 month, and 4 months after operation. The patient's VAS scores and image measurement results were assessed with the paired <it>t</it>-test and Pearson correlation tests; Mann-Whitney U test was used for VAS subgroup comparison. Significance was defined as <it>p </it>< 0.05.</p> <p>Results</p> <p>IVCs in patients with not-severely collapsed VCFs were detected in 21 vertebrae (72.4%) by MRI, in 15 vertebrae (51.7%) by preoperative SuLR, and in 7 vertebrae (24.1%) by preoperative StLR. Using the MRI as a gold standard to detect IVCs, SuLR exhibit a sensitivity of 0.71 as compared to StLR that yield a sensitivity of 0.33. In patients with VCFs with IVCs detected on SuLR, the average of the postoperative restoration in vertebral height ratio was significantly higher than that in those without IVCs (17.1% vs. 6.4%). There was no statistical difference in the VAS score between severely collapsed VCFs with IVCs detected on SuLR and not-severely collapsed VCFs at any follow-up time point.</p> <p>Conclusions</p> <p>The SuLR efficiently detects an IVC in VCF, which indicates a better vertebral height correction after vertebroplasty compared to VCF without IVC. Before performing a costly MRI, SuLR can identify more IVCs than StLR in patients with severely collapsed VCFs, whom may become the candidates for vertebroplasty.</p

National profile of foot orthotic provision in the United Kingdom, part 1 : practitioners and scope of practice.

Foot orthoses have been advocated in the management of a wide range of clinical foot and lower limb problems and are within the scope of podiatry, orthotic and physiotherapy practice. Previous reports into the provision of orthoses have consistently identified significant issues with services and devices, but data were never specific to foot orthoses. The aim of this first of a series of papers was to report the first ever national multi professional profile of foot orthosis provision in the United Kingdom. Quantitative and qualitative data were collected from podiatrists, orthotists and physiotherapists via an online questionnaire. The topics, questions and answers were developed through a series of pilot phases. The professions were targeted through electronic and printed materials. Data were captured over a 10 month period in 2016. A total of 499 responses were included in analysis, including 357 podiatrists, 93 orthotists and 49 physiotherapists. The results reveal wide ranging practices across podiatrists, orthotists and physiotherapists, provision of orthoses through different health care departments (uni and multidisciplinary), for different health conditions (acute and chronic), and involving different types of orthoses (prefabricated and customised). Foot orthoses in the United Kingdom are provided in areas of well recognised health and rehabilitation priorities. A wide range of orthotic devices and practices are employed and different professions provide foot orthoses in different ways

Correlates of Untreated Hypercholesterolemia in Older Adults: A Community-Based Household Survey in China.

Hypercholesterolemia is common in older adults and less treated, but little is known about correlates of untreated hypercholesterolemia. Using a standard interview method we examined a random sample of 7,572 participants aged 60 years in a community-based household survey across 7 provinces of China during 2007–2012, and documented 328 cases of hypercholesterolemia from self-reported doctor diagnosis. Compared to participants with normal cholesterol, older adults with hypercholesterolemia had higher socioeconomic position and larger body mass index. In patients with hypercholesterolemia, 209 were not treated using lipid-lowering medications (63.7%, 95% confidence interval (CI) 58.5%– 68.9%). Untreated hypercholesterolemia was significantly associated with female sex (adjusted odds ratio 2.13, 95%CI 1.17–3.89), current smoking (3.48, 1.44–8.44), heavy alcohol drinking (3.13,1.11–8.84), chronic bronchitis (2.37,1.14–4.90) and high level of meat consumptions (2.85,1.22–6.65). Although having coronary heart disease exposed participants for treatment, half of participants with coronary heart disease did not receive lipid-lowering medications. Among hypercholesterolemia participants with stroke, hypertension or diabetes, more than half of them did not receive lipid-lowering medications. The high proportion of untreated hypercholesterolemia in older, high-risk Chinese adults needs to be mitigated through multi-faceted primary and secondary prevention strategies to increase population opportunities of treating hypercholesterolemia. PLOS ONEThe BUPA Foundation (Grants Nos. 45NOV06, and TBF-M09-05), and Alzheimer's Research, UK (Grant Nos. ART/PPG2007B/2

The Role of Imported Cases and Favorable Meteorological Conditions in the Onset of Dengue Epidemics

Dengue/dengue hemorrhagic fever is the world's most widely spread mosquito-borne arboviral disease and threatens more than two-thirds of the world's population. Cases are mainly distributed in tropical and subtropical areas in accordance with vector habitats for Aedes aegypti and Ae. albopictus. However, the role of imported cases and favorable meteorological conditions has not yet been quantitatively assessed. This study verified the correlation between the occurrence of indigenous dengue and imported cases in the context of weather variables (temperature, rainfall, relative humidity, etc.) for different time lags in southern Taiwan. Our findings imply that imported cases have a role in igniting indigenous outbreaks, in non-endemics areas, when favorable weather conditions are present. This relationship becomes insignificant in the late phase of local dengue epidemics. Therefore, early detection and case management of imported cases through timely surveillance and rapid laboratory-diagnosis may avert large scale epidemics of dengue/dengue hemorrhagic fever. An early-warning surveillance system integrating meteorological data will be an invaluable tool for successful prevention and control of dengue, particularly in non-endemic countries

Micro RNAs of Epstein-Barr Virus Promote Cell Cycle Progression and Prevent Apoptosis of Primary Human B Cells

Cellular and viral microRNAs (miRNAs) are involved in many different processes of key importance and more than 10,000 miRNAs have been identified so far. In general, relatively little is known about their biological functions in mammalian cells because their phenotypic effects are often mild and many of their targets still await identification. The recent discovery that Epstein-Barr virus (EBV) and other herpesviruses produce their own, barely conserved sets of miRNAs suggests that these viruses usurp the host RNA silencing machinery to their advantage in contrast to the antiviral roles of RNA silencing in plants and insects. We have systematically introduced mutations in EBV's precursor miRNA transcripts to prevent their subsequent processing into mature viral miRNAs. Phenotypic analyses of these mutant derivatives of EBV revealed that the viral miRNAs of the BHRF1 locus inhibit apoptosis and favor cell cycle progression and proliferation during the early phase of infected human primary B cells. Our findings also indicate that EBV's miRNAs are not needed to control the exit from latency. The phenotypes of viral miRNAs uncovered by this genetic analysis indicate that they contribute to EBV-associated cellular transformation rather than regulate viral genes of EBV's lytic phase