Percutaneous cement augmentation for the treatment of depression fractures of the tibial plateau

The management of insufficiency fractures of the tibial plateau in osteoporotic patients can be very challenging, since it is difficult to achieve a stable fixation, an essential condition for the patients' early mobilization. We present a minimally invasive technique for the treatment of proximal tibial plateau fractures, "tibiaplasty”, using percutaneous polymethylmethacrylate augmentation. Five osteoporotic patients (7 fractures) with a non-traumatic insufficiency tibial plateau fracture were treated with this technique at the authors' institution from 2006 to 2008. The patients' median age was 79 (range 62-88) years. The intervention was performed percutaneously under general or spinal anesthesia; after the intervention, immediate full weight bearing was allowed. The technique was feasible in all patients and no complications related to the intervention were observed. All patients reported a relevant reduction in pain, were able to mobilize with full weight bearing and would undergo the operation again. No secondary loss of reduction or progression of arthrosis was observed in radiological controls; no revision surgery was required. Our initial results indicate that tibiaplasty is a good treatment option for the management of insufficiency in tibial plateau fractures in osteoporotic patients. The technique is minimally invasive, safe and allows immediate mobilization without restrictions. In our group of patients, we found excellent early to mid-term result

Antitubercular specific activity of ibuprofen and the other 2-arylpropanoic acids using the HT-SPOTi whole-cell phenotypic assay

Objectives: Lead antituberculosis (anti-TB) molecules with novel mechanisms of action are urgently required to fuel the anti-TB drug discovery pipeline. The aim of this study was to validate the use of the high-throughput spot culture growth inhibition (HT-SPOTi) assay for screening libraries of compounds against Mycobacterium tuberculosis and to study the inhibitory effect of ibuprofen (IBP) and the other 2-arylpropanoic acids on the growth inhibition of M tuberculosis and other mycobacterial species. Methods: The HT-SPOTi method was validated not only with known drugs but also with a library of 47 confirmed anti-TB active compounds published in the ChEMBL database. Three over-the-counter non-steroidal anti-inflammatory drugs were also included in the screening. The 2-arylpropanoic acids, including IBP, were comprehensively evaluated against phenotypically and physiologically different strains of mycobacteria, and their cytotoxicity was determined against murine RAW264.7 macrophages. Furthermore, a comparative bioinformatic analysis was employed to propose a potential mycobacterial target. Results: IBP showed antitubercular properties while carprofen was the most potent among the 2-arylpropanoic class. A 3,5-dinitro-IBP derivative was found to be more potent than IBP but equally selective. Other synthetic derivatives of IBP were less active, and the free carboxylic acid of IBP seems to be essential for its anti-TB activity. IBP, carprofen and the 3,5-dinitro-IBP derivative exhibited activity against multidrug-resistant isolates and stationary phase bacilli. On the basis of the human targets of the 2-arylpropanoic analgesics, the protein initiation factor infB (Rv2839c) of M tuberculosis was proposed as a potential molecular target. Conclusions: The HT-SPOTi method can be employed reliably and reproducibly to screen the antimicrobial potency of different compounds. IBP demonstrated specific antitubercular activity, while carprofen was the most selective agent among the 2-arylpropanoic class. Activity against stationary phase bacilli and multidrug-resistant isolates permits us to speculate a novel mechanism of antimycobacterial action. Further medicinal chemistry and target elucidation studies could potentially lead to new therapies against TB

Audio-assisted movie dialogue detection

An audio-assisted system is investigated that detects if a movie scene is a dialogue or not. The system is based on actor indicator functions. That is, functions which define if an actor speaks at a certain time instant. In particular, the cross-correlation and the magnitude of the corresponding the cross-power spectral density of a pair of indicator functions are input to various classifiers, such as voted perceptions, radial basis function networks, random trees, and support vector machines for dialogue/non-dialogue detection. To boost classifier efficiency AdaBoost is also exploited. The aforementioned classifiers are trained using ground truth indicator functions determined by human annotators for 41 dialogue and another 20 non-dialogue audio instances. For testing, actual indicator functions are derived by applying audio activity detection and actor clustering to audio recordings. 23 instances are randomly chosen among the aforementioned 41 dialogue instances, 17 of which correspond to dialogue scenes and 6 to non-dialogue ones. Accuracy ranging between 0.739 and 0.826 is reported. © 2008 IEEE

Characterisation of ATP-dependent Mur ligases involved in the biogenesis of cell wall peptidoglycan in Mycobacterium tuberculosis.

ATP-dependent Mur ligases (Mur synthetases) play essential roles in the biosynthesis of cell wall peptidoglycan (PG) as they catalyze the ligation of key amino acid residues to the stem peptide at the expense of ATP hydrolysis, thus representing potential targets for antibacterial drug discovery. In this study we characterized the division/cell wall (dcw) operon and identified a promoter driving the co-transcription of mur synthetases along with key cell division genes such as ftsQ and ftsW. Furthermore, we have extended our previous investigations of MurE to MurC, MurD and MurF synthetases from Mycobacterium tuberculosis. Functional analyses of the pure recombinant enzymes revealed that the presence of divalent cations is an absolute requirement for their activities. We also observed that higher concentrations of ATP and UDP-sugar substrates were inhibitory for the activities of all Mur synthetases suggesting stringent control of the cytoplasmic steps of the peptidoglycan biosynthetic pathway. In line with the previous findings on the regulation of mycobacterial MurD and corynebacterial MurC synthetases via phosphorylation, we found that all of the Mur synthetases interacted with the Ser/Thr protein kinases, PknA and PknB. In addition, we critically analyzed the interaction network of all of the Mur synthetases with proteins involved in cell division and cell wall PG biosynthesis to re-evaluate the importance of these key enzymes as novel therapeutic targets in anti-tubercular drug discovery

A novel long non-coding natural antisense RNA is a negative regulator of Nos1 gene expression

Long non-coding natural antisense transcripts (NATs) are widespread in eukaryotic species. Although recent studies indicate that long NATs are engaged in the regulation of gene expression, the precise functional roles of the vast majority of them are unknown. Here we report that a long NAT (Mm-antiNos1 RNA) complementary to mRNA encoding the neuronal isoform of nitric oxide synthase (Nos1) is expressed in the mouse brain and is transcribed from the non-template strand of the Nos1 locus. Nos1 produces nitric oxide (NO), a major signaling molecule in the CNS implicated in many important functions including neuronal differentiation and memory formation. We show that the newly discovered NAT negatively regulates Nos1 gene expression. Moreover, our quantitative studies of the temporal expression profiles of Mm-antiNos1 RNA in the mouse brain during embryonic development and postnatal life indicate that it may be involved in the regulation of NO-dependent neurogenesis

Analogues of Disulfides from Allium stipitatum demonstrate potent anti-tubercular activities through drug efflux pump and Biofilm inhibition

Disulfides from Allium stipitatum, commonly known as Persian shallot, were previously reported to possess antibacterial properties. Analogues of these compounds, produced by S-methylthiolation of appropriate thiols using S-methyl methanethiosulfonate, exhibited antimicrobial activity, with one compound inhibiting the growth of Mycobacterium tuberculosis at 17 µM (4 mg L-1) and other compounds inhibiting Escherichia coli and multi-drug-resistant (MDR) Staphylococcus aureus at concentrations ranging between 32-138 µM (8-32 mg L-1). These compounds also displayed moderate inhibitory effects on Klebsiella and Proteus species. Whole-cell phenotypic bioassays such as the spot-culture growth inhibition assay (SPOTi), drug efflux inhibition, biofilm inhibition and cytotoxicity assays were used to evaluate these compounds. Of particular note was their ability to inhibit mycobacterial drug efflux and biofilm formation, while maintaining a high selectivity towards M. tuberculosis H37Rv. These results suggest that methyl disulfides are novel scaffolds which could lead to the development of new drugs against tuberculosis (TB)

Tetrahydroisoquinolines affect the whole-cell phenotype of Mycobacterium tuberculosis by inhibiting the ATP-dependent MurE ligase

Objectives (S)-Leucoxine, isolated from the Colombian Lauraceae tree Rhodostemonodaphne crenaticupula Madriñan, was found to inhibit the growth of Mycobacterium tuberculosis H37Rv. A biomimetic approach for the chemical synthesis of a wide array of 1-substituted tetrahydroisoquinolines was undertaken with the aim of elucidating a common pharmacophore for these compounds with novel mode(s) of anti-TB action. Methods Biomimetic Pictet–Spengler or Bischler–Napieralski synthetic routes were employed followed by an evaluation of the biological activity of the synthesized compounds. Results In this work, the synthesized tetrahydroisoquinolines were found to inhibit the growth of M. tuberculosis H37Rv and affect its whole-cell phenotype as well as the activity of the ATP-dependent MurE ligase, a key enzyme involved in the early stage of cell wall peptidoglycan biosynthesis. Conclusions As the correlation between the MIC and the half-inhibitory enzymatic concentration was not particularly strong, there is a credible possibility that these compounds have pleiotropic mechanism(s) of action in M. tuberculosis

Quantifying the short-term effects of air pollution on health in the presence of exposure measurement error: A simulation study of multi-pollutant model results

Background: Most epidemiological studies estimate associations without considering exposure measurement error. While some studies have estimated the impact of error in single-exposure models we aimed to quantify the effect of measurement error in multi-exposure models, specifically in time-series analysis of PM2.5, NO2,and mortality using simulations, under various plausible scenarios for exposure errors. Measurement error in multi-exposure models can lead to effect transfer where the effect estimate is overestimated for the pollutant estimated with more error to the one estimated with less error. This complicates interpretation of the independent effects of different pollutants and thus the relative importance of reducing their concentrations in air pollution policy. Methods: Measurement error was defined as the difference between ambient concentrations and personal exposure from outdoor sources. Simulation inputs for error magnitude and variability were informed by the literature. Error-free exposures with their consequent health 16outcome and error-prone exposures of various error types (classical/Berkson) were generated. Bias was quantified as the relative difference in effect estimates of the error-free and error-prone exposures. Results: Mortality effect estimates were generally underestimated with greater bias observed when low ratios of the true exposure variance over the error variance were assumed (27.4% 21underestimation for NO2). Higher ratios resulted in smaller, but still substantial bias (up to 19% for both pollutants).Effect transfer was observed indicating that less precise measurements for one pollutant (NO2) yield more bias, while the co-pollutant(PM2.5) associations were found closer to the true. Interestingly, the sum of single-pollutant model effect estimates was found closer to the summed true associations than those from multi-pollutant models, due to cancelling out of confounding and measurement error bias. Conclusions: Our simulation study indicated an underestimation of true independent health effects of multiple exposures due to measurement error. Using error parameter information in future epidemiological studies should provide more accurate concentration-response functions

Pre-Clinical Tools for Predicting Drug Efficacy in Treatment of Tuberculosis

Combination therapy has, to some extent, been successful in limiting the emergence of drug-resistant tuberculosis. Drug combinations achieve this advantage by simultaneously acting on different targets and metabolic pathways. Additionally, drug combination therapies are shown to shorten the duration of therapy for tuberculosis. As new drugs are being developed, to overcome the challenge of finding new and effective drug combinations, systems biology commonly uses approaches that analyse mycobacterial cellular processes. These approaches identify the regulatory networks, metabolic pathways, and signaling programs associated with M. tuberculosis infection and survival. Different preclinical models that assess anti-tuberculosis drug activity are available, but the combination of models that is most predictive of clinical treatment efficacy remains unclear. In this structured literature review, we appraise the options to accelerate the TB drug development pipeline through the evaluation of preclinical testing assays of drug combinations

Pediatric tuberculosis-human immunodeficiency virus co-infection in the United Kingdom highlights the need for better therapy monitoring tools: a case report.

BACKGROUND: Tuberculosis is an infection that requires at least 6 months of chemotherapy in order to clear the bacteria from the patient's lungs. Usually, therapeutic monitoring is dependent on smear microscopy where a decline in acid-fast bacilli is observed. However, this might not be indicative of the actual decline of bacterial load and thus other tools such as culture and molecular assays are required for patient management. CASE PRESENTATION: Here, we report the case of a 12-year-old Black African boy co-infected with tuberculosis and human immunodeficiency virus who remained smear culture positive and liquid culture negative for a prolonged period of time following chemotherapy. In order to determine whether there was any live bacteria present in his specimens, we applied the newly developed molecular bacterial load assay that detects the presence of 16S ribosomal ribonucleic acid derived from the bacteria. Using this methodology, we were able to quantify his bacterial load and inform the management of his treatment in order to reduce the disease burden. Following this intervention he went on to make a complete recovery. CONCLUSIONS: This case report highlights the value of improved biomarkers for monitoring the treatment of tuberculosis and the role of molecular assays such as the molecular bacterial load assay applied here. The molecular bacterial load assay detects bacterial ribonucleic acid which corresponds closely with the number of live bacilli as compared with polymerase chain reaction that detects deoxyribonucleic acid and may include dead bacteria