Controlled release from zein matrices: Interplay of drug hydrophobicity and pH

Purpose: In earlier studies, the corn protein zein is found to be suitable as a sustained release agent, yet the range of drugs for which zein has been studied remains small. Here, zein is used as a sole excipient for drugs differing in hydrophobicity and isoelectric point: indomethacin, paracetamol and ranitidine. Methods: Caplets were prepared by hot-melt extrusion (HME) and injection moulding (IM). Each of the three model drugs were tested on two drug loadings in various dissolution media. The physical state of the drug, microstructure and hydration behaviour were investigated to build up understanding for the release behaviour from zein based matrix for drug delivery. Results: Drug crystallinity of the caplets increases with drug hydrophobicity. For ranitidine and indomethacin, swelling rates, swelling capacity and release rates were pH dependent as a consequence of the presence of charged groups on the drug molecules. Both hydration rates and release rates could be approached by existing models. Conclusion: Both the drug state as pH dependant electrostatic interactions are hypothesised to influence release kinetics. Both factors can potentially be used factors influencing release kinetics release, thereby broadening the horizon for zein as a tuneable release agent

Interleukin-17 regulates matrix metalloproteinase activity in human pulmonary tuberculosis.

Tuberculosis (TB) is characterized by extensive pulmonary matrix breakdown. Interleukin-17 (IL-17) is key in host defence in TB but its role in TB-driven tissue damage is unknown. We investigated the hypothesis that respiratory stromal cell matrix metalloproteinase (MMP) production in TB is regulated by T-helper 17 (TH -17) cytokines. Biopsies of patients with pulmonary TB were analysed by immunohistochemistry (IHC), and patient bronchoalveolar lavage fluid (BALF) MMP and cytokine concentrations were measured by Luminex assays. Primary human airway epithelial cells were stimulated with conditioned medium from human monocytes infected with Mycobacterium tuberculosis (Mtb) and TH -17 cytokines. MMP secretion, activity, and gene expression were determined by ELISA, Luminex assay, zymography, RT-qPCR, and dual luciferase reporter assays. Signalling pathways were examined using phospho-western analysis and siRNA. IL-17 is expressed in TB patient granulomas and MMP-3 is expressed in adjacent pulmonary epithelial cells. IL-17 had a divergent, concentration-dependent effect on MMP secretion, increasing epithelial secretion of MMP-3 (p < 0.001) over 72 h, whilst decreasing that of MMP-9 (p < 0.0001); mRNA levels were similarly affected. Both IL-17 and IL-22 increased fibroblast Mtb-dependent MMP-3 secretion but IL-22 did not modulate epithelial MMP-3 expression. Both IL-17 and IL-22, but not IL-23, were significantly up-regulated in BALF from TB patients. IL-17-driven MMP-3 was dependent on p38 MAP kinase and the PI3K p110α subunit. In summary, IL-17 drives airway stromal cell-derived MMP-3, a mediator of tissue destruction in TB, alone and with monocyte-dependent networks in TB. This is regulated by p38 MAP kinase and PI3K pathways. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland

Hypoxia and tissue destruction in pulmonary TB.

BACKGROUND: It is unknown whether lesions in human TB are hypoxic or whether this influences disease pathology. Human TB is characterised by extensive lung destruction driven by host matrix metalloproteinases (MMPs), particularly collagenases such as matrix metalloproteinase-1 (MMP-1). METHODS: We investigated tissue hypoxia in five patients with PET imaging using the tracer [18F]-fluoromisonidazole ([18F]FMISO) and by immunohistochemistry. We studied the regulation of MMP secretion in primary human cell culture model systems in normoxia, hypoxia, chemical hypoxia and by small interfering RNA (siRNA) inhibition. RESULTS: [18F]FMISO accumulated in regions of TB consolidation and around pulmonary cavities, demonstrating for the first time severe tissue hypoxia in man. Patlak analysis of dynamic PET data showed heterogeneous levels of hypoxia within and between patients. In Mycobacterium tuberculosis (M.tb)-infected human macrophages, hypoxia (1% pO2) upregulated MMP-1 gene expression 170-fold, driving secretion and caseinolytic activity. Dimethyloxalyl glycine (DMOG), a small molecule inhibitor which stabilises the transcription factor hypoxia-inducible factor (HIF)-1α, similarly upregulated MMP-1. Hypoxia did not affect mycobacterial replication. Hypoxia increased MMP-1 expression in primary respiratory epithelial cells via intercellular networks regulated by TB. HIF-1α and NF-κB regulated increased MMP-1 activity in hypoxia. Furthermore, M.tb infection drove HIF-1α accumulation even in normoxia. In human TB lung biopsies, epithelioid macrophages and multinucleate giant cells express HIF-1α. HIF-1α blockade, including by targeted siRNA, inhibited TB-driven MMP-1 gene expression and secretion. CONCLUSIONS: Human TB lesions are severely hypoxic and M.tb drives HIF-1α accumulation, synergistically increasing collagenase activity which will lead to lung destruction and cavitation.Medical Research CouncilThis is the final version of the article. It first appeared from the British Medical Journal via https://doi.org/10.1136/thoraxjnl-2015-20740

Optimal management of adults with pharyngitis – a multi-criteria decision analysis

BACKGROUND: Current practice guidelines offer different management recommendations for adults presenting with a sore throat. The key issue is the extent to which the clinical likelihood of a Group A streptococcal infection should affect patient management decisions. To help resolve this issue, we conducted a multi-criteria decision analysis using the Analytic Hierarchy Process. METHODS: We defined optimal patient management using four criteria: 1) reduce symptom duration; 2) prevent infectious complications, local and systemic; 3) minimize antibiotic side effects, minor and anaphylaxis; and 4) achieve prudent use of antibiotics, avoiding both over-use and under-use. In our baseline analysis we assumed that all criteria and sub-criteria were equally important except minimizing anaphylactic side effects, which was judged very strongly more important than minimizing minor side effects. Management strategies included: a) No test, No treatment; b) Perform a rapid strep test and treat if positive; c) Perform a throat culture and treat if positive; d) Perform a rapid strep test and treat if positive; if negative obtain a throat culture and treat if positive; and e) treat without further tests. We defined four scenarios based on the likelihood of group A streptococcal infection using the Centor score, a well-validated clinical index. Published data were used to estimate the likelihoods of clinical outcomes and the test operating characteristics of the rapid strep test and throat culture for identifying group A streptococcal infections. RESULTS: Using the baseline assumptions, no testing and no treatment is preferred for patients with Centor scores of 1; two strategies – culture and treat if positive and rapid strep with culture of negative results – are equally preferable for patients with Centor scores of 2; and rapid strep with culture of negative results is the best management strategy for patients with Centor scores 3 or 4. These results are sensitive to the priorities assigned to the decision criteria, especially avoiding over-use versus under-use of antibiotics, and the population prevalence of Group A streptococcal pharyngitis. CONCLUSION: The optimal clinical management of adults with sore throat depends on both the clinical probability of a group A streptococcal infection and clinical judgments that incorporate individual patient and practice circumstances

Isolation of a wide range of minerals from a thermally treated plant: Equisetum arvense, a Mare’s tale

Silica is the second most abundant biomineral being exceeded in nature only by biogenic CaCO3. Many land plants (such as rice, cereals, cucumber, etc.) deposit silica in significant amounts to reinforce their tissues and as a systematic response to pathogen attack. One of the most ancient species of living vascular plants, Equisetum arvense is also able to take up and accumulate silica in all parts of the plant. Numerous methods have been developed for elimination of the organic material and/or metal ions present in plant material to isolate biogenic silica. However, depending on the chemical and/or physical treatment applied to branch or stem from Equisetum arvense; other mineral forms such glass-type materials (i.e. CaSiO3), salts (i.e. KCl) or luminescent materials can also be isolated from the plant material. In the current contribution, we show the chemical and/or thermal routes that lead to the formation of a number of different mineral types in addition to biogenic silica

Principles of meiotic chromosome assembly revealed in S. cerevisiae

During meiotic prophase, chromosomes organise into a series of chromatin loops emanating from a proteinaceous axis, but the mechanisms of assembly remain unclear. Here we use Saccharomyces cerevisiae to explore how this elaborate three-dimensional chromosome organisation is linked to genomic sequence. As cells enter meiosis, we observe that strong cohesin-dependent grid-like Hi-C interaction patterns emerge, reminiscent of mammalian interphase organisation, but with distinct regulation. Meiotic patterns agree with simulations of loop extrusion with growth limited by barriers, in which a heterogeneous population of expanding loops develop along the chromosome. Importantly, CTCF, the factor that imposes similar features in mammalian interphase, is absent in S. cerevisiae, suggesting alternative mechanisms of barrier formation. While grid-like interactions emerge independently of meiotic chromosome synapsis, synapsis itself generates additional compaction that matures differentially according to telomere proximity and chromosome size. Collectively, our results elucidate fundamental principles of chromosome assembly and demonstrate the essential role of cohesin within this evolutionarily conserved process

WHO guideline for non-surgical management of chronic primary low back pain in adults in primary and community care settings

The purpose of the guideline is to provide evidence-based recommendations on nonsurgical interventions for chronic primary LBP (CPLBP) in adults, including older people, that can be delivered in primary and community care settings to improve CPLBP-related health and well-being outcomes. For this reason, the guideline does not consider interventions typically delivered in secondary or tertiary care settings (e.g. surgical or other invasive procedures) or workplace interventions. The target audience is health workers of all disciplines working in the primary and community care settings. In this context, the guideline is intended to be discipline neutral. The guidelines will be of use to clinical staff including medical doctors, nurses, allied health workers including chiropractors, occupational therapists, physiotherapists, pharmacists, psychologists and community health workers, as well as public health programme and system managers

The Shapes of Tight Composite Knots

We present new computations of tight shapes obtained using the constrained gradient descent code RIDGERUNNER for 544 composite knots with 12 and fewer crossings, expanding our dataset to 943 knots and links. We use the new data set to analyze two outstanding conjectures about tight knots, namely that the ropelengths of composite knots are at least 4\pi-4 less than the sums of the prime factors and that the writhes of composite knots are the sums of the writhes of the prime factors.Comment: Summary text file of tight knot lengths and writhing numbers stored in anc/ropelength_data.txt. All other data freely available at http:://www.jasoncantarella.com/ and through Data Conservanc

COVID-19 impacts and adaptations in Asia and Africa's aquatic food value chains

The COVID-19 pandemic is a shock affecting all areas of the global food system. We tracked the impacts of COVID-19 and associated policy responses on the availability and price of aquatic foods and production inputs during 2020, using a high frequency longitudinal survey of 768 respondents in Bangladesh, Egypt, India, Myanmar, Nigeria. We found the following: (1) Aquatic food value chains were severely disrupted but most effects on the availability and accessibility of aquatic foods and production inputs were short-lived. (2) Impacts on demand for aquatic foods, production inputs, and labor have been longer lasting than impacts on their supply. (3) Retail prices of aquatic foods spiked briefly during March-May 2020 but trended down thereafter, whereas prices of production inputs rose. These trends suggest a deepening ‘squeeze’ on the financial viability of producers and other value chain actors. (4) Survey respondents adapted to the challenges of COVID-19 by reducing production costs, sourcing alternative inputs, diversifying business activities, leveraging social capital, borrowing, seeking alternative employment, and reducing food consumption. Many of these coping strategies are likely to undermine well-being and longer-term resilience, but we also find some evidence of proactive strategies with potential to strengthen business performance. Global production of aquatic food likely contracted significantly in 2020. The importance of aquatic food value chains in supporting livelihoods and food and nutrition security in Asia and Africa makes their revitalization essential in the context of COVID-19 recovery efforts. We outline immediate and longer-term policies and interventions to support this goal.Additional co-authors: Arun Padiyar, Suresh Rajendran, A B C Mohan, Ravi Babu, Michael Joseph Akester, Ei Ei Phyo, Khin Maung Soe, Ajibola Olaniyi, Sunil N Siriwardena, Michael Phillips, Shakuntala H Thilste