Molecular constraints on tolerance-resistance trade-offs: Is there a cost?

Plants possess myriad defenses against their herbivores, including constitutive and inducible chemical compounds and regrowth strategies known as tolerance. Recent studies have shown that plant tolerance and resistance are positively associated given they are co-localized in the same molecular pathway, the oxidative pentose phosphate pathway. However, given that both defensive strategies utilize carbon skeletons from a shared resource pool in the oxidative pentose phosphate pathway there are likely costs in maintaining both resistance-tolerance strategies. Here we investigate fitness costs in maintaining both strategies by utilizing a double knockout of cyp79B2 and cyp79B3, key enzymes in the biosynthetic process of indole glucosinolates, which convert tryptophan to indole-3-acetaldoxime (IAOx) and is further used to produce indole glucosinolates. These mutant plants are devoid of any indole glucosinolates thus reducing plant resistance. Results show that knocking out indole glucosinolate production and thus one of the resistance pathways leads to an approximate 94% increase in fitness compensation shifting the undercompensating wild-type Columbia-0 to an overcompensating genotype following damage. We discuss the potential mechanistic basis for the observed patterns.

New magnetic chelating sorbent for chromium speciation by magnetic solid phase extraction on-line with inductively coupled plasma optical emission spectrometry.

A novel sorbent material employing magnetic nanoparticles (MNPs) coupled to graphene oxide (GO) functionalized with 4-aminobenzenesulfonic acid (M@GO-ABS) has been synthesized and applied to develop an inexpensive and automatic method for Cr(III) and Cr(VI) speciation in environmental samples; the developed method combines inductively coupled plasma optical emission spectrometry (ICP-OES) with on-line magnetic solid phase extraction (MSPE). Two magnetic-knotted reactors containing M@GO-ABS were installed in the eight-port injection valve of a flow injection (FI) manifold. Two different eluents were used, one for Cr(VI) (the most toxic chromium species) and one for total Cr concentration. Cr(III) concentration was calculated by the difference between Cr(VI) concentration and total Cr concentration. The optimized method presented detection limits (LOD, peak height) of 0.1 µg L-1 for chromium (VI) and 0.08 µg L-1 for total chromium, and enrichment factors of 15 and 23, respectively. Certified reference materials (TMDA 54.5 fortified lake water and SPS-SW2 surface water) and spiked aqueous samples were used to validate the developed method. The developed method was fruitfully applied to chromium speciation in environmental water samples such as seawater, well water and tap water collected in Málaga (Spain). The obtained values were in good agreement with the certified values, and the recoveries were found in the range of 91-108% for the spiked samples.

Semiautomatic method for the ultra-trace arsenic speciation in environmental and biological samples via magnetic solid phase extraction prior to HPLC-ICP-MS determination.

A novel magnetic functionalized material based on graphene oxide and magnetic nanoparticles (MGO) was used to develop a magnetic solid phase extraction method (MSPE) to enrich both, inorganic and organic arsenic species in environmental waters and biological samples. An automatic flow injection (FI) system was used to preconcentrate the arsenic species simultaneously, while the ultra-trace separation and determination of arsenobetaine (AsBet), cacodylate, AsIII and AsV species were achieved by high performance liquid chromatography combined with inductively coupled plasma mass spectrometry (HPLC-ICP-MS). The sample was introduced in the FI system where the MSPE was performed, then 1 mL of eluent was collected in a chromatographic vial, which was introduced in the autosampler of HPLC-ICP-MS. Therefore, preconcentration and separation/determination processes were automatic and conducted separately. To the best of our knowledge, this is the first method combining an automatic MSPE with HPLC-ICP-MS for arsenic speciation, using a magnetic nanomaterial based on MGO for automatic MSPE. Under the optimized conditions, the LODs for the arsenic species were 3.8 ng L-1 AsBet, 0.5 ng L-1 cacodylate, 1.1 ng L-1 AsIII and 0.2 ng L-1 AsV with RSDs <5%. The developed method was validated by analyzing Certified Reference Materials for total As concentration (fortified lake water TMDA 64.3 and seawater CASS-6 NRC) and also by recovery analysis of the arsenic species in urine, well-water and seawater samples collected in Málaga. The developed method has shown promise for routine monitoring of arsenic species in environmental waters and biological fluids.

Endovascular and medical therapy of May-Thurner syndrome: Case series and scoping literature review.

INTRODUCTION: May-Thurner syndrome has been recognized as a cause of chronic venous insufficiency and a trigger for venous thromboembolism. There is no consensus about the definition, diagnosis, and therapeutic approach. We are aiming to describe its characteristics and a scoping literature review. METHODS: A retrospective review of patients with May-Thurner syndrome from March 2010 to May 2018 and scoping literature review were made. RESULTS: Seven patients were identified. All patients were female with a median age of 36 (20-60) years. The median time from the first symptom to diagnosis was 3.41 (0.01-9) years. The primary clinical presentation was post-thrombotic syndrome (4 patients). Six patients had at least one risk factor for deep venous thrombosis. All patients underwent angioplasty with stent; patients with acute deep venous thrombosis, furthermore mechanic thrombectomy with or without catheter-directed thrombolysis were done. There were three complications (one patient, lymphedema, and two venous stent thrombosis). Scoping review results were descriptively summarized. CONCLUSION: May-Thurner syndrome has a varied spectrum of clinical presentation, and clinical awareness is paramount for diagnosis. Its principal complication is the post-thrombotic syndrome, which is associated with high morbidity. There is no consensus on the antithrombotic treatment approach.

Direct solid sampling for speciation of Zn2+ and ZnO nanoparticles in cosmetics by graphite furnace atomic absorption spectrometry.

The application of nanoparticles (NPs) in science and technology is a fast growing field. Therefore, reliable and straightforward analytical methods are required for their fast determination in different types of samples. This work investigates a method that enables the determination of ZnO NPs, discriminating them from ionic zinc in cosmetic samples. The method is based on direct solid sampling high-resolution continuum source electrothermal atomic absorption spectrometry (SS-HR-CS-GFAAS), and has been applied to determination of ZnO NPs, Zn2+ and total Zn in eye shadow samples. In this work the deconvolution of the atomization peak and the calibration by standard additions have been done in order to discriminate and quantify ionic zinc and ZnO NPs. A Zn wavelength with low sensitivity was selected. The proper optimization of the graphite furnace temperature program, minimizing the mineralization of the sample matrix, enables different atomization profiles between the different chemical species of the analyte. Two multiple response surface designs have been used in order to optimize the adequate furnace program to achieve our aims. All the optimization experiments were performed using a sample of eye shadow. Further, a method for the determination of total Zn by direct solid sampling with calibration by aqueous standards, was also optimized. The optimized method was successfully applied to the determination of ionic Zn and ZnO NPs in different eye shadow samples, and has been validated by recovery assays, obtaining recovery percentages between 80 and 125%. Total Zn concentration in the solid samples was validated by the determination of total Zn by direct solid sampling and by the analysis of the same eye shadow samples digested in microwave oven.

Moving bed biofilm reactor as an alternative wastewater treatment process for nutrient removal and recovery in the circular economy model.

Over the last years, an increasing concern has emerged regarding the eco-friendly management of wastewater. Apart from the role of wastewater treatment plants (WWTPs) for wastewater and sewage sludge treatment, the increasing need of the recovery of the resources contained in wastewater, such as nutrients and water, should be highlighted. This would allow for transforming a wastewater treatment plant (WWTP) into a sustainable technological system. The objective of this review is to propose a moving bed biofilm reactor (MBBR) as a novel technology that contributes to the circularity of the wastewater treatment sector according to the principles of circular economy. In this regard, this paper aims to consider the MBBR process as the initial step for water reuse, and nutrient removal and recovery, within the circular economy model.

Individual and interactive effects of herbivory on plant fitness: endopolyploidy as a driver of genetic variation in tolerance and resistance.

Previous studies have shown a causal link between mammalian herbivory, tolerance, and chemical defense in Arabidopsis thaliana, driven by the process of endoreduplication (replication of the genome without mitosis). Removal of the apical meristem by mammalian herbivores lowers auxin, which triggers entry into the endocycle. Increasing chromosome number through endoreduplication, and therefore gene copy number, provides a means of increasing gene expression promoting rapid regrowth rates, higher defensive chemistry and enhanced fitness. Here, we assess whether insect leaf-feeding elicits the same compensatory response as the removal of apical dominance. Insect feeding has been shown to downregulate auxin production, which should trigger endoreduplication. Results here support this contention; insect leaf-feeding by Trichoplusia ni elicited a compensatory response similar to that of mammalian herbivores-an ecotype-specific response consistent with the level of endoreduplication. The interactive effects of mammalian and insect herbivory were also assessed to determine whether interactions were additive (pairwise) or non-additive (diffuse) on tolerance (fitness). Specifically, results indicate that herbivory is either diffuse (a significant clipping × T. ni interaction) or pairwise (no significant interaction between clipping and T. ni herbivory), dependent upon plant genotype and compensatory ability. In general, herbivore-induced changes in plant quality appear to be responsible for the observed differences in herbivory and fitness compensation. We discuss the importance of evaluating endoreduplication among plants within a population to avoid masking the association between tolerance and resistance and the fitness consequences of multi-herbivore interactions.

[Consensus statement on the use of acetaminophen/tramadol in patients with moderate-severe pain]. / Documento de consenso sobre el uso de la combinación paracetamol/tramadol en pacientes con dolor moderado-intenso.

OBJECTIVES: To present recommendations on the use of the paracetamol/tramadol (P/T) combination in patients with moderate-intense pain based on best evidence and experience. METHODS: The method of nominal groups and Delphi was followed, and supported by a systematic literature review (SLR). A multidisciplinary panel of 12 experts in pain management was selected. In the first nominal group meeting, the aim, scope, users, and sections of the consensus document, were defined, along with the preliminary general recommendations. For the SLR, the inclusion and exclusion criteria, as well as the search strategies, were defined. Two reviewers selected and analysed the articles. This evidence was discussed in a second nominal group meeting, and definitive recommendations were developed. For each recommendation, the evidence levels and grade of recommendation grades were classified according to the Oxford model, and the grade according to the Delphi technique. It was defined as an agreement if at least 70% of the participants scored ≥7 for each recommendation (1=total disagreement to 10=total agreement). RESULTS: A total of 20 recommendations were produced, which covered general aspects, such as the assessment of pain, and those specific to P/T management. These latter included the indications of the P/T combination (patient profile, dosing, prescription, formulations), risk management (contraindications, precautions, interactions, concomitant use with other medications, follow-up, special situations), and patient education. CONCLUSIONS: These recommendations attempt to resolve any of the routine clinical questions, and help in the making of decisions on the use of the P/T combination in patients with moderate-intense pain.

Immunomodulatory tetracyclines shape the intestinal inflammatory response inducing mucosal healing and resolution.

BACKGROUND AND PURPOSE: Immunomodulatory tetracyclines are well-characterized drugs with a pharmacological potential beyond their antibiotic properties. Specifically, minocycline and doxycycline have shown beneficial effects in experimental colitis, although pro-inflammatory actions have also been described in macrophages. Therefore, we aimed to characterize the mechanism behind their effect in acute intestinal inflammation. EXPERIMENTAL APPROACH: A comparative pharmacological study was initially used to elucidate the most relevant actions of immunomodulatory tetracyclines: doxycycline, minocycline and tigecycline; other antibiotic or immunomodulatory drugs were assessed in bone marrow-derived macrophages and in dextran sodium sulfate (DSS)-induced mouse colitis, where different barrier markers, inflammatory mediators, microRNAs, TLRs, and the gut microbiota composition were evaluated. The sequential immune events that mediate the intestinal anti-inflammatory effect of minocycline in DSS-colitis were then characterized. KEY RESULTS: Novel immunomodulatory activity of tetracyclines was identifed; they potentiated the innate immune response and enhanced resolution of inflammation. This is also the first report describing the intestinal anti-inflammatory effect of tigecycline. A minor therapeutic benefit seems to derive from their antibiotic properties. Conversely, immunomodulatory tetracyclines potentiated macrophage cytokine release in vitro, and while improving mucosal recovery in colitic mice, they up-regulated Ccl2, miR-142, miR-375 and Tlr4. In particular, minocycline initially enhanced IL-1ß, IL-6, IL-22, GM-CSF and IL-4 colonic production and monocyte recruitment to the intestine, subsequently increasing Ly6C- MHCII+ macrophages, Tregs and type 2 intestinal immune responses. CONCLUSIONS AND IMPLICATIONS: Immunomodulatory tetracyclines potentiate protective immune pathways leading to mucosal healing and resolution, representing a promising drug reposition strategy for the treatment of intestinal inflammation.

Immunomodulatory tetracyclines ameliorate DNBS-colitis: Impact on microRNA expression and microbiota composition.

OBJECTIVE: The use of immunomodulatory antibiotics to simultaneously target different factors involved in intestinal inflammatory conditions is an interesting but understudied pharmacological strategy. A great therapeutic potential has been obtained with minocycline and doxycycline in experimental colitis. Therefore, understanding the contribution of the different activities of immunomodulatory tetracyclines is crucial for the improvement and translation of their use into clinic. DESIGN: A comparative pharmacological study including tetracyclines and other antibiotic or immunomodulatory drugs was performed in 2,4-dinitrobenzene sulfonic acid (DNBS)-induced colitis in mice. The correlation between the therapeutic efficacy of each drug and changes in the gut microbiota composition, markers of barrier integrity, inflammatory mediators, microRNAs and TLRs was analysed to identify the main mechanisms of action. RESULTS: Tetracyclines counteracted most of the markers found altered in DNBS-colitis, which differed from effects of corticosteroid treatment. Of note, administration of tetracyclines led to increased mucosal protection, associated with up-regulated expression of CCL2, miR-142 and miR-375. All drugs with antibiotic activity ameliorated the progression of inflammation and reduced neutrophil-related genes, such as miR-223, despite their effects were not associated with restored intestinal dysbiosis. However, reduced bacterial richness was correlated with increased expression of TLR2 and TLR9 in antibiotic-treated groups and TLR6 was also up-regulated by the immunomodulatory tetracyclines with higher efficacy (doxycycline, minocycline and tigecycline). CONCLUSION: The anti-inflammatory effect of tetracyclines involves specific modifications in TLR and microRNA expression leading to an improved microbial-derived signalling and mucosal protection. These results support the potential of immunomodulatory tetracyclines to prevent inflammation-associated tissue damage in acute intestinal inflammation.

Factors associated with ATXN2 CAG/CAA repeat intergenerational instability in Spinocerebellar ataxia type 2.

Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder caused by the unstable expansion of a cytosine-adenine-guanine (CAG)/cytosine-adenine-adenine (CAA) repeat in the ATXN2 gene, which normally encodes 22 glutamines (Q22). A large study was conducted to characterize the CAG/CAA repeat intergenerational instability in SCA2 families. Large normal alleles (Q24-31) were significantly more unstable upon maternal transmissions. In contrast, expanded alleles (Q32-750) were significantly more unstable during paternal transmissions, in correlation with repeat length. Significant correlations were found between the instability and the age at conception in paternal transmissions. In conclusion, intergenerational instability at ATXN2 locus is influenced by the sex, repeat length and age at conception of the transmitting parent. These results have profound implications for genetic counseling services.

Molecular constraints on resistance-tolerance trade-offs.

Plants have numerous mechanisms to cope with the negative effects of herbivory, including plant resistance, structural and chemical traits that reduce damage, and plant tolerance, the ability to compensate for tissues lost. It has been argued that resistance and tolerance represent alternate strategies and thus there should be a trade-off between resistance and tolerance. However, resistance and tolerance are controlled via the same molecular pathway, the oxidative pentose phosphate pathway and the process of endoreduplication. Endoreduplication is the replication of the genome without mitosis, which leads to an increase in cellular chromosome number. Increasing chromosome number and therefore gene copy number provides a means of increasing gene expression that has been shown to enhance compensation following herbivory. By measuring glucosinolate levels and seed production following the removal of apical dominance in genotypes of Arabidopsis thaliana we show that there is a positive association between tolerance and induced chemical defense. Similarly, the direct association between tolerance and resistance is demonstrated by genetically manipulating the endoreduplication pathway. By overexpressing ILP1, a positive regulator of endoreduplication, and thus compensation, we experimentally increased glucosinolate production and tolerance in the Col-0 genotype. We suggest that many herbaceous plants that endoreduplicate (~90%) would show a positive relationship between compensation and chemical defense, given that the molecular pathways are shared in common. We discuss these findings in light of contrasting results on measures of tolerance and resistance, given that the true relationship can be masked by ignoring genetic variation in endoreduplication and the timing of chemical measurement.

Exploring disparities in incidence and mortality rates of breast and gynecologic cancers according to the Human Development Index in the Pan-American region.

OBJECTIVE: To evaluate whether a country's Human Development Index (HDI) can help explain the differences in the country's breast cancer and gynecological cancer incidence and mortality rates in the Pan-American region. STUDY DESIGN: Ecological analysis. METHODS: Pan-American region countries with publicly available data both in GLOBOCAN 2012 and the United Nations Development Report 2012 were included (n = 28). Incidence and mortality rates age-standardized per 100,000 were natural log-transformed for breast cancer, ovarian cancer, corpus uteri cancer, and cervical cancer. The mortality-to-incidence ratio (MIR) was calculated for each site. Pearson's correlation test and a simple linear regression were performed. RESULTS: The HDI showed a positive correlation with breast cancer and ovarian cancer incidence and mortality rates, respectively, and a negative correlation with cervical cancer incidence and mortality rates. The HDI and corpus uteri cancer showed no association. MIR and the HDI showed a negative correlation for all tumor types except ovarian cancer. An increment in 1 HDI unit leads to changes in cancer rates: in breast cancer incidence ß = 4.03 (95% confidence interval [CI] 2.61; 5.45) P < 0.001, breast cancer mortality ß = 1.76 (95% CI 0.32; 3.21) P = 0.019, and breast cancer-MIR ß = -0.705 (95% CI 0.704; 0.706) P < 0.001; in cervical cancer incidence ß = -3.28 (95% CI -4.78; -1.78) P < 0.001, cervical cancer mortality ß = -4.63 (95% CI -6.10; -3.17) P < 0.001, and cervical cancer-MIR ß = -1.35 (95% CI -1.83; -0.87) P < 0.001; in ovarian cancer incidence ß = 3.26 (95% CI 1.78; 4.75) P < 0.001, ovarian cancer mortality ß = 1.82 (95% CI 0.44; 3.20) P = 0.012, and ovarian cancer-MIR ß = 5.10 (95% CI 3.22; 6.97) P < 0.001; in corpus uteri cancer incidence ß = 2.37 (95% CI -0.33; 5.06) P = 0.83, corpus uteri cancer mortality ß = 0.68 (95% CI -2.68; 2.82) P = 0.96, and corpus uteri cancer-MIR ß = -2.30 (95% CI -3.19; -1.40) P < 0.001. CONCLUSIONS: A country's HDI should be considered to understand disparities in breast cancer and gynecological cancer in the Pan-American region.

Réplica a la carta al director: «Terminología y comunicación entre niveles asistenciales» / Reply to letter to the editor: «Terminology and communication between healthcare levels»

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Fluorescence spectroscopy and parallel factor analysis as a dissolved organic monitoring tool to assess treatment performance in drinking water trains.

Fluorescence excitation emission matrix (FEEM) spectroscopy was used to evaluate its applicability as a tool to track dissolved organic matter (DOM) in a drinking water treatment plant (DWTP) that incorporates a conventional line (consisting in ozonation and GAC filtration) and a membrane-based line (consisting in ultrafiltration, reverse osmosis and mineralization) working in parallel. Seven sampling points within the different process stages were characterized monthly during 2014. A global Parallel Factor Analysis (PARAFAC) was used to pull out underlying organic fractions from the fluorescence spectra. Accordingly a five components model was selected to describe the system and the pros and cons of the model were discussed by analysis of the residuals. Among the five fluorescent components, those associated to humic-like matter (C1, C3 and C4) showed a similar season variability in the river water feeding the DWTP (which resembled that of UV254 and TOC), whereas the two components associated to protein-like matter (C2 and C5) exhibited a different behavior. The maximum fluorescence intensity values (Fmax) were used to quantify DOM removals across the plant. Compared to the conventional line, water from the UF/RO membrane-based line showed between 6 and 14 times lower fluorescence intensity signal for the humic-like components and between 1 and 3 for the protein-like components as compared to the conventional line. The differences in DOM composition due to seasonal variations and along the treatment trains point out the suitability of using fluorescence measurements over other parameters such as UV254 as a monitoring tool to help optimize operation conditions of each treatment stage and improve produced water quality in a DWTP.

Boceprevir plus pegylated interferon/ribavirin to re-treat hepatitis C virus genotype 1 in HIV-HCV co-infected patients: final results of the Spanish BOC HIV-HCV Study.

INTRODUCTION: Boceprevir (BOC) was one of the first oral inhibitors of hepatitis C virus (HCV) NS3 protease to be developed. This study assessed the safety and efficacy of BOC+pegylated interferon-α2a/ribavirin (PEG-IFN/RBV) in the retreatment of HIV-HCV co-infected patients with HCV genotype 1. METHODS: This was a phase III prospective trial. HIV-HCV (genotype 1) co-infected patients from 16 hospitals in Spain were included. These patients received 4 weeks of PEG-IFN/RBV (lead-in), followed by response-guided therapy with PEG-IFN/RBV plus BOC (a fixed 44 weeks was indicated in the case of cirrhosis). The primary endpoint was the sustained virological response (SVR) rate at 24 weeks post-treatment. Efficacy and safety were evaluated in all patients who received at least one dose of the study drug. RESULTS: From June 2013 to April 2014, 102 patients were enrolled, 98 of whom received at least one treatment dose. Seventy-three percent were male, 34% were cirrhotic, 23% had IL28b CC, 65% had genotype 1a, and 41% were previous null responders. The overall SVR rate was 67%. Previous null-responders and cirrhotic patients had lower SVR rates (57% and 51%, respectively). Seventy-six patients (78%) completed the therapy scheme; the most common reasons for discontinuation were lack of response at week 12 (12 patients) and adverse events (six patients). CONCLUSIONS: Response-guided therapy with BOC in combination with PEG-IFN/RBV led to an overall SVR rate of 67%, but an SVR rate of only 51% in patients with cirrhosis. The therapy was generally well tolerated. Although the current standards of care do not include BOC+PEG-IFN/RBV, the authors believe that this combination can be beneficial in situations where new HCV direct antiviral agent interferon-free therapies are not available yet.

Effect of aqueous and particulate silk fibroin in a rat model of experimental colitis.

Silk fibroin (SF) has anti-inflammatory properties and promotes wound healing. Moreover, SF particles act as carriers of active drugs against intestinal inflammation due to their capacity to deliver the compound to the damaged colonic tissue. The present work assesses the effect of SF in the trinitrobenzenesulfonic acid model of rat colitis that resembles human intestinal inflammation. SF (8mg/kg) was administered in aqueous solution orally and in two particulate formats by intrarectal route, following two technologies: spray drying to make microparticles and desolvation in organic solvent to produce nanoparticles. SF treatments ameliorated the colonic damage, reduced neutrophil infiltration and improved the compromised oxidative status of the colon. They also reduced the gene expression of pro-inflammatory cytokines like IL-1ß and the anti-inflammatory cytokine IL-10. Moreover, they improved the intestinal wall integrity by increasing the gene expression of some of its markers (villin, trefoil factor-3 and mucins), thus accelerating the healing. The immunomodulatory properties of SF particles were also tested in vitro in macrophages: they activated the immune response in basal conditions without increasing it after a pro-inflammatory insult. In conclusion, SF particles could be useful as carriers to deliver active drugs to the damaged intestinal colon with additional anti-inflammatory and healing properties.