Drug delivery systems for potential treatment in intracellular bacterial infections

Despite the advent of a considerable number of new antibiotics, treatment of intracellular pathogens still represents a major pharmaceutical challenge. The antibiotic concentration in those specialized niches are often subtherapeutic, for which high doses of antibiotics must often be used. This is not only costly but may also increase localized or systemic side effects. There is therefore an urgent need for materials and methods to enable clinicians to achieve therapeutically effective intracellular concentration of those antibiotics which show good efficiency in vitro. In this setting, the possible use of drug delivery systems (DDS) loaded with antibiotics that exhibit a high in vitro bactericidal activity deserves to be considered. Entrapping or encapsulating the drug within a delivery system provides a greater control of the pharmacokinetic behavior of the active molecule. This more efficient use of antibiotics may diminish their drawbacks and provide the basis for shortening the current time required by classical treatments. This review will focus on the role of DDS as a potential tool against intracellular bacteria

Prognostic value of replication errors on chromosomes 2p and 3p in non-small-cell lung cancer

As chromosomes 2p and 3p are frequent targets for genomic instability in lung cancer, we have addressed whether alterations of simple (CA)n DNA repeats occur in non-small-cell lung cancer (NSCLC) at early stages. We have analysed by polymerase chain reaction (PCR) assay replication errors (RER) and loss of heterozygosity (LOH) at microsatellites mapped on chromosomes 2p and 3p in 64 paired tumour-normal DNA samples from consecutively resected stage I, II or IIIA NSCLC. DNA samples were also examined for K-ras and p53 gene mutations by PCR-single-stranded conformational polymorphism (PCR-SSCP) analysis and cyclic sequencing, as well as their relationship with clinical outcome. Forty-two of the 64 (66%) NSCLC patients showed RER at single or multiple loci. LOH was detected in 23 tumours (36%). Among patients with stage I disease, the 5-year survival rate was 80% in those whose tumours had no evidence of RER and 26% in those with RER (P = 0.005). No correlation was established between RER phenotype and LOH, K-ras or p53 mutations. RER remained a strong predictive factor (hazard ratio for death, 2.89; 95% confidence interval, 2.23-3.79; P = 0.002) after adjustment for all other evaluated factors, including p53, K-ras, LOH, histological type, tumour differentiation and TNM stage, suggesting that microsatellite instability on chromosomes 2p and 3p may play a role in NSCLC progression through a different pathway from the traditional tumour mechanisms of oncogene activation and/or tumour-suppressor gene inactivation

Diagnosis of immediate reactions to amoxicillin: Comparison of basophil activation markers CD63 and CD203c in a prospective study

Amoxicillin (AX) combined or not with clavulanic acid (CLV) is frequently involved in IgE-mediated reactions. Drug provocation test (DPT) is considered as the gold standard for diagnosis, although contraindicated in high-risk patients. Basophil activation test (BAT) can help diagnose immediate reactions to beta-lactams, although controversy exists regarding the best activation marker. We have performed a real-life study in a prospective cohort to analyze the real value of BAT as diagnostic tool and the best activation marker, CD63 and CD203c, for the evaluation of immediate reactions to these drugs.We thank Claudia Corazza for her invaluable English language support; Verónica Prados and Ana Molina for their help in technical support in flow cytometry methods. This work has been supported by Institute of Health “Carlos III” (ISCIII) of the Ministry of Economy and Competitiveness (MINECO; grants co-funded by European Regional Development Fund: PI15/01206, PI17/01237, PI18/00095, PI20/01734, RETICS ARADYAL RD16/0006/0001, and RICORS REI (RD21/0002/0008); Andalusian Regional Ministry of Health (grants PI-0241-2016, PE-0172-2018, and PI-0127-2020); Spanish Ministerio de Ciencia e Innovación Proyectos de I + D + I «Programación Conjunta Internacional», EuroNanoMed 2019 (PCI2019-111825-2)). AA holds a Senior Postdoctoral Contract (RH-0099-2020) with the Andalusian Regional Ministry of Health (cofunded by European Social Fund (ESF): "Andalucía se mueve con Europa". GB holds a “Juan Rodes” contract (JR18/00054) by ISCIII of MINECO (cofounded by ESF). ID holds a clinical research stabilization contract by Andalusian Regional Ministry of Health (RB-0001-2022). ML holds a “Rio Hortega” contract (CM20/00210) by ISCIII of MINECO (cofounded by ESF). CF holds a Marie Skłodowska-Curie Individual Fellowship by the European Union's Horizon 2020 research and innovation program (agreement n° PI-0241-2016101027955). CM holds a “Nicolas Monardes” research contract by Andalusian Regional Ministry of Health (RC-0004-2021). // Funding for open access charge: Universidad de Málaga / CBUA

'Amiga' strawberry

‘Amiga’ is a short-day strawberry cultivar developed by the Spanish public breeding program. ‘Amiga’ has a very high fruit firmness, high production, long fruit shape, and good appearance. An agronomic and sensory characterization of this new cultivar, in comparison with the well-adapted cultivars Camarosa, Carisma, Marina and Medina, was undertaken during the 2000 and 2001 crop seasons. Most strawberries produced in Spain are shipped fresh to destinations throughout Europe. Growers therefore need cultivars producing fruit that, in addition to attractiveness and top-class sensory attributes, ensures maintenance of quality after long-distance shipment. During the crop season 2006, a total of 58.3% of the total strawberry output at Huelva (312,066 t) was shipped fresh to market (Anonymous, 2006). The main destinations were Germany, France, and the United Kingdom. As a result of the economic and social significance of strawberry production in Spain, which is currently the leading European producer of fresh-market strawberries (López-Aranda et al., 2003), a number of public institutions, including the Instituto Nacional de Investigaciones Agrarias (INIA), the Instituto de Investigacio´n y Formacio´n Agraria y Pesquera (IFAPA), and the Instituto Valenciano de Investigaciones Agrarias (IVIA), are carrying out a breeding program to develop new strawberry cultivars well adapted to growing conditions in Spanish production areas, and particularly in Huelva. ‘Amiga’ is the latest cultivar released from this program in cooperation with the private partner, Viveros California, S.L. Previous cultivars released include ‘Andana’ (Bartual et al., 1997), ‘Carisma’ (Bartual et al., 2002), ‘Marina’ (López-Aranda et al., 2004), ‘Medina’ (López-Aranda et al., 2005a), and ‘Aguedilla’ (López-Aranda et al., 2005b). The new short-day strawberry (Fragaria · ananassa Duch.) cultivar Amiga is remarkable for its very high firmness, high production in annual production systems, long fruit shape, and good appearance. Its harvest season is early, which is extremely important for economic production on the southwest coast of Spain, and its firmness is essential for long-distance shipment

Characterizing the involvement of FaMADS9 in the regulation of strawberry fruit receptacle development

FaMADS9 is the strawberry (Fragaria x ananassa) gene that exhibits the highest homology to the tomato (Solanum lycopersicum) RIN gene. Transgenic lines were obtained in which FaMADS9 was silenced. The fruits of these lines did not show differences in basic parameters, such as fruit firmness or colour, but exhibited lower Brix values in three of the four independent lines. The gene ontology MapMan category that was most enriched among the differentially expressed genes in the receptacles at the white stage corresponded to the regulation of transcription, including a high percentage of transcription factors and regulatory proteins associated with auxin action. In contrast, the most enriched categories at the red stage were transport, lipid metabolism and cell wall. Metabolomic analysis of the receptacles of the transformed fruits identified significant changes in the content of maltose, galactonic acid-1,4-lactone, proanthocyanidins and flavonols at the green/white stage, while isomaltose, anthocyanins and cuticular wax metabolism were the most affected at the red stage. Among the regulatory genes that were differentially expressed in the transgenic receptacles were several genes previously linked to flavonoid metabolism, such as MYB10, DIV, ZFN1, ZFN2, GT2, and GT5, or associated with the action of hormones, such as abscisic acid, SHP, ASR, GTE7 and SnRK2.7. The inference of a gene regulatory network, based on a dynamic Bayesian approach, among the genes differentially expressed in the transgenic receptacles at the white and red stages, identified the genes KAN1, DIV, ZFN2 and GTE7 as putative targets of FaMADS9. A MADS9-specific CArG box was identified in the promoters of these genes

The climate-smart village approach: Framework of an integrative strategy for scaling up adaptation options in agriculture

Increasing weather risks threaten agricultural production systems and food security across the world. Maintaining agricultural growth while minimizing climate shocks is crucial to building a resilient food production system and meeting developmental goals in vulnerable countries. Experts have proposed several technological, institutional, and policy interventions to help farmers adapt to current and future weather variability and to mitigate greenhouse gas (GHG) emissions. This paper presents the climate-smart village (CSV) approach as a means of performing agricultural research for development that robustly tests technological and institutional options for dealing with climatic variability and climate change in agriculture using participatory methods. It aims to scale up and scale out the appropriate options and draw out lessons for policy makers from local to global levels. The approach incorporates evaluation of climate-smart technologies, practices, services, and processes relevant to local climatic risk management and identifies opportunities for maximizing adaptation gains from synergies across different interventions and recognizing potential maladaptation and trade-offs. It ensures that these are aligned with local knowledge and link into development plans. This paper describes early results in Asia, Africa, and Latin America to illustrate different examples of the CSV approach in diverse agroecological settings. Results from initial studies indicate that the CSV approach has a high potential for scaling out promising climate-smart agricultural technologies, practices, and services. Climate analog studies indicate that the lessons learned at the CSV sites would be relevant to adaptation planning in a large part of global agricultural land even under scenarios of climate change. Key barriers and opportunities for further work are also discussed

Sugar-added beverages consumption among kindergarten children of Crete: effects on nutritional status and risk of obesity

<p>Abstract</p> <p>Objective</p> <p>To assess the intake of sugar-added beverages such as soft drinks and commercially available fruit juices in kindergarten children, and to examine its association with obesity indices, physical activity levels and dietary habits.</p> <p>Methods</p> <p>A total of 856 children aged 4–7 years living in Crete, Greece in 2004–5 were included in this cross-sectional study. Nutrient and food intake was assessed with the use of 3-day weighed food records. Body measurements were used in order to assess BMI and waist circumference, and moderate-to-vigorous physical activity was calculated with the use of a questionnaire.</p> <p>Results</p> <p>Approximately 59.8% of all children consumed sugar-added beverages on a daily basis. High intake of sugar-added beverages (> 250 g/day) was associated with low intakes of calcium (p < 0.001), vitamin A and E (p < 0.010), fruits and vegetables (p = 0.007), and milk and yogurt (p = 0.048). Compared to non or low consumers, high consumers of sugar-added beverages (> 250 g/day) had higher BMI levels and two times greater risk of being overweight and/or obese (OR:2.35, p = 0.023).</p> <p>Conclusion</p> <p>High intake of sugar-added beverages in kindergarten children is associated with poor eating habits and inadequate nutrient intake, as well as increased risk for developing childhood obesity.</p

Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial

IMPORTANCE: Immune dysregulation contributes to poorer outcomes in COVID-19. OBJECTIVE: To investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-masked, placebo-controlled clinical trial using a master protocol to investigate immunomodulators added to standard care for treatment of participants hospitalized with COVID-19 pneumonia. The results of 3 substudies are reported from 95 hospitals at 85 clinical research sites in the US and Latin America. Hospitalized patients 18 years or older with confirmed SARS-CoV-2 infection within 14 days and evidence of pulmonary involvement underwent randomization between October 2020 and December 2021. INTERVENTIONS: Single infusion of abatacept (10 mg/kg; maximum dose, 1000 mg) or infliximab (5 mg/kg) or a 28-day oral course of cenicriviroc (300-mg loading dose followed by 150 mg twice per day). MAIN OUTCOMES AND MEASURES: The primary outcome was time to recovery by day 28 evaluated using an 8-point ordinal scale (higher scores indicate better health). Recovery was defined as the first day the participant scored at least 6 on the ordinal scale. RESULTS: Of the 1971 participants randomized across the 3 substudies, the mean (SD) age was 54.8 (14.6) years and 1218 (61.8%) were men. The primary end point of time to recovery from COVID-19 pneumonia was not significantly different for abatacept (recovery rate ratio [RRR], 1.12 [95% CI, 0.98-1.28]; P = .09), cenicriviroc (RRR, 1.01 [95% CI, 0.86-1.18]; P = .94), or infliximab (RRR, 1.12 [95% CI, 0.99-1.28]; P = .08) compared with placebo. All-cause 28-day mortality was 11.0% for abatacept vs 15.1% for placebo (odds ratio [OR], 0.62 [95% CI, 0.41-0.94]), 13.8% for cenicriviroc vs 11.9% for placebo (OR, 1.18 [95% CI 0.72-1.94]), and 10.1% for infliximab vs 14.5% for placebo (OR, 0.59 [95% CI, 0.39-0.90]). Safety outcomes were comparable between active treatment and placebo, including secondary infections, in all 3 substudies. CONCLUSIONS AND RELEVANCE: Time to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04593940