Use of tramadol and the risk of bleeding complications in patients on oral anticoagulants: a systematic review and meta-analysis.

PURPOSE: This systematic review and meta-analysis aimed to determine whether tramadol intake increases the risk of bleeding in patients receiving oral anticoagulants. METHODS: This systematic review was registered on PROSPERO, CRD42022327230. We searched PubMed and Embase up to 14 April 2022, and references and citations of included studies were screened. Comparative and non-comparative studies exploring bleeding complications among adult patients on oral anticoagulants and tramadol were included. Risk of bias was assessed using an adaptation of the Drug Interaction Probability Scale for case reports and case series and the Newcastle-Ottawa Scale for comparative studies. A meta-analysis was performed for the risk of serious bleeding (leading to hospitalisation or death) associated with tramadol in patients on vitamin K antagonists. RESULTS: A total of 17 studies were included: 1 case series, 12 case reports, 2 case-control studies and 2 cohort studies. Most of the studies described tramadol-vitamin K antagonists' concomitant use; one case-control study also assessed dabigatran and rivaroxaban; one case report involved dabigatran. Among case reports/series, a total of 33 patients had a bleeding complication while using tramadol and an oral anticoagulant. The 4 comparative studies reported an increased bleeding risk during tramadol and vitamin K antagonist intake which was statistically significant in one study; the pooled risk ratio of serious bleeding was 2.68 [95% CI: 1.45 to 4.96; p < 0.001]. CONCLUSION: This systematic review confirms an association between tramadol use and risk of bleeding in patients on vitamin K antagonists. Evidence is too limited to assess whether this risk extends to patients on direct oral anticoagulants, and further studies are needed.

Molecular basis for three-dimensional elaboration of the Aquilegia petal spur.

By enforcing specific pollinator interactions, Aquilegia petal nectar spurs maintain reproductive isolation between species. Spur development is the result of three-dimensional elaboration from a comparatively two-dimensional primordium. Initiated by localized, oriented cell divisions surrounding the incipient nectary, this process creates a pouch that is extended by anisotropic cell elongation. We hypothesized that the development of this evolutionary novelty could be promoted by non-mutually exclusive factors, including (i) prolonged, KNOX-dependent cell fate indeterminacy, (ii) localized organ sculpting and/or (iii) redeployment of hormone-signalling modules. Using cell division markers to guide transcriptome analysis of microdissected spur tissue, we present candidate mechanisms underlying spur outgrowth. We see dynamic expression of factors controlling cell proliferation and hormone signalling, but no evidence of contribution from indeterminacy factors. Transcriptome dynamics point to a novel recruitment event in which auxin-related factors that normally function at the organ margin were co-opted to this central structure. Functional perturbation of the transition between cell division and expansion reveals an unexpected asymmetric component of spur development. These findings indicate that the production of this three-dimensional form is an example of organ sculpting via localized cell division with novel contributions from hormone signalling, rather than a product of prolonged indeterminacy.

Cutaneous retinoic acid levels determine hair follicle development and downgrowth.

Retinoic acid (RA) is essential during embryogenesis and for tissue homeostasis, whereas excess RA is well known as a teratogen. In humans, excess RA is associated with hair loss. In the present study, we demonstrate that specific levels of RA, regulated by Cyp26b1, one of the RA-degrading enzymes, are required for hair follicle (hf) morphogenesis. Mice with embryonic ablation of Cyp26b1 (Cyp26b1(-/-)) have excessive endogenous RA, resulting in arrest of hf growth at the hair germ stage. The altered hf development is rescued by grafting the mutant skin on immunodeficient mice. Our results show that normalization of RA levels is associated with reinitiation of hf development. Conditional deficiency of Cyp26b1 in the dermis (En1Cre;Cyp26b1f/-) results in decreased hair follicle density and specific effect on hair type, indicating that RA levels also influence regulators of hair bending. Our results support the model of RA-dependent dermal signals regulating hf downgrowth and bending. To elucidate target gene pathways of RA, we performed microarray and RNA-Seq profiling of genes differentially expressed in Cyp26b1(-/-) skin and En1Cre;Cyp26b1f/- tissues. We show specific effects on the Wnt-catenin pathway and on members of the Runx, Fox, and Sox transcription factor families, indicating that RA modulates pathways and factors implicated in hf downgrowth and bending. Our results establish that proper RA distribution is essential for morphogenesis, development, and differentiation of hfs.

Sulfinylated azadecalins act as functional mimics of a pollen germination stimulant in Arabidopsis pistils.

Polarized cell elongation is triggered by small molecule cues during development of diverse organisms. During plant reproduction, pollen interactions with the stigma result in the polar outgrowth of a pollen tube, which delivers sperm cells to the female gametophyte to effect double fertilization. In many plants, pistils stimulate pollen germination. However, in Arabidopsis, the effect of pistils on pollen germination and the pistil factors that stimulate pollen germination remain poorly characterized. Here, we demonstrate that stigma, style, and ovules in Arabidopsis pistils stimulate pollen germination. We isolated an Arabidopsis pistil extract fraction that stimulates Arabidopsis pollen germination, and employed ultra-high resolution electrospray ionization (ESI), Fourier-transform ion cyclotron resonance (FT-ICR) and MS/MS techniques to accurately determine the mass (202.126 Da) of a compound that is specifically present in this pistil extract fraction. Using the molecular formula (C10H19NOS) and tandem mass spectral fragmentation patterns of the m/z (mass to charge ratio) 202.126 ion, we postulated chemical structures, devised protocols, synthesized N-methanesulfinyl 1- and 2-azadecalins that are close structural mimics of the m/z 202.126 ion, and showed that they are sufficient to stimulate Arabidopsis pollen germination in vitro (30 µm stimulated approximately 50% germination) and elicit accession-specific response. Although N-methanesulfinyl 2-azadecalin stimulated pollen germination in three species of Lineage I of Brassicaceae, it did not induce a germination response in Sisymbrium irio (Lineage II of Brassicaceae) and tobacco, indicating that activity of the compound is not random. Our results show that Arabidopsis pistils promote germination by producing azadecalin-like molecules to ensure rapid fertilization by the appropriate pollen.

Impact of Coal-fired Power Plant Emissions on Children's Health: A Systematic Review of the Epidemiological Literature.

Coal-based energy production is the most utilized method of electricity production worldwide and releases the highest concentration of gaseous, particulate, and metallic pollutants. This article aims to systematically review the public health impact of coal-fired power plant emissions on children's health. PubMed, Web of Science, and Toxline databases were queried for the past 20 years. Inclusion criteria included original scientific articles with (a) coal-fired power plant exposure assessment, (b) at least one primary pediatric health outcome, and (c) assessment of potential sources of confounding and bias. Only morbidity and mortality studies were included; economic analysis and risk assessment studies without a primary health outcome were not included. Of 513 articles initially retrieved, 17 epidemiological articles were included in the final systematic review after screening and eligibility. The articles reviewed showed a statistically significant adverse effect on pediatric neurodevelopment; birth weight and pediatric respiratory morbidity was associated with exposure to coal-fired power plant emissions, primarily particulate matter and polyaromatic hydrocarbon exposure. There is a lack of consistency of exposure assessment and inadequate control of significant potential confounders such as social economic status. Future research should focus on improving exposure assessment models with an emphasis on source-apportionment and geographic information system methods to model power plant-specific emissions.

Adaptation of health systems to climate-related migration in Sub-Saharan Africa: Closing the gap.

Health systems worldwide need to be adapted to cope with growing numbers of migrants and to climate-exacerbated morbidity. Heatwaves, water stress, desertification, flooding, and sea level rise are environmental stressors that increase morbidity, mortality, and poor mental health in Sub-Saharan Africa. While most migration is intra-African, climate change is also affecting migration patterns outside the continent. To tackle the health challenges induced by these events, such as infectious diseases and malnutrition, health care providers in Sub-Saharan Africa and in receiving countries in Europe must adapt their systems to provide appropriate health services to these communities. While health systems differ greatly across the global north and south, adaptation measures are similar and should be integrated. We present recommendations for adaptation of health systems to climate-related migration, including strengthening health systems, providing access to healthcare, culturally-appropriate services, policy-oriented research and training, and inter-sectoral collaboration.

A rapid, inexpensive, and semi-quantitative method for determining pollen tube extension using fluorescence.

BACKGROUND: Pollen tubes extend rapidly when pollen grains are incubated in defined media. Tube extension requires many critical functions of plant cells including molecular signaling, cytoskeleton remodeling, secretion, and cell wall synthesis. Consequently, pollen tube growth has been established as a way to conduct primary screens of chemical libraries to identify compounds that perturb key cellular processes in plants. RESULTS: Here we report a simple, inexpensive, rapid and semi-quantitative method for measurement of pollen tube growth in microtiter plates. The method relies on Congo Red binding to pollen tubes and correlates dye fluorescence to tube length. CONCLUSIONS: This method can be used in any laboratory without specialized equipment, and has the potential to enable larger screens as chemical libraries grow and to make chemical screening accessible to researchers building specialized libraries designed to probe pathways in plant biology.