Heat and desiccation tolerances predict bee abundance under climate change.

Climate change could pose an urgent threat to pollinators, with critical ecological and economic consequences. However, for most insect pollinator species, we lack the long-term data and mechanistic evidence that are necessary to identify climate-driven declines and predict future trends. Here we document 16 years of abundance patterns for a hyper-diverse bee assemblage1 in a warming and drying region2, link bee declines with experimentally determined heat and desiccation tolerances, and use climate sensitivity models to project bee communities into the future. Aridity strongly predicted bee abundance for 71% of 665 bee populations (species × ecosystem combinations). Bee taxa that best tolerated heat and desiccation increased the most over time. Models forecasted declines for 46% of species and predicted more homogeneous communities dominated by drought-tolerant taxa, even while total bee abundance may remain unchanged. Such community reordering could reduce pollination services, because diverse bee assemblages typically maximize pollination for plant communities3. Larger-bodied bees also dominated under intermediate to high aridity, identifying body size as a valuable trait for understanding how climate-driven shifts in bee communities influence pollination4. We provide evidence that climate change directly threatens bee diversity, indicating that bee conservation efforts should account for the stress of aridity on bee physiology.

Advances in Treatment of Diffuse Midline Gliomas.

PURPOSE OF REVIEW: Diffuse midline gliomas (DMGs) generally carry a poor prognosis, occur during childhood, and involve midline structures of the central nervous system, including the thalamus, pons, and spinal cord. RECENT FINDINGS: To date, irradiation has been shown to be the only beneficial treatment for DMG. Various genetic modifications have been shown to play a role in the pathogenesis of this disease. Current treatment strategies span targeting epigenetic dysregulation, cell cycle, specific genetic alterations, and the immune microenvironment. Herein, we review the complex features of this disease as it relates to current and past therapeutic approaches.

A Quality Improvement Pilot Project for Noise Reduction in the NICU.

BACKGROUND: Increased noxious noise leads to adverse short-term and long-term effects on the growing neonate. The American Academy of Pediatrics recommends maintaining a noise level of less than 45 decibels (dBA). The average baseline noise level in an open-pod neonatal intensive care unit (NICU) was 62.6 dBA. PURPOSE: The purpose of this pilot project was to reduce the average noise levels by 39% at the end of an 11-week period. METHODS: The location of the project was in a large, high-acuity level IV open-pod layout NICU that consisted of 4 pods, one of which was cardiac-focused. The average baseline noise level in the cardiac pod was 62.6 dBA in a 24-hour period. Noise levels were not monitored before this pilot project. This project was implemented over an 11-week period. Several modes of education were used for parents and staff. Post-education, Quiet Times were implemented at set times twice daily. Noise levels were monitored for 4 weeks during Quiet Times, with weekly noise level updates for staff. General noise levels were collected a final time to evaluate the overall change in the average noise levels. RESULTS: At the end of the project, noise levels decreased from 62.6 dBA to 54 dBA, a 13.7% reduction. IMPLICATIONS FOR PRACTICE AND RESEARCH: At the end of this pilot project it was noted that: Online modules were the best way to educate staff. Parents should be included in the implementation of quality improvement. Healthcare providers need to know and understand that they can make preventative changes to improve the outcomes of the population.

A critical review of undergraduate education and teaching in forensic psychiatry.

BACKGROUND: Although forensic psychiatry is recognised as a full medical speciality in the UK, training in it is not routinely offered to medical students. With growth both in forensic psychiatry and availability of medical school places, it is a good time to explore the nature and quality of experience already available. AIMS: 1. To map the literature against the guideline for reporting evidence-based practice educational interventions and teaching checklist. 2. To critically review research and scholarship. 3. To identify gaps in evidence-based education for medical students in forensic psychiatry. METHOD: A systematic search of three bibliographic databases from inception to December 2021 was undertaken using keywords related to medical students and forensic psychiatry between December 2021 and March 2022. The search was supplemented by citation and hand searching. RESULTS: Eight articles were identified. Collectively, they suggest that education and teaching were implemented at a local level and not linked to theories of learning. Exposure to forensic psychiatry stimulated positive attitudes, which amplified interest in psychiatry. There was insufficient evidence to determine optimal undergraduate education and teaching practice in forensic psychiatry. CONCLUSIONS: Forensic psychiatry appears to have much to offer the medical undergraduate as part of core learning in psychiatry, including universal skills and knowledge such as ethical decision-making and handling emotions. There appears to be considerable opportunity for education, teaching and research innovation in undergraduate education and teaching in forensic psychiatry. Interesting areas for development include simulated and coproduced education.

Response assessment in paediatric intracranial ependymoma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group.

Response criteria for paediatric intracranial ependymoma vary historically and across different international cooperative groups. The Response Assessment in the Pediatric Neuro-Oncology (RAPNO) working group, consisting of an international panel of paediatric and adult neuro-oncologists, neuro-radiologists, radiation oncologists, and neurosurgeons, was established to address both the issues and the unique challenges in assessing the response in children with CNS tumours. We established a subcommittee to develop response assessment criteria for paediatric ependymoma. Current practice and literature were reviewed to identify major challenges in assessing the response of paediatric ependymoma to clinical trial therapy. For areas in which data were scarce or unavailable, consensus was reached through an iterative process. RAPNO response assessment recommendations include assessing disease response on the basis of changes in tumour volume, and using event-free survival as a study endpoint for patients entering clinical trials without bulky disease. Our recommendations for response assessment include the use of brain and spine MRI, cerebral spinal fluid cytology, neurological examination, and steroid use. Baseline postoperative imaging to assess for residual tumour should be obtained 24-48 h after surgery. Our consensus recommendations and response definitions should be prospectively validated in clinical trials.

Molecular classification and outcome of children with rare CNS embryonal tumors: results from St. Jude Children's Research Hospital including the multi-center SJYC07 and SJMB03 clinical trials.

Methylation profiling has radically transformed our understanding of tumors previously called central nervous system primitive neuro-ectodermal tumors (CNS-PNET). While this marks a momentous step toward defining key differences, reclassification has thrown treatment into disarray. To shed light on response to therapy and guide clinical decision-making, we report outcomes and molecular features of children with CNS-PNETs from two multi-center risk-adapted studies (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort. Seventy patients who had a histological diagnosis of CNS-PNET or CNS embryonal tumor from one of the new categories that has supplanted CNS-PNET were included. This cohort was molecularly characterized by DNA methylation profiling (n = 70), whole-exome sequencing (n = 53), RNA sequencing (n = 20), and germline sequencing (n = 28). Clinical characteristics were detailed, and treatment was divided into craniospinal irradiation (CSI)-containing (SJMB03 and SJMB03-like) and CSI-sparing therapy (SJYC07 and SJYC07-like). When the cohort was analyzed in its entirety, no differences were observed in the 5-year survival rates even when CSI-containing therapy was compared to CSI-sparing therapy. However, when analyzed by DNA methylation molecular grouping, significant survival differences were observed, and treatment particulars provided suggestions of therapeutic response. Patients with CNS neuroblastoma with FOXR2 activation (CNS-NB-FOXR2) had a 5-year event-free survival (EFS)/overall survival (OS) of 66.7% ± 19.2%/83.3% ± 15.2%, and CIC rearranged sarcoma (CNS-SARC-CIC) had a 5-year EFS/OS both of 57.1% ± 18.7% with most receiving regimens that contained radiation (focal or CSI) and multidrug chemotherapy. Patients with high-grade neuroepithelial tumor with BCOR alteration (HGNET-BCOR) had abysmal responses to upfront chemotherapy-only regimens (5-year EFS = 0%), but survival extended with salvage radiation after progression [5-year OS = 53.6% ± 20.1%]. Patients with embryonal tumor with multilayered rosettes (ETMR) or high-grade glioma/glioblastoma multiforme (HGG/GBM) did not respond favorably to any modality (5-year EFS/OS = 10.7 ± 5.8%/17.9 ± 7.2%, and 10% ± 9.0%/10% ± 9.0%, respectively). As an accompaniment, we have assembled this data onto an interactive website to allow users to probe and query the cases. By reporting on a carefully matched clinical and molecular cohort, we provide the needed insight for future clinical management.

Selective population of triplet excited states in heavy-atom-free BODIPY-C60 based molecular assemblies.

Photophysical studies on a BODIPY-fullerene-distyryl BODIPY triad (BDP-C60-DSBDP) and its reference dyads (BODIPY-fullerene; BDP-C60 and distyryl BODIPY-fullerene; DSBDP-C60) are presented herein. In the triad, the association of the two chromophore units linked by a fullerene moiety leads to strong near UV-Visible light absorption from 300 to 700 nm. The triplet-excited state was observed upon visible excitation in all these assemblies, and shown to be localized on the C60 or BODIPY moieties. Using quantitative nanosecond transient absorption, we provide a complete investigation on the lifetime and formation quantum yield of the triplet-excited state. In the BDP-C60 dyad, the triplet excited state of C60 (τ = 7 ± 1 µs) was obtained with a quantum yield of 40 ± 8%. For the DSBDP-C60 dyad and BDP-C60-DSBDP triad, a longer-lived triplet excited state with a lifetime of around 250 ± 20 µs centered on the DSBDP moiety was formed, with respective quantum yields of 37 ± 8 and 20 ± 4%. Triplet-triplet annihilation up-conversion is characterized in the BDP-C60 dyad and the bichromophoric triad in the presence of perylene and DSBDP-monomer as respective annihilators. The photo-induced formation of a long-lived 3DSBDP* in the triad coupled with panchromatic light absorption offers potential applications as a heavy-atom-free organic triplet photosensitizer.

Indigenous health equity in health register ascertainment and data quality: a narrative review.

BACKGROUND: Health registers play an important role in monitoring distribution of disease and quality of care; however, benefit is limited if ascertainment (i.e., the process of finding and recruiting people on to a register) and data quality (i.e., the accuracy, completeness, reliability, relevance, and timeliness of data) are poor. Indigenous peoples experience significant health inequities globally, yet health data for, and about, Indigenous peoples is often of poor quality. This narrative review aimed to (i) identify perceived barriers for the ascertainment of Indigenous peoples on health registers, and (ii) collate strategies identified and used by health registers to support comprehensive ascertainment and high-quality data for Indigenous peoples. METHODS: A Kaupapa Maori theoretical framework was utilized to guide this work. Four electronic databases were systematically searched for original articles and screened for eligibility. Studies involving health registers with Indigenous population(s) identified were included if either ascertainment or data quality strategies were described. Data extraction focused on the reporting of research involving Indigenous peoples using the CONSIDER checklist domains, ascertainment, and data quality. RESULTS: Seventeen articles were included spanning publication between 1992 and 2020. Aspects of four of eight CONSIDER domains were identified to be included in the reporting of studies. Barriers to ascertainment were themed as relating to 'ethnicity data collection and quality', 'systems and structures', 'health services/health professionals', and 'perceptions of individual and community-level barriers'. Strategies to support ascertainment were categorized as 'collaboration', 'finding people', and 'recruitment processes'. Categorized strategies to support data quality were 'collaboration', 'ethnicity data collection and quality', 'systems-level strategies', and 'health service/health professional-level strategies'. CONCLUSIONS: Poor-quality data for Indigenous peoples in health registers prevents the achievement of health equity and exemplifies inaction in the face of need. When viewed through a critical structural determinants lens, there are visible gaps in the breadth of strategies, particularly relating to the inclusion of Indigenous peoples in health register and research governance, and actions to identify and address institutional racism. Indigenous led research, meaningful collaboration, and a sharing of knowledge and experiences between health registers is recommended to enable research and health registers that support Indigenous self-determination and health equity.

Learning the subtle dance: The experience of therapists who deliver mentalisation-based therapy for borderline personality disorder.

OBJECTIVES: This study aimed to understand therapists' lived experiences of delivering mentalisation-based therapy (MBT), including their experiences of service user change. METHOD: One-to-one semi-structured interviews or focus groups were conducted with 14 MBT therapists and analysed using interpretative phenomenological analysis (IPA). RESULTS: Four superordinate themes were identified: (1) experiencing the challenges and complexities of being with service users during MBT; (2) being on a journey of discovery and change; (3) being an MBT therapist: a new way of working and developing a new therapeutic identity; and (4) being a therapist in the group: seeing it all come together. CONCLUSION: Our findings highlight the complexity, challenges and individualised experience of working therapeutically with service users with a diagnosis of BPD. The study provides a perspective of service use change that is enriched by idiosyncrasies within the therapeutic encounter. We conclude with a consideration of implications for MBT research and clinical practice.

Synthesis, Aromaticity, and Application of peri-Pentacenopentacene: Localized Representation of Benzenoid Aromatic Compounds.

We report the synthesis and optoelectronic properties of TIPS-peri-pentacenopentacene (TIPS-PPP), a vertical extension of TIPS-pentacene (TIPS-PEN) and a low-band-gap material with remarkable stability. We found the synthetic conditions to avoid the competition between 1,2- and 1,4-addition of lithium acetylide on the large aromatic dione. The high stability of TIPS-PPP is due to the peri-fusion which increases the aromaticity by generating two localized aromatic sextets that are flanked with 2 diene fragments, similar to two fused-anthracenes. Like TIPS-PEN, TIPS-PPP shows the archetypal 2D brickwall motif in crystals with a larger transfer integral and smaller reorganization energy. The high mobility of up to 1 cm2 V-1 s-1 was obtained in an organic field-effect transistor fabricated by a wet process. Also, TIPS-PPP was used as a near-infrared (NIR) emitter for NIR organic-light-emitting-diode devices resulting in a high external quantum efficiency at 800 nm.

Outcomes after first relapse of childhood intracranial ependymoma.

BACKGROUND: Ependymoma is the third most common malignant CNS tumor in children. Despite multimodal therapy, prognosis of relapsed ependymoma remains poor. Approaches to therapy for relapsed ependymoma are varied. We present a single-institution retrospective review of the outcomes after first relapse of intracranial ependymoma in children. PROCEDURE: We performed a retrospective, IRB-approved chart review of patients with recurrent intracranial ependymoma treated at Dana-Farber/Boston Children's Cancer and Blood Disorders Center from 1990 to 2019. RESULTS: Thirty-four patients with relapsed intracranial ependymoma were identified. At initial diagnosis, 11 patients had supratentorial disease, 22 with posterior fossa disease and one with metastatic disease. Median time-to-first relapse was 14.9 months from initial diagnosis (range 1.4-52.5). Seven patients had metastatic disease at first relapse. Gross total resection (GTR) was associated with improved 5-year progression-free survival (PFS) relative to subtotal resection (STR) and no surgery (p = .005). Localized disease at relapse was associated with improved 5-year overall survival (OS) when compared to metastatic disease (p = .02). Irradiation at first relapse seemed to delay progression but was not associated with statistically prolonged PFS or OS. Tumor location, histology, and chromosomal 1q status did not impact outcome at first relapse, although available molecular data were limited making definitive conclusions difficult. Median time-to-second relapse was 10 months (range 0.7-124). Five-year PFS and OS after first relapse were 19.9% and 45.1%, respectively. Median PFS and OS were 10.0 and 52.5 months after first relapse, respectively. CONCLUSIONS: Relapsed intracranial ependymoma has a poor prognosis despite multimodal therapy. Novel therapeutic strategies are desperately needed for this disease.

A POETIC Phase II study of continuous oral everolimus in recurrent, radiographically progressive pediatric low-grade glioma.

BACKGROUND: To evaluate efficacy, pharmacokinetics (PK) and pharmacodynamics of single-agent everolimus in pediatric patients with radiographically progressive low-grade glioma (LGG). METHODS: Everolimus was administered at 5 mg/m2 once daily as a tablet or liquid for a planned 48-week duration or until unacceptable toxicity or disease progression. Patients with neurofibromatosis type 1 were excluded. PK and pharmacodynamic endpoints were assessed in consenting patients. RESULTS: Twenty-three eligible patients (median age 9.2 years) were enrolled. All patients received prior chemotherapy (median number of prior regimens two) and/or radiotherapy (two patients). By week 48, two patients had a partial response, 10 stable disease, and 11 clinical or radiographic progression; two discontinued study prior to 1 year (toxicity: 1, physician determination: 1). With a median follow up of 1.8 years (range 0.2-6.7 years), the 2-, 3-, and 5-year progression-free survivals (PFS) were 39 ± 11%, 26 ± 11%, and 26 ± 11%, respectively; two patients died of disease. The 2-, 3-, and 5-year overall survival (OS) were all 93 ± 6%. Grade 1 and 2 toxicities predominated; two definitively related grade 3 toxicities (mucositis and neutropenia) occurred. Grade 4 elevation of liver enzymes was possibly related in one patient. Predose blood levels showed substantial variability between patients with 45.5% below and 18.2% above the target range of 5-15 ng/mL. Pharmacodynamic analysis demonstrated significant inhibition in phospho-S6, 4E-BP1, and modulation of c-Myc expression. CONCLUSION: Daily oral everolimus provides a well-tolerated, alternative treatment for multiple recurrent, radiographically progressive pediatric LGG. Based on these results, everolimus is being investigated further for this patient population.

Standard set of patient-reported outcomes for personality disorder.

PURPOSE: The purpose of the article is to present standard set of outcomes for people with personality disorder (PD), in order to facilitate patient outcome measurement worldwide. METHODS: The International Consortium for Health Outcomes Measurement (ICHOM) gathered a multidisciplinary international working group, consisting of 16 experts, including clinicians, nurses, psychologists, methodologists and patient representatives, to develop a standard set of outcome measures for people with PD. The Delphi method was used to reach consensus on the scope of the set, outcome domains, outcome measures, case-mix variables and time points for measuring outcomes in service users. For each phase, a project team prepared materials based on systematic literature reviews and consultations with experts. RESULTS: The working group decided to include PD, as defined by International Classification of Diseases 11th revision (ICD-11). Eleven core outcomes and three optional outcomes across four health domains (mental health, behaviour, functioning and recovery) were defined as those relevant for people with PD. Validated measures for the selected outcomes were selected, some covering more than one outcome. Case-mix variables were aligned to other ICHOM mental health standard sets and consisted of demographic factors and those related to the treatment that people received. The group recommended that most outcomes are measured at baseline and annually. CONCLUSION: The international minimum standard set of outcomes has the potential to improve clinical decision making through systematic measurement and comparability. This will be key in improving the standard of health care for people with PD across the world.

Bee phenology is predicted by climatic variation and functional traits.

Climate change is shifting the environmental cues that determine the phenology of interacting species. Plant-pollinator systems may be susceptible to temporal mismatch if bees and flowering plants differ in their phenological responses to warming temperatures. While the cues that trigger flowering are well-understood, little is known about what determines bee phenology. Using generalised additive models, we analyzed time-series data representing 67 bee species collected over 9 years in the Colorado Rocky Mountains to perform the first community-wide quantification of the drivers of bee phenology. Bee emergence was sensitive to climatic variation, advancing with earlier snowmelt timing, whereas later phenophases were best explained by functional traits including overwintering stage and nest location. Comparison of these findings to a long-term flower study showed that bee phenology is less sensitive than flower phenology to climatic variation, indicating potential for reduced synchrony of flowers and pollinators under climate change.

Anaplastic Astrocytoma in a Child With Coffin-Siris Syndrome and a Germline SMARCE1 Mutation: A Case Report.

Coffin-Siris syndrome (CSS) is a rare congenital disorder with variable clinical phenotype consisting of developmental delay and characteristic facial features. It is caused by mutations in the chromatin remodeling switch/sucrose nonfermenting complex. Although SWI/SNF genes are widely implicated in tumorigenesis, only 8 cases of neoplasm have been reported in patients with CSS. We report a case of anaplastic astrocytoma (WHO grade III) in an 18-month-old child with CSS due to a de novo germline missense SMARCE1 mutation. Additional molecular features of the tumor are described as well. The role of missense SMARCE1 mutations in tumor predisposition in children with CSS should be further investigated to better inform genetic counselling.

Increasing value of autopsies in patients with brain tumors in the molecular era.

BACKGROUND: Pediatric brain tumors are associated with high morbidity and mortality, in part due to insufficient understanding of tumor biology. With limited tissue allocation for research from surgical specimens, a key barrier to improving biological understanding, brain tumor autopsies have become an increasingly valuable resource. This study reviews the brain tumor autopsy practice at our institution and describes specific emerging research utilization patterns beyond the clinical autopsy report. METHODS: We performed a retrospective analysis of brain tumor autopsies at Boston Children's Hospital (BCH) between 2007 and 2017 and reviewed their consents, neuropathology reports and final diagnoses. We reviewed the method of tissue triaging for research consented autopsies (bioregistry, frozen and fresh tissue) and documented their specific uses. RESULTS: Ninety-six deaths at BCH were due to brain tumors; 56 autopsies were performed (58.3%), of which 49 (87.5%) were consented for research. Tumor mapping was performed on all cases and tissue was allocated for DNA- and RNA-based sequencing studies (published and ongoing). Three tissue allocations with a postmortem interval of 8 h or less resulted in successful cell lines. Tissue from 14 autopsies was contributed to the National DIPG Registry. CONCLUSION: Our institutional pediatric brain tumor autopsy clinical experience demonstrates the increased utility and wide utilization of autopsy-derived tissue for multiple types of research. These results support the increased efforts to obtain research consent for brain tumor autopsy and active collection of unfixed autopsy material in the molecular era.

Cutaneous reactions to targeted therapies in children with CNS tumors: A cross-sectional study.

BACKGROUND: MAPK (RAS-RAF-MEK-ERK-MAP) and mTOR inhibitors are novel treatments for pediatric central nervous system (CNS) tumors. The literature on common cutaneous adverse reactions to these therapies is sparse in the pediatric population. The aim of this study was to describe common cutaneous adverse reactions to BRAF, MEK, and mTOR inhibitors in children with CNS tumors. METHODS: In this cross-sectional study, patients younger than 21 years of age receiving BRAF, MEK, and mTOR inhibitor monotherapy for a CNS tumor were enrolled over a one-year period. Full body skin examination, photographs of dermatologic findings, and initial treatment recommendations were included at the initial visit, and follow-up skin examinations were recommended every three months. RESULTS: Twenty-two patients were enrolled in the study. Fifty percent (11/22) received trametinib, a MEK inhibitor, 27.3% (6/22) received dabrafenib, a BRAF inhibitor, and 22.7% (5/22) received everolimus, an mTOR inhibitor. Median age at visit was 11 years (range, 3-19). Median time from treatment initiation to skin examination was 4.5 months (range, 0-43). Ninety-six percent (21/22) of all patients had at least one skin reaction. The most common reactions across treatment groups included follicular/acneiform eruptions and xerosis. Two patients on MEK inhibitors and one patient on a BRAF inhibitor required therapy cessation due to severe cutaneous reactions. CONCLUSIONS: Cutaneous reactions to targeted anticancer therapy in children are common, treatable, and rarely require drug dose reduction or discontinuation. Routine surveillance and early intervention may improve quality of life and facilitate continuation of life-saving therapy.

Heterochiral Ala/(αMe)Aze sequential oligopeptides: Synthesis and conformational study.

α-Amino acid residues with a ϕ,ψ constrained conformation are known to significantly bias the peptide backbone 3D structure. An intriguing member of this class of compounds is (αMe)Aze, characterized by an Nα -alkylated four-membered ring and Cα -methylation. We have already reported that (S)-(αMe)Aze, when followed by (S)-Ala in the homochiral dipeptide sequential motif -(S)-(αMe)Aze-(S)-Ala-, tends to generate the unprecedented γ-bend ribbon conformation, as formation of a regular, fully intramolecularly H-bonded γ-helix is precluded, due to the occurrence of a tertiary amide bond every two residues. In this work, we have expanded this study to the preparation and 3D structural analysis of the heterochiral (S)-Ala/(R)-(αMe)Aze sequential peptides from dimer to hexamer. Our conformational results show that members of this series may fold in type-II ß-turns or in γ-turns depending on the experimental conditions.

Specialty certification and clinical flexibility.

The ability for PAs to easily move from one specialty to another without additional formal training is a unique feature of the profession that is valued by PAs and their employers. Specialty certification has been viewed as a threat to this flexibility, yet 73% of PAs are in specialty practice. How can the desire to preserve flexibility be balanced against the desire of specialized PAs to distinguish themselves in their chosen specialty? This article reviews the issue of specialty certification in the context of contemporary PA practice and concludes that although specialty certification remains a threat to the flexibility of the PA model, it may be appropriate in some situations. In particular, specialty certification may be appropriate as a means for promotion within healthcare systems so long as it is not used as a requirement for entry into specialty practice, credentialing, or third-party reimbursement. A portfolio model may give stakeholders an alternative way to assess the experience and competencies of PAs in specialty practice areas.

Oleoylethanolamine and palmitoylethanolamine modulate intestinal permeability in vitro via TRPV1 and PPARα.

Cannabinoids modulate intestinal permeability through cannabinoid receptor 1 (CB1). The endocannabinoid-like compounds oleoylethanolamine (OEA) and palmitoylethanolamine (PEA) play an important role in digestive regulation, and we hypothesized they would also modulate intestinal permeability. Transepithelial electrical resistance (TEER) was measured in human Caco-2 cells to assess permeability after application of OEA and PEA and relevant antagonists. Cells treated with OEA and PEA were stained for cytoskeletal F-actin changes and lysed for immunoassay. OEA and PEA were measured by liquid chromatography-tandem mass spectrometry. OEA (applied apically, logEC50 -5.4) and PEA (basolaterally, logEC50 -4.9; apically logEC50 -5.3) increased Caco-2 resistance by 20-30% via transient receptor potential vanilloid (TRPV)-1 and peroxisome proliferator-activated receptor (PPAR)-α. Preventing their degradation (by inhibiting fatty acid amide hydrolase) enhanced the effects of OEA and PEA. OEA and PEA induced cytoskeletal changes and activated focal adhesion kinase and ERKs 1/2, and decreased Src kinases and aquaporins 3 and 4. In Caco-2 cells treated with IFNγ and TNFα, OEA (via TRPV1) and PEA (via PPARα) prevented or reversed the cytokine-induced increased permeability compared to vehicle (0.1% ethanol). PEA (basolateral) also reversed increased permeability when added 48 or 72 h after cytokines (P < 0.001, via PPARα). Cellular and secreted levels of OEA and PEA (P < 0.001-0.001) were increased in response to inflammatory mediators. OEA and PEA have endogenous roles and potential therapeutic applications in conditions of intestinal hyperpermeability and inflammation.-Karwad, M. A., Macpherson, T., Wang, B., Theophilidou, E., Sarmad, S., Barrett, D. A., Larvin, M., Wright, K. L., Lund, J. N., O'Sullivan, S. E. Oleoylethanolamine and palmitoylethanolamine modulate intestinal permeability in vitro via TRPV1 and PPARα.