Proximity-Based Emergency Response Communities for Patients With Allergies Who Are at Risk of Anaphylaxis: Clustering Analysis and Scenario-Based Survey Study

BACKGROUND: Anaphylaxis is a potentially fatal allergic reaction. However, many patients at risk of anaphylaxis who should permanently carry a life-saving epinephrine auto injector (EAI) do not carry one at the moment of allergen exposure. The proximity-based emergency response communities (ERC) strategy suggests speeding EAI delivery by alerting patient-peers carrying EAI to respond and give their EAI to a nearby patient in need. OBJECTIVES: This study had two objectives: (1) to analyze 10,000 anaphylactic events from the European Anaphylaxis Registry (EAR) by elicitor and location in order to determine typical anaphylactic scenarios and (2) to identify patients' behavioral and spatial factors influencing their response to ERC emergency requests through a scenario-based survey. METHODS: Data were collected and analyzed in two phases: (1) clustering 10,000 EAR records by elicitor and incident location and (2) conducting a two-center scenario-based survey of adults and parents of minors with severe allergy who were prescribed EAI, in Israel and Germany. Each group received a four-part survey that examined the effect of two behavioral constructs-shared identity and diffusion of responsibility-and two spatial factors-emergency time and emergency location-in addition to sociodemographic data. We performed descriptive, linear correlation, analysis of variance, and t tests to identify patients' decision factors in responding to ERC alerts. RESULTS: A total of 53.1% of EAR cases were triggered by food at patients' home, and 46.9% of them were triggered by venom at parks. Further, 126 Israeli and 121 German participants completed the survey and met the inclusion criteria. Of the Israeli participants, 80% were parents of minor patients with a risk of anaphylaxis due to food allergy; their mean age was 32 years, and 67% were women. In addition, 20% were adult patients with a mean age of 21 years, and 48% were female. Among the German patients, 121 were adults, with an average age of 47 years, and 63% were women. In addition, 21% were allergic to food, 75% were allergic to venom, and 2% had drug allergies. The overall willingness to respond to ERC events was high. Shared identity and the willingness to respond were positively correlated (r=0.51, P<.001) in the parent group. Parents had a stronger sense of shared identity than adult patients (t243= -9.077, P<.001). The bystander effect decreased the willingness of all patients, except the parent group, to respond (F1,269=28.27, P<.001). An interaction between location and time of emergency (F1,473=77.304, P<.001) revealed lower levels of willingness to respond in strange locations during nighttime. CONCLUSIONS: An ERC allergy app has the potential to improve outcomes in case of anaphylactic events, but this is dependent on patient-peers' willingness to respond. Through a two-stage process, our study identified the behavioral and spatial factors that could influence the willingness to respond, providing a basis for future research of proximity-based mental health communities

Targeting of peptide-binding receptors on cancer cells with peptide-drug conjugates

Specifically addressing cell surface molecules on cancer cells facilitates targeted cancer therapies that offer the potential to selectively destroy malignant cells, while sparing healthy tissue. Thus, undesired side-effects in tumor patients are highly reduced. Peptide-binding receptors are frequently overexpressed on cancer cells and therefore promising targets for selective tumor therapy. In this review, peptide-binding receptors for anti-cancer drug delivery are summarized with a focus on peptide ligands as delivery agents. In the first part, some of the most studied peptide-binding receptors are presented, and the ghrelin receptor and the Y1 receptor are introduced as more recent targets for cancer therapy. Furthermore, nonpeptidic small molecules for receptor targeting on cancer cells are outlined. In the second part, peptide conjugates for the delivery of therapeutic cargos in cancer therapy are described. The essential properties of receptor-targeting peptides are specified, and recent developments in the fields of classical peptide-drug conjugates with toxic agents, radiolabeled peptides for radionuclide therapy, and boronated peptides for boron neutron capture therapy are presented

Investigation of MicroRNA-134 as a Target against Seizures and SUDEP in a Mouse Model of Dravet Syndrome

Dravet syndrome (DS) is a catastrophic form of pediatric epilepsy mainly caused by noninherited mutations in the SCN1A gene. DS patients suffer severe and life-threatening focal and generalized seizures which are often refractory to available anti-seizure medication. Antisense oligonucleotides (ASOs) based approaches may offer treatment opportunities in DS. MicroRNAs are short noncoding RNAs that play a key role in brain structure and function by post-transcriptionally regulating gene expression, including ion channels. Inhibiting miRNA-134 (miR-134) using an antimiR ASO (Ant-134) has been shown to reduce evoked seizures in juvenile and adult mice and reduce epilepsy development in models of focal epilepsy. The present study investigated the levels of miR-134 and whether Ant-134 could protect against hyperthermia-induced seizures, spontaneous seizures and mortality (SUDEP) in F1.Scn1a(1/)tm1kea mice. At P17, animals were intracerebroventricular in-jected with 0.1–1 nmol of Ant-134 and subject to a hyperthermia challenge at postnatal day (P)18. A second cohort of P21 F1.Scn1a(1/)tm1kea mice received Ant-134 and were followed by video and EEG monitoring until P28 to track the incidence of spontaneous seizures and SUDEP. Hippocampal and cortical levels of miR-134 were similar between wild-type (WT) and F1.Scn1a(1/)tm1kea mice. Moreover, Ant-134 had no effect on hyperthermia-induced seizures, spontaneous seizures and SUDEP incidence were unchanged in Ant-134-treated DS mice. These findings suggest that targeting miR-134 does not have therapeutic applications in DS

Characterisation of the key determinants of Phd antitoxin mediated Doc toxin inactivation in Salmonella

In the search for novel antimicrobial therapeutics, toxin-antitoxin (TA) modules are promising yet underexplored targets for overcoming antibiotic failure. The bacterial toxin Doc has been associated with the persistence of Salmonella in macrophages, enabling its survival upon antibiotic exposure. After developing a novel method to produce the recombinant toxin, we have used antitoxin-mimicking peptides to thoroughly investigate the mechanism by which its cognate antitoxin Phd neutralizes the activity of Doc. We reveal insights into the molecular detail of the Phd–Doc relationship and discriminate antitoxin residues that stabilize the TA complex from those essential for inhibiting the activity of the toxin. Coexpression of Doc and antitoxin peptides in Salmonella was able to counteract the activity of the toxin, confirming our in vitro results with equivalent sequences. Our findings provide key principles for the development of chemical tools to study and therapeutically interrogate this important class of protein–protein interactions

Radiation Hardness Studies in a CCD with High-Speed Column Parallel Readout

Charge Coupled Devices (CCDs) have been successfully used in several high energy physics experiments over the past two decades. Their high spatial resolution and thin sensitive layers make them an excellent tool for studying short-lived particles. The Linear Collider Flavour Identification (LCFI) collaboration is developing Column-Parallel CCDs (CPCCDs) for the vertex detector of the International Linear Collider (ILC). The CPCCDs can be read out many times faster than standard CCDs, significantly increasing their operating speed. The results of detailed simulations of the charge transfer inefficiency (CTI) of a prototype CPCCD are reported and studies of the influence of gate voltage on the CTI described. The effects of bulk radiation damage on the CTI of a CPCCD are studied by simulating the effects of two electron trap levels, 0.17 and 0.44 eV, at different concentrations and operating temperatures. The dependence of the CTI on different occupancy levels (percentage of hit pixels) and readout frequencies is also studied. The optimal operating temperature for the CPCCD, where the effects of the charge trapping are at a minimum, is found to be about 230 K for the range of readout speeds proposed for the ILC. The results of the full simulation have been compared with a simple analytic model.Comment: 3 pages, 6 figures; presented at IEEE'07, ALCPG'07, ICATPP'0

Food-induced fatal anaphylaxis: from epidemiological data to general prevention strategies

BACKGROUND: Anaphylaxis hospitalisations are increasing in many countries, in particular for medication and food triggers in young children. Food-related anaphylaxis remains an uncommon cause of death, but a significant proportion of these are preventable. AIM: To review published epidemiological data relating to food-induced anaphylaxis and potential risk factors of fatal and/or near-fatal anaphylaxis cases, in order to provide strategies to reduce the risk of severe adverse outcomes in food anaphylaxis. METHODS: We identified 32 published studies available in MEDLINE (1966-2017), EMBASE (1980-2017), CINAHL (1982-2017), using known terms and synonyms suggested by librarians and allergy specialists. RESULTS: Young adults with a history of asthma, previously known food allergy particularly to peanut/tree nuts are at higher risk of fatal anaphylaxis reactions. In some countries, cow's milk and seafood/fish are also becoming common triggers of fatal reactions. Delayed adrenaline injection is associated with fatal outcomes, but timely adrenaline alone may be insufficient. There is still a lack of evidence regarding the real impact of these risk factors and co-factors (medications and/or alcohol consumption, physical activities, and mast cell disorders). CONCLUSIONS: General strategies should include optimization of the classification and coding for anaphylaxis (new ICD 11 anaphylaxis codes), dissemination of international recommendations on the treatment of anaphylaxis, improvement of the prevention in food and catering areas and, dissemination of specific policies for allergic children in schools. Implementation of these strategies will involve national and international support for ongoing local efforts in relationship with networks of centres of excellence to provide personalized management (which might include immunotherapy) for the most at-risk patients. This article is protected by copyright. All rights reserved

Antagomir-mediated suppression of microRNA-134 reduces kainic acid-induced seizures in immature mice

MicroRNAs are short non-coding RNAs that negatively regulate protein levels and perform important roles in establishing and maintaining neuronal network function. Previous studies in adult rodents have detected upregulation of microRNA-134 after prolonged seizures (status epilepticus) and demonstrated that silencing microRNA-134 using antisense oligonucleotides, termed antagomirs, has potent and long-lasting seizure-suppressive effects. Here we investigated whether targeting microRNA-134 can reduce or delay acute seizures in the immature brain. Status epilepticus was induced in 21 day-old (P21) male mice by systemic injection of 5 mg/kg kainic acid. This triggered prolonged electrographic seizures and select bilateral neuronal death within the CA3 subfield of the hippocampus. Expression of microRNA-134 and functional loading to Argonaute-2 was not significantly changed in the hippocampus after seizures in the model. Nevertheless, when levels of microRNA-134 were reduced by prior intracerebroventricular injection of an antagomir, kainic acid-induced seizures were delayed and less severe and mice displayed reduced neuronal death in the hippocampus. These studies demonstrate targeting microRNA-134 may have therapeutic applications for the treatment of seizures in children

Olive‐Oil‐Derived Polyphenols Effectively Attenuate Inflammatory Responses of Human Keratinocytes by Interfering with the NF‐κB Pathway

Scope: Extra virgin olive oil (EVOO) is rich in phenolic compounds, including hydroxytyrosol (HTy) and hydroxytyrosyl acetate (HTy-Ac), which have presented multiple beneficial properties. Their impact on inflammatory responses in human keratinocytes and modes of action have not been addressed yet. Methods and results: Primary human keratinocytes are pretreated with HTy-Ac or HTy for 30 min and stimulated with IL-1β or Toll-like receptor 3 ligand (TLR3-l). Thymic stromal lymphopoietin (TSLP), measured by ELISA, is attenuated by both polyphenols in a dose-dependent manner. The expression of several inflammation-related genes, including distinct TSLP isoforms and IL-8, are assessed by quantitative RT-PCR and likewise inhibited by HTy-Ac/HTy. Mechanistically, EVOO phenols counteracts I κB degradation and translocation of NF-κB to the nucleus, a transcription factor of essential significance to TSLP and IL-8 transcriptional activity; this is evidenced by immunoblotting. Accordingly, NF-κB recruitment to critical binding sites in the TSLP and IL-8 promoter is impeded in the presence of HTy-Ac/HTy, as demonstrated by chromatin immunoprecipitation. Promoter reporter assays finally reveal that the neutralizing effect on NF-κB induction has functional consequences, resulting in reduced NF-κB-directed transcription. Conclusion EVOO phenols afford protection from inflammation in human keratinocytes by interference with the NF-κB pathway