The microRNA-7-mediated reduction in EPAC-1 contributes to vascular endothelial permeability and eNOS uncoupling in murine experimental retinopathy

To investigate the consequences of oxidative stress and hypoxia on EPAC-1 expression during retinopathy. Oxygen-induced retinopathy was induced in mice and EPAC-1 expression investigated by immunofluorescence. In silico analyses were used to identify a link between EPAC-1 expression and microRNA-7-5p in endothelial cells and confirmed by western blot analyses on cells expressing microRNA-7-5p. In vitro, endothelial cells were either incubated at 2% oxygen or transfected with microRNA-7-5p, and the effects of these treatments on EPAC-1 expression, endothelial hyperpermeability and NO production were assessed. In the Ins2Akita mouse model, levels of EPAC-1 expression as well as microRNA-7-5p were assessed by qPCR. Endothelial nitric oxide synthase was assessed by immunoblotting in the Ins2Akita model. Hypoxia induces the expression of microRNA-7-5p that translationally inhibits the expression of EPAC-1 in endothelial cells, resulting in hyperpermeability and the loss of eNOS activity. Activation of EPAC-1 by the cAMP analogue 8-pCPT-2'-O-Me-cAMP reduced the sensitivity of EPAC-1 to oxidative stress and restored the endothelial permeability to baseline levels. Additionally, 8-pCPT-2'-O-Me-cAMP rescued eNOS activity and NO production. In mouse models of retinopathy, i.e., oxygen-induced retinopathy and the spontaneous diabetic heterozygous Ins2(Akita) mice, EPAC-1 levels are decreased which is associated with an increase in microRNA-7-5p expression and reduced eNOS activity. In retinopathy, EPAC-1 expression is decreased in a microRNA-7-mediated manner, contributing to endothelial dysfunction. Pharmacological activation of remnant EPAC-1 rescues endothelial function. Collectively, these data indicate that EPAC-1 resembles an efficacious and druggable target molecule for the amelioration of (diabetic) retinopathy

Evaluation of an emergency safe supply drugs and managed alcohol program in COVID-19 isolation hotel shelters for people experiencing homelessness

BACKGROUND: During a COVID-19 outbreak in the congregate shelter system in Halifax, Nova Scotia, Canada, a multidisciplinary health care team provided an emergency “safe supply” of pharmaceutical-grade medications and beverage-grade alcohol to facilitate isolation in COVID-19 hotel shelters for residents who are dependent on these substances. We aimed to evaluate (a) substances and dosages provided, and (b) effectiveness and safety of the program. METHODS: We retrospectively reviewed medical records of all COVID-19 isolation hotel shelter residents during May 2021. We extracted data on medication and alcohol dosages provided each day. The primary outcome was residents prematurely leaving isolation against public health orders. Adverse events included (a) overdose; (b) intoxication; and (c) diversion, selling, or sharing of medications or alcohol. RESULTS: Over 25 days, 77 isolation hotel residents were assessed (mean age 42 ± 14 years; 24% women). Sixty-two (81%) residents were provided medications, alcohol, or cigarettes. Seventeen residents (22%) received opioid agonist treatment medications (methadone, buprenorphine, or slow-release oral morphine) and 27 (35%) received hydromorphone tablets. Thirty-one (40%) residents received stimulant tablets with methylphenidate (27; 35%), dextroamphetamine (8; 10%), or lisdexamfetamine (2; 3%). Six residents (8%) received benzodiazepines. Forty-two (55%) residents received alcohol, including 41 (53%) with strong beer, three (3%) with wine, and one (1%) with hard liquor. Over 14 days in isolation, mean daily dosages increased of hydromorphone (45 ± 32 to 57 ± 42mg), methylphenidate (51 ± 28 to 77 ± 37mg), dextroamphetamine (33 ± 16 to 46 ± 13mg), and alcohol (12.3 ± 7.6 to 13.0 ± 6.9 standard drinks). Six residents (8%) left isolation prematurely, but four of those residents returned. Over 1,059 person-days in isolation, there were zero overdoses. Documented concerns regarding intoxication occurred six times (0.005 events/person-day) and medication diversion or sharing three times (0.003 events/person-day). CONCLUSIONS: An emergency safe supply and managed alcohol program, paired with housing, was associated with low rates of adverse events and high rates of successful completion of the 14-day isolation period in COVID-19 isolation hotel shelters. This supports the effectiveness and safety of emergency safe supply prescribing and managed alcohol in this setting

Prehospital risk stratification in patients with chest pain

OBJECTIVES: The History, ECG, Age, Risk Factors and Troponin (HEART) Score is a decision support tool applied by physicians in the emergency department developed to risk stratify low-risk patients presenting with chest pain. We assessed the potential value of this tool in prehospital setting, when applied by emergency medical services (EMS), and derived and validated a tool adapted to the prehospital setting in order to determine if it could assist with decisions regarding conveyance to a hospital. METHODS: In 2017, EMS personnel prospectively determined the HEART Score, including point-of-care (POC) troponin measurements, in patients presenting with chest pain, in the north of the Netherlands. The primary endpoint was a major adverse cardiac event (MACE), consisting of acute myocardial infarction or death, within 3 days. The components of the HEART Score were evaluated for their discriminatory value, cut-offs were calibrated for the prehospital setting and sex was substituted for cardiac risk factors to develop a prehospital HEART (preHEART) Score. This score was validated in an independent prospective cohort of 435 patients in 2018. RESULTS: Among 1208 patients prospectively recruited in the first cohort, 123 patients (10.2%) developed a MACE. The HEART Score had a negative predictive value (NPV) of 98.4% (96.4-99.3), a positive predictive value (PPV) of 35.5% (31.8-39.3) and an area under the receiver operating characteristic curve (AUC) of 0.81 (0.78-0.85). The preHEART Score had an NPV of 99.3% (98.1-99.8), a PPV of 49.4% (42.0-56.9) and an AUC of 0.85 (0.82-0.88), outperforming the HEART Score or POC troponin measurements on their own. Similar results were found in a validation cohort. CONCLUSIONS: The HEART Score can be used in the prehospital setting to assist with conveyance decisions and choice of hospitals; however, the preHEART Score outperforms both the HEART Score and single POC troponin measurements when applied by EMS personnel in the prehospital setting

De Zuid-Oost Veluwezoom: Parels rijgen in de regio

Eindrapport van het Raakproject 'Veluwezoom: parels rijgen in de regio &#39

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conference focuses on accomplishments and future challenges in Aviation Psychology. EAAP was founded as WEAAP, Western European Association for Aviation Psychology, in 1956 by nine Aviation Psychologists meeting in Scheveningen, the Netherlands. Shortly thereafter the association was officially registered in Amsterdam. In 1994 the association was renamed into EAAP to account for the whole of Europe, after the fall of the Berlin Wall. Thus it was finally decided to host and organise the 2006 EAAP jubilee conference near Berlin in the SEMINARIS Hotel (www.seminaris.de) within the picturesque and historical vicinity of Potsdam. The beginning of the conference is dedicated to reflect on the history and achievements within the various domains and areas of aviation psychology. The board of EAAP has invited several honory members who are witnesses of the early years of EAAP. The board hopes that some of them are able to attend the conference. Invited speakers give an overview on human engineering aspects, selection and training of aviation personnel as well as incident and accident investigations. Overviews are also given on human factors aspects in Regulation and Certification, in ATC/ATM and in Maintenance

Anti-human Vascular Endothelial Growth Factor (VEGF) Antibody Selection for Immunohistochemical Staining of Proliferating Blood Vessels

Nine commercially available vascular endothelial growth factor (VEGF) antibodies were investigated for their ability to immunostain vascular malformations (VMs) with or without immature capillary proliferation. First, all antibodies were optimized for their performance in IHC, with placenta and colon adenocarcinoma as positive control tissues. Five antibodies were regarded as unfit for VEGF immunostaining based on poor immunostaining criteria. Subsequently, Western blot analysis using VEGF rabbit polyclonal antibody (Thermo RB-9031) revealed a clear 45-kDa band in tissue extracts from VMs with immature capillary proliferation and a high Ki67-labeling index, whereas tissue extracts from mature VMs without microvascular proliferation and no Ki67-labeling index demonstrated only a very weak 45-kDa band. In contrast, two VEGF antibodies, including the popular Santa Cruz A-20, revealed bands at 45 kDa of similar intensity in tissue extracts from both types of VMs. Staining characteristics of the 45-kDa band were reflected in the results obtained in IHC. (J Histochem Cytochem 58:109–118, 2010

Thyroid incidentalomas in patients with multiple endocrine neoplasia type 1

OBJECTIVE: Currently, little is known about the prevalence of thyroid tumors in multiple endocrine neoplasia type 1 (MEN1) patients and it is unclear whether tumorigenesis of these thyroid tumors is MEN1-related. The aim of the study was to assess the prevalence of thyroid incidentalomas in MEN1 patients compared with nonMEN1 patients and to verify whether thyroid tumorigenesis is MEN1-related. DESIGN: A cross-sectional study. METHODS: The study included two groups: patients with MEN1 and a matched non-MEN1 control group without known thyroid disease, who underwent an ultrasound of the neck for the localization of parathyroid adenoma. Ninety-five MEN1 patients underwent ultrasound of the neck and were matched on gender and age with non-MEN1 patients. The prevalence of thyroid incidentalomas described in the ultrasound report was scored. Multinodular goiters, solitary nodes, and cysts were scored as incidentalomas. Presence of nuclear menin expression was evaluated by menin immunostaining of the thyroid tumors. RESULTS: In the MEN1 group, 43 (45%) patients had a thyroid incidentaloma compared with 48 (51%) in the non-MEN1 group, of which 14 (15%) and 16 (17%), respectively, were solitary nodes. Menin was expressed in the nuclei of all evaluated thyroid tumors. CONCLUSIONS: MEN1 patients do not have a higher prevalence of thyroid incidentalomas compared with primary hyperparathyroidism patients without the diagnosis of MEN1. Menin was expressed in the thyroid tumors of MEN1 patients