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Background: Early cardiopulmonary resuscitation and defibrillation is key to increasing survival following an out-of-hospital-cardiac-arrest (OHCA). However, automated external defibrillators (AEDs) are used in a very small percentage of cases. Despite large numbers of AEDs in the community, the absence of a unified system for registering their locations across the UK’s ambulance services may have resulted in missed opportunities to save lives. Therefore, representatives from the resuscitation community worked alongside ambulance services to develop a single repository for data on the location of AEDs in the UK. Methods: A national defibrillator network, “The Circuit”, was developed by the British Heart Foundation in collaboration with the Association of Ambulance Chief Executives, the UK ambulance services, the Resuscitation Council UK and St John Ambulance. The database allows individuals or organisations to record information about AED location, accessibility, and availability. The database synchronises with ambulance computer aided dispatch systems to provide UK ambulance services with real-time information on the nearest, available AED. Results: The Circuit was successfully rolled out to all 14 UK ambulance services. Since 2019, 82,108 AEDs have been registered. Of the AED data collected by The Circuit, 54% were not previously registered to any ambulance service, and are therefore new registrations. Conclusion: The Circuit provides ambulance services with a single point of access to AED locations in the UK. Since the launch of the system the number of defibrillators registered has doubled. Linking the Circuit data with patient outcome data will help understand whether improving the accessibility to AEDs is associated with increased survival.

This paper reports the in silico prediction of biological activities of lignans from Diphylleia cymosa and Podophyllum hexandrum combined with an in vitro bioassays. The extracts from the leaves, roots and rhizomes of both species were evaluated for their antibacterial, anticholinesterasic, antioxidant and cytotoxic activities. A group of 27 lignans was selected for biological activities prediction using the Active-IT system with 1987 ligand-based bioactivity models. The in silico approach was properly validated and several ethnopharmacological uses and known biological activities were confirmed, whilst others should be investigated for new drugs with potential clinical use. The extracts from roots of D. cymosa and from rhizomes and roots of P. hexandrum were very effective against Bacillus cereus and Staphylococcus aureus, while podophyllotoxin inhibited the growth of Staphylococcus aureus and Escherichia coli. D. cymosa leaves and roots showed anticholinesterasic and antioxidant activities, respectively. The evaluated extracts showed to be moderately toxic to THP-1 cells. The chromatographic characterization indicated that podophyllotoxin was the major constituent of P. hexandrum extract while kaempferol and its hexoside were the main constituents of D. cymosa leaves and roots, respectively. These results suggest that the podophyllotoxin could be the major antibacterial lignan, while flavonoids could be responsible for the antioxidant activity.

Decreased upright cerebral blood flow (CBF) with hyperpnea and hypocapnia is seen in a minority of patients with postural tachycardia syndrome (POTS). More often, CBF is not decreased despite upright neurocognitive dysfunction. This may result from time-dependent changes in CBF. We hypothesized that increased oscillations in CBF occurs in POTS (N=12) compared to healthy controls (N=9), and tested by measuring CBF velocity (CBFv) by transcranial Doppler ultrasound of the middle cerebral artery, mean arterial pressure (MAP) and related parameters, supine and during 70o upright tilt. Autospectra for mean CBFv and MAP, and transfer function analysis were obtained over the frequency range of 0.0078 to 0.4 Hz. Upright HR was increased in POTS (125±8 vs 86±2 bpm), as was diastolic BP (74±3 vs 65±3 mmHg) compared to control, while peripheral resistance, cardiac output, and mean CBFv increased similarly with tilt. Upright BP variability (BPV), low frequency (LF) power (.04 - 0.13 Hz) , and peak frequency of BPV were increased in POTS (24.3±4.1, and 18.4±4.1 mmHg2/Hz at .091 Hz vs 11.8±3.3, and 8.8 ± 2 mmHg2/Hz c at 0.071 Hz), as was upright overall CBFv variability, low frequency power and peak frequency of CBFv variability (29.3±4.7, and 22.1±2.7 [cm/s]2/Hz at .092 Hz vs 14.7±2.6, and 6.7 ± 1.2 [cm/s]2/Hz at 0.077Hz). Autospectra were sharply peaked in POTS. LF phase was decreased in POTS (-14 ± 4 vs -25 ± 10 degrees) while upright. LF gain was increased (1.51 ± 0.09 vs 0.86 ± 0.12 [cm/s]/ mmHg) while coherence was increased (0.96 ± 0.01 vs 0.80 ± 0.04). Increased oscillatory BP in upright POTS patients is closely coupled to oscillatory CBFv over a narrow bandwidth corresponding to the Mayer wave frequency. Therefore combined increased oscillatory BP and increased LF gain markedly increases CBFv oscillations in a narrow bandwidth. This close coupling of CBF to MAP indicates impaired cerebral autoregulation that may underlie upright neurocognitive dysfunction in POTS.

The arterial baroreflexes, located in the carotid sinus and along the arch of the aorta, are essential for the rapid short term autonomic regulation of blood pressure. In the past, they were believed to be inactivated during exercise because blood pressure, heart rate and sympathetic activity were radically changed from their resting functional relationships with blood pressure. However, it was discovered that all relationships between carotid sinus pressure and either HR or sympathetic vasoconstriction maintained their curvilinear sigmoidal shape but were reset or shifted so as to best defend BP during exercise. To determine whether resetting also occurs during orthostasis, we examined the arterial baroreflexes measured supine and upright tilt. We studied the relationships between systolic BP and HR (the cardiovagal baroreflex), mean BP and ventilation (the ventilatory baroreflex) and diastolic BP and sympathetic nerve activity (the sympathetic baroreflex). We accomplished these measurements by using the modified Oxford method in which BP was rapidly varied with bolus injections of sodium nitroprusside followed 1 minute later by bolus injections of phenylephrine. Both the cardiovagal and ventilatory baroreflexes were reset with no change in gain or response range. In contrast, the sympathetic baroreflex was augmented as well as shifted causing an increase in peripheral resistance that improved the subjects' defense against hypotension. This contrasts with findings during exercise in which peripheral resistance in active skeletal muscle is not increased. This difference is likely selective for exercising muscle and may represent the actions of functional sympatholysis by which exercise metabolites interfere with adrenergic vasoconstriction.

Considerable interest has centred on the Podophyllum-based lignans as lead compounds for the development of new drugs. The successful introduction of the anticancer drugs etoposide® and teniposide® and the development of new derivatives such as etopophos® have created a demand for podophyllotoxin. Currently it is obtained from the rhizomes and roots of wild populations of Podophyllum hexandrum, and thus the availability of this natural product is limited. There is an urgent need for a maintainable supply of P. hexandrum plants, a rare and threatened species. In the present work, a protocol was developed for the sterilisation and germination of seeds of P. hexandrum. Ripe fruits were harvested from seed-derived plants cultivated at the University of Nottingham. Seeds were removed from fruits, left for 20 – 30 min in running water, and washed three times with sterile, reverseosmosis water. Seeds were surface sterilised in (5, 10, 15 and 20%; v:v) Domestos bleach solution with 0.2% (v:v) Tween 20 for 5, 10, 15 and 20 min, followed by three washes in sterile, reverse-osmosis water. The effect of storage as a pre-treatment for the germination of seeds was also investigated. Sterilised seeds were kept in Petri dishes and maintained in the dark at 22 ± 1°C for 30 d. Ten stored seeds were cultured per dish containing a moist sterile filter paper disk. Cultures were incubated in the dark (22 ± 1 °C). Seeds with emerged radicles were individually transferred onto full-strength MS medium containing IAA (0.00875 mg l-1) in combination with kinetin (0.03 mg l-1) and folic acid (0.01 mg l-1) designated BGS medium. Seeds were also transferred onto full-strength MS medium lacking growth regulators (MSO medium). Media were supplemented with 3.0% (v:v) sucrose and solidified with 0.8% (w:v) agar. Cultures were maintained under diffuse light (3.8 µmol m-2 s-1) at 22 ± 1°C for three weeks and then transferred to a 16 h photoperiod under fluorescent light (42 µmol m-2 s-1) at 22 ± 1°C. Seed sterilisation was best achieved with 20% (v:v) Domestos and 0.2% (v:v) Tween 20 for 20 min. The results from these studies confirm that a post-harvest ripening period of 30 d was required for in vitro seed germination. If seeds are stored in moist and dark conditions, spontaneous germination occurs within 35 to 40 d. Axenic cultures were successfully established either on full-strength BGS medium with growth regulators or fullstrength MS medium lacking growth regulators. However, the overall growth of plants showing a normal morphology was superior on the latter medium. The in vitro-grown seedlings can be used as an alternative source of plant material for tissue culture experiments.

Antibodies with conformational specificity are important for detecting and interfering with polypeptide aggregation linked to several human disorders. We are developing a motif-grafting approach for designing lead antibody candidates specific for amyloid-forming polypeptides such as the Alzheimer peptide (Aβ). This approach involves grafting amyloidogenic peptide segments into the complementarity-determining regions (CDRs) of single-domain (VH) antibodies. Here we have investigated the impact of polar mutations inserted at the edges of a large hydrophobic Aβ42 peptide segment (Aβ residues 17-42) in CDR3 on the solubility and conformational specificity of the corresponding VH domains. We find that VH expression and solubility are strongly enhanced by introducing multiple negatively charged or asparagine residues at the edges of CDR3, whereas other polar mutations are less effective (glutamine and serine) or ineffective (threonine, lysine, and arginine). Moreover, Aβ VH domains with negatively charged CDR3 mutations show significant preference for recognizing Aβ fibrils relative to Aβ monomers, whereas the same VH domains with other polar CDR3 mutations recognize both Aβ conformers. We observe similar behavior for a VH domain grafted with a large hydrophobic peptide from islet amyloid polypeptide (residues 8-37) that contains negatively charged mutations at the edges of CDR3. These findings highlight the sensitivity of antibody binding and solubility to residues at the edges of CDRs, and provide guidelines for designing other grafted antibody fragments with hydrophobic binding loops.

Rationale: Sarcoidosis is a granulomatous disorder of unclear cause notable for abnormal elevation of blood and tissue ACE1 (angiotensin converting enzyme 1) levels and activity. ACE1 regulates the renin-angiotensin-aldosterone system (RAAS), the terminal product of which is aldosterone, which selectively engages mineralocorticoid receptors to promote inflammation. Objectives: We sought to determine whether the RAAS promotes sarcoidosis granuloma formation and related inflammatory responses. Methods: Using an established ex vivo model, we first determined whether aldosterone was produced by sarcoidosis granulomas and verified the presence of CYP11B2, the enzyme required for its production. We then evaluated the effects of selective inhibitors of ACE1 (captopril), angiotensin type 1 receptor (losartan), and mineralocorticoid receptors (spironolactone, eplerenone) on granuloma formation, reflected by computer image analysis–generated granuloma area, and selected cytokines incriminated in sarcoidosis pathogenesis. Measurements and Main Results: Aldosterone was spontaneously produced by sarcoidosis peripheral blood mononuclear cells, and both intra- and extracellular levels steadily increased during granuloma formation. In parallel, peripheral blood mononuclear cells were shown to express more CYP11B2 during granuloma formation. Significant inhibition of sarcoidosis granulomas and related cytokines (TNFα, IL-1β, IFNγ, IL-10) was observed in response to pretreatments with captopril, losartan, spironolactone, or eplerenone, comparable to that of prednisone. Conclusions: The RAAS is intact in sarcoidosis granulomas and contributes significantly to early granuloma formation and to related inflammatory mediator responses, with important implications for clinical management. [ABSTRACT FROM AUTHOR]

In this article, we present two TEDx Talks that focus on career planning. The presenters present diametrically opposing perspectives on whether passion fuels great careers or whether one finds passion after choosing one's career. The versatility of these resources is highlighted both in terms of the audience (i.e., undergraduate or graduate) and the activity (in-person or online discussion, or as an assignment). We have found that these two presenters have been instrumental in student understanding of various core career planning concepts, such as the benefits of career planning, barriers to career planning, and career anchors. [ABSTRACT FROM AUTHOR]

This letter discusses the impact of different anticoagulants on monocyte distribution width (MDW), a biomarker for sepsis. The study found that blood samples collected in heparin sodium (HS) tubes had higher MDW values compared to samples collected in ethylenediaminetetraacetic acid (EDTA) tubes after a 4-hour incubation. The increase in MDW in HS samples was not associated with inflammasome activation, suggesting that other factors such as osmotic properties or cell clumping may be responsible. The findings raise questions about the use of heparin in sepsis screening and highlight the need for further research. [Extracted from the article]