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However, a significant gap in knowledge of the spatiotemporal interactions between cell populations as well as relative quantities and localization within each compartment of the lung necessary for its proper growth and function remains. This review will provide an update on cells currently used for reseeding decellularized scaffolds with outcomes of recent lung engineering attempts. Focus will then be on how data obtained from advanced single-cell analyses, coupled with multiomics approaches and high-resolution 3D imaging, can guide current lung bioengineering efforts for the development of fully functional, transplantable lungs.Hyperoxia can lead to respiratory failure and death. Our previous work demonstrates that oxidant and mitochondrial injury play a critical role in hyperoxia-induced acute lung injury (HALI). Recently, thyroid hormone has been demonstrated to promote mitochondrial survival in other models of lung injury, but its role in hyperoxia is unknown. Adult wild-type (WT) mice were pretreated with either nebulized triiodothyronine (T3, 40 μg/kg) for 1 or 3 days, or with propylthiouracil (PTU, 100 μg/kg), for 3 days. Following pretreatment, WT mice underwent 72 h of hyperoxia exposure. WT and PINK1-/- mice were pretreated with either nebulized T3 (40 μg/kg) for 3 days or no pretreatment before 72 h continuous hyperoxia exposure. Bronchoalveolar lavage (BAL), histological changes in cellular composition, and type I cytokine induction were assessed. Lung lysates for mitochondrial cellular bioenergetics markers were analyzed by Western blot. Hyperoxia caused a significant increase in BAL total cell counts and lung cellular infiltrates. Administration of PTU enhanced HALI, whereas T3 attenuated HALI, inflammation, and oxidants in WT mice. In addition, T3 pretreatment increased mitochondrial biogenesis/fusion/mitophagy and decreased ER stress and apoptosis. PINK1-/- mice were more susceptible to hyperoxia than WT mice. Notably, pretreatment with T3 did not attenuate HALI in PINK1-/- mice. In addition, T3 pretreatment increased mitochondrial anti-ROS potential, improved mitochondrial bioenergetics and mitophagy, and attenuated mitochondria-regulated apoptosis, all in a PINK1-dependent manner. Our results highlight a novel protective role for PINK1 in mediating the cytoprotective effects of thyroid hormone in HALI. Therefore, thyroid hormone may represent a potential therapy for ALI.Donepezil is a centrally acting acetylcholinesterase (AChE) inhibitor with therapeutic potential in inflammatory diseases; however, the underlying autonomic and cholinergic mechanisms remain unclear. Here, we assessed effects of donepezil on mean arterial pressure (MAP), heart rate (HR), HR variability, and body temperature in conscious adult male C57BL/6 mice to investigate the autonomic pathways involved. Central versus peripheral cholinergic effects of donepezil were assessed using pharmacological approaches including comparison with the peripherally acting AChE inhibitor, neostigmine. Drug treatments included donepezil (2.5 or 5 mg/kg sc), neostigmine methyl sulfate (80 or 240 μg/kg ip), atropine sulfate (5 mg/kg ip), atropine methyl bromide (5 mg/kg ip), or saline. Donepezil, at 2.5 and 5 mg/kg, decreased HR by 36 ± 4% and 44 ± 3% compared with saline (n = 10, P less then 0.001). Donepezil, at 2.5 and 5 mg/kg, decreased temperature by 13 ± 2% and 22 ± 2% compared with saline (n = 6, P less then 0.001). Modest (P less then 0.001) increases in MAP were observed with donepezil after peak bradycardia occurred. Atropine sulfate and atropine methyl bromide blocked bradycardic responses to donepezil, but only atropine sulfate attenuated hypothermia. The pressor response to donepezil was similar in mice coadministered atropine sulfate; however, coadministration of atropine methyl bromide potentiated the increase in MAP. Neostigmine did not alter HR or temperature, but did result in early increases in MAP. Despite the marked bradycardia, donepezil did not increase normalized high-frequency HR variability. Orlistat supplier We conclude that donepezil causes marked bradycardia and hypothermia in conscious mice via the activation of muscarinic receptors while concurrently increasing MAP via autonomic and cholinergic pathways that remain to be elucidated.
Early diagnosis is key to managing scaphoid fractures effectively. Computed tomography (CT) imaging can be effective if plain radiographs are negative. With increasing pressure on face-to-face clinics, consultant-led virtual fracture clinics (VFCs) are becoming increasingly popular. This study evaluates the management of patients with suspected scaphoid fractures using a standardised treatment protocol involving CT imaging and VFC evaluation.
The study was conducted at a busy district general hospital. The pathway began in February 2018. Patients presenting to the emergency department with a clinically suspected scaphoid fracture but an indeterminate radiograph had a CT scan, which was then reviewed in the VFC. Patients with a confirmed fracture were seen in a face-to-face clinic; patients without a confirmed fracture were discharged. Patient pathway outcome measures were analysed pre- and post-pathway, and a cost analysis was performed.
A total of 164 pre-pathway patients (93%) were given a face-to-face fracture clinic appointment; 76 were discharged after their first visit. Nine patients seen in clinic had a CT scan and were discharged with no fracture. If these patients had been referred to the VFC, had CT scans and been directly discharged, it would have saved £1,629. A total of 41 patients from the post-pathway group (37%) had a CT scan and were discharged from the VFC. Avoiding face-to-face clinic appointments saved £7,421. Extrapolating, the annual savings would be £29,687.
This study shows that a VFC/CT pathway to manage patients with a suspected scaphoid fracture is cost-effective. It limits face-to-face appointments by increasing use of CT to exclude fractures.
This study shows that a VFC/CT pathway to manage patients with a suspected scaphoid fracture is cost-effective. It limits face-to-face appointments by increasing use of CT to exclude fractures.
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