ABSTRACT
Lethal COVID-19 is associated with respiratory failure that is thought to be caused by acute respiratory distress syndrome (ARDS) secondary to pulmonary infection. To date, the cellular pathogenesis has been inferred from studies describing the expression of ACE2, a transmembrane protein required for SARS-CoV-2 infection, and detection of viral RNA or protein in infected humans, model animals, and cultured cells. To functionally test the cellular mechanisms of COVID-19, we generated hACE2fl animals in which human ACE2 (hACE2) is expressed from the mouse Ace2 locus in a manner that permits cell-specific, Cre-mediated loss of function. hACE2fl animals developed lethal weight loss and hypoxemia within 7 days of exposure to SARS-CoV-2 that was associated with pulmonary infiltrates, intravascular thrombosis and patchy viral infection of lung epithelial cells. Deletion of hACE2 in lung epithelial cells prevented viral infection of the lung, but not weight loss, hypoxemia or death. Inhalation of SARS-CoV-2 by hACE2fl animals resulted in early infection of sustentacular cells with subsequent infection of neurons in the neighboring olfactory bulb and cerebral cortex-- events that did not require lung epithelial cell infection. Pharmacologic ablation of the olfactory epithelium or Foxg1Cre mediated deletion of hACE2 in olfactory epithelial cells and neurons prevented lethality and neuronal infection following SARS-CoV-2 infection. Conversely, transgenic expression of hACE2 specifically in olfactory epithelial cells and neurons in Foxg1Cre; LSL-hACE2 mice was sufficient to confer neuronal infection associated with respiratory failure and death. These studies establish mouse loss and gain of function genetic models with which to genetically dissect viral-host interactions and demonstrate that lethal disease due to respiratory failure may arise from extrapulmonary infection of the olfactory epithelium and brain. Future therapeutic efforts focused on preventing olfactory epithelial infection may be an effective means of protecting against severe COVID-19.
ABSTRACT
Objective To compare the clinical outcomes of arthroscopy-assisted Tightrope technique and clavicular hook plating for the treatment of acromioclavicular joint dislocation of Rockwood Type Ⅲ in aduhs.Methods The clinical data were reviewed of the 60 patients who had been treated for acromioclavicular joint dislocation of Rockwood Type Ⅲ from January 2012 to December 2015 at Department of Orthopedics,Jinhua Municipal Central Hospital.Their age ranged from 34 to 62 years (mean,40 years).Injury was at the left side in 28 cases and at the right in 32 ones.They were randomly assigned to receive treatment either using arthroscopy-assisted Tightrope technique (group A,30 cases) or using clavicular hook plate (group B,30 cases).The 2 groups were compared in terms of incision length,operation time,blood loss,visual analogue scale (VAS) and Constant-Murley shoulder function scores at postoperative 3 and 12 months.Results The 2 groups were compatible because there were no significant between-group differences in gender,age,injury laterality,Rockwood fracture typing or injury cause (P ＞ 0.05).All the patients were followed up for a mean of 10 months (from 6 to 12 months).Primary incision healing was achieved in both groups with no neural lesion.The incision length in group A (3.4 ± 0.6 cm) was significantly shorter than that in group B (8.8 ± 1.8 cm),and the blood loss in the former (40.0 ± 8.2 mL) significantly less than that in the latter (70.9 ± 9.8 mL) (P ＜ 0.05).The VAS scores and Constant-Murley shoulder function scores at postoperative 3 and 12 months in group A (respectively:2.2±1.1 and 1.1 ±0.9 points;85.5±2.1 and 98.0±3.1points) were significantly better than those in group B (respectively:3.2 ± 1.8 and 2.1 ± 1.2 points;75.0 ±4.1 and 85.1 ±2.9 points) (P ＜ 0.05).There were no obvious complications during the follow-up period in either group.Conclusions Although both arthroscopy-assisted Tightrope technique and clavicular hook plating can relieve shoulder pain in the adult patients with acromioclavicular joint dislocation of Rockwood Type Ⅲ,the former shows advantages of a smaller incision,less bleeding,lower VAS scores,and reduced pain and financial cost for the patients due to no trouble of implant removal.
