The image quality and diagnostic performance of CT perfusion-derived CT angiography versus that of conventional CT angiography.

Background: The combination of computed tomography angiography (CTA) and computed tomography perfusion (CTP) evaluation of cerebral perfusion status and vascular conditions can improve the diagnostic accuracy of infarction, ischemia, and vascular occlusion in stroke patients, as well as a comprehensive assessment of cerebral edema, collateral circulation, and blood perfusion in the lesion area. However, the consequent radiation safety and contrast agent nephropathy have aroused increasing concern. The purpose of this study was to assess the image quality and diagnostic accuracy of CTA images derived from CTP data, and to explore the feasibility of replacing conventional CTA. Methods: A total of 31 consecutive patients with suspected acute ischemic stroke were retrospectively analyzed. All patients underwent head and neck CTA and brain CTP examinations. All the CTP images were transmitted to the ShuKun artificial intelligence system, which reconstructs CTA derived from CTP (CTA-DF-CTP). The images were divided into 2 groups, including CTA-DF-CTP (Group A) and conventional CTA (Group B). The CT attenuation values, subjective image noise, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), image quality, CT volume dose index (CTDIvol), dose length product (DLP), and effective radiation dose (ED) were compared between the 2 groups. Moreover, the consistency of vascular stenosis and stenosis degree between the 2 groups were measured and evaluated. Results: There were no significant differences in image noise, SNR, or CNR between Groups A and B (P>0.05). The CT attenuation values of the arteries were higher in Group A than in B [internal carotid artery (ICA) =548±112 vs. 454±85 Hounsfield units (HU), middle cerebral artery (MCA) =453±118 vs. 388±70 HU, and basilar artery (BA) =431±99 vs. 360±83 HU] (P<0.01). The image quality of the 2 groups met the requirement of clinical diagnosis (4.97±0.18 vs. 4.94±0.25). No significant difference was found in subjective evaluation (P>0.05). In Group A compared with Group B, the following reductions were observed: CTDIvol (10.7%; 100.8 vs. 112.9 mGy), DLP (23.0%; 1,613±0 vs. 2,093±88 mGy·cm), and ED (23.0%; 5.00±0.00 vs. 6.49±0.27 mSv). Conclusions: CTA-DF-CTP data provide diagnostic accuracy and image quality similar to those of conventional CTA of head and neck CTA.

Bronchial morphological changes are associated with postoperative intractable cough after right upper lobectomy in lung cancer patients.

BACKGROUND: To date, postoperative intractable cough (PIC) has not received adequate attention, and the complex perioperative factors when performing pulmonary resection often prevent researchers from addressing this issue. This study aimed to investigate the clinicopathological and radiographic indicators related to PIC in lung cancer patients. METHODS: In all, 112 patients who had had right upper lobectomy for primary lung cancer from January 2019 to December 2020 were retrospectively reviewed. We collected data via the electronic medical database of our department. Bronchial morphological features were investigated comprehensively via three-dimensional chest computer tomography reconstruction images. RESULTS: During outpatient follow-up visits, 41 (36.6%) patients complained about persistent dry cough after surgery. Compared with the non-cough group, patients in the refractory cough group showed significant differences in smoking history, right upper lobe stump length, changes of right bronchus intermedius (RBI) diameter, changes of right lower lobe (RLL) basal bronchus diameter, changes of RBI/RLL bronchial angle, and bronchial kink. However, according to multivariable regression analysis, stump length, bronchial kink, and diameter change of the right lower lobe basal bronchus were independently associated with postoperative refractory cough. A nebulization drug was prescribed for the 41 patients diagnosed with PIC, and 33 (80.5%) patients had improved by the next visit. CONCLUSIONS: After right upper lobectomy, the morphology of the remaining bronchial tree in the residual lung changed significantly. The bronchial morphological alterations were independent risk factors for PIC.

Expression of DUSP12 Reduces Lung Vascular Endothelial Cell Damage in a Murine Model of Lipopolysaccharide-Induced Acute Lung Injury via the Apoptosis Signal-Regulating Kinase 1 (ASK1)-Jun N-Terminal Kinase Activation (JNK) Pathway.

BACKGROUND Acute lung injury (ALI) results from damage to the alveolar capillary endothelial cells and can result in acute respiratory distress syndrome (ARDS). This study aimed to investigate murine lung vascular endothelial cells (MLECs) damage in a murine model of lipopolysaccharide (LPS)-induced ALI. MATERIAL AND METHODS Mice were injected with LPS to induce an acute lung injury model. An adenovirus transfection system was used to overexpress or knockdown DUSP12 in mice. MLECs were isolated, cultured and transfected with DUSP12-overexpressing adenovirus or with DUSP12 siRNA to knockdown DUSP12. LPS was used to establish a cell injury model. ELISA and RT-PCR were used to examine cell inflammation. LPS-induced oxidative stress was also evaluated using commercial kits. RESULTS A decreased level of DUSP12 was observed in MLECs treated with LPS. DUSP12 overexpression in mice attenuated LPS-induced lung inflammation and lung injury, as reflected by reduced levels of proinflammatory cytokines. Mice with DUSP12 knockdown exhibited worsened lung inflammation and injury. In vitro, DUSP12 overexpression in endothelial cells ameliorated LPS-induced inflammation, apoptosis, and oxidative stress. DUSP12 silencing in endothelial cells aggravated LPS-induced inflammation, apoptosis, and oxidative stress. Furthermore, we found that DUSP12 directly bound to apoptosis signal-regulating kinase 1 (ASK1) to inhibit Jun N-terminal kinase activation (JNK). A JNK1/2 inhibitor and ASK1 siRNA ameliorated the exacerbating effects of DUSP12 knockdown in vitro. CONCLUSIONS Our data demonstrated that DUSP12 suppressed MLEC injury in response to LPS insult by regulating the ASK1/JNK pathway.

Differentiation of pulmonary sclerosing pneumocytoma from solid malignant pulmonary nodules by radiomic analysis on multiphasic CT.

PURPOSE: To investigate the diagnostic value and feasibility of radiomics-based texture analysis in differentiating pulmonary sclerosing pneumocytoma (PSP) from solid malignant pulmonary nodules (SMPN) on single- and three-phase computed tomography (CT) images. MATERIALS AND METHODS: A total of 25 PSP patients and 35 SMPN patients with pathologically confirmed results were retrospectively included in this study. For each patient, the tumor regions were manually labeled in images acquired at the noncontrast phase (NCP), arterial phase (AP), and venous phase (VP). The least absolute shrinkage and selection operator (LASSO) method was used to select the most useful predictive features extracted from the CT images. The predictive models that discriminate PSP from SMPN based on single-phase CT images (NCP, AP, and VP) or three-phase CT images (Combined model) were developed and validated through fivefold cross-validation using a logistic regression classifier. Model performance was evaluated using receiver operating characteristic (ROC) analysis. The predictive performance was also compared between the Combined model and human readers. RESULTS: Four, five, and five features were selected from NCP, AP, and VP CT images for the development of radiomic models, respectively. The NCP, AP, and VP models exhibited areas under the curve (AUCs) of 0.748 (95% confidence interval [CI], 0.620-0.852), 0.749 (95% CI, 0.620-0.852), and 0.790 (95% CI, 0.665-0.884) in the validation dataset, respectively. The Combined model based on three-phase CT images outperformed the NCP, AP, and VP models (all p < 0.05), yielding an AUC of 0.882 (95% CI, 0.773-0.951) in the validation dataset. The Combined model displayed noninferior performance compared to two senior radiologists; however, it outperformed two junior radiologists (p = 0.004 and 0.001, respectively). CONCLUSION: The Combined model based on radiomic features extracted from three-phase CT images achieved radiologist-level performance and could be used as promising noninvasive tool to differentiate PSP from SMPN.

FNDC5 promotes paclitaxel sensitivity of non-small cell lung cancers via inhibiting MDR1.

Therapeutic benefits and clinical application of paclitaxel for treating non-small cell lung cancers (NSCLCs) are extremely hampered due to the chemoresistance. A recent study found that fibronectin type III domain-containing protein 5 (FNDC5) was downregulated in NSCLCs cells and negatively correlated with the clinicopathological characteristics in patients with NSCLCs. However, the role and potential molecular basis for FNDC5 in paclitaxel sensitivity of NSCLCs remain unclear. Paclitaxel-sensitive or resistant NSCLCs cell lines were exposed to small interfering RNA against FNDC5 (siFndc5) or recombinant irisin in the presence or absence of paclitaxel. NSCLCs cell lines have decreased FNDC5 expression compared with the normal human lung epithelial cells, which was further downregulated in paclitaxel-resistant cells. Irisin treatment suppressed, whereas Fndc5 silence promoted NSCLCs cells proliferation under basal conditions. Besides, we found that FNDC5 increased paclitaxel chemosensitivity in paclitaxel-sensitive or resistant NSCLCs cell lines via downregulating multidrug resistance protein 1 (MDR1). Further studies revealed that FNDC5 inhibited MDR1 expression via blocking nuclear factor-κB (NF-κB) activation. FNDC5 promotes paclitaxel sensitivity of NSCLCs cells via inhibiting NF-κB/MDR1 signaling, and FNDC5 might be a novel therapeutic target for the treatment of NSCLCs.

Salivary gland function in nasopharyngeal carcinoma before and late after intensity-modulated radiotherapy evaluated by dynamic diffusion-weighted MR imaging with gustatory stimulation.

BACKGROUND: Xerostomia caused by radiation-induced salivary glands injury has a considerable impact on patients' quality of life. Nowadays, the existed different methods of evaluating xerostomia in clinical practice there are still some disadvantages and limitations. This study used diffusion-weighted magnetic resonance imaging (DW-MRI) with gustatory stimulation to assess salivary glands function after intensity-modulated radiotherapy (IMRT) in patients with nasopharyngeal carcinoma (NPC). METHODS: DW-MRI was performed in 30 NPC patients and swab method was used to calculate rest and stimulated salivary flow rates (SFR). DW sequence at rest and then repeated ten times during stimulation were obtained. Apparent diffusion coefficients (ADCs) maps of three glands were calculated. Patients before and after RT were recorded as xerostomia and non-xerostomia groups separately. Rest and stimulated ADCs, ADCs increase rates (IRs), time to maximum ADCs (Tmax), ADCs change rates (CRs), rest and stimulated SFR, SFR increase rates (IRs) and SFR change rates (CRs) before and after RT were assessed. RESULTS: The rest and stimulated ADCs of three glands after RT were higher than those before RT (p < 0.001). The rest and stimulated SFR of all salivary glands after RT were lower than those before RT (p < 0.001). A correlation existed between rest ADCs of submandibular glands and rest SFR of submandibular mixed with sublingual glands and full three glands before RT (p = 0.019, p = 0.009), stimulated ADCs and stimulated SFR in parotid glands before RT (p = 0.047). The rest ADCs of parotid glands after RT correlated to XQ scores (p = 0.037). CONCLUSIONS: The salivary glands' ADCs increased after RT both in rest and stimulated state due to the radiation injury and the ADCs correlated with SFR and XQ scores of evaluating the xerostomia in clinical practice.

Colon Interposition for Corrosive Esophageal Stricture: Single Institution Experience with 119 Cases.

The colon is an alternative graft organ for esophageal reconstruction. The present study reviewed our experience with the colon interposition for esophageal replacement following corrosive ingestion, to evaluate the outcomes of colon interposition based on our surgical experience. The clinical data of 119 patients who underwent colon interposition for esophageal replacement from January 2005 to March 2017 were retrospectively analyzed. The routes of the colon interposition were retrosternal in 119 (100%). The median operative time was 390 min (range: 290-610 min) and the median blood loss was 615 mL (range: 270-2500 mL). Of these 119 patients, the cervical anastomosis was performed at the hypopharynx (n=20, 16.8%), the larynx (n=3, 2.5%), and the cervical esophagus (n=96, 80.7%). Five patients experienced cervical anastomotic leakage (4 cases for esophagus-colon, and one for hypopharynx-colon). One patient experienced wound infection of the abdominal wall. Three patients had injury of recurrent laryngeal nerve and hoarseness. Three patients had stress ulcer with bleeding and treated with octreotide. Two patients suffered from incomplete intestinal obstruction. The postoperative follow-up was made for 12 months in all patients and all of them were alive. In conclusion, The colon is well-suited for esophageal reconstruction. The selection of the colon graft should be flexible and be based on the inspection of blood supply and the length needed. We must therefore make every effort to reduce the number of postoperative complications, and improve the quality of life for patients.

Predictive value of the thymofatty specimen weight index in outcomes of extended thymectomy due to non-thymomatous myasthenia gravis.

OBJECTIVES: To evaluate the predictive value of the intraoperative thymofatty specimen weight (TFSW) index on predicting the prognosis of extended thymectomy (ET) for non-thymomatous myasthenia gravis. METHODS: This is a prospective non-interventional study in which patients who underwent ET between January 2012 and June 2015 were enrolled. Resected thymus and surrounding adipose tissues were weighed using an electronic scale intraoperatively and adjusted to the body surface area (BSA) to calculate the TFSW index. The primary end point was defined as complete stable remission (CSR) according to the Myasthenia Gravis Foundation of America (MGFA) guidelines. RESULTS: One hundred and eighteen patients who completed postoperative follow-up were included in this study. After a mean follow-up period of 44 months, 68 (57.6%) patients reached clinical CSR. The MGFA class, histopathology and TFSW index were associated with a postoperative CSR in univariate analysis. When the Cox hazard multiple regression model was used, the TFSW index was found to be an independent predictor for CSR (hazard ratio 2.056; 95% confidence interval 1.182-3.576). Based on ROC analysis, an optimal TFSW index cut-off value (35.9 g/m2) with the highest sensitivity and specificity was determined. CONCLUSIONS: The TFSW index is an important independent predictor for mid-term CSR after ET in non-thymomatous myasthenia gravis patients. During the ET surgery, every effort should be made to take a tissue specimen with a TFSW index more than 35.9 g/m2.

Ivor-Lewis esophagectomy for esophageal cancer after distal gastrectomy.

We report the use of gastric remnant for esophageal substitution after distal gastrectomy in a 53-year-old man with esophageal cancer. This patient had a 4-month history of progressive dysphagia for solid food. An upper gastrointestinal endoscopy showed a 7.0 cm bulge tumor in the middle-lower esophagus, wherein the upper margin was located 28 cm from the dental arcade. Computed tomography (CT) of the chest revealed wall thickening in the middle-lower esophagus. In this case, radical en bloc esophagectomy with a two-field lymph node dissection was performed in the upper abdomen and mediastinum via a posterolateral right thoracotomy through the fifth intercostal space. Esophagogastric anastomosis was performed mechanically in the apex of the chest using a circular stapler. The gastric remnant was used for reconstruction of the esophago-gastrostomy and placed in the right thoracic cavity. The patient was discharged on the 12th postoperative day without complications. The gastric remnant may be used for reconstruction in patients with esophageal cancer as a substitute organ after distal gastrectomy.

[Values of magnetic resonance spectrum imaging in the diagnosis of hepatic fibrosis of rats].

OBJECTIVE: To explore the values of magnetic resonance spectrum (MRS) in early diagnosis, quantization analysis and staging of hepatic fibrosis. METHODS: A rat model of hepatic fibrosis was established by the method of carbon tetra carbon (CCl4). A total of 47 SD rats were divided into model (n = 40) and control (n = 7) groups. 1H-MRS was performed. The model rats of hepatic fibrosis were grouped according to their pathological stages. The ratio of peak height and peak area of metabolites and lipid (Cho/Lip, Glx/Lip, Lac/Lip and Cr/Lip) were calculated and compared respectively. RESULTS: The ratios of peak height of metabolites and lipid were as follows: ratio of Cho and Lip: significant differences existed between control and grades 3 and 4 model groups (P < 0.05); ratio of Glx and Lip: significant differences existed between control and grades 2, 3 and 4 model groups (P < 0.05); ratio of Cr and Lip: significant differences existed between control and grade 3 model groups (P < 0.05). The peak area ratio of main metabolites and lipid of liver were as follows: ratio of Cho and Lip: significant differences existed between control and grade 4 model groups (P < 0.05); ratio of Glx and Lip: significant differences existed between control and other groups (P < 0.05); ratio of Cr and Lip: significant differences existed between control and grade 4 model groups (P < 0.05); ratio of Lac and Lip: no significant differences existed between these groups (P > 0.05). CONCLUSION: The ratios of peak height and peak area of Cho/Lip, Glx/Lip and Cr/Lip are important for the staging of hepatic fibrosis.

Esophageal reconstruction with remnant stomach: a case report and review of literature.

The number of patients developing esophageal cancer after gastrectomy has increased. However, gastric remnant is very rarely used for reconstruction in esophageal cancer surgery because of the risk of anastomotic leakage resulting from insufficient blood flow. We present a case of esophageal cancer using gastric remnant for esophageal substitution after distal gastrectomy in a 57-year-old man who presented with a 1-month history of mild dysphagia and a background history of alcohol abuse. Gastroscopy showed a 1.2 cm × 1.0 cm bulge tumor of the lower third esophagus with the upper margin located 39 cm from the dental arcade. Computed tomography of the chest showed lower third esophageal wall thickening. The patient underwent en bloc radical esophagectomy with a two-field lymph node dissection of the upper abdomen and mediastinum via a left-sided posterolateral thoracotomy through the seventh intercostal space. The upper end of the esophagus was resected 5 cm above the tumor. The gastric remnant was used for reconstruction of the esophago-gastrostomy and placed in the left thoracic cavity. The patient started a liquid diet on postoperative day 8 and was discharged on the 10(th) postoperative day without complications. In this report, we demonstrate that the gastric remnant may be used for reconstruction in patients with esophageal cancer as a substitute organ after distal gastrectomy.

[Injury repairing and magnetic resonance tracing of transplanted bone marrow stromal cells in rat liver with hepatic fibrosis].

OBJECTIVE: To explore the recurring patterns of migration and distribution of transplanted bone marrow stromal cells (BMSCs) in rat model with hepatic fibrosis and the feasibility of magnetic resonance (MR) tracing. METHODS: BMSCs labeled with 5-bromodeoxyuridine (Brdu) and super para-magnetic iron oxide (SPIO) were transplanted into rat model with hepatic fibrosis via portal vein. MR scan was performed at Hour 2, Day 3, Day 7 and Week 2 post-transplantation to analyze the hepatic features of MR signal intensity and pathohistology of BMSCs. RESULTS: Multiple hypo-intense lesions appeared in hepatic hilar region at Hour 2 and became smaller with the elapsing time. Hemosiderin and Brdu immunohistochemical stains showed that positive cells were found in portal vein of hepatic porta at Hour 2, small branches of portal vein, sinus hepaticus and around central veins of hepatic lobules at Day 3 and liver parenchyma (esp. in area of lesion) at Day 7 and Week 2. Some of transplanted BMSCs were tightly connected with liver cell to form liver cell cord. The signal intensity changes of MRI corresponded to histological findings at different timepoints. CONCLUSION: The transplanted BMSCs are gradually scattered in whole liver (esp. in lesion area) so that it may help to repair hepatic lesions. And the recurring patterns of MR signal intensity changes reflected the condition of distribution, immigration and differentiation of transplanted cells.

Heat shock proteins reduce alpha-synuclein aggregation induced by MPP+ in SK-N-SH cells.

Alpha-synuclein has been implicated in the pathogenesis of Parkinson's disease (PD). Heat shock proteins (HSPs) can reduce protein misfolding and accelerate the degradation of misfolded proteins. 1-methyl-4-phenylpyridinium ion (MPP+) is the compound responsible for the PD-like neurodegeneration caused by MPTP. In this study, we found that MPP+ could increase the expression of alpha-synuclein mRNA but could not elevate proteasome activity sufficiently, leading to alpha-synuclein protein accumulation followed by aggregation. Both HSPs and HDJ-1, a homologue of human Hsp40, can inhibit MPP+-induced alpha-synuclein mRNA expression, promote ubiquitination and elevate proteasome activity. These findings suggest that HSPs may inhibit the MPP+-induced alpha-synuclein expression, accelerate alpha-synuclein degradation, thereby reducing the amount of alpha-synuclein protein and accordingly preventing its aggregation.

[Recombinant plasmid pIRES2-EGFP-HCN2 improved pacing function in canine model of sick sinus syndrome].

OBJECTIVE: To construct plasmid expressing pacemaker gene pIRES2-EGFP-HCN2 and study its effects in transfected atrial myocytes in vitro and in canine model of sick sinus syndrome (SSS). METHODS: mHCN2 gene was isolated from PTR plasmids and cloned into eukaryotic expression plasmid pIRES2-EGFP. Recombinant plasmids pIRES2-EGFP-HCN2 was transfected with by electroporation into neonatal atrial cardiomyocytes or injected to the sinoatrial (SA) region of canines with SSS induced by catheter and chemical ablation. pIRES2-EGFP-HCN2 expression was detected under fluorescence microscope and confirmed by reverse transcription-polymerase chain reaction (RT-PCR). Spontaneous beating rate in atrial cardiomyocytes was detected with light microscope. RESULTS: EGFP expression was seen in transfected atrial cardiomyocytes 24 to 48 hours after transfection and the spontaneous beating rate was significantly increased than that in non-transfected atrial cardiomyocytes [(180 +/- 11) bpm vs (140 +/- 14) bpm, P < 0.05]. Heart rate was significantly increased 24 hours post recombinant plasmids pIRES2-EGFP-HCN2 injection compared to saline injection in canines with SSS [(150 +/- 13) bpm vs (105 +/- 17) bpm, P < 0.05]. Green fluorescence was also detected in frozen SA tissue sections of canines injected with recombinant plasmids pIRES2-EGFP-HCN2 and the production amplified by RT-PCR was about 300 bp which is consistent with mHCN2 gene fragment. CONCLUSION: The recombinant eukaryotic expression plasmid pIRES2-EGFP-HCN2 can improve pacing function in atrial myocytes and in canine model of SSS.

Heat shock proteins reduce toxicity of 1-methyl-4-phenylpyridinium ion in SK-N-SH cells.

The pathology of Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra. However, the pathogenesis of PD remains unclear. Heat shock proteins (HSPs) have many functions, including inhibition of apoptosis and necrosis, protection from oxidative stress, and maintenance of the mitochondrial membrane potential, that are related to neurodegenerative diseases. 1-Methyl-4-phenylpyridinium ion (MPP(+)) is a neurotoxin that selectively inhibits the mitochondrial functions of DA neurons in the substantia nigra. MPP(+) administration is accepted as a model for PD. In the present study, we found that MPP(+) induced a concentration- and time-dependent decrease in cell viability. Lower concentrations of MPP(+) induced mainly early apoptosis, and, as the concentration increased, the number of late apoptotic and necrotic cells significantly increased. However, treated by heat shock preconditioning or transfection with HDJ-1, a homologue of human Hsp40, cells showed marked improvement in viability after exposure to the same concentrations of MPP(+). Compared with heat shock, HDJ-1 appeared to improve cell viability obviously. Similarly, HDJ-1 elicited significantly stronger protective effects against apoptosis and necrosis. In addition, HDJ-1 transfection maintained more injured cells in early apoptotic stages and inhibited the occurrence of late apoptotic/necrotic events. Heat shock and HDJ-1 both ameliorated MPP(+)-induced cytotoxicity by maintaining the mitochondrial membrane potential and reducing reactive oxygen species (ROS). Therefore, the effects of HSPs, such as reducing apoptosis and necrosis, preserving mitochondrial functions and decreasing oxidative stress, may bring a novel approach for PD therapy.

PACAP protects neuronal differentiated PC12 cells against the neurotoxicity induced by a mitochondrial complex I inhibitor, rotenone.

In vivo and in vitro studies have suggested a neuroprotective role for Pituitary adenylate cyclase activating polypeptide (PACAP) against neuronal insults. Here, we showed that PACAP27 protects against neurotoxicity induced by rotenone, a mitochondrial complex I inhibitor that has been implicated in the pathogenesis of Parkinson's disease (PD). The neuroprotective effect of PACAP27 was dose-dependent and blocked by its specific receptor antagonist, PACAP6-27. The effects of PACAP27 on rotenone-induced cell death were mimicked by dibutyryl-cAMP (db-cAMP), forskolin and prevented by the PKA inhibitor H89, the ERK inhibitor PD98059 and the p38 inhibitor SB203580. PACAP27 administration blocked rotenone-induced increases in the level of caspase-3-like activity, whereas could not restore mitochondrial activity damaged by rotenone. Thus, our results demonstrate that PACAP27 has a neuroprotective role against rotenone-induced neurotoxicity in neuronal differentiated PC12 cells and the neuroprotective effects of PACAP are associated with activation of MAP kinase pathways by PKA and with inhibition of caspase-3 activity; the signaling mechanism appears to be mediated through mitochondrial-independent pathways.