Effect of intravenous lidocaine on the ED50 of propofol for inserting gastroscope without body movement in adult patients: a randomized, controlled study.

BACKGROUND: Circulatory and respiratory depression are common problems that occur in propofol alone sedation during gastroscopy. As a widely used analgesic adjuvant, intravenous lidocaine can reduce the consumption of propofol during Endoscopic retrograde cholangiopancreatography (ERCP) or colonoscopy. However, it is still unknown the median effective dose (ED50) of propofol when combined with lidocaine intravenously. This study aimed to compare the ED50 of propofol with or without intravenous lidocaine for inserting gastrointestinal endoscope successfully. METHODS: Fifty nine patients undergoing gastroscopy or gastrointestinal (GI) endoscopy were randomly divided into control group (Group C, normal saline + propofol) or lidocaine group (Group L, lidocaine + propofol). Patients were initially injected a bolus of 1.5 mg/kg lidocaine in Group L, whereas equivalent volume of 0.9% saline in Group C. Anaesthesia was then induced with a single bolus of propofol in all subjects. The induction dose of propofol was determined by the modified Dixon's up-and-down method, and the initial dose was 1.5 mg/kg in both groups. The primary outcome was the ED50 of propofol induction dose with or without intravenous lidocaine. The secondary outcomes were the induction time, the first propofol bolus time (FPBT: from MOAA/S score ≤ 1 to first rescue bolus propofol), and adverse events (AEs: hypoxemia, bradycardia, hypotension, and body movements). RESULTS: Totally, 59 patients were enrolled and completed this study. The ED50 of propofol combined with lidocaine was 1.68 ± 0.11 mg/kg, significantly reduced compared with the normal saline group, 1.88 ± 0.13 mg/kg (P = 0.002). There was no statistical difference in induction time (P = 0.115) and the FPBT (P = 0.655) between the two groups. There was no significantly difference about the AEs between the two groups. CONCLUSION: The ED50 of propofol combined with intravenous lidocaine for successful endoscope insertion in adult patients, was 1.68 ± 0.11 mg/kg significantly reduced compared with the control group. TRIAL REGISTRATION: Chinese Clinical Trial Registry, No: ChiCTR2200059450. Registered on 29 April 2022. Prospective registration. http://www.chictr.org.cn .

rs1990622 variant associates with Alzheimer's disease and regulates TMEM106B expression in human brain tissues.

BACKGROUND: It has been well established that the TMEM106B gene rs1990622 variant was a frontotemporal dementia (FTD) risk factor. Until recently, growing evidence highlights the role of TMEM106B in Alzheimer's disease (AD). However, it remains largely unclear about the role of rs1990622 variant in AD. METHODS: Here, we conducted comprehensive analyses including genetic association study, gene expression analysis, eQTLs analysis, and colocalization analysis. In stage 1, we conducted a genetic association analysis of rs1990622 using large-scale genome-wide association study (GWAS) datasets from International Genomics of Alzheimer's Project (21,982 AD and 41,944 cognitively normal controls) and UK Biobank (314,278 participants). In stage 2, we performed a gene expression analysis of TMEM106B in 49 different human tissues using the gene expression data in GTEx. In stage 3, we performed an expression quantitative trait loci (eQTLs) analysis using multiple datasets from UKBEC, GTEx, and Mayo RNAseq Study. In stage 4, we performed a colocalization analysis to provide evidence of the AD GWAS and eQTLs pair influencing both AD and the TMEM106B expression at a particular region. RESULTS: We found (1) rs1990622 variant T allele contributed to AD risk. A sex-specific analysis in UK Biobank further indicated that rs1990622 T allele only contributed to increased AD risk in females, but not in males; (2) TMEM106B showed different expression in different human brain tissues especially high expression in cerebellum; (3) rs1990622 variant could regulate the expression of TMEM106B in human brain tissues, which vary considerably in different disease statuses, the mean ages at death, the percents of females, and the different descents of the selected donors; (4) colocalization analysis provided suggestive evidence that the same variant contributed to AD risk and TMEM106B expression in cerebellum. CONCLUSION: Our comprehensive analyses highlighted the role of FTD rs1990622 variant in AD risk. This cross-disease approach may delineate disease-specific and common features, which will be important for both diagnostic and therapeutic development purposes. Meanwhile, these findings highlight the importance to better understand TMEM106B function and dysfunction in the context of normal aging and neurodegenerative diseases.

Circulating serum vitamin D levels and total body bone mineral density: A Mendelian randomization study.

Until recently, randomized controlled trials have not demonstrated convincing evidence that vitamin D, or vitamin D in combination with calcium supplementation could improve bone mineral density (BMD), osteoporosis and fracture. It remains unclear whether vitamin D levels are causally associated with total body BMD. Here, we performed a Mendelian randomization study to investigate the association of vitamin D levels with total body BMD using a large-scale vitamin D genome-wide association study (GWAS) dataset (including 79 366 individuals) and a large-scale total body BMD GWAS dataset (including 66,628 individuals). We selected three Mendelian randomization methods including inverse-variance weighted meta-analysis (IVW), weighted median regression and MR-Egger regression. All these three methods did not show statistically significant association of genetically increased vitamin D levels with total body BMD. Importantly, our findings are consistent with recent randomized clinical trials and Mendelian randomization study. In summary, we provide genetic evidence that increased vitamin D levels could not improve BMD in the general population. Hence, vitamin D supplementation alone may not be associated with reduced fracture incidence among community-dwelling adults without known vitamin D deficiency, osteoporosis, or prior fracture.

Improvements in Left Ventricular Diastolic Mechanics After Parachute Device Implantation in Patients With Ischemia Heart Failure: A Cardiac Computerized Tomographic Study.

BACKGROUND: Percutaneous ventricular restoration therapy with the use of a left ventricle (LV)-partitioning Parachute device has emerged as a clinical treatment option for LV apical aneurysm after extensive anterior myocardial infarction (AMI). We assessed changes of diastolic mechanics and functional improvements following LV Parachute device implantation by means of cardiac computerized tomography (CCT). METHODS AND RESULTS: CCT data were obtained from 28 patients before and after LV Parachute device implantation. Diastolic functional indices were determined by means of quantitative CCT assessment: 1) transmitral velocities in early (E) and late (A) diastole and ratio (E/A); 2) early diastolic mitral septal tissue velocity (Ea) and E/Ea; and 3) vortex formation time (VFT). Functional improvements were assessed with the use of New York Heart Association (NYHA) functional classification. Among the study patients, there were no significant differences in all transmitral velocities and E/A, though there was significantly increased Ea, reduced E/Ea, and greater VFT 6 months after LV Parachute device implantation. Finally, the improvement of diastolic functional indices after Parachute treatment correlated with observed clinical functional alterations (Δ E/Ea and Δ NYHA functional class:, r = 0.563; P = .002; Δ VFT and Δ NYHA functional class: r = -0.507; P = .006). CONCLUSIONS: LV Parachute device implantation therapy in heart failure caused by AMI and LV apical aneurysm formation showed improvements in several diastolic functional mechanics according to CCT-based measures.

Reversal of Beta-Amyloid-Induced Neurotoxicity in PC12 Cells by Curcumin, the Important Role of ROS-Mediated Signaling and ERK Pathway.

Progressive accumulation of beta-amyloid (Aß) will form the senile plaques and cause oxidative damage and neuronal cell death, which was accepted as the major pathological mechanism to the Alzheimer's disease (AD). Hence, inhibition of Aß-induced oxidative damage and neuronal cell apoptosis by agents with potential antioxidant properties represents one of the most effective strategies in combating human AD. Curcumin (Cur) a natural extraction from curcuma longa has potential of pharmacological efficacy, including the benefit to antagonize Aß-induced neurotoxicity. However, the molecular mechanism remains elusive. The present study evaluated the protective effect of Cur against Aß-induced cytotoxicity and apoptosis in PC12 cells and investigated the underlying mechanism. The results showed that Cur markedly reduced Aß-induced cytotoxicity by inhibition of mitochondria-mediated apoptosis through regulation of Bcl-2 family. The PARP cleavage, caspases activation, and ROS-mediated DNA damage induced by Aß were all significantly blocked by Cur. Moreover, regulation of p38 MAPK and AKT pathways both contributed to this protective potency. Our findings suggested that Cur could effectively suppress Aß-induced cytotoxicity and apoptosis by inhibition of ROS-mediated oxidative damage and regulation of ERK pathway, which validated its therapeutic potential in chemoprevention and chemotherapy of Aß-induced neurotoxicity.

Induction of G1 Cell Cycle Arrest in Human Glioma Cells by Salinomycin Through Triggering ROS-Mediated DNA Damage In Vitro and In Vivo.

Chemotherapy has always been one of the most effective ways in combating human glioma. However, the high metastatic potential and resistance toward standard chemotherapy severely hindered the chemotherapy outcomes. Hence, searching effective chemotherapy drugs and clarifying its mechanism are of great significance. Salinomycin an antibiotic shows novel anticancer potential against several human tumors, including human glioma, but its mechanism against human glioma cells has not been fully elucidated. In the present study, we demonstrated that salinomycin treatment time- and dose-dependently inhibited U251 and U87 cells growth. Mechanically, salinomycin-induced cell growth inhibition against human glioma was mainly achieved by induction of G1-phase arrest via triggering reactive oxide species (ROS)-mediated DNA damage, as convinced by the activation of histone, p53, p21 and p27. Furthermore, inhibition of ROS accumulation effectively attenuated salinomycin-induced DNA damage and G1 cell cycle arrest, and eventually reversed salinomycin-induced cytotoxicity. Importantly, salinomycin treatment also significantly inhibited the U251 tumor xenograft growth in vivo through triggering DNA damage-mediated cell cycle arrest with involvement of inhibiting cell proliferation and angiogenesis. The results above validated the potential of salinomycin-based chemotherapy against human glioma.

Early Diagnosis of Tuberculosis-Associated IgA Nephropathy with ESAT-6.

IgA nephropathy (IgAN) is the most common cause of primary renal diseases worldwide, and the early secreted antigenic target of 6 (ESAT-6) which was secreted by Mycobacterium tuberculosis (MTB) may be involved in the development and progression of IgAN. This study aimed to investigate the role of ESAT-6 for early diagnosis of IgAN caused by MTB infection. From 2011 to 2014, 21 patients with renal tuberculosis (RTB), 25 with IgAN, and 46 with IgAN infected with MTB (IgAN/MTB) were enrolled. Serum levels of antibodies against Mycobacterium tuberculosis antigen 85A (Ag85A) were measured by ELISA. Urine culture and phage amplified biologically assay were performed to detect MTB. HE staining was used to observe the morphological changes in kidney tissues. Immunohistochemistry was applied to detect the expression of ESAT-6. Immunofluorescence staining was conducted to detect IgA1. Positive rates of serum anti-Ag85A antibody and urine culture for MTB were higher in the RTB and IgAN/MTB groups than those in the IgAN group. The positive rates of plaques were also higher in RTB and IgAN/MTB groups than the positive rate in the IgAN group. By contrast, the positive rate of ESAT-6 was lower in the IgAN group than that in the RTB group or the IgAN/MTB group, whereas the expression levels of IgA1 were higher in the IgAN and IgAN/MTB groups, compared with the RTB group. Our findings suggest that ESAT-6 and IgA1 may be helpful for early diagnosis of IgAN caused by MTB infection.

Enhanced Neuroprotection of Minimally Invasive Surgery Joint Local Cooling Lavage against ICH-induced Inflammation Injury and Apoptosis in Rats.

Hypothermia treatment is one of the neuroprotective strategies that improve neurological outcomes effectively after brain damage. Minimally invasive surgery (MIS) has been an important treatment of intracerebral hemorrhage (ICH). Herein, we evaluated the neuroprotective effect and mechanism of MIS joint local cooling lavage (LCL) treatment on ICH via detecting the inflammatory responses, oxidative injury, and neuronal apoptosis around the hematoma cavity in rats. ICH model was established by type IV collagenase caudatum infusion. The rats were treated with MIS 6 h after injection, and then were lavaged by normothermic (37 °C) and hypothermic (33 °C) normal saline in brain separately. The results indicated that MIS joint LCL treatment showed enhanced therapeutic effects against ICH-induced inflammation injury and apoptosis in rats, as convinced by the decline of TUNEL-positive cells, followed by the decrease of IL-1ß and LDH and increase of IL-10 and SOD. This study demonstrated that the strategy of using MIS joint LCL may achieve enhanced neuroprotection against ICH-induced inflammation injury and apoptosis in rats with potential clinic application.

Induction of S-Phase Arrest in Human Glioma Cells by Selenocysteine, a Natural Selenium-Containing Agent Via Triggering Reactive Oxygen Species-Mediated DNA Damage and Modulating MAPKs and AKT Pathways.

Selenocysteine (SeC) a natural available selenoamino acid exhibits novel anticancer activities against human cancer cell lines. However, the growth inhibitory effect and mechanism of SeC in human glioma cells remain unclear. The present study reveals that SeC time- and dose-dependently inhibited U251 and U87 human glioma cells growth by induction of S-phase cell cycle arrest, followed by the marked decrease of cyclin A. SeC-induced S-phase arrest was achieved by inducing DNA damage through triggering generation of reactive oxygen species (ROS) and superoxide anion, with concomitant increase of TUNEL-positive cells and induction of p21waf1/Cip1 and p53. SeC treatment also caused the activation of p38MAPK, JNK and ERK, and inactivation of AKT. Four inhibitors of MAPKs and AKT pathways further confirmed their roles in SeC-induced S-phase arrest in human glioma cells. Our findings advance the understanding on the molecular mechanisms of SeC in human glioma management.

Caudatin induces caspase-dependent apoptosis in human glioma cells with involvement of mitochondrial dysfunction and reactive oxygen species generation.

Caudatin as one species of C-21 steroidal from Cynanchum bungei decne displays potential anticancer activity. However, the underlying mechanisms remain elusive. In the present study, the growth suppressive effect and mechanism of caudatin on human glioma U251 and U87 cells were evaluated in vitro. The results indicated that caudatin significantly inhibited U251 and U87 cell growth in both a time- and dose-dependent manner. Flow cytometry analysis revealed that caudatin-induced cell growth inhibition was achieved by induction of cell apoptosis, as convinced by the increase of Sub-G1 peak, PARP cleavage and activation of caspase-3, caspase-7 and caspase-9. Caudatin treatment also resulted in mitochondrial dysfunction which correlated with an imbalance of Bcl-2 family members. Further investigation revealed that caudatin triggered U251 cell apoptosis by inducing reactive oxygen species (ROS) generation through disturbing the redox homeostasis. Moreover, pretreatment of caspase inhibitors apparently weakens caudatin-induced cell killing, PARP cleavage and caspase activation and eventually reverses caudatin-mediated apoptosis. Importantly, caudatin significantly inhibited U251 tumour xenografts in vivo through induction of cell apoptosis involving the inhibition of cell proliferation and angiogenesis, which further validate its value in combating human glioma in vivo. Taken together, the results described above all suggest that caudatin inhibited human glioma cell growth by induction of caspase-dependent apoptosis with involvement of mitochondrial dysfunction and ROS generation.

Attenuation of Cisplatin-Induced Neurotoxicity by Cyanidin, a Natural Inhibitor of ROS-Mediated Apoptosis in PC12 Cells.

Cisplatin-based chemotherapy in clinic is severely limited by its adverse effect, including neurotoxicity. Oxidative damage contributes to cisplatin-induced neurotoxicity, but the mechanism remains unclearly. Cyanidin, a natural flavonoid compound, exhibits powerful antioxidant activity. Hence, we investigated the protective effects of cyanidin on PC12 cells against cisplatin-induced neurotoxicity and explored the underlying mechanisms. The results showed that cisplatin-induced cytotoxicity was completely reversed by cyanidin through inhibition of PC12 cell apoptosis, as proved by the attenuation of Sub-G1 peak, PARP cleavage, and caspases-3 activation. Mechanistically, cyanidin significantly inhibited reactive oxygen species (ROS)-induced DNA damage in cisplatin-treated PC12 cells. Our findings revealed that cyanidin as an apoptotic inhibitor effectively blocked cisplatin-induced neurotoxicity through inhibition of ROS-mediated DNA damage and apoptosis, predicating its therapeutic potential in prevention of chemotherapy-induced neurotoxicity. Cisplatin caused DNA damage, activated p53, and subsequently induced PC12 cells apoptosis by triggering ROS overproduction. However, cyanidin administration effectively inhibited DNA damage, attenuated p53 phosphorylation, and eventually reversed cisplatin-induced PC12 cell apoptosis through inhibition ROS accumulation.

Qualitative and semi-quantitative evaluation of myocardium perfusion with 3 T stress cardiac MRI.

BACKGROUND: 3 T MRI has been adopted by some centers as the primary choice for assessment of myocardial perfusion over conventional 1.5 T MRI. However, there is no data published on the potential additional value of incorporating semi-quantitative data from 3 T MRI. This study sought to determine the performance of qualitative 3 T stress magnetic resonance myocardial perfusion imaging (3 T-MRMPI) and the potential incremental benefit of using a semi-quantitative perfusion technique in patients with suspected coronary artery disease (CAD). METHODS: Fifty eight patients (41 men; mean age: 59 years) referred for elective diagnostic angiography underwent stress 3 T MRMPI with a 32-channel cardiac receiver coil. The MR protocol included gadolinium-enhanced stress first-pass perfusion (0.56 mg/kg, dipyridamole), rest perfusion, and delayed enhancement (DE). Visual analysis was performed in two steps. Ischemia was defined as a territory with perfusion defect at stress study but no DE or a territory with DE but additional peri-infarcted perfusion defect at stress study. Semi-quantitative analysis was calculated by using the upslope of the signal intensity-time curve during the first pass of contrast medium during dipyridamole stress and at rest. ROC analysis was used to determine the MPRI threshold that maximized sensitivity. Quantitative coronary angiography served as the reference standard with significant stenosis defined as >70 % diameter stenosis. Diagnostic performance was determined on a per-patient and per-vessel basis. RESULTS: Qualitative assessment had an overall sensitivity and specificity for detecting significant stenoses of 77 % and 80 %, respectively. By adding MPRI analysis, in cases with negative qualitative assessment, the overall sensitivity increased to 83 %. The impact of MPRI differed depending on the territory; with the sensitivity for detection of left circumflex (LCx) stenosis improving the most after semi-quantification analysis, (66 % versus 83 %). CONCLUSIONS: Pure qualitative assessment of 3 T MRI had acceptable performance in detecting severe CAD. There is no overall benefit of incorporating semi-quantitative data; however a higher sensitivity can be obtained by adding MPRI, especially in the detection of LCx lesions.

Adenylate cyclase activates the cAMP signalling pathway to enhance platelet-rich plasma-treated Achilles tendon disease, a theoretical bioinformatics-based study.

The effectiveness of platelet-rich plasma (PRP) for the treatment of Achilles tendon disorders still needs to be evaluated through a series of prospective studies, but genomic analysis can reveal the existence of complementary PRP treatment options. Based on the 96 platelet activation-related genes in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, we performed Gene Ontology functional enrichment analysis and KEGG enrichment analysis, pathway correlation analysis, and enrichment mapping to determine the enrichment results of the gene set enrichment analysis and found that the cAMP signalling pathway may be the key to enhancing the effectiveness of PRP treatment. The cAMP signalling pathway interacts with the Rap1 signalling pathway and cGMP-PKG signalling pathway to mediate the entire pathophysiological process of Achilles tendon disease. Moreover, ADCY1-9 may be the key to the activation of the cAMP signalling network. Further based on the data in the Gene Expression Omnibus database, it was found that ADCY4 and ADCY7 may be the players that play a major role, associated with the STAT4-ADCY4-LAMA5 axis and the GRbeta-ADCY7-SEMA3C axis, which is expected to be a complementary target for enhancing the efficacy of PRP in the treatment of Achilles tendon disease.

Effects of individualized positive end-expiratory pressure on intraoperative oxygenation in thoracic surgical patients: study protocol for a prospective randomized controlled trial.

BACKGROUND: Intraoperative hypoxemia and postoperative pulmonary complications (PPCs) often occur in patients with one-lung ventilation (OLV), due to both pulmonary shunt and atelectasis. It has been demonstrated that individualized positive end-expiratory pressure (iPEEP) can effectively improve intraoperative oxygenation, increase lung compliance, and reduce driving pressure, thereby decreasing the risk of developing PPCs. However, its effect during OLV is still unknown. Therefore, we aim to investigate whether iPEEP ventilation during OLV is superior to 5 cmH2O PEEP in terms of intraoperative oxygenation and the occurrence of PPCs. METHODS: This study is a prospective, randomized controlled, single-blind, single-center trial. A total of 112 patients undergoing thoracoscopic pneumonectomy surgery and OLV will be enrolled in the study. They will be randomized into two groups: the static lung compliance guided iPEEP titration group (Cst-iPEEP Group) and the constant 5 cmH2O PEEP group (PEEP 5 Group). The primary outcome will be the oxygenation index at 30 min after OLV and titration. Secondary outcomes are oxygenation index at other operative time points, PPCs, postoperative adverse events, ventilator parameters, vital signs, pH value, inflammatory factors, and economic indicators. DISCUSSION: This trial explores the effect of iPEEP on intraoperative oxygenation during OLV and PPCs. It provides some clinical references for optimizing the lung protective ventilation strategy of OLV, improving patient prognosis, and accelerating postoperative rehabilitation. TRIAL REGISTRATION: www.Chictr.org.cn ChiCTR2300073411 . Registered on 10 July 2023.

Retraction of "Ravoxertinib Improves Long-Term Neurologic Deficits after Experimental Subarachnoid Hemorrhage through Early Inhibition of Erk1/2".

[This retracts the article DOI: 10.1021/acsomega.3c01296.].

Relationship between leaf vein traits of three dominant Quercus species and ecological factors in the Qinling Mountains, China.

We investigated the inter- and intra-species differences of leaf vein traits of three dominant Quercus species, Q. wutaishanica, Q. aliena var. acutiserrata, and Q. variabilis of Niubeiling (subtropical humid climate) and Taohuagou (warm temperate semi-humid climate), located in the eastern and western Qinling Mountains. The nine examined leaf vein traits included primary leaf vein width, secondary leaf vein width, mean fine vein width, primary vein density, fine vein density, vein areole diameter, areole density, 3D fine vein surface area, and fine vein volume. We further elucidated the influencing mechanisms and regulatory pathways of biotic and abiotic factors on leaf vein traits. The results showed that species identity had significant effects on eight out of nine leaf vein traits except 3D fine vein surface area, while habitat had significant effects on primary leaf vein width, secondary leaf vein width, vein areole diameter, fine vein density, and areole density. Altitude had significant effects on primary vein density, mean fine vein width, vein areole diameter, fine vein density and areole density. Habitat, tree species identity, and altitude had significantly interactive effects on primary leaf vein density, 3D fine vein surface area, and fine vein volume. There were significant differences in primary leaf vein width, mean fine vein width, areole density, 3D fine vein surface area, fine vein volume, primary vein density of Q. wutaishanica between the two studied habitats, but the differences were only found in secondary leaf vein width and areole density of Q. aliena var. acutiserrata and Q. variabilis. The examined leaf vein traits were influenced both by biotic and abiotic factors, with varying effect sizes. Among the biotic factors, petiole length, leaf length and width ratio had strong effect on leaf vein traits. Among the abiotic factors, climatic and soil factors had high effect size on vein traits, with the former being higher than the latter. Leaf vein traits were affected directly by biotic factors, but indirectly by abiotic factors (soil and climatic factors) via regulating biotic factors (leaf stoichiometry and leaf phenotypic traits).

Corrigendum: TAT-HSP27 peptide improves neurologic deficits via reducing apoptosis after experimental subarachnoid hemorrhage.

[This corrects the article DOI: 10.3389/fncel.2022.878673.].

How far can the radiation dose be lowered in head CT with iterative reconstruction? Analysis of imaging quality and diagnostic accuracy.

OBJECTIVE: To evaluate the imaging quality of head CT at lowered radiation dose by combining filtered back projection (FBP) and iterative reconstruction (IR) algorithms. METHODS: Experimental group A (n = 66) underwent CT with 43 % tube current reduction, and group B (n = 58) received an equivalent reduced dose by lowering the tube voltage. An age- and sex-matched control group (n = 72) receiving the conventional radiation dose was retrospectively collected. Imaging for the control group was reconstructed by FBP only, while images for groups A and B were reconstructed by FBP and IR. The signal-to-noise ratios (SNRs), contrast-to-noise ratios (CNRs), sharpness, number of infarcts and severity of subcortical arteriosclerotic encephalopathy (SAE) were compared to assess imaging quality and diagnostic accuracy. RESULTS: There were no significant differences in SNRs and CNRs between group A and the control group. There were significantly decreased SNRs and increased CNRs in group B. Image sharpness decreased in both groups. Correlations between detected infarcts and severity of SAE across FBP and IR were high (r = 0.73-0.93). Head diameter was the only significant factor inversely correlated with infratentorial imaging quality. CONCLUSION: Head CT with 43 % reduced tube current reconstructed by IR provides diagnostic imaging quality for outpatient management. KEY POINTS: • Cranial CT using iterative reconstruction provides diagnostic images with 43 % mAs reduction. • Blurring of infratentorial images becomes evident using low-radiation head CT. • Head diameter was inversely correlated with imaging quality in the infratentorium. • Lowering tube kilovoltage requires a higher radiation dose to maintain image quality.

PEGylation of cationic, shell-crosslinked-knedel-like nanoparticles modulates inflammation and enhances cellular uptake in the lung.

The airway provides a direct route for administration of nanoparticles bearing therapeutic or diagnostic payloads to the lung, however optimization of nanoplatforms for intracellular delivery remains challenging. Poly(ethylene glycol) (PEG) surface modification improves systemic performance but less is known about PEGylated nanoparticles administered to the airway. To test this, we generated a library of cationic, shell crosslinked knedel-like nanoparticles (cSCKs), including PEG (1.5 kDa PEG; 2, 5, 10 molecules/polymer arm) on the outer shell. Delivery of PEGylated cSCK to the mouse airway showed significantly less inflammation in a PEG dose-dependent manner. PEGylation also enhanced the entry of cSCKs in lung alveolar epithelial cells and improved surfactant penetration. The PEGylation effect could be explained by the altered mechanism of endocytosis. While non-PEGylated cSCKs used the clathrin-dependent route for endocytosis, entry of PEGylated cSCK was clathrin-independent. Thus, nanoparticle surface modification with PEG represents an advantageous design for lung delivery. FROM THE CLINICAL EDITOR: In this study, the effects of PEGylation were studied on cross linked knedel-like nanoparticles in drug delivery through the lungs, demonstrating less airway inflammation in the studied model than with non-PEGylated nanoparticles, which suggests an overall favorable profile of PEGylated nanoparticles for alveolar delivery.