Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination.

Autophagy, a cellular self-eating mechanism, is important for maintaining cell survival and tissue homeostasis in various stressed conditions. Although the molecular mechanism of autophagy induction has been well studied, how cells terminate autophagy process remains elusive. Here, we show that ULK1, a serine/threonine kinase critical for autophagy initiation, is a substrate of the Cul3-KLHL20 ubiquitin ligase. Upon autophagy induction, ULK1 autophosphorylation facilitates its recruitment to KLHL20 for ubiquitination and proteolysis. This autophagy-stimulated, KLHL20-dependent ULK1 degradation restrains the amplitude and duration of autophagy. Additionally, KLHL20 governs the degradation of ATG13, VPS34, Beclin-1, and ATG14 in prolonged starvation through a direct or indirect mechanism. Impairment of KLHL20-mediated regulation of autophagy dynamics potentiates starvation-induced cell death and aggravates diabetes-associated muscle atrophy. Our study identifies a key role of KLHL20 in autophagy termination by controlling autophagy-dependent turnover of ULK1 and VPS34 complex subunits and reveals the pathophysiological functions of this autophagy termination mechanism.

Non-Contrast-Enhanced MR Arteriography of Potential Living-Related Liver Donor: Using Contrast Enhanced CT Arteriography as Standard Reference.

BACKGROUND: Contrast-enhanced computed tomography angiography (CTA) and magnetic resonance angiography (MRA) are the primary modalities to assess donors' vessels before transplant surgery. Radiation and contrast medium are potentially harmful to donors. PURPOSE: To compare the image quality and visualization scores of hepatic arteries on CTA and balanced steady-state free-precession (bSSFP) non-contrast-enhanced MRA (NC-MRA), and to evaluate if bSSFP NC-MRA can potentially be a substitute for CTA. STUDY TYPE: Prospective. POPULATION: Fifty-six consecutive potential living-related liver donors (30.9 ± 8.4 years; 31 men). FIELD STRENGTH/SEQUENCE: 1.5T; four bSSFP NC-MRA sequences: respiratory-triggered (Inhance inflow inversion recovery [IFIR]) and three breath-hold (BH); and CTA. ASSESSMENT: The artery-to-liver contrast (Ca-l) was quantified. Three radiologists independently assigned visualization scores using a four-point scale to potential origins, segments, and branches of the hepatic arteries, determined the anatomical variants based on Hiatt's classification, and assessed the image quality of NC-MRA sequences. STATISTICAL TESTS: Fleiss' kappa to evaluate the readers' agreement. Repeat measured ANOVA or Friedman test to compare Ca-l of each NC-MRA. Friedman test to compare overall image quality and visualization scores; post hoc analysis using Wilcoxon signed-rank test. P-value <0.05 was considered statistically significant. RESULTS: Inhance IFIR Ca-l was significantly higher than all BH bSSFP Ca-l (0.56 [0.45-0.64] vs. 0.37 [0.29-0.47] to 0.41 [0.23-0.51]). Overall image quality score of BH bSSFP TI1200 was significantly higher than other NC-MRA (4 [4-4] vs. 4 [3 to 4-4]). The median visualization scores of almost all arteries on CTA were significantly higher than on NC-MRA (4 [3 to 4-4] vs. 1 [1-2] to 4 [4-4]). The median visualization scores were all 4 [4-4 ] on Inhance IFIR with >92.3% observed scores ≥3, except the segment 4 branch (3 [1-4], 53.6%). The identification rates of arterial variants were 92.9%-97% on Inhance IFIR. DATA CONCLUSIONS: Although CTA is superior to the NC-MRA, all NC-MRA depict the donor arterial anatomy well. Inhance IFIR can potentially be an alternative image modality for CTA to evaluate the arterial variants of living donors. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Context-specific roles of diphthamide deficiency in hepatocellular carcinogenesis.

Diphthamide biosynthesis protein 1 (DPH1) is biochemically involved in the first step of diphthamide biosynthesis, a post-translational modification of eukaryotic elongation factor 2 (EEF2). Earlier studies showed that DPH1, also known as ovarian cancer-associated gene 1 (OVCA1), is involved in ovarian carcinogenesis. However, the role of DPH1 in hepatocellular carcinoma (HCC) remains unclear. To investigate the impact of DPH1 in hepatocellular carcinogenesis, we performed data mining from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset. We found that reduced DPH1 levels were associated with advanced stages and poor survival of patients with HCC. Also, we generated hepatocyte-specific Dph1-deficient mice and showed that diphthamide-deficient EEF2 resulted in a reduced translation elongation rate in the hepatocytes and led to mild liver damage with fatty accumulation. After N-diethylnitrosamine (DEN)-induced acute liver injury, p53-mediated pericentral hepatocyte death was increased, and compensatory proliferation was reduced in Dph1-deficient mice. Consistent with these effects, Dph1 deficiency decreased the incidence of DEN-induced pericentral-derived HCC and revealed a protective effect against p53 loss. In contrast, Dph1 deficiency combined with Trp53- or Trp53/Pten-deficient hepatocytes led to increased tumor loads associated with KRT19 (K19)-positive periportal-like cell expansion in mice. Further gene set enrichment analysis also revealed that HCC patients with lower levels of DPH1 and TP53 expression had enriched gene-sets related to the cell cycle and K19-upregulated HCC. Additionally, liver tumor organoids obtained from 6-month-old Pten/Trp53/Dph1-triple-mutant mice had a higher frequency of organoid re-initiation cells and higher proliferative index compared with those of the Pten/Trp53-double-mutant. Pten/Trp53/Dph1-triple-mutant liver tumor organoids showed expression of genes associated with stem/progenitor phenotypes, including Krt19 and Prominin-1 (Cd133) progenitor markers, combined with low hepatocyte-expressed fibrinogen genes. These findings indicate that diphthamide deficiency differentially regulates hepatocellular carcinogenesis, which inhibits pericentral hepatocyte-derived tumors and promotes periportal progenitor-associated liver tumors. © 2022 The Pathological Society of Great Britain and Ireland.

Bilateral theta-burst stimulation on emotional processing in major depressive disorder: A functional neuroimaging study from a randomized, double-blind, sham-controlled trial.

AIM: Bilateral theta-burst stimulation (biTBS; intermittent TBS over the left dorsolateral prefrontal cortex [DLPFC] and continuous TBS over the right DLPFC) has demonstrated efficacy in improving symptoms in patients with major depressive disorder (MDD). However, the underlying brain mechanisms remain unknown. The authors aimed to investigate the antidepressant efficacy of biTBS monotherapy and its effects on the brain responses measured by functional magnetic resonance imaging (fMRI) during emotional processing in MDD. METHODS: The authors conducted a double-blind, randomized, sham-controlled trial of patients with MDD who exhibited no responses to at least one adequate antidepressant treatment for the prevailing episode. Recruited patients were randomly assigned to 10 biTBS monotherapy or sham stimulation sessions. The fMRI scans during performing emotional recognition task were obtained at baseline and after 10 sessions of treatment. Depressive symptoms were assessed using the 21-item Hamilton Rating Scale for Depression at baseline and the weeks 4, 8, 12, 16, 20, and 24 week. RESULTS: The biTBS group (n = 17) exhibited significant decreases in depression scores compared with the sham group (n = 11) at week 8 (70% vs 40%; P = 0.02), and the significant differences persisted during the 24-week follow-up periods. At week 4, when the treatment course was completed, patients in the biTBS group, but not in the sham group, exhibited increased brain activities over the left superior and middle frontal gyrus during negative emotional stimuli. CONCLUSION: The authors' findings provide the first evidence regarding the underlying neural mechanisms of biTBS therapy to improve clinical symptoms in patients with MDD.

Two-thirds anteroposterior ramus length is the preferred osteotomy point for intraoral vertical ramus osteotomy.

OBJECTIVES: This study aimed to investigate the mandibular canal of ramus and design a suitable osteotomy line for intraoral vertical ramus osteotomy (IVRO) using cone-beam computed tomography (CBCT). MATERIALS AND METHODS: Ninety patients were classified into class I, II, and III skeletal pattern groups. When extended from the horizontal base plane (0 mm, mandibular foramen [MF]), with a 2-mm section interval, to 10 mm above and 10 mm below the MF, the following landmarks were identified: external oblique ridge (EOR), posterior border of the ramus (PBR), and posterior lateral cortex of ramus (PLC): IVRO osteotomy point. RESULTS: In the base plane (0-mm plane), the EOR-PBR distance of class III (34.78 mm) and the IOR-PBR distance of class II (32.72 mm) were significantly higher than those of class I (32.95 mm and 30.03 mm). Compared to the EOR-PLC distance, the designed osteotomy point (two-thirds EOR-PBR length) has a 3.49-mm safe zone at the base plane and ranging from 0.89 mm (+ 10-mm plane) to 8.37 mm (- 10-mm plane). CONCLUSIONS: The position at two-thirds EOR-PBR length (anteroposterior diameter of the ramus) can serve as a reference distance for the IVRO osteotomy position. CLINICAL RELEVANCE: Mandibular setback operations for treating mandibular prognathism mainly include sagittal split ramus osteotomy (SSRO) and IVRO. IVRO has a markedly lower incidence of postoperative lower lip paraesthesia than SSRO. Our design presented a reference point for identification during IVRO, to prevent damage to the inferior alveolar neurovascular bundle.

Clinical significance of postoperative skeletal relapse in the treatment of mandibular prognathism: Receiver operating characteristic curve analysis.

BACKGROUND/PURPOSE: Postoperative skeletal relapse is the most important issue in patients undergoing orthognathic surgery. This study aimed to investigate clinical skeletal relapse (≥2 mm) after mandibular setback surgery (intraoral vertical ramus osteotomy: IVRO) using receiver operating characteristic curve (ROC curve) analysis. METHODS: Serial cephalograms of 40 patients with mandibular prognathism were obtained at different time points: (1) before surgery (T1), (2) immediately after surgery (T2), and (3) at least with a 2-year follow-up postoperatively (T3). The menton (Me) was used as the landmark for measuring the amount of mandibular setback and postoperative skeletal relapse. Postoperative stability (T32) was divided into groups A and B by skeletal relapse ≥2 mm and <2 mm, respectively. The area under the ROC curve (AUC) was used to determine the cut-off point for mandibular setback. RESULTS: At the immediate surgical setback (T21), the amount of setback in group A (15.55 mm) was significantly larger than in group B (10.97 mm). Group A (T32) showed a significant relapse (4.07 mm), while group B showed a significant posterior drift (1.23 mm). The amount of setback had the highest AUC area (0.788). The cut-off point was 14.1 mm (T21) that would lead to a clinical relapse of 2 mm (T32). CONCLUSION: In IVRO, the postoperative mandibular positions reveal posterior drift and anterior displacement (relapse). The experience of clinical observation and patient perception of postoperative skeletal relapse was ≥2 mm. In the ROC curve analysis, the cut-off point of setback was 14.1 mm.

Management of Mandibular Subcondylar Fracture Through an Intraoral Approach Using a Trans-Buccal Trocar With Ramus Buccal Decortication.

PURPOSE: The aim of this study was to review retrospectively the functional recoveries of subcondylar fracture patients that underwent open reduction surgery using an extraoral approach or an intraoral approach using a trans-buccal trocar and involving ramus buccal decortication. MATERIALS AND METHODS: Of 47 patients with mandibular condyle fracture who visited Pusan National University Dental Hospital Department of Oral and Maxillofacial Surgery between May 2015 and November 2020, 38 patients underwent open reduction and were classified according to the surgical method used. Preauricular, submandibular, and retro-mandibular approaches were all classified as extraoral approaches condyle fractures were classified as described by Spiessl and Schroll (1972). Distances between bone fragments on panorama radiographs before and after surgery were measured. RESULTS: Thirty-eight patients were included in this study, 9 patients received subcondylar fracture surgery. Open reduction surgery using an extraoral approach had a greater mean operation time than the intraoral approach using a trocar. Of the 17 patients treated with an intraoral approach, the average distance between bone fragments right after surgery was 1.27 ± 1.41mm, which was significantly greater than that of the extraoral approach (0.72 ± 0.35 mm). CONCLUSIONS: Favorable results can be obtained by mandibular condylar fracture surgery through an intraoral approach using a trans-buccal trocar with ramus buccal decortication. This technique minimizes scarring, secures accessibility using a trocar, and sufficiently secures the field of view through buccal cortical bone reduction.

Correlation Between Sports-Related Maxillofacial Injuries and Head Injuries: A Five-Year Retrospective Study.

PURPOSE: As sports have become more diverse and demanding, the number of patients with a maxillofacial injury accompanied by a cranial injury or neurological symptoms has increased. This study examined the correlation between sports-related maxillofacial injuries and head injuries. PATIENTS AND METHODS: Among the patients who visited the emergency department of Pusan National University Dental Hospital due to a maxillofacial injury from sporting activities between 2014 and 2018, those who additionally had head injuries were retrospectively examined. Sporting activities were classified according to the American Academy of Pediatrics classification, and severity of injuries was determined using the Facial Injury Severity Scale (FISS). Patients whose medical records showed neurological symptoms and who underwent brain computed tomography for concomitant head injury were selected. The association between each of these variables, including age and gender, was statistically analyzed. RESULTS: A total of 95 patients were included in this study, most of whom were male teenagers, and cycling was the most common cause of injuries. The meanFISS score was 0.79. Brain computed tomography was conducted for 91 patients, and 28 patients reported neurological symptoms. Only 11 patients underwent advanced evaluation in the neurology or neurosurgery department. Most patients were diagnosed with contusion and concussion and were monitored without any treatment. CONCLUSIONS: Higher FISS values did not reflect the severity of maxillofacial and head injury. In this study, there were some patients with cranial fracture and cerebral hemorrhage with mild neurosurgical symptoms of facial trauma. Although the incidence of head trauma is not high, the necessity of wearing protective equipment cannot be overemphasized because severe trauma is permanent. Neurological signs and symptoms of patients with maxillofacial trauma should not be overlooked and require a thorough evaluation.

Importance in the occurrence rate of shortest buccal bone marrow distance (<1 mm) for sagittal split ramus osteotomy.

BACKGROUND/PURPOSE: The neurosensory disturbance is a common complication following sagittal split ramus osteotomy (SSRO) whereas the shortest buccal bone marrow (SBM) is an important risk factor. The present study aimed to investigate the relationship between the occurrence rates of SBM among three skeletal patterns. METHODS: The cone-beam computed tomography (CBCT) images of 90 participants were divided into skeletal Class I, II, and III. There were six horizontal planes separated apart by a 2 mm interval; it started with plane 0 (original intact mandibular canal) to plane 5 which was 10 mm below. The data of SBM were divided into two groups (SBM ≥ 1 mm and SBM < 1 mm). With an SBM value < 1 mm, we defined a high occurrence rate of postoperative neurosensory abnormality or unfavorable split. RESULTS: The Class III patients had the smallest SBM value (1.31-1.75 mm) whereas the Class II patients had the largest SBM value (1.57-2.09 mm). For the Class III patients, the highest and lowest occurrence rates of SBM were 56.5% and 43.5% respectively. For the Class II patients, the highest and lowest occurrence rates of SBM were 37.1% and 17.7% respectively. The patients with Class III malocclusion had higher occurrence rates of SBM than the patients with Class II malocclusion. CONCLUSION: Class III had a significantly higher occurrence of probability (SBM < 1 mm) than Class II. Therefore, patients with Class III were more likely to experience postoperative neurosensory abnormalities and unfavorable split than patients with Class II.

How do lateral hinge and distraction affect three-dimensional rotation in open wedge high tibial osteotomy?

BACKGROUND: Open-wedge high tibial osteotomy (OWHTO) has extensively been used for the correction of medial knee osteoarthritis. The proximal tibia is osteotomized and distracted to enable the rotation of tibial fragments around the lateral hinge. Both, wedge inclination on the medial side and saw progression near the lateral cortex determine the hinge orientation. This study focused on the interaction between hinge orientation and distraction sites on the coronal, sagittal, and horizontal planes of the distracted plateau. METHODS: Three parameters of wedge inclination, saw progression, and distraction site (i.e., posterior, middle, and anterior) were systematically varied. Using a three-dimensional (3D)-printing technique, the osteotomized tibiae were manufactured as the specimens for the in vitro experiments. In total, 27 variations (3 × 3 × 3) were tested. After distraction, the specimens were scanned by computed tomography and spatially registered with the original tibia to compare the 3D angles of the distracted plateaus. RESULTS: Coronal rotation is the main purpose of OWHTO; therefore, all the values of the coronal angles were positive and significantly higher than the other two. The sagittal and horizontal angles had relatively similar values. Distraction in the middle site seems to have the least impact on sagittal rotation. Large angles of hinge orientation show the superior ability in adjusting the sagittal rotation than small angles. However, the larger the horizontal angles the greater the wedge inclination. CONCLUSIONS: The wedge inclination, saw progression, and distraction site constitute a complex mechanism that affects 3D rotations of the distracted plateau. The coronal angles are sensitive to hinge orientation and distraction site. The intraoperative planning of manipulating hinge orientation is an effective method to adjust sagittal rotation. A large angle of wedge inclination is an indicator of horizontal rotation, and it should be carefully mitigated to reduce the risk of cracking in the lateral hinge.

The influence of obesity on cerebral blood flow in young adults using arterial spin labeling MRI.

Obesity causes damage to several organs, including the brain. Recent studies have been focusing on understanding the mechanisms through which obesity affects brain structure and function using neuroimaging techniques. A functional biomarker, such as cerebral blood flow (CBF), is a powerful tool that can be used to explore neural dysfunction. However, there is currently limited information regarding the association between CBF and obesity. The study was conducted to investigate the potential effect of obesity on brain perfusion in a young cohort aged 20-30 years. A total of 21 obese (body mass index (BMI) > 26 kg/m2 ) and 21 lean (BMI < 24 kg/m2 ) right-handed volunteers were included in this study. CBF was acquired using the 2D single post-labeling delay (PLD) arterial spin labeling (ASL) technique on a 3 T MRI scanner. A multiple regression analysis was performed to examine the difference in global and regional gray matter (GM) CBF between the groups. CBF value was assigned as the dependent variable, whereas age, sex, and group (obese or lean) were considered as the independent variables. Results showed that group-related differences in CBF were homogeneous across brain regions, as obese subjects had significantly lower global GM CBF than lean subjects (P < 0.05). In the voxelwise analysis, obese individuals had significantly lower CBF in the left pulvinar of the thalamus and visual association areas, including Brodmann area (BA) 7, BA18, and BA19, than lean subjects. Although the signal-to-noise ratio was slightly compromised for 2D sequences and subject-specific arterial transit time was not estimated due to a single PLD sequence, this study demonstrated alterations in CBF in obese subjects, particularly in regions of the pulvinar of the thalamus and its synchronously related areas such as visual association areas. These results suggest that ASL provides a potential platform for further obesity-related research.

Short- and long-term reproducibility of BOLD signal change induced by breath-holding at 1.5 and 3 T.

Cerebrovascular reactivity (CVR) can give insight into the cerebrovascular function. CVR can be estimated by measuring a blood-oxygen-level-dependent (BOLD) response combined with breath-holding (BH). The reproducibility of this technique has been addressed and existing studies have focused on short-term reproducibility using a 3 T magnetic resonance imaging (MRI) system. However, little is known about the long-term reproducibility of this procedure and the corresponding reproducibility using a 1.5 T MRI system. Here, we systematically examined the short- and long-term reproducibility of BOLD responses to BH across field strengths. Nine subjects participated in three MRI sessions separated by 30 minutes (sessions 1 and 2: short term) and 68-92 days (sessions 1 and 3, long term) at both 1.5 and 3 T MRI. Our findings revealed that significant differences between field strengths were detected in the activated gray matter volume and BOLD signal change (both P < 0.001), with smaller magnitudes at 1.5 T. However, activation patterns were reproducible, independent of the time interval, brain region or field strength. All interscan coefficient of variation values were below the 33% fiducial limit, and the intraclass correlation coefficient values were above 0.4, which is usually considered the acceptability limit in functional studies. These findings suggest that the response of BOLD signal to BH for assessing CVR is reproducible over time at 1.5 and 3 T. This technique can be considered a tool for monitoring longitudinal changes in patients with cerebrovascular diseases, and its use should be encouraged for clinical 1.5 T MRI systems.

Increased risk of developing peripheral artery disease in hemodialysis patients receiving statin treatments: a population-based cohort study in Taiwan.

BACKGROUND: Few investigations have evaluated the influences on peripheral arterial disease (PAD) risk of statin treatment in hemodialysis (HD) subjects with hyperlipidemia (HL). METHODS: From the National Health Insurance Research Dataset, we identified 3658 HD patients with statin therapy for HL as the statin cohort, and then selected, by 1:1 propensity score matching, 3658 HD patients with HL but without statin use as the nonstatin cohort in 2000-07. The cohorts were followed through until the end of 2011. We used Cox proportional hazards regression analysis to assess the hazard ratio (HR) of PAD development. RESULTS: The average follow-up period was 4.18 years; the incident PAD risk was 1.35-fold greater in statin users than in nonusers (16.87 versus 12.46/1000 person-years), with an adjusted HR (aHR) of 1.34 for PAD [95% confidence interval (CI) 1.12-1.62]. The PAD risk increases were significant for patients receiving fluvastatin (aHR 1.88; 95% CI 1.12-3.14) and atorvastatin (aHR 1.60; 95% CI 1.24-2.08). The risk increased with higher annual average statin dosage (P for trend <0.0001); the risk was higher for those receiving moderate-intensity statin treatment. The sensitivity test revealed similar findings. CONCLUSIONS: HD patients with HL on statin medication were at increased PAD risk, which increased with cumulative statin dosage. Thorough considerations are needed before prescribing statins to HD patients.

Traditional and cortical trajectory screws of static and dynamic lumbar fixation- a finite element study.

BACKGROUND: Two types of screw trajectories are commonly used in lumbar surgery. Both traditional trajectory (TT) and cortical bone trajectory (CBT) were shown to provide equivalent pull-out strengths of a screw. CBT utilizing a laterally-directed trajectory engaging only cortical bone in the pedicle is widely used in minimal invasive spine posterior fusion surgery. It has been demonstrated that CBT exerts a lower likelihood of violating the facet joint, and superior pull-out strength than the TT screws, especially in osteoporotic vertebral body. No design yet to apply this trajectory to dynamic fixation. To evaluate kinetic and kinematic behavior in both static and dynamic CBT fixation a finite element study was designed. This study aimed to simulate the biomechanics of CBT-based dynamic system for an evaluation of CBT dynamization. METHODS: A validated nonlinearly lumbosacral finite-element model was used to simulate four variations of screw fixation. Responses of both implant (screw stress) and tissues (disc motion, disc stress, and facet force) at the upper adjacent (L3-L4) and fixed (L4-L5) segments were used as the evaluation indices. Flexion, extension, bending, and rotation of both TT and CBT screws were simulated in this study for comparison. RESULTS: The results showed that the TT static was the most effective stabilizer to the L4-L5 segment, followed by CBT static, TT dynamic, and the CBT dynamic, which was the least effective. Dynamization of the TT and CBT fixators decreased stability of the fixed segment and alleviate adjacent segment stress compensation. The 3.5-mm diameter CBT screw deteriorated stress distribution and rendered it vulnerable to bone-screw loosening and fatigue cracking. CONCLUSIONS: Modeling the effects of TT and CBT fixation in a full lumbosacral model suggest that dynamic TT provide slightly superior stability compared with dynamic CBT especially in bending and rotation. In dynamic CBT design, large diameter screws might avoid issues with loosening and cracking.

Striatal functional connectivity in chronic ketamine users: a pilot study.

Background: The striatum supports motivated behavior and impulse control. Altered striatal activation and connectivity has been observed in link with impulse control dysfunction in individuals with drug addiction.Objectives: We examined how resting state functional connectivity (rsFC) of the striatum is altered as a result of chronic ketamine misuse.Methods: Thirty-six ketamine users (10 women) and 20 healthy controls (9 women) completed an assessment with the Barratt Impulsiveness Scale (BIS-11) and magnetic resonance imaging. In SPM we examined voxel-wise connectivities of the caudate, pallidum, putamen, and ventral striatum in ketamine users (versus healthy controls) and in association with BIS-11 score and duration of use, all at a corrected threshold.Results: Compared to controls, ketamine users showed higher connectivity between caudate and dorsal anterior cingulate cortex and between pallidum and bilateral cerebellum. In ketamine users, putamen showed higher connectivity with the left orbitofrontal cortex (OFC) in association with both BIS-11 score and months of ketamine use. Mediation analyses suggest that the connectivity z score mediated the relationship between impulsivity and duration of use.Conclusions: These preliminary findings highlighted altered striatal connectivity in chronic ketamine users, and the potential role of putamen OFC connectivity in supporting the correlation between impulsivity and duration of ketamine use. If replicated in a larger sample, these findings may represent neural markers of ketamine misuse.

Recognizing the peak bone mass (age 30) as a cutoff point to achieve the success of orthodontic implants.

The aim of present study was to investigate the critical risk factor (age 30: peak bone mass) to evaluate the success of orthodontic implants. A total of 426 orthodontic implants were placed in 270 patients as orthodontic anchorages. Data were analyzed according to patient's characteristics, location of placement, implant categories, and orthodontic force. The young patients were the age ≤ 30 years and the older patients were the age > 30 years. Statistical analysis was performed and a p value < 0.05 was considered to indicate statistical significance. The Chi-square or Fisher exact test was used depending on sample sizes. The null hypothesis was no statistically significant correlation between age ≤ 30 years and age > 30 years. The overall success rate (with and without predrill) was 89.2%. The success rate of orthodontic implants was significantly larger in younger patients (89.9%) than in older patients (76.1%). Recognizing age-related factor in the success rates, older patient (> 30 years) were significant lower than young patients (≤ 30 years) in the gender (female and male), malocclusion (Class II), facial pattern (ortho and hyperdivergent), location (infrazygomatic crest), jaw (maxilla), side (right), material (titanium and stainless), length (9 mm and 10 mm), diameter (2 mm), load (< 3 weeks), and force (intrusion). Therefore, the null hypothesis was rejected. Age 30 is a cutoff point to achieve the success of orthodontic implants. The success rates of older patients (age > 30 years) were significant lower than young patients (age ≤ 30 years), especially in female.

Pten Haplodeficiency Accelerates Liver Tumor Growth in miR-122a-Null Mice via Expansion of Periportal Hepatocyte-Like Cells.

This study aimed to shed light on the molecular and cellular mechanisms responsible for initiation and progression of liver malignancies by examining the role of phosphatase and tensin homolog on chromosome 10 (Pten) in liver tumor progression in miR-122a (Mir122a)-null mice. We generated and monitored liver tumor initiation in Mir122a-null Pten heterozygous (Mir122a-/-;Pten+/- and Mir122a-/-;Alb-Cre;Ptenfx/+) mice and compared the results with those in Mir122a-/- mice. Both Mir122a-/-;Pten+/- and Mir122a-/-;Alb-Cre;Ptenfx/+ mice developed visible liver tumor nodules at 6 months of age. In premalignant livers of Mir122a-/-;Pten+/- mice, decreased PTEN and increased phosphorylated AKT were specifically observed in periportal cells, associated with inflammatory and fibrotic microenvironments. Furthermore, IL-1ß and tumor necrosis factor-α levels significantly increased in Mir122a-/-;Pten+/- premalignant livers at 6 months of age. Oval cells expressing A6, epithelial cell adhesion molecule, keratin (K) 8, K19, and SRY (sex determining region Y)-box 9 (SOX9) were present in both Mir122a-/- and Mir122a-/-;Pten+/- livers. Interestingly, a hybrid hepatocyte-like population with intermediate levels of K8, HNF4α, and SOX9 was located proximally to the oval cells in Mir122a-/-;Pten+/- livers. Lineage-tracing experiments revealed that these intermediate levels of K8 hepatocyte-like cells may be the cells of origin for Mir122a-/-;Pten+/- liver tumors. These findings suggest that inflammatory microenvironments in the periportal area of Mir122a-null mice may locally cause Pten down-regulation and expand tumor-initiating cells, causing hepatocellular carcinoma.

Targeted inactivation of murine Ddx3x: essential roles of Ddx3x in placentation and embryogenesis.

The X-linked DEAD-box RNA helicase DDX3 (DDX3X) is a multifunctional protein that has been implicated in gene regulation, cell cycle control, apoptosis, and tumorigenesis. However, the precise physiological function of Ddx3x during development remains unknown. Here, we show that loss of Ddx3x results in an early post-implantation lethality in male mice. The size of the epiblast marked by Oct3/4 is dramatically reduced in embryonic day 6.5 (E6.5) Ddx3x-/Y embryos. Preferential paternal X chromosome inactivation (XCI) in extraembryonic tissues of Ddx3x heterozygous (Ddx3x-/+) female mice with a maternally inherited null allele leads to placental abnormalities and embryonic lethality during development. In the embryonic tissues, Ddx3x exhibits developmental- and tissue-specific differences in escape from XCI. Targeted Ddx3x ablation in the epiblast leads to widespread apoptosis and abnormal growth, which causes embryonic lethality in the Sox2-cre/+;Ddx3xflox/Y mutant around E11.5. The observation of significant increases in γH2AX and p-p53Ser15 indicates DNA damage, which suggests that loss of Ddx3x leads to higher levels of genome damage. Significant upregulation of p21WAF1/Cip1 and p15Ink4b results in cell cycle arrest and apoptosis in Ddx3x-deficient cells. These results have uncovered that mouse Ddx3x is essential for both embryo and extraembryonic development.

MRI-based measurements of whole-brain global cerebral blood flow: Comparison and validation at 1.5T and 3T.

BACKGROUND: Whole-brain global cerebral blood flow (CBF) determined by MRI techniques, calculated using total CBF (TCBF) from phase-contrast MRI (PC-MRI), and brain parenchyma volume (BPV) from T1 -weighted image, have become increasingly popular in many applications. PURPOSE/HYPOTHESIS: To determine if MRI-based measurements of whole-brain global CBF data obtained across different field strengths could be merged, TCBF and BPV data acquired at 1.5T and 3T were compared. STUDY TYPE: Prospective study. POPULATION: Seventeen healthy subjects (eight females, aged 21-29 years old). FIELD STRENGTH/SEQUENCE: Fast spoiled gradient echo (FSPGR) and PC-MRI at both 1.5T and 3T. ASSESSMENT: TCBF and BPV data acquired at 1.5T and 3T were compared. STATISTICAL TESTS: The relationships of TCBF and whole-brain global CBF between two field strengths were examined by using the Pearson correlation coefficient analysis and intraclass correlation coefficient (ICC). RESULTS: Regression analysis revealed a strong correlation between TCBF at two field strengths (R2 = 0.78, P < 0.001), and the ICC was 0.85, suggesting measurements of TCBF at 1.5T were comparable and correlated with those at 3T. There was a significant difference in BPV between field strengths, where the white matter estimate was significantly larger at 1.5T when compared with that at 3T (P < 0.001). When TCBF was further normalized to the brain parenchyma mass to obtain whole-brain global CBF, it only showed a moderate correlation between measurements at the two field strengths (R2 = 0.46, P = 0.003) and lower ICC of 0.66, reflecting the slightly higher interstrength variability in the whole-brain global CBF measurements. DATA CONCLUSION: TCBF measurements could be performed equally well with comparable results at both field strengths, but specific attention should be given when TCBF is further normalized to BPV to obtain whole-brain global CBF. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:1273-1280.

Facial profile and frontal changes after bimaxillary surgery in patients with mandibular prognathism.

BACKGROUND/PURPOSE: Patients are always concerned about their postoperative appearance before surgery for facial deformity correction. The present study investigated the facial profile and frontal changes following two-jaw surgery. METHODS: Forty patients who underwent two-jaw surgery were divided by the amount of mandibular setback (group I: ≤8 mm and group II: >8 mm). Cephalometric radiograms (lateral and frontal) were collected and analyzed at three intervals: preoperatively (T1), immediately postoperatively (T2), and final follow-up (T3). The following points were identified: cheek points (C1-C5), pronasale (Prn, tip of the nose), anterior nasal spine (ANS), subnasal (Sn), point A, labrale superius (Ls), incision superius (Is), labrale inferius (Li), incision inferius (Ii), point B, labiomental sulcus (Si), pogonion (Pog), soft tissue pogonion (PogS), ramus point (RP), and gonion (Go). The immediate postoperative changes (T21), final postoperative changes (T32), and final stability (T31) were calculated and analyzed. RESULTS: In T31, the cheek line showed significant advancements of 2.3 mm (group I) and 1.6 mm (group II). The soft:hard tissue ratios were significantly correlated: Prn:ANS (0.37:1), Prn:A (0.39:1), Sn:A (0.85:1), C3:A (0.82:1), Ls:Is (0.92:1), Li:Ii (0.91:1), Si:B (0.88:1), and PogS:Pog (group I, 0.78:1 and group II, 0.93:1). The intercondylion and intergonial widths of group II (T31) significantly increased 1.8 and 4 mm, respectively. Regarding the postoperative skeletal stability (T32), group I showed significant correlations between amounts of mandibular setback, but group II did not. CONCLUSION: In the facial profile, the cheek line showed significant advancement postoperatively. The frontal mandibular transverse dimensions were significantly increased.