Does age affect patient outcomes after humeral head replacement in the treatment of acute proximal humeral fractures? A comparative cohort study with a minimum 10 years long-term follow-up.

BACKGROUND: Humeral head replacement (HHR) is now rarely recommended for complex proximal humeral fractures (PHFs) in older patients. However, in relatively young and active patients with unreconstructable complex PHFs, controversy still exists regarding the treatment options of reverse shoulder arthroplasty and HHR. The goal of this study was to compare the survival, functional, and radiographic outcomes of HHR in patients aged <70 years and those aged ≥70 years after a minimum 10 years follow-up. METHODS: Eighty-seven out of 135 patients undergoing primary HHR were enrolled and then divided into 2 groups based on age: <70 years and ≥70 years. Clinical and radiographic evaluations were performed with a minimum follow-up of 10 years. RESULTS: There were 64 patients (mean, 54.9 years) in the younger group and 23 patients (mean, 73.5 years) in the older group. The younger and older groups had comparable 10-year implant survivorship (98.4% vs. 91.3%). Patients aged ≥70 years had worse American Shoulder and Elbow Surgeons scores (74.2 vs. 81.0, P = .042) and lower satisfaction rates (12% vs. 64%, P < .001) than younger patients. At the final follow-up, older patients had worse forward flexion (117° vs. 129°, P = .047) and internal rotation (17 vs. 15, P = .036). More greater tuberosity complications (39% vs. 16%, P = .019), glenoid erosion (100% vs. 59%, P = .077), and humeral head superior migration (80% vs. 31%, P = .037) were also identified in patients aged ≥70 years. CONCLUSIONS: Unlike the increased risk for revision and functional deterioration over time after reverse shoulder arthroplasty for PHFs in younger patients, a high implant survival rate with lasting pain relief and stable functional outcomes could be observed in younger patients after HHR during long-term follow-up. Patients aged ≥70 years had worse clinical outcomes, lower patient satisfaction, more greater tuberosity complications, and more glenoid erosion and humeral head superior migration than those aged <70 years. HHR should not be recommended for the treatment of unreconstructable complex acute PHFs in older patient populations.

Targeting MET endocytosis or degradation to overcome HGF-induced gefitinib resistance in EGFR-sensitive mutant lung adenocarcinoma.

The overexpression of hepatic growth factor(HGF) is one of the important reasons for the development of gefitinib resistance in EGFR-sensitive mutant lung adenocarcinoma cells. Targeting the HGF receptor MET through endocytosis inhibition or degradation induction has been proposed as a potential strategy to overcome this resistance. However, the effectiveness of this approach remains needs to be evaluated. In this study, we observed that MET receptors undergo persistent endocytosis but rarely enter the degradation pathway in HGF-overexpressing cells. We showed that MET endocytosis can be inhibited by using gene silence method or MET inhibitors. CHC or DNM2 gene silence slightly increases the sensitivity of resistant cells to gefitinib without affecting MET activity, while GRB2 gene silence can simultaneously inhibit MET endocytosis and reduce MET activity, resulting in a significant reversal effect of gefitinib resistance. Similarly, MET inhibitors significantly reverse drug resistance, accompanied by simultaneous inhibition of MET endocytosis and activity, highlighting the importance of both endocytosis and activity in HGF-induced gefitinib resistance. Additionally, we demonstrated that promoting MET degradation through deubiquitinase (USP8 or USP32) gene silence is another effective method for reversing drug resistance. Overall, our findings suggest that targeting MET receptor endocytosis and degradation is an attractive strategy for overcoming HGF-induced gefitinib resistance in EGFR-sensitive mutant lung adenocarcinoma.

Human amnion-derived mesenchymal stem cells improve subclinical hypothyroidism by immunocompetence mediating apoptosis inhibition on thyroid cells in aged mice.

Subclinical hypothyroidism (SCH) affects 10% of the global population, which is most prevalent in women and the elderly. However, it remains debatable whether the elderly with subclinical hypothyroidism needs thyroxine supplement. Human amnion-derived mesenchymal stem cells (hAMSCs) could play important roles in autoimmune diseases, suggesting that hAMSC be a candidate to regulate the thyroid function of female age-related subclinical hypothyroidism. Herein, we established the model of SCH in the aged female mice. This study was designed to investigate whether human amnion-derived mesenchymal stem cells (hAMSC) could effect on immune regulation, apoptosis inhibition of thyroid cells, thyroid function, blood lipid levels, and heart function. In addition, qualified hAMSCs were intravenously injected into aged female SCH mice via the tail vein on day 0 and day 10. The levels of thyroid hormone and blood lipids as well as cardiac function, serum immunological indexes, and apoptosis of thyroid cells were then analyzed on day 5, 10, 15, and 20; meanwhile, the quantity of Th1, Th2, Th17, and Treg immune cells in peripheral blood was evaluated before and on day 20 post-injection. Our study demonstrated that after hAMSC transplantation, the thyroid functions, blood lipid levels, and heart function indexes of age-related SCH (AR-SCH) mice were significantly improved. Consistent with this, Th1 and Treg cells increased significantly, while Th2 and Th17 cells decreased in peripheral blood. Apoptosis was also suppressed in the thyroid cells. In summary, hAMSC delivery can potentially be a safe and effective therapy for treating SCH in the elderly, improving related complications by immunomodulatory and apoptosis inhibition.

What Are the Long-term Outcomes of Locking Plates for Nonosteoporotic Three-part and Four-part Proximal Humeral Fractures With a Minimum 10-year Follow-up Period?

BACKGROUND: Proximal humeral fractures (PHFs) often occur in elderly individuals who experience low-energy falls. Open reduction and internal fixation (ORIF) of the proximal humerus is typically performed in young, active patients because of their good bone quality and high functional demands. Although good short-term results have been reported after ORIF in young patients, few studies have specifically evaluated long-term outcomes. QUESTIONS/PURPOSES: (1) What are the long-term clinical outcomes scores and (2) radiologic outcomes of nonosteoporotic three-part and four-part PHFs treated with locking plates? (3) What complications occurred after treatment, and what factors are associated with poor postoperative functional outcomes scores and avascular necrosis (AVN) of the humeral head after ORIF? METHODS: Between June 2005 and December 2012, we surgically treated 774 patients for displaced two-, three-, and four-part PHFs. Approximately 75% (581 of 774) underwent ORIF, 10% (77 of 774) underwent hemiarthroplasty, 7% (54 of 774) underwent intramedullary nailing, 5% (39 of 774) underwent reverse shoulder arthroplasty, and the remaining 3% (23 of 774) underwent other surgical treatments. We considered those who had ORIF as potentially eligible. Based on that criterion, 75% (581) were eligible. However, only patients with nonosteoporotic three- and four-part PHFs (cortical thickness of the proximal humeral diaphysis greater than 6 mm on a preoperative AP radiograph of the affected shoulder) and a minimum of 10 years of follow-up were included. Sixty-four percent (498 of 774) of the patients were excluded because of simple or osteoporotic fractures, 1% (7 of 774) were excluded because of ipsilateral limb multiple fractures, 0.3% (2 of 774) were excluded because of pathologic PHFs, and another 2% (13 of 774) were lost before the minimum study follow-up of 10 years, leaving 8% (61 of 774) for analysis here. The mean age at surgery was 45 ± 12 years, with a mean follow-up of 13 years. Fifty-seven percent (35 of 61) of the patients were men. Patient-reported outcomes were evaluated using the University of California Loas Angeles (UCLA) score (range 0 to 35; higher scores represent better shoulder function) and Constant score (range 0 to 100; higher scores represent better shoulder function) at least 10 years postoperatively. Postoperative radiographs were reviewed to assess the cortical bone thickness of the proximal humerus, neck-shaft angle, head-to-tuberosity distance, and radiologically confirmable complications. Logistic regression analysis was performed to evaluate factors associated with poor postoperative functional scores (UCLA score ≤ 27 or Constant score ≤ 70) and AVN of the humeral head; the association between AVN and postoperative functional outcomes was also assessed. RESULTS: At the most-recent follow-up, these patients had a mean UCLA score of 31 ± 3 and a Constant score of 88 ± 10. The mean neck-shaft angle was 133° ± 10°, and 23% (14 of 61) of patients experienced AVN of the humeral head during follow-up. Twenty-nine complications in 30% (18 of 61) of patients were reported. After controlling for potentially confounding variables such as age and gender, we found that the presence of greater tuberosity malposition (odds ratio 18 [95% confidence interval 2 to 167]; p = 0.01) and immediate postoperative neck-shaft angle less than 130° (OR 19 [95% CI 3 to 127]; p = 0.002) were associated with poor postoperative functional scores. Four-part PHFs (OR 13 [95% CI 2 to 82]; p = 0.008) and metaphyseal extension less than 8 mm (OR 7 [95% CI 1 to 35]; p = 0.03) were associated with AVN of the humeral head. For patients who met the criteria for anatomic reduction (achievement of all of the following three criteria: neck-shaft angle ≥ 130°, head-shaft displacement < 5 mm, and head-to-tuberosity distance greater than or equal to 3 mm and less than or equal to 20 mm), there were no differences in postoperative functional scores between patients with AVN and those without. CONCLUSION: ORIF of nonosteoporotic proximal humeral fractures with locking plates led to favorable functional and radiologic outcomes at a minimum of 10 years of follow-up. When encountering complex PHFs in patients with good bone quality, every effort must be made to achieve an anatomic reduction of the fracture as far as possible, which may not reduce the risk of AVN (this occurred in nearly one-fourth of patients). However, good outcomes can usually be expected, even in patients with AVN. Because this was a retrospective study with a high risk of bias owing to sparse data, the factors associated with poor postoperative functional outcomes must be further investigated in large prospective studies. LEVEL OF EVIDENCE: Level III, therapeutic study.

Postoperative Nursing Care of Obese Patients with Aortic Dissection Receiving Modified Prone Position Mechanical Ventilation: A Report of Two Cases.

Background: Aortic dissection is a critical cardiovascular disease, with Stanford Type A aortic dissection (TAAD) posing significant concern due to its high mortality rate, especially in obese patients. Acute respiratory distress syndrome (ARDS) is among the most common postoperative complications. Therefore, preventing ARDS is critically important for TAAD patients. Objective: This study aims to investigate the impact of enhanced prone mechanical ventilation on oxygenation levels, early extubation rates, and length of stay in the intensive care unit (ICU) among obese TAAD patients. The goal is to assess its potential to improve patient clinical outcomes and provide a scientific foundation for clinical practice. Case Presentation: Following evaluation by the attending physician, two hypoxemic patients underwent prone mechanical ventilation on postoperative day 3 for 12 hours daily, consecutively for 3-5 days. Patients' oxygenation significantly improved, and mechanical ventilation was discontinued after respiratory exercises. Successful removal of oral intubation was achieved, followed by individualized nursing care. No complications arose during intensive care, and both patients were transferred out of the ICU and subsequently discharged. Conclusions: The early implementation of modified prone position ventilation effectively mitigates postoperative hypoxemia in obese patients with aortic dissection. It increases the rate of early postoperative oral extubation and reduces the length of stay in the ICU.

Arthroscopic Repair Benefits Reparable Rotator Cuff Tear Patients Aged 65 Years or Older With a History of Traumatic Events.

PURPOSE: To evaluate the clinical outcomes of arthroscopic rotator cuff repair at 2-year follow-up in patients aged 65 years or older with a history of traumatic events divided into groups based on symptom duration (<3 months, 3-6 months, and >6 months from injury to surgery) and to compared patient-reported outcomes among the 3 groups. METHODS: Between 2015 and 2020, 110 patients who met the inclusion criteria were enrolled in this study; these patients were divided into 3 groups according to symptom duration: less than 3 months (group A), 3 to 6 months (group B) and more than 6 months (group C). Preoperative and 2-year postoperative clinical outcomes were compared, including American Shoulder and Elbow Surgeons, Constant-Murley, University of California, Los Angeles, Simple Shoulder Test, and visual analog scale scores; forward elevation; external rotation; and internal rotation. The minimal clinically important difference (MCID), patient acceptable symptom state, substantial clinical benefit, and maximum outcome improvement were also compared among the groups. RESULTS: The American Shoulder and Elbow Surgeons score, as the primary outcome, improved significantly from 41.0 ± 18.5 to 85.4 ± 8.1 in group A, from 53.7 ± 14.3 to 86.3 ± 11.7 in group B, and from 49.7 ± 18.5 to 83.9 ± 11.9 in group C. All the other parameters showed statistically significant improvements at 2-year follow-up in each group (all P < .05). There was no significant difference in each parameter among the 3 groups except the visual analog scale score, which did not achieve the MCID. Overall, 86 patients (78.2%) exceeded the MCID, 87 patients (79.1%) achieved the patient acceptable symptom state, 77 patients (70.0%) achieved substantial clinical benefit, and 62 patients (56.4%) achieved maximum outcome improvement without significant differences among the 3 groups. CONCLUSIONS: In rotator cuff tear patients aged 65 years or older with a history of traumatic events, arthroscopic rotator cuff repair significantly improves clinical outcomes at 2-year follow-up regardless of symptom duration if the tear is fully reparable. LEVEL OF EVIDENCE: Level III, prognostic retrospective study.

Long-term outcomes of shoulder hemiarthroplasty for acute proximal humeral fractures.

PURPOSE: Shoulder hemiarthroplasty (HA) is now rarely indicated for complex proximal humeral fractures due to its unpredictable characteristic of the greater tuberosity (GT) healing. Despite the increasing popularity of reverse shoulder arthroplasty (RSA) in fracture treatment, there are still concerns about failure revision and its application in young populations. The complete negation of HA for fracture treatment is still under debate. METHODS: Eighty-seven out of 135 patients with acute proximal humeral fractures treated with HA were enrolled. Clinical and radiographic evaluations were performed. RESULTS: With a mean follow-up time of 14.7 years, the 10-year prosthetic survival rate was 96.6%. The mean ASES score and Constant score were 79.3 and 81.3, respectively, the mean VAS was 1.1, the average forward flexion was 125.9°, external rotation was 37.2°, and internal rotation was at the L4 level. Nineteen patients (21.8%) displayed GT complications and showed significantly worse outcomes. Glenoid erosion was observed in 64.9% of the patients and resulted in inferior outcomes. The patients who showed good postoperative two year functional outcomes and good acromiohumeral distances usually maintained their results without deterioration over time. CONCLUSIONS: With strict patient selection, a proper surgical technique and closely supervised postoperative rehabilitation, HA could achieve a 96.6% ten year survival rate and good pain relief at an average follow-up of 15 years. Although rarely indicated, HA should have a role in the treatment of acute complex proximal humeral fractures in relatively young and active patients with good GT bone and intact cuff.

Comparison of gut microbiota compositions and corresponding genetic and metabolic features between guttate and plaque psoriasis by metagenomic sequencing.

BACKGROUND: Guttate psoriasis (GP) and psoriasis plaques (PP) are common subtypes of psoriasis. Previous studies have fully researched the association between psoriasis and gut microbiota. However, the differences in gut microbiota between GPs and PPs are still unknown. METHODS: Fecal samples were collected from 30 psoriatic patients (15 GP and 15 PP) and 15 healthy subjects. Metagenomic sequencing was then used to compare gut microbiota compositions and corresponding genetic and metabolic features between GP and PP. RESULTS: We found that the genus Megamonas was increased in PP and reduced in GP. The genus Eubacterium was increased in GP and decreased in PP. Ten KEGG pathway were significantly enriched in GP: bacterial secretion system, ribosome, sphingolipid signaling pathway, steroid hormone biosynthesis, complement and coagulation cascades, proteoglycans in cancer, FOXO signaling pathway, cGMP-PKG signaling pathway, insulin resistance, and Epstein-Barr virus infection. Ten metabolites were significantly differentially abundant between GP and PP. Among them, thiamine, biotin, butylamine, phenylethylamine, folic acid, 1,2-propanediol, and 4-aminobutyrate were enriched in PP and l-glutamate, l-glutamine, and propanoate were enriched in GP. CONCLUSIONS: These results provide a theoretical basis for the microbiome-guided stratification of patients with psoriasis.

Cholesterol inhibits autophagy in RANKL-induced osteoclast differentiation through activating the PI3K/AKT/mTOR signaling pathway.

BACKGROUND: A dysregulated balance between bone formation and bone resorption controlled by osteoblast and osteoclast will lead to osteoporosis. Cholesterol (CHO) is a crucial factor leading to osteoporosis, and autophagy appears to involve it. Therefore, we aimed to study the molecular mechanism of autophagy in CHO-induced osteoclasts differentiation. METHODS: Nuclear factor-κ B ligand as a receptor activator was used to induce osteoclasts differentiation of murine macrophage RAW264.7 treated with CHO, PI3-kinase inhibitor (LY294002), and Rapamycin (RAPA), respectively. Western blot assay was used to detect the expression of TRAP/ACP5 and the proteins involved in autophagy and the PI3K/AKT/mTOR signaling pathway. In addition, TRAP staining, bone resorption assay, and F-actin immunofluorescence were performed to evaluate the ability of osteoclast formation. Transmission electron microscopy and immunofluorescence were also executed to observed the expression of LC3B, and autophagosome. RESULTS: When RAW264.7 was treated with 20 µg/mL CHO for 5 consecutive days, It exhibited the optimal osteoclast activity. In addition, CHO could inhibit autophagy and activate the PI3K/AKT/mTOR signaling pathway. Moreover, the effects of CHO on osteoclast differentiation and autophagy could partially be reversed by LY294002 and RAPA. CONCLUSION: Therefore, our results demonstrated that CHO could inhibit autophagy during osteoclast differentiation by activating the PI3K/AKT/mTOR signaling pathway. These findings provided important theoretical basis for CHO in bone resorption and formation.

Pentraxin-3 as a predictive marker of mortality in sepsis: an updated systematic review and meta-analysis.

BACKGROUND: The purpose of this study was to clarify the prognostic value of Pentraxin-3 (PTX3) on the mortality of patients with sepsis. METHODS: Publications published up to January 2021 were retrieved from PubMed, EMBASE, and the Cochrane library. Data from eligible cohort and case-control studies were extracted for the meta-analysis. Multivariate regression analysis was used to evaluate the correlation of the outcomes with sample size and male proportion. RESULTS: A total of 17 studies covering 3658 sepsis patients were included. PTX3 level was significantly higher in non-survivor compared to survivor patients (SMD (95% CI): -1.06 (-1.43, -0.69), P < 0.001). Increased PTX3 level was significantly associated with mortality (HR (95% CI): 2.09 (1.55, 2.81), P < 0.001). PTX3 showed good predictive capability for mortality (AUC:ES (95% CI): 0.73 (0.70, 0.77), P < 0.001). The outcome comparing PTX3 level in non-survivors vs. survivors and the outcome of the association between PTX3 and mortality were associated with sample size but not male proportion. AUC was associated with both sample size and male proportion. CONCLUSIONS: PTX3 level was significantly higher in non-survivor compared to survivor patients with sepsis. Elevated PTX3 level was significantly associated with mortality. Furthermore, the level of PTX3 might predict patient mortality.

Structural and Functional Changes in the Cerebellum and Brainstem in Patients with Benign Paroxysmal Positional Vertigo.

Benign paroxysmal positional vertigo (BPPV) is one of the most common peripheral vestibular diseases. Since the peripheral vestibular system connects with the cerebellum via the brainstem, repeated episodic vertigo may result in progressive structural and functional changes in the cerebellum and brainstem. In the present work, voxel-based morphometry (VBM) of T1-weighted images and resting-state functional magnetic resonance imaging (fMRI) in 32 patients with BPPV and 32 matched healthy controls were used to assess cerebellar and brainstem anatomical and spontaneous resting-state brain activity alterations associated with BPPV. We used a spatially unbiased infratentorial template toolbox in combination with VBM to analyze cerebellar and brainstem gray matter volume (GMV), fractional amplitude of low-frequency fluctuations (fALFF), and regional homogeneity (ReHo). Patients with BPPV showed decreased GMV in the right cerebellum posterior lobe/cerebellar tonsil extending to the cerebellum anterior lobe and pons relative to healthy controls. BPPV patients also exhibited significantly higher fALFF values in the right pons and left pons and higher ReHo values in the left cerebellum posterior lobe/Crus2 than the controls. Furthermore, the fALFF z-scores in the pons were positively correlated with the duration of vertigo at baseline and dizziness visual analog scale scores 1 week after canalith repositioning procedures (CRPs). BPPV patients exhibited structural and functional changes in the cerebellum and pons, which may reflect the adaptation and plasticity of these anatomical structures after repeated attacks of episodic vertigo. These results indicate that the changes in pons function may be closely related to residual dizziness after CRPs.

Case series of aortoenteric fistulas: a rare cause of gastrointestinal bleeding.

BACKGROUND: Aortoenteric fistula (AEF) is a rare cause of gastrointestinal bleeding and is often misdiagnosed in clinical practice. Herein, a case series of AEFs are presented and the clinical characteristics, diagnosis, and management strategies are summarized. METHODS: A retrospective analysis was performed on consecutive hospitalized patients with a final diagnosis of AEF at Beijing Friendship Hospital, Capital Medical University, between January 1, 2007 and March 31, 2020. The clinical data including diagnostic and management procedures as well as outcomes were collected and summarized. RESULTS: A total of nine patients were included in this study, five with primary AEF and four with secondary AEF. Eight of the patients were male, and the median age was 63 years. The fistulas were located in both the small intestine and the colon. All patients presented with gastrointestinal bleeding and pain, followed by weight loss, anorexia, and fever. A typical abdominal triad was found in only two cases. Seven patients experienced complications with preoperative abdominal infections and sepsis, and multiple organ failure occurred in four of these patients. All patients were assessed by computed tomography and five underwent abdominal and/or iliac aorta angiography. Two of these patients showed contrast agent leakage from the abdominal aorta into the intestine. Two cases were diagnosed with AEF by endoscopy before the operation. Eight patients received surgery and six patients survived. CONCLUSIONS: AEF is a rare cause of gastrointestinal bleeding that is associated with high mortality. Gastrointestinal bleeding and pain are the most common presentations. Timely diagnosis and multidisciplinary management are crucial to achieve a positive outcome.

Arthroscopic Autologous Scapular Spine Bone Graft Combined With Bankart Repair for Anterior Shoulder Instability With Subcritical (10%-15%) Glenoid Bone Loss.

PURPOSE: The purpose of our study is to prove that the autologous scapular spine bone graft is an alternative for the treatment of anterior shoulder instability and the clinical and radiological results are promising. METHOD: From July 2016 to August 2018, patients who were diagnosed as having anterior shoulder instability with subcritical (10%-15%) glenoid bone loss were treated by arthroscopic repair with autologous scapular spine bone graft. The inclusion criteria were (1) anterior shoulder instability underwent arthroscopic autologous scapular spine bone graft; (2) glenoid bone loss was within 10% to 15% (measured by Sugaya's method); (3) three complete sets of computed tomography (CT) scans (preoperative, 1 week after surgery, and 1 year after surgery) available; and (4) clinical follow-up time was at least 2 years. The exclusion criteria were (1) concomitant rotator cuff tear; (2) concomitant remplissage or SLAP repair; (3) previous surgery of the affected shoulder; (4) open surgery; and (5) incomplete radiological or clinical follow-up. The preoperative and postoperative Constant-Murley score, dietary approaches to stop hypertension (DASH) score, visual analog scale (VAS) score, and range of motion (ROM) were recorded. CT scans with 3-dimensional reconstruction were obtained at the first week after operation and at 1 year after operation; the graft resorption rate was consequently calculated. RESULTS: Twenty-seven patients were qualified and enrolled in the study. No severe complication was recorded during follow-up. No redislocation or subluxation was found, and the apprehension tests were all negative. At the last follow-up, the mean Constant-Murley score was 89.74 ± 3.71, the mean DASH score was 9.77 ± 5.31, the mean VAS score was 0.74 ± 0.64, which are all improved significantly compared with preoperative scores (P = .00,.00,.00, respectively). At the last follow-up, the ROM including anterior flexion, external rotation by side, and the internal rotation were well restored without significant difference compared with the contralateral shoulder (P =.48, .08, .47, respectively). At 1 year after operation, the resorption rate of the bone graft was 19.4%. CONCLUSION: This study found that anterior shoulder instability with subcritical (10%-15%) glenoid bone loss treated with arthroscopic autologous scapular spine bone graft with suture anchor fixation is safe and could achieve satisfactory result at short-term follow-up. LEVEL OF EVIDENCE: Therapeutic case series.

Teneligliptin Promotes Bile Acid Synthesis and Attenuates Lipid Accumulation in Obese Mice by Targeting the KLF15-Fgf15 Pathway.

Bile acids (BAs) play essential physiological roles not only by facilitating the absorption and transport of nutrients but also by acting as a complex molecular signaling system. Reduced levels of BAs have been observed in obesity and other metabolic disorders. In the present study, we explored the effect of the dipeptidyl peptidase-4 (DPP-4) inhibitor teneligliptin on BA synthesis, both in vitro and in vivo. In our in vivo experiments, we found that teneligliptin increased the liver, ileal, and serum BA concentrations in mice undergoing teneligliptin treatment for 10 weeks. We further found that in mice fed a high-fat diet, teneligliptin prevented an increase in markers of obesity (body weight, total cholesterol, total triglyceride, adipocyte size) while increasing the total serum and ileal levels of BA. Mechanistically, teneligliptin increased BA synthesis through the alternative synthesis pathway, as the levels of both 7α-hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27A1) along with downstream oxysterol 7α-hydroxylase (CYP7B1) but not sterol 12α-hydroxylase (CYP8B1) were increased. Importantly, teneligliptin suppressed the expression of the BA synthesis inhibitory factor Fgf15, which was mediated through phosphatidylinositol 3-kinase (PI3K)/AKT/Krüppel-like factor 15 (KLF15) signaling. Inhibition of KLF15 abolished this effect. Together, our results provide evidence of the potential benefit of teneligliptin in the treatment of metabolic disorders via increased BA production.

Assessment of Tendon Retraction in Large to Massive Rotator Cuff Tears: A Modified Patte Classification Based on 2 Coronal Sections on Preoperative Magnetic Resonance Imaging With Higher Specificity on Predicting Reparability.

PURPOSE: To propose a modified Patte classification (evaluating tendon retraction on 2 coronal sections) and analyze whether this classification was better at predicting irreparability and retear of large to massive rotator cuff tears (RCTs). METHODS: A retrospective study was performed. Imaging evaluation including tendon retraction, fatty infiltration, the acromiohumeral distance (AHD), and the tangent sign was performed using magnetic resonance imaging. The modified Patte classification was used to assess tendon retraction. Intraobserver and interobserver reliability was analyzed by calculating intraclass correlation coefficients. Factors affecting irreparability and retear were analyzed using both univariate and multivariate analyses. Sensitivity and specificity of tendon retraction to predict irreparability and retear were calculated. RESULTS: A total of 121 shoulders with large to massive RCTs underwent arthroscopic rotator cuff repairs. The modified Patte classification system had excellent interobserver and intraobserver reliability. Several factors were associated with reparability and retear in the univariate analysis. However, in binary logistic regression analysis, the only factors affecting reparability were AHD less than 0.4 cm (P = .007) and modified Patte stage III tendon retraction (P = .023). Low-grade repair quality (P = .001) and modified Patte stage III tendon retraction (P = .031) were independent factors for retear. Modified Patte stage III had a high specificity for predicting irreparability (93.58%) and retear (98.78%), whereas the specificity of original Patte stage III was 76.15% and 84.15%, respectively. CONCLUSIONS: For large to massive RCT repairs, modified Patte stage III tendon retraction with evaluation of 2 coronal cuts reveals higher specificity on predicting tendon irreparability and postoperative retear. An AHD less than 0.4 cm on magnetic resonance imaging and modified Patte stage III tendon retraction were independent risk factors for irreparability. Low-grade repair quality and modified Patte stage III tendon retraction were independent risk factors for postoperative retear. LEVEL OF EVIDENCE: Level III, case-control study.

Establishment of a True En Face View in the Evaluation of Glenoid Morphology for Treatment of Traumatic Anterior Shoulder Instability.

PURPOSE: To develop an accurate and reproducible method for establishment of a true en face view of the glenoid with a traumatic bone defect. METHODS: A total of 50 sets of computed tomography images of the glenoid were used for 3-dimensional reconstruction. Both a quantitative definition and a practical method were designed for creation of the true en face view of the glenoid with a traumatic bone defect. The accuracy and reliability of the quantitative definition and the practical method were evaluated by calculating the maximal projection area and the simulated bone defect size. RESULTS: The glenoid surface could be fit with a sphere with a radius of 26.11 ± 2.15 mm (P < .001, R2 = 0.98). The true en face view could be established with the quantitative definition, which resulted in the maximal projection area, whereas any tilt would lead to decreased values (P < .05). To establish the true en face view on the glenoid with a traumatic bone defect, a vector from the center of the best-fit sphere of the glenoid surface to the middle point of an arc connecting the supraglenoid and infraglenoid tubercles was generated, which served as a perpendicular for glenoid reorientation. Cases off the true en face view would result in less accurate estimation of the bone defect size (P < .05). CONCLUSIONS: This study provided a quantitative definition and a practical method for generation of the true en face view in the presence of a traumatic bone defect based on the best-fit sphere of the glenoid surface as well as the anatomic landmark of the supraglenoid and infraglenoid tubercles. This study may improve the reliability of the quantification of traumatic bone defects of the glenoid. CLINICAL RELEVANCE: The practical method for establishment of the true en face view of the glenoid would be useful in decision making for the treatment of traumatic anterior shoulder instability.

Toll-like receptor 5-mediated IL-17C expression in intestinal epithelial cells enhances epithelial host defense against F4+ ETEC infection.

Enterotoxigenic Escherichia coli (ETEC) are an important cause of post-weaning diarrhea (PWD) in piglets. The IL-17 cytokine family is well known to play important roles in the host defense against bacterial infections at the mucosa. Previously, we reported the potential role of IL-17A in clearing an ETEC infection in piglets. IL-17C, another member of the IL-17 family, is highly expressed in the intestinal epithelium, however, its role during an ETEC infection is still unclear. In this study, we demonstrate that F4+ ETEC induce IL-17C mRNA and protein expression in intestinal tissues as well as in porcine intestinal epithelial cells (IPEC-J2). This IL-17C production is largely dependent on TLR5 signaling in IPEC-J2 cells. Both F4+ ETEC infection and exogenous IL-17C increased the expression of antimicrobial peptides and tight junction proteins, such as porcine beta-defensin (pBD)-2, claudin-1, claudin-2 and occludin in IPEC-J2 cells. Taken together, our data demonstrate that TLR5-mediated IL-17C expression in intestinal epithelial cells enhances mucosal host defense responses in a unique autocrine/paracrine manner in the intestinal epithelium against ETEC infection.

Genetic programs in human and mouse early embryos revealed by single-cell RNA sequencing.

Mammalian pre-implantation development is a complex process involving dramatic changes in the transcriptional architecture. We report here a comprehensive analysis of transcriptome dynamics from oocyte to morula in both human and mouse embryos, using single-cell RNA sequencing. Based on single-nucleotide variants in human blastomere messenger RNAs and paternal-specific single-nucleotide polymorphisms, we identify novel stage-specific monoallelic expression patterns for a significant portion of polymorphic gene transcripts (25 to 53%). By weighted gene co-expression network analysis, we find that each developmental stage can be delineated concisely by a small number of functional modules of co-expressed genes. This result indicates a sequential order of transcriptional changes in pathways of cell cycle, gene regulation, translation and metabolism, acting in a step-wise fashion from cleavage to morula. Cross-species comparisons with mouse pre-implantation embryos reveal that the majority of human stage-specific modules (7 out of 9) are notably preserved, but developmental specificity and timing differ between human and mouse. Furthermore, we identify conserved key members (or hub genes) of the human and mouse networks. These genes represent novel candidates that are likely to be key in driving mammalian pre-implantation development. Together, the results provide a valuable resource to dissect gene regulatory mechanisms underlying progressive development of early mammalian embryos.

Lnc-SNHG1 Activates the TGFBR2/SMAD3 and RAB11A/Wnt/ß-Catenin Pathway by Sponging MiR-302/372/373/520 in Invasive Pituitary Tumors.

BACKGROUND/AIMS: Long noncoding RNAs (lncRNAs) are critical regulators in various diseases including human cancer and could function as competing endogenous RNAs (ceRNAs) to regulate microRNAs (miRNAs). METHODS: Quantitative real-time PCR (qRT-PCR) was used to analyze the expression of lnc-SNHG1 and miR-302/372/373/520 in pituitary tumor tissues and cell lines. Cell proliferation was investigated using MTT and cell count assays. The mechanisms by which lnc-SNHG1 affects pituitary tumor progression were investigated using Western blot assays, transwell migration assays, immunohistochemistry, immunofluorescence, luciferase reporter assays, tumor xenografts, and flow cytometry Results: We found that lnc-SNHG1 was overexpressed in invasive pituitary tumor tissues and cell lines. Ectopic expression of lnc-SNHG1 promoted cell proliferation, migration, and invasion, as well as the epithelial-mesenchymal transition (EMT), by affecting the cell cycle and cell apoptosis in vitro and tumor growth in vivo. Further study indicated that overexpression of lnc-SNHG1 markedly inhibited the expression of miR-302/372/373/520 (miRNA-pool) which is down-regulated in invasive pituitary tumor cells. Moreover, overexpression of lnc-SNHG1 significantly promoted the expression of TGFBR2 and RAB11A, the direct targets of miR-302/372/373/520. Finally, lnc-SNHG1 activates the TGFBR2/SMAD3 and RAB11A/Wnt/ß-catenin pathways in pituitary tumor cells via sponging miR-302/372/373/520. CONCLUSIONS: Our data suggest that lnc-SNHG1 promotes the progression of pituitary tumors and is a potential therapeutic target for invasive pituitary tumor.

Actively Targeted Deep Tissue Imaging and Photothermal-Chemo Therapy of Breast Cancer by Antibody-Functionalized Drug-Loaded X-Ray-Responsive Bismuth Sulfide@Mesoporous Silica Core-Shell Nanoparticles.

A theranostic platform combining synergistic therapy and real-time imaging attracts enormous attention but still faces great challenges, such as tedious modifications and lack of efficient accumulation in tumor. Here, a novel type of theranostic agent, bismuth sulfide@mesoporous silica (Bi2S3@ mPS) core-shell nanoparticles (NPs), for targeted image-guided therapy of human epidermal growth factor receptor-2 (HER-2) positive breast cancer is developed. To generate such NPs, polyvinylpyrrolidone decorated rod-like Bi2S3 NPs are chemically encapsulated with a mesoporous silica (mPS) layer and loaded with an anticancer drug, doxorubicin. The resultant NPs are then chemically conjugated with trastuzumab (Tam, a monoclonal antibody targeting HER-2 overexpressed breast cancer cells) to form Tam-Bi2S3@mPS NPs. By in vitro and in vivo studies, it is demonstrated that the Tam-Bi2S3@mPS bear multiple desired features for cancer theranostics, including good biocompatibility and drug loading ability as well as precise and active tumor targeting and accumulation (with a bismuth content in tumor being ≈16 times that of nontargeted group). They can simultaneously serve both as an excellent contrast enhancement probe (due to the presence of strong X-ray-attenuating bismuth element) for computed tomography deep tissue tumor imaging and as a therapeutic agent to destruct tumors and prevent metastasis by synergistic photothermalchemo therapy.