Association of gustatory dysfunction and Alzheimer.

BACKGROUND: Chemosensory dysfunction has been reported to be involved in the pathogenesis of Alzheimer’s disease (AD). Compared with olfaction, gustatory dysfunction in AD has not been evaluated in depth. We reviewed previously published studies regarding gustatory dysfunction in patients with AD compared with healthy controls. METHODS: A systematic review was conducted by searching the MEDLINE, Cochrane Library, Embase, and PubMed databases covering publications from January 2000 to February 2023. The search was performed using the keyword "Alzheimer* AND (gustatory OR taste OR gustation)." Only studies that performed gustatory function testing and compared the results between patients with AD and healthy controls were included. A random-effects meta-analysis was performed. RESULTS: Twelve articles were finally included, and various gustatory tests including taste strips, the taste disk test, taste solutions, and subjective questionnaires were applied. Overall gustatory function based on the taste strip test was significantly decreased in patients with AD compared with controls in two out of three papers. The overall gustatory function of patients with AD was significantly decreased in all studies based on the taste disk and taste solution tests. We also found that the sweet taste test showed low heterogeneity across all the included studies, and there was low publication bias. In studies using subjective questionnaires, gustatory function was not significantly different between patients with AD and healthy controls in the meta-analysis. CONCLUSIONS: Based on these studies, gustatory dysfunction diagnosed by gustatory function testing was closely related to AD. However, the results of subjective questionnaires were not significantly different between patients with AD and healthy controls in the current meta-analysis. As the number of studies and enrolled subjects was limited and unified gustatory function testing was lacking, further studies are needed to confirm this relationship.

Microlens array camera with variable apertures for single-shot high dynamic range (HDR) imaging.

We report a microlens array camera with variable apertures (MACVA) for high dynamic range (HDR) imaging by using microlens arrays with various sizes of apertures. The MACVA comprises variable apertures, microlens arrays, gap spacers, and a CMOS image sensor. The microlenses with variable apertures capture low dynamic range (LDR) images with different f-stops under single-shot exposure. The reconstructed HDR images clearly exhibit expanded dynamic ranges surpassing LDR images as well as high resolution without motion artifacts, comparable to the maximum MTF50 value observed among the LDR images. This compact camera provides, what we believe to be, a new perspective for various machine vision or mobile devices applications.

Cancer drugs with high repositioning potential for Alzheimer's disease.

INTRODUCTION: Despite the recent full FDA approval of lecanemab, there is currently no disease modifying therapy (DMT) that can efficiently slow down the progression of Alzheimer's disease (AD) in the general population. This statement emphasizes the need to identify novel DMTs in the shortest time possible to prevent a global epidemic of AD cases as the world population experiences an increase in lifespan. AREAS COVERED: Here, we review several classes of anti-cancer drugs that have been or are being investigated in Phase II/III clinical trials for AD, including immunomodulatory drugs, RXR agonists, sex hormone therapies, tyrosine kinase inhibitors, and monoclonal antibodies. EXPERT OPINION: Given the overall course of brain pathologies during the progression of AD, we express a great enthusiasm for the repositioning of anti-cancer drugs as possible AD DMTs. We anticipate an increasing number of combinatorial therapy strategies to tackle AD symptoms and their underlying pathologies. However, we strongly encourage improvements in clinical trial study designs to better assess target engagement and possible efficacy over sufficient periods of drug exposure.

Probiotic mixture (Bacillus subtilis and Bacillus licheniformis) a potential in-feed additive to improve broiler production efficiency, nutrient digestibility, caecal microflora, meat quality and to diminish hazardous odour emission.

This research aimed to assess the impact of probiotic supplementation in the broiler diet on growth performance, nutrient utilization, noxious gas emissions, excreta micromiota and meat quality. One thousand six hundred and twenty male Ross 380 broilers (one-day-old, body weight, 42 ± 0.5 g and 5-week trial) were arbitrarily chosen and assigned to three nutritive treatments (basal diet and basal diet included with 0.1%, and 0.2% probiotic mixture [Bacillus subtilis 7.0 × 107 cfu/g, Bacillus licheniformis 4.1 × 107 cfu/g]) with 30 duplicates (18 birds each). Probiotic inclusion linearly increased (p < 0.05) broiler body weight gain (BWG) during Phases 1, 2 and the overall period and decreased (p < 0.05) feed conversion ratio (FCR) linearly on Phase 2 and the overall period. However, feed intake (FI) and mortality rate remained unaffected (p > 0.05). Though nutrient digestibility of nitrogen (N) tendency to increase (p < 0.05), dry matter (DM) and energy (E) did not influence (p > 0.05). Inclusion of a probiotic supplement linearly increased (p < 0.05) Lactobacillus and reduced Salmonella (p < 0.05) counts in broilers. Moreover, broilers fed a diet supplement with probiotic addition linearly decreased (p < 0.05) NH3 , H2 S, C2 O and acetic acid emissions. The graded level of probiotic addition linearly reduced (p < 0.05) cooking loss and the tendency to decrease (p < 0.05) weight of bursa of Fabricius, but had no effect (p > 0.05) on other meat quality measures. These findings indicated that increasing the level of probiotics in feed could improve growth efficiency, nutrient absorption, microbial index, meat quality and reduce gas emissions in broilers.

[Efficacy of high-dose dual therapy for Helicobacter pylori infection eradication in servicemen: a randomized controlled trial].

Objective: To assess the efficacy and cost-effectiveness of high-dose dual therapy compared with bismuth-containing quadruple therapy for treating Helicobacter pylori(H.pylori) infection in servicemen patients. Methods: A total of 160 H. pylori-infected, treatment-naive servicemen, including 74 men and 86 women, aged from 20 years to 74 years, with a mean (SD) age of 43 (13) years, tested in the First Center of Chinese PLA General Hospital from March 2022 to May 2022 were enrolled in this open-label, randomized controlled clinical trial. Patients were randomly allocated into 2 groups: the 14-day high-dose dual therapy group and the bismuth-containing quadruple therapy group. Eradication rates, adverse events, patient compliance, and drug costs were compared between the two groups. The t-test was used for continuous variables, and the Chi-square test for categorical variables. Results: No significant difference in H. pylori eradication rates were found between high-dose dual therapy and bismuth-containing quadruple therapy by ITT, mITT and PP analysis[ITT:90.0% (95%CI 81.2%-95.6%) vs. 87.5% (95%CI 78.2%-93.8%), χ2=0.25, P=0.617;mITT:93.5% (95%CI 85.5%-97.9%) vs. 93.3% (95%CI 85.1%-97.8%), χ2<0.01, P=1.000; PP: 93.5% (95%CI 85.5%-97.9%) vs. 94.5% (95%CI 86.6%-98.5%), χ2<0.01, P=1.000 ]. The dual therapy group exhibited significantly less overall side effects compared with the quadruple therapy group [21.8% (17/78) vs. 38.5% (30/78), χ2=5.15,P=0.023]. There were no significant differences in the compliance rates between the two groups [98.7%(77/78) vs. 94.9%(74/78), χ2=0.83,P=0.363]. The cost of medications in the dual therapy was 32.0% lower compared with that in the quadruple therapy (472.10 RMB vs. 693.94 RMB). Conclusions: The dual regimen has a favorable effect on the eradication of H. pylori infection in servicemen patients. Based on the ITT analysis, the eradication rate of the dual regimen is grade B (90%, good). Additionally, it exhibited a lower incidence of adverse events, better compliance and significantly reduced cost. The dual regimen is expected to be a new choice for the first-line treatment of H. pylori infection in servicemen but needs further evaluation.

Novel insight into the role of clusterin on intraocular pressure regulation by modifying actin polymerization and extracellular matrix remodeling in the trabecular meshwork.

This study provides comprehensive mechanistic evidence for the role of clusterin, a stress-response secretory chaperone protein, in the modulation of intraocular pressure (IOP) by regulating the trabecular meshwork (TM) actin cytoskeleton and the extracellular matrix (ECM). The pathological stressors on TM known to elevate IOP significantly lowered clusterin protein levels indicating stress-related clusterin function loss. Small interfering RNA-mediated clusterin loss in human TM cells in vitro induced actin polymerization and stabilization via protein kinase D1, serine/threonine-protein kinase N2 (PRK2), and LIM kinase 1 (LIMK1), and the recruitment and activation of adhesome proteins including paxillin, vinculin, and integrin αV and ß5. A complete loss of clusterin as seen in clusterin knockout mice (Clu-/- ) led to significant IOP elevation at postnatal Day 70. Contrarily, constitutive clusterin expression using adenovirus (AdCLU) in HTM cells resulted in the loss of actin polymerization via decreased PRK2, and LIMK1 and negative regulation of integrin αV and ß5. Furthermore, we found that AdCLU treatment in HTM cells significantly decreased the ECM protein expression and distribution by significantly increasing matrix metalloprotease 2 (MMP2) activity and lowering the levels of pro-fibrotic proteins such as transforming growth factor-ß2 (TGFß2), thrombospondin-1 (TSP-1), and plasminogen activator inhibitor-1 (PAI-1). Finally, we found that HTM cells supplemented with recombinant human clusterin attenuated the pro-fibrotic effects of TGFß2. For the first time this study demonstrates the importance of clusterin in the regulation of TM actin cytoskeleton - ECM interactions and the maintenance of IOP, thus making clusterin an interesting target to reverse elevated IOP.

Analysis of predisposing factors in unilateral maxillary sinus fungal ball: the predictive role of odontogenic and anatomical factors.

BACKGROUND: The pathogenesis of maxillary sinus fungal ball (MSFB) is explained by aerogenic and odontogenic factors. We evaluated the predisposing factors, including intranasal anatomical and dental factors for increased diagnostic accuracy. METHODOLOGY: In this study, 117 patients who underwent endoscopic sinus surgery for unilateral MSFB were included. Preoperative computed tomography (CT) scans were used to analyze the presence of anatomical variations (anterior and posterior nasal septal deviation (NSD), concha bullosa (CB), infraorbital cell (haller cell), paradoxical middle turbinate, everted uncinate process and MS size). Dental factors including history of dental procedures and findings on CT scans were reviewed. RESULTS: Anterior and posterior NSD toward non-affected side were significantly associated with the presence of FB. The presence of CB and infraorbital cell was higher in the non-affected side rather than in the lesion side. Compared to non-affected MS, FB-presence MS was shallower and had a larger height to depth ratio. The presence of dental history was significantly higher on FB-presence MS than non-affected MS. In multivariable analysis, posterior NSD toward non-affected side, dental history increased the aOR of MSFB, while the presence of CB and infraorbital cell decreased the aOR of MSFB. CONCLUSIONS: The occurrence of MSFB seems to be associated with ipsilateral odontogenic factors, followed by anatomic variations including posterior NSD toward non-affected side and absence of CB and infraorbital cell.

Red blood cell transfusion requirements for patients on extracorporeal membrane oxygenation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a rescue procedure used for cardiac and pulmonary dysfunction. Patients on ECMO often require blood transfusions to maintain oxygen delivery and recover from bleeding complications. Goals of the current study were to determine transfusion requirements while on ECMO, and incidence and transfusion requirements for bleeding complications. METHODS: Packed red blood cell (PRBC) transfusions and bleeding complications were identified by retrospective chart review of patients on ECMO from 2010 to 2018 at our institution. Patients were categorized into those who did not bleed (group A) and those who bled (group B). Incidence, sites of bleed, and transfusion requirement for each bleeding were analyzed. RESULTS: Among 217 patients including veno-arterial (VA) (n = 148) and veno-venous (VV) (n = 69) ECMO, we identified 62 patients without bleeding complications (group A) and 155 patients with bleeding complications (group B). In group A, transfusion requirement was 0.6 PRBC/day for VA-ECMO (n = 42) and 0.2 PRBC/day for VV-ECMO (n = 20) (p = 0.0015). In group B, number of PRBC given per event per day for bleeding complications during ECMO was mediastinal/thoracic bleed (83 events, 4.7 PRBC/event/day), gastrointestinal bleed (59 events, 4.8 PRBC/event/day), cannulation site bleed (88 events, 3.6 PRBC/event/day), and nasopharyngeal bleed (103 events, 2.8 PRBC/event/day). Thirty-day hospital mortality rate was co-related to transfusion requirement (area under ROC curve: 0.70). CONCLUSION: Patients without clinical bleeding still required transfusion, with higher rates observed with VA- than VV-ECMO. Transfusion requirements dramatically increased when patients developed various bleeding complications and had a significant impact on 30-day mortality rate.

[Relation of smoking status to family health and personality traits in residents aged over 18 years in China].

OBJECTIVE: To explore the relation of smoking status to family health and personality traits in residents aged over 18 years in China by binary Logistic regression analysis, to identify the psychosocial factors that influence tobacco use, and to provide evidence to predict smoking susceptibility based on personality traits and prevent smoking at individual and family levels. METHODS: Residents aged over 18 years in China were selected from "the Survey of Chinese Family Health Index (2021)". General characteristic questionnaire, short-form of family health scale, 10-item big five inventory were used to collect sociodemographic information, family health function and personality traits. And the relation of smoking status to family health and personality traits were analyzed by binary Logistic regression analysis. RESULTS: Totally 10 315 adults were collected, of whom there were 2 171 smokers. The smoking rate was 21.05%, 41.76% of the residents were male, 3.69% female, 20.03% urban, 23.77% rural, 12.60% aged between 18 and 35 years, 27.11% aged between 36 and 59 years, 34.35% aged over 60 years, and the smoking rate varied in gender, location, age, education, marital status, family types, and average household monthly income (P < 0.05). Furthermore, the scores of family health, family social and emotional health processes, family healthy lifestyle, family health resources, family external social support, agreeableness, openness, and neuroticism among smokers were lower than those of the non-smokers (P < 0.05). The results of binary Logistic regression analysis showed that the residents over 35 years old, with low educational level and divorced were the risk factors to smoking (P < 0.05), while female, unmarried, nuclear family, high scores of family social and emotional health processes and family health resources, openness, neuroticism, and agreeableness were the protective factors to smoking (P < 0.05). CONCLUSION: Besides gender, age, location, education, marital status, family types and average household monthly income, family health, and personality traits were also important factors influencing smoking status. Tobacco control based on personality traits and family health is essential, and more convincing research is necessary to determine the relation of tobacco use, tobacco dependence and smoking cessation to family health and personality traits.

Efficacy and Safety of IV Sildenafil in the Treatment of Newborn Infants with, or at Risk of, Persistent Pulmonary Hypertension of the Newborn (PPHN): A Multicenter, Randomized, Placebo-Controlled Trial.

OBJECTIVE: To investigate the efficacy and safety of sildenafil added to inhaled nitric oxide (iNO) for newborn infants with persistent pulmonary hypertension of newborn (PPHN) or hypoxic respiratory failure (HRF) at risk of PPHN. STUDY DESIGN: Part A of a multinational, randomized, double-blind, placebo-controlled trial. Infants ≤96 hours' old, >34 weeks of gestation, receiving iNO (10-20 ppm on ≥50% FiO2) for PPHN or HRF at risk of PPHN, and oxygen index >15 to <60, were randomized (1:1) to intravenous (IV) sildenafil (loading: 0.1 mg/kg, over 30 minutes; maintenance: 0.03 mg/kg/h) or placebo, for up to 14 days. Coprimary end points were treatment failure rate (day 14/discharge) and time on iNO without treatment failure. Secondary end points included time on ventilation and oxygenation measures. RESULTS: Of 87 infants screened, 29 were randomized to IV sildenafil and 30 to placebo; 13 discontinued treatment (sildenafil, n = 6; placebo: n = 7), including 3 deaths (sildenafil: n = 2; placebo: n = 1). Treatment failure rates did not differ with sildenafil (27.6%) vs placebo (20.0%; P = .4935). Mean time on iNO was not different with sildenafil (4.1 days) vs placebo (4.1 days; P = .9850). No differences were noted in secondary end points. Most common adverse events (AEs) with sildenafil (≥10% infants) were hypotension (n = 8/29), hypokalemia (n = 7/29), anemia, drug withdrawal syndrome (n = 4/29, each), and bradycardia (n = 3/29). One serious AE (hypotension) was considered treatment-related. CONCLUSIONS: IV sildenafil added to iNO was not superior to placebo in infants with PPHN or HRF at risk of PPHN. A review of AEs did not identify any pattern of events indicative of a safety concern with IV sildenafil. Infants will have developmental follow-up (Part B). TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT01720524.

13 C NMR of glutamate for monitoring the pentose phosphate pathway in myocardium.

After administration of 13 C-labeled glucose, the activity of the pentose phosphate pathway (PPP) is often assessed by the distribution of 13 C in lactate. However, in some tissues, such as the well-oxygenated heart, the concentration of lactate may be too low for convenient analysis by NMR. Here, we examined 13 C-labeled glutamate as an alternative biomarker of the PPP in the heart. Isolated rat hearts were perfused with media containing [2,3-13 C2 ]glucose and the tissue extracts were analyzed. Metabolism of [2,3-13 C2 ]glucose yields [1,2-13 C2 ]pyruvate via glycolysis and [2,3-13 C2 ]pyruvate via the PPP. Pyruvate is in exchange with lactate or is further metabolized to glutamate through pyruvate dehydrogenase and the TCA cycle. A doublet from [4,5-13 C2 ]glutamate, indicating flux through the PPP, was readily detected in 13 C NMR of heart extracts even when the corresponding doublet from [2,3-13 C2 ]lactate was minimal. Benfotiamine, known to induce the PPP, caused an increase in production of [4,5-13 C2 ]glutamate. In rats receiving [2,3-13 C2 ]glucose, brain extracts showed well-resolved signals from both [2,3-13 C2 ]lactate and [4,5-13 C2 ]glutamate in 13 C NMR spectra. Assessment of the PPP in the brain based on glutamate had a strong linear correlation with lactate-based assessment. In summary, 13 C NMR analysis of glutamate enabled detection of the low PPP activity in isolated hearts. This analyte is an alternative to lactate for monitoring the PPP with the use of [2,3-13 C2 ]glucose.

Development of cell-based high throughput luminescence assay for drug discovery in inhibiting OCT4/DNA-PKcs and OCT4-MK2 interactions.

Amplification-independent c-MYC overexpression is suggested in multiple cancers. Targeting c-MYC activity has therapeutic potential, but efforts thus far have been mostly unsuccessful. To find a druggable target to modulate c-MYC activity in cancer, we identified two kinases, MAPKAPK2 (MK2) and the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which phosphorylate the Ser111 and the Ser93 residues of OCT4, respectively, to transcriptionally activate c-MYC. Using these observations, we present here a novel cell-based luminescence assay to identify compounds that inhibit the interaction between these kinases and OCT4. After screening approximately 80,000 compounds, we identified 56 compounds ("hits") that inhibited the luminescence reaction between DNA-PKcs and OCT4, and 65 hits inhibiting the MK2-OCT4 interaction. Using custom antibodies specific for pOCT4S93 and pOCT4S111 , the "hits" were validated for their effect on OCT4 phosphorylation and activation. Using a two-step method for validation, we identified two candidate compounds from the DNA-PKcs assay and three from the MK2 assay. All five compounds demonstrate a significant ability to kill cancer cells in the nanomolar range. In conclusion, we developed a cell-based luminescence assay to identify novel inhibitors targeting c-MYC transcriptional activation, and have found five compounds that may function as lead compounds for further development.

Vorinostat and fenretinide synergize in preclinical models of T-cell lymphoid malignancies.

T-cell lymphoid malignancies (TCLMs) are in need of novel and more effective therapies. The histone deacetylase (HDAC) inhibitors and the synthetic cytotoxic retinoid fenretinide have achieved durable clinical responses in T-cell lymphomas as single agents, and patients who failed prior HDAC inhibitor treatment have responded to fenretinide. We have previously shown fenretinide synergized with the class I HDAC inhibitor romidepsin in preclinical models of TCLMs. There exist some key differences between HDAC inhibitors. Therefore, we determined if the pan-HDAC inhibitor vorinostat synergizes with fenretinide. We demonstrated cytotoxic synergy between vorinostat and fenretinide in nine TCLM cell lines at clinically achievable concentrations that lacked cytotoxicity for non-malignant cells (fibroblasts and blood mononuclear cells). In vivo, vorinostat + fenretinide + ketoconazole (enhances fenretinide exposures by inhibiting fenretinide metabolism) showed greater activity in subcutaneous TCLM xenograft models than other groups. Fenretinide + vorinostat increased reactive oxygen species (ROS, measured by 2',7'-dichlorodihydrofluorescein diacetate dye), resulting in increased apoptosis (via transferase dUTP nick end labeling assay) and histone acetylation (by immunoblotting). The synergistic cytotoxicity, apoptosis, and histone acetylation of fenretinide + vorinostat was abrogated by the antioxidant vitamin C. Like romidepsin, vorinostat combined with fenretinide achieved synergistic cytotoxic activity and increased histone acetylation in preclinical models of TCLMs, but not in non-malignant cells. As vorinostat is an oral agent and not a P-glycoprotein substrate it may have advantages in such combination therapy. These data support conducting a clinical trial of vorinostat combined with fenretinide in relapsed and refractory TCLMs.

Tumor-Associated Macrophages as Multifaceted Regulators of Breast Tumor Growth.

Breast cancer is the most commonly occurring cancer in women of Western countries and is the leading cause of cancer-related mortality. The breast tumor microenvironment contains immune cells, fibroblasts, adipocytes, mesenchymal stem cells, and extracellular matrix. Among these cells, macrophages or tumor-associated macrophages (TAMs) are the major components of the breast cancer microenvironment. TAMs facilitate metastasis of the breast tumor and are responsible for poor clinical outcomes. High TAM density was also found liable for the poor prognosis of breast cancer. These observations make altering TAM function a potential therapeutic target to treat breast cancer. The present review summarizes the origin of TAMs, mechanisms of macrophage recruitment and polarization in the tumor, and the contributions of TAMs in tumor progression. We have also discussed our current knowledge about TAM-targeted therapies and the roles of miRNAs and exosomes in re-educating TAM function.

Intratumoral CD103-positive tumour-infiltrating lymphocytes are associated with favourable prognosis in patients with triple-negative breast cancer.

AIMS: Cluster of differentiation 103 (CD103), a marker of tissue resident memory T cells, is expressed on subsets of CD8+ T lymphocytes. We investigated the prognostic significance of CD103+ intra-epithelial tumour-infiltrating lymphocytes (iTILs) in invasive breast cancer (IBC). METHODS AND RESULTS: Immunohistochemistry was performed for CD103, CD8 and TGF-ß isoforms (1, 2 and 3) on tissue microarrays of 1187 IBC samples. CD103+ and CD8+ iTILs were present in 904 (76.2%) and 854 (74%) cases with an overall mean ± standard deviation of 38.2 ± 100.2/mm2 and 30.4 ± 89.7/mm2 , respectively. The numbers of CD103+ and CD8+ iTILs were positively correlated, and CD103+ iTILs outnumbered CD8+ iTILs in HER2-positive and triple-negative breast cancer (TNBC). CD103+ and CD8+ iTIL densities were significantly higher in tumours of histological grade 3, absence of lymphovascular invasion, high Ki-67 index, high stromal TIL density or TGF-ß3 expression. High CD103+ iTIL density was associated with better disease-free survival (DFS, P = 0.007), but no significant association was observed for overall survival (OS). Subgroup analysis by cancer molecular subtype showed that CD103+ iTIL count was prognostic only for TNBC (OS, P = 0.035; DFS, P = 0.009). CD8+ iTIL density was significant for DFS, but not for OS, in the entire cohort and TNBC. In multivariate analysis, CD103+ iTIL density was an independent prognostic factor of OS (P = 0.02) and DFS (P = 0.007) in TNBC, while CD8+ iTIL density was not significant for survival. CONCLUSIONS: CD103 iTIL density can serve as a predictor of good prognosis in patients with TNBC.

Trabecular bone score value is associated with new bone formation independently of fat metaplasia on spinal magnetic resonance imaging in patients with ankylosing spondylitis.

OBJECTIVE: To evaluate the association between trabecular bone score (TBS) and new bone formation in ankylosing spondylitis (AS) patients, and to investigate whether TBS is independently associated with new bone formation. METHOD: Sixty-eight patients with AS underwent spinal magnetic resonance imaging (MRI) and dual-energy X-ray absorptiometry of the lumbar spine to measure TBS and bone mineral density at baseline. Lateral radiographs of the cervical and lumbar spine (baseline and 2 years) were assessed for new bone formation (syndesmophyte formation and/or growth combined), and spinal MRIs were assessed for the presence or absence of fat metaplasia (FM) at the first to fourth lumbar vertebrae. The factors associated with new bone formation were analysed at the patient level and the vertebral level. RESULTS: New bone formation had developed in 17 patients (25%) at 2 year follow-up. Patients with new bone formation had a higher prevalence of FM and lower TBS at baseline than patients without new bone formation (p = 0.013 and p = 0.041). At the patient level, FM on MRI and low TBS (< 1.23) were significantly associated with new bone formation. At the vertebral level, new bone formation had developed in 25 out of 231 vertebrae (11%) after 2 years. Vertebrae with both FM on MRI and low TBS tended to have more new bone formation (p < 0.001). Syndesmophytes and low TBS (< 1.23) independently increased the risk of new bone formation at the level of individual vertebrae. CONCLUSION: At both patient and individual vertebral levels, low TBS was associated with new bone formation independently of FM on MRI.

Deep neuromuscular blockade during spinal surgery reduces intra-operative blood loss: A randomised clinical trial.

BACKGROUND: Spinal surgery is usually performed in the prone position using a posterior approach. However, the prone position may cause venous engorgement in the back and thus increase surgical bleeding with interruption of surgery. The prone position also affects cardiac output since large vessels are compressed decreasing venous return to the heart. OBJECTIVE: We hypothesised that deep neuromuscular blockade would be associated with less surgical bleeding during spinal surgery in the prone position. DESIGN: Randomised, single blinded trial. SETTING: University teaching hospital. PARTICIPANTS: Eighty-eight patients in two groups. INTERVENTIONS: Patients were randomly assigned to moderate neuromuscular blockade or deep neuromuscular blockade. In the moderate neuromuscular blockade group, administration of rocuronium was adjusted such that the train-of-four count was one to two. In the deep neuromuscular blockade group, rocuronium administration was adjusted such that the train-of-four count was zero with a posttetanic count 2 or less. MAIN OUTCOME MEASURES: The primary outcome was the volume of intra-operative surgical bleeding. The surgeon's satisfaction with operating conditions, haemodynamic and respiratory status, and postoperative pain scores were evaluated. RESULTS: The median [IQR] volume of intra-operative surgical bleeding was significantly less in the deep neuromuscular blockade group than in the moderate neuromuscular blockade group; 300 ml [200 to 494] vs. 415 ml [240 to 601]; difference: 117 ml (95% CI, 9 to 244; P = 0.044). The mean ±â€ŠSD surgeon's satisfaction with the intra-operative surgical conditions was greater in the deep neuromuscular blockade group than in the moderate neuromuscular blockade group; 3.5 ±â€Š1.0 vs. 2.9 ±â€Š0.9 (P = 0.004). In intergroup comparisons of respiratory variables, peak inspiratory pressure was lower in the deep neuromuscular blockade group overall (P < 0.001). The median [IQR] postoperative pain score was lower in the deep neuromuscular blockade group than the moderate neuromuscular blockade group; 50 [36 to 60] vs. 60 [50 to 70], (P = 0.023). CONCLUSION: Deep neuromuscular blockade reduced intra-operative surgical bleeding in patients undergoing spinal surgery. This may be related to greater relaxation in the back muscles and lower intra-operative peak inspiratory pressure when compared with moderate neuromuscular blockade. TRIAL REGISTRATION: KCT0001264 (http://cris.nih.go.kr).

Reliability and Validity of Patient-Reported, Rater-Based, and Hybrid Physical Activity Assessments in COPD: A Systematic Review.

Selecting valid and reliable PA assessments in chronic obstructive pulmonary disease (COPD) is crucial to ensure that the information obtained is accurate, valuable, and meaningful. The purpose of this systematic review was to compare the validity and reliability among PA assessments in COPD. An electronic database search of PubMed and CINAHL was completed in December 2019 using MeSH terms on physical activity, COPD, validation, and questionnaires. Transparency in reporting was assessed with the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) checklist while methodological quality was assessed with the modified Quality Appraisal tool for Reliability studies (QAREL) for reliability studies and the Quality Appraisal of Validity Studies (QAVALS) for validity studies. The search yielded fifteen different measures. The Stanford 7-day recall (PAR) demonstrated the strongest correlations with SenseWear Armband on energy expenditure (r = 0.83; p < 0.001) and moderate correlations for time spent in activity over 3 METs (r = 0.54, p < 0.001). The Multimedia Activity Recall (MARCA) also demonstrated moderate to good correlations with both SenseWear and Actigraph GT3X + accelerometers (r = 0.66-0.74). Assisted and computerized PRO measures (PAR and MARCA) and hybrid measures (C-PPAC and D-PPAC) demonstrate better psychometric properties as compared to other subjective measures and may be considered for quantification of PA in COPD. However, observations drawn from single validation studies limit strength of recommendations and further research is needed to replicate the findings.

High-mobility group box 1 protein induces epithelialmesenchymal transition in upper airway epithelial cells.

BACKGROUND: In the treatment of rhinosinusitis, nasal polyps are a major problem, and the epithelial-to-mesenchymal transition (EMT) process is considered pivotal in their development. Although various studies have addressed the role of high mobility group box 1 (HMGB1) nuclear protein in this setting, its impact on EMT has yet to be evaluated. Our aim was the pathogenic mechanism of HMGB1 in EMT and EMT-induced upper respiratory nasal polyps. METHODS: We investigated the EMT-related effects of HMGB1 in human nasal epithelial (HNE) cells using western blot analysis, transepithelial-electrical resistance (TEER) testing, wound healing assay, and immunofluorescence. HNE cells were incubated in a low-oxygen environment to evaluate the role of HMGB1 in hypoxia-induced EMT. Further support for our in vitro findings was obtained through murine models. Human nasal polyps and nasal lavage fluid samples were collected for western blotting, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA). RESULTS: HMGB1 increased mesenchymal markers and decreased epithelial markers in HNE cells. Hypoxia-induced HMGB1 in turn induced EMT, apparently through RAGE signaling. We verified HMGB1-induced EMT in the upper respiratory epithelium of mice by instilling intranasal HMGB1. In testing of human nasal polyps, HMGB1 and mesenchymal markers were heightened, whereas epithelial markers were reduced, compared with tissue controls. CONCLUSION: HMGB1 secretion in nasal epithelium may be a major pathogenic factor in upper respiratory EMT, contributing to nasal polyps.

[Experimental study on improvement of alcoholic liver disease by polysaccharides from Balanophora henryi through targeting miR-122a].

The aim of this paper was to investigate the effect of total polysaccharide from Balanophora henryi(TBP) on alcoholic liver disease(ALD) and explore the possible mechanism. C57 BL/6 N mice were randomly divided into 4 groups: pair-feeding group, alcohol-feeding model group, model+TBP group and TBP drug control group. The Gao-binge method was used to prepare the chronic ALD model, and at the same time, 400 mg·kg~(-1) TBP was given for interventional therapy. After feeding for 6 weeks, the serum, liver and colon tissues were collected for detection. As compared with the pair-feeding group, the model group mice showed obvious fatty degeneration and a large number of infiltration of inflammatory cells in the liver, with increased serum ALT and AST levels. After TBP intervention, histopathological changes in liver tissues were significantly improved, with decreased lipid deposition, closer arrangement of hepatocytes, lower expression level of inflammatory factors, and reduced activity of serum ALT and AST, indicating that TBP had a significant improvement effect on ALD. The observation of colonic tissues in mice showed that TBP effectively maintained the integrity of intestinal tissue structure of mice with ALD, enhanced the expression of tight junction protein occludin and reduced miR-122 a expression level. More importantly, TBP significantly reduced serum lipopolysaccharide(LPS) level in model mice. These results indicated that TBP may improve ALD by maintaining and enhancing intestinal barrier function. In vitro experiments showed that TBP significantly inhibited the expression level of miR-122 a in Caco-2 cells exposed to ethanol. Overexpression of miR-122 a in Caco-2 cells induced the inhibition of occludin protein production, and the addition of TBP significantly interfered with the effect. These results suggested that TBP could improve ALD by maintaining the stability of intestinal barrier function and reducing LPS content into the liver, and the mechanism may be partially related to inhibiting miR-122 a expression.