[Implementation Status of Palliative Care for Patients Died in Peking Union Medical College Hospital,2019].

Objective To reveal the current situation of palliative care for patients who died in Peking Union Medical College Hospital,so as to guide the practice of palliative care for patients in terminal stage. Methods A retrospective study was conducted on patients who died in Peking Union Medical College Hospital from January 1,2019 to December 31,2019.The general clinical data of the patients,whether they received palliative care,and the treatment details including invasive rescue measures,symptom controlling,and psychological,social,and spiritual care status before dying were collected for descriptive analysis. Results A total of 244 inpatients died in 2019,including 135 males and 109 females,with an average age of (65.9±16.4) years (1 day to 105 years).Among the 244 patients,112 (45.9%) died of neoplastic diseases and 132 (54.1%) died of non-neoplastic diseases.Sixty-one (25.0%) patients received palliative care before death,and they were mainly distributed in internal medicine departments such as nephrology (100.0%),gastroenterology (80.0%),and geriatrics (72.7%).Twenty-nine patients received sound palliative care,with all symptoms under control and no invasive treatment before death,and twenty-six patients received psychological,social,and spiritual care.Compared with the patients who were not exposed to the concept of palliative care,the patients who received palliative care showed decreased probabilities of cardiopulmonary resuscitation (0 vs 20.2%;χ2=13.009,P<0.001),tracheal intubation (3.3% vs 48.6%;χ2=38.327,P<0.001),and invasive mechanical ventilation (4.9% vs 47.5%;χ2=33.895,P<0.001) and an increased probability of psychological,social,and spiritual care (54.1% vs 2.4%;χ2=91.486,P<0.001). Conclusion The concept of palliative care has a positive impact on the death of end-stage patients.Palliative care services can increase the probability of end-stage patients receiving psychological,social,and spiritual care and reduce the use of invasive treatment.

[Effect of Concept and Practice of Palliative Care on the Death Status of Patients in Peking Union Medical College Hospital].

Objective To analyze the changes of death status of the inpatients in Peking Union Medical College Hospital before and after the development of palliative care.Methods All the death cases of Peking Union Medical College Hospital in 2013 (384 cases) and 2019 (244 cases) were included in this study,and the general information of the patients and the details of diagnosis and treatment before death were collected.Results The departments of intensive care,emergency,and respiratory diseases and the international medical services had highest number of deaths in both 2013 and 2019,with the cumulative constituent ratios of 67.7% and 62.7%,respectively.The number of clinical departments that involved or implemented palliative care increased from 7 in 2013 to 14 in 2019.The number of patients who died in 2019 and exposed to palliative care increased (P<0.001) compared with that in 2013,and increasing patients received humanistic care (P<0.001).Compared with 2013,2019 witnessed reducing patients receiving vasoactive drugs (P=0.006),cardiopulmonary resuscitation (P=0.002),endotracheal intubation (P=0.002),invasive mechanical ventilation (P<0.001),and invasive operation (P<0.001) before death in 2019.Conclusion The concept and practice of palliative care have significantly reduced the proportion of terminal patients receiving traumatic treatment.

GSK3ß-Ikaros-ANXA4 signaling inhibits high-glucose-induced fibroblast migration.

Previous studies showed that the activation of Wnt signaling reduced high glucose (HG)-mediated fibroblast damage, but the molecular basis for this phenomenon remains elusive. This study aimed to analyze the level of phosphorylation of GSK3ß Ser9 (pGSK3ß Ser9) during HG damage. Moreover, the phosphomimic form of pGSK3ß Ser9 was expressed to analyze its effect on cell migration via the phosphorylation of Ikaros. The results revealed that HG treatment significantly reduced the pGSK3ß Ser9 level. The overexpression of GSK3ß Ser9D and GSK3ß Ser9A accelerated and inhibited fibroblast cell migration, respectively. P110α knockdown or treatment with SP600125, an inhibitor of JNK, also reduced the pGSK3ß Ser9 level under HG condition. Treatment with SP600125 inhibited the migration of fibroblasts, but not in GSK3ß Ser9D-expressing cells. Further, yeast two-hybrid screening and biochemical analysis identified that GSK3ß interacted and phosphorylated Ikaros at Ser391. Besides, GSK3ß Ser9D, but not GSK3ß Ser9A, activated Ikaros Ser391 phosphorylation. Expressing Ikaros or ß-catenin significantly promoted cell migration, suggesting that GSK3ß modulated cell migration partially via the activation of Ikaros besides ß-catenin signaling under HG condition. The expression of the phosphomimic form of Ikaros Ser391D resulted in a significant increase in the extent of cell migration compared with Ikaros under HG condition. Moreover, the Ikaros Ser391D DNA-binding affinity toward the ANXA4 promoter increased, and ANXA4 suppression promoted cell migration. In conclusion, the results of this study provided a new regulatory mechanism by which GSK3ß negatively regulated human skin fibroblast cell migration.

Conjunctival myxoid stromal tumour: a distinctive clinicopathological and immunohistochemical study.

BACKGROUND/AIMS: To describe the clinicopathological and immunohistochemical characteristics of 10 patients representing a new entity of benign conjunctival myxoid stromal tumours. METHODS: Retrospective review of clinical findings, histopathological and immunohistochemical studies identified 10 cases of low-grade conjunctival myxoid stromal tumours. Specimens were routinely processed and stained with H&E. Immunohistochemical stains for CD34, CD68, vimentin, S100, smooth muscle actin (SMA), myosin, desmin, actin, Bcl-2 and Ki-67 were performed. Specific stains for Alcian-blue periodic acid-Schiff (AB-PAS) and aldehyde fuchsin stains were also performed. RESULTS: Ten patients with an average age of 45.6±11.1 years had a tender white or faint yellow to red mass on the bulbar conjunctiva. All the lesions were completely removed, and none of the patients relapsed. Histologically, all neoplasms consisted of spindle-shaped cells that showed signs of pseudonuclear inclusions, multinuclear cells and had no atypia. The stroma consisted of a large amount of mucus and was infiltrated with delicate to ropey collagens, a few mast cells and new vessels. Immunohistochemical stains were positive for CD34, vimentin and Bcl-2; partial positive for CD68; very low for Ki-67; and negative for S100, SMA, myosin, desmin and actin. AB-PAS suggested that the stroma was mucinous. CONCLUSIONS: These rare benign mesenchymal conjunctival tumours are mostly unilateral and occur in the bulbar conjunctiva. Complete resection is the radical treatment. These lesions are characterised by multiple spindle cells, a large amount of mucus, and sharing similar basic histopathological features with conjunctival myxoma and conjunctival stromal tumour. We suggest naming these lesions 'conjunctival myxoid stromal tumours'.

Wnt3a-regulated TCF4/ß-catenin complex directly activates the key Hedgehog signalling genes Smo and Gli1.

The Wnt and Hedgehog signalling pathways serve key roles in diverse developmental processes. However, the molecular associations between these two signalling pathways remains unclear. Previous transcriptome studies on human foreskin fibroblasts have indicated that Wnt signalling activation induces the expression of key Hedgehog signalling genes, including smoothened, frizzled class receptor (Smo) and GLI family zinc finger 1 (Gli1). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) results revealed that Wnt3a treatment induced the expression of the key Hedgehog signalling genes, including Smo, patched (PTCH), Gli1, Gli2 and Gli3. In addition, western blot analyses demonstrated that Wnt3a treatment resulted in the accumulation of cellular Smo and Gli proteins. Furthermore, promoter sequence analysis revealed that the putative ß-catenin/T-cell factor (TCF)-4 complex binding motifs (T/AC/GAAAG) were located within 1.5 kb of the Smo and Gli1 promoters. Results of the chromatin immunoprecipitation experiments and yeast-one hybrid assays revealed that TCF4 directly binds to the Smo and Gli1 promoters, with two binding sites for Smo and a single binding site for Gli1. Further analysis showed that the ß-catenin/TCF4 complex binds to the Smo and Gli1 promoters. To investigate the functions of TCF4 and ß-catenin in transcriptional regulation of Smo and Gli1, TCF4 and ß-catenin were transiently expressed in fibroblast cells. RT-qPCR results demonstrated that overexpression of TCF4 and ß-catenin induced the expression of Smo and Gli1. In addition, small interfering RNA-mediated suppression of ß-catenin resulted in the downregulation of Smo and Gli1 expression levels, even under Wnt3a treatment. Suppression of ß-catenin and Gli1 expression inhibited cell proliferation. Taken together, the results of the present study suggested that the ß-catenin/TCF4 complex directly activates Smo and Gli1 by binding to their promoters, which in turn controls cell proliferation in human fibroblasts.

Activation of Wnt signaling reduces high-glucose mediated damages on skin fibroblast cells.

OBJECTIVES: High-glucose (HG) stress, a mimic of diabetes mellitus (DM) in culture cells, alters expression of a large number of genes including Wnt and NF-κB signaling-related genes; however, the role of Wnt signaling during HG-mediated fibroblast damage and the relationship between Wnt and NF-κB signaling have not been understood. In this study, we aimed to investigate the ffects of Wnt signaling on HG-mediated damages. MATERIALS AND METHODS: Wnt3a was treated to HG-stressed human primary foreskin fibroblasts and the levels of Wnt signaling markers and cell proliferation were monitored. In addition, Wnt3a and NF-κB signaling inhibitor were assisted to analyze the relationship between two pathways. RESULTS: The results indicated that HG treatment repressed ß-catenin level, and Wnt3a treatment increased the levels of ß-catenin and FZD8 as well as cell proliferation. RNA-seq based transcriptome analysis identified 207 up-regulated and 200 down-regulated genes upon Wnt3a supply. These altered genes are distributed into 20 different pathways. In addition, gene ontology (GO) analysis indicates that 20 GO terms are enriched. Wnt signaling genes were further verified by qRT-PCR and the results were similar with RNA-seq assay. Since NF-κB signaling negatively regulates Wnt marker gene expression, Bay117082, a typical NF-κB signaling inhibitor and Wnt3a were supplemented for testing ß-catenin and phosphorylated IκBα (p-IκBα), respectively. CONCLUSION: HG positively inhibits Wnt signaling, and signaling activation via supplementation of Wnt3a rescued the defect caused by HG. NF-κB signaling negatively regulates accumulation of ß-catenin, but Wnt signaling has no effects on IκBα activation.

Annexin A2 functions downstream of c­Jun N­terminal kinase to promote skin fibroblast cell migration.

Delayed healing of skin wounds is one of the outcomes of diabetes mellitus (DM), a condition that affects a significant number of patients worldwide. However, the underlying mechanisms remain unknown. In order to examine proteome alterations in DM, a rat model of type 1 diabetes was developed using streptozotocin injections. The proteomic responses of normal and DM rat skin were analyzed by two­dimensional electrophoresis, and differentially expressed proteins were identified using a liquid chromatography/mass spectrometry system. DM induced 36 and repressed 41 differentially expressed proteins, respectively. Altered proteins were involved in a number of biological processes, including RNA and protein metabolism, the tricarboxylic acid cycle, glycolysis, cytoskeleton regulation, hydrogen detoxification and calcium­mediated signal transduction. In addition, overexpression of annexin A2, one of the signaling proteins altered by DM, accelerated the rate of human skin fibroblast cell migration. Application of SP600125, an inhibitor of a key regulator of cell migration c­Jun N­terminal kinase (JNK), inhibited the migration of normal cells. By contrast, SP600125 treatment did not inhibit the migration of annexin A2­overexpressed cells, indicating that annexin A2 may function downstream of JNK. In conclusion, the results of the present study reveal the potential proteomic responses to DM in skin tissues, and demonstrate a positive functional role of annexin A2 in fibroblast cell migration.

Clinical features and surgical outcomes of primary canaliculitis with concretions.

The purpose of our study is to analyze the clinical, ultrasonic, microbiologic, and histopathologic characteristics, management, and outcomes in a series of primary canaliculitis with concretions patients who underwent canaliculotomy with curettage.Thirty-six patients were reviewed for age, sex, location and laterality, duration of symptoms, clinical symptoms, ultrasonic signs, result of microbiologic culture and histopathologic examination, treatment, and outcomes. Main outcomes were the clinical, ultrasonic, and microbiological characteristics of the canalicular concretions; the histopathologic profiles; and the treatment effect.Thirty-six patients were identified with concretions in all 37 cases of the patients with canaliculitis. There were 30 (83.3%) female patients with a mean age of 54.2 years. Twenty-eight (77.8%) patients were misdiagnosed or delayed diagnosed, and the mean duration was 17.1 months. The common most clinical presentations were discharge (100%), epiphora (66.7%), erythema (52.8%), and swelling (47.2%), and concretions were found in 31 of 37 patients by typical clinical manifestations and in 5 of 6 patients by ultrasonic. Actinomyces was found in 8 of 13 histopathologic specimens, and microbiological cultures were positive in 13 of 24 patients. All patients underwent canaliculotomy with curettage to completely remove all concretions and contents; 35 of 36 patients' symptoms improved and 1 recurred after treatment at a median of 21.7 months follow-up according to the telephonic questionnaires.Canalicular concretions play an important role in primary canaliculitis. Canaliculotomy with curettage is a standard therapy with canalicular concretions, and the surgical removal of all possible concretions is essential for cure.

Application of citrate as a tricarboxylic acid (TCA) cycle intermediate, prevents diabetic-induced heart damages in mice.

OBJECTIVES: Higher cellular reactive oxygen species (ROS) levels is important in reducing cellular energy charge (EC) by increasing the levels of key metabolic protein, and nitrosative modifications, and have been shown to damage the cardiac tissue of diabetic mice. However, the relation between energy production and heart function is unclear. MATERIALS AND METHODS: Streptozotocin (STZ, 150 mg/kg body weight) was injected intraperitoneally once to mice that had been fasted overnight for induction of diabetes. After diabetic induction, mice received citrate (5 µg/kg) through intraperitoneal injection every other day for 5 weeks. The caspase-3, plasminogen activator inhibitor 1 (PAI1), protein kinase B (PKB), commonly known as AKT and phosphorylated-AKT (p-AKT) proteins were examined to elucidate inflammation and apoptosis in the heart. For histological analysis, heart samples were fixed with 10% formalin and stained with hematoxylin-eosin (HE) and Sirius red to assess pathological changes and fibrosis. The expression levels[AGA1] of marker proteins, tyrosine nitration, activity of ATP synthase and succinyl-CoA3-ketoacid coenzyme A transferase-1 (SCOT), and EC were measured. RESULTS: Intraperitoneal injection of citrate significantly reduced caspase-3 and PAI-1 protein levels and increased p-AKT level on the 5(th) week; EC in the heart was found to be increased as well. Further, the expression level, activity, and tyrosine nitration of ATP synthase and SCOT were not affected after induction of diabetes. CONCLUSION: Results indicate that application of citrate, a tricarboxylic acid (TCA) cycle intermediate, might alleviate cardiac dysfunction by reducing cardiac inflammation, apoptosis, and increasing cardiac EC.

Association of Genotyping of Bacillus cereus with Clinical Features of Post-Traumatic Endophthalmitis.

Bacillus cereus is the second most frequent cause of post-traumatic bacterial endophthalmitis. Although genotyping of B. cereus associated with gastrointestinal infections has been reported, little is known about the B. cereus clinical isolates associated with post-traumatic endophthalmitis. This is largely due to the limited number of clinical strains available isolated from infected tissues of patients with post-traumatic endophthalmitis. In this study, we report successful isolation of twenty-four B. cereus strains from individual patients with different disease severity of post-traumatic endophthalmitis. Phylogenetic analysis showed that all strains could be categorized into three genotypes (GTI, GTII and GTIII) and the clinical score showed significant differences among these groups. We then further performed genotyping using the vrrA gene, and evaluated possible correlation of genotype with the clinical features of B. cereus-caused post-traumatic endophthalmitis, and with the prognosis of infection by conducting follow-up with patients for up to 2 months. We found that the disease of onset and final vision acuity were significantly different among the three groups. These results suggested that the vrrA gene may play a significant role in the pathogenesis of endophthalmitis, and genotyping of B. cereus has the potential for predicting clinical manifestation and prognosis of endophthalmitis. To the best of our knowledge, this is the first report of isolation of large numbers of clinical isolates of B. cereus from patients with endophthalmitis. This work sets the foundation for future investigation of the pathogenesis endophthalmitis caused by B. cereus infection.

Transcriptomic study of high­glucose effects on human skin fibroblast cells.

Skin ulcers are a common complication of diabetes mellitus (DM). Fibroblasts are located within the dermis of skin tissue and can be damaged by diabetes. However, the underlying mechanism of how DM affects fibroblasts remains elusive. To understand the effects of DM on fibroblasts, the current study mimicked DM by high­glucose (HG) supplementation in the culture medium of human foreskin primary fibroblast cells, and the analysis of transcriptomic changes was conducted. RNA sequencing­based transcriptome analysis identified that, upon HG stress, 463 genes were upregulated and 351 genes downregulated (>1.5­fold changes; P<0.05). These altered genes were distributed into 20 different pathways. In addition, gene ontology (GO) analysis indicated that 31 GO terms were enriched. Among the pathways identified, nuclear factor κB (NF­κB) pathway genes were highly expressed, and the addition of Bay11­7082, a typical NF­κB signaling inhibitor, blocked the previously observed alterations in plasminogen activator inhibitor 1 (PAI1), an inflammation marker and frizzled class receptor 8 (FZD8), a Wnt signaling gene, expression that resulted from HG stress. Furthermore, an inhibitor of Wnt signaling diminished the role of Bay11­7082 in the regulation of PAI1 expression under HG conditions, suggesting that Wnt signaling may function downstream of the NF­κB pathway to protect fibroblast cells from HG stress. To the best of our knowledge, the current study is the first analysis of transcriptomic responses under HG stress in human fibroblasts. The data provided here may aid the understanding of the molecular mechanisms by which fibroblast cells are damaged in the skin of patients with DM.

Prediction of liver injury using the BP-ANN model with metabolic parameters in overweight and obese Chinese subjects.

Nonalcoholic fatty liver disease (NAFLD) is often associated with dyslipidemia. Metabolic disequilibrium, resulting from being overweight and obesity, increases risk to cardiovascular system and chronic liver disease. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) are standard clinical markers for liver injury. In this study, we examined association of body mass index (BMI) and metabolic markers with serum ALT, AST and GGT activity in an overweight and obese Chinese population. A total of 421 overweight and obese Chinese adults (211 males and 210 females) from The First Affiliated Hospital of Wenzhou Medical University were recruited in this study in 2014. All participants underwent anthropometric measures and phlebotomy after an overnight fast. Elevated ALT, AST and GGT levels were found in 17%, 5% and 24%, respectively. There were significant correlations between ALT and BMI, plasma triglycerides (TG), cholesterol, HDL and glucose, and between AST and plasma TG and cholesterol. GGT also correlated with plasma TG, cholesterol and glucose. The levels of ALT, AST and GGT could be predicted by BMI, plasma TG, cholesterol, HDL and glucose using the back propagation artificial neural network model (BP-ANN). These data suggest that abnormal metabolic markers could be used to monitor liver function to determine whether liver damage has occurred in overweight and obese individuals. This approach has clinical utility with respect to early scanning of liver injury or NAFLD based on routinely available metabolic data in overweight and obese population.

MAPT rs242562 and GSK3B rs334558 are associated with Parkinson's Disease in central China.

BACKGROUND: Microtubule-associated protein tau (MAPT) is a neuronal protein involved in the pathogenesis of several neurodegenerative diseases including Parkinson's Disease (PD). Glycogen synthase kinase 3 beta (GSK3B) catalyzes phosphorylation in multiple sites of tau protein. However, whether or not there is any association between the GSK3B gene alteration, MAPT haplotype and PD remains unexplored in Chinese population, especially in central Chinese population. RESULTS: Here, we aimed at studying the effect of MAPT rs242562 and GSK3B rs334558 on the risk of PD by performing a case-control association study in central China. Our data showed that all PD patients and controls were of MAPT H1/H1 diplotype in our study, thus confirming that the distribution of the MAPT H1 haplotype is common in China. GG genotype of MAPT rs242562 serves protection effect on PD risk in central Chinese population, while genotype of GSK3B rs334558 showed no difference between PD patients and controls. CONCLUSIONS: We conclude that the MAPT rs242562 is associated with PD in central China in the background of MAPT H1/H1 diplotype. The GG genotype of rs242562 displays protection against PD in subgroup with GSK3B rs334558 T carrier.

Glucocerebrosidase L444P mutation confers genetic risk for Parkinson's disease in central China.

BACKGROUND: Mutations of the glucocerebrosidase (GBA) gene have reportedly been associated with Parkinson disease (PD) in various ethnic populations such as Singaporean, Japanese, Formosan, Canadian, American, Portuguese, Greek, Brazilian, British, Italian, Ashkenazi Jewish, southern and southwestern Chinese. The purpose of this study is to determine in central China whether or not the reported GBA mutations remain associated with PD. METHODS: In this project, we conducted a controlled study in a cohort of 208 central Chinese PD patients and 298 controls for three known GBA mutations (L444P, N370S and R120W). RESULTS: Our data reveals a significantly higher frequency of L444P mutation in GBA gene of PD cases (3.4%) compared with the controls (0.3%) (P = 0.007, OR = 10.34, 95% CI = 1.26 - 84.71). Specifically, the frequency of L444P mutation was higher in the late onset PD (LOPD) cases compared with that in control subjects. The N370S and R120W mutations were detected in neither the PD group nor the control subjects. CONCLUSIONS: Our observations demonstrated that the GBA L444P mutation confers genetic risk for PD, especially LOPD, among the population in the central China area.

Japanese encephalitis accompanied by cerebral venous sinus thrombosis: a case report.

BACKGROUND: Cerebral venous sinus thrombosis (CVST) is a relatively rare cerebrovascular condition which accounts for 0.5% of all strokes. Risk of CVST has been documented in patients with numerous conditions including central nervous system infections, however, Japanese encephalitis (JE, epidemic encephalitis type B) with CVST has not been reported previously. CASE PRESENTATION: Here, we present a case of JE with CVST in a 17-year-old man. On admission, the patient was initially diagnosed as intracranial infection, and soon after, brain magnetic resonance (MR) imaging (MRI) and MR Venography (MRV) confirmed the diagnosis of CVST. Moreover, the blood JE-specific IgM antibody which proved weakly positive at first, turned positive one week later. Consequently, our patient was diagnosed as CVST accompanied by JE. Anticoagulant and anti-infective therapy were initiated, which eventually lead to gradual recovery of the patient. CONCLUSIONS: To our knowledge, this is the first case report of CVST associated with JE. MRI and MRV represent a prime method for the diagnosis of CVST, while the positivity of JE virus IgM antibody, especially increased antibody levels within a short period, is of great significance to diagnose JE. The early diagnosis and timely treatment of this potentially lethal condition would improve its prognosis significantly.