Magnesium exposure increases hip fracture risks in patients with chronic kidney disease: a population-based nested case-control study.

This population-based study demonstrates a strong link between Mg-containing antacid exposure and hip fracture risk in nondialysis CKD and dialysis patients. As an Mg-containing antacid, MgO is also commonly used as a stool softener, which can be effortlessly replaced by other laxatives in CKD patients to maintain bone health. PURPOSE: Bone fracture is a severe complication in chronic kidney disease (CKD) patients, leading to disability and reduced survival. In CKD patients, blood magnesium (Mg) concentrations are usually above the normal range due to reduced kidney excretion of Mg. The present study examines the association between Mg-containing antacid exposure and the risk of hip fracture of CKD patients. METHODS: In this nationwide nested case-control study, we enrolled 44,062 CKD patients with hip fracture and 44,062 CKD matched controls, among which the mean age was 77.1 years old, and 87.9% was nondialysis CKD. RESULTS: As compared to non-users, Mg-containing antacid users were significantly more likely to experience hip fracture (adjusted odds ratio (OR) 1.36, 95% CI, 1.32 to 1.41; p < 0.001). Subgroup analysis showed that such risk exists in both nondialysis CKD patients and long-term dialysis patients. In contrast, aluminum or calcium-containing-antacid use did not reveal such association. Next, we examined the influence of Mg-containing antacid dosage on hip fracture risk, the adjusted ORs in the first quartile (Q1), Q2, Q3, and Q4 were 1.20 (95% CI, 1.15 to 1.25; p < 0.001), 1.35 (95% CI, 1.30 to 1.41; p < 0.001), 1.49 (95% CI, 1.43 to 1.56; p < 0.001), and 1.54 (95% CI, 1.47 to 1.61; p < 0.001), respectively, showing that such risk exists regardless of the antacid dosage. A receiver operating characteristic curve analysis demonstrated that the best cutoff value of the exposed Mg dose to discriminate the hip fracture is 532 mEq during the follow-up period. CONCLUSION: This population-based study demonstrates a strong link between Mg-containing antacid exposure and the hip fracture risk in both nondialysis CKD and dialysis patients.

OTX1 is a novel regulator of proliferation, migration, invasion and apoptosis in lung adenocarcinoma.

OBJECTIVE: Orthodenticle Homeobox 1 (OTX1) has been found to be closely related to the development of several human tumours. However, the function and underlying molecular mechanisms of OTX1 in non-small cell lung cancer (NSCLC) are unclear. This research was performed to investigate the effects of downregulating OTX1 gene expression on the proliferation, migration, invasion, cell cycle and apoptosis of human NSCLC cell lines. PATIENTS AND METHODS: Cultured NCI-H292 and XWLC cells were transfected with control small interfering RNA (siNC) or experimental siRNA (siOTX1). The mRNA levels were detected using a quantitative real-time PCR (RT-qPCR) assay. A Cell Counting Kit-8 (CCK-8) and a Real Time Cell Analyzer (RTCA) were used to determine cell activity. The RTCA and transwell chambers were used to assess cell migration and invasion. In addition, cell cycle progression and apoptosis were measured using flow cytometry, and the expression levels of key signalling pathway proteins were examined by Western blotting. RESULTS: The results revealed that compared with the control group, the experimental group exhibited significantly decreased cell activity (***p<0.001), significantly decreased migration and invasion abilities (***p<0.001), and cell cycle arrest in G2/M phase (*p<0.05). However, the number of apoptotic cells was higher in the experimental group than in the control group (*p<0.05). The Western blotting results were consistent with the functional experiment results. CONCLUSIONS: Silencing the OTX1 gene suppressed the proliferation, migration and invasion of NCI-H292 and XWLC cells, impeded the cell cycle transition from G2 to M phase, and accelerated apoptosis, revealing OTX1, a regulator of NSCLC, as a potential new therapeutic target.

TRIM59 attenuates inflammation and apoptosis caused by myocardial ischemia reperfusion injury by activating the PI3K/Akt signaling pathway.

The article "TRIM59 attenuates inflammation and apoptosis caused by myocardial ischemia reperfusion injury by activating the PI3K/Akt signaling pathway, Z.-Q. Lv, C.-Y. Yang, Q.-S. Xing, published in Eur Rev Med Pharmacol Sci 2020; 24(7): 4005-4015. DOI: 10.26355/eurrev_202004_20870. PMID: 32329876" has been withdrawn from the authors. The Publisher apologizes for any inconvenience this may cause.

TRIM59 attenuates inflammation and apoptosis caused by myocardial ischemia reperfusion injury by activating the PI3K/Akt signaling pathway.

OBJECTIVE: Myocardial ischemia reperfusion injury (MIRI) is a common factor in heart-related diseases. The aim of this study was to explore the effect of TRIM59 gene on MIRI and its mechanism. MATERIALS AND METHODS: Rats were used to construct MIRI models, and TRIM59 gene was overexpressed in myocardium by Entranster technique to detect the effects of TRIM59 on myocardial oxidative stress, myocardial injury, and ATPase. In addition, rat myocardial H9c2 cells were cultured, and a hypoxia-reoxygenation model of H9c2 cells was constructed to detect the effect of TRIM59 overexpression on the inflammation and apoptosis of H9c2 cells. Finally, the PI3K/Akt signaling pathway inhibitor LY294002 was used to study the effect of TRIM59 on the PI3K/Akt signaling pathway. RESULTS: Overexpression of TRIM59 in vivo effectively reduced the expressions of MDA, CK, and LDH, and increased the expression of SOD and the activity of Na+-K+-ATPase and Ca2+-Mg2+-ATPase. In addition, overexpression of TRIM59 in H9c2 cells significantly reduced the expression of inflammatory cytokines (IL-1ß, IL-6, and TNF-α) and oxidative stress (ROS) levels. TRIM59 also significantly increased the activity of PI3K/Akt signaling pathway and promoted the phosphorylation of Akt. CONCLUSIONS: TRIM59 reduces the level of inflammation and apoptosis of myocardial cells caused by MIRI by activating the PI3K/Akt signaling pathway, thereby reducing myocardial injury.

CircRNA_100876 promote proliferation and metastasis of breast cancer cells through adsorbing microRNA-361-3p in a sponge form.

OBJECTIVE: This study was designed to investigate the expression level of circRNA_100876 in breast cancer (BC) tissues or cells, and to further explore whether it can promote cell metastasis and proliferative capacity via targeting microRNA- 361-3 p. PATIENTS AND METHODS: Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was performed to examine the expression of circRNA_100876 in 50 pairs of BC tissue specimens and corresponding adjacent ones, and the correlation between circRNA_100876 expression and prognosis of patients with BC was analyzed. Meanwhile, qRT-PCR was further performed to verify circRNA_100876 level in BC cell lines. In addition, circRNA_100876 knockdown model was constructed using lentivirus and transfected in BC cells. Subsequently, the impact of circRNA_100876 on BC cell function was analyzed using Cell Counting Kit-8 (CCK-8), transwell and clone formation assays. The interplay between circRNA_100876 and microRNA- 361-3 p was verified using the Luciferase reporter gene assay and cell reverse experiment. RESULTS: QRT-PCR results showed that circRNA_100876 level in BC tissues was conspicuously higher than that in the adjacent tissues, and the patients with distant metastasis had higher expression than those without. Moreover, patients with a high expression of circRNA_100876 had a relatively lower overall survival rate. Compared with the NC group, the cell proliferation and invasion ability of circRNA_100876 knockdown group was conspicuously decreased. QRT-PCR revealed that microRNA-361-3p and circRNA_100876 showed a negative correlation in the expression level of genes in BC tissues. In addition, the results of the Luciferase reporter gene assay confirmed that circRNA_100876 can be targeted by microRNA-361-3p through their binding site. CONCLUSIONS: High expression of circRNA_100876 is conspicuously positively relevant to poor prognosis of BC patients. Additionally, circRNA_100876 is able to promote BC metastasis as well as proliferative capacity by modulating microRNA-361-3p expression.

Validation of a nomogram to predict the risk of cancer in patients with intraductal papillary mucinous neoplasm and main duct dilatation of 10 mm or less.

BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) is premalignant pancreatic lesion. International guidelines offer limited predictors of individual risk. A nomogram to predict individual IPMN malignancy risk was released, with good diagnostic performance based on a large cohort of Asian patients with IPMN. The present study validated a nomogram to predict malignancy risk and invasiveness of IPMN using both Eastern and Western cohorts. METHODS: Clinicopathological and radiological data from patients who underwent pancreatic resection for IPMN at four centres each in Eastern and Western countries were collected. After excluding patients with missing data for at least one malignancy predictor in the nomogram (main pancreatic duct diameter, cyst size, presence of mural nodule, serum carcinoembryonic antigen and carbohydrate antigen (CA) 19-9 levels, and age). RESULTS: In total, data from 393 patients who fit the criteria were analysed, of whom 265 were from Eastern and 128 from Western institutions. Although mean age, sex, log value of serum CA19-9 level, tumour location, main duct diameter, cyst size and presence of mural nodule differed between the Korean/Japanese, Eastern and Western cohorts, rates of malignancy and invasive cancer did not differ significantly. Areas under the receiver operating characteristic (ROC) curve values for the nomogram predicting malignancy were 0·745 for Eastern, 0·856 for Western and 0·776 for combined cohorts; respective values for the nomogram predicting invasiveness were 0·736, 0·891 and 0·788. CONCLUSIONS: External validation of the nomogram showed good performance in predicting cancer in both Eastern and Western patients with IPMN lesions.

ANTECEDENTES: La neoplasia mucinosa papilar intraductal (intraductal papillary mucinous neoplasm, IPMN) es una lesión pancreática premaligna. Las guías internacionales incluyen un número limitado de factores predictivos de riesgo individual. Para predecir el riesgo individual de malignidad del IPMN se ha propuesto un nomograma con un buen rendimiento diagnóstico, basado en una gran cohorte de pacientes asiáticos con IPMN. Este estudio validó el nomograma para predecir el riesgo de cáncer y de invasión de la IPMN utilizando cohortes tanto orientales como occidentales. MÉTODOS: Se recogieron datos clínico-patológicos y radiológicos de pacientes en los que se realizó una resección de páncreas por IPMN en 4 centros en países orientales y en 4 centros de países occidentales. Se excluyeron los pacientes en los que en el nomograma faltaba ≥ 1 factor(es) predictivo(s) de malignidad (diámetro del conducto pancreático principal, tamaño del quiste, presencia de nódulo mural, niveles séricos de CEA y CA19-9, y edad). RESULTADOS: En total, se analizaron datos de 393 pacientes que cumplían con los criterios de inclusión, de los cuales 265 eran de centros orientales y 128 de centros occidentales. Aunque la edad media, el sexo, el valor logarítmico del nivel sérico de CA19-9, la localización del tumor, el diámetro del conducto principal, el tamaño del quiste y la presencia de un nódulo mural difirieron entre las cohortes de Corea/Japón y las cohortes oriental y occidental, las tasas de malignidad y de cáncer invasivo no fueron significativamente diferentes. Las áreas bajo la curva operativa del receptor (area under the receiver operating curve, AUC) que mostró el nomograma para predecir la malignidad fueron: cohorte oriental: 0,745; cohorte occidental: 0,856 y cohortes combinadas: 0,776; y para predecir la invasión tumoral fueron: cohorte oriental: 0,736; cohorte occidental: 0,891, y cohortes combinadas: 0,788. CONCLUSIÓN: La validación externa del nomograma mostró un buen rendimiento en la predicción de cáncer, tanto en pacientes orientales como occidentales con lesiones IPMN.

Association between lactic acid sting test scores, self-assessed sensitive skin scores and biophysical properties in Chinese females.

BACKGROUND: Lactic acid sting test (LAST) is a classical method to identify sensitive skin. However, some subjects with self-perceived sensitive skin are negative for LAST. OBJECTIVE: To determine whether LAST scores are associated with specific phenotype of sensitive skin. METHODS: A total of 292 subjects with self-perceived sensitive skin were enrolled in this study. The Sensitive Scale was used to evaluate the severity of burning, stinging, itching, tautness, erythema and scaling based on 0-10 scale scores. In addition to the assessment of LAST scores, epidermal biophysical properties were measured using an MPA system. RESULTS: The Sensitive Scale scores of stinging, itching, tautness and scaling were significantly different between the LAST-positive and -negative groups. However, burning and erythema scores did not differ between the LAST-positive and -negative groups. LAST scores were positively correlated with the Sensitive Scale scores for stinging, itching, tautness and scaling, but not for burning and erythema scores. Moreover, LAST scores negatively correlated with stratum corneum hydration, but positively with transepidermal water loss (TEWL) rates. CONCLUSIONS: Lactic acid sting test scores positively correlated with TEWL rates. LAST scores could be used to identify subjects with sensitive skin characterized mainly by stinging and itching, but not those mainly by burning and erythema.

CONTEXTE: Le test de la piqûre d'acide lactique (LAST) est une méthode classique pour identifier les peaux sensibles. Cependant, certaines personnes s'évaluant ayant une peau sensible sont négatifs au test LAST. OBJECTIF: Déterminer si le score du LAST est associé à un phénotype spécifique de peau sensible. MÉTHODES: Au total, 292 personnes s'évaluant ayant une peau sensible ont été inclus dans cette étude. L'échelle de sensibilité a été utilisée pour évaluer la sévérité de la brûlure, du picotements, de la démangeaison, de la tension, de l'érythème et des desquamations basée sur une échelle de 0-10. En plus de l'évaluation du score LAST, les propriétés biophysiques épidermiques ont été mesurées à l'aide d'un système MPA. RÉSULTATS: Les scores de l'échelle de sensibilité pour le picotement, les démangeaisons, la tension et la desquamation étaient significativement différents entre la groupe LAST positif et celle du LAST négatif. Cependant, les scores de la brûlure et de l'érythème n'étaient pas différents entre les deux groupes. Le score LAST était positivement corrélé avec les scores de l'échelle de sensibilité du picotement, des démangeaisons, de la tension et des desquamations, mais pas pour la brûlure et l'érythème. En plus, les scores LAST étaient négativement corrélés avec l'hydratation du stratum corneum, mais positivement corrélés avec le taux de perte en eau transépidermique (TEWL). CONCLUSIONS: Les scores LAST étaient corrélés positivement avec le taux de perte en eau transépidermique. Les scores LAST pourraient être utilisés pour identifier les personnes avec la peau sensible caractérisée principalement le picotement et les démangeaisons, mais pas la brûlure et l'érythème.

Hyperbaric oxygen inhibits the HMGB1/RAGE signaling pathway by upregulating Mir-107 expression in human osteoarthritic chondrocytes.

OBJECTIVE: MicroRNA (miRNA)107 expression is downregulated but high mobility group box 1 (HMGB-1), Toll-like receptors (TLRs), and receptor for advanced glycation end products (RAGE) are upregulated in osteoarthritic (OA) cartilage. We investigated mir-107/HMGB-1 signaling in OA after hyperbaric oxygen (HBO) treatment. DESIGN: MiR-107 mimic was transfected and the HMGB-1 was analyzed in OA chondrocytes. MiRNA targets were identified using bioinformatics and a luciferase reporter assay. After HBO treatment, the mRNA or protein levels of HMGB-1, RAGE, TLR2, TLR4, and inducible nitric oxide (NO) synthase (iNOS) and phosphorylation of mitogen-activated protein kinase (MAPK) were evaluated. The secreted HMGB-1 and matrix metalloproteases (MMPs) levels were quantified. Finally, we detected the HMGB-1 and iNOS expression in rabbit cartilage defects. RESULTS: Overexpression of miR-107 suppressed HMGB-1 expression in OA chondrocytes. The 3'UTR of HMGB-1 mRNA contained a 'seed-matched-sequence' for miR-107. MiR-107 was induced by HBO and a marked suppression of HMGB-1 was observed simultaneously in OA chondrocytes. Knockdown of miR-107 upregulated HMGB-1 expression in hyperoxic cells. HBO downregulated the mRNA and protein expression of HMGB-1, RAGE, TLR2, TLR4, and iNOS, and the secretion of HMGB-1. HBO decreased the nuclear translocation of nuclear factor (NF)-κB, downregulated the phosphorylation of MAPK, and significantly decreased the secretion of MMPs. Morphological and immunohistochemical observation demonstrated that HBO markedly enhanced cartilage repair and the area stained positive for HMGB-1 and iNOS tended to be lower in the HBO group. CONCLUSIONS: HBO inhibits HMGB-1/RAGE signaling related pathways by upregulating miR-107 expression in human OA chondrocytes.

Relationship between fasting plasma glucose and incidence of diabetes in children and adolescents.

AIM: To investigate the appropriate fasting plasma glucose threshold by which to define prediabetes in children and adolescents, based on its ability to predict incident paediatric diabetes. METHODS: In a nationwide survey of diabetes and renal disease conducted between 1992 and 2000 in all school-aged children in Taiwan, those with abnormal results in repeated urine tests received further physical examination and blood tests. Students who had blood tests for at least two time points were selected for the present study (N = 12 119). The incidence of paediatric diabetes, adjusted hazard ratio and predictive power of fasting plasma glucose were analysed. RESULTS: The incidence of paediatric diabetes increased with increasing fasting plasma glucose levels. Groups with fasting plasma glucose >5.6 mmol/l had a higher adjusted hazard ratio. The adjusted hazard ratio of incident diabetes for participants with higher fasting plasma glucose rose continuously when using a higher threshold for fasting plasma glucose. The area under the receiver-operating characteristic curve for fasting plasma glucose was 0.628 for predicting paediatric diabetes. The association between fasting plasma glucose and incident paediatric diabetes and the area under the receiver-operating characteristic curve were similar in boys and girls and were higher in the age group 12-18 years. According to receiver-operating characteristic curve analysis, the optimal thresholds, sensitivity and specificity were 4.75 mmol/l, 65% and 51%, respectively, for those aged 6-11 years and 5.19 mmol/l, 60% and 73%, respectively, for those aged 12-18 years. CONCLUSION: Fasting plasma glucose is associated with the incidence of paediatric diabetes. The results of the present study can be used as reference data to suggest a cut-off value to define paediatric prediabetes.

Randomized trial of oral versus enteral feeding for patients with postoperative pancreatic fistula after pancreatoduodenectomy.

BACKGROUND: Whether continued oral feeding may have a negative impact on healing of postoperative pancreatic fistula (POPF) is unclear. The aim was to test the hypothesis that oral feeding is non-inferior to enteral feeding in closure of POPF after pancreatoduodenectomy, and to clarify the effects of oral feeding on the duration and grade of POPF. METHODS: This multicentre, non-inferiority randomized trial of oral or enteral feeding of patients with POPF after pancreatoduodenectomy recruited patients between August 2013 and September 2016. The primary efficacy outcome was the 30-day fistula closure rate. The prespecified non-inferiority margin was 15 per cent. Other efficacy outcomes included grade of fistula, and hospital stay and costs. RESULTS: A total of 114 patients were included, and received oral (57) or enteral (57) feeding. The two groups were balanced in baseline characteristics and no patient was lost to follow-up. In intention-to-treat analysis, oral feeding was non-inferior to enteral feeding in terms of 30-day fistula closure rate (88 versus 89 per cent respectively; difference -1·8 per cent, lower limit of 95 per cent c.i. -14·4 per cent; P = 0·020 for non-inferiority). Compared with enteral feeding, oral feeding significantly reduced hospital costs and duration of stay. No significant differences were noted in the number of patients whose POPF evolved into grade B/C, or other outcomes. CONCLUSION: Oral feeding in patients with POPF after pancreatoduodenectomy did not increase the duration or grade of POPF, and was associated with reduced duration of stay and hospital costs. Registration number: NCT01755260 (http://www.clinicaltrials.gov).

Ptprj-as1 mediates inflammatory injury after intracerebral hemorrhage by activating NF-κB pathway.

OBJECTIVE: We aimed at investigating the expression of long non-coding RNA (lncRNA) Ptprj-as1 and the role of lncRNAPtprj-as1 in inflammatory cells after intracerebral hemorrhage and its potential mechanism. MATERIALS AND METHODS: The rat model of intracerebral hemorrhage was established. Expressions of Ptprj-as1 and inflammatory cytokines in inflammatory cells were detected by quantitative Real-time PCR (qRT-PCR). After BV2 cells were transfected with lentivirus, cell proliferation, migrative ability and apoptosis were detected by cell counting kit-8 (CCK-8) assay, transwell chamber and flow cytometry, respectively. Immunofluorescence was used to explore the ratio of M1 and M2 glial cells. The detection of tumor necrosis factor alpha (TNF-α) expression was performed using enzyme-linked immunosorbent assay (ELISA). Moreover, the expressions of key genes in NF-κB pathway were evaluated using Western blot. RESULTS: Ptprj-as1 was highly expressed in inflammatory tissues caused by intracerebral hemorrhage (ICH). Overexpressed Ptprj-as1 promoted the migration of BV2 cells and expression levels of inflammatory cytokines such as TNF-α, interleukin-1ß (IL-1ß), interleukin-6 (IL-6), iNOS and NO. Meanwhile, Ptprj-as1 enhanced the proportion of M1 glial cells, the mechanism of which might be related to the activation of NF-κB pathway. CONCLUSIONS: Ptprj-as1 activates NF-κB pathway in microglia and promotes the secretion of inflammatory cytokines, which is involved in inflammatory injury caused by intracerebral hemorrhage.

Isolated Crystalloid Podocytopathy With Focal Segmental Glomerulosclerosis in Renal Allograft: An Unusual Presentation of Post-Transplant Monoclonal Gammopathy of Renal Significance-A Case Report.

BACKGROUND: Monoclonal gammopathy of renal significance denotes a spectrum of hematologic disorders that cause direct or indirect renal damage. CASE PRESENTATION: A 51-year-old man had received a living-donor kidney transplant from his wife in 2008. He had gradual increased proteinuria 4 years later. His renal biopsy results revealed cytoplasmic crystalloid inclusions in the podocytes. No crystalloid inclusion was found in other renal cells. Despite that immunofluorescent examination failed to show light-chain deposition, the serum immuno-electrophoresis revealed monoclonal immunoglobulin-Gκ. Bone marrow biopsy showed interstitial infiltration of plasma cells of approximately 10%. A follow-up renal biopsy was performed in 2016. Light microscopy showed focal segmental glomerulosclerosis. The immunofluorescent examination remained negative for light chain, but κ-light chain could be demonstrated after antigen retrieval. Similar to previous biopsy results, cytoplasmic inclusions were found only in podocytes without involving other renal cells. CONCLUSIONS: To the best of our knowledge, this is the first report of monoclonal gammopathy of renal significance presenting as isolated crystalloid podocytopathy in the allograft kidney. The mechanism of preferential podocyte deposition of crystalloid immunoglobulin remains unclear. The inherent features of crystalloid podocytopathy may mislead the pathologic diagnosis.

Analysis of mechanism of PM2.5 and house dust mite antigen Der p1 in attack stage of child asthma.

OBJECTIVE: We analyzed the influence of PM2.5 and house dust mite antigen Der p1 on the treatment of child asthma attack. PATIENTS AND METHODS: A total of 96 children with asthma attack were included into the study. The patients were randomly divided into the PM2.5 group, the house dust mite antigen group, the synergistic group and the control group (n= 24 in each group). RESULTS: The PM2.5 concentration in the PM2.5 group was twice higher than standard level (≤ the average value of PM2.5 in local air). All cases were given with same treatment, and the treatment effects were compared and analyzed. It was found that the asthma control rate in the control group was significantly higher than that in the PM2.5 group and the house dust mite antigen group, and the synergistic group was the lowest. The control time in the synergistic group was significantly longest, followed by the PM2.5 group and the house dust mite antigen group, and the control group was significantly short (p<0.05). After the intervention, the FVC, FEV1, and PEF levels were all increased. Those in control group were significantly higher than those of PM2.5 group and Dermatophagoides pteronyssinus group. Indicators in the collaborative group were the lowest. Differences were statistically significant (p<0.05). The differences in the PM2.5 group and Dermatophagoides pteronyssinus group were not statistically significant. The contents of serum IL-25, TSLP, and malondialdehyde after treatment of the control group significantly lowered while the other three groups showed a significant higher (p<0.05). CONCLUSIONS: The PM2.5 and house dust mite antigen Der p1 can influence the treating effects of child asthma attack by an inflammatory reaction and oxidative stress.

Protein disulfide isomerase a4 acts as a novel regulator of cancer growth through the procaspase pathway.

Protein disulfide isomerase a4 (PDIA4) is implicated in the growth and death of tumor cells; however, its molecular mechanism and therapeutic potential in cancer are unclear. Here, we found that PDIA4 expression was upregulated in a variety of tumor cell lines and human lung adenocarcinoma tissues. Knockdown and overexpression of PDIA4 in tumor cells showed that PDIA4 facilitated cell growth via the reduction of caspases 3 and 7 activity. Consistently, Lewis lung carcinoma cells overexpressing PDIA4 grew faster than did parental cells in tumor-bearing mice, as shown by a reduced survival rate, increased tumor size and metastasis, and decreased cell death and caspases 3 and 7 activity. PDIA4 knockdown resulted in opposite outcomes. Moreover, results obtained in mice with spontaneous hepatoma indicated that PDIA4 deficiency significantly reduced hepatic tumorigenesis and cyst formation and increased mouse survival, tumor death, and caspases 3 and 7 activity. Mechanistic studies illustrated that PDIA4 negatively regulated tumor cell death by inhibiting degradation and activation of procaspases 3 and 7 via their mutual interaction in a CGHC-dependent manner. Finally, we found that 1,2-dihydroxytrideca-5,7,9,11-tetrayne, a PDIA4 inhibitor, reduced tumor development via enhancement of caspase-mediated cell death in TSA tumor-bearing mice. These findings characterize PDIA4 as a negative regulator of cancer cell apoptosis and suggest that PDIA4 is a potential therapeutic target for cancer.

ADAMTS and ADAM metalloproteinases in osteoarthritis - looking beyond the 'usual suspects'.

INTRODUCTION: Matrix metalloproteinases (MMPs) and 'aggrecanase' a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) are well established to play key roles in osteoarthritis (OA) through degradation of extracellular matrix (ECM) type II collagen and aggrecan, and are thus potential targets for development of OA therapies. OBJECTIVE: This paper aims to provide a comprehensive review of the expression and potential roles of other, lesser-known ADAMTSs and related adamalysins (or a disintegrin and metalloproteinases (ADAMs)) in cartilage, with a view to identifying potentially protective or homeostatic metalloproteinases in the joint and informing consequent selective inhibitor design. DESIGN: A comprehensive literature search was performed using PubMed terms 'osteoarthritis' and 'ADAMTS' or 'ADAM'. RESULTS: Several ADAMTSs and ADAMs were identified as having reportedly increased expression in OA. These include enzymes likely to play roles in cartilage matrix anabolism (e.g., the procollagen N-proteinases ADAMTS-2, ADAMTS-3 and ADAMTS-14), chondrocyte differentiation and proliferation (e.g., ADAM9, ADAM10, ADAM12), as well as enzymes contributing to cartilage catabolism (e.g., Cartilage oligomeric protein (COMP)-degrading ADAMTS-7 and ADAMTS-12). CONCLUSIONS: In addition to the well-characterised MMPs, ADAMTS-4 and ADAMTS-5, many other ADAMTSs and ADAMs are expressed in cartilage and several show significantly altered expression in OA. Studies aimed at elucidating the pathophysiological roles of these enzymes in cartilage will contribute to our understanding of OA pathogenesis and enable design of targeted inhibitors that effectively target metalloproteinase-mediated cartilage degradation while sparing cartilage repair pathways.

Long-term risk of stroke in type 2 diabetes patients with diabetic ketoacidosis: A population-based, propensity score-matched, longitudinal follow-up study.

AIM: To investigate the long-term risk of stroke in type 2 diabetes (T2D) patients with previous episodes of diabetic ketoacidosis (DKA). METHODS: This retrospective nationwide population-based cohort study was conducted using Taiwan's National Health Insurance database. Claims data from 2000 to 2002 were extracted for 3572 T2D patients with DKA and 7144 controls matched for age, gender, diabetes complications severity index, frequency of clinical visits and baseline comorbidities. Patients with type 1 diabetes (T1D), identified by glucagon C-peptide stimulation or glutamic acid decarboxylase (GAD) antibody blood tests and possession of a catastrophic illness certificate were excluded. All patients were tracked until a new stroke diagnosis, death or the end of 2011. RESULTS: Of the 3572 selected patients, 270 with DKA and 404 of the 7144 controls were diagnosed with a new stroke, giving an incidence rate ratio (IRR) of 1.56 (95% CI: 1.34-1.82; P<0.0001). DKA patients had a higher risk of ischaemic stroke than those without DKA (IRR: 1.62, 95% CI: 1.34-1.96; P<0.0001), and DKA patients with hypertension and hyperlipidaemia were at even greater risk of stroke. Also, DKA patients were at particular risk for stroke during the first half-year following DKA diagnosis. After adjusting for patient characteristics and comorbidities, these patients were 1.55 times more likely to have a stroke than those without DKA (95% CI: 1.332-1.813, P<0.0001). CONCLUSION: T2D patients with previous DKA have a higher risk of stroke, especially ischaemic strokes.

Landing strategies focusing on the control of tibial rotation in the initial contact period of one-leg forward hops.

Anterior cruciate ligament (ACL) reconstruction (ACLR) surgeries successfully restore anterior tibial translation but not tibial rotation. This study aimed to explore landing strategies focusing on the control of tibial rotation at landing when the ACL is most vulnerable. Three groups of male subjects (50 ACLRs, 26 basketball players, and 31 controls) participated in one-leg forward hop tests for determining the tibial rotatory landing strategies adopted during the initial landing phase. The differences in knee kinematics and muscle activities between internal and external tibial rotatory (ITR, ETR) landing strategies were examined. A higher proportion of basketball players (34.6%) were found to adopt ITR strategies (controls: 6.5%), exhibiting significantly greater hopping distance and knee strength. After adjusting for hopping distance, subjects adopting ITR strategies were found to hop faster with straighter knees at foot contact and with greater ITR and less knee adduction angular displacement during the initial landing phase. However, significantly greater angular displacement in knee flexion, greater medial hamstring activities, and greater co-contraction index of hamstrings and medial knee muscles were also found during initial landing. Our results support the importance of the recruitments of medial hamstrings or the local co-contraction in assisting the rotatory control of the knee during initial landing for avoiding ACL injuries.

Responses to thermal and salinity stress in wild and farmed Pacific oysters Crassostrea gigas.

The Pacific oyster Crassostrea gigas was introduced from Japan to many countries in the world for oyster farming, resulting in the establishment of wild populations in intertidal zones and resource competition with local faunas. This study examined physiological responses of wild oysters and farmed oysters to thermal (15°C, 25°C, 37°C and 44°C) and salinity stress (39, 50 and 60ppt). The wild oysters produced more 72kDa heat shock proteins when the temperature increased from 15°C to 25°C and 37°C and the salinity increased from 39 to 50 and 60ppt. However, the amount of 69kDa heat shock protein was similar between farmed and wild oysters when the temperature increased from 15°C to the sublethal temperature 37°C, but it was lower in wild oysters than in farmed oysters when the temperature increased from 15°C to the lethal temperature 44°C. In the tissues, wild oysters used more glycogen to promote metabolic activities by increasing the level of AEC (adenylate energy charge). The results suggest that farmed oysters might have limited ability to cope with heat stress due to low energy reserve and glycolysis activity for HSP synthesis. This study provides experimental evidence on differential responses between wild and farmed oysters to temperature and salinity changes, leading to a better understanding on the pattern of distribution for invading oyster species in the marine environment and the adaptation of marine invertebrates to the threat of climate change.

Factors associated with subsequent nontuberculous mycobacterial lung disease in patients with a single sputum isolate on initial examination.

Very few studies have focused on the outcome and management of patients with a single sputum isolate of nontuberculous mycobacterium (NTM) on initial examination. Patients with a single isolate of Mycobacterium avium complex (MAC), M. chelonae-abscessus, M. kansasii, or M. fortuitum from at least three sputum samples collected within 1 month were retrospectively identified. Those with follow-up sputum samples within 1 year were included in the analysis. Among the 202 patients included, M. fortuitum (n = 71, 35.1%) and MAC (n = 70, 34.7%) were the most common NTM species isolated, followed by M. chelonae-abscessus (n = 40, 19.8%) and M. kansasii (n = 21, 10.4%). The mean clinical follow-up period was 26.2 months. Forty-four patients (21.8%) had subsequent positive cultures of the same NTM species, while eight (4.0%) had bronchiectasis and developed NTM lung disease (NTM-LD). Neither patients without bronchiectasis nor those with M. fortuitum subsequently developed NTM lung disease. Among bronchiectatic patients with NTM other than M. fortuitum, age ≤65 years (p 0.006, OR 32.13), malignancy (p 0.048, OR 14.35), and initial radiographic score >2 (p 0.027, OR 20.06) were associated with subsequent NTM-LD. In all of the NTM patients, bronchiectasis (p <0.001, OR 5.46) and age ≤65 years (p 0.002, OR 3.29) were significantly associated with subsequent positive NTM culture. In patients with a single isolation of NTM from respiratory specimens, the presence of bronchiectasis and younger age indicates higher risk of subsequent culture-positivity and NTM-LD. Single isolation of M. fortuitum is of little clinical significance. Other patients with NTM, younger age, and more severe radiographic pulmonary lesion also warrant further attention.

Strontium ranelate related Stevens-Johnson syndrome: a case report.

Strontium ranelate is a relatively new medication with good safety profile for the treatment of postmenopausal osteoporosis. However, severe cutaneous adverse drug reactions have been reported, such as drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). We report the case of a 70-year-old woman who developed multiple itching erythematous macules and plaques about 1 month after beginning strontium ranelate medication. The cutaneous lesions progressed over the entire body with severe oral and ocular mucosa involvement. Probable mild SJS was diagnosed, compatible with the pathology findings, and strontium ranelate was discontinued immediately. Systemic methylprednisolone was administered to suppress the overactive immune system and ameliorate cutaneous symptoms. With early recognition and prompt treatment, the patient's prognosis was good.