Glucose-Lowering Agents and the Risk of Hypoglycemia: a Real-world Study.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1RA) are increasingly recommended in type 2 diabetes. Hypoglycemia is a serious adverse effect of glucose-lowering agents. Real-world comparison of hypoglycemic risks among SGLT2i, GLP1RA, dipeptidyl peptidase-4 inhibitor (DPP4i), and sulfonylureas is limited. OBJECTIVE: Quantify the risk of hypoglycemia associated with SGLT2i, GLP1RA, DPP4i, and sulfonylureas (the primary reference group). DESIGN: Retrospective cohort study conducted using electronic health records from Geisinger Health, Pennsylvania (2015-2019). PARTICIPANTS: A total of 10,713 patients with type 2 diabetes who newly received SGLT2i (n=1487), GLP1RA (n=1241), DPP4i (n=2938), or sulfonylureas (n=5047). Propensity score-based inverse probability of treatment weighting was used to balance patient characteristics across four treatment groups simultaneously. MAIN MEASURES: Hypoglycemia was defined as capillary blood glucose <70 mg/dL; severe hypoglycemia was defined as capillary blood glucose <54 mg/dL. A weighted Cox proportional hazards regression model was used to estimate the risk of outcomes for pairwise comparisons of SGTL2i, GLP1RA, DPP4i, and sulfonylureas. KEY RESULTS: Median follow-up was 21.3 months. Compared with sulfonylureas, the risk of hypoglycemia was lower with SGLT2i (hazard ratio 0.60 [95% confidence interval 0.48-0.75]), GLP1RA (0.49 [0.34-0.69]), and DPP4i (0.60 [0.48-0.78]). The risk of severe hypoglycemia was also lower with SGLT2i (0.43 [0.35-0.74]), GLP1RA (0.50 [0.28-0.87]), and DPP4i (0.64 [0.46-0.90]) compared to sulfonylureas. The risks of hypoglycemia and severe hypoglycemia were similar across the SGLT2i, GLP1RA, and DPP4i groups (SGLT2i vs. DPP4i: 0.95 [0.67-1.34]; GLP1RA vs. DPP4i: 0.81 [0.55-1.19]; SGLT2i vs. GLP1RA: 1.17 [0.76-1.82] for hypoglycemia). CONCLUSION: SGLT2i and GLP1RA confer a lower risk of hypoglycemia compared with sulfonylureas and similar risk compared with DPP4i. Given the known cardiovascular benefits associated with SGLT2i and GL1PRA, our results suggesting the safety of SGLT2i and GL1PRA further support their use.

Trimethoprim-sulfamethoxazole and the risk of a hospital encounter with hyperkalemia: a matched population-based cohort study.

BACKGROUND: Trimethoprim-sulfamethoxazole (TMP-SMX) can cause hyperkalemia by reducing renal potassium excretion. We assessed the risk of hyperkalemia after initiating TMP-SMX versus amoxicillin and determined if this risk is modified by a patient's baseline kidney function [estimated glomerular filtration rate (eGFR)]. METHODS: We conducted a population-based cohort study in Ontario, Canada involving adults ≥66 years of age newly treated with TMP-SMX (n = 58 999) matched 1:1 with those newly treated with amoxicillin (2008-2020). The primary outcome was a hospital encounter with hyperkalemia defined by a laboratory serum potassium value ≥5.5 mmol/L within 14 days of antibiotic treatment. Secondary outcomes included a hospital encounter with acute kidney injury (AKI) and all-cause hospitalization. Risk ratios (RRs) were obtained using a modified Poisson regression. RESULTS: A hospital encounter with hyperkalemia occurred in 269/58 999 (0.46%) patients treated with TMP-SMX versus 80/58 999 (0.14%) in those treated with amoxicillin {RR 3.36 [95% confidence interval (CI) 2.62-4.31]}. The absolute risk of hyperkalemia in patients treated with TMP-SMX versus amoxicillin increased progressively with decreasing eGFR (risk difference of 0.12% for an eGFR ≥60 ml/min/1.73 m2, 0.42% for eGFR 45-59, 0.85% for eGFR 30-44 and 1.45% for eGFR <30; additive interaction P < .001). TMP-SMX versus amoxicillin was associated with a higher risk of a hospital encounter with AKI [RR 3.15 (95% CI 2.82-3.51)] and all-cause hospitalization [RR 1.43 (95% CI 1.34-1.53)]. CONCLUSIONS: The 14-day risk of a hospital encounter with hyperkalemia was higher in patients newly treated with TMP-SMX versus amoxicillin and the risk was highest in patients with a low eGFR.

Electron Temperature Measurements Using a Two-Filter Soft X-ray Array in VEST.

A multichannel soft X-ray (SXR) array has been developed to measure the electron temperature in the Versatile Experiment Spherical Torus (VEST). To estimate electron temperature using the two-filter method applied to SXR intensity, we designed a pinhole camera that has two photodiode arrays with different metallic filters. We also adopted a filter wheel and tested various filter parameters to find the optimal filter set. Through tests, the combination of aluminum and beryllium was found to be the most suitable for the current experimental conditions in VEST. The filtered SXR signals were acquired with a low-noise preamplifier, exhibiting sufficient signal-to-noise ratios for electron temperature estimation based on the intensity ratio of two signals obtained with different filters. The estimated electron temperature from the developed two-filter SXR array showed reasonably matched levels and consistent trends with Thomson scattering measurements. Error contribution from impurity line emission is also discussed.

Hepatitis A virus strains identified in jogaejeot associated with outbreaks in Seoul, South Korea.

Jogaejeot, seasoned Venerupis philippinarum, is a traditional Korean fermented food, and hepatitis A virus (HAV) can be transmitted through contaminated food, especially bivalve shellfish, causing acute gastroenteritis worldwide. Here, we carried out a phylogenetic analysis to identify and characterize HAV strains in jogaejeot samples associated with hepatitis A (HA) outbreaks in Seoul, South Korea, in 2019. The HAV strains were identified using blast and molecular analysis of the amplified HAV VP1-P2B genome region. The HAV strains identified in the five jogaejeot samples shared at least 99% sequence identity, were all classified as genotype IA and were most closely related to strains that are widespread in East Asia. These results support a link between the consumption of jogaejeot and the HA outbreaks observed in 2019 in Seoul. In addition, they indicate a need for more stringent enforcement of food safety regulations for the shellfish industry, especially against HAV, and the value of widespread vaccination.

Irisin promotes odontogenic differentiation and angiogenic potential in human dental pulp cells.

AIM: To determine whether irisin, a newly discovered myokine that links exercise-induced and metabolic homeostasis, is able to promote odontogenic differentiation and angiogenesis in human dental pulp cells (HDPCs). METHODOLOGY: Cell viability in the presence of irisin was measured. Real-time PCR and Western blot analysis were performed to evaluate the expression levels of irisin, odontogenic and angiogenic markers. The involvement of mitogen-activated protein kinase (MAPK) and the protein kinase B (Akt) signalling pathway was evaluated by Western blot. To evaluate mineralization nodule formation, alkaline phosphatase (ALP) staining and alizarin red S staining were performed. Scratch wound assays were performed to evaluate the effects of irisin on cell migration. The data were analysed using one-way analysis of variance (anova) followed by Tukey post hoc test and Student's t-test. Statistical significance was considered at P < 0.05. RESULTS: Irisin significantly promoted odontogenic differentiation as evidenced by formation of mineralized nodules, induction of ALP activity and upregulation of odontogenic and angiogenic markers (P < 0.05). Scratch wound assays revealed that irisin significantly increased migration of HDPCs (P < 0.05). Phosphorylation of both MAPK and Akt was increased by irisin. MAPK and Akt inhibitors inhibited mineralization, cell migration and the increased expression of odontogenic and angiogenic markers. CONCLUSIONS: Irisin promoted odontogenic differentiation and mineralization and has the potential for angiogenesis through activation of the MAPK and Akt signalling pathways in HDPCs.

Baby boy blue and mommy too! A rare case of methaemoglobinaemia presenting simultaneously in a mother-neonate pair.

Methaemoglobinaemia occurs when there is >1% methaemoglobin in erythrocytes. In an infant, they can present either congenitally or in an acquired form. We present a rare case of methaemoglobinaemia presenting simultaneously in a mother and infant pair. The mother and infant were discharged well on Day-4 post-delivery with both mother and baby recording oxygen saturation levels of 100%. On Day-7, during a routine clinic visit, they were incidentally found to be centrally cyanosed. There were no other abnormalities. On investigation, the methaemoglobin levels were elevated in the infant (23.9%) and mother (14.3%). Treatment with ascorbic acid normalised mother's methaemoglobin levels; but baby's levels remained high until the administration of oral methylene blue. Both baby and mother remained well and pink at last follow-up at 2 years 8 months of age. This case illustrates difficulties in ascertaining the cause of methaemoglobinaemia. Postdelivery, the mother-neonate pair were pink, and their haemoglobin electrophoresis were normal, hence it was unlikely to be congenital methaemoglobinaemia. The team could not identify any triggering factors for acquired methaemoglobinaemia. There was also the uncertainty of the necessity to treat the baby. This is because treatment is not without harmful effects and despite the high methaemoglobin levels, the infant was otherwise well. Only a single published paper recommended that high methaemoglobin levels must be treated, and the recommendation was not supported by evidence. Lessons learnt from our case are that neonates with methaemoglobinaemia can be safely treated with oral methylene blue, but more research is needed on the benefitrisk profile of treatment.

Role of tumour location and surgical extent on prognosis in T2 gallbladder cancer: an international multicentre study.

BACKGROUND: In gallbladder cancer, stage T2 is subdivided by tumour location into lesions on the peritoneal side (T2a) or hepatic side (T2b). For tumours on the peritoneal side (T2a), it has been suggested that liver resection may be omitted without compromising the prognosis. However, data to validate this argument are lacking. This study aimed to investigate the prognostic value of tumour location in T2 gallbladder cancer, and to clarify the adequate extent of surgical resection. METHODS: Clinical data from patients who underwent surgery for gallbladder cancer were collected from 14 hospitals in Korea, Japan, Chile and the USA. Survival and risk factor analyses were conducted. RESULTS: Data from 937 patients were available for evaluation. The overall 5-year disease-free survival rate was 70·6 per cent, 74·5 per cent for those with T2a and 65·5 per cent among those with T2b tumours (P = 0·028). Regarding liver resection, extended cholecystectomy was associated with a better 5-year disease-free survival rate than simple cholecystectomy (73·0 versus 61·5 per cent; P = 0·012). The 5-year disease-free survival rate was marginally better for extended than simple cholecystectomy in both T2a (76·5 versus 66·1 per cent; P = 0·094) and T2b (68·2 versus 56·2 per cent; P = 0·084) disease. Five-year disease-free survival rates were similar for extended cholecystectomies including liver wedge resection versus segment IVb/V segmentectomy (74·1 versus 71·5 per cent; P = 0·720). In multivariable analysis, independent risk factors for recurrence were presence of symptoms (hazard ratio (HR) 1·52; P = 0·002), R1 resection (HR 1·96; P = 0·004) and N1/N2 status (N1: HR 3·40, P < 0·001; N2: HR 9·56, P < 0·001). Among recurrences, 70·8 per cent were metastatic. CONCLUSION: Tumour location was not an independent prognostic factor in T2 gallbladder cancer. Extended cholecystectomy was marginally superior to simple cholecystectomy. A radical operation should include liver resection and adequate node dissection.

ANTECEDENTES: En el cáncer de vesícula biliar, la ubicación del tumor subdivide el estadio T2 en tumores con invasión del lado peritoneal y del lado del hígado (T2a y T2b). Para los tumores que invaden el lado peritoneal (T2a) se sugiere que se puede obviar la resección hepática sin que ello comprometa el pronóstico. Sin embargo, este argumento no ha sido validado. El estudio tuvo como objetivo investigar el valor pronóstico de la localización del tumor en el cáncer de vesícula biliar T2 y establecer la extensión adecuada de la resección quirúrgica. MÉTODOS: Se recogieron los datos clínicos de pacientes que se sometieron a cirugía por cáncer de vesícula biliar en 14 hospitales de Corea, Japón, Chile y Estados Unidos. Se realizaron análisis de la supervivencia y de los factores de riesgo. RESULTADOS: Se dispuso de datos de 937 pacientes para ser evaluados. La tasa de supervivencia global libre de enfermedad a los 5 años fue del 70,6%, y las de T2a y T2b del 74,5% y 65,5% (P = 0,028). Con respecto a la resección hepática, la colecistectomía extendida presentó una tasa mejor de supervivencia libre de enfermedad a los 5 años que la colecistectomía simple (73,0% versus 61,5%, P = 0,012). La tasa de supervivencia libre de enfermedad a los 5 años fue marginalmente mejor para la colecistectomía extendida que para la colecistectomía simple tanto en T2a (76,5% versus 66,1%, P = 0,094) como en T2b (68,2% versus 56,2%, P = 0,084). Las tasas de supervivencia libre de enfermedad a los 5 años no fueron diferentes entre la resección hepática en cuña y la segmentectomía S4b+S5 (74,1% versus 71,5%, P = 0,720). En el análisis multivariable, los factores de riesgo independientes para la recidiva fueron la presencia de síntomas (cociente de riesgos instantáneos, hazard ratio, HR 1,52, P = 0,002), la resección R1 (HR 1,96, P = 0,004) y el estadio N1/N2 (N1 HR 3,40, P < 0,001; N2 HR 9,56, P < 0,001). El 70,8% de las recidivas eran metastásicas. CONCLUSIÓN: La localización del tumor no fue un factor pronóstico independiente en el cáncer de vesícula biliar T2. La colecistectomía extendida fue marginalmente superior que la colecistectomía simple. La cirugía radical debe incluir una resección hepática y una linfadenectomía adecuada.

Incidence of oral anticoagulant interruption among stroke patients with atrial fibrillation and subsequent stroke.

BACKGROUND AND PURPOSE: We analyzed the incidence and causes of oral anticoagulant (OAC) cessation and subsequent stroke after OAC withdrawal in a cohort of Korean stroke patients with atrial fibrillation. METHODS: The Korean Atrial Fibrillation Evaluation Registry in Ischemic Stroke patients (K-ATTENTION) is a multicenter cohort study, merging stroke registries from 11 tertiary centers in Korea. The number of OAC interruption episodes and the reasons were reviewed from hospital records. Stroke after OAC withdrawal was defined when a patient experienced ischaemic stroke within 31 days after OAC withdrawal. Clinical variables were compared between patients who experienced stroke recurrence during OAC interruption and those who did not experience recurrence. RESULTS: Among 3213 stroke patients with atrial fibrillation, a total of 329 episodes of OAC interruption were detected in 229 patients after index stroke (mean age 72.9 ± 8.3 years, 113 female patients). The most frequent reason for OAC withdrawal was poor compliance [103 episodes (31.3%)] followed by extracranial bleeding [96 episodes (29.2%)]. Stroke after OAC withdrawal was noted in 13 patients. Mean age, vascular risk factor profile and mean CHA2 DS2 -VASc score were not significantly different between patients with and without recurrent stroke. CONCLUSIONS: A considerable number of stroke patients with atrial fibrillation experienced temporary interruption of OAC after index stroke, which was associated with stroke recurrence of 4.0 cases per 100 interruption episodes.

Enhancing ultraviolet-to-visible rejection ratio by inserting an intrinsic NiO layer in p-NiO/n-Si heterojunction photodiodes.

Conventionally, p-NiO/n-Si (p-n) heterojunction photodiodes (HPDs) exhibit a larger visible response than the ultraviolet response due to the thick Si substrate; hence, it is used as a broadband photodetector with a poor ultraviolet (UV)-to-visible rejection ratio. Herein, an intrinsic NiO (i-NiO) layer is inserted between the p-NiO and the n-Si substrate to fabricate p-NiO/i-NiO/n-Si (p-i-n) HPDs, significantly suppressing leakage current and visible response. Compared with the conventional p-n HPDs, the insertion of the i-NiO layer significantly reduces leakage current by approximately 241 times and enhances the rectification ratio from 13.8 to 3228 for the p-n and p-i-n HPDs. The insertion of an i-NiO layer not only increases the UV-response but also suppresses the visible response. These issues enhance the UV-to-visible rejection ratio from 72.2 in p-n HPDs to 915.3 in p-i-n HPDs. The p-NiO reveals a poorer crystalline structure than the i-NiO film because the Ag dopants accumulate at the grain boundary and inhibit crystalline growth. The Ag diffusion in the Si substrate causes defect states within the Si bandgap, whereas it is retarded by the i-NiO layer in the p-i-n HPDs. The poor crystallinity in the p-NiO and defect states within the Si bandgap contributes to a high leakage current and visible response in p-n HPDs. The p-i-n HPDs demonstrate a higher UV-response due to absorption by the i-NiO layer. Because visible light cannot be absorbed by the i-NiO layer, visible response is suppressed in p-i-n HPDs.

Blood transfusions in total knee arthroplasty: a retrospective analysis of a multimodal patient blood management programme.

PURPOSE: Transfusion is associated with increased perioperative morbidity and mortality in patients undergoing total knee arthroplasty (TKA). Patient blood management (PBM) is an evidence-based approach to maintain blood mass via haemoglobin maintenance, haemostasis optimisation, and blood loss minimisation. The aim of the present study was to assess the effectiveness of a multimodal PBM approach in our centre. METHODS: This was a single-centre retrospective study of patients who underwent primary TKA in Queen Mary Hospital in Hong Kong in 2013 or 2018, using data from the Clinical Data Analysis and Reporting System and a local joint registry database. Patient demographics, preoperative haemoglobin, length of stay, readmission, mean units of transfusion, postoperative prosthetic joint infection, and mortality data were compared between groups. RESULTS: In total, 262 and 215 patients underwent primary TKA in 2013 and 2018, respectively. The mean transfusion rate significantly decreased after PBM implementation (2013: 31.3%; 2018: 1.9%, P<0.001); length of stay after TKA also significantly decreased (2013: 14.49±8.10 days; 2018: 8.77±10.14 days, P<0.001). However, there were no statistically significant differences in readmission, early prosthetic joint infection, or 90-day mortality rates between the two groups. CONCLUSION: Our PBM programme effectively reduced the allogeneic blood transfusion rate in patients undergoing TKA in our institution. Thus, PBM should be considered in current TKA protocols to reduce rates of transfusions and related complications.

TLR5 activation induces expression of the pro-inflammatory mediator Urokinase Plasminogen Activator via NF-κB and MAPK signalling pathways in human dental pulp cells.

AIM: To explore the involvement of TLR5 in pulp inflammation and to examine the effects of TLR5 activation with its ligand, FlaB protein, on pro-inflammatory gene expression. METHODOLOGY: TLR5 expression in dental pulp tissues and human dental pulp cells (hDPCs) were determined by immunohistochemistry, immunocytochemistry, Western blots and RT-PCR analyses. To examine the role of TLR5, hDPCs were treated with recombinant FlaB protein (500 ng mL-1 ) to activate the receptor or with a small interfering RNA against TLR5 (si-TLR5) to downregulate the receptor. After exposure to FlaB, the expression of inflammation-related proteins was screened using a protein array kit. Western blots or qRT-PCR analyses were performed to identify changes in the expression of uPA (urokinase plasminogen activator), TIMPs (tissue inhibitor of metalloproteinases), and IL-6 and to determine their signalling pathways. Statistical analysis was performed using one-way analysis of variance (anova) with Tukey post hoc test; P < 0.05 was considered statistically significant. RESULT: TLR5 expression was identified in pulp tissues and hDPCs. In the protein array analysis, treatment with FlaB significantly increased uPA expression (P < 0.01) and significantly decreased TIMP1/4 (P < 0.05). FlaB treatment also significantly increased expression of the inflammatory marker IL-6 (P < 0.01). FlaB treatment increased phosphorylation of the NF-κB p65 subunit, JNK, p38 and ERK. Chemical inhibitors of NF-κB (Bay11-7082), p38 (SB202190) or ERK (U0126) decreased the FlaB induction of uPA expression. Downregulation of TLR5 expression by siRNA decreased the FlaB induction of uPA protein and p65 phosphorylation. CONCLUSION: TLR5 activation with FlaB treatment induced the expression of uPA via the NF-κB and MAPK signalling pathways. Flagellin-bearing oral bacteria may cause pulp inflammation through TLR5. The findings provide new clues to control pulpal diseases by targeting TLR5 signalling pathways.

Factors associated with regression from prediabetes to normal glucose tolerance in a Korean general population: A community-based 10-year prospective cohort study.

AIM: A proportion of people with prediabetes convert back to normal glucose tolerance. We sought to determine the clinical variables associated with conversion from prediabetes to normal glucose tolerance, with a focus on insulin secretory capacity, insulin sensitivity and body composition. METHODS: We followed 1731 people with prediabetes at baseline from the Korean Genome and Epidemiology Study every 2 years for 10 years. Oral glucose tolerance tests (OGTT) were performed, and muscle and fat mass were estimated using bioelectrical impedance analysis. RESULTS: During 10 years of follow-up, 36% (623/1731) of people with prediabetes converted to normal glucose tolerance. Higher baseline fasting glucose, 2-h OGTT glucose and triglyceride levels were inversely associated with this conversion. Higher 60-min insulinogenic index (IGI60 ) at baseline was independently associated with this conversion [HR per sd (95% CI) 1.09 (1.02-1.17); P = 0.01]. However, other indices reflecting insulin sensitivity, including the composite insulin sensitivity index, were not associated with this conversion. In addition, a higher baseline muscle to fat ratio was independently associated with conversion to normal glucose tolerance [HR per sd (95% CI) 1.15 (1.04-1.26); P = 0.005]. People with conversion to normal glucose tolerance showed a greater increase in the 60-min insulinogenic index and disposition index and a smaller decrease in the composite insulin sensitivity index compared with people without conversion during 10 years of follow-up (all p-values < 0.001). CONCLUSION: A higher insulin secretory capacity at baseline and during follow-up and higher baseline muscle to fat ratio were independently associated with an improvement in glucose tolerance in Korean adults with prediabetes.

Differential activation of immune/inflammatory response-related co-expression modules in the hippocampus across the major psychiatric disorders.

The Stanley Neuropathology Consortium Integrative Database (SNCID, http://sncid.stanleyresearch.org) is a data-mining tool that includes 379 neuropathology data sets from hippocampus, as well as RNA-Seq data measured in 15 well-matched cases in each of four groups: schizophrenia, bipolar disorder (BPD), major depression (MD) and unaffected controls. We analyzed the neuropathology data from the hippocampus to identify those abnormalities that are shared between psychiatric disorders and those that are specific to each disorder. Of the 379 data sets, 20 of them showed a significant abnormality in at least one disorder as compared with unaffected controls. GABAergic markers and synaptic proteins were mainly abnormal in schizophrenia and the two mood disorders, respectively. Two immune/inflammation-related co-expression modules built from RNA-seq data from both schizophrenia and controls combined were associated with disease status, as well as negatively correlated with the GABAergic markers. The correlation between immune-related modules and schizophrenia was replicated using microarray data from an independent tissue collection. Immune/inflammation-related co-expression modules were also built from RNA-seq data from BPD cases or from MD cases but were not preserved when using data from control cases. Moreover, there was no overlap in the genes that comprise the immune/inflammation response-related modules across the different disorders. Thus, there appears to be differential activation of the immune/inflammatory response, as determined by co-expression of genes, which is associated with the major psychiatric disorders and which is also associated with the abnormal neuropathology in the disorders.

Effects of a novel light-curable material on odontoblastic differentiation of human dental pulp cells.

AIM: To assess the biological effects, including odontoblastic differentiation of a novel light-curable material (TheraCal), on human dental pulp cells (hDPCs). METHODOLOGY: The hDPCs were isolated from freshly extracted, caries-free third molars. Ten discs of TheraCal and MTA (8 mm in diameter and 3 mm in height) were incubated in α-minimum essential medium (α-MEM) and the supernatant collected. Viability of hDPCs in response to TheraCal and MTA was measured using the WST-1 assay. RT-PCR and real-time PCR were used to detect the gene expression of dentine sialophosphoprotein (DSPP) and dentine matrix protein-1 (DMP-1). ALP staining and Alizarin red S staining were used to evaluate the expression of alkaline phosphatase (ALP) and mineralization behaviour. One-way analysis of variance and Tukey's post hoc test were used to determine the statistically significant differences as a result of the variation in test materials (P < 0.05). RESULTS: The effects of TheraCal and MTA on cell viability were similar except at the highest concentration. The mRNA level of DSPP increased significantly in the MTA group relative to the control at day 1 and 3 (P < 0.05). Also, the mRNA level of DSPP increased significantly in the TheraCal group relative to the control at day 3 (P < 0.05). The increased mRNA level of DMP-1 was 2.5-fold and 2.3-fold each in the MTA and TheraCal groups relative to the control (P < 0.05). Cells exposed to MTA exhibited a 1.4-fold increase of ALP staining relative to control (P < 0.05). In the mineralization assay, increased calcium nodule formation was twofold and 1.3-fold each in the MTA and TheraCal groups compared to the control (P < 0.05). CONCLUSIONS: TheraCal and MTA had the ability to induce odontoblastic differentiation and mineralization of hDPCs.

Behaviour of human dental pulp cells cultured in a collagen hydrogel scaffold cross-linked with cinnamaldehyde.

AIM: To investigate the effects of the cross-linking agent cinnamaldehyde (CA) on differentiation of human dental pulp cells (hDPCs) cultured in a collagen hydrogel, which may be useful as a scaffold for regenerative endodontic therapy. METHODOLOGY: The odontogenic potential of hDPCs exposed to CA was examined using alkaline phosphatase (ALP) activity, Alizarin red S staining and real-time polymerase chain reaction for odontogenic gene expression. The morphological features of hDPCs cultured in CA-treated collagen were evaluated by scanning electron microscopy. Determination of cell numbers for evaluating proliferation was assessed by optical and fluorescence microscopy. To assess the mechanical properties of collagen treated with CA, setting time, compressive strength and surface roughness were measured. Statistical analysis was performed using Student's t-test compared with control (P = 0.05). RESULTS: CA per se did not increase ALP activity, calcium nodule formation and expression of odontogenic-related markers (P > 0.05). On the contrary, the proliferation and odontogenic differentiation of hDPCs cultured in a collagen scaffold was promoted in the presence of CA (P < 0.05). The setting time was significantly shortened, and the compressive strength and surface roughness were increased by treatment with CA (P < 0.05). CONCLUSIONS: Cross-linking of collagen scaffolds by CA had beneficial effects with respect to attachment, proliferation and differentiation of hDPCs. Consequently, the application of cross-linking agents such as CA may represent a new strategy for dentine-pulp complex regeneration.

Simvastatin inhibits the expression of inflammatory cytokines and cell adhesion molecules induced by LPS in human dental pulp cells.

AIM: To investigate the effect of simvastatin on lipopolysaccharide (LPS)-stimulated inflammatory cytokines, cell adhesion molecules and nuclear factor-κB (NF-κB) transcription factors in human dental pulp cells (HDPCs). METHODOLOGY: The effect of LPS and simvastatin on human dental pulp cell (HDPCs) viability was measured using a 3-[4, 5-dimethylthiazol-2-yl]-2, 5 diphenyltetrazolium bromide (MTT) assay. The expression of inflammatory cytokines and cell adhesion molecules was evaluated by reverse-transcription polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. NF-κB transcription factors were evaluated by Western blot analysis. Statistical analysis was performed with analysis of variance (anova). RESULTS: The viability of cells exposed to different concentrations of E. coli LPS, P. gingivalis LPS and simvastatin was not significantly different compared with that of control cells (P > 0.05). LPS significantly increased interleukin (IL)-1ß (P < 0.05) and IL-6 mRNA expression (P < 0.05) and vascular cell adhesion molecule-1 (VCAM-1) (P < 0.05) and intercellular adhesion molecule-1 (ICAM-1) protein expression (P < 0.05) in HDPCs. Treatment with simvastatin significantly attenuated LPS-stimulated production of IL-1ß, IL-6, VCAM-1 and ICAM-1 (P < 0.05). Treatment with simvastatin decreased LPS-induced expression of p65 and phosphorylation of IκB and also significantly decreased the phosphorylation of p65 and IκB in the cytoplasm and the level of p65 in the nucleus (P < 0.05). CONCLUSIONS: Simvastatin has a suppressing effect on LPS-induced inflammatory cytokine, cell adhesion molecules and NF-κB transcription factors in HDPCs. Therefore, simvastatin might be a useful candidate as a pulp-capping agent in vital pulp therapy.

Malva verticillata seed extracts upregulate the Wnt pathway in human dermal papilla cells.

OBJECTIVE: Mesenchymal-epithelial interactions are important in controlling hair growth and the hair cycle. The ß-catenin pathway of dermal papilla cells (DPCs) plays a pivotal role in morphogenesis and normal regeneration of hair follicles. Deletion of ß-catenin in the dermal papilla reduces proliferation of the hair follicle progenitor cells that generate the hair shaft and induces an early onset of the catagen phase. In this study, a modulator of the Wnt/ß-catenin activity was studied in oriental herb extracts on cultured human DPCs. METHODS: The effect of Malva verticillata (M. verticillata) seeds on human DPCs was investigated by a Wnt/ß-catenin reporter activity assay system (ß-catenin-TCF/LEF reporter gene) and cell proliferation analysis. The synthesis of the factors related to hair growth and cycling was measured at both the mRNA and the protein level by semi-quantitative PCR and Western blot analysis, respectively. RESULTS: An extract from M. verticillata seeds increased Wnt reporter activity in a concentration-dependent manner and also led to increased ß-catenin levels in cultured human DPCs. Myristoleic acid, identified as an effective compound of M. verticillata seeds, stimulated the proliferation of DPCs in a dose-dependent manner and increased transcription levels of the downstream targets: IGF-1, KGF, VEGF and HGF. Myristoleic acid also enhanced the phosphorylation of MAPKs (Akt and p38). CONCLUSION: Overall, the data suggest that this extract of M. verticillata seeds could be a good candidate for treating hair loss by modulating the Wnt/ß-catenin pathway in DPCs.

Visceral abdominal fat accumulation predicts the conversion of metabolically healthy obese subjects to an unhealthy phenotype.

BACKGROUND: A proportion of obese subjects appear metabolically healthy (MHO) but little is known about the natural history of MHO and factors predicting its future conversion to metabolically unhealthy obese (MUO). OBJECTIVES: The aim was to determine prospectively the frequency of conversion of MHO to MUO and the clinical variables that independently predicted this conversion, with a particular focus on the role of body composition. METHODS: We identified 85 Japanese Americans with MHO (56 men, 29 women), aged 34-73 years (mean age 49.8 years) who were followed at 2.5, 5 and 10 years after enrollment with measurements of metabolic characteristics, lifestyle and abdominal and thigh fat areas measured by computed tomography. Obesity was defined using the Asian body mass index criterion of ⩾25 kg m(-2). Metabolically healthy was defined as the presence of ⩽2 of 5 metabolic syndrome components proposed by the National Cholesterol Education Program Adult Treatment Panel III, while metabolically unhealthy was defined as ⩾3 components. RESULTS: Over 10 years of follow-up, 55 MHO individuals (64.7%) converted to MUO. Statistically significant univariate predictors of conversion included dyslipidemia, greater insulin resistance and greater visceral abdominal (VAT) and subcutaneous abdominal fat area (SAT). In multivariate analysis, VAT (odds ratio per 1-s.d. increment (95% confidence interval) 2.04 (1.11-3.72), P=0.021), high-density lipoprotein (HDL) cholesterol (0.24 (0.11-0.53), P<0.001), fasting plasma insulin (2.45 (1.07-5.62), P=0.034) and female sex (5.37 (1.14-25.27), P=0.033) were significantly associated with future conversion to MUO. However, SAT was not an independent predictor for future conversion to MUO. CONCLUSIONS: In this population, MHO was a transient state, with nearly two-thirds developing MUO over 10 years, with higher conversion to MUO independently associated with VAT, female sex, higher fasting insulin level and lower baseline HDL cholesterol level.

Atypical antipsychotic drugs and the risk for acute kidney injury and other adverse outcomes in older adults: a population-based cohort study.

BACKGROUND: Several adverse outcomes attributed to atypical antipsychotic drugs, specifically quetiapine, risperidone, and olanzapine, are known to cause acute kidney injury (AKI). Such outcomes include hypotension, acute urinary retention, and the neuroleptic malignant syndrome or rhabdomyolysis. OBJECTIVE: To investigate the risk for AKI and other adverse outcomes associated with use of atypical antipsychotic drugs versus nonuse. DESIGN: Population-based cohort study. SETTING: Ontario, Canada, from 2003 to 2012. PATIENTS: Adults aged 65 years or older who received a new outpatient prescription for an oral atypical antipsychotic drug (n=97,777) matched 1:1 with those who did not receive such a prescription. MEASUREMENTS: The primary outcome was hospitalization with AKI (assessed by using a hospital diagnosis code and, in a subpopulation, serum creatinine levels) within 90 days of prescription for atypical antipsychotic drugs. RESULTS: Atypical antipsychotic drug use versus nonuse was associated with a higher risk for hospitalization with AKI (relative risk [RR], 1.73 [95% CI, 1.55 to 1.92]). This association was consistent when AKI was assessed in a subpopulation for which information on serum creatinine levels was available (5.46% vs. 3.34%; RR, 1.70 [CI, 1.22 to 2.38]; absolute risk increase, 2.12% [CI, 0.80% to 3.43%]). Drug use was also associated with hypotension (RR, 1.91 [CI, 1.60 to 2.28]), acute urinary retention (RR, 1.98 [CI, 1.63 to 2.40]), and all-cause mortality (RR, 2.39 [CI, 2.28 to 2.50]). LIMITATION: Only older adults were included in the study. CONCLUSION: Atypical antipsychotic drug use is associated with an increased risk for AKI and other adverse outcomes that may explain the observed association with AKI. The findings support current safety concerns about the use of these drugs in older adults. PRIMARY FUNDING SOURCE: Academic Medical Organization of Southwestern Ontario.