Performance of Long-Term CT and PET/CT Surveillance for Detection of Distant Recurrence in Patients with Resected Stage IIIA-D Melanoma.

BACKGROUND: Follow-up for patients with resected stage IIIA-D melanoma may include computed tomography (CT) or positron emission tomography (PET)/CT imaging to identify distant metastases. The aim of this study was to evaluate the test performance over follow-up time, of structured 6- and 12-monthly follow-up imaging schedules in these patients. METHODS: We conducted a retrospective analysis of consecutive resected stage IIIA-D melanoma patients from Melanoma Institute Australia (2000-2017). Patients were followed until a confirmed diagnosis of distant metastasis, end of follow-up schedule, or death. Test accuracy was evaluated by cross-classifying the results of the test against a composite reference standard of histopathology, cytology, radiologic imaging, and/or clinical follow-up, and then quantified longitudinally using logistic regression models with random effects. RESULTS: In total, 1373 imaging tests were performed among 332 patients. Distant metastases were detected in 110 (33%) patients during a median follow-up of 61 months (interquartile range 38-86), and first detected by imaging in 86 (78%) patients. 152 (68%) patients had at least one false-positive result. Sensitivity of the schedule over 5 years was 79% [95% confidence interval (CI) 70-86%] and specificity was 88% (95% CI 86-90%). There was no evidence of a significant difference in test performance over follow-up time or by American Joint Committee on Cancer (AJCC) substage. The positive predictive value ranged between 33 and 48% over follow-up time, reflecting a ratio of 1:2 false-positives per true-positive finding. CONCLUSIONS: Regular 6- or 12-monthly surveillance imaging using CT or PET/CT has reasonable and consistent sensitivity and specificity over 5-year follow-up for resected stage IIIA-D melanoma patients. These data are useful when discussing the risks and benefits of long-term follow-up.

Medication risk management and health equity in New Zealand general practice: a retrospective cross-sectional study.

BACKGROUND: Despite an overt commitment to equity, health inequities are evident throughout Aotearoa New Zealand. A general practice electronic alert system was developed to notify clinicians about their patient's risk of harm due to their pre-existing medical conditions or current medication. We aimed to determine whether there were any disparities in clinician action taken on the alert based on patient ethnicity or other demographic factors. METHODS: Sixty-six New Zealand general practices from throughout New Zealand participated. Data were available for 1611 alerts detected for 1582 patients between 1 and 2018 and 1 July 2019. The primary outcome was whether action was taken following an alert or not. Logistic regression was used to assess if patients of one ethnicity group were more or less likely to have action taken. Potential confounders considered in the analyses include patient age, gender, ethnicity, socio-economic deprivation, number of long term diagnoses and number of long term medications. RESULTS: No evidence of a difference was found in the odds of having action taken amongst ethnicity groups, however the estimated odds for Maori and Pasifika patients were lower compared to the European group (Maori OR 0.88, 95 %CI 0.63-1.22; Pasifika OR 0.88, 95 %CI 0.52-1.49). Females had significantly lower odds of having action taken compared to males (OR 0.76, 95 %CI 0.59-0.96). CONCLUSIONS: This analysis of data arising from a general practice electronic alert system in New Zealand found clinicians typically took action on those alerts. However, clinicians appear to take less action for women and Maori and Pasifika patients. Use of a targeted alert system has the potential to mitigate risk from medication-related harm. Recognising clinician biases may improve the equitability of health care provision.

Proton Pump Inhibitors and Infant Pneumonia/Other Lower Respiratory Tract Infections: National Nested Case-control Study.

OBJECTIVE: The possible association between the use of proton pump inhibitors (PPIs) and community-acquired pneumonia (CAP) or another lower respiratory tract infection (LRTI) remains uncertain. We conducted a nested case-control study using routinely collected national health and drug dispensing data in New Zealand to examine the risk of CAP or another LRTI resulting in hospitalization or death in infants dispensed a PPI. STUDY DESIGN: The cohort included 21,991 patients without a history of CAP or another LRTI who were born between 1 January 2005 and 31 December 2012 and were dispensed omeprazole, lansoprazole, or pantoprazole (the PPIs available in New Zealand during the study period) on at least one occasion during the first year of life. Cases had a first diagnosis after cohort entry (first PPI dispensing) of CAP (n = 65) validated by hospital discharge letter or death record, and chest radiography; or LRTI (including CAP) (n = 566) validated by hospital discharge letter or death record, with or without chest radiography. Up to 10 controls, matched by sex and date of birth, were randomly selected for each case. We conducted complete case analyses for the fully adjusted models. RESULTS: In the adjusted analysis based on CAP cases and their controls, the matched odds ratio for current versus past use of PPIs was 0.88 (95% confidence interval 0.36-2.16). For all LRTI cases and their controls, the matched odds ratio was 1.13 (0.87-1.48). CONCLUSION: In otherwise healthy community-dwelling infants, current use of a PPI does not appear to increase the risk of CAP or other LRTIs.

Patterns of use of long-acting bronchodilators in patients with COPD: A nationwide follow-up study of new users in New Zealand.

BACKGROUND AND OBJECTIVE: While several studies have found that prescribing practices do not conform to chronic obstructive pulmonary disease (COPD) treatment guidelines, none have examined longitudinal patterns of use of long-acting beta2 -agonist (LABA) and long-acting muscarinic antagonist (LAMA) therapy across an entire country. We undertook a nationwide follow-up study to describe treatment patterns in new users of long-acting bronchodilators. METHODS: National health and pharmaceutical dispensing data were used to identify patients aged ≥45 years who initiated LABA and/or LAMA therapy for COPD between 1 February 2006 and 31 December 2013. Dispensings of LABAs, LAMAs and inhaled corticosteroids (ICSs) were aggregated into episodes of use of therapeutic regimens. Kaplan-Meier curves, sunburst plots and sequence index plots were generated to summarize, respectively, the duration of the first regimen, the sequences in which unique regimens were used and the patterns of use and non-use during follow-up. RESULTS: The study cohort included 83 435 patients with 290 400 person-years of follow-up. The most commonly initiated regimen was a LABA with an ICS. ICS use was inconsistent with international guidelines: over- and under-treatment occurred in patients with infrequent and frequent exacerbations, respectively, and ICS monotherapy was common. The median duration of the first regimen was 46 days. Many patients used multiple regimens over time and periods of non-use were common. CONCLUSION: In this nationwide study, patterns of use of LABAs, LAMAs and ICSs were complex and often did not comply with treatment guidelines. Further work is required to address the discrepancy between guidelines and prescribing practices.

Telomere length and periodontal attachment loss: a prospective cohort study.

AIM: The aim of the study was to examine the association between telomere erosion and periodontitis in a long-standing prospective cohort study of New Zealand adults. Specific hypotheses tested were as follows: (i) that exposure to periodontitis at ages 26 and 38 was associated with accelerated leucocyte telomere erosion and (ii) that accelerated leucocyte telomere erosion was associated with higher rates of periodontitis by ages 26 and 38. MATERIALS AND METHODS: Periodontal attachment loss data were collected at ages 26 and 38. Blood samples taken at the same ages were analysed to obtain estimates of leucocyte telomere length and erosion over a 12-year period. RESULTS: Overall, the mean telomere length was reduced by 0.15 T/S ratio (adjusted) from age 26 to 38 among the 661 participants reported on here. During the same period, the mean attachment loss increased by 10%, after adjusting for sex, socio-economic status and smoking. Regression models showed that attachment loss did not predict telomere length, and that telomere erosion did not predict attachment loss. CONCLUSIONS: Although both periodontitis and telomere length are age-dependent, they do not appear to be linked, suggesting that determination of leucocyte telomere length may not be a promising clinical approach at this age for identifying people who are at risk for periodontitis.

Community Water Fluoridation and Intelligence: Prospective Study in New Zealand.

Objectives. This study aimed to clarify the relationship between community water fluoridation (CWF) and IQ. Methods. We conducted a prospective study of a general population sample of those born in Dunedin, New Zealand, between April 1, 1972, and March 30, 1973 (95.4% retention of cohort after 38 years of prospective follow-up). Residence in a CWF area, use of fluoride dentifrice and intake of 0.5-milligram fluoride tablets were assessed in early life (prior to age 5 years); we assessed IQ repeatedly between ages 7 to 13 years and at age 38 years. Results. No clear differences in IQ because of fluoride exposure were noted. These findings held after adjusting for potential confounding variables, including sex, socioeconomic status, breastfeeding, and birth weight (as well as educational attainment for adult IQ outcomes). Conclusions. These findings do not support the assertion that fluoride in the context of CWF programs is neurotoxic. Associations between very high fluoride exposure and low IQ reported in previous studies may have been affected by confounding, particularly by urban or rural status.

Reliability and validity of the Brief Pain Inventory-Short Form in individuals with rotator cuff-related shoulder pain.

PURPOSE: To investigate the test-retest reliability and construct validity of the Brief Pain Inventory-Short Form (BPI-SF) in individuals with rotator cuff-related shoulder pain (RCRSP). METHODS: Sixty-one participants with RCRSP completed the BPI-SF twice with an interval of two to seven days and Shoulder Pain and Disability Index (SPADI) at the initial visit. The BPI-SF pain severity subscale, pain interference subscale, and stand-alone pain severity items were analysed using intraclass correlation coefficients (ICCs) and minimal detectable change at the 95% confidence interval (MDC95). The construct validity of BPI-SF was assessed against SPADI using Pearson's correlation. RESULTS: The BPI-SF pain severity and pain interference subscales presented moderate test-retest reliability (ICC = 0.73, 0.53) and MDC95 were 2.05 and 2.36. All stand-alone BPI-SF pain severity items presented a moderate reliability (ICC = 0.62, 0.70). BPI-SF interference items presented poor to moderate reliability (ICC = 0.39, 0.68). The correlation coefficients between the BPI-SF and SPADI subscales or total scores were large (r = 0.61, 0.75). CONCLUSIONS: BPI-SF pain severity and pain interference subscales have a moderate reliability in individuals with RCRSP. BPI-SF pain severity and interference subscales showed high construct validity in individuals with RCRSP. MDC95 values are useful metrics for interpreting a true change in BPI-SF scores following interventions in individuals with RCRSP.

Our findings support the use of the Brief Pain Inventory-Short Form (BPI-SF) pain severity and interference subscales in patients with rotator-cuff related shoulder pain (RCRSP).Our findings support the use of the stand-alone pain severity item (i.e., "worst pain") in individuals with RCRSP.The BPI-SF has good construct validity in individuals with RCRSP.

Earthquake forecasting from paleoseismic records.

Forecasting large earthquakes along active faults is of critical importance for seismic hazard assessment. Statistical models of recurrence intervals based on compilations of paleoseismic data provide a forecasting tool. Here we compare five models and use Bayesian model-averaging to produce time-dependent, probabilistic forecasts of large earthquakes along 93 fault segments worldwide. This approach allows better use of the measurement errors associated with paleoseismic records and accounts for the uncertainty around model choice. Our results indicate that although the majority of fault segments (65/93) in the catalogue favour a single best model, 28 benefit from a model-averaging approach. We provide earthquake rupture probabilities for the next 50 years and forecast the occurrence times of the next rupture for all the fault segments. Our findings suggest that there is no universal model for large earthquake recurrence, and an ensemble forecasting approach is desirable when dealing with paleoseismic records with few data points and large measurement errors.

Vitamin K2 ameliorates osteoarthritis by suppressing ferroptosis and extracellular matrix degradation through activation GPX4's dual functions.

Vitamin K2 (VK2) is an effective compound for anti-ferroptosis and anti-osteoporosis, and Semen sojae praeparatum (Dandouchi in Chinese) is the main source of VK2. Chondrocyte ferroptosis and extracellular matrix (ECM) degradation playing a role in the pathogenesis of osteoarthritis (OA). Glutathione peroxidase 4 (GPX4) is the intersection of two mechanisms in regulating OA progression. But no studies have elucidated the therapeutic effects and mechanisms of VK2 on OA. This study utilized an in vivo rat OA model created via anterior cruciate ligament transection (ACLT) and an in vitro chondrocyte oxidative damage model induced by TBHP to investigate the protective effects and mechanisms of action of VK2 in OA. Knee joint pain in mice was evaluated using the Von Frey test. Micro-CT and Safranin O-Fast Green staining were employed to observe the extent of damage to the tibial cartilage and subchondral bone, while immunohistochemistry and PCR were used to examine GPX4 levels in joint cartilage. The effects of VK2 on rat chondrocyte viability were assessed using CCK-8 and flow cytometry assays, and chondrocyte morphology was observed with toluidine blue and alcian blue staining. The impact of VK2 on intracellular ferroptosis-related markers was observed using fluorescent staining and flow cytometry. Protein expression changes were detected by immunofluorescence and Western blot analysis. Furthermore, specific protein inhibitors were applied to confirm the dual-regulatory effects of VK2 on GPX4. VK2 can increase bone mass and cartilage thickness in the subchondral bone of the tibia, and reduce pain and the OARSI score induced by OA. Immunohistochemistry results indicate that VK2 exerts its anti-OA effects by regulating GPX4 to delay ECM degradation. VK2 can inhibit the activation of the MAPK/NFκB signaling pathway caused by reduced expression of intracellular GPX4, thereby decreasing ECM degradation. Additionally, VK2 can reverse the inhibitory effect of RSL3 on GPX4, increase intracellular GSH content and the GSH/GSSG ratio, reduce MDA content, and rescue chondrocyte ferroptosis. The protective mechanism of VK2 may involve its dual-target regulation of GPX4, reducing chondrocyte ferroptosis and inhibiting the MAPK/NFκB signaling pathway to decelerate the degradation of the chondrocyte extracellular matrix.

Biochanin A abrogates osteoclastogenesis in type 2 diabetic osteoporosis via regulating ROS/MAPK signaling pathway based on integrating molecular docking and experimental validation.

BACKGROUND: There are accumulating type 2 diabetes patients who have osteoporosis simultaneously. More effective therapeutic strategies should be discovered. Biochanin A (BCA) has been indicated that can play a role in improving metabolic disorders of type 2 diabetes and preventing osteoporosis. But whether BCA can treat type 2 diabetic osteoporosis has not been studied. PURPOSE: To investigate if the BCA can protect against type 2 diabetic osteoporosis and clarify the mechanism. METHODS: Micro-CT and histology assays were performed to detect the trabecular bone and analyze the bone histomorphology effect of BCA. CCK-8 assay was performed to detect the toxicity of BCA. TRAcP staining, immunofluorescence and hydroxyapatite resorption assay were used to observe osteoclasts differentiation and resorptive activity. Molecular docking provided evidence about BCA regulating the MAPK axis via prediction by the algorithm. QRT-PCR and Western Blotting were utilized to detect the expression of osteoclastogenesis-related markers and MAPK signaling pathway. RESULTS: Accumulation of bone volume after BCA treatment could be found based on the 3D reconstruction. Besides, there were fewer osteoclasts in db/db mice treated with BCA than db/db mice treated with saline. In vitro, we found that BCA hadn't toxicity in osteoclasts precursor, but also inhibited differentiation of osteoclasts. Further, we found that BCA suppresses osteoclastogenesis via ROS/MAPK signaling pathway. CONCLUSION: BCA can prevent type 2 diabetic osteoporosis by restricting osteoclast differentiation via ROS/MAPK signaling pathway.

Cardamonin attenuates iron overload-induced osteoblast oxidative stress through the HIF-1α/ROS pathway.

BACKGROUND: Osteoporosis(OP) is a bone disease under research. Iron overload is a significant risk factor. Iron balance is crucial for bone metabolism and biochemical processes. When there is an excess of iron in the body, it tends to produce reactive oxygen species (ROS) which can cause oxidative damage to cells. The flavonoid compound, Cardamonin (CAR), possesses potent anti-inflammatory and anti-iron overload properties that can be beneficial in mitigating the risk of OP. PURPOSE: This study investigates the potential therapeutic interventions and underlying mechanisms of CAR for treating OP in individuals with iron overload. METHODS: The model of iron-overloaded mice was established by intraperitoneally injecting iron dextran(ID) into the mice. OP severity was evaluated with micro-CT and Hematoxylin-Eosin (HE) staining in vivo. In vitro, the iron-overloaded osteoblast model was induced by ferric ammonium citrate. Cell counting kit 8 assay to evaluate cell viability, Annexin V-FITC/PI assay to detect cell apoptosis. A range of cellular markers were detected, including the variation in mitochondrial membrane potential (MMP), levels of malondialdehyde (MDA), ROS, and lipid hydroperoxide (LPO). RESULTS: CAR can reverse bone loss in iron overload-induced OP mouse models in vivo. CAR attenuates the impairment of iron overload on the activity and apoptosis of MC3T3-E1 cells as well as the accumulation of ROS and LPO activation via HIF-1α/ROS pathways. CONCLUSION: CAR downregulating HIF-1α pathways prevents inhibition of iron overload-induced osteoblasts dysfunctional by attenuating ROS accumulation, reducing oxidative stress, promotes bone formation, and alleviates OP.

Perinatal psychotropic dispensing: A descriptive population-based study in New Zealand.

INTRODUCTION: Decisions about using psychotropics during pregnancy are complex as risks of untreated illness are balanced against risks of fetal exposure to medication. The objective was to describe perinatal psychotropic dispensing patterns in New Zealand. METHODS: Nationwide data from the New Zealand National Maternity Collection between January 1, 2011 and December 31, 2017 identified 399 715 pregnancies. These were linked with dispensing records to determine the proportion of pregnancies during which at least 1 psychotropic was dispensed. Proportions were calculated separately for each class, year, pregnancy period, and across maternal characteristics. The pattern of dispensing (including discontinuations) was also determined for the 25 841 women who were dispensed at least 1 psychotropic drug prior to pregnancy. RESULTS: From the 399 715 pregnancies in the study cohort, 6.6% were dispensed at least 1 psychotropic during pregnancy. Antidepressants (5.1%) were the most dispensed, followed by hypnotics (1.2%), anxiolytics (0.7%), and antipsychotics (0.7%). From the 25 841 pregnancies during which a psychotropic was dispensed pre-pregnancy, 91% and 90% discontinued hypnotics and anxiolytics respectively, prior to or during pregnancy. This was followed by lithium (71%), antipsychotics (66%), and antidepressants (66%). DISCUSSION: Dispensing of psychotropics during pregnancy occurs in approximately 6.6% of pregnancies in New Zealand. Two-thirds of women (66%) on antidepressants or antipsychotics discontinue dispensing before or during pregnancy. This may have implications for maternal mental health, suggesting there is a need to investigate how healthcare providers and women are making decisions about psychotropic use during pregnancy.

Test-retest reliability of movement-evoked pain and sensitivity to movement-evoked pain in patients with rotator cuff-related shoulder pain.

BACKGROUND: The number of researchers and clinicians using movement-evoked pain and sensitivity to movement-evoked pain to assess shoulder pain has increased. However, the intrarater test-retest reliability of movement-evoked pain and sensitivity to movement-evoked pain in people with rotator cuff-related shoulder pain (RCRSP) is still unknown. OBJECTIVE: We examined the intrarater test-retest reliability of movement-evoked pain and sensitivity to movement-evoked pain in participants with RCRSP. METHODS: Seventy-four participants with RCRSP performed five trials of active shoulder abduction to elicit pain under two experimental conditions: active shoulder abduction to the onset of pain and maximum range of motion (ROM). The primary outcome measures were pain intensity and ROM. Test-retest reliability of movement-evoked pain and sensitivity to movement-evoked pain was examined using intraclass correlation coefficient (ICC3,1) and minimal detectable change (MDC90). RESULTS: The reliability of movement-evoked pain under both experimental conditions was good to excellent (ICC: 0.81 to 0.95), while the reliability of sensitivity to movement-evoked pain was poor in both conditions (ICC≤0.45). The MDC90 for pain intensity was 1.6 and 1.8 during shoulder abduction to the onset of pain and maximum ROM, respectively. The MDC90 for ROM was 17.5° and 11.2° during shoulder abduction to the onset of pain and maximum ROM condition, respectively. CONCLUSION: This study confirms movement-evoked pain testing during active shoulder abduction to the onset of pain or maximum ROM condition is reliable to assess pain associated with movement in patients with RCRSP. The minimal detectable change score of movement-evoked pain can guide clinicians and researchers on how to interpret changes in these outcomes.

Initial effect of high-volume mobilisation with movement on shoulder range of motion and pain in patients with rotator cuff-related shoulder pain: protocol for a randomised controlled trial (Evolution Trial).

INTRODUCTION: Mobilisation with movement (MWM) is commonly used for treating patients with rotator cuff-related shoulder pain (RCRSP). However, the evidence supporting MWM efficacy for improving shoulder range of motion (ROM) and pain in patients with RCRSP is limited. It is also unclear whether higher volume MWM leads to better clinical outcomes compared with lower volume MWM in patients with RCRSP. The primary aim of this study is to assess the effect of MWM on the angular onset of pain during shoulder abduction in patients with RCRSP. METHODS AND ANALYSIS: Sixty participants with RCRSP will be randomised to receive either MWM or sham MWM intervention. The primary outcome is the angular onset of pain during shoulder abduction, and secondary outcomes are pain intensity at the angular onset of pain during shoulder abduction, maximum shoulder ROM, pain intensity during maximum shoulder abduction, pressure pain threshold, mechanical temporal summation, global rating of change scale (GROC) and Brief Pain Inventory-Short Form (BPI-SF). The angular onset of pain and the pain intensity at that range will be assessed at baseline, after 1 set and 3 sets of 10 repetitions of MWM or sham MWM. The GROC will be measured immediately after receiving 3 sets of interventions and on day 3 after interventions. The BPI-SF will be measured on days 1, 3, 5 and 7 after interventions. Other secondary outcomes will be assessed at baseline and after 3 sets of interventions. A linear mixed effects model with a random intercept will be used to compare changes in the outcome measures between MWM and sham MWM interventions. ETHICS AND DISSEMINATION: This study has been approved by the University of Otago Ethics Committee (Ref. H21/117). Findings from this study will be disseminated through presentations at international and national conferences and will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ACTRN 12621001723875.

Combination of curcumin and catalase protects against chondrocyte injury and knee osteoarthritis progression by suppressing oxidative stress.

Knee Osteoarthritis (KOA) is an age-related progressive degenerative joint disease, which is featured with pain, joint deformity, and disability. Accumulating evidence indicated oxidative stress plays a crucial role in the occurrence and development of KOA. Curcumin is a polyphenolic compound with significant antioxidant activity among various diseases while catalase (CAT) is an enzyme degrading hydrogen peroxide in treating oxidative diseases. We previously showed that the expression of CAT was low in cartilage. However, the combination of curcumin and CAT in KOA is still elusive. In this study, we demonstrated that the combination of curcumin and CAT has the potential to inhibit the IL1ß-induced chondrocyte apoptosis without cytotoxicity in vitro. Mechanistically, we found that the synergistic application curcumin and CAT not only promotes curcumin's regulation of the NRF2/HO-1 signaling pathway to enhance antioxidant enzyme expression to remove superoxide radicals, but also CAT can further remove downstream hydrogen peroxide which enhances the ability to scavenge reactive oxygen species (ROS). In vivo, studies revealed that combination of curcumin and catalase could better inhibit oxidative stress-induced chondrocyte injury by promoting the expression of ROS scavenging enzymes. In sum, the combination of curcumin and catalase can be used to treat KOA. Thus, combination of curcumin and catalase may act as a novel therapeutic agent to manage KOA and our research gives a rationale for their combined use in the therapeutic of KOA.

Arctiin attenuates iron overload­induced osteoporosis by regulating the PI3K/Akt pathway.

Iron overload is a prevalent pathological factor observed among elderly individuals and those with specific hematological disorders, and is frequently associated with an elevated incidence of osteoporosis. Although arctiin (ARC) has been shown to possess antioxidant properties and the ability to mitigate bone degeneration, its mechanism of action in the treatment of iron overload­induced osteoporosis (IOOP) remains incompletely understood. To explore the potential molecular mechanisms underlying the effects of ARC, the MC3T3­E1 cell osteoblast cell line was used. Cell Counting Kit was used to assess MC3T3­E1 cell viability. Alkaline phosphatase staining and alizarin red staining were assessed for osteogenic differentiation. Calcein AM assay was used to assess intracellular iron concentration. In addition, intracellular levels of reactive oxygen species (ROS), lipid peroxides, mitochondrial ROS, apoptosis rate and mitochondrial membrane potential changes in MC3T3­E1 cells were examined using flow cytometry and corresponding fluorescent dyes. The relationship between ARC and the PI3K/Akt pathway was then explored by western blotting and immunofluorescence. In addition, the effects of ARC on IOOP was verified using an iron overload mouse model. Immunohistochemistry was performed to evaluate expression of osteogenesis­related proteins. Micro-CT and H&E were used to analyze bone microstructural parameters and histomorphometric indices in the bone tissue. Notably, ARC treatment reversed the decreased viability and increased apoptosis in MC3T3­E1 cells originally induced by ferric ammonium citrate, whilst promoting the formation of mineralized bone nodules in MC3T3­E1 cells. Furthermore, iron overload induced a decrease in the mitochondrial membrane potential, augmented lipid peroxidation and increased the accumulation of ROS in MC3T3­E1 cells. ARC not only positively regulated the anti­apoptotic and osteogenic capabilities of these cells via modulation of the PI3K/Akt pathway, but also exhibited antioxidant properties by reducing oxidative stress. In vivo experiments confirmed that ARC improved bone microarchitecture and biochemical parameters in a mouse model of iron overload. In conclusion, ARC exhibits potential as a therapeutic agent for IOOP by modulating the PI3K/Akt pathway, and via its anti­apoptotic, antioxidant and osteogenic properties.

Metformin suppresses Oxidative Stress induced by High Glucose via Activation of the Nrf2/HO-1 Signaling Pathway in Type 2 Diabetic Osteoporosis.

BACKGROUND: Metformin (MET) is widely used as a first-line hypoglycemic agent for the treatment of type 2 diabetes mellitus (T2DM) and was also confirmed to have a therapeutic effect on type 2 diabetic osteoporosis (T2DOP). However, the potential mechanisms of MET in the treatment of T2DOP are unclear. OBJECTIVE: To clarify the effect of MET in T2DOP and to explore the potential mechanism of MET in the treatment of T2DOP. METHODS: In vitro, we used MC3T3-E1 cells to study the effects of MET on osteogenic differentiation and anti-oxidative stress injury in a high glucose (Glucose 25 mM) environment. In vivo, we directly used db/db mice as a T2DOP model and assessed the osteoprotective effects of MET by Micro CT and histological analysis. RESULTS: In vitro, we found that MET increased ALP activity in MC3T3-E1 cells in a high-glucose environment, promoted the formation of bone mineralized nodules, and upregulated the expression of the osteogenesis-related transcription factors RUNX2, Osterix, and COL1A1-related genes. In addition, MET was able to reduce high glucose-induced reactive oxygen species (ROS) production. In studies on the underlying mechanisms, we found that MET activated the Nrf2/HO-1 signaling pathway and alleviated high-glucose-induced oxidative stress injury. In vivo results showed that MET reduced bone loss and bone microarchitecture destruction in db/db mice. CONCLUSION: Our results suggest that MET can activate the Nrf2/HO-1 signaling pathway to regulate the inhibition of osteogenic differentiation induced by high glucose thereby protecting T2DOP.

Cardamonin protects against iron overload induced arthritis by attenuating ROS production and NLRP3 inflammasome activation via the SIRT1/p38MAPK signaling pathway.

Iron homeostasis plays an essential role in joint health, while iron overload can cause damage and death of cartilage cells. Cardamonin (CAR) is a substance found in the fruit of the chasteberry plant and has anti-inflammatory and anti-tumor activities. We first administered iron dextran (500 mg/kg) intraperitoneally to establish an iron overload mouse model and surgically induced osteoarthritis. The extent of OA and iron deposition were assessed using Micro-ct, Safranin-O/fast green staining, H&E staining, and Prussian Blue 10 weeks later. We administered primary chondrocytes with Ferric Ammonium Citrate (FAC) to evaluate the chondrocyte changes. Chondrocytes were identified in vitro by toluidine blue staining, and chondrocyte viability was evaluated by CCK-8. The rate of apoptosis was determined by Annexin V-FITC/PI assay. The mechanism of action of CAR was verified by adding the SIRT1 inhibitor EX527, and the expression of SIRT1 and MAPK signaling pathways was detected by Western blot. Iron overload also promoted chondrocyte apoptosis, a process that was reversed by CAR. In addition, CAR reduced NLRP3 inflammasome production via the SIRT1-MAPK pathway, and the SIRT1 inhibitor EX527 inhibited the treatment of OA by CAR.CAR inhibited cartilage degeneration induced by iron overload both in vivo and in vitro. Besides, our study showed that iron overload not only inhibited type II collagen expression but also induced MMP expression by catalyzing the generation of NLRP3 inflammasome. Our results suggest that CAR can treat KOA by promoting SIRT1 expression and inhibiting p38MAPK pathway expression to reduce the production of NLRP3 inflammasome vesicles.

Staying at home: the potential cost savings related to triage advice provided by the New Zealand National Poisons Centre.

INTRODUCTION: Evidence from multiple countries suggests poisons centres create value in several ways including the provision of expert clinical advice, decreased hospital length of stay and triage of exposures enabling safe management without further medical utilisation. Data specific to the New Zealand context are lacking. Therefore, this study aimed to estimate one aspect of poison centre value, namely the potential savings to the health system related to triage advice provided by the New Zealand National Poisons Centre (NZNPC). METHODS: A prospective survey was conducted over a 2-week period where eligible NZNPC callers - who were advised their exposure did not require further medical assessment - were asked what alternative action they would have taken in the hypothetical absence of the NZNPC. The potential cost savings associated with the alternative actions respondents would have taken were calculated using publicly available information and extrapolated to the population level using annual NZNPC call numbers for 2019. RESULTS: Among 554 eligible callers, 399 were recruited to participate and 396 provided responses. The single most common alternative action was "search the Internet" (54/396, 14%). In-person medical assessment would have been sought by 25% (100/396), and 39% (154/396) would have called an alternative provider within the healthcare system. The estimated cost associated with alternative actions for the study period was NZ$25,637. When extrapolated to the 2019 year, the potential savings from avoided healthcare utilisation was NZ$1,061,551. CONCLUSION: In 2019, in the absence of NZNPC triage advice, a conservatively estimated NZ$1,061,551 would have been spent on healthcare related to poisoning exposures that were appropriate for management without further medical utilisation. It is important to note that this estimate is only one aspect of the total value created by the NZNPC and is consistent with findings of value from other poisons centres internationally.