Noninvasive ROS imaging and drug delivery monitoring in the tumor microenvironment.

Reactive oxygen species (ROS) that are overproduced in certain tumors can be considered an indicator of oxidative stress levels in the tissue. Here, we report a magnetic resonance imaging (MRI)-based probe capable of detecting ROS levels in the tumor microenvironment (TME) using ROS-responsive manganese ion (Mn2+)-chelated, biotinylated bilirubin nanoparticles (Mn@bt-BRNPs). These nanoparticles are disrupted in the presence of ROS, resulting in the release of free Mn2+, which induces T1-weighted MRI signal enhancement. Mn@BRNPs show more rapid and greater MRI signal enhancement in high ROS-producing A549 lung carcinoma cells compared with low ROS-producing DU145 prostate cancer cells. A pseudo three-compartment model devised for the ROS-reactive MRI probe enables mapping of the distribution and concentration of ROS within the tumor. Furthermore, doxorubicin-loaded, cancer-targeting ligand biotin-conjugated Dox/Mn@bt-BRNPs show considerable accumulation in A549 tumors and also effectively inhibit tumor growth without causing body weight loss, suggesting their usefulness as a new theranostic agent. Collectively, these findings suggest that Mn@bt-BRNPs could be used as an imaging probe capable of detecting ROS levels and monitoring drug delivery in the TME with potential applicability to other inflammatory diseases.

Trajectories of Handgrip Strength and Their Associations with Mortality among Older Adults in Korea: Analysis of the Korean Longitudinal Study of Aging.

BACKGROUND: Handgrip strength (HGS) is a good predictor of adverse health outcomes in later life. This prospective study aimed to investigate whether HGS trajectory patterns were associated with all-cause mortality among older adults in Korea. METHODS: This study used the database of the 2006-2016 Korean Longitudinal Study of Aging. Study participants included 3,069 adults aged ≥65 years without a previous history of cancer. The trajectory model was developed to identify different homogeneous trajectory patterns of HGS according to study period. Cox proportional hazards models were then applied to investigate the association between HGS and all-cause mortality. RESULTS: The survival probability according to HGS during the follow-up period decreased as base HGS weakened. We identified four distinct trajectory groups of HGS among men and three among women. The risk of mortality increased as the HGS of both males and females decreased. Compared with the highest HGS group, the adjusted hazard ratios for all-cause mortality of the lowest, lower-mid, and upper-mid HGS groups among males were 3.46 (95% confidence interval [CI], 2.17-6.69), 2.26 (95% CI, 1.47-3.48), and 1.58 (95% CI, 1.07-2.32). Those of the low and mid HGS groups among females were 2.69 (95% CI, 1.39-5.21) and 1.97 (95% CI, 1.05-3.69). CONCLUSION: The faster HGS declined over time, the greater the all-cause mortality risk increased compared with the slowly decreasing or maintained HGS groups among men and women. HGS measurement among older adults will be helpful in assessing their health statuses and pre-assessing disease-associated morbidity.

Trajectories of Body Mass Index and Their Associations with Mortality among Older Adults in Korea: Analysis of the Korean Longitudinal Study of Aging.

BACKGROUND: Weight change is a known risk factor for mortality. Previous Korean studies only considered mortality consequences of weight change between two time points over relatively short periods. This study investigated whether body mass index (BMI) trajectory patterns were associated with all cause-mortality based on continuous BMI observations during a 10-year follow-up period among Korean older adults. METHOD: This study analyzed data from the 2006-2016 Korean Longitudinal Study of Aging database. The participants included in this study were 3,478 people aged 65 years or older who had no previous cancer history. A trajectory model was developed to classify different homogeneous trajectory subgroups according to BMI, and Cox proportional hazards models were used to investigate the association of BMI trajectory with all-cause mortality. RESULT: We identified four trajectory groups: obese (OG); overweight (OWG); high normal weight (HNWG); and low normal weight (LNWG). The LNWG and HNWG experienced continuous weight loss during the study period. Trajectories with higher BMI were associated with lower mortality. The adjusted hazard ratios (95% confidence intervals) for all-cause mortality in the LNWG, HNWG, and OWG were 2.40 (1.69-3.40), 1.75 (1.26-2.45), and 1.38 (0.99-1.96), respectively, compared with those in the OG. CONCLUSION: We found that the lower the BMI of the weight trajectory group, the higher the mortality over 10 years in Korean older adults. This result suggested that baseline obesity status and degree of weight loss during follow-up contributed to mortality in later life.

Fear of Falling and Mortality among Older Adults in Korea: Analysis of the Korean Longitudinal Study of Aging.

BACKGROUND: The fear of falling (FOF) has been reported in a high percentage of elderly people. An excessive FOF is a major concern among the elderly because it can lead to permanent disability. However, the impact of FOF on mortality has been insufficiently studied. The aim of this study was to investigate the impact of FOF on mortality among the elderly in Korea. METHODS: This was a prospective study carried out using the database of the Korean Longitudinal Study of Aging, a nationwide study of community-dwelling adults in Korea. Study participants included 3,421 adults, aged 65 years or older, without either severe cognitive impairment (Korean version of Mini-Mental Status Examination ≥10), or previous history of cancer. We used Cox proportional hazards models to investigate the association between FOF and all-cause mortality. RESULTS: This study included 1,474 men and 1,947 women. Cox regression showed that participants with FOF had an increased risk of mortality (mild: hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.01-1.54; moderate: HR, 1.59; 95% CI, 1.23-2.05) after adjusting for confounding variables. In a subgroup analysis, FOF was still a significant risk factor of mortality for patients with no previous history of falling after adjusting for other risk factors, as in the full model, except for history of falling (HR, 1.65; 95% CI, 1.27-2.13). CONCLUSION: We found that FOF was a significant risk factor for mortality in the elderly in Korea. Further studies on the effects and mechanism of FOF on mortality are needed.

Anti-fracture Efficacy of Monthly Risedronate Compared with That of Weekly Risedronate in Postmenopausal Korean Women with Osteoporosis: A Nationwide Cohort Study.

BACKGROUND: Intermittent dosing regimens for oral risedronate (once-monthly and once-weekly) were developed for patient convenience. While several studies have reported the anti-fracture efficacy of weekly dosing, few have assessed monthly dosing. The lower efficacy of monthly dosing has been previously suggested. The aim of this study was to compare the anti-fracture efficacy of monthly and weekly dosing. METHODS: We obtained information from the Korea National Health Insurance Service database from 2012 to 2017 of Korean women of ≥50 years of age who used weekly or monthly risedronate. We compared the time of occurrence of the first osteoporotic fracture after the first prescription of risedronate. Using a Cox proportional model, we assessed incidence rate ratios (IRRs) with 95% confidence intervals (CIs) for fractures at any site, and the hip, vertebral, and non-vertebral sites between both regimens. Propensity score weighting was used to balance the treatment groups. RESULTS: The study populations were distributed according to dosing frequency (monthly, 27,329; weekly, 47,652). There was no significant difference in the incidence rate of new fractures in any site (IRR, 1.008; 95% CI,0.963- 1.055; P=0.737), hip (IRR, 0.999; 95% CI, 0.769-1.298; P=0.996), vertebral (IRR, 0.962; 95% CI, 0.890-1.040; P=0.330), or non-vertebral (1.022; 95% CI, 0.968-1.078; P=0.439) sites between monthly and weekly risedronate. CONCLUSION: The anti-fracture efficacy at any site and the examined individual sites was similar for the monthly and weekly risedronate regimens. Large-scale randomized controlled trials are required for confirmation.

Comparison of the efficacy between once-monthly oral ibandronate and risedronate among Korean women with osteoporosis: a nationwide population-based study.

Using a nationwide database from the Korean National Health Insurance Service, this study showed that once-monthly oral ibandronate (150 mg) had better anti-fracture efficacy than once-monthly oral risedronate (150 mg), as seen on assessing overall and non-vertebral fractures among Korean elderly women with osteoporosis. INTRODUCTION: Once-monthly oral bisphosphonates have been used widely without appropriate comparison. Therefore, we aimed to compare the anti-fracture efficacy of once-monthly ibandronate (150 mg) and once-monthly risedronate (150 mg). METHODS: We conducted a retrospective cohort study among Korean women aged ≥ 60 years from 2006 to 2015 using a nationwide database from the National Health Insurance Service Senior Cohort. The primary outcome was the first occurrence of fracture related to osteoporosis after the initial prescription of bisphosphonates. A Cox proportional model was used to estimate the incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for overall and site-specific fractures between the two treatments, after adjusting for possible confounding factors. RESULTS: After propensity score matching, the ibandronate and risedronate groups, with 3454 patients each, were assembled from 36,701 new once-monthly ibandronate or risedronate users. After 4 years of follow-up, the ibandronate group had significantly lower incidence rates of overall and non-vertebral fractures than the risedronate group (IRR 0.822, 95% CI 0.698-0.968, P = 0.919 and IRR 0.798, 95% CI 0.647-0.985, P = 0.036, respectively). CONCLUSIONS: Once-monthly ibandronate (150 mg) shows better anti-fracture efficacy than once-monthly risedronate (150 mg). However, further large-scale studies are required to confirm our findings and to determine site-specific differences, especially regarding the vertebral and hip areas.

The Relationship between Handgrip Strength and Cognitive Function in Elderly Koreans over 8 Years: A Prospective Population-Based Study Using Korean Longitudinal Study of Ageing.

BACKGROUND: Decreased physical performance, such as weakened handgrip strength and cognitive decline, is associated with disability and premature death in old age. We investigated the association between handgrip strength and cognitive impairment in Korean elderly adults with normal cognitive function. METHODS: This prospective study used the database from the Korean Longitudinal Study of Ageing. The participants included 2,378 adults aged 65 years or older with normal cognitive function (Korean Mini-Mental Status Evaluation [K-MMSE] score ≥21). Using a mixed-effects model, we examined the associations at baseline and over an 8-year follow-up period between handgrip strength and K-MMSE score. We investigated handgrip strength as a predictor of change in cognitive function. RESULTS: This study included 1,138 women (mean maximum handgrip strength 19.2 kg, mean K-MMSE score 25.1) and 1,240 men (mean maximum handgrip strength 30.7 kg, mean MMSE score 26.2). The baseline handgrip strength was positively associated with the baseline K-MMSE score (b=0.18, P<0.001). Using a mixed-effects model, we found that higher handgrip strength at baseline can predict MMSE scores positively over time (b=0.14, P<0.001) and the change of handgrip strength over time was a predictor of high MMSE scores over the study period (b=0.01, P<0.01). CONCLUSION: We observed significant associations between baseline handgrip strength and baseline and change of cognition, as well as the longitudinal influence of handgrip strength on the change of cognitive function in elderly Korean adults with normal cognitive function.

The effect of magnesium sulfate concentration on the effective concentration of rocuronium, and sugammadex-mediated reversal, in isolated left phrenic nerve hemi-diaphragm preparations from the rat.

BACKGROUND: Perioperative magnesium sulfate (MgSO4) is used for analgesic, anti-arrhythmic, and obstetric purposes. The effects of MgSO4 on the neuromuscular blockade (NMB) induced by rocuronium, and the sugammadex reversal thereof, have not been clearly quantified. We investigated the effect of various MgSO4 concentrations on the NMB by rocuronium, and sugammadex reversal, in isolated left phrenic nerve hemi-diaphragm (PNHD) preparations from the rat. METHODS: Rat PNHD preparations were randomly allocated to one of four groups varying in terms of MgSO4 concentration (1, 2, 3, and 4 mM, each n = 10, in Krebs solution). The train-of-four (TOF) and twitch height responses were recorded mechanomyographically. The preparations were treated with incrementally increasing doses of rocuronium and each group's effective concentration (EC)50, EC90, and EC95 of rocuronium were calculated via nonlinear regression. Then, sugammadex was administered in doses equimolar to rocuronium. The recovery index, time to T1 height > 95% of control, and the time to a TOF ratio > 0.9 after sugammadex administration were measured. RESULTS: The EC50, EC90, and EC95 of rocuronium fell significantly as the magnesium level increased. The EC50, EC90, and EC95 of rocuronium did not differ between the 3 and 4 mM groups. The recovery index, time to T1 height > 95% of control, and time to a TOF ratio > 0.9 after sugammadex administration did not differ among the four groups. CONCLUSIONS: Increases in the magnesium concentration in rat PNHD preparations proportionally enhanced the NMB induced by rocuronium but did not affect reversal by equimolar amounts of sugammadex.

Effect of Fenofibrate Medication on Renal Function.

BACKGROUND: Fibrates are widely used to treat hypertriglyceridemia, a risk factor for arteriosclerosis, but these compounds have been associated with renal dysfunction. This study aimed to investigate the effects of fibrates on renal function in relatively healthy adult subjects with no cardiovascular diseases. METHODS: This retrospective study included 558 outpatients who were prescribed 160 mg fenofibrate (fenofibrate group) or 10 mg atorvastatin (control group) between August 2007 and October 2015. The groups were randomly matched using propensity scores at a 1:1 ratio. Serum creatinine levels and estimated glomerular filtration rates before and after treatment were compared between the two groups. RESULTS: Patients in the fenofibrate group showed greater changes in serum creatinine levels than those in the control group (9.73%±9.83% versus -0.89%±7.37%, P<0.001). Furthermore, 55.1% of patients in the fenofibrate group, but only 6.1% of those in the control group, exhibited a serum creatinine level increase ≥0.1 mg/dL (P<0.001). The fenofibrate group showed significantly greater declines in the estimated glomerular filtration rate than the control group (-10.1%±9.48% versus 1.42%±9.42%, P<0.001). Moreover, 34.7% of the fenofibrate group, but only 4.1% of the control group, exhibited an estimated glomerular filtration rate decrease ≥10 mL/min·1.73 m2 (P<0.001). CONCLUSION: Fenofibrate treatment resulted in increased serum creatinine levels and reduced estimated glomerular filtration rates in a primary care setting. Therefore, regular renal function monitoring should be considered essential during fibrate administration.

Effect of an epinephrine mixture for interscalene block on hemodynamic changes after the beach chair position under general anesthesia: a retrospective study.

BACKGROUND: The beach chair position (BCP) can cause significant hypotension. Epinephrine is used to prolong the duration of local anesthetics; it is also absorbed into blood and can exert systemic effects. This study determined the effects of epinephrine mixed with ropivacaine for an interscalene block (ISB) on hemodynamic changes related to BCP. METHODS: Patient data collected from March 2013 to August 2014 were used retrospectively. We divided the patients into three groups: 1) ISB only, 2) I+G (general anesthesia after ISB without epinephrine), and 3) I+E+G (general anesthesia after ISB with epinephrine). Mean blood pressure (MBP) and heart rate (HR) were measured for 30 minutes at 5-minute intervals. RESULTS: The study analyzed data from 431 patients. MBP tended to decrease gradually in the groups I+G and I+E+G. There were significant differences in MBP between the groups I+G and I, and between the groups I+G and I+E+G. Group I+E+G showed a significant increase in HR compared with the other two groups. CONCLUSIONS: ISB with an epinephrine mixture did not prevent hypotension caused by the BCP after general anesthesia. HR increased only in response to the epinephrine mixture. A well-planned prospective study is required to compare hemodynamic changes in that context.