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Jaesik Park,1 Kwon Hui Seo,2 Jueun Kwak,2 Hyebin Baek2 1Department of Anesthesiology and Pain Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 2Department of Anesthesiology and Pain Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of KoreaCorrespondence: Kwon Hui Seo, Department of Anesthesiology and Pain Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 10 63-ro, Yeoungdeungpo-gu, Seoul, 07345, Republic of Korea, Tel +82-2-3779-1268, Fax +82-2-783-0368, Email julianakh@hanmail.netPurpose: Pharmacokinetic and pharmacodynamic (PKPD) models exist for remimazolam, but data for target-controlled infusion (TCI) are limited. The Schüttler PKPD model, a three-compartment model including body weight as a covariate, does not account for age as a variable. This study aimed to investigate remimazolam’s effect-site concentration (Ce) in different age groups during sedation and general anesthesia with TCI using Schüttler PKPD model.Patients and methods: Records of patients who underwent remimazolam TCI with the Schüttler model were reviewed. During anesthesia induction, the target Ce of remimazolam was gradually increased until loss of responsiveness, and it was titrated to maintain bispectral index of 40– 70 during operation. Patients were categorized into young (20– 40 years, n=24), middle-aged (41– 60 years, n=27), and elderly (61– 80 years, n=35) groups. Bispectral index and hemodynamic variables were also assessed.Results: The elderly group had significantly lower remimazolam Ce compared to the young and middle-aged groups at all sedation levels, intubation, and surgery. Mean highest intraoperative Ce was 0.78± 0.10, 0.71± 0.07, and 0.61± 0.10 μg/mL in young, middle-aged, and elderly groups, respectively (P< 0.001). The recovery of responsiveness during emergence occurred at significantly lower Ce in the elderly group (0.28± 0.06 μg/mL) than in the young (0.41± 0.07 μg/mL) and middle-aged groups (0.35± 0.07 μg/mL, P< 0.001). Ce during sedation and general anesthesia was comparable between the young and middle-aged groups. The bispectral index was similar across groups but fluctuated more in the elderly group during general anesthesia. Elderly patients also showed the greatest systolic blood pressure suppression (18.4 ± 13.29% before intubation and 34.31 ± 14.91% during surgery).Conclusion: Older patients may require lower target Ce during remimazolam TCI for sedation and anesthesia, with emergence occurring at lower Ce. Blood pressure suppression may be greater in elderly patients under deep sedation or general anesthesia.Keywords: remimazolam, pharmacology, anesthesia, general, sedation, elderly

Jeonghoon Ha,1 Hansang Baek,1 Chaiho Jeong,2 Hyunsam Kim,3 Ki-Hyun Baek,4 Moo Il Kang,1 Dong-Jun Lim1 1Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea; 2Division of Endocrinology and Metabolism, Department of Internal Medicine, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Korea; 3Department of Internal Medicine, Dongshin Hospital, Seoul, Korea; 4Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, KoreaCorrespondence: Dong-Jun LimDivision of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, KoreaEmail ldj6026@catholic.ac.krPurpose: Studies investigating the association between vitamin D and metabolic parameters have reported inconsistent results depending on the characteristics of the subjects. We aimed to investigate the association between vitamin D levels and various metabolic indicators in healthy Korean adults by using nationally representative data.Methods: A total of 3640 participants were included after excluding subjects who were ≤ 19 years of age and had a history of treatment for dyslipidemia, hypertension, or diabetes and a history of other chronic diseases such as liver and kidney diseases. After dividing the 25-hydroxyvitamin D (25(OH)D) level into quartiles, the risk of having each metabolic parameter higher than the median value was determined according to the 25(OH)D quartile by using regression analysis.Results: In a multivariate regression analysis, a higher 25(OH)D quartile tended to have a significantly lower risk of having a triglyceride (TG) level higher than the median value (103.1 mg/dl). As the quartile increased, the risk of having a waist circumference or body mass index higher than the median value also decreased, but the difference was not statistically significant. No significant changes were observed in fasting glucose or glycated hemoglobin level according to quartile.Conclusion: We demonstrated that subjects with a higher 25(OH)D quartile exhibited a significantly lower risk of having a TG level higher than the median value in a representative Korean population. More evidence from a prospective study on whether vitamin D supplementation improves serum TG levels in healthy adults is needed.Keywords: 25-hydroxyvitamin D, triglyceride, glucose, body mass index, waist circumference

Hyunjeong Baek,1,* Seunghoon Han,2,3,* Dong-Seok Yim,2,3 Sung Joo Kim,4 Soo-Youn Lee,5 Hye Ryoun Jang,6 Jung Eun Lee,6 Dae Joong Kim,6 Yoon-Goo Kim,6 Ha Young Oh,6 Wooseong Huh6 1Department of Medicine, Kangwon National University School of Medicine, Chuncheon, Republic of Korea; 2Department of Pharmacology, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea; 3PIPET (Pharmacometrics Institute for Practical Education and Training), Seoul, Republic of Korea; 4Department of Surgery, 5Department of Laboratory Medicine and Genetics, 6Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea *These authors equally contributed to this work Abstract: This study aimed to evaluate the change in the pharmacokinetics (PK) of cyclosporine in the non-steady-state period in the first week after renal transplantation; the factors influencing this change, including genetic variability; and the time point concentration that correlated best with drug exposure. Data were obtained from 69 patients, and PK studies were conducted on postoperative days (PODs) 2, 3, and 7. Samples were taken pre-dose and at 1, 2, 3, 4, 6, 8, and 12 hours after drug administration. MDR1, CYP3A4, and CYP3A5 were genotyped. A population PK analysis and correlational analysis between the concentration at each time point and the area under the time–concentration curve were performed. A two-compartment model with first-order absorption was chosen. The rate and extent of drug absorption showed a significant increase on POD3, followed by a slight decrease on POD7. Until POD3, 8 hours post-dose was the single time point concentration that correlated best with drug exposure and 3 hours was the best time point on POD7. In both analyses, the MDR1 genotype showed potential as a factor influencing PK change. We conclude that oral administration of cyclosporine and dose adjustment based on a single concentration measurement might result in unexpected drug exposure during this early posttransplantation period. Keywords: renal transplantation, multidrug resistance 1 (MDR1) gene, cytochrome P450

ObjectiveEpratuzumab, a monoclonal antibody that targets CD22, modulates B cell signaling without substantial reductions in the number of B cells. The aim of this study was to report the results of 2 phase III multicenter randomized, double-blind, placebo-controlled trials, the EMBODY 1 and EMBODY 2 trials, assessing the efficacy and safety of epratuzumab in patients with moderately to severely active systemic lupus erythematosus (SLE).MethodsPatients met ≥4 of the American College of Rheumatology revised classification criteria for SLE, were positive for antinuclear antibodies and/or anti-double-stranded DNA antibodies, had an SLE Disease Activity Index 2000 (SLEDAI-2K) score of ≥6 (increased disease activity), had British Isles Lupus Assessment Group 2004 index (BILAG-2004) scores of grade A (severe disease activity) in ≥1 body system or grade B (moderate disease activity) in ≥2 body systems (in the mucocutaneous, musculoskeletal, or cardiorespiratory domains), and were receiving standard therapy, including mandatory treatment with corticosteroids (5-60 mg/day). BILAG-2004 grade A scores in the renal and central nervous system domains were excluded. Patients were randomized 1:1:1 to receive either placebo, epratuzumab 600 mg every week, or epratuzumab 1,200 mg every other week, with infusions delivered for the first 4 weeks of each 12-week dosing cycle, for 4 cycles. Patients across all 3 treatment groups also continued with their standard therapy. The primary end point was the response rate at week 48 according to the BILAG-based Combined Lupus Assessment (BICLA) definition, requiring improvement in the BILAG-2004 score, no worsening in the BILAG-2004 score, SLEDAI-2K score, or physician's global assessment of disease activity, and no disallowed changes in concomitant medications. Patients who discontinued the study medication were classified as nonresponders.ResultsIn the EMBODY 1 and EMBODY 2 trials of epratuzumab, 793 patients and 791 patients, respectively, were randomized, 786 (99.1%) and 788 (99.6%), respectively, received study medication, and 528 (66.6%) and 533 (67.4%), respectively, completed the study. There was no statistically significant difference in the primary end point between the groups, with the week 48 BICLA response rates being similar between the epratuzumab groups and the placebo group (response rates ranging from 33.5% to 39.8%). No new safety signals were identified.ConclusionIn patients with moderate or severely active SLE, treatment with epratuzumab + standard therapy did not result in improvements in response rates over that observed in the placebo + standard therapy group.

Time-lapse geophysical monitoring has potential as a tool for reservoir characterization, that is, for determining reservoir properties such as permeability. Onset times, the calendar times at which geophysical observations begin to deviate from their initial or background values, provide a useful basis for such characterization. We found that, in contrast to time-lapse amplitude changes, onset times were not sensitive to the exact method used to related changes in fluid saturation to changes in seismic velocities. As a consequence of this, we found that an inversion for effective permeability based upon onset times was robust with respect to variations in the rock-physics model. In particular, inversions of synthetic onset times calculated using Voigt and Reuss averaging techniques, but inverted using sensitivities from Hill's averaging method, resulted in almost identical misfit reductions and similar permeability models. All solutions based on onset times recovered the large-scale, resolvable features of the reference model. Synthetic tests indicated that reliable onset times can be obtained from noisy seismic amplitudes. Testing also indicated that large-scale permeability variations can be recovered even if we used onset times from seismic surveys that were spaced as much as 300 days apart.

OBJECTIVE: Metformin is a medication used to treat type 2 diabetes by inhibiting hepatic glucose production through adenosine monophosphate-activated protein kinase (AMPK) activation. Autophagy is closely related to the homeostasis and stress mechanisms of the body. In recent years, much research has arisen on therapeutic methods utilizing autophagy mechanisms to treat diagnoses such as metabolic diseases, tumors, and Alzheimer's disease. This study thus aimed to investigate the effects of metformin treatment on the differentiation of osteoclasts and changes in AMPK mechanisms, which play an important role in regulating energy homeostasis, and mTOR, a highly conserved kinase that regulates autophagy. MATERIALS AND METHODS: Experimentation, including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, tartrate-resistant acid phosphate (TRAP) staining, pit formation assay, immunofluorescence, western blotting, and real-time polymerase chain reaction (PCR) was performed to investigate the effects of metformin on osteoclast differentiation. Additionally, to investigate its association with AMPK and pathways, the AMPK inhibitor compound C and mammalian targets of rapamycin (mTOR) activator leucine were used to examine the expression of osteoclast- or autophagy-related proteins, genes, and TRAP-positive cells. RESULTS: Metformin showed no cytotoxic effects on mouse osteoblastic cell lines (MC3T3-E1) and murine macrophage cell lines (RAW264.7) but did inhibit osteoclast differentiation. Furthermore, metformin was found to inhibit osteoclast differentiation through AMPK activation and mTOR inhibition. In turn, AMPK inhibition using compound C promoted osteoclast differentiation, and mTOR activation using leucine inhibited autophagy and osteoclast differentiation. CONCLUSIONS: Metformin activates the AMPK pathway while functioning as an activator of mTOR, thereby leading to the inhibition of autophagy and osteoclast differentiation. [ABSTRACT FROM AUTHOR]

Resting heart rate (RHR), a simple physiological indicator, has been demonstrated to be associated with inflammation and even metabolic disorders. This study aimed to investigate whether RHR is associated with natural killer cell activity (NKA) in a large population of healthy adults using a novel assay to measure NKA. This cross-sectional study included 7,500 subjects in the final analysis. NKA was estimated by measuring the amount of interferon-gamma (IFN-γ) released by activated natural killer cells; low NKA was defined as IFN-γ level

Investment in U.S. real estate is becoming increasingly competitive due to increased capital flows and improving industry fundamentals. U.S. Real Estate Investment Trusts (REITs) are seeking new investment opportunities through international investments. This paper reviews the research literature to determine possible investor reaction to international diversification strategies by U.S. REITs and identifies recent diversification trends. We find that the US REITs that specialize in corporate real estate are beginning to diversify internationally through joint ventures with local firms. Empirical evidence shows that Tobin's Q ratios are positively related to international investment in 2003 when asset size and property types are controlled for. The relationship, however, disappeared in a 2006 sample., INTRODUCTION U.S. real estate investment has become increasingly competitive in the last few years due to increased capital flows and improving industry fundamentals. Real estate sales to institutional investors, including [...]