Characterization of rhodanine derivatives as potential disease-modifying drugs for experimental mouse osteoarthritis.

OBJECTIVE: This study was performed to characterize selected rhodanine derivatives as potential preclinical disease-modifying drugs for experimental osteoarthritis (OA) in mice. METHODS: Three rhodanine derivatives, designated rhodanine (R)-501, R-502, and R-503, were selected as candidate OA disease-modifying drugs. Their effects were evaluated by intra-articular (IA) injection in OA mouse models induced by DMM (destabilization of the medial meniscus) or adenoviral overexpression in joint tissues of hypoxia-inducible factor (HIF)-2α or zinc importer ZIP8. The regulatory mechanisms impacted by the rhodanine derivatives were examined in primary-culture chondrocytes and fibroblast-like synoviocytes (FLS). RESULTS: All three rhodanine derivatives inhibited OA development caused by DMM or overexpression of HIF-2α or ZIP8. Compared to vehicle-treated group, for example, IA injection of R-501 in DMM-operated mice reduced median OARSI grade from 3.78 (IQR 3.00-5.00) to 1.89 (IQR 0.94-2.00, P = 0.0001). R-502 and R-503 also reduced from 3.67 (IQR 2.11-4.56) to 2.00 (IQR 1.00-2.00, P = 0.0030) and 2.00 (IQR 1.83-2.67, P = 0.0378), respectively. Mechanistically, the rhodanine derivatives inhibited the nuclear localization and transcriptional activity of HIF-2α in chondrocytes and FLS. They did not bind to Zn2+ or modulate Zn2+ homeostasis in chondrocytes or FLS; instead, they inhibited the nuclear localization and transcriptional activity of the Zn2+-dependent transcription factor, MTF1. HIF-2α, ZIP8, and interleukin-1ß could upregulate matrix-degrading enzymes in chondrocytes and FLS, and the rhodanine derivatives inhibited these effects. CONCLUSION: IA administration of rhodanine derivatives significantly reduced OA pathogenesis in various mouse models, demonstrating that these derivatives have disease-modifying therapeutic potential against OA pathogenesis.

Improved Neutron Lifetime Measurement with UCNτ.

We report an improved measurement of the free neutron lifetime τ_{n} using the UCNτ apparatus at the Los Alamos Neutron Science Center. We count a total of approximately 38×10^{6} surviving ultracold neutrons (UCNs) after storing in UCNτ's magnetogravitational trap over two data acquisition campaigns in 2017 and 2018. We extract τ_{n} from three blinded, independent analyses by both pairing long and short storage time runs to find a set of replicate τ_{n} measurements and by performing a global likelihood fit to all data while self-consistently incorporating the ß-decay lifetime. Both techniques achieve consistent results and find a value τ_{n}=877.75±0.28_{stat}+0.22/-0.16_{syst} s. With this sensitivity, neutron lifetime experiments now directly address the impact of recent refinements in our understanding of the standard model for neutron decay.

Cell-free culture supernatant of Lactobacillus curvatus Wikim38 inhibits RANKL-induced osteoclast differentiation and ameliorates bone loss in ovariectomized mice.

This study was conducted to investigate the inhibitory effects of the cell-free culture supernatant of Lactobacillus curvatus Wikim 38 (LC38-CS) on RANKL-induced osteoclast differentiation and bone loss in a mice model of ovariectomy-induced post-menopausal osteoporosis. LC38-CS inhibited the RANKL-induced differentiation of bone marrow-derived macrophages (BMDMs) into osteoclasts in a dose-dependent manner. F-actin ring formation and bone resorption were also reduced by LC38-CS treatment of RANKL-treated BMDMs. In addition, LC38-CS decreased the RANKL-induced activation of the TRAF6/NF-κB/MAPKs axis at the early stage and the expression of osteoclastogenesis-related genes in BMDMs treated with RANKL. PRMT1 and ADMA levels, new biomarkers for osteoclastogenesis, were decreased by LC38-CS treatment. The administration of LC38-CS increased bone volume and bone mineral density in ovariectomized mice in µ-CT analysis. These findings suggest that LC38-CS inhibited RANKL-induced osteoclast differentiation by the downregulation of molecular mechanisms and exerted anti-osteoporotic effects.

Search for Sub-eV Sterile Neutrinos at RENO.

We report a search result for a light sterile neutrino oscillation with roughly 2200 live days of data in the RENO experiment. The search is performed by electron antineutrino (ν[over ¯]_{e}) disappearance taking place between six 2.8 GW_{th} reactors and two identical detectors located at 294 m (near) and 1383 m (far) from the center of the reactor array. A spectral comparison between near and far detectors can explore reactor ν[over ¯]_{e} oscillations to a light sterile neutrino. An observed spectral difference is found to be consistent with that of the three-flavor oscillation model. This yields limits on sin^{2}2θ_{14} in the 10^{-4}≲|Δm_{41}^{2}|≲0.5 eV^{2} region, free from reactor ν[over ¯]_{e} flux and spectrum uncertainties. The RENO result provides the most stringent limits on sterile neutrino mixing at |Δm_{41}^{2}|≲0.002 eV^{2} using the ν[over ¯]_{e} disappearance channel.

Topically applied treatments for external genital warts in nonimmunocompromised patients: a systematic review and network meta-analysis.

Selecting a topical treatment from among the numerous topical agents for external genital warts remains challenging without clear evidence. Our aim was to evaluate comparatively the efficacy and safety of topical agents for external genital warts using a network meta-analysis. We included all randomized controlled trials that evaluated any topically applied treatment for external genital warts. Using the R package netmeta, network meta-analyses were performed with a frequentist approach. We identified 41 relevant studies comprising 6371 patients. Among conventional agents, podophyllotoxin 0·5% solution (odds ratio 1·94, 95% confidence interval 1·02-3·71) was significantly more efficacious than imiquimod 5% cream for lesion clearance; however, it was associated with a higher overall adverse event rate. Sinecatechins 15% ointment (odds ratio 0·21, 95% confidence interval 0·12-0·34) was significantly less efficacious than imiquimod 5% cream. Idoxuridine, polyhexamethylene biguanide, cidofovir and SB206 showed comparable therapeutic efficacies with conventional therapies. None of the treatments were significantly different from each other with respect to recurrence, patients with severe adverse events, or patients who withdrew because of treatment-related adverse events. Conventional modalities were efficacious and well tolerated, although each of them had their advantages and disadvantages. Additional efficacy and safety studies are warranted for unconventional agents.

Lack of association between early menopause and non-alcoholic fatty liver disease in postmenopausal women.

Background: The possibility of an association between early menopause and the risk of non-alcoholic fatty liver disease (NAFLD) is as yet unclear.Methods: The subjects consisted of 4354 postmenopausal women who participated in the 2010-2012 Korea National Health and Nutrition Examination Survey. Early, normal, and late menopause were defined as age at menopause <45 years, 45-54 years, and ≥55 years, respectively. NAFLD was defined by a hepatic steatosis index of >36.Results: When compared with normal menopausal women, early or late menopausal women had no significant differences in the odds ratios (ORs) of NAFLD: OR = 1.05, 95% confidence interval (CI), 0.83-1.32 and OR = 1.02, 95% CI, 0.75-1.39, respectively. These results remained similar after adjustment for known risk factors for NAFLD, reproductive factors, and comorbidities. The OR for NAFLD per 1-year increase in age at menopause was 1.01 (95% CI, 0.99-1.03; p = 0.329). The prevalence of advanced fibrosis was 2.1% (95% CI, 0.7-6.4%), 2.2% (95% CI, 1.3-3.8%), and 3.9% (95% CI, 1.2-12.2%) in early, normal, and late menopausal women, respectively.Conclusions: This study provides no evidence for an association of early menopause with NAFLD risk. However, NAFLD-related advanced fibrosis is highly prevalent in postmenopausal women.

Fuel-Composition Dependent Reactor Antineutrino Yield at RENO.

We report a fuel-dependent reactor electron antineutrino (ν[over ¯]_{e}) yield using six 2.8 GW_{th} reactors in the Hanbit nuclear power plant complex, Yonggwang, Korea. The analysis uses 850 666 ν[over ¯]_{e} candidate events with a background fraction of 2.0% acquired through inverse beta decay (IBD) interactions in the near detector for 1807.9 live days from August 2011 to February 2018. Based on multiple fuel cycles, we observe a fuel ^{235}U dependent variation of measured IBD yields with a slope of (1.51±0.23)×10^{-43} cm^{2}/fission and measure a total average IBD yield of (5.84±0.13)×10^{-43} cm^{2}/fission. The hypothesis of no fuel-dependent IBD yield is ruled out at 6.6σ. The observed IBD yield variation over ^{235}U isotope fraction does not show significant deviation from the Huber-Mueller (HM) prediction at 1.3 σ. The measured fuel-dependent variation determines IBD yields of (6.15±0.19)×10^{-43} and (4.18±0.26)×10^{-43} cm^{2}/fission for two dominant fuel isotopes ^{235}U and ^{239}Pu, respectively. The measured IBD yield per ^{235}U fission shows the largest deficit relative to the HM prediction. Reevaluation of the ^{235}U IBD yield per fission may mostly solve the reactor antineutrino anomaly (RAA) while ^{239}Pu is not completely ruled out as a possible contributor to the anomaly. We also report a 2.9 σ correlation between the fractional change of the 5 MeV excess and the reactor fuel isotope fraction of ^{235}U.

Correction to: Factors associated with poorer outcomes in the surgical treatment of multiligament knee injuries.

The author would like to correct the following errors in the publication of the original article.

Factors predictive of poorer outcomes in the surgical repair of multiligament knee injuries.

PURPOSE: To investigate the influence of injury and treatment factors on clinical/functional outcomes in multiligament knee injuries (MLKI). METHODS: Thirty-nine consecutive patients with confirmed and surgically treated MLKI who met inclusion criteria were scheduled for a follow-up visit to obtain: SF-12 and subjective feeling of normalcy between the operated and healthy knee, and IKDC, active range of motion (ROM), and stability exam (Lachman test, posterior drawer, and dial test at 30°). A chart review was used to obtain data on injury and treatment factors. RESULTS: The postoperative mean (SD) outcomes were: IKDC score 62.7 (25.9), flexion-extension ROM 125° (29°), and percentage of normalcy 74% (20%). The postoperative normal/nearly normal stability exam was: Lachman test 36 (95%) patients, posterior drawer at 90° 38 (97%) patients, and dial test of 39 (100%) patients. There were 24 (61.5%) and 23 (59%) patients with complications and reoperations, respectively. The presence of bicruciate injuries was associated with worse Lachman (p = 0.03) and posterior drawer tests (p = 0.03). Presence of injury to meniscal structures was associated with worse Lachman test (p = 0.03), lower percentage of normalcy (p = 0.02) and extension lag (p = 0.04). Injury to cartilage structures was associated with worse IKDC scores (p = 0.04). IKDC was lower in cases of posterolateral corner reconstruction (p = 0.03) and use of allograft tendons for reconstruction (p = 0.02); ROM was lower in allograft reconstruction (p = 0.02) and need for meniscal repair (p = 0.01). Bicruciate reconstruction led to worst posterior drawer test (p = 0.006). CONCLUSIONS: The outcomes of MLKI might be negatively influenced by bicruciate ligament, meniscal, and cartilage injuries; with regards to treatment characteristics, need for posterolateral corner or bicruciate ligament reconstruction, use of allografts, or need for meniscal repair may similarly diminish outcomes. While surgical treatment provides good overall function, ROM and stability, it rarely results in a "normal" knee and the chances of complications and reoperations are high. LEVEL OF EVIDENCE: Cross-sectional comparative study, Level III.

Global transcriptome analysis identifies weight regain-induced activation of adaptive immune responses in white adipose tissue of mice.

OBJECTIVE: Studies have indicated that weight regain following weight loss predisposes obese individuals to metabolic disorders; however, the molecular mechanism of this potential adverse effect of weight regain is not fully understood. Here we investigated global transcriptome changes and the immune response in mouse white adipose tissue caused by weight regain. DESIGN: We established a diet switch protocol to compare the effects of weight regain with those of weight gain without precedent weight loss, weight loss maintenance and chow diet. We conducted a time course analysis of global transcriptome changes in gonadal white adipose tissue (gWAT) during the weight fluctuation. Co-expression network analysis was used to identify functional modules associated with the weigh regain phenotype. Immune cell populations in gWAT were characterized by flow-cytometric immunophenotyping. Metabolic phenotypes were monitored by histological analysis of adipose tissue and liver, and blood-chemistry and body weight/composition analyses. RESULTS: In total, 952 genes were differentially expressed in the gWAT in the weight regain vs the weight gain group. Upregulated genes were associated with immune response and leukocyte activation. Co-expression network analysis showed that genes involved in major histocompatibility complex I and II-mediated antigen presentation and T-cell activation function were upregulated. Consistent with the transcriptome analysis results, flow cytometry demonstrated significant increases in subsets of T cells and proinflammatory M1 macrophages in the gWAT in the weight regain as compared to the weight gain group. In addition, upregulation of adaptive immune responses was associated with high incidence of adipocyte death and upregulation of high mobility group box 1, a well-known component of damage-associated molecular patterns. CONCLUSIONS: Our global transcriptome analysis identified weight regain-induced activation of adaptive immune responses in mouse white adipose tissue. Results suggest that activation of adipocyte death-associated adaptive immunity in adipose tissue may contribute to unfavorable metabolic effects of weight regain following weight loss.

Measurement of Reactor Antineutrino Oscillation Amplitude and Frequency at RENO.

The RENO experiment reports more precisely measured values of θ_{13} and |Δm_{ee}^{2}| using ∼2200 live days of data. The amplitude and frequency of reactor electron antineutrino (ν[over ¯]_{e}) oscillation are measured by comparing the prompt signal spectra obtained from two identical near and far detectors. In the period between August 2011 and February 2018, the far (near) detector observed 103 212 (850 666) ν[over ¯]_{e} candidate events with a background fraction of 4.8% (2.0%). A clear energy and baseline dependent disappearance of reactor ν[over ¯]_{e} is observed in the deficit of the measured number of ν[over ¯]_{e}. Based on the measured far-to-near ratio of prompt spectra, we obtain sin^{2}2θ_{13}=0.0896±0.0048(stat)±0.0047(syst) and |Δm_{ee}^{2}|=[2.68±0.12(stat)±0.07(syst)]×10^{-3} eV^{2}.

Search for the Neutron Decay n→X+γ, Where X is a Dark Matter Particle.

Fornal and Grinstein recently proposed that the discrepancy between two different methods of neutron lifetime measurements, the beam and bottle methods, can be explained by a previously unobserved dark matter decay mode, n→X+γ. We perform a search for this decay mode over the allowed range of energies of the monoenergetic γ ray for X to be dark matter. A Compton-suppressed high-purity germanium detector is used to identify γ rays from neutron decay in a nickel-phosphorous-coated stainless-steel bottle. A combination of Monte Carlo and radioactive source calibrations is used to determine the absolute efficiency for detecting γ rays arising from the dark matter decay mode. We exclude the possibility of a sufficiently strong branch to explain the lifetime discrepancy with 97% confidence.

Forebrain-specific ablation of phospholipase Cγ1 causes manic-like behavior.

Manic episodes are one of the major diagnostic symptoms in a spectrum of neuropsychiatric disorders that include schizophrenia, obsessive-compulsive disorder and bipolar disorder (BD). Despite a possible association between BD and the gene encoding phospholipase Cγ1 (PLCG1), its etiological basis remains unclear. Here, we report that mice lacking phospholipase Cγ1 (PLCγ1) in the forebrain (Plcg1f/f; CaMKII) exhibit hyperactivity, decreased anxiety-like behavior, reduced depressive-related behavior, hyperhedonia, hyperphagia, impaired learning and memory and exaggerated startle responses. Inhibitory transmission in hippocampal pyramidal neurons and striatal dopamine receptor D1-expressing neurons of Plcg1-deficient mice was significantly reduced. The decrease in inhibitory transmission is likely due to a reduced number of γ-aminobutyric acid (GABA)-ergic boutons, which may result from impaired localization and/or stabilization of postsynaptic CaMKII (Ca2+/calmodulin-dependent protein kinase II) at inhibitory synapses. Moreover, mutant mice display impaired brain-derived neurotrophic factor-tropomyosin receptor kinase B-dependent synaptic plasticity in the hippocampus, which could account for deficits of spatial memory. Lithium and valproate, the drugs presently used to treat mania associated with BD, rescued the hyperactive phenotypes of Plcg1f/f; CaMKII mice. These findings provide evidence that PLCγ1 is critical for synaptic function and plasticity and that the loss of PLCγ1 from the forebrain results in manic-like behavior.

Neutrophilic urticarial dermatosis and Sweet-like neutrophilic dermatosis: under-recognized neutrophilic dermatoses in lupus erythematosus.

Background/Objectives Neutrophilic dermatoses can be associated with autoimmune connective tissue diseases such as systemic lupus erythematosus (SLE). We analyzed clinical and histological features of neutrophilic urticarial dermatosis (NUD) and Sweet-like neutrophilic dermatosis (SLND)-the most recently delineated entities of the neutrophilic dermatoses. Methods We retrieved database medical records of patients with SLE whose skin biopsy demonstrated a neutrophilic-predominant infiltrate of the skin, and included those whose biopsies revealed findings of SLND or NUD. Results SLND skin lesions lasted longer than those of NUD and were localized to sun-exposed areas. All NUD cases resolved within one week either spontaneously or with treatment such as antihistamines, but SLND skin lesions lasted longer than one week; prednisone was used in four of these five patients. All NUD cases were found in existing SLE patients and were not associated with systemic signs of flare-up of SLE. However, 80% of SLND cases experienced flare-up of SLE; and in 60%, SLND developed concomitantly with SLE as a presenting sign. Conclusion Different clinical courses and relationships with SLE suggest that NUD and SLND have different pathogeneses for neutrophilic inflammatory reactions.

The relationship between clinical characteristics including presence of exposed lesions and health-related quality of life (HRQoL) in patients with psoriasis: analysis from the nationwide epidemiologic study for psoriasis in Korea (EPI-PSODE study).

BACKGROUND: Psychological aspect and quality of life should be considered in treating patients with psoriasis. OBJECTIVE: We sought to ascertain which clinical characteristics including presence of exposed lesions are associated with impairment of health-related quality of life (HRQoL) in patients with psoriasis. METHODS: The EPI-PSODE study was a nationwide, multicenter, cross-sectional study conducted in Korea that included 1260 adult patients with psoriasis. In addition to clinical characteristics including presence of exposed lesions, data were collected using the Psoriatic Arthritis (PsA) Screening and Evaluation (PASE), Dermatology Life Quality Index (DLQI), MOS 36-Item Short-Form Health Survey (SF-36), Work Productivity and Activity Impairment Questionnaire Psoriasis (WPAI: PSO) and Medication Satisfaction Questionnaire (MSQ). RESULTS: Patients with a DLQI score > 5 (n = 990) were younger, had an earlier onset of psoriasis, scored higher on the Psoriasis Area and Severity Index (PASI), had higher body surface area (BSA) and had higher PASE scores than patients with DLQI ≤ 5 (n = 266). The group of patients with exposed lesions (n = 871) were younger and male predominance, earlier onset of psoriasis, longer disease duration, higher PASI/BSA score and a higher proportion with drinking and smoking history each than the group of patients without exposed lesions (n = 389). Presence of exposed lesions negatively influenced DLQI, 36-Item Short-Form Health Survey (SF-36) (mental component), presenteeism, total work productivity impairment and total activity impairment in the WPAI: PSO. In multiple regression model, PASI score was the only variable which was significantly associated with all HRQoL measures. Presence of exposed lesions was a significant factor affecting DLQI and SF-36 (mental). CONCLUSION: The presence of exposed lesions has a negative impact on quality of life, mental health and work productivity. Therefore, effective treatments are particularly needed for psoriasis patients with exposed lesions.

Development and clinical application of an evidence-based pharmaceutical care service algorithm in acute coronary syndrome.

WHAT IS KNOWN AND OBJECTIVE: Drug therapies are critical for preventing secondary complications in acute coronary syndrome (ACS). The purpose of this study was to develop and apply a pharmaceutical care service (PCS) algorithm for ACS and confirm that it is applicable through a prospective clinical trial. METHODS: The ACS-PCS algorithm was developed according to extant evidence-based treatment and pharmaceutical care guidelines. Quality assurance was conducted through two methods: literature comparison and expert panel evaluation. The literature comparison was used to compare the content of the algorithm with the referenced guidelines. Expert evaluations were conducted by nine experts for 75 questionnaire items. A trial was conducted to confirm its effectiveness. Seventy-nine patients were assigned to either the pharmacist-included multidisciplinary team care (MTC) group or the usual care (UC) group. The endpoints of the trial were the prescription rate of two important drugs, readmission, emergency room (ER) visit and mortality. RESULTS AND DISCUSSION: The main frame of the algorithm was structured with three tasks: medication reconciliation, medication optimization and transition of care. The contents and context of the algorithm were compliant with class I recommendations and the main service items from the evidence-based guidelines. Opinions from the expert panel were mostly positive. There were significant differences in beta-blocker prescription rates in the overall period (P = .013) and ER visits (four cases, 9.76%, P = .016) in the MTC group compared to the UC group, respectively. WHAT IS NEW AND CONCLUSION: We developed a PCS algorithm for ACS based on the contents of evidence-based drug therapy and the core concept of pharmacist services.

Effects of clioquinol on the scuticociliatosis-causing protozoan Miamiensis avidus in olive flounder Paralichthys olivaceus.

Scuticociliatosis is a devastating and intractable protozoal disease in olive flounder, leading to a significant loss throughout the year. This study aimed to investigate a systemically effective antiscuticociliatosis agent for olive flounder for better absorption into the infected internal organs. The in vitro and in vivo antiscuticociliatosis effects of clioquinol (CQ) were examined after screening 30 biocidal agents against the highly pathogenic scuticociliate Miamiensis avidus. CQ was the most potent in vitro drug of those tested against cultured M. avidus. CQ was the least toxic in healthy olive flounder among the drugs that exhibit high potencies. In olive flounder, a single intramuscular injection of 40 mg/kg CQ significantly reduced mortality caused by artificial infection with M. avidus, and 10-20 mg/kg CQ increased fish survival times. CQ was also effective in naturally infected scuticociliatosis. Ciliate cell numbers were lower when CQ was injected in most organs, including the brain. CQ was well absorbed by the internal organs after intramuscular injection. This study suggests that CQ can be considered as a potential antiscuticociliatosis agent for systemic administration in olive flounder.

The Processing Time for Recanalization and Size of Ischemic Lesions on DWI is Related With Complete Reperfusion After Mechanical Thrombectomy.

Recent studies demonstrated that modified thrombolysis in cerebral infarction (TICI) 3 reperfusion have better functional outcomes than modified TICI 2b after mechanical thrombectomy in acute ischemic stroke with large vessel occlusion. The purpose of this study was to determine significant factors to forecast the presence of complete reperfusion after mechanical thrombectomy based on multimodal magnetic resonance imaging (MRI). We investigated 96 consecutive patients with acute large intracranial artery occlusion of anterior circulation who based on multimodal MRI. Also, we compared clinical and radiologic parameters between patients with modified TICI 3 and those with modified TICI 0-2b. Among 96 eligible subjects received mechanical thrombectomy, 39 patients (40.6%) showed complete reperfusion and 57 partial or nonreperfusion (mTICI 2b-26, mTICI 2a-9, mTICI 1-8, and mTICI 0-14) after mechanical thrombectomy. Patients with mTICI 3 had significantly smaller initial Diffusion weighted images (DWI) lesion volume (P < .01) and much shorter time interval from onset to reperfusion (P < .01) than those patients with mTICI (0-2b). In multivariate analysis, smaller initial DWI volume (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.23-2.57; P < .01) and faster reperfusion time (OR, 1.07; 95% CI 1.01-1.14; P = .015) had an independence significance for complete reperfusion after mechanical thrombectomy. In this study, the ischemic lesion volume on DWI and faster processing time are critical factor to predict the state of complete reperfusion after mechanical thrombectomy.

A pharmacogenomic study on the pharmacokinetics of tacrolimus in healthy subjects using the DMETTM Plus platform.

Genetic association studies on the pharmacokinetics of tacrolimus have reported conflicting results, except for the role of the CYP3A5*3 polymorphism. The objective of this study was to identify genetic variants affecting the pharmacokinetics of tacrolimus using the DMETTM Plus microarray in 42 healthy males. Aside from CYP3A5*3, the rs3814055 polymorphism in the NR1I2 gene was associated with the tacrolimus pharmacokinetics based on false discovery rate-corrected multiple tests and the least absolute shrinkage and selection operator analysis. The area under the concentration-time curve to the last quantifiable time point (AUClast) was 3.42 times greater in subjects with homozygous mutations in both genes (CYP3A5*3/*3 and NR1I2 T/T) than in wild-type subjects. The two variants explained the 54% variability in the tacrolimus AUClast. An in vitro luciferase reporter assay indicated that downregulation of PXR expression is the likely molecular mechanism responsible for the increased exposure to tacrolimus in subjects carrying the rs3814055 C>T variant.