Clinical implication of children's depression rating scale-revised score: Linking the children's depression rating scale-revised score and clinical global impression using patients data from clinical trials.

Background and Aims: The Children's Depression Rating Scale-Revised (CDRS-R) score has been widely used to assess the severity of major depression in children and adolescents; however, the clinical implications of changes in the CDRS-R score remain unclear. We evaluated these clinical implications by assessing the relationship between changes in the CDRS-R score and changes in the Clinical Global Impression of Improvement (CGI-I), in clinical research on major depression. Methods: We used data from four clinical trials involving two antidepressants and evaluated the relationship between CDRS-R score changes and the CGI-I score using the equipercentile linking method. Results: CDRS-R score changes corresponding to a minimally improved (score of 3) CGI-I score was approximately 14 points. Conclusion: Our findings from the linking analyses are useful for interpreting the clinical implications of changes in the CDRS-R score.

Efficacy and safety of equine anti-thymocyte immunoglobulin (eATG) in three Japanese patients with moderate to very severe aplastic anemia: a case series.

Aplastic anemia results from lymphocyte-mediated destruction of hematopoietic stem cells. Immunosuppressive therapy with anti-thymocyte globulin (ATG) and cyclosporine is the standard front-line treatment for patients with severe aplastic anemia who are not suitable candidates for stem cell transplants. PF-06462700 is a potent equine ATG that targets T-lymphocytes and has been approved as a treatment for aplastic anemia outside of Japan for over 30 years. Due to the high medical need for PF-06462700, the Ministry of Health, Labor and Welfare requested its development for Japanese patients with aplastic anemia. In this case series, the efficacy and safety of PF-06462700, administered intravenously at 40 mg/kg/day for 4 days, were assessed over a 24-week period. This was as an open-label, single-arm, multicenter clinical study designed to enroll a minimum of three Japanese participants with aplastic anemia. Two participants met the primary outcome of hematologic response at week 12 and improvements in disease severity were observed. No deaths or serious adverse events were reported. The efficacy results from this case series suggest that administration of PF-06462700 is generally well-tolerated and produces a hematologic response in Japanese patients with aplastic anemia, which should be further evaluated in real-world studies.ClinicalTrials.gov identifier: NCT04350606.

Efficacy, General Safety, and Joint Safety of Tanezumab in Japanese Patients with Osteoarthritis: Subgroup Analyses from Two Randomized, Phase 3 Studies.

INTRODUCTION: Tanezumab is a monoclonal antibody against nerve growth factor that is under investigation for the treatment of osteoarthritis (OA) pain. We conducted subgroup analyses of two randomized phase 3 studies to summarize efficacy, general safety, and adjudicated joint safety of tanezumab in Japanese patients with moderate-to-severe OA. METHODS: In Study 1 (NCT02528188), patients received subcutaneous tanezumab 2.5 mg or 5 mg every 8 weeks or daily oral nonsteroidal anti-inflammatory drugs (NSAID) for 56 weeks. The co-primary efficacy endpoints were change from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain subscale score and WOMAC Physical Function subscale score at Week 16 (overall study and Japan-specific endpoints) as well as Patient Global Assessment (PGA)-OA score at Week 16 (overall study endpoint only). In Study 2 (NCT02709486), patients received subcutaneous tanezumab 2.5 mg, 5 mg, or placebo every 8 weeks for 24 weeks. Safety monitoring included adjudicated composite joint safety endpoint (CJSE) including rapidly progressive osteoarthritis type 1 (RPOA1), RPOA2, primary osteonecrosis, pathological fracture, or subchondral insufficiency fracture. RESULTS: For Study 1, Japanese patients (n = 200) treated with tanezumab 2.5 mg and 5 mg showed numerically greater improvements in WOMAC Pain, WOMAC Physical Function, and PGA-OA scores versus NSAID at Week 16. Incidences of treatment-emergent adverse events were generally similar between tanezumab 2.5 mg, 5 mg, and NSAID groups. In the integrated safety analysis (Studies 1 + 2; n = 306), ten patients were adjudicated to have a component of CJSE: RPOA1 [tanezumab 2.5 mg (n = 2), tanezumab 5 mg (n = 5)], RPOA2 [tanezumab 2.5 mg (n = 1), tanezumab 5 mg (n = 1)], or primary osteonecrosis [tanezumab 2.5 mg (n = 1)]. Time-adjusted adjudicated rates of RPOA1 and RPOA2 were higher with tanezumab than NSAID or placebo and increased with dose of tanezumab. CONCLUSION: Observations from the Japanese subgroup were generally consistent with the overall study populations.

Item Response Analyses of the Children's Depression Rating Scale-Revised Using Data from Clinical Studies.

Objective: We aimed to identify which of the 17 items comprising the Children's Depression Rating Scale-Revised (CDRS-R) can sensitively capture changes in depression severity. Methods: We used data from four studies involving two antidepressants. For each of the 17 CDRS-R items, we conducted item response analyses to identify and evaluate those that reflect changes in depression severity. We created plots of the item characteristic curves (ICCs) estimated by the graded response model, and option characteristic curves and ICCs using nonparametric item response theory. The change from baseline in the CDRS-R subscale score with specified reflective items by item response analyses and the effect size between the treatment group and placebo group were calculated and compared with those of the CDRS-R total score. Results: CDRS-R items #2 (difficulty having fun), #3 (social withdrawal), #10 (low self-esteem), #11 (depressed feelings), and #15 (depressed facial expression) have favorable profiles that reflect disease severity. Changes from baseline in the CDRS-R total score (least square mean ± standard error) at week 8 were -22.3 ± 0.7 and -23.9 ± 0.7 in the placebo group and treatment group, respectively (difference, -1.5; estimated effect size, -0.113), changes from baseline in the CDRS-R5 (CDRS-R subscale consisting of the specified reflective items [#2, #3, #10, #11, and #15]) score at week 8 were -8.4 ± 0.3 and -9.6 ± 0.3 in each group, respectively (difference, -1.2; effect size, -0.202). Conclusions: The item response analyses clarified the properties of 17 items of the CDRS-R for major depressive disorder in children and adolescents. The CDRS-R5 might optimize the assessment of changes in overall depression severity and differentiation of treatment responses.

Tanezumab for chronic low back pain: a long-term, randomized, celecoxib-controlled Japanese Phase III safety study.

Aim & methods: This trial investigated long-term (56-week treatment/24-week follow-up) use of subcutaneous tanezumab (5 or 10 mg every 8 weeks) or oral celecoxib (200 mg/day) in Japanese patients with chronic low back pain. Results & conclusion: Tanezumab safety was consistent with previous studies, except overall adverse events (tanezumab 5 mg = 63.0%, tanezumab 10 mg = 54.8%, celecoxib = 67.4%) and events of abnormal peripheral sensation (tanezumab 5 mg = 9.8%, tanezumab 10 mg = 4.3%, celecoxib = 4.3%) were more frequent with 5 mg than 10 mg tanezumab. Joint safety event rates were 1.1% for tanezumab 5 mg, 2.2% for tanezumab 10 mg and 0% for celecoxib. All treatments improved pain and function throughout the treatment period. Clinical trial registration number: NCT02725411.

In this study, researchers looked at the safety of tanezumab (a medication that blocks nerve growth factor) in Japanese people with chronic low back pain (CLBP). Researchers also looked at how well tanezumab improves the symptoms (pain and difficulty doing activities) of CLBP. People in the study were given oral (taken by mouth) celecoxib (a medication commonly used to treat CLBP) or injections of tanezumab (5 or 10 mg doses) under the skin of the belly or upper leg every 8 weeks for a total of 56 weeks. Side effects (something expected or unexpected that people experienced during the study that may or may not be due to the medication they received) occurred in 63.0% of people receiving tanezumab 5 mg, 54.8% of people receiving tanezumab 10 mg and 67.4% of patients receiving celecoxib. More people receiving tanezumab 5 mg (9.8% of people) had a side effect related to abnormal peripheral sensation (tingling, burning, numbness or sensitivity to heat or cold hands or feet) than people receiving tanezumab 10 mg (4.3% of people) or celecoxib (4.3% of people). More people receiving tanezumab (5 mg = 1.1% of people, 10 mg = 2.2% of people) had a problem with one of their joints (knees or hips) during the study than people receiving celecoxib (0% of people). All treatments improved pain and the ability to do activities. Overall, the researchers concluded that tanezumab was well tolerated in most people and may improve the symptoms of CLBP.

Clinical and Tumor Characteristics of Patients with High Serum Levels of Growth Differentiation Factor 15 in Advanced Pancreatic Cancer.

We aimed to evaluate the association of circulating growth differentiation factor 15 (GDF-15) with cachexia symptoms and the biological activity of advanced pancreatic cancer (APC). Treatment-naïve patients with liver metastasis of APC or with benign pancreatic disease were retrospectively analyzed. Clinical data, blood samples, and biopsy specimens of liver metastasis were collected prior to anti-cancer treatment. Serum GDF-15 levels and multiple protein expressions in lysates extracted from liver metastasis were measured by enzyme-linked immuno-sorbent assay and reverse-phase protein array, respectively. The cut-off for serum GDF-15 was determined as 3356.6 pg/mL, the mean plus two standard deviations for benign pancreatic disease. The high-GDF-15 group was characterized as showing low Karnofsky performance status (KPS) (p = 0.037), poor Eastern Cooperative Oncology Group performance status (ECOG-PS) (p = 0.049), severe appetite loss (p = 0.011), and high serum levels of carbohydrate antigen 19-9 (p = 0.019) and C-reactive protein (p = 0.009). Tumors of the high-GDF-15 group expressed high levels of phosphorylated (p)JNK (p = 0.007) and pAkt (p = 0.040). APC patients with high serum GDF-15 showed signatures of cachexia and activation of the signaling pathways involving Akt and JNK in the tumor. This study indicated circulating GDF-15 could be associated with cachectic symptoms in APC.

Clinical Comparison of Unilateral Biportal Endoscopic Laminectomy versus Microendoscopic Laminectomy for Single-Level Laminectomy: A Single-Center, Retrospective Analysis.

BACKGROUND: The purpose of this study was to compare clinical results of microendoscopic laminectomy (MEL) with those of unilateral biportal endoscopic laminectomy (UBEL) in patients with single-level lumbar spinal canal stenosis. METHODS: The subjects consisted of 181 patients who underwent MEL (139 cases) and UBEL (42 cases) who were followed up for at least 6 months. All patients had lumber canal stenosis for 1 level. Outcomes of the patients were assessed with the duration of surgery, the bone resection area in 3-dimensional computed tomography, the facet preservation rates in computed tomography axial imagery, Visual Analog Scale (VAS) for low back pain, the Oswestry Disability Index, and the EuroQol 5-Dimensions questionnaire. RESULTS: The bone resection area in 3-dimensional computed tomography was 1.5 for MEL versus 1.0 cm2 for UBEL (P < 0.05). The facet preservation rates on the advancing side and the opposite side were 78% versus 86% (advancing side: MEL vs. UBEL) and 85% versus 94% (opposite side) (P < 0.05). The VAS (low back pain) score, VAS (leg pain), Oswestry Disability Index, and EuroQol 5-Dimension questionnaire significantly dropped in both groups at the final period (P < 0.05), however, exhibiting no difference between the 2 groups at each period. MEL resulted in greater numbers of complications, including 5 cases of hematoma paralysis, 8 cases of dura injury, 2 cases of reoperation, as opposed to zero cases of hematoma paralysis and only 2 cases of dura injury resulting from UBEL. CONCLUSIONS: The UBEL method is a more useful technique than the MEL method as it requires a smaller bone resection area and produces fewer complications.

Effect of riboflavin deficiency on development of the cerebral cortex in Slc52a3 knockout mice.

Riboflavin transporter 3 (RFVT3), encoded by the SLC52A3 gene, is important for riboflavin homeostasis in the small intestine, kidney, and placenta. Our previous study demonstrated that Slc52a3 knockout (Slc52a3-/-) mice exhibited neonatal lethality and metabolic disorder due to riboflavin deficiency. Here, we investigated the influence of Slc52a3 gene disruption on brain development using Slc52a3-/- embryos. Slc52a3-/- mice at postnatal day 0 showed hypoplasia of the brain and reduced thickness of cortical layers. At embryonic day 13.5, the formation of Tuj1+ neurons and Tbr2+ intermediate neural progenitors was significantly decreased; no significant difference was observed in the total number and proliferative rate of Pax6+ radial glia. Importantly, the hypoplastic phenotype was rescued upon riboflavin supplementation. Thus, it can be concluded that RFVT3 contributes to riboflavin homeostasis in embryos and that riboflavin itself is required during embryonic development of the cerebral cortex in mice.

Postoperative Outcomes After Transsacral Epiduroscopic Laser Decompression in Japanese Patients: Denervation Therapy for Discogenic Low-Back Pain.

Background: Transsacral epiduroscopic laser decompression (SELD) is a very noninvasive surgery, so it is effective for elderly patients and athletes and is a new and minimally invasive therapeutic technique that may be useful in many patients with discogenic low-back pain (LBP) having high signal intensity zone (HIZ) in magnetic resonance imaging (MRI). We investigated the clinical outcomes of SELD in Japanese patients with discogenic LBP having HIZ as a first trial. Methods: The subjects consisted of 52 patients who underwent SELD and were followed up for at least 6 months. All patients with LBP with HIZ were operative using the SELD technique. Outcomes of the patients were assessed with visual analogue scale (VAS) for LBP, the Oswestry disability index (ODI), and the EuroQol 5 dimension (EQ-5D). Statistical analyses were carried out using a paired t-test. A p-value of <0.05 was considered significant. For statistical analysis, we used the SPSS software program. Results: At 12 months after the procedure, the average VAS score for LBP fell to 1.2 from 5.6 (p-value <0.05). The ODI score also dropped from the preoperative level of 22.3 to 8.8. The EQ-5D score also significantly increased from the preoperative level of 0.865 (SD 0.10) to 0.950 (SD 0.05). Eight cases of intraoperative cervical pain were observed as complications with no cases of hematomas, infections, and postoperative neurosis was observed. Conclusions: SELD provides a novel minimally invasive technique capable of performing multilevel intervertebral surgery. We believe that SELD is an effective method of treating discogenic LBP due to HIZs.

Changes in thermal comfort, core temperature, and body weight during simulated parcel home-delivery in summer and winter.

Our aim was to determine differences in thermal comfort during simulated one-day parcel home delivery between summer and winter. Six young healthy males performed experiments in summer (up to 31°C) and winter (up to 8°C). After baseline measurement in a chamber, subjects drove a truck to a prespecified location for outside measurements. They performed 4 sets of 100-m walk with carrying 5-kg plate during the first 50-m walk at 100 m/min, separated by 7-min driving in each of the morning and the afternoon. Subjects could ingest water ad libitum in outside and set the cockpit temperature by themselves during driving. Thermal sensation and comfort were recorded using a subjective scale at the first and the last sets of each morning and afternoon session, while esophageal temperature (Tes) was monitored (thermocouples). Body weight was measured before and the end of experiment. We found that 1) whole-body comfort decreased in summer and the decrease was greater than winter with higher Tes and 2) changes in body weight were 0.7 and 0.3 kg through whole day in summer and winter, respectively. In summary, thermal comfort during working worsened in summer, possibly related with higher core temperature and greater decrease in body weight.

Layer-specific myocardial function in asymptomatic cats with obstructive hypertrophic cardiomyopathy assessed using 2-dimensional speckle-tracking echocardiography.

BACKGROUND: Hypertrophic cardiomyopathy (HCM), a primary disorder of the myocardium, is the most common cardiac disease in cats. However, determination of layer-specific myocardial function with 2D speckle-tracking echocardiography in cats with asymptomatic HCM has not yet been reported. OBJECTIVES: To quantitatively measure layer-specific myocardial function of asymptomatic cats with HCM. ANIMALS: Ten client-owned, asymptomatic cats with obstructive HCM and 13 healthy cats. METHODS: A retrospective, case-control study. Cats underwent assessment of layer-specific myocardial function (whole, endocardial, and epicardial) in the longitudinal and circumferential directions by using 2D speckle-tracking echocardiography. RESULTS: Longitudinal strains were significantly lower in cats with HCM than controls in the whole (-15.5% vs -19.1%), endocardial (-18.3% vs -21.8%), and epicardial (-13.1% vs -16.8%) layers. Circumferential strains in whole and epicardial layers also were significantly lower in cats with HCM as compared with controls (-15.0% vs -20.2% and - 4.4% vs -9.4%, respectively). However, no significant difference was found between cats with HCM and controls in the global circumferential strain in the endocardial layer (-31.2% vs -34.2%). The circumferential endocardial-to-epicardial strain ratio was significantly higher in cats with HCM than in controls (6.1 vs 3.5). CONCLUSIONS AND CLINICAL IMPORTANCE: Layer-specific myocardial function assessed by 2D speckle-tracking echocardiography differed in asymptomatic cats with obstructive HCM compared to controls despite their apparently normal systolic function, as determined by conventional echocardiography. The maintained endocardial circumferential strain and higher circumferential endocardial-to-epicardial strain ratio may reflect compensation for occult systolic dysfunction in cats with obstructive HCM.

Severe oesophageal constriction due to an aberrant right subclavian artery with Kommerell's diverticulum in a cat.

CASE SUMMARY: A 6-month-old female cat with a history of chronic regurgitation presented with weight loss. CT angiography (CTA) showed severe constriction of the oesophagus due to an aberrant right subclavian artery and Kommerell's diverticulum. The cat was surgically treated and remained clinically normal. More than 1 year after surgery, the general condition of the cat was stable and body weight had increased. RELEVANCE AND NOVEL INFORMATION: This case report describes the clinical findings and surgical management of a cat diagnosed with severe oesophageal constriction caused by an aberrant right subclavian artery with Kommerell's diverticulum (markedly dilated origin of the aberrant right subclavian artery), which are rare vascular anomalies in veterinary medicine and specifically in cats. The Kommerell's diverticulum compressed the oesophagus and contributed to the severe oesophageal constriction in this case. Preoperative CTA was useful in the diagnosis and treatment planning.

Early detection of myocardial dysfunction using two-dimensional speckle tracking echocardiography in a young cat with hypertrophic cardiomyopathy.

CASE SUMMARY: A 5-month-old intact female Scottish Fold cat was presented for cardiac evaluation. Careful auscultation detected a slight systolic murmur (Levine I/VI). The findings of electrocardiography, thoracic radiography, non-invasive blood pressure measurements and conventional echocardiographic studies were unremarkable. However, two-dimensional speckle tracking echocardiography revealed abnormalities in myocardial deformations, including decreased early-to-late diastolic strain rate ratios in longitudinal, radial and circumferential directions, and deteriorated segmental systolic longitudinal strain. At the follow-up examinations, the cat exhibited echocardiographic left ventricular hypertrophy and was diagnosed with hypertrophic cardiomyopathy using conventional echocardiography. RELEVANCE AND NOVEL INFORMATION: This is the first report on the use of two-dimensional speckle tracking echocardiography for the early detection of myocardial dysfunction in a cat with hypertrophic cardiomyopathy; the myocardial dysfunction was detected before the development of hypertrophy. The findings from this case suggest that two-dimensional speckle tracking echocardiography can be useful for myocardial assessment when conventional echocardiographic and Doppler findings are ambiguous.

Riboflavin Transporters RFVT/SLC52A Mediate Translocation of Riboflavin, Rather than FMN or FAD, across Plasma Membrane.

Riboflavin (vitamin B2) plays a role in various biochemical oxidation-reduction reactions. Flavin mononucleotide (FMN) and FAD, the biologically active forms, are made from riboflavin. Riboflavin transporters (RFVTs), RFVT1-3/Slc52a1-3, have been identified. However, the roles of human (h)RFVTs in FMN and FAD homeostasis have not yet been fully clarified. In this study, we assessed the contribution of each hRFVT to riboflavin, FMN and FAD uptake and efflux using in vitro studies. The transfection of hRFVTs increased cellular riboflavin concentrations. The uptake of riboflavin by human embryonic kidney cells transfected with hRFVTs was significantly increased, and the efflux was accelerated in a time-dependent manner. However, the uptake and efflux of FMN and FAD hardly changed. These results strongly suggest that riboflavin, rather than FMN or FAD, passes through plasma membranes via hRFVTs. Our findings could suggest that hRFVTs are involved in riboflavin homeostasis in the cells, and that FMN and FAD concentrations are regulated by riboflavin kinase and FAD synthase.

Determination of multidirectional myocardial deformations in cats with hypertrophic cardiomyopathy by using two-dimensional speckle-tracking echocardiography.

Objectives Hypertrophic cardiomyopathy, a primary disorder of the myocardium, is the most common cardiac disease in cats. However, determination of myocardial deformation with two-dimensional speckle-tracking echocardiography in cats with various stages of hypertrophic cardiomyopathy has not yet been reported. This study was designed to measure quantitatively multidirectional myocardial deformations of cats with hypertrophic cardiomyopathy. Methods Thirty-two client-owned cats with hypertrophic cardiomyopathy and 14 healthy cats serving as controls were enrolled and underwent assessment of myocardial deformation (peak systolic strain and strain rate) in the longitudinal, radial and circumferential directions. Results Longitudinal and radial deformations were reduced in cats with hypertrophic cardiomyopathy, despite normal systolic function determined by conventional echocardiography. Cats with severely symptomatic hypertrophic cardiomyopathy also had lower peak systolic circumferential strain, in addition to longitudinal and radial strain. Conclusions and relevance Longitudinal and radial deformation may be helpful in the diagnosis of hypertrophic cardiomyopathy. Additionally, the lower circumferential deformation in cats with severe hypertrophic cardiomyopathy may contribute to clinical findings of decompensation, and seems to be related to severe cardiac clinical signs. Indices of multidirectional myocardial deformations by two-dimensional speckle-tracking echocardiography may be useful markers and help to distinguish between cats with hypertrophic cardiomyopathy and healthy cats. Additionally, they may provide more detailed assessment of contractile function in cats with hypertrophic cardiomyopathy.

Disruption of Slc52a3 gene causes neonatal lethality with riboflavin deficiency in mice.

Homeostasis of riboflavin should be maintained by transporters. Previous in vitro studies have elucidated basic information about riboflavin transporter RFVT3 encoded by SLC52A3 gene. However, the contribution of RFVT3 to the maintenance of riboflavin homeostasis and the significance in vivo remain unclear. Here, we investigated the physiological role of RFVT3 using Slc52a3 knockout (Slc52a3-/-) mice. Most Slc52a3-/- mice died with hyperlipidemia and hypoglycemia within 48 hr after birth. The plasma and tissue riboflavin concentrations in Slc52a3-/- mice at postnatal day 0 were dramatically lower than those in wild-type (WT) littermates. Slc52a3-/- fetuses showed a lower capacity of placental riboflavin transport compared with WT fetuses. Riboflavin supplement during pregnancy and after birth reduced neonatal death and metabolic disorders. To our knowledge, this is the first report to indicate that Rfvt3 contributes to placental riboflavin transport, and that disruption of Slc52a3 gene caused neonatal mortality with hyperlipidemia and hypoglycemia owing to riboflavin deficiency.

Functional involvement of RFVT3/SLC52A3 in intestinal riboflavin absorption.

Riboflavin, also known as vitamin B2, is transported across the biological membrane into various organs by transport systems. Riboflavin transporter RFVT3 is expressed in the small intestine and has been suggested to localize in the apical membranes of the intestinal epithelial cells. In this study, we investigated the functional involvement of RFVT3 in riboflavin absorption using intestinal epithelial T84 cells and mouse small intestine. T84 cells expressed RFVT3 and conserved unidirectional riboflavin transport corresponding to intestinal absorption. Apical [(3)H]riboflavin uptake was pH-dependent in T84 cells. This uptake was not affected by Na(+) depletion at apical pH 6.0, although it was significantly decreased at apical pH 7.4. The [(3)H]riboflavin uptake from the apical side of T84 cells was prominently inhibited by the RFVT3 selective inhibitor methylene blue and significantly decreased by transfection of RFVT3-small-interfering RNA. In the gastrointestinal tract, RFVT3 was expressed in the jejunum and ileum. Mouse jejunal and ileal permeabilities of [(3)H]riboflavin were measured by the in situ closed-loop method and were significantly reduced by methylene blue. These results strongly suggest that RFVT3 would functionally be involved in riboflavin absorption in the apical membranes of intestinal epithelial cells.

Involvement of riboflavin transporter RFVT2/Slc52a2 in hepatic homeostasis of riboflavin in mice.

Riboflavin (vitamin B2) acts as an intermediary during various biochemical oxidation-reduction reactions in the liver. Hepatic riboflavin homeostasis is suggested to be maintained through its transporter(s). Riboflavin transporters, RFVT2/Slc52a2 and RFVT3/Slc52a3, have been identified in rodents. However, the role of each RFVT in the hepatic homeostasis of riboflavin has not yet been fully clarified. In this study, we assessed the contribution of each RFVT to riboflavin uptake into the liver using in vitro and in vivo studies. The uptake of riboflavin by mouse primary hepatocytes increased in a time-dependent and a concentration-dependent manner. Riboflavin transport was independent of extracellular Na(+). However, the uptake decreased slightly along with the extracellular pH increases. Real-time PCR analysis revealed that the mRNA level of Slc52a2, or coding for mouse (m)RFVT2, in the mouse liver was 10 times higher than that of Slc52a3 (coding for mRFVT3). The uptake of riboflavin at pH 7.4 by primary hepatocytes was significantly decreased by the transfection of Slc52a2-small interfering RNA (siRNA), but not Slc52a3-siRNA. Furthermore, we also confirmed the contribution of riboflavin transporters in vivo. The riboflavin concentrations in plasma, but not in the liver, were significantly decreased in mice fed on a riboflavin-deficient diet for 8 weeks. The expression of Slc52a2 mRNA was significantly upregulated by riboflavin deprivation. These results strongly suggest that mRFVT2 was involved in hepatic riboflavin homeostasis.