Search

Background The post-dialysis plasma level of human atrial natriuretic peptide (hANP) reflects the fluid volume in patients on hemodialysis. The threshold hANP level is reportedly 100 pg/mL; however, the clinical usefulness of the threshold hANP level for volume control has not been sufficiently studied. Methods We conducted a single-center, retrospective, observational study that included 156 hemodialysis patients without atrial fibrillation. First, we examined the usefulness of the threshold hANP level (100 pg/mL) for predicting hypoxemia due to congestion in a short-term observational study from December 30, 2015 to January 5, 2016. Subsequently, we conducted a 5-year follow-up study wherein the outcomes were hospitalization due to acute heart failure (AHF), development of cardiovascular diseases (CVD), and all-cause death. Finally, we collected echocardiography data to investigate the relationship between cardiac function and hANP. Results Our short-term observational study showed that patients with an hANP level ≥ 100 pg/mL developed hypoxemia due to congestion (odds ratio, 3.52; 95% confidence interval, 1.06–11.71; P = 0.040). At the 5-year follow-up, patients with an hANP level ≥ 100 pg/mL had significantly higher rates of hospitalization due to AHF, CVD, and all-cause death based on the log-rank test (P = 0.003, P = 0.019, P Conclusions The hANP level is indicative of both fluid volume and cardiac dysfunction. A threshold hANP level of 100 pg/mL can serve as a predictive marker for AHF and a practical indicator for volume control.

Angioimmunoblastic T-cell lymphoma (AITL), a hematological malignancy, originates from follicular helper T cells. The primary site of AITL is the lymph nodes, but extranodal presentation is frequent in patients with advanced stages. Here, we report a rare case of a patient with AITL presenting with rapidly progressive glomerulonephritis (RPGN). The patient underwent computed tomography, which showed systemic lymph node swelling. RPGN was noted at the time of admission. Livedo was observed in the lower limbs with purpura on the foot. The patient was diagnosed with AITL based on lymph node biopsy. Skin biopsy revealed vasculitis with immunoglobulin A (IgA) deposits. Renal biopsy revealed endocapillary proliferative glomerulonephritis with massive subendothelial deposits and intraluminal thrombi. Immunofluorescence showed IgA, IgG, and complement component 3c-predominant granular staining pattern in the capillary and mesangial areas. Electron micrographs demonstrated dense cylindrical-like deposits in the subendothelial space. Chemotherapy drugs were administered, but the patient's respiratory distress increased until death. Upon autopsy, membranoproliferative glomerulonephritis and extensive necrotizing cellular crescent formation were observed in the glomeruli. Taken together, this case is a rare combination of AITL and RPGN showing both cylinder-like deposits suggestive of cryoglobulinemic glomerulonephritis (CN) and IgA vasculitis.

We present a family of two female Alport syndrome patients with a family history of impaired glucose tolerance. Whole exome sequencing identified a novel heterozygous variant of COL4A5 NM_033380.3: c.2636 C > A (p.S879*) and a rare variant of GCK NM_001354800.1: c.1135 G > A (p.A379T) as the causes of Alport syndrome and monogenic diabetes, respectively. Two independent pathogenic variants affected the clinical phenotypes. Clinical next-generation sequencing is helpful for identifying the causes of patients’ manifestations.

Background Blood coagulation factor XIII (FXIII) promotes cross-linking between fibrin molecules at the final stage of the blood coagulation cascade. However, its expression in cells or tissues and function, particularly factor XIII subunit B (FXIII-B), remains controversial. Hemorrhagic FXIII deficiency following anti-interleukin-6 (IL-6) receptor antibody treatment has been reported in patients with rheumatoid arthritis (RA). Patients receiving this biologics have reduced FXIII activity when compared to the activity in those treated with other biologics. The relationship between pro-inflammatory cytokines and FXIII expression remains unknown. Methods To investigate the expression pattern of FXIII in synovial tissues, immunohistochemistry, RT-qPCR, and western blotting were performed. FXIII-A expressed monocyte-derived macrophages were treated with recombinant IL-6 and anti-IL-6 receptor antibody. RNA sequencing of FXIII-B-overexpressing cells was performed to clarify the function of FXIII-B. Results The immunohistochemical analysis of synovial tissues revealed that factor XIII subunit A (FXIII-A) was expressed in M2 macrophages, and FXIII-B was expressed in fibroblast-like synoviocytes. IL-6 stimulation upregulated FXIII-A expression in IL-4-induced monocyte-derived macrophages, and the anti-IL-6 receptor antibody suppressed FXIII-A expression. FXIII-B was more abundantly secreted in the supernatant of fibroblast-like synoviocytes compared with that of other cells. RNA sequencing showed that FXIII-B elevated the expression of genes associated with anti-apoptotic molecules and chemokines. Conclusions Our findings highlight that synovial tissue is one of the sources of FXIII production. We also have demonstrated IL-6-dependent FXIII-A expression and the novel potential functions of FXIII-B.

Myelofibrosis is characterized by stem cell-derived clonal proliferation potentially resulting in bone marrow fibrosis. As the disease progresses, extramedullary hematopoiesis is frequently detected in the spleen and the liver but rarely in other organs. We report a case of a 68-year-old woman with myelofibrosis with a JAK2 mutation, showing extramedullary hematopoiesis (EMH) in various organs with a marked increase in reticulin fibers, and myeloproliferative neoplasm (MPN)-related necrotizing crescent glomerulonephritis. She was admitted to our hospital owing to respiratory discomfort. Computed tomography revealed a mass in the anterior mediastinum. Ten days later, the patient died owing to respiratory distress. At autopsy, EMH were detected in the anterior mediastinum, heart, lung, spleen, and the kidney with a marked increase in reticulin fibers. We considered that respiratory distress was partially caused by EMH. In the kidney, necrotizing crescent glomerulonephritis was observed. Immunohistochemically, the glomerular basement and mesangial area were IgA- and C3d-positive. Ultrastructural examination revealed the presence of dense deposits in the subendothelial space and the mesangial and paramesangial areas. Thus, we suspected that MPN-related necrotizing crescentic glomerulonephritis harbored a pathogenesis similar to that of IgA-dominant post-infectious glomerulonephritis or IgA nephropathy. This case report could widen the spectrum of MPN- or EMH-related lesions.

Immunohistochemical analysis of somatostatin receptor 2 (SSTR2) provides important information regarding the potential therapeutic efficacy of somatostatin analogues (SSAs) in patients with neuroendocrine tumors. HER2 scoring has been proposed to interpret SSTR2 immunoreactivity but their reproducibility was relatively low because of its intrinsic subjective nature. Digital image analysis (DIA) has recently been proposed as an objective and more precise method of evaluating immunoreactivity. Therefore, in this study, we used DIA for analyzing SSTR2 immunoreactivity in pancreatic neuroendocrine tumors (PanNETs) to obtain its H score and "(%) strong positive cells" and compared the results with those of manually obtained HER2 scores. Membranous SSTR2 immunoreactivity evaluated by DIA was calculated by two scales as: "Membrane Optical Density" and "Minimum Membrane Completeness". PanNETs with HER2 score of > 2 demonstrated the highest concordance with results of "(%) strong positive cells" obtained by DIA when "Minimum Membrane Completeness" was tentatively set at 80%. The SSTR2 immunoreactivity, evaluated based on all scoring systems, was different between grades G1 and G2 in insulinoma but not in non-functional PanNETs. DIA provided reproducible results of SSTR2 immunoreactivity in PanNETs and yielded important information as to the potential application of SSAs.

Background Pulmonary carcinoid tumors rarely coexist with non-small cell lung carcinoma, and only nine cases have been reported previously. The pathogenesis and origin of these combined tumors remain unclear because of its rarity. Case presentation We examined two cases of adenocarcinoma coexisting with a typical or atypical carcinoid tumor: Case 1 was a 77-year-old woman and Case 2 was an 83-year-old woman. Both of these cases had no respiratory symptoms, and underwent pulmonary lobectomies due to incidentally detected lung nodules. Recurrence and metastases were not detected after the surgery. Histologically, carcinoid and adenocarcinoma components were present in both cases. The two components coexisted without mixing with each other. Next-generation sequencing was performed on the two components in these cases. In each case, no common genetic variants were detected. Conclusion We considered that our cases could histologically and genetically represent collision tumors that did not share common progenitor cells. Comprehensive analyses such as whole genome sequencing could provide important information for elucidating the pathogenesis of adenocarcinoma and carcinoid components.

IgA nephropathy (IgAN) is a chronic glomerular disease that causes end-stage renal disease in 20–40 % of patients within 20 years. The efficacy of tonsillectomy combined with steroid pulse (SP) administration (TSP) for clinical remission of IgAN has been reported. Particularly in Japan, TSP has been performed widely. However, the optimum method for steroid administration in TSP has not been established. We retrospectively compared clinical remission in IgAN patients treated with tonsillectomy combined with two different steroid administration methods: (1) three courses of SP therapy and oral prednisolone administered on alternate days (group 3A; n = 25); and (2) one course of SP therapy and oral prednisolone administered on consecutive days (group 1C; n = 22). There was no significant difference in the clinical remission rates between the two groups at 12 (48.0 vs. 40.9 %, P = 0.77) and 24 months after starting treatment (68.0 vs. 72.7 %, P = 0.76) and at the final observation (76.0 vs. 81.8 %, P = 0.73). The mean period from starting treatment to remission of hematuria in group 3A was significantly shorter than that in group 1C (5.7 ± 4.4 vs. 9.9 ± 5.9 months, P = 0.03). Dyslipidemic patients treated for the first time with statin after the SP therapy were more present in group 3A at 24 months (P = 0.02). In IgAN patients, treatment of group 3A may be effective for inducing rapid remission of hematuria. Further studies are needed to establish an appropriate protocol for TSP.

The p.E66Q variant of the α-galactosidase A gene (GLA) is frequently found during screening for Fabry disease in dialysis patients in Japan. However, recent reports suggest that the p.E66Q variant is not a disease-causing mutation but is a risk factor for cerebral small-vessel occlusion. To evaluate the role of the p.E66Q in the progression of renal diseases, we performed a genetic association study in patients with chronic kidney disease (CKD). In this study, we enrolled 1651 chronic hemodialysis and 941 non-dialysis patients who attended medical institutions in the Niigata Prefecture, Japan. The frequency of the p.E66Q allele was compared between hemodialysis and non-dialysis patients, with data from a previously published study of Japanese male newborns. In addition, we compared estimated glomerular filtration rates (eGFR) in the presence or absence of the p.E66Q variant in non-dialysis patients. Of the 2233 alleles in hemodialysis and 1447 alleles in non-dialysis patients, 21 and nine harbored p.E66Q, respectively. However, p.E66Q allele frequencies did not differ between the two patient groups (0.90 versus 0.62 %, P = 0.35), and no significant difference in p.E66Q allele frequency was observed between male hemodialysis patients and the general Japanese population (0.52 versus 0.63 %, P = 0.67). Moreover, eGFR did not significantly differ between non-dialysis patients with the p.E66Q variant and patients with the wild-type allele (65.5 ± 10.7 versus 62.7 ± 16.6 mL/min/1.73 m2, P = 0.69). This study indicated that the p.E66Q variant of GLA does not affect the progression of CKD.

This study aimed to evaluate the effects of green tea on the pharmacokinetics and pharmacodynamics of the β-blocker nadolol. Ten healthy volunteers received a single oral dose of 30 mg nadolol with green tea or water after repeated consumption of green tea (700 ml/day) or water for 14 days. Catechin concentrations in green tea and plasma were determined. Green tea markedly decreased the maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC0–48) of nadolol by 85.3% and 85.0%, respectively (P < 0.01), without altering renal clearance of nadolol. The effects of nadolol on systolic blood pressure were significantly reduced by green tea. [3H]-Nadolol uptake assays in human embryonic kidney 293 cells stably expressing the organic anion–transporting polypeptides OATP1A2 and OATP2B1 revealed that nadolol is a substrate of OATP1A2 (Michaelis constant (Km) = 84.3 μmol/l) but not of OATP2B1. Moreover, green tea significantly inhibited OATP1A2-mediated nadolol uptake (half-maximal inhibitory concentration, IC50 = 1.36%). These results suggest that green tea reduces plasma concentrations of nadolol possibly in part by inhibition of OATP1A2-mediated uptake of nadolol in the intestine. Clinical Pharmacology & Therapeutics (2014); 95 4, 432–438. doi:10.1038/clpt.2013.241

Cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A are major factors involved in the metabolism of clinically prescribed drugs. Because the time course after drug treatment discontinuation has received little attention, we aimed to clarify the chronological changes of rifampicin-induced CYP enzyme activities after rifampicin discontinuation. Thirteen volunteers took 450 mg of rifampicin once daily, and the cocktail method, which uses caffeine, losartan, omeprazole, dextromethorphan, and midazolam as CYP-specific probes, was repeatedly used for the evaluation of CYP levels. Concentrations of probes and metabolites were determined by liquid chromatography–tandem mass spectrometry. Seven-day rifampicin administration increased CYP2C19 and CYP3A enzyme activities. The induced CYP2C19 and CYP3A activities remained elevated at 4 days after rifampicin discontinuation and returned to baseline levels 8 days after rifampicin discontinuation. CYP1A2 and CYP2D6 enzyme activities showed no significant changes, and CYP2C9 enzyme activity was increased with rifampicin administration, with a tendency toward statistical significance. Drug interactions can occur even after rifampicin discontinuation. Clinical Pharmacology & Therapeutics (2013); 94 6, 702–708. doi:10.1038/clpt.2013.167

Reducing cryogenic heat leaks is critical for superconducting applications. Reduction of heat leak at the terminals is essential for uses with short-length applications, where cryogenic losses at the terminals dominate. We are developing a 200-m-class superconducting direct current (DC) transmission and distribution system (CASER-2), and have used a Peltier current lead (PCL) for heat insulation at the terminals. The PCL consists of thermoelectric elements and copper leads, which enhance the performance of superconducting systems. As DC flows through the current lead, thermoelectric elements on opposite terminations of a superconducting line can be used to decrease the heat ingress to the cryogenic environment (n-type on one end, p-type on the opposite end). During the current feeding and cooling test, a large temperature difference was observed across thermoelectric elements in the PCL. This demonstrates that we have successfully insulated the heat leak at the current lead. During the fourth cooling test, we established a new PCL design with p-type elements at terminal B, and then compared the performance of the terminals. Several improvements were implemented, including balancing the resistances of the PCL to enhance the stability of the superconducting systems.

In this paper, we present the structure and the dynamics of highly charged heavy ions studied through dielectronic recombination (DR) observations performed with the Tokyo electron beam ion trap. By measuring the energy dependence of the ion abundance ratio in the trap at equilibrium, we have observed DR processes for open shell systems very clearly. Remarkable relativistic effects due to the generalized Breit interaction have been clearly shown in DR for highly charged heavy ions. We also present the first result for the coincidence measurement of two photons emitted from a single DR event.

Thermoelectric materials are promising candidates for use in energy-saving devices in many fields. They are also useful in superconducting applications such as those using Peltier current leads (PCLs) to reduce system heat loss. In the case of PCLs, consideration must be given to Joule heating. Furthermore, the performance of PCLs is intricately dependent on their thermoelectric properties. In addition to the figure of merit Z, consideration of the electrical conductivity is also important for the design of high-performance PCLs. In this paper, we discuss the resistivity dependence of the performance of PCLs using model parameters obtained from real devices.

Neotermes koshunensis is a lower termite that secretes endogenous β-glucosidase in the salivary glands. This β-glucosidase (G1NkBG) was successfully expressed in Aspergillus oryzae. G1NkBG was purified to homogeneity from the culture supernatant through ammonium sulfate precipitation and anion exchange, hydrophobic, and gel filtration chromatographies with a 48-fold increase in purity. The molecular mass of the native enzyme appeared as a single band at 60 kDa after gel filtration analysis, indicating that G1NkBG is a monomeric protein. Maximum activity was observed at 50 °C with an optimum pH at 5.0. G1NkBG retained 80% of its maximum activity at temperatures up to 45 °C and lost its activity at temperatures above 55 °C. The enzyme was stable from pH 5.0 to 9.0. G1NkBG was most active towards laminaribiose and p-nitrophenyl-β-D-fucopyranoside. Cellobiose, as well as cello-oligosaccharides, was also well hydrolyzed. The enzyme activity was slightly stimulated by Mn(2+) and glycerol. The K(m) and V(max) values were 0.77 mM and 16 U/mg, respectively, against p-nitrophenyl-β-D-glucopyranoside. An unusual finding was that G1NkBG was stimulated by 1.3-fold when glucose was present in the reaction mixture at a concentration of 200 mM. These characteristics, particularly the stimulation of enzyme activity by glucose, make G1NkBG of great interest for biotechnological applications, especially for bioethanol production.

Wood-feeding termites have evolved an efficient cellulose-decomposing system. The termite has two independent cellulose-digesting systems: one in the midgut and the other in the hindgut. Because the digestion system in the midgut should be the sole source of soluble sugars for the host termite, the details of the decomposition of wood particles in the midgut were clarified in one of the most common pest species, Coptotermes formosanus. The spatial distribution of cellulase in the midgut was found by immunohistochemistry, and the amount of endogenous cellulases and the volume of the endoperitrophic space were determined. The size of wood particles in the foregut and the midgut were compared. The results showed that one of the characteristics of wood degradation by termites is the mechanical grinding of food by the mandibles and the cuticular apparatus of the foregut. This process greatly increases the surface area of the substrates. Extremely high concentrations of cellulase attack the ground-up wood in the midgut, and the glucose produced is removed quickly through the peritrophic membrane.

Huntington's disease patients commonly have glutamine (Q) repeats longer than 37 residues in the Huntingtin protein. This unusual protein will misfold and aggregate to form insoluble amyloid-like fibrils. Although the determination of polyQ structure is very important for elucidation of the aggregation mechanism, this has not yet been accomplished due to the experimental difficulties. In this study, we performed in silico mutation analysis to examine the stability of polyQ peptide on the basis of the beta-helix structure which is known as a possible model. From the results of molecular dynamics simulations for 10ns, some mutant models were found to be unstable, and their stabilities were largely dependent on the position of replaced residues. Besides, to examine the relationship between the aggregation mechanism of polyQ and the stability of the corresponding monomer, we constructed trimer models. Through the trimer studies, we confirmed that the stability of the monomer contributes significantly to that of the oligomer, and found that some mutant polyQs have the ability to inhibit polyQ aggregation. Furthermore, we estimated the free energies in solution and the conformational entropic contributions with normal mode analysis. The entropic contributions were not exhibiting remarkable differences between the models under study compared to the differences in the free energies in solution. Supposing that the stability of monomer is associated with aggregation process, the beta-helix structure has been found to be somewhat inconsistent with the experimental results in this study. Our results thus indicate the necessity for the revalidation of the beta-helix model.

We report a patient with refractory multiple myeloma (MM) who developed platelet transfusion refractoriness (PTR). A 61-year-old woman was diagnosed with MM in July 2003. She underwent high-dose chemotherapy followed by autologous stem cell transplantation, and achieved a very good partial response. However, she relapsed in June 2006, and was referred to our hospital in October of the same year. Laboratory examinations showed pancytopenia and increased plasma cells in the peripheral blood. Platelet transfusions from random donors became ineffective, and anti-HLA class I antibody (83.8% positive) was detected in the serum by flow cytometry assay (Flow PRA). Therefore, she was considered to have developed PTR due to anti-HLA class I antibody caused by the previous blood transfusions. She was transfused with HLA-matched platelets, and then treated with bortezomib plus dexamethasone (BD) for refractory MM. The serum IgG level decreased from 7,451 to 1,735 mg/dL, and HLA class I antibody was markedly decreased to 1.9%. In addition, platelet transfusion from random donors showed clinical effects after BD therapy. This case suggests that bortezomib might be effective in different types of immune disease by inhibiting allo-reactive antibody.

We present a study on the β decays of the neutron-rich isotopes 37Al and 38Al, produced by projectile fragmentation of a 48Ca beam with an energy E = 345 A MeV at the RIKEN Nishina Center. The half-lives of 37Al and 38Al have been measured to 11.5(4)ms and 9.0(7)ms, respectively, using the CAITEN implantation and decay detector setup. The level schemes for 37Si and 38Si were deduced by employing γ-γ coincidence spectroscopy following the event-by-event identification of the implanted nuclei. Comparison to large scale nuclear shell model calculations allowed for a tentative assignment of spin and parity of the populated states. The data indicate that the classical shell gap at magic neutron number N = 28 between the νf7/2 and νp3/2 orbits gets reduced by 0.3 MeV in this region leading to low-energy states with intruder configuration in 37Si.

An overview is given of the current spectroscopic effort on the Oxford electron beam ion trap. Recent results from three different experiments are discussed: a precision measurement of the 1s2s3S1–1s2p3P2 transition in helium-like neon by VUV emission spectroscopy, a measurement of the two-electron contribution to the ground state energy of helium-like argon using absorption edge spectroscopy, and a study of the lifetime of the 1s22s2p3P2 level in beryllium-like argon.

Reactive hyperaemia, the cardiovascular response to transient occlusion of a vessel, was examined and compared in the right coronary artery (RCA) and the left anterior descending coronary artery (LAD) in the same heart of an open-chest dog. First, to study the relationship between reactive hyperaemia and occlusion time in the RCA and LAD, respective flows were measured and reactive hyperaemia was induced with different occlusion times. Occlusion time required for half the maximum peak percentage reactive hyperaemic flow (%PRH), t 1/2, for the RCA was approximately twice that of the LAD: 11.4 +/- 2.3 s versus 5.9 +/- 1.4 s. Maximum %PRH of the RCA was significantly greater than that of the LAD while the percentage repayment of the RCA was lower than that of the LAD. Augmentation of right ventricular oxygen consumption shortened t 1/2 and increased percentage repayment significantly. Second, to determine "critical pressure", which was defined as the perfusion pressure below which reactive hyperaemia was abolished completely, the RCA and LAD were perfused through a shunt from the carotid artery, perfusion pressure was varied in the range of 100 to 20 mmHg and reactive hyperaemia was induced. Critical pressure in the RCA was significantly lower than in the LAD: 32.2 +/- 5.7 mmHg versus 41.5 +/- 5.0 mmHg. These results suggest that the RCA has a greater flow reserve than the LAD. These results were consistent with the difference of oxygen metabolism between the right and left ventricles. The difference of oxygen metabolism between the two ventricles would, at least partly, account for these results.

Background Symbiotic relationships between intracellular bacteria and eukaryotes are widespread in nature. Genome sequencing of the bacterial partner has provided a number of key insights into the basis of these symbioses. A challenging aspect of sequencing symbiont genomes is separating the bacteria from the host tissues. In the present study, we describe a simple method of endosymbiont purification from complex environment, using Blattabacterium cuenoti inhabiting in cockroaches as a model system. Findings B. cuenoti cells were successfully purified from the fat bodies of the cockroach Panesthia angustipennis by a combination of slow- and fast-speed centrifugal fractionations, nylon-membrane filtration, and centrifugation with Percoll solutions. We performed pulse-field electrophoresis, diagnostic PCR and random sequencing of the shoutgun library. These experiments confirmed minimal contamination of host and mitochondrial DNA. The genome size and the G+C content of B. cuenoti were inferred to be 650 kb and 32.1 ± 7.6%, respectively. Conclusion The present study showed successful purification and characterization of the genome of B. cuenoti. Our methodology should be applicable for future symbiont genome sequencing projects. An advantage of the present purification method is that each step is easily performed with ordinary microtubes and a microcentrifuge, and without DNase treatment.

Objective Tacrolimus is a largely used immunosuppressive drug with a narrow therapeutic range and wide interindividual variation in its pharmacokinetics. Recently, it has been reported that polymorphisms in P-glycoprotein (the product of the multiple drug resistant gene MDR1) altered pharmacokinetic profiles of its substrate drugs. The aim of this study was to clarify the influence of MDR1 gene polymorphisms on pharmacokinetics of tacrolimus in renal transplant recipients. Methods Blood tacrolimus concentrations after intravenous and oral administration were measured in 31 Japanese renal transplant recipients. The blood concentration and polymorphisms in exon 21 (G2677A/T) and exon 26 (C3435T) of MDR1 genotype were determined by a microparticle enzyme immunoassay and polymerase chain reaction-restriction fragment length polymorphism, respectively. Results There were 16 homozygous C/C (51.6%), 11 heterozygous C/T (35.5%) and 4 homozygous T/T (12.9%) genotypes in the recipients. Dose-adjusted trough concentrations of tacrolimus in C/C, C/T and T/T genotypes were 93.4±44.9, 63.4±49.0 and 115±46.5 ng/ml/mg/kg (mean±SD), respectively, and the difference of each group was not significant. The ratio of AUC(0–6) for oral dosing to AUC(0–6) for intravenous dosing in T/T genotype was significantly higher than in C/C and C/T genotypes. Conclusion These findings suggested that the MDR1 polymorphism altered the pharmacokinetics of tacrolimus. Clinical Pharmacology & Therapeutics (2004) 75, P17–P17; doi: 10.1016/j.clpt.2003.11.062