[Career Path of a Physician in the Pharmaceutical Industry].

Pharmaceuticals play a central role in medical care. Working for a pharmaceutical company that develops and provides pharmaceuticals is an extension of our responsibilities as medical doctors. For physicians with a desire to contribute to a wide range of medical care, public health, and society, working for a pharmaceutical company is one of the options to realize self-fulfillment and achieve their life goals.

Altered microbiota by a high-fat diet accelerates lethal myeloid hematopoiesis associated with systemic SOCS3 deficiency.

The suppressors of cytokine signaling (SOCS) proteins are negative regulators of cytokine signaling required to prevent excessive cellular responses. In particular, SOCS3 is involved in the regulation of metabolic syndromes, such as obesity and diabetes, by suppressing leptin and insulin signals. SOCS3 also suppresses the inflammatory response associated with metabolic stress, but this specific role remains undefined. Wild-type mice on a high-fat diet (HFD) exhibited only fatty liver, whereas systemic deletion of SOCS3 resulted in excessive myeloid hematopoiesis and hepatic inflammation. In addition, depletion of the gut microbiota resulted in considerable improvement in excess granulopoiesis and splenomegaly, halting the progression of systemic inflammation in SOCS3KO mice on the HFD. This result suggests that intestinal dysbiosis is involved in inflammation associated with SOCS3KO. Although contributing to diet-induced obesity and fatty liver, SOCS3 is nevertheless critical to suppress excess myeloid hematopoiesis and severe systemic inflammation associated with intestinal dysbiosis on HFD.

Osteoclastogenic Potential of Tissue-Engineered Periosteal Sheet: Effects of Culture Media on the Ability to Recruit Osteoclast Precursors.

Cell culture media influence the characteristics of human osteogenic periosteal sheets. We have previously found that a stem cell medium facilitates growth and collagen matrix formation in vitro and osteogenesis in vivo. However, it has not yet been demonstrated which culture medium is superior for osteoclastogenesis, a prerequisite for reconstruction of normal bone metabolic basis. To address this question, we compared chemotaxis and osteoclastogenesis in tissue-engineered periosteal sheets (TPSs) prepared with two types of culture media. Periosteal tissues obtained from adult volunteers were expanded with the conventional Medium 199 or with the stem cell medium, MesenPRO. Hematopoietic enhanced-green-fluorescent-protein (EGFP)-nude mice were prepared by γ-irradiation of Balb/c nu/nu mice and subsequent transplantation of bone marrow cells from CAG-EGFP C57BL/6 mice. TPSs were implanted subcutaneously into the chimeric mice and retrieved after intervals for immunohistopathological examination. EGFP+ cells were similarly recruited to the implantation site in both the TPSs prepared, whereas the distribution of CD11b+ cells was significantly lower in the TPS prepared with the stem cell medium. Instead, osteoclastogenesis was higher in the TPS prepared with the stem cell medium than in the one prepared with the conventional medium. These findings suggest that the stem cell medium is preferable for the preparation of more functional TPSs.

A Retrospective, Cross-Sectional Study on the Prevalence of Hyperuricemia Using a Japanese Healthcare Database.

OBJECTIVES: This study aims to evaluate the prevalence of hyperuricemia (HU) considering both serum uric acid (SUA) levels and medication status of urate-lowering drugs (ULDs), and the association between HU and its comorbidities using a Japanese healthcare database. MATERIALS AND METHODS: The study population consisted of 60,828 subjects who had at least one serum uric acid measurement between the fiscal years (FYs) 2010 and 2014 in a Japanese employment-based health insurance database (MinaCare Co., Ltd., Tokyo, Japan), which includes mutually linked medical/pharmaceutical claims data and health check-up data. Hyperuricemia was defined as a SUA level >7.0 mg/dL of the health check-up data and/or a prescription for a ULD. The association between HU and comorbidities were analyzed by comparing the prevalence of HU of each subgroup defined by presence or absence of comorbidity. RESULTS: The prevalence of HU in FY 2014 was 26.8% [95% confidence interval (CI): 26.2 to 27.3%] in male subjects and 0.9% (95% CI: 0.7 to 1.0%) in female subjects. According to the analyses by sex and age, a trend of increasing prevalence with age was observed in both males and females. The prevalence of HU remained stable both in males and females from FYs 2010 to 2014. The positive association between HU and well-known comorbidities were confirmed with the exception of diabetes mellitus and smoking status in male subjects. CONCLUSION: Our results provided a more accurate prevalence of HU in Japanese population. It is important to increase the awareness on HU in the society to reduce the burden of HU-related diseases.

Application of focused ion-beam sampling for sidewall-roughness measurement of free-standing sub-µm objects by atomic force microscopy.

In the present study, a free-standing object-sampling technique for microelectromechanical systems (MEMS) is developed to measure their sidewall surface roughnesses by atomic force microscopy (AFM). For this purpose, a conventional focused ion beam (FIB) sampling technique widely used for cross-sectional transmission electron microscope specimen preparation was applied. The sub-nm-order roughness parameters were quantitatively measured for sidewalls of Si-bridge test samples. The roughness parameters were compared before and after H2 annealing treatment, which induced smoothing of the surface by migration of the Si atoms. The reduction in the surface roughness by a factor of approximately one-third with 60-s H2 annealing was quantitatively evaluated by AFM. The present study confirms that the developed FIB-AFM technique is one potential approach for quantitatively evaluating the surface-roughness parameters on the oblique faces of free-standing objects in MEMS devices.

Treatment procedures and associated medical costs of methicillin-resistant Staphylococcus aureus infection in Japan: A retrospective analysis using a database of Japanese employment-based health insurance.

OBJECTIVES: This study aimed to determine the patient characteristics, treatment procedures, and medical costs of methicillin-resistant Staphylococcus aureus infections in clinical practice in Japan. METHODS: Using the MinaCare database of healthcare information covering nearly 3 million individuals, of which 90% were aged 20-59 years, we extracted and analyzed data of patients who were aged ⩾15 years and diagnosed with methicillin-resistant S. aureus during hospitalization between April 2010 and August 2015. RESULTS: A total of 684 patients with methicillin-resistant S. aureus infection were listed in the database, of which 365 were eligible to be included in this study. Mean patient age was 52.9 years, and 31.5% of the patients were females. Methicillin-resistant S. aureus bacteremia was the most common methicillin-resistant S. aureus infection (32.9%) with a mean age of 48.5 years, followed by pneumonia (24.1%) with a mean age of 61.0 years and methicillin-resistant S. aureus surgical site infection (6.3%) with a mean age of 49.7 years. Vancomycin was the most frequently prescribed anti-methicillin-resistant S. aureus drug used as the first-line therapy (68.5%), followed by teicoplanin (14.2%), linezolid (7.9%), arbekacin (5.8%), and daptomycin (3.6%). The mortality rate was 11.0%, and the mean treatment duration was 13.3 days. The median total medical cost per patient was US$5083. The median treatment cost for methicillin-resistant S. aureus bacteremia was the highest among the methicillin-resistant S. aureus infections at US$9099, followed by methicillin-resistant S. aureus pneumonia at US$3676 and surgery site infections at US$2084. CONCLUSION: Although the proportion of patients with methicillin-resistant S. aureus is very small in the employment-based health insurance database, methicillin-resistant S. aureus bacteremia is the most common methicillin-resistant S. aureus infection in the working-age population and requires the highest medical cost. Methicillin-resistant S. aureus pneumonia is more common in the elderly and is a cause of high mortality.

The effects of topiroxostat on vascular function in patients with hyperuricemia.

Xanthine oxidoreductase (XOR) inhibitors, such as allopurinol and febuxostat, inhibit the catalysis of serum uric acid (SUA) synthesis. In doing so, they are thought to improve vascular endothelial function in patients with hyperuricemia and cardiovascular risk by reducing increases in SUA and reactive oxygen species levels. We performed a retrospective cohort study to evaluate the effects of topiroxostat, a novel XOR inhibitor, on vascular function measured by flow-mediated dilation (FMD) on ultrasonography. In total, 23 patients with hyperuricemia were enrolled. After approximately 8 weeks, topiroxostat was associated with a significant increase in the peak percentage change in diameter (∆FMD) from 4.53% ± 2.09% to 5.54% ± 3.08% (P = .045). It also significantly reduced the SUA levels from 7.31 ± 1.43 to 5.44 ± 1.11 mg/dL (P < .001). Although further studies are needed to validate these results, it appears that topiroxostat improves vascular endothelial function in patients with hyperuricemia.

Rapid Growth of Pelvic Cyst during Pregnancy: A Case Report.

We describe a patient with bilateral cystic tumors of the pelvis. The left one rapidly grew during pregnancy and combined with the right one, whose clinical course made diagnosis difficult. A pregnant woman with a history of laparotomy was referred to us due to suspected bilateral pelvic cysts. The left-sided cyst had rapidly grown to 27 cm in diameter and merged with the right cyst, forming a large cyst occupying the entire pelvic cavity in the third trimester. Considering this rapid growth, cesarean section and resection of the cyst were performed at 37th week. The resected cyst consisted of two components: a large unilocular cyst containing serous fluid and a multilocular cyst suggestive of ovarian mucinous cystadenoma in the right ovary. The wall of the former largely lacked lining epithelium, but it was partly continuous with the latter mucinous epithelium. Immunohistochemically, estrogen and progesterone receptors were focally positive in the cyst wall, suggesting that pregnancy-associated sex-hormones may have contributed to the rapid growth of the cyst. We diagnosed this condition as a peritoneal inclusion cyst margining with a right ovarian mucinous cystadenoma. Peritoneal inclusion cyst should be considered in the differential diagnosis of a rapidly growing pelvic mass during pregnancy.

Database Analysis of Eplerenone Use in Japanese Hypertensive Patients in Clinical Practice.

Eplerenone, a mineralocorticoid receptor antagonist (MRA), is available in Japan, but details of its use in clinical settings have not been thoroughly investigated. Thus, this study was aimed at examining the characteristics of eplerenone-prescribed hypertensive patients in Japan, describing the combination patterns of antihypertensive medications, and comparing eplerenone's mean doses with respect to concomitant diseases. Data of 160,992 hypertensive patients who used the same drugs for six months or more were collected from an insurance database from January 1, 2009, to December 31, 2013. The number of MRA-receiving patients among the extracted population was 3,274 (2%). Compared to patients on eplerenone or spironolactone, patients on neither drug had fewer comorbidities. Eplerenone was administered in combination with calcium channel blockers and angiotensin II receptor blockers in 23.1% and as monotherapy in 6.6% of cases. The most frequent initial daily dose of eplerenone was 50 mg/day followed by 25 mg/day irrespective of the presence of a comorbidity. MRA use was as low as 2%, but its use was more frequent in patients with comorbidities compared to that of other antihypertensives. Despite studies showing eplerenone's efficacy and safety in high-risk hypertensive patients with albuminuria, the drug is not widely used.

Platelet-Rich Fibrin Extract: A Promising Fetal Bovine Serum Alternative in Explant Cultures of Human Periosteal Sheets for Regenerative Therapy.

In 2004, we developed autologous periosteal sheets for the treatment of periodontal bone defects. This regenerative therapy has successfully regenerated periodontal bone and augmented alveolar ridge for implant placement. However, the necessity for 6-week culture is a limitation. Here, we examined the applicability of a human platelet-rich fibrin extract (PRFext) as an alternative to fetal bovine serum (FBS) for the explant culture of periosteal sheets in a novel culture medium (MSC-PCM) originally developed for maintaining mesenchymal stem cells. Small periosteum tissue segments were expanded in MSC-PCM + 2% PRFext for 4 weeks, and the resulting periosteal sheets were compared with those prepared by the conventional method using Medium199 + 10% FBS for their growth rate, cell multilayer formation, alkaline phosphatase (ALP) activity, and surface antigen expression (CD73, CD90, and CD105). Periosteal sheets grew faster in the novel culture medium than in the conventional medium. However, assessment of cell shape and ALP activity revealed that the periosteal cells growing in the novel medium were relatively immature. These findings suggest that the novel culture medium featuring PRFext offers advantages by shortening the culture period and excluding possible risks associated with xeno-factors without negatively altering the activity of periosteal sheets.

Takotsubo syndrome occurring concomitantly with pre-eclampsia: A case report.

Takotsubo syndrome (TTS) patients show transient ventricular dysfunction without coronary artery stenosis. We report a pregnant woman with TTS occurring concomitantly with severe pre-eclampsia (PE). A primiparous woman complained of dyspnea at 35 weeks of gestation. She showed severe PE, and cardiac ultrasound identified akinesis of the anterior lower wall. On the same day, emergent cesarean section was performed due to a nonreassuring fetus status, yielding a male infant with an umbilical artery pH of 6.851. Unfortunately, the neonate died of multiple organ failure. Following the delivery, her cardiac function markedly improved, and coronary angiography showed no coronary artery stenosis. Considering the clinical findings, we diagnosed the patient with TTS. Regarding antenatally occurring TTS, only six patients have been reported including the present one. Of the six patients, three had severe PE. Although previous reports on pregnancy-associated TTS described good maternal outcomes, antenatally occurring TTS complicated by severe PE may become critical for fetuses.

Recent Trends in the Practice of Procedural Sedation Under Local Anesthesia for Catheter Ablation, Gastrointestinal Endoscopy, and Endoscopic Surgery in Japan: A Retrospective Database Study in Clinical Practice from 2012 to 2015.

OBJECTIVES: To investigate changes in sedation practice during 2012-2015, using a large health claims database, for catheter ablation (CA), gastrointestinal endoscopic examination (EE), and surgery (ES) after dexmedetomidine (DEX) was approved for procedural sedation in 2013. We assessed the trends of sedative utilization, sedative-analgesic combinations, and, additionally, incidence of complications from 2012 to 2015. METHODS: Using the database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan), annual utilization proportions of the sedatives and sedative-analgesic combinations and occurrence of complications were calculated in patients with a record of local anesthesia and CA, EE, and/or ES but without general anesthesia used on the same day. The sedatives studied were DEX, propofol (PF), midazolam (MDZ), diazepam, flunitrazepam, thiamylal (TIA), thiopental (TIO), and ketamine. RESULTS: DEX was used most often for CA, followed by PF. From 2012 to 2015, the proportion of DEX increased from 30 to 36%, and that of PF slightly decreased from 29 to 27%. The order of utilization proportions did not change for EE or ES. The use of benzodiazepines, particularly MDZ, predominated. The top five sedative-analgesic combination patterns changed during the study period for CA, but not for EE or ES. The most common complications with CA, EE, and ES were bradycardia, nausea and vomiting, and respiratory depression, respectively. There were no changes in the complications' trends for the procedures. CONCLUSION: The approved use of DEX for procedural sedation resulted in changes for CA, but not for EE or ES. The complication trends did not change.

Possibility of Database Research as a Means of Pharmacovigilance in Japan Based on a Comparison with Sertraline Postmarketing Surveillance.

BACKGROUND: Many pharmacoepidemiologic studies using large-scale databases have recently been utilized to evaluate the safety and effectiveness of drugs in Western countries. In Japan, however, conventional methodology has been applied to postmarketing surveillance (PMS) to collect safety and effectiveness information on new drugs to meet regulatory requirements. Conventional PMS entails enormous costs and resources despite being an uncontrolled observational study method. This study is aimed at examining the possibility of database research as a more efficient pharmacovigilance approach by comparing a health care claims database and PMS with regard to the characteristics and safety profiles of sertraline-prescribed patients. METHODS: The characteristics of sertraline-prescribed patients recorded in a large-scale Japanese health insurance claims database developed by MinaCare Co. Ltd. were scanned and compared with the PMS results. We also explored the possibility of detecting signals indicative of adverse reactions based on the claims database by using sequence symmetry analysis. Diabetes mellitus, hyperlipidemia, and hyperthyroidism served as exploratory events, and their detection criteria for the claims database were reported by the Pharmaceuticals and Medical Devices Agency in Japan. RESULTS: Most of the characteristics of sertraline-prescribed patients in the claims database did not differ markedly from those in the PMS. There was no tendency for higher risks of the exploratory events after exposure to sertraline, and this was consistent with sertraline's known safety profile. CONCLUSIONS: Our results support the concept of using database research as a cost-effective pharmacovigilance tool that is free of selection bias . Further investigation using database research is required to confirm our preliminary observations.

Contact Dermatitis after Prescription of an Ophthalmic Ointment Containing Fradiomycin Sulfate: A Retrospective Database Study Using Japanese Health Insurance Claims Data.

BACKGROUND: Topical ointments containing fradiomycin sulfate, such as fradiomycin sulfate/methylprednisolone (F/M) and fradiomycin sulfate/betamethasone sodium phosphate (F/B), are known to cause allergic contact dermatitis (CD) in some patients, especially when used for the periocular region. F/M is commonly prescribed to patients for various conditions; however, there are no reports with respect to the incidence of CD caused by F/M in actual practice. OBJECTIVE: The aim was to investigate the incidence of CD using a data-based retrospective cohort study. METHODS: Using a Japanese health insurance claims database [MinaCare Co. Ltd. healthcare database (MinaCare HDB)], a comparative assessment was conducted of F/M and another combination drug (F/B) and two single-drug treatments (ophthalmic ointments with either an antibiotic or a steroid). The total data set consisted of 1,176,082 individuals in the MinaCare HDB, with 54,016 having received prescriptions for one of the four investigational drug regimens. RESULTS: Overall, the incidences of CD were similar in three of the four groups in this study (F/M 0.091; F/B 0.092; steroids 0.102), while being lower in the fourth group (antibiotics 0.060). Even after confirmation of a diagnosis of CD, prescriptions for the investigational drugs were repeatedly filled for some patients. CONCLUSION: This study demonstrated that there was no clear difference in the incidence of CD after filling prescriptions for F/M, F/B, and ophthalmic ointment containing a steroid, while the incidence with antibiotics was lower by 0.03-0.04 compared with the other groups. Considering the observation that the investigational drugs were repeatedly prescribed even after the diagnosis of CD, it is critical that the risk of CD with these prescribed topical ointments is better understood by primary care physicians in order to take appropriate countermeasures.

Corrigendum to "High glucose concentration-induced expression of pentraxin-3 in a rat model of continuous peritoneal dialysis".

This correct the article DOI: 10.14670/HH-11-756.

High glucose concentration-induced expression of pentraxin-3 in a rat model of continuous peritoneal dialysis.

BACKGROUND: Continuous exposure to peritoneal dialysis fluids (PDFs) is associated with pathological responses such as persistent micro-inflammation, which leads to ultrafiltration failure. Pentraxin-3 (PTX3), a multifunctional soluble pattern recognition receptor, is produced at sites of inflammation by a wide range of cell types. This study investigates the in vivo expression of PTX3 in the peritoneal membrane of a rat continuous peritoneal dialysis (PD) model, as well as the effect of high glucose on the in vitro expression of PTX3. METHODS: The expression of PTX3 was analyzed using RT-PCR, real-time PCR, immunohistochemistry and western blotting in a PD rat model receiving saline or conventional PDF containing 3.86% glucose for 8 weeks. The effects of high glucose on the expression of PTX3 were examined in cultured rat peritoneal mesothelial cells (RPMCs), mouse macrophage-like cells, and mouse fibroblasts. RESULTS: In a rat model of PD, eight-week instillation of the conventional PDF produced increased submesothelial thickening, followed by substantially enhanced PTX3 protein levels in the submesothelial layer of peritoneal membrane. PTX3 was detected in peritoneal mesothelial cells, macrophages and fibroblasts in the thickened submesothelial area. Glucose was found to induce PTX3 protein expression in RPMCs as well as macrophage-like cells and fibroblasts. CONCLUSION: Continuous exposure to conventional PDF induces PTX3 expression in the peritoneal membrane of rats. High glucose may be involved in the mechanism of PDF-induced local micro-inflammation in the peritoneum.

A retrospective, cross-sectional study of real-world values of cardiovascular risk factors using a healthcare database in Japan.

BACKGROUND: Data collected by the Japanese Ministry of Health, Labour and Welfare (MHLW), namely data from the Specific Health Checkups and Specific Health Guidance (MHLW-SH) and the National Health and Nutrition Survey (MHLW-H&N) allow assessment of blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), and hemoglobin A1c (HbA1c) in Japan. Recently, a large database of employment-based health insurance has been developed by MinaCare Co. Ltd. METHODS: A retrospective, cross-sectional study using the Japanese healthcare checkup database developed by MinaCare Co. Ltd. was designed to investigate the distribution of real-world values of BP, LDL-C, and HbA1c in Japan. Data in the MinaCare database were also compared with those in the two national data sources to assess the extent to which the health status in Japan is reflected in each data source. RESULTS: Of the healthcare checkup results of 232515 subjects in the 2011 MinaCare database, 49.9% were male and 50.1% were female. The age of the subjects ranged from < 20 to > 70 years. The proportion of subjects with systolic BP (SBP) ≥ 140 mmHg, LDL-C ≥ 140 mg/dL, and HbA1c ≥ 6.1% generally increased with increasing age. If one focused on the upper-end age group representing the majority of the MinaCare study population (i.e. age range, 55-59 years), the proportions of subjects with SBP ≥ 140 mmHg, LDL-C ≥ 140 mg/dL, and HbA1c ≥ 6.1% were 19.0%/12.2% (males/females), 27.2%/42.7%, and 13.5%/5.4%, respectively. The MinaCare database was mostly comparable with the two national data sources; however, some notable differences in BP and lipid parameters were found between MHLW-H&N and the other two data sources. CONCLUSIONS: Analysis of the MinaCare database indicated that a substantial proportion of subjects did not achieve the target BP, LDL-C, and HbA1c levels to reduce the risk of future cardiovascular and cerebrovascular disease events. The results were generally consistent with those of the national data sources. Considering its characteristics of low selection bias, large sample size, wide age distribution, and high flexibility in analysis of subject-level data, the MinaCare database is highly valuable for studying the health status of the population covered by employment-based health insurance.

Safety and pharmacokinetics of PF-04360365 following a single-dose intravenous infusion in Japanese subjects with mild-to-moderate Alzheimer's disease: a multicenter, randomized, double-blind, placebo-controlled, dose-escalation study.

OBJECTIVE: PF-04360365 is a humanized IgG(2)Δa anti-amyloid ß (Aß) antibody designed to improve outcome in Alzheimer's disease (AD). Single doses of 0.1 - 10 mg/kg were safe and well tolerated in Western (mostly Caucasian) subjects with mild-to-moderate AD. This Phase 1, multicenter, randomized, double-blind, dose-escalation study was the first to evaluate the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of PF-04360365 in Japanese subjects. MATERIALS AND METHODS: 30 subjects with mild-to-moderate AD were enrolled. In each cohort, 3 subjects received PF-04360365 (0.1, 0.5, 1, 5, or 10 mg/kg) and 1 subject received placebo as a single 2-hour intravenous infusion. Subjects were monitored as inpatients for 24 hours and then as outpatients for 1 year. RESULTS: All subjects completed the study. There were no serious or National Cancer Institute Common Terminology Criteria for Adverse Events grade ≥ 3 adverse events, hypersensitivity reactions, or antidrug antibodies. No clinical or MRI evidence of brain microhemorrhage, cerebral edema, or encephalitis was observed. PF-04360365 plasma concentrations increased with dose, and pharmacokinetics were consistent with a small steady-state volume of distribution, slow clearance, and long elimination half-life. Cerebrospinal fluid (CSF):plasma ratios were < 0.5%. Plasma Aß species showed dose-dependent increases in C(max) and AUC(∞), but CSF biomarkers did not differ clearly between treatment arms. CONCLUSIONS: PF-04360365 was safe and well tolerated in Japanese subjects. Pharmacokinetics and plasma pharmacodynamic responses in Japanese subjects were comparable to those in Western subjects. *No longer affiliated with Pfizer.

[The first case of adenine phosphoribosyltransferase deficiency with APRT*Q0 (M1I) mutation in Japan].

Adenine phosphoribosyltransferase (APRT) deficiency is an enzyme deficiency associated with purine metabolism, a hereditary disease that causes recurrent 2, 8-DHA stone formation due to a complete or partial APRT defect and slowly damages the renal function. Since APRT deficiency can be treated to prevent its progression to renal insufficiency, it is important to detect APRT gene mutations and make a definite diagnosis early. A 3.5-year-old girl presented with painful urination and dysuria, and was admitted to our hospital. The analysis of stones collected after spontaneous passage revealed 2, 8-dihydroxyadenine (DHA) urolithiasis. To make a definite diagnosis, we searched for the APRT gene mutations reported in Japanese. However, no APRT Q0 mutation was identified. Only a heterogeneous mutation, APRT J, was noted. Subsequently, we screened the gene mutation regions reported from Europe and the United States and identified a heterogeneous mutation at the start codon of APRT Q0 from methionine to valine. This is the first report of this mutation in Japan. She was diagnosed with APRT deficiency caused by a compound heterogeneous mutation: APRT Q0/(M1V) APRT J (M136T). We believe that the same gene mutation has been inherited among other Japanese. For the future genetic diagnosis of APRT deficiency, this is a valuable case.