Transcriptomic analysis of immunoglobulin novel antigen receptor (IgNAR) heavy chain constant domains of brownbanded bamboo shark (Chiloscyllium punctatum).

Cartilaginous fish are the evolutionarily oldest group of animals which possess antibodies, T cell receptors and major histocompatibility complex (MHC). The immunoglobulin novel antigen receptor (IgNAR) found in cartilaginous fish is a heavy chain homodimer which lacks light chain. The presence of non-canonical cysteine molecules and lack of CDR2 region make it more significant. To synthesize active binding domains based on variable region of IgNAR (VNAR), knowledge on the constant region dynamics play a significant role. The IgNAR exhibit species variations in its primary sequence features; hence, this study was conducted to determine the IgNAR heavy chain constant domain of the brownbanded bamboo shark (Chiloscyllium punctatum). Peripheral blood leukocytes (PBL) isolated from adult bamboo sharks were used to synthesize a cDNA library. A total of four billion residues of two million sequences (average length 218.41 bp) were obtained. Assembled sequences were aligned with published cartilaginous fish IgNAR constant region sequences. Transcriptome analysis revealed two distinct types of IgNAR in the brownbanded bamboo shark. Also, constant-1 domain sequences displayed 13 unique sequences which may reflect the least number of IgNAR gene clusters. The phylogenetic analysis revealed the closest relationship with the nurse shark (Ginglymostoma cirratum) followed by the wobbegong shark (Orectolobus maculatus) which belong to the same order Orectolobiformes. Analysis of the constant domains of the brownbanded bamboo shark IgNAR revealed an evolutionarily conserved nature and this knowledge can be used to design primers for VNAR cloning. Furthermore, knowledge on the structural features in IgNAR constant domains that increase the stability could be useful in the process of stabilizing human immunoglobulins.

Effects of Nutrition Therapy in Older Stroke Patients Undergoing Rehabilitation: A Systematic Review and Meta-Analysis.

OBJECTIVE: To systematically review evidence on the effects of nutrition therapy in older stroke patients undergoing rehabilitation and identify its effectiveness using meta-analysis. METHODS: PubMed (MEDLINE), EMBASE (via Dialog), Cochrane Central Register of Controlled Trial, World Health Organization International Clinical Trials Registry Platform and Ichu-shi Web were searched for relevant articles. Randomized controlled trials investigating the effects of nutrition therapy compared to control interventions in older stroke patients undergoing rehabilitation were considered eligible. The primary outcome was activities of daily living (ADL), and secondary outcomes were all-cause mortality, infections, pneumonia incidence, disability level, walking ability, fall, stroke recurrence, and quality of life. The risk of bias of each trial was assessed using the Cochrane Collaboration Tool, and the quality of the body of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Eight randomized controlled trials with a total of 5484 participants were included in the meta-analysis. The meta-analysis for ADL showed no significant effects (mean difference, 4.16; 95% confidence interval [CI], -0.88 to 9.20; I2=53%, low-quality evidence). The meta-analyses for secondary outcomes revealed a significant effect of reduced infections (risk ratio, 0.65; 95% CI, 0.51 to 0.84; I2=0%; low-quality evidence), with no significant effects on the other outcomes. CONCLUSION: Nutrition therapy had no statistically significant effect on ADL. However, it reduced the incidence of infections. More high-quality trials are warranted to clarify the effects of nutrition therapy in older stroke patients undergoing rehabilitation.

Mucocutaneous inflammation in the Ikaros Family Zinc Finger 1-keratin 5-specific transgenic mice.

BACKGROUND: Our genomewide association study documented an association between cold medicine-related Stevens-Johnson syndrome/toxic epidermal necrolysis (CM-SJS/TEN) and Ikaros Family Zinc Finger 1 (IKZF1). Few studies examined biological and pathological functions of IKZF1 in mucosal immunity. We hypothesized that IKZF1 contributes to the mucocutaneous inflammation. METHODS: Human skin and conjunctival tissues were obtained for immunohistological studies. Primary human conjunctival epithelial cells (PHCjECs) and adult human epidermal keratinocytes (HEKa) also used for gene expression analysis. We also generated K5-Ikzf1-EGFP transgenic mice (Ikzf1 Tg) by introducing the Ik1 isoform into cells expressing keratin 5, which is expressed in epithelial tissues such as the epidermis and conjunctiva, and then examined them histologically and investigated gene expression of the epidermis. Moreover, Ikzf1 Tg were induced allergic contact dermatitis. RESULTS: We found that human epidermis and conjunctival epithelium expressed IKZF1, and in PHCjECs and HEKa, the expression of IKZF1 mRNA was upregulated by stimulation with polyI:C, a TLR3 ligand. In Ikzf1 Tg, we observed dermatitis and mucosal inflammation including the ocular surface. In contact dermatitis model, inflammatory infiltrates in the skin of Ikzf1 Tg were significantly increased compared with wild type. Microarray analysis showed that Lcn2, Adh7, Epgn, Ifi202b, Cdo1, Gpr37, Duoxa1, Tnfrsf4, and Enpp5 genes were significantly upregulated in the epidermis of Ikzf1 Tg compared with wild type. CONCLUSION: Our findings support the hypothesis that Ikaros might participate in mucocutaneous inflammation.

Usefulness of CTC and DTC-BM Detection for Adjuvant Therapy Effects and Prognosis Prediction in Early Breast Carcinoma: Results of 8-11 Years of Follow-up Evaluation.

BACKGROUND: Circulating tumor cells (CTCs) reportedly have been detected in the peripheral blood of more than 50% of breast carcinoma cases with distant metastases. Moreover, the survival period is shorter for patients who had more than five CTCs after a single chemotherapy treatment. However, a few data show the relationships between CTCs and expressions of disseminated tumor cells in the bone marrow (DTCs-BM), including treatment effects and prognoses in early breast carcinomas. METHODS: In this study, CTCs and DTC-BMs were measured by the CellSearch System for 20 patients with stages 1-3 carcinomas, who were followed for 8-11 years. RESULTS: CTCs in 2 (10%) of 20 breast carcinomas, more than 1 CTC was detected before adjuvant therapy, and both cases showed a decrease to 0 after chemotherapy. DTC-BMs in 19 (95%) of the 20 primary cases, more than 1 cell was found in the BM. After adjuvant therapy, 16 cases showed a decrease to 0-10 cells, 2 cases to 11-20 cells, and 2 cases to more than 21 cells. Six patients experienced recurrence. One of the two CTC-positive cases (>21 cells) had bone and liver metastasis within 11 months. Among the DTC-BM cases, only 1 (16.7%) of the 6 primary patients with 11-20 cells had recurrence, whereas 4 (80%) of the 5 patients with more than 21 cells had recurrence 3-6 years later. CONCLUSIONS: Detection of DTC-BMs is useful for observing adjuvant therapy effects and for predicting relatively late-phase metastasis. The cluster status of CTCs suggests early relapsing.

The increase of aqueous tear volume by diquafosol sodium in dry-eye patients with Sjögren's syndrome: a pilot study.

PurposeTo investigate the effect of 3% diquafosol sodium ophthalmic solution (DQS) on aqueous tear volume increase in dry-eye patients with Sjögren's syndrome (SS).MethodsIn this pilot study, 17 dry-eye patients with SS (1 male and 16 females; mean age: 66.4 years) were enrolled and underwent topical instillation of two ophthalmic solutions, artificial tears (AT) in one eye and DQS in the fellow eye, in a masked manner. The central lower tear meniscus radius (TMR) curvature was measured before and at 15 min after instillation by video-meniscometry. Simultaneously, all patients self-evaluated their symptoms of wetness and stinging using a visual analog scale (VAS, in millimeters).ResultsTopical instillation of DQS significantly increased the TMR at 15 min (mean: 0.21±0.08 (SD) mm) compared with at baseline (mean: 0.16±0.07 mm) (P<0.001, paired t-test), whereas AT had no effect at baseline (mean: 0.18±0.09 mm) or at 15 min (mean: 0.18±0.09 mm). The visual VAS score of wetness at 15-min post-instillation increased in both groups compared with at baseline. In the DQS-treated eyes, the post-instillation change in TMR from baseline was not correlated with the baseline value of the Schirmer test, corneal staining score, or conjunctival staining score.ConclusionsTopical instillation of DQS increased aqueous tear volume on the ocular surface of dry-eye patients with SS, with its action being independent of lacrimal gland function.

The FGF23/KLOTHO Regulatory Network and Its Roles in Human Disorders.

The functions of Klotho (KL) are multifaceted and include the regulation of aging and mineral metabolism. It was originally identified as the gene responsible for premature aging-like symptoms in mice and was subsequently shown to function as a coreceptor in the fibroblast growth factor (FGF) 23 signaling pathway. The discovery of KL as a partner for FGF23 led to significant advances in understanding of the molecular mechanisms underlying phosphate and vitamin D metabolism, and simultaneously clarified the pathogenic roles of the FGF23 signaling pathway in human diseases. These novel insights led to the development of new strategies to combat disorders associated with the dysregulated metabolism of phosphate and vitamin D, and clinical trials on the blockade of FGF23 signaling in X-linked hypophosphatemic rickets are ongoing. Molecular and functional insights on KL and FGF23 have been discussed in this review and were extended to how dysregulation of the FGF23/KL axis causes human disorders associated with abnormal mineral metabolism.

5'-flanking sequences of zebrafish fast myosin heavy chain genes regulate unique expression in the anterior, medial subsection and posterior tail somites of the skeletal muscle.

In zebrafish, fast muscle-specific myosin heavy chain genes have their unique expression patterns in a well-defined and restricted region of the skeletal muscle. However, the transcriptional regulatory mechanisms involved have remained unclear. Here, we examined the regulation of spatio-temporal expression patterns of myhz1 (myhz1.1, myhz1.2 and myhz1.3) and myhz2 during their development by using transient gene and stable transgenic techniques. Embryos microinjected with different length 5'-flanking sequences of myhz1 conjugated with the enhanced green fluorescent protein (EGFP) gene showed EGFP expression in the anterior and medial subsections of somites, but not in the tail somite region. In contrast, embryos microinjected with different length 5'-flanking sequences of myhz2 showed EGFP expression exclusively at the posterior tail somite domain. Promoter deletion analyses demonstrated that reduced EGFP fluorescence typically is correlated with smaller 5'-flanking sequences. The immunohistochemical observation revealed that zebrafish larvae provided with the transient gene and those from stable transgenic lines consistently expressed EGFP in the fast muscle fibers. r-VISTA plot identified one common conserved region of about 140°bp among myhz1.1, myhz1.2 and myhz1.3. Deletion of this conserved region from the 5'-flanking sequence of each myhz1 markedly reduced EGFP expression in its unique spatial somite region. Deletion mutation analysis demonstrated that myhz2 expression in the tail somite region might be mediated by Tbx (family of transcription factors having a common DNA-binding sequence known as T-box) binding elements. In summary, 5'-flanking sequences of myhz1 and myhz2 regulate their unique expression patterns in a well-defined and restricted somite region of the skeletal muscle in zebrafish.

Three percent diquafosol ophthalmic solution as an additional therapy to existing artificial tears with steroids for dry-eye patients with Sjögren's syndrome.

PURPOSE: To investigate the long-term results of 3% diquafosol ophthalmic solution as an alternative therapy to existing ophthalmic solutions, including topical immunosuppression, for the treatment of dry eye in patients with Sjögren's syndrome. METHODS: This study involved 14 female dry-eye patients (mean age: 62.4 years) with Sjögren's syndrome who insufficiently responded to their current therapy. In all patients, 3% diquafosol ophthalmic solution was administered six times daily for 12 months in substitution for artificial tears and sodium hyaluronate ophthalmic solution. Their use of corticosteroid eye drops remained unchanged from that prior to the treatment with diquafosol sodium. The subjective symptoms assessed, and ocular signs including tear meniscus radius and the tear film breakup time, and ocular-surface epithelial damage score were examined at 1, 2, 3, 4, 5, 6, 9, and 12 months after initiating treatment. RESULTS: Among the subjective symptoms, significant improvement was obtained in dryness at 2 months post treatment, in eye fatigue at 1, 2, 3, 4, and 12 months post treatment, and in pain at 1, 2, 6, and 12 months post treatment. Difficulty in opening the eye, foreign body sensation, and redness were also significantly ameliorated at various time-points. The tear meniscus radius and the tear film breakup time were significantly improved throughout the observation period, and the corneal epithelial staining scores were significantly decreased at 3 months post treatment. CONCLUSIONS: In dry-eye patients with Sjögren's syndrome, treatment with 3% diquafosol ophthalmic solution improved both symptoms and signs, and that effectiveness was maintained for 12 months.

Betaine prevents homocysteine-induced memory impairment via matrix metalloproteinase-9 in the frontal cortex.

Betaine plays important roles that include acting as a methyl donor and converting homocysteine (Hcy) to methionine. Elevated plasma Hcy levels are known as hyperhomocysteinemia (HHcy) and contribute to impairments of learning and memory. Although it is commonly known that betaine plays an important role in Hcy metabolism, the effects of betaine on Hcy-induced memory impairment have not been investigated. Previously, we demonstrated the beneficial effects of betaine on acute stress and lipopolysaccharide-induced memory impairment. In the present study, we investigated whether betaine ameliorates Hcy-induced memory impairment and the underlying mechanisms of this putative effect. Mice were treated with Hcy (0.162mg/kg, s.c.) twice a day for nine days, and betaine (25mg/kg, s.c.) was administered 30min before the Hcy injections. The memory functions were evaluated using a spontaneous alternation performance test (Y-maze) at seven days and a step-down type passive avoidance test (SD) at nine and ten days after Hcy injection. We found that betaine suppressed the memory impairment induced by repeated Hcy injections. However, the blood concentrations of Hcy were significantly increased in the Hcy-treated mice immediately after the passive avoidance test, and betaine did not prevent this increase. Furthermore, Hcy induces redox stress in part by activating matrix metalloproteinase-9 (MMP-9), which leads to BBB dysfunction. Therefore, we tested whether betaine affected MMP-9 activity. Interestingly, treatment with betaine significantly inhibited Hcy-induced MMP-9 activity in the frontal cortex but not in the hippocampus after acute Hcy injection. These results suggest that the changes in MMP-9 activity after betaine treatment might have been partially responsible for the amelioration of the memory deficits and that MMP-9 might be a candidate therapeutic target for HHcy.

Implantation of refractive multifocal intraocular lens with a surface-embedded near section for cataract eyes complicated with a coexisting ocular pathology.

PURPOSE: To evaluate the postoperative outcomes of cataract eyes complicated with coexisting ocular pathologies that underwent implantation of a refractive multifocal intraocular lens (MIOL) with a surface-embedded near section. METHODS: LENTIS MPlus (Oculentis GmbH) refractive MIOLs were implanted in 15 eyes with ocular pathologies other than cataract (ie, six high-myopia eyes with an axial length longer than 28 mm, two fundus albipunctatus eyes, two branch retinal-vein occlusion eyes, four glaucoma eyes (one with high myopia), and two keratoconus eyes). Uncorrected or corrected distance and near visual acuity (VA) (UDVA, UNVA, CDVA, and CNVA), contrast sensitivity, and defocus curve were measured at 1 day and 6 months postoperatively, and each patient completed a 6-month postoperative questionnaire regarding vision quality and eyeglass use. RESULTS: Thirteen eyes (87%) registered 0 or better in CDVA and 12 eyes (73%) registered better than 0 in CNVA. Contrast sensitivity in the eyes of all patients was comparable to that of normal healthy subjects. No patient required eyeglasses for distance vision, but three patients (20%) required them for near vision. No patient reported poor or very poor vision quality. CONCLUSION: With careful case selection, sectorial refractive MIOL implantation is effective for treating cataract eyes complicated with ocular pathologies.

Characterization and antimicrobial susceptibility of motile aeromonads isolated from freshwater ornamental fish showing signs of septicaemia.

A total of 74 phenotypically identified presumptive motile Aeromonas isolates recovered from septicaemic freshwater ornamental fish in Sri Lanka were genetically characterized by sequencing of rpoD and gyrB genes. rpoD/gyrB phylogeny confirmed only 53 isolates as Aeromonas, among which A. veronii was the predominant species (79.2%), followed by A. hydrophila (7.5%), A. caviae (5.7%), A. jandaei (1.9%), A. dhakensis (3.8%) and A. entero pelogenes (1.9%). The aeromonads confirmed by sequencing were further subjected to 16S rDNA PCR-RFLP which substantiated sequencing results for 83% of isolates. Fingerprinting of A. enteropelogenes (n = 42) using ERIC-PCR revealed no dominant clones, and the majority were genetically distinct. All isolates were screened by PCR for 7 virulence determinant genes (aer, act, ast, alt, fla, ser, exu) and 2 integrase encoding genes (intI1, intI2). Each isolate contained ≥3 of the virulence genes tested for, with a heterogeneous distribution. Of the isolates, 77% harboured the intI1 gene, while none had intI2. In vitro antimicrobial susceptibility testing showed highest resistances towards tetracycline (58.5%) and erythromycin (54.7%). Our results indicate the diverse range of aeromonads that could potentially be associated with motile aeromonad septicaemia in ornamental fish. This is the first isolation of A. dhakensis from a septicaemic ornamental fish since its original description from the same host.

DPP and DSP are Necessary for Maintaining TGF-ß1 Activity in Dentin.

Porcine dentin sialophosphoprotein (DSPP) is the most abundant non-collagenous protein in dentin. It is processed by proteases into 3 independent proteins: dentin sialoprotein (DSP), dentin glycoprotein (DGP), and dentin phosphoprotein (DPP). We fractionated DPP and DSP along with TGF-ß activity by ion exchange (IE) chromatography from developing pig molars and measured their alkaline phosphatase (ALP)-stimulating activity in human periodontal (HPDL) cells with or without TGF-ß receptor inhibitor. We then purified TGF-ß-unbound or -bound DPP and DSP by reverse-phase high-performance liquid chromatography (RP-HPLC) using the ALP-HPDL system. The TGF-ß isoform bound to DPP and DSP was identified as being TGF-ß1 by both ELISA and LC-MS/MS analysis. We incubated carrier-free human recombinant TGF-ß1 (CF-hTGF-ß1) with TGF-ß-unbound DPP or DSP and characterized the binding on IE-HPLC using the ALP-HPDL system. When only CF-hTGF-ß1 was incubated, approximately 3.6% of the ALP-stimulating activity remained. DPP and DSP rescued the loss of TGF-ß1 activity. Approximately 19% and 10% of the ALP stimulating activities were retained by the binding of TGF-ß to DPP and DSP, respectively. The type I collagen infrequently bound to CF-hTGF-ß1. We conclude that both DPP and DSP help retain TGF-ß1 activity in porcine dentin.

Quantification of allergic and irritant patch test reactions using ImageJ.

BACKGROUND/AIMS: It is often difficult to differentiate between allergic and irritant patch test reactions by visual inspection. The purpose of this study was to test an image analysis-based method that differentiates between the two reactions by quantifying the degree of erythema at the patch test site. METHODS: A total of 172 Japanese patients were patch-tested with sodium lauryl sulfate (SLS) and nickel sulfate, followed by digital photography and visual evaluation of the patch test areas by dermatologists at 48 and 72 h. The digital images were converted to erythema index (EI) images by image processing, and changes in ΔEI (the difference in the EI between the patch test site and the adjacent normal skin) values were analyzed. RESULTS: The ΔEI was significantly increased at 72 h relative to that at 48 h for positive nickel sulfate reactions (P < 0.0001), while no significant difference in the ΔEI was found for SLS reactions. CONCLUSION: Using image analysis, allergic patch test reactions may be distinguished from irritant reactions by evaluating the change in the degree of erythema at 48 and 72 h.

Human periodontal ligament cell sheets cultured on amniotic membrane substrate.

OBJECTIVE: Periodontal ligament (PDL) cells and their substrates play key roles in periodontal regeneration. However, there has been no report on the use of amniotic membrane (AM) as a substrate for culturing PDL cells. In the current study, we conducted an analysis of PDL cells cultivated on AM to determine the distribution of factors responsible for maintaining the characteristics of PDL. MATERIALS AND METHODS: Amniotic membrane was obtained from women undergoing cesarean sections, whereas PDL tissue was obtained from human maxillary third molars. The harvested PDL cells were maintained in explant culture for three or four passages, following which they were cultured on AM. RESULTS: After 3 weeks of culture, the PDL cells had grown well on AM. Immunofluorescence showed that these cells were capable of proliferating and potentially maintaining their PDL-like properties. In addition, strong cell-cell adhesion structures, namely desmosomes and tight junctions, were shown to be present between cells. Electron microscopy images showed that the cultured PDL cells had differentiated and proliferated on AM with lateral conjugation and adhesion to AM. CONCLUSION: We conclude that AM may represent a suitable substrate for culturing PDL cells and that PDL cells cultured on AM show sheet formation.

Alignment of crystal orientations of the multi-domain photonic crystals in Parides sesostris wing scales.

It is known that the wing scales of the emerald-patched cattleheart butterfly, Parides sesostris, contain gyroid-type photonic crystals, which produce a green structural colour. However, the photonic crystal is not a single crystal that spreads over the entire scale, but it is separated into many small domains with different crystal orientations. As a photonic crystal generally has band gaps at different frequencies depending on the direction of light propagation, it seems mysterious that the scale is observed to be uniformly green under an optical microscope despite the multi-domain structure. In this study, we have carefully investigated the structure of the wing scale and discovered that the crystal orientations of different domains are not perfectly random, but there is a preferred crystal orientation that is aligned along the surface normal of the scale. This finding suggests that there is an additional factor during the developmental process of the microstructure that regulates the crystal orientation.

Structural color of a lycaenid butterfly: analysis of an aperiodic multilayer structure.

We investigated the structural color of the green wing of the lycaenid butterfly Chrysozephyrus brillantinus. Electron microscopy revealed that the bottom plate of the cover scale on the wing consists of an alternating air-cuticle multilayer structure. However, the thicknesses of the layers were not constant but greatly differed depending on the layer, unlike the periodic multilayer designs often adopted for artificial laser-reflecting mirrors. The agreement between the experimentally determined and theoretically calculated reflectance spectra led us to conclude that the multilayer interference in the aperiodic system is the primary origin of the structural color. We analyzed optical interference in this aperiodic system using a simple analytical model and found that two spectral peaks arise from constructive interference among different parts of the multilayer structure. We discuss the advantages and disadvantages of the aperiodic system over a periodic one.

Turn-over orbital septal flap and levator recession for upper-eyelid retraction secondary to thyroid eye disease.

BACKGROUND: A turn-over septal flap has been reported as a spacer for levator lengthening in a single case report. This study reports the preliminary outcomes of this technique in a series of patients with upper-lid retraction (ULR) associated with thyroid eye disease (TED) causing symptomatic exposure keratopathy (EK). METHODS: Retrospective, multicenter study of 12 eyelids of 10 patients with TED undergoing a transcutaneous levator-lengthening technique using the reflected orbital septum (OS) as a spacer. Change in palpebral aperture (PA) and contour, position of the skin crease (SC), symptoms of EK, and complications were recorded. RESULTS: The average age was 47.5 years. Two patients were excluded, as their septa were found to be very thin at surgery. At an average of 13 months postoperatively, the PA was reduced by 2.5 mm on average (P<0.001) and was within 1 mm of the contralateral eyelid in 11 cases (92%); the position of the SC was within 1 mm of the desired position in all cases. EK resolved in all cases. Complications included one case of overcorrection and one case of recurrent lateral flare. CONCLUSIONS: The turn-over orbital septal flap technique may be a viable option as an autogenous spacer for the treatment of ULR in TED. This technique may be possible in cases where the OS has been opened by previous surgery but may not be feasible in patients in whom the septum is very thin.

A whole-genome association study of major determinants for allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are severe, cutaneous adverse drug reactions that are rare but life threatening. Genetic biomarkers for allopurinol-related SJS/TEN in Japanese were examined in a genome-wide association study in which Japanese patients (n=14) were compared with ethnically matched healthy controls (n=991). Associations between 890 321 single nucleotide polymorphisms and allopurinol-related SJS/TEN were analyzed by the Fisher's exact test (dominant genotype mode). A total of 21 polymorphisms on chromosome 6 were significantly associated with allopurinol-related SJS/TEN. The strongest association was found at rs2734583 in BAT1, rs3094011 in HCP5 and GA005234 in MICC (P=2.44 × 10(-8); odds ratio=66.8; 95% confidence interval, 19.8-225.0). rs9263726 in PSORS1C1, also significantly associated with allopurinol-related SJS/TEN, is in absolute linkage disequilibrium with human leukocyte antigen-B*5801, which is in strong association with allopurinol-induced SJS/TEN. The ease of typing rs9263726 makes it a useful biomarker for allopurinol-related SJS/TEN in Japanese.