FUT2 non-secretor status is associated with Type 1 diabetes susceptibility in Japanese children.

AIM: To examine the contribution of the FUT2 gene and ABO blood type to the development of Type 1 diabetes in Japanese children. METHODS: We analysed FUT2 variants and ABO genotypes in a total of 531 Japanese children diagnosed with Type 1 diabetes and 448 control subjects. The possible association of FUT2 variants and ABO genotypes with the onset of Type 1 diabetes was statistically examined. RESULTS: The se2 genotype (c.385A>T) of the FUT2 gene was found to confer susceptibility to Type 1A diabetes in a recessive effects model [odds ratio for se2/se2, 1.68 (95% CI 1.20-2.35); corrected P value = 0.0075]. CONCLUSIONS: The FUT2 gene contributed to the development of Type 1 diabetes in the present cohort of Japanese children.

Variants associated with autoimmune Type 1 diabetes in Japanese children: implications for age-specific effects of cis-regulatory haplotypes at 17q12-q21.

AIMS: The aim of this study was to clarify the significance of previously reported susceptibility variants in the development of autoimmune Type 1 diabetes in non-white children. Tested variants included rs2290400, which has been linked to Type 1 diabetes only in one study on white people. Haplotypes at 17q12-q21 encompassing rs2290400 are known to determine the susceptibility of early-onset asthma by affecting the expression of flanking genes. METHODS: We genotyped 63 variants in 428 Japanese people with childhood-onset autoimmune Type 1 diabetes and 457 individuals without diabetes. Possible association between variants and age at diabetes onset was examined using age-specific quantitative trait locus analysis and ordered-subset regression analysis. RESULTS: Ten variants, including rs2290400 in GSDMB, were more frequent among the people with Type 1 diabetes than those without diabetes. Of these, rs689 in INS and rs231775 in CTLA4 yielded particularly high odds ratios of 5.58 (corrected P value 0.001; 95% CI 2.15-14.47) and 1.64 (corrected P value 5.3 × 10-5 ; 95% CI 1.34-2.01), respectively. Age-specific effects on diabetes susceptibility were suggested for rs2290400; heterozygosity of the risk alleles was associated with relatively early onset of diabetes, and the allele was linked to the phenotype exclusively in the subgroup of age at onset ≤ 5.0 years. CONCLUSIONS: The results indicate that rs2290400 in GSDMB and polymorphisms in INS and CTLA4 are associated with the risk of Type 1 diabetes in Japanese children. Importantly, cis-regulatory haplotypes at 17q12-q21 encompassing rs2290400 probably determine the risk of autoimmune Type 1 diabetes predominantly in early childhood.

Emergence of resistant variants detected by ultra-deep sequencing after asunaprevir and daclatasvir combination therapy in patients infected with hepatitis C virus genotype 1.

Daclatasvir (DCV) and asunaprevir (ASV) are NS5A and NS3 protease-targeted antivirals respectively, currently under development for the treatment of chronic hepatitis C virus (HCV) infection. We analysed the relationship between pre-existing drug-resistant variants and clinical outcome of the combination treatment with DCV and ASV. Ten patients with HCV genotype 1b were orally treated with a combination of ASV and DCV for 24 weeks. The frequencies of amino acid (aa) variants at NS3 aa positions 155, 156 and 168 and at NS5A aa31 and 93 before and after treatment were analysed by ultra-deep sequencing. We established a minimum variant frequency threshold of 0.3% based on plasmid sequencing. Sustained virological response (SVR) was achieved in 8 out of 10 patients (80%), and relapse of HCV RNA after cessation of the treatment and viral breakthrough occurred in the other two patients. Pre-existing DCV-resistant variants (L31V/M and/or Y93H; 0.9-99.4%) were detected in three out of eight patients who achieved SVR. Pre-existing DCV-resistant variants were detected in a relapsed patient (L31M, Y93H) and in a patient with viral breakthrough (Y93H); however, no ASV-resistant variants were detected. In these patients, HCV RNA rebounded with ASV- and DCV- double resistant variants (NS3 D168A/V plus NS5A L31M and Y93H). While pre-existing DCV-resistant variants might contribute to viral breakthrough in DCV and ASV combination therapy, the effectiveness of prediction of the outcome of therapy based on ultra-deep sequence analysis of pre-existing resistant variants appears limited.

Relationship between midgut malrotation and anatomy of the hepatoduodenal ligament: a rare anatomical variation in a deceased donor.

INTRODUCTION: Anatomical variations around the hepatoduodenal ligament greatly influence surgical procedures and the difficulty of operations. Here, we report the case of a deceased donor with midgut malrotation (MgM) and anatomical variation. We also present an anatomical comparison between MgM and normal cases. CASE REPORT: The donor, a male in his 60s, was diagnosed with MgM based on preoperative computed tomography. Intraoperatively, the liver graft was harvested from the proper hepatic artery (PHA), but its length was too short for reconstruction. Therefore, the hepatic artery was reconstructed at both the left and right hepatic arteries. METHODS: The length of the proper hepatic artery (l-PHA) and main trunk of the portal vein (l-PV) was compared between MgM and control groups (n = 9) using computed tomography. The ratio of PHA (r-PHA) and PV (r-PV), which was calculated as the l-PHA or l-PV divided by the patient's height, was also compared. RESULTS: The r-PV was 1.3% in the MgM group and 1.6% in the control group (P = .09). The r-PHA was 0.23% in the MgM group and 0.92% in the control group (P < .01). Thus, the PHA was significantly shorter in the MgM group. Additionally, anatomical variations of the hepatic artery were confirmed in four cases. CONCLUSION: Preoperative radiological evaluation is not always adequate for identifying anatomical abnormalities in deceased donors. MgM is a rare but important anomaly because of the possibility of associated anatomical variations of the hepatic artery.

Tunable Dirac cone in the topological insulator Bi(2-x)Sb(x)Te(3-y)Se(y).

The three-dimensional topological insulator is a quantum state of matter characterized by an insulating bulk state and gapless Dirac cone surface states. Device applications of topological insulators require a highly insulating bulk and tunable Dirac carriers, which has so far been difficult to achieve. Here we demonstrate that Bi(2-x)Sb(x)Te(3-y)Se(y) is a system that simultaneously satisfies both of these requirements. For a series of compositions presenting bulk-insulating transport behaviour, angle-resolved photoemission spectroscopy reveals that the chemical potential is always located in the bulk band gap, whereas the Dirac cone dispersion changes systematically so that the Dirac point moves up in energy with increasing x, leading to a sign change of the Dirac carriers at x~0.9. Such a tunable Dirac cone opens a promising pathway to the development of novel devices based on topological insulators.

Direct measurement of the out-of-plane spin texture in the Dirac-cone surface state of a topological insulator.

We have performed spin- and angle-resolved photoemission spectroscopy of Bi(2)Te(3) and present the first direct evidence for the existence of the out-of-plane spin component on the surface state of a topological insulator. We found that the magnitude of the out-of-plane spin polarization on a hexagonally deformed Fermi surface of Bi(2)Te(3) reaches maximally 25% of the in-plane counterpart, while such a sizable out-of-plane spin component does not exist in the more circular Fermi surface of TlBiSe(2), indicating that the hexagonal deformation of the Fermi surface is responsible for the deviation from the ideal helical spin texture. The observed out-of-plane polarization is much smaller than that expected from the existing theory, suggesting that an additional ingredient is necessary for correctly understanding the surface spin polarization in Bi(2)Te(3).

Low serum potassium levels and risk of type 2 diabetes: the Toranomon Hospital Health Management Center Study 1 (TOPICS 1).

AIMS/HYPOTHESIS: Evidence has suggested that low serum potassium concentrations decrease insulin secretion, leading to glucose intolerance, and that hypokalaemia induced by diuretics increases the risk for diabetes in hypertensive individuals. However, no prospective study has investigated the association between serum potassium and the development of type 2 diabetes in a healthy cohort comprised of Asian individuals not being administered antihypertensive medications. This study aimed to investigate whether low serum potassium is associated with increased risk of type 2 diabetes in apparently healthy Japanese men. METHODS: We followed 4,409 Japanese men with no history of diabetes, use of antihypertensives, renal dysfunction or liver dysfunction (mean ± SD age, 48.4 ± 8.4 years). Cox proportional hazards regression was used to estimate HRs for incident diabetes (fasting plasma glucose level ≥ 7.0 mmol/l, HbA(1c) ≥ 6.5% or self-reported) including serum potassium concentration as either a categorical or a continuous variable. RESULTS: During a 5 year follow-up, 250 individuals developed type 2 diabetes. The lowest tertile of serum potassium (2.8-3.9 mmol/l) was independently associated with the development of diabetes after adjustment for known predictors (HR 1.57 [95% CI, 1.15-2.15]) compared with the highest tertile (4.2-5.4 mmol/l). Every 0.5 mmol/l lower increment in the baseline serum potassium level was associated with a 45% (12-87%) increased risk of diabetes. CONCLUSIONS/INTERPRETATION: Mild to moderately low serum potassium levels, within the normal range and without frank hypokalaemia, could be predictive of type 2 diabetes in apparently healthy Japanese men.

Source of N-nitrosodimethylamine in river waters of the upper Tone River basin in Japan.

The presence of N-nitrosodimethylamine (NDMA) in the Hirose River and its tributaries, located in the upper Tone River basin, in the Kanto region of Japan, was investigated. NDMA was detected at high levels in the Arato River, one of the tributaries of the Hirose River, at high concentrations (up to 2,100 ng/L). Due to the confluence of the Arato River, NDMA concentration in the Hirose River increased (up to 61 ng/L). The NDMA in the Arato River was due to industrial discharge from a livestock processing plant located near the river. There were three discharges at the plant, with NDMA concentrations of 78, 11, and 33,000 ng/L. The industrial discharges from the livestock processing plant did not contain significant amounts of NDMA precursors on chloramination. On the other hand, sewage effluent was shown to contain NDMA precursors. The amounts of NDMA precursors in the sewage effluent that were rapidly transformed into NDMA were considered to be lower than those slowly transformed into NDMA.

Reconsideration of insulin signals induced by improved laboratory animal diets, Japanese and American diets, in IRS-2 deficient mice.

Current Japanese and American diets and Japanese diet immediately after the War were converted to laboratory animal diets. As a result, current laboratory animal diet (CA-1, CLEA) unexpectedly resembled the diet of Japanese after the War. This is considered to result in an under-evaluation of diabetes research using laboratory animals at present. Therefore, changes in insulin signals caused by current Japanese and American diets were examined using IRS-2 deficient mice ( IRS2(-/-) mice) and mechanisms of aggravation of type 2 diabetes due to modern diets were examined. IRS2(-/-) mice at 6 weeks of age were divided into three groups: Japanese diet (Jd) group, American diet (Ad) group and CA-1 diet [regular diet (Rd)] group. Each diet was given to the dams from 7 days before delivery. When the IRS2(-/-) mice reached 6 weeks of age, the glucose tolerance test (GTT), insulin tolerance test (ITT) and organ sampling were performed. The sampled organs and white adipose tissue were used for analysis of RNA, enzyme activity and tissues. In GTT and ITT, the Ad group showed worse glucose tolerance and insulin resistance than the Rd group. Impaired glucose tolerance of the Jd group was the same as that of the Rd group, but insulin resistance was worse than in the Rd group. These results were caused an increase in fat accumulation and adipocytes in the peritoneal cavity by lipogenic enzyme activity in the liver and muscle, and the increase in TNFalpha of hypertrophic adipocyte origin further aggravated insulin resistance and the increase in resistin also aggravated the impaired glucose tolerance, leading to aggravation of type 2 diabetes. The Japanese and American diets given to the IRS2(-/-) mice, which we developed, showed abnormal findings in some IRS2(-/-) mice but inhibited excessive reactions of insulin signals as diets used in ordinary nutritional management.

Fulminant type 1 diabetes mellitus observed in insulin receptor substrate 2 deficient mice.

The objective of this study was to characterise the fulminant type 1 diabetes mellitus (DM) accompanying abrupt hyperglycaemia and ketonuria observed in insulin receptor substrate 2 (IRS2)-deficient mice. IRS2-deficient mice backcrossed onto the original C57BL/6J:Jc1 background (B6J-IRS2(-/-) mice) for more than 10 generations were used. Eight male IRS2-deficient mice with ketonuria and abrupt increase in plasma glucose concentrations over 25 mmol/l were used as the fulminant type 1 diabetic mice (diabetic mice) and 8 male IRS2-deficient mice (8 weeks old) without glycosuria were used as the control mice. Plasma metabolite, immunoreactive insulin (IRI) and C-peptide concentrations, hepatic energy metabolism related enzyme activities and histopathological change in pancreatic islets were investigated. The diabetic mice showed significantly higher plasma glucose and cholesterol concentrations and lower plasma IRI and C-peptide concentrations than the control mice. In livers of the diabetic mice, glycolytic and malate-aspartate shuttle enzyme activities decreased significantly and gluconeogenic, lipogenic and ketone body synthesis enzyme activities increased significantly compared to those in the control mice. The pancreatic islets of the diabetic mice decreased significantly in size and number of beta cells. The diabetic IRS2-deficient mice did not show the islet-related antibodies observed in the diabetic NOD mice in their sera. The characteristics of the diabetic IRS2-deficient mice resembled those of the human nonautoimmune fulminant type 1 DM. IRS2-deficient mice may be a useful animal model for studying the degradation mechanism of pancreatic beta cells in the process of development of fulminant type 1 DM.

DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers.

For more than a decade, researchers have refined criteria for the diagnosis of dementia with Lewy bodies (DLB) and at the same time have recognized that cognitive impairment and dementia occur commonly in patients with Parkinson disease (PD). This article addresses the relationship between DLB, PD, and PD with dementia (PDD). The authors agreed to endorse "Lewy body disorders" as the umbrella term for PD, PDD, and DLB, to promote the continued practical use of these three clinical terms, and to encourage efforts at drug discovery that target the mechanisms of neurodegeneration shared by these disorders of alpha-synuclein metabolism. We concluded that the differing temporal sequence of symptoms and clinical features of PDD and DLB justify distinguishing these disorders. However, a single Lewy body disorder model was deemed more useful for studying disease pathogenesis because abnormal neuronal alpha-synuclein inclusions are the defining pathologic process common to both PDD and DLB. There was consensus that improved understanding of the pathobiology of alpha-synuclein should be a major focus of efforts to develop new disease-modifying therapies for these disorders. The group agreed on four important priorities: 1) continued communication between experts who specialize in PDD or DLB; 2) initiation of prospective validation studies with autopsy confirmation of DLB and PDD; 3) development of practical biomarkers for alpha-synuclein pathologies; 4) accelerated efforts to find more effective treatments for these diseases.

Establishment of immortalized dental follicle cells for generating periodontal ligament in vivo.

The dental follicle is a mesenchymal tissue that surrounds the developing tooth germ. During tooth root formation, periodontal components, viz., cementum, periodontal ligament (PDL), and alveolar bone, are created by dental follicle progenitors. Here, we report the presence of PDL progenitors in mouse dental follicle (MDF) cells. MDF cells were obtained from mouse incisor tooth germs and immortalized by the expression of a mutant human papilloma virus type 16 E6 gene lacking the PDZ-domain-binding motif. MDF cells expressing the mutant E6 gene (MDF( E6-EGFP ) cells) had an extended life span, beyond 150 population doublings (PD). In contrast, normal MDF cells failed to proliferate beyond 10 PD. MDF( E6-EGFP ) cells expressed tendon/ligament phenotype-related genes such as Scleraxis (Scx), growth and differentiation factor-5, EphA4, Six-1, and type I collagen. In addition, the expression of periostin was observed. To elucidate the differentiation capacity of MDF( E6-EGFP ) cells in vivo, the cells were transplanted into severe combined immunodeficiency mice. At 4 weeks, MDF( E6-EGFP ) cell transplants had the capacity to generate a PDL-like tissue that expressed periostin, Scx, and type XII collagen and the fibrillar assembly of type I collagen. Our findings suggest that MDF( E6-EGFP ) cells can act as PDL progenitors, and that these cells may be a useful research tool for studying PDL formation and for developing regeneration therapies.

Intrauterine administration of autologous peripheral blood mononuclear cells promotes implantation rates in patients with repeated failure of IVF-embryo transfer.

BACKGROUND: There are few effective approaches to infertile patients with repeated failure in IVF-embryo transfer therapy. Since recent evidence suggests that some populations of maternal immune cells positively support embryo implantation, we have developed a new approach using peripheral blood mononuclear cells (PBMCs). METHODS: Patients who had not experienced successful pregnancy despite four or more IVF-embryo transfer sessions were enrolled in this study (n = 35, 35 cycles). PBMCs were obtained from patients on the day of oocyte retrieval and were cultured with HCG for 48 h. Two days later, PBMCs were freshly isolated from patients again, combined with cultured PBMC and then administered to the intrauterine cavity of the patients. Blastocyst transfer was performed on day 5, and the success of implantation in the PBMC-treated group was compared with that in the non-treated group. RESULTS: Clinical pregnancy rate, implantation rate and live birth rate in the PBMC-treated group (41.2, 23.4 and 35.3%; n = 17, 47 and 16, respectively) were significantly higher than those in the non-treated group (11.1, 4.1 and 5.5%; n = 18, 49 and 18, respectively). CONCLUSION: Intrauterine administration of autologous PBMC may be an effective approach to improve embryo implantation in patients with repeated IVF failures.

Brain site-specific gene expression analysis in Alzheimer's disease patients.

BACKGROUND: Alzheimer's disease (AD) is an age-related neurodegenerative disorder that is characterized by a progressive loss of higher cognitive functions. The brain of an individual with AD exhibits extracellular senile plaques (SPs) of aggregated amyloid-beta peptide (Abeta) and intracellular neurofibrillary tangles (NFTs). Given the critical role of neuronal transport of both proteins and organelles, it is not surprising that perturbation of microtubule-based transport may play a major role in the pathogenesis of AD. MATERIALS AND METHODS: We used the cDNA subtraction methodology and in vitro neural cell culture analyses to study the meaning of the brain site-specific gene expression pattern in cerebral tissue obtained from AD patients and also from control subjects at autopsy. RESULTS: We observed that cytoskeleton-associated proteins were down-regulated in AD subjects. We also noted an altered expression of the microtubule-associated protein 1B (MAP1B), the heat-shock protein (HSP)-90 (a key chaperone molecule), the tripartite motif-containing proteins (TRIM)-32/37 (an anti apoptotic enzyme with ubiquitin-protein ligase activity) and the Reticulon-3 (a modulator of the amyloid-precursor-protein (APP) cleavage) in AD brains. Additional molecular- and cell-biological studies revealed that small interfering RNA (siRNA)-mediated down-regulation of MAP1B expression leads to neuronal cell death in vitro. CONCLUSION: Altered expression of MAP1B, HSP90, TRIM32/37 and Reticulon-3 provides new clues by which the ubiquitin-proteasome-, the protein-chaperon- and the APP-processing systems are disturbed in AD, thus, leading to neuritic amyloid plaques and neurofibrillary tangles.

Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.

The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Neuronal gap junctions in the mouse main olfactory bulb: morphological analyses on transgenic mice.

In the present study we analyzed the structural features of extraglomerular gap junction-forming processes in mouse olfactory bulb electron microscopically. This work complements a previous study in which we analyzed the structural features of neuronal gap junction-forming processes within the glomerulus itself. Furthermore we examined connexin 36 expressing cells in the mouse olfactory bulb by analyzing transgenic mice in which the connexin 36 coding sequence was replaced with histological reporters. In extraglomerular regions, the mitral/tufted cell somata, dendrites and axon hillocks made gap junctions and mixed synapses with interneuronal processes. These gap junctions and synapses were associated with various types of interneuronal processes, including a particular type of sheet-like or calyx-like process contacting the somata or large dendrites of mitral/tufted cells. In the olfactory bulbs of the transgenic mice, connexin 36 was expressed in mitral cells, tufted cells, presumed granule cells and periglomerular cells. Multiple immunofluorescent labelings further revealed that presumed interneurons expressing connexin 36 in the periglomerular region rarely expressed calbindin, calretinin or tyrosine hydroxylase and are likely to comprise a chemically uncharacterized class of neurons. Similarly, interneurons expressing connexin 36 in the granule cell layer were rarely positive for calretinin, which was expressed in numerous presumed granule cells in the mouse main olfactory bulb. In summary, these findings revealed that mitral/tufted cells make gap junctions with diverse types of neurons; in the glomeruli gap junction-forming interneuronal processes originated from some types of periglomerular cells but others from a hitherto uncharacterized neuron type(s), and in the extraglomerular region gap-junction forming processes originate mainly from a subset of cells within the granule cell layer.

Intraglomerular dendritic link connected by gap junctions and chemical synapses in the mouse main olfactory bulb: electron microscopic serial section analyses.

Glomeruli of the main olfactory bulb are considered to serve as functional units in processing the olfactory information. Thus the fine tuning of the output level from each glomerulus is important to the information processing in the olfactory system. The interactions among neuronal elements in glomeruli might be one of main mechanisms regulating this output level. In the mouse main olfactory bulb neuronal connections via chemical synapses and gap junction in glomeruli were analyzed by the serial electron microscopical reconstruction. Gap junctions were encountered between diverse types of dendritic processes, between mitral/tufted cell dendrites, between mitral/tufted cell dendrites and periglomerular cell dendrites and between mitral/tufted cell dendrites and dendrites of some interneurons different from periglomerular cells. Then these morphological observations indicate that we must consider both direct coupling between mitral/tufted cells via gap junctions and indirect coupling between mitral/tufted cells via intervening interneuronal processes. One of gap junction-forming processes presynaptic in asymmetrical synapses was traced back to the soma of its origin located in the glomerular layer, which was thus identified as an external tufted cell. However, interestingly, it showed apparently different ultrastructural features from other external tufted cells located at the border between the glomerular and external plexiform layers; the latter resemble so-called mitral/tufted cells located in the external plexiform and mitral cell layers. Then external tufted cells were assumed to be heterogeneous in their ultrastructural features. We occasionally encountered several dendrites connected by gap junctions, which furthermore made chemical synapses with each other and with other surrounding processes. Thus both chemical synapses and gap junctions interconnect complexly various processes in the glomerulus, where the local circuit among intermingled olfactory nerves, mitral/tufted cell dendrites and interneuron dendrites is far more complex than previously schematized.

The effects of dissolved organic matter on the decomposition of di-n-butyl phthalate by ozone/hydrogen peroxide process.

The effects of the dissolved organic matter (DOM) on the ozone decay and the di-n-butyl phthalate (DBP) decomposition during ozone/hydrogen peroxide (O3/H2O2) process were investigated (DBP-d4 was used instead of DBP). Four surface waters, two secondary municipal sewage effluents (SMSEfs) and Suwannee river natural organic matter were used as DOM. The ozone decompositions in the DOM solutions were separated by instantaneous ozone consumption and slower ozone decay. The effect of H2O2 addition on the ozone decay was clearly observed at slower ozone decay. Ozone decomposition rate at slower ozone decay increased linearly with H2O2 dose. DBP-d4 was exponentially decreased with ozone consumption. Ozone consumption required to decompose 90% of DBP-d4 ((deltaO3)90%) in SMSEFs was higher than those in surface waters. The (deltaO3)90% per DOC of DOM values were from 22 to 23 micromole/mgC for SMSEFs and from 10 to 17 micromole/mgC for surface waters. The (deltaO3)90% values were correlated to specific ultraviolet absorbance at 254 nm (SUVA254) for surface waters.

Association in Japanese patients between neuroleptic malignant syndrome and functional polymorphisms of the dopamine D(2) receptor gene.

A genetic predisposition to the development of neuroleptic malignant syndrome (NMS) has been suggested by clinical studies. Although the molecular basis of NMS is unclear, a dopaminergic blockade mechanism has been considered the main cause. We therefore investigated the association between NMS and three functional polymorphisms of the dopamine D(2) receptor (DRD(2)) gene: TaqI A, -141C Ins/Del, and Ser311Cys. Subjects included 32 Japanese patients, previously diagnosed with NMS, and 132 schizophrenic patients treated with neuroleptics without occurrence of NMS. Polymerase chain reaction and restriction fragment length polymorphism analyses were performed to determine each genotype. We found significant differences in genotypic and allelic frequencies of the -141C Ins/Del polymorphism between patients with and without NMS. The -141C Del allele was significantly more frequent in the NMS group (23.4 vs 11.7%, P=0.026). Similarly, the proportion of -141C Del allele carriers was significantly higher in the NMS group (40.6 vs 20.5%, P=0.022). No significant differences between the two groups were seen for allelic and genotypic frequencies of the TaqI A and Ser311Cys polymorphisms. This result suggests that the -141C Ins/Del polymorphism is likely to predispose toward the development of NMS, probably together with other unidentified factors.