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IntroductionThis study aimed to identify the associations between lifestyle factors and intrapancreatic fat deposition in patients with type 2 diabetes.Research design and methodsThe participants were 185 patients with type 2 diabetes who were hospitalized at Osaka University Hospital between 2008 and 2020 and underwent abdominal CT during hospitalization. Information regarding lifestyle factors, including the number of meals consumed per day, snacking habits, exercise habits, exercise at work, smoking habits, alcohol intake, insomnia, sleep apnea syndrome, and night-shift working, was acquired from self-administered questionnaires or medical records. We measured the mean CT values for the pancreas (P), liver (L), and spleen (S), and the visceral fat area (VFA), and quantified intrapancreatic and liver ectopic fat accumulation as P−S and L−S, respectively.ResultsAfter adjustment for age, sex, hemoglobin A1c, and body mass index (BMI), participants who consumed two meals per day had significantly lower P−S (higher intrapancreatic fat deposition, p=0.02) than those who consumed three meals per day. There were no significant associations between the number of meals consumed and liver ectopic fat accumulation and VFA (p=0.73 and p=0.67, respectively).ConclusionsPatients with diabetes who consumed two meals per day showed greater intrapancreatic fat deposition than those who consumed three meals per day, even after adjustment for BMI. These findings support the current guideline for diabetes treatment that skipping meals should be avoided.

Pancreatic islet cells have plasticity, such as the abilities to dedifferentiate and transdifferentiate. Islet cell conversion to other characteristic cell is largely determined by transcription factors, but significance of expression patterns of these transcription factors in human islet cells remained unclear. Here, we present the NKX6.1-positive ratio of glucagon-positive cells (NKX6.1+/GCG+ ratio) and the ARX-negative ratio of glucagon-positive cells (ARX−/GCG+ ratio) in 34 patients who were not administered antidiabetic agents. Both of NKX6.1+/GCG+ ratio and ARX−/GCG+ ratio negatively associated with relative beta cell area. And these ratios did not have significant correlation with other parameters including age, body mass index, hemoglobin A1c, fasting plasma glucose level or relative alpha-cell area. Our data demonstrate that these expression ratios of transcription factors in glucagon-positive cells closely correlate with the reduction of beta-cell volume in human pancreas.

Some preceding studies have provided evidence that hypoxia-inducible factor (HIF)-prolyl hydroxylase (PH) inhibitors have therapeutic potential against tubular interstitial fibrosis (TIF). Recently, transformation of renal interstitial fibroblasts (RIFs) into α-smooth muscle actin-positive myofibroblasts with loss of their hypoxia-inducible erythropoietin (EPO) expression has been hypothesized as the central mechanism responsible for TIF with renal anemia (the RIF hypothesis). These reports have suggested that HIF-PH inhibitors may suppress TIF via suppressing transformation of RIFs. However, the direct effect of HIF-PH inhibitors on transformation of RIFs has not been demonstrated because there has been no appropriate assay system. Here, we established a novel in vitro model of the transformation of RIFs. This model expresses key phenotypic changes such as transformation of RIFs accompanied by loss of their hypoxia-inducible EPO expression, as proposed by the RIF hypothesis. Using this model, we demonstrated that JTZ-951, a newly developed HIF-PH inhibitor, stabilized HIF protein in RIFs, suppressed transformation of RIFs, and maintained their hypoxia-inducible EPO expression. JTZ-951 also suppressed the expression of FGF2, FGF7, and FGF18, which are upregulated during transformation of RIFs. Furthermore, expression of Fgf2, Fgf7, and Fgf18 was correlated with TIF in an animal model of TIF. We also demonstrated that not only FGF2, which is a well-known growth-promoting factor, but also FGF18 promoted proliferation of RIFs. These data suggest that JTZ-951 has therapeutic potential against TIF with renal anemia. Furthermore, FGF2, FGF7, and FGF18, which faithfully reflect the anti-TIF effects of JTZ-951, have potential as TIF biomarkers.

Aims/Introduction The relationship between pancreatic fatty infiltration and diabetes is widely known, whereas the causal relationship is not clear. Furthermore, it is uncertain whether pathogenesis of pancreatic fat is similar to that of liver fat. We aimed to clarify the contribution of this type of fat to glucose metabolism in type 2 diabetes patients by cross‐sectional and longitudinal analyses. Material and Methods A total of 56 patients with type 2 diabetes who had been hospitalized twice were analyzed. We evaluated the mean computed tomography values of the pancreas (P), liver (L) and spleen (S). Lower computed tomography values indicate a greater fat content. We defined indices of pancreatic or liver fat content as the differences between P or L and S. We assessed the associations among fat content for the two organs (P‐S, L‐S) and clinical parameters at the first hospitalization, and then analyzed the associations between these fat contents and changes in glycometabolic markers (the second data values minus the first). Results In the cross‐sectional study, P‐S negatively correlated with the increment of C‐peptide in the glucagon stimulation test (r = −0.71, P, In patients with type 2 diabetes, pancreatic fat was less associated with obesity‐related indicators than liver fat, but was more strongly associated with the longitudinal decrease in endogenous insulin‐secreting capacity.

X-chromosomal short tandem repeats (X-STRs) are useful for the identification of absent single parents and complex blood relations. In the present study, we aimed to identify novel STR loci for use as DNA markers by conducting polymorphism and haplotype analyses. We detected three novel STR loci (LC552061, LC552062, and LC552063, with repetitive structures of (GGAA)n(GGGA)m, (CCTT)n(CCCT)m, and (ATTT)n, respectively) in the p11.4 region of the X chromosome. For these X-STRs, the polymorphism information content values ranged from 0.5766 to 0.6377 and the power of discrimination in males and females ranged from 0.6269 to 0.6844 and from 0.8105 to 0.8537, respectively. The linkage disequilibrium analysis revealed p values of

IntroductionChronic inflammation is observed in type 2 diabetes islets, and fat deposition in the pancreas affects insulin secretion and glucose tolerance. However, the relationship between this inflammation and pancreatic fat deposition has not been elucidated.Research design and methodsWe examined pancreatic sections from 60 Japanese patients obtained by pancreatectomy. We evaluated pancreatic fat-cell area (%) and CD68-positive (CD68+) cells per islet histologically and examined the relationships between these histological findings and various clinical parameters.ResultsThe number of CD68+ cells per islet in the diabetes group was significantly higher than that in the normal glucose tolerance group (p=0.026). Moreover, CD68+ cells per islet were significantly correlated with body mass index (r=0.33, p=0.0080), fasting C-peptide immunoreactivity (r=0.46, p=0.0042), homeostasis model assessment insulin resistance (r=0.38, p=0.016), C-peptide index (r=0.38, p=0.018), the area under the glucose concentration curve (AUCglucose) at the 75 g oral glucose tolerance test (r=0.49, p=0.0065) and fat-cell area (r=0.51, p=0.0027) and AUCglucose (β=0.453, p=0.0042) were the independent and significant determinants of CD68+ cells per islet.ConclusionThe inflammation of islets is associated with pancreatic fatty infiltration and hyperglycemia, which may further aggravate glucose tolerance.

In humans, mutations in genes encoding homologs of the DNA mismatch repair endonuclease MutL cause a hereditary cancer that is known as Lynch syndrome. Here, we determined the crystal structures of the N-terminal domain (NTD) of MutL from the thermophilic eubacterium Aquifex aeolicus (aqMutL) complexed with ATP analogs at 1.69–1.73 A. The structures revealed significant structural similarities to those of a human MutL homolog, postmeiotic segregation increased 2 (PMS2). We introduced five Lynch syndrome-associated mutations clinically found in human PMS2 into the aqMutL NTD and investigated the protein stability, ATPase activity, and DNA-binding ability of these protein variants. Among the mutations studied, the most unexpected results were obtained for the residue Ser34. Ser34 (Ser46 in PMS2) is located at a previously identified Bergerat ATP-binding fold. We found that the S34I aqMutL NTD retains ATPase and DNA-binding activities. Interestingly, CD spectrometry and trypsin-limited proteolysis indicated the disruption of a secondary structure element of the S34I NTD, destabilizing the overall structure of the aqMutL NTD. In agreement with this, the recombinant human PMS2 S46I NTD was easily digested in the host Escherichia coli cells. Moreover, other mutations resulted in reduced DNA-binding or ATPase activity. In summary, using the thermostable aqMutL protein as a model molecule, we have experimentally determined the effects of the mutations on MutL endonuclease; we discuss the pathological effects of the corresponding mutations in human PMS2.

Context:Fulminant type 1 diabetes mellitus (T1DM) is thought to be partly caused by virus infection.Objective:This study investigated the mechanism of β cell destruction in fulminant T1DM after drug-induced hypersensitivity syndrome (DIHS).Methods:We determined the localization of human cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6), and Epstein-Barr virus (EBV) and the expression of interferon regulatory factor 3 (IRF3) and viral receptors of Z-DNA binding protein 1 (ZBP1) and retinoic acid-inducible gene I (RIG-I), together with inflammatory cells, by immunohistochemistry of the autopsy pancreas of a patient with fulminant T1DM with DIHS and in seven subjects with normal glucose tolerance who underwent pancreatectomy.Results:HCMV-positive cells were detected in islets and exocrine areas in the patient with fulminant T1DM. Greater numbers of macrophages and CD4+ and CD8+ T lymphocytes had infiltrated into HCMV-positive islets than into HCMV-negative islets, and 52.6% of HCMV-positive cells were also positive for IRF3. α Cells expressed IRF3, ZBP1, or RIG-I. No HCMV-positive cells were detected in the control subjects. HHV-6−positive, but not EBV-positive, cells were present in the patient and the control subjects.Conclusions:These findings indicate that the immunoresponse caused by HCMV infection was associated with β cell injury.

DNA testing using X-chromosomal short tandem repeat (X-STR) polymorphisms has been used in maternity/paternity and complex kinship cases. Analyses of repeat sequences, surveys on racial statistics, and development of practical applications for DNA testing continue to be reported. In this study, we identified four novel tetranucleotide STR loci located in the X chromosome, which is the basis of X-STR research. These four tetranucleotide STRs were located within 71 kb of the chromosome Xp22.3 region. Using sequence analysis of the structure of repeat sequences, we identified simple repeat sequences of TAAA, CTTT, TATC, and GATA with rare insertions. We then calculated forensic statistical parameters using base length analysis. In the Japanese population, the polymorphism information content was 0.597-0.687, power of discrimination in females was 0.829-0.884, and power of discrimination in males was 0.635-0.729. As these tetranucleotide STRs are closely linked, we conducted haplotype analysis and detected that three loci (LC149476, LC149479, and LC149480) were in linkage disequilibrium. We demonstrated that the simultaneous analysis of these loci may be useful in complex kinship cases. Because these four loci can be detected by multiplex PCR, the detection of alleles at these loci can be rapidly and easily achieved. We conclude that the X-STR loci detected in this study may be useful tools in complex kinship cases and may increase the reliability of genetic testing.

Cancer survivors face many challenges, and cancer support groups provide a range of support. Several reports have shown the benefits of support groups. However, it is not clear how Japanese cancer survivors use them. This study aimed to examine cancer survivors' awareness of and reasons for participation or non-participation in cancer support groups. We conducted a cross-sectional questionnaire survey with ambulatory patients with cancer across eight designated cancer hospitals. The questionnaire covered patients' demographics, disease characteristics, participation/non-participation in cancer support groups, and reasons for participation/non-participation. In total, 569 questionnaires were distributed, and responses were received from 275 patients with cancer. Of these, 135 patients were aware of support groups and 23 had participated in a group. Patients who were aware of support groups were more likely to be young, female patients. Many patients learned about support groups from hospital notices. Most support group participants expected to receive information about the disease and treatment (91%). They also wanted to hear about other patients' experiences (73%). The most common reasons for non-participation were "no particular reason" (38%) and "family or friends support me" (27%). About half of participating patients were unaware of support groups. Even among patients who were aware, many did not attend a support group. Developing a better understanding of support group use in cancer survivors may enhance provision of adequate care based on individual needs.

Investigation of drug-related crimes, such as violation of the Stimulant Drug Control Law, requires identifying the used drug (mainly stimulant drugs, methamphetamine hydrochloride) from a drug solution and the DNA type of the drug user from a trace of blood left in the syringe used to inject the drug. In current standard test procedures, DNA typing and methamphetamine detection are performed as independent tests that use two separate portions of a precious sample. The sample can be entirely used up by either analysis. Therefore, we developed a new procedure involving partial lysis of a stimulant-containing blood sample followed by separation of the lysate into a precipitate for DNA typing and a liquid-phase fraction for methamphetamine detection. The method enables these two tests to be run in parallel using a single portion of sample. Samples were prepared by adding methamphetamine hydrochloride water solution to blood. Samples were lysed with Proteinase K in PBS at 56°C for 20min, cooled at -20°C after adding methanol, and then centrifuged at 15,000rpm. Based on the biopolymer-precipitating ability of alcohol, the precipitate was used for DNA typing and the liquid-phase fraction for methamphetamine detection. For DNA typing, the precipitate was dissolved and DNA was extracted, quantified, and subjected to STR analysis using the AmpFℓSTR® Identifiler® Plus PCR Amplification Kit. For methamphetamine detection, the liquid-phase fraction was evaporated with N2 gas after adding 20μL acetic acid and passed through an extraction column; the substances captured in the column were eluted with a solvent, derivatized, and quantitatively detected using gas chromatograph/mass spectrometry. This method was simple and could be completed in approximately 2h. Both DNA typing and methamphetamine detection were possible, which suggests that this method may be valuable for use in criminal investigations.

Anemia is a common complication in patients with chronic kidney disease (CKD). Erythropoiesis-stimulating agents (ESAs) are the standard therapy for anemia in CKD. It has been expected that hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibition may have the potential to provide therapeutic benefits over pre-existing ESAs for anemia in CKD. Enarodustat (JTZ-951) is an oral HIF-PH inhibitor. In preclinical studies, enarodustat has been found to increase HIF-alpha proteins, erythropoietin production and erythropoiesis. Enarodustat also shows efficient iron utilization in iron-related parameters during erythropoiesis. Clinical trials have shown that enarodustat improved anemia both in non-dialysis-dependent CKD patients and dialysis patients. The safety results in clinical trials demonstrate that enarodustat is generally well tolerated. On the basis of these results, enarodustat was approved in September 2020 in Japan for the treatment of anemia associated with CKD. This manuscript will review enarodustat, its pharmacological characteristics in preclinical studies, and its efficacy and safety in clinical trials with anemic patients in CKD.

“δ”, a latent variable constructed from cognitive performance and functional status measures, can accurately diagnose dementia. The minimal assessment needed is unknown. We have constructed a δ homolog, “dTEXAS”, from Telephone Executive Assessment Scale (TEXAS) items, and validated it in a convenience sample of Japanese persons (n = 176). dTEXAS scores correlated strongly with both Instrumental Activities of Daily Living (IADL) (r = –0.86, p < 0.001) and Clinical Dementia Rating Scale (CDR) (r = 0.71, p < 0.001). Constructed independently of their diagnoses, dTEXAS scores accurately distinguished dementia versus controls [area under the receiver operating curve (AUC; ROC) = 0.92, dementia versus mild cognitive impairment (MCI) (AUC = 0.80) and controls versus MCI (AUC = 0.74)]. These AUCs are higher than those of multiple observed executive measures, as reported recently by Matsuoka et al., 2014. A dTEXAS score of –0.58 best discriminated between dementia versus controls with 90.1% sensitivity and 80.0% specificity.

The latent variable “δ”, can accurately diagnose dementia. Its generalizability across populations is unknown. We constructed a δ homolog (“dT2J”) in data collected by the Texas Alzheimer’s Research and Care Consortium (TARCC). From this, we calculated a composite d-score “d”. We then tested d’s generalizability across random subsets of TARCC participants and to a convenience sample of elderly Japanese persons with normal cognition (NC), mild cognitive impairment (MCI), and dementia (AD) (n = 176). dT2J was indicated by Instrumental Activities of Daily Living and psychometric measures. Embedded in this battery were the Mini-Mental Status Examination (MMSE) and an executive clock-drawing task (CLOX). Only MMSE and CLOX were available in both TARCC and the Japanese cohort. Therefore, a second composite variable, “T2J”, was constructed solely from the factor loadings of CLOX and MMSE on d. The diagnostic accuracy of T2J was estimated in the validation sample, the remainder of the TARCC cohort, and in the Japanese sample. The areas under the receiver operating curve (AUC; ROC) for T2J were compared in each sample, and against d in TARCC. The AUCs for T2J were statistically indiscriminable within TARCC, and in Japanese persons. In Japanese persons, AUCs for T2J were 0.97 for the discrimination between AD versus NC, 0.86 for AD versus MCI, and 0.79 for NC versus MCI. The AUCs for T2J in Japanese persons were higher than any individual psychometric measure in that sample. Valid d-score composites can be extracted from a subset of δ’s indicators. Moreover, those composites are exportable across cultural and linguistic boundaries.

Dysfunction of the fronto-striato-thalamic circuit routing through the orbitofrontal cortex (OFC) is thought to play the main role in the pathophysiology of obsessive-compulsive disorder (OCD). Repetitious stimulation of the OFC–ventral striatum (VS) projections in mice has been shown to increase the firing of the postsynaptic VS cells and the frequency of OCD-like symptoms. Moreover, increased functional connectivity (FC) between the OFC and the VS has been reported in patients with OCD. While FC is a synchronous, non-directed correlation, the directed influence between these brain regions remains unclear in patients with OCD. We obtained resting state functional magnetic resonance imaging scans from 37 non-medicated patients with OCD and 38 matched healthy volunteers, and calculated bivariative voxel-wise Granger Causality (GC) to and from three striatal regions of interest (ROI) using a blind deconvolution procedure. Additionally, we conducted multivariative GC analysis to determine if the effect revealed by the bivariative voxel-wise GCA is mediated by another seed ROI. We found a significant hyper-influence of the OFC over the VS of subjects with OCD (p

The augmentation of selective serotonin reuptake inhibitors with antipsychotics that have a high dopamine-receptor-D2 affinity may be effective in treatment-resistant obsessive-compulsive disorder and somatic symptom disorder, which is similar to illness anxiety disorder. Blonanserin, a novel antipsychotic developed in Japan, has a high affinity for the D2 receptor and weak or very little affinity for other receptors. This article presents two case studies that demonstrate the efficacy of blonanserin augmentation for treatment-resistant somatic symptom disorder. Two patients with treatment-resistant somatic symptom disorder were prescribed concomitant use of blonanserin. Augmentation with blonanserin resulted in the remarkable amelioration of all symptoms. Sedative adverse drug reactions produced by aripiprazole were improved after replacing it with blonanserin. Blonanserin is effective in treatment-resistant somatic symptom disorder. Furthermore, compared with aripiprazole, blonanserin is more likely to result in medication adherence in patients with somatic symptom disorder because it reduced adverse drug reactions.

Background Many studies reported the high prevalence of problematic internet use (PIU) among adolescents (13–50%), and PIU was associated with various psychiatric symptoms. In contrast, only a few studies investigated the prevalence among the adult population (6%). This study aimed to investigate the prevalence of PIU and psychiatric co-morbidity among adult psychiatric patients. Methods Three hundred thirty-three adult psychiatric patients were recruited over a 3-month period. Two hundred thirty-one of them completed the survey (response rate: 69.4%, 231/333; Male/Female/Transgender: 90/139/2; mean age = 42.2). We divided participants into “normal internet users” and “problematic internet users” using a combination of Young’s Internet Addiction Test (IAT) and the Compulsive Internet Use Scale (CIUS). Demographic data and comorbid psychiatric symptoms were compared between the two groups using self-rating scales measuring insomnia (Athens Insomnia Scale, AIS), depression (Beck Depression Inventory, BDI), anxiety (State-trait Anxiety Inventory, STAI), attention deficit hyperactivity disorder (ADHD) (Adult ADHD Self-report Scale, ASRS), autism (Autism Spectrum Quotient, AQ), obsessive-compulsive disorder (OCD) (Obsessive-Compulsive Inventory, OCI), social anxiety disorder (SAD) (Liebowitz Social Anxiety Scale, LSAS), alcohol abuse, and impulsivity (Barratt Impulsive Scale, BIS). Results Among 231 respondents, 58 (25.1%) were defined as problematic internet users, as they scored high on the IAT (40 or more) or CIUS (21 or more). The age of problematic internet users was significantly lower than that of normal internet users (p

Insulinoma and insulin or insulin receptor (IR) autoantibodies are the main causes of hyperinsulinemic hypoglycemia in adults, but the exact cause in other cases remains obscure. This study is to determine the genetic basis of hyperinsulinemic hypoglycemia in two cases without the above abnormalities. Sequence analysis of IR gene in two patients with adult-onset hyperinsulinemic hypoglycemia and their relatives were performed, and the mutant gene observed in one case was analyzed. Both cases had normal levels of fasting plasma glucose (FPG), fasting hyperinsulinemia, low insulin sensitivity, and hypoglycemia with excessive insulin secretion during oral glucose tolerance test (OGTT). Both reported adult-onset postprandial hypoglycemic symptoms. In one patient, a missense mutation (Arg256Cys) was detected in both alleles of the IR gene, and his parents had the same mutation in only one allele but no hypoglycemia. The other had a novel nonsense mutation (Trp1273X) followed by a mutation (Gln1274Lys) in one allele, and his 9-year old son had the same mutation in one allele, together with hyperinsulinemic hypoglycemia during OGTT. Overexpression experiments of the mutant gene found in Case 1 in mammalian cells showed abnormal processing of the IR protein and demonstrated reduced function of Akt/Erk phosphorylation by insulin in the cells. In two cases of hyperinsulinemic hypoglycemia in adults, we found novel mutations in IR gene considered to be linked to hypoglycemia. We propose a disease entity of adult-onset hyperinsulinemic hypoglycemia syndrome associated with mutations in IR gene.

Objective "δ", a latent variable constructed from batteries that contain both cognitive and functional status measures, can accurately diagnose dementia relative to expert clinicians. The minimal assessment needed is unknown. Methods We validated 2 δ homologs in a convenience sample of elderly Japanese persons with normal cognition (NC), mild cognitive impairment (MCI), and dementia (n = 176). The latent δ homolog "d" (for dementia) was constructed from Instrumental Activities of Daily Living (IADL) and Japanese translations of the Executive Clock-Drawing Task (CLOX), Frontal Assessment Battery (FAB), and Executive Interview (EXIT25). The latent delta homolog "d3" was constructed from a restricted set of d's factor loadings. Results d and d3 were highly intercorrelated (r = .97) and strongly related to both IADL and dementia severity, as rated blindly by the Clinical Dementia Rating Scale (CDR). d was more strongly related to IADL and CDR than any of its indicators. In multivariate regression, d explained more variance in CDR scores than all of its indicators combined. d's areas under the receiver operating characteristic curve (AUC) were 0.95 for the discrimination between Alzheimer's disease (AD) vs. NC, 0.84 for AD vs. MCI and 0.81 for NC vs. MCI. d3's AUC's were statistically indiscriminable. These AUC's are higher than any of d's indicators, as reported recently by Matsuoka et al. (2014), as well as the Mini-Mental State Examination (MMSE), which had been made available by Matsuoka et al. to the CDR raters. Conclusions Latent variables can improve upon a battery's diagnostic performance and offer the potential for accurate dementia case-finding after a minimal bedside assessment.

We herein report the first covalent G-site-binding inhibitor for GST, GS-ESF (1), which irreversibly inhibited the GSTP

Aim/introduction The patients with type 1 diabetes are classified into three subtypes: acute-onset, fulminant, and slowly progressive in Japan. Acute-onset type 1 diabetes would be equivalent to type 1A diabetes, the typical type 1 diabetes in Western countries. The insulin secretion capacity in Japanese subjects with long-standing type 1A diabetes is unclear. The aim of this study is to clarify the course of endogenous insulin secretion during long-term follow-up and factors associated with residual insulin secretion in patients with acute-onset type 1 diabetes (autoimmune). Materials and Methods We retrospectively investigated endogenous insulin secretion capacity in 71 patients who fulfilled the diagnostic criteria for acute-onset type 1 diabetes (autoimmune) in Japan. To assess the residual insulin secretion capacity, we evaluated randomly measured C-peptide levels and results of glucagon stimulation test in 71 patients. Results In the first year of disease, the child- and adolescent-onset patients had significantly more in residual insulin secretion than the adult-onset patients (34 patients in total). C-peptide levels declined more rapidly in patients whose onset were younger than 18 years old have than in patients whose onset were older than 19 years old. Endogenous insulin secretion capacity stimulated by glucagon was completely lost in almost all patients at more than 15 years after onset (61 patients in total). Conclusions Most patients with acute-onset type 1 diabetes (autoimmune) completely lose their endogenous insulin secretion capacity during the disease duration in Japan. Age of onset may affect the course of insulin secretion. This article is protected by copyright. All rights reserved.

The evaluation of elastic properties of bone matrix has been investigated using several techniques such as nanoindentation and scanning acoustic microscopy (SAM). These techniques make use of good spatial resolution, which can prevent effects due to microstructures at the level of several hundreds of microns. In this paper, micro-Brillouin scattering (μ-BR) is introduced as another possible technique to characterize the elastic properties of bone. This technique is well known as a non-contact and non-destructive method to evaluate viscoelastic properties of transparent materials in the GHz range. Using thin, translucent bone specimens with thicknesses of around 100 μm, and the reflection induced optical geometry, ultrasonic wave velocities in the GHz range were obtained. Because this technique optically measures thermal phonons in the specimen, we can easily measure in-plane anisotropy of wave velocities by rotating the specimen. In a single trabecula, the site matched data between SAM and μ-BR showed good correlation, revealing the applicability of this technique to characterize material properties of bone. Some recent results on the anisotropy in a trabecula and the elasticity evaluation of newly and matured bones are also introduced.

There has been an increasing interest in white matter abnormalities in patients with anorexia nervosa (AN). However, to date, there have been only a few diffusion tensor imaging (DTI) studies investigating AN, and the results are inconsistent. In this study, we employed tract-based spatial statistics (TBSS), a robust technique for whole-brain analysis of DTI data, to detect white matter abnormalities in AN patients compared with healthy controls. Seventeen women with AN and 18 age matched healthy women were included. The mean body mass index of patients was 13.6 kg/m(2) (controls: 19.9 kg/m(2)). DTI data were acquired on a 3-Tesla magnetic resonance imaging system. Fractional anisotropy (FA) and mean diffusivity (MD) maps were calculated from the DTI data of each patient, and voxel-wise group comparisons of FA and MD were performed using TBSS. Compared with the healthy comparisons, the patients showed a significantly higher MD value in the fornix and lower FA value in the left cerebellum. We also found significant positive correlations between the mean FA value of the left cerebellar hemisphere cluster and BMI, as well as between the mean MD value of the cluster in the anterior body of the fornix and the duration of illness. The results suggest that the white matter abnormalities in the fornix and the cerebellum may be related to the pathophysiology of AN.

Background:The aim of the study was to develop the Japanese versions of Executive Interview (J-EXIT25) and Executive Clock Drawing Task (J-CLOX) and to evaluate the aspects of executive function that these two tests will be examining.Methods:The concurrent validity and reliability of J-EXIT25 and J-CLOX were first examined in all participants (n = 201). Next, the relationship between the two tests was examined using receiver operating characteristic (ROC), correlation, and regression analyses in healthy participants (n = 45) and participants with mild cognitive impairment (n = 36) and dementia (n = 95).Results:Satisfactory concurrent validity and reliability of J-EXIT25 and J-CLOX were shown. ROC analysis indicated that J-EXIT25 and J-CLOX1 were superior to the Frontal Assessment Battery, but inferior to the Mini-Mental State Examination (MMSE), in discriminating between non-dementia and dementia. J-EXIT25, J-CLOX1, and J-CLOX2 scores were significantly correlated with age, scores on the MMSE, Instrumental Activities of Daily Living (IADL) and Physical Self-Maintenance Scale (PSMS), and care level. In stepwise regression analyses of IADL scores, MMSE and J-EXIT25 were significantly independent predictors in men, and MMSE, age, and J-CLOX1 were significantly independent predictors in women. J-EXIT25, MMSE, and J-CLOX1 were significantly independent predictors in stepwise regression analysis of PSMS scores, and J-EXIT25 was the only significantly independent predictor in stepwise regression analysis of care level.Conclusions:J-EXIT25 and J-CLOX are valid and reliable instruments for assessment of executive function in older people. The present results suggest that these tests have common and distinct psychometric properties in the assessment of executive function.

JTZ-951 (enarodustat) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor. JTZ-951 has inhibitory activities on human HIF-prolyl hydroxylase 1-3, but not on various receptors or enzymes. In Hep3B cells, JTZ-951 increased HIF-1α and HIF-2α protein levels, erythropoietin (EPO) mRNA levels, and EPO production. In normal rats, after a single oral dose of JTZ-951, the hepatic and renal EPO mRNA levels and plasma EPO concentrations were also increased. In 5/6-nephrectomized rats, repeated oral doses of JTZ-951 once daily or intermittent dosing showed the erythropoiesis stimulating effect. The administration of JTZ-951 at a high dose increased plasma vascular endothelial growth factor (VEGF) levels; however, retinal VEGF mRNA levels and the retinal vascular permeability were not changed. Finally, we evaluated the effect of JTZ-951 in a colorectal cancer cell-inoculated mouse model. Although JTZ-951 at a high dose increased the plasma VEGF, it had no effect on tumor growth. In summary, JTZ-951 induces erythropoiesis without affecting VEGF function. Therefore, it is expected that JTZ-951 will be a new oral candidate that increases and maintains hemoglobin concentrations in renal anemia patients.

Objectives Postoperative delirium is a common psychiatric disorder among patients who undergo cardiac surgery. Although several studies have investigated risk factors for delirium after cardiac surgery, the association between delirium and cerebral white-matter hyperintensities (WMH) on magnetic resonance (MR) imaging has not been previously studied. The aim of this study was to identify general risk factors for delirium, as well as to examine the specific relationship between WMH and delirium. Design Retrospective chart review. Setting University hospital. Participants A total of 130 patients who underwent cardiac surgery. Measurements Variables recorded included patient demographics, comorbidities, mental health, laboratory data, surgical information, and cerebrovascular disease. The presence of WMH was assessed using MR images. Two groups of patients were compared (patients with and without delirium) using both univariate and multiple logistic analyses. Results Delirium occurred in 18 patients (13.8%) and patients with delirium were significantly older than patients who did not develop delirium. The prevalence of severe WMH (Fazekas score = 3) was significantly higher in patients with delirium. Three independent predictors of delirium were identified: abnormal creatinine (odds ratio [OR]: 4.5; 95% confidence interval [CI]: 1.4–13.9), severe WMH (OR: 3.9; 95% CI: 1.2–12.5), and duration of surgery (OR: 1.4; 95% CI: 1.0–1.8). Conclusions The results of this study suggest that white-matter abnormality is one of the most important risk factors for development of delirium after cardiac surgery. These factors can be used for prediction and prevention of delirium following cardiac surgery.

Patients with head and neck cancer often suffer from breathing, speaking, and eating deficits, which negatively affect their quality of life. These patients are often observed to repeatedly contract aspiration pneumonia, resulting in prolonged hospital stays. To help prevent aspiration pneumonia, enteral nutrition is often provided. Although this method helps avoid pneumonia, patients need to give up eating by mouth. Because oral intake of food is closely related to patient quality of life, abandoning eating results in a strong internal conflict. This report describes the case of a cancer patient who experienced repeated aspiration pneumonias after neck surgery. The patient required enteral nutrition to avoid repeated bouts of pneumonia. However, the patient opted for laryngeal closure surgery to regain the ability to take food orally, at the expense of his voice. The patient's choice caused an ethical conflict for the attending medical professionals, highlighting the need for physicians to communicate with their patients to understand their patients' sense of values.

Despite the fact that many cancer patients worldwide die in general hospitals, there are few reports of the analysis of delirium in terminally ill cancer patients in this setting.This study aimed to identify predictive factors for agitation severity of hyperactive delirium in terminally ill cancer patients in a general hospital.Participants were 182 consecutively admitted terminally ill cancer patients who died in a Japanese general hospital between April 2009 and March 2011. Variables present one week before death were extracted from the clinical records for regression analysis of factors potentially related to agitation severity of delirium. The prevalence and agitation severity of delirium were evaluated retrospectively. Multivariate ordered logistic regression analysis was performed to identify predictive factors.Male sex [odds ratio (OR)=2.125, 95% confidence interval (CI)=1.111-4.067; P=0.0227]; total bilirubin (T-bil) [OR=1.557, CI=1.082-2.239; P=0.017]; antibiotics [OR=0.450, CI=0.219-0.925; P=0.0298]; nonsteroidal antiinflammatory drugs (NSAIDs) [OR=2.608, CI=1.374-4.950; P=0.0034]; and hematological malignancy [OR=3.903, CI=1.363-11.179; P=0.0112] were found to be statistically significant predictors for agitation severity of hyperactive delirium.Our study indicates that male sex, T-bil, antibiotic therapy, NSAID therapy, and hematological malignancy are significant predictors for agitation severity of hyperactive delirium in terminally ill cancer patients in a general hospital setting.

Background Knowledge of the epidemiology of adverse drug events (ADEs) and medication errors in psychiatric inpatients is limited outside Western countries. The nature of ADEs and medication errors are important for improving the quality of care worldwide; therefore, we conducted the Japan Adverse Drug Events Study, a series of cohort studies at several settings in Japan. Methods This report included 448 inpatients with 22,733 patient-days in a psychiatric hospital and psychiatric units at a tertiary care teaching hospital over 1 year. Four psychiatrists and two other physicians reviewed all medical charts and related documents to identify suspected incidents. The physicians later classified those incidents into ADEs, potential ADEs, medication errors, or exclusions and evaluated the severity and preventability if the incidents were events. Results During the study period, we identified 955 ADEs and 398 medication errors (incidence: 42.0 and 17.5 per 1000 patient-days, respectively). Among ADEs, 1.4 %, 28 %, and 71 % were life-threatening, serious, and significant, respectively. Antipsychotics were associated with half of all ADEs. The incidence of medication errors was higher in medical care units than in acute and nursing care units (40.9, 15.6, and 17.4 per 1000 patient-days, respectively). The monitoring and ordering stages were the most common error stages (39 % and 34 % of all medication errors, respectively), and 76 % of medication errors with ADEs were found at the monitoring stage. Non-psychiatric drugs were three times as likely to cause ADEs with errors compared to psychiatric drugs. Conclusions Antipsychotic use, inadequate monitoring, and treatment of physical ailments by psychiatrists may contribute to the high incidence of medication errors and ADEs among psychiatric inpatients in Japan. Psychiatrists should be cautious in prescribing antipsychotics or unfamiliar medications for physical problems in their psychiatric patients, and should monitor patients after medication administration.

Objective: To clarify the physical and psychological effects of head massage performed in the supine position using Ayurveda-based techniques (head treatment). Design: Twenty-four healthy female students were included in the study. Using a crossover study design, the same participants were enrolled in both the head treatment intervention group and control group. There was an interval of 1 week or more between measurements. Outcome measures: The physiologic indices measured included blood pressure and heart rate fluctuations (high frequency and low frequency/high frequency). The psychological markers measured included liveliness, depression, and boredom using the visual analogue scale method. State anxiety was measured using the State-Trait Anxiety Inventory method. Results: The parasympathetic nerve activity increased immediately after head treatment. Upon completion of head treatment, the parasympathetic nerve predominance tended to gradually ease. Head treatment boosted freshness and relieved anxiety. Conclusions: The results suggest that head treatment has a relaxing and refreshing effect and may be used to provide comfort.

Background: Frontostriatal and frontoamygdalar connectivity alterations in patients with obsessive–compulsive disorder (OCD) have been typically described in functional neuroimaging studies. However, structural covariance, or volumetric correlations across distant brain regions, also provides network-level information. Altered structural covariance has been described in patients with different psychiatric disorders, including OCD, but to our knowledge, alterations within frontostriatal and frontoamygdalar circuits have not been explored.Methods: We performed a mega-analysis pooling structural MRI scans from the Obsessive–compulsive Brain Imaging Consortium and assessed whole-brain voxel-wise structural covariance of 4 striatal regions (dorsal and ventral caudate nucleus, and dorsal-caudal and ventral-rostral putamen) and 2 amygdalar nuclei (basolateral and centromedial-superficial). Images were preprocessed with the standard pipeline of voxel-based morphometry studies using Statistical Parametric Mapping software.Results: Our analyses involved 329 patients with OCD and 316 healthy controls. Patients showed increased structural covariance between the left ventral-rostral putamen and the left inferior frontal gyrus/frontal operculum region. This finding had a significant interaction with age; the association held only in the subgroup of older participants. Patients with OCD also showed increased structural covariance between the right centromedial-superficial amygdala and the ventromedial prefrontal cortex.Limitations: This was a cross-sectional study. Because this is a multisite data set analysis, participant recruitment and image acquisition were performed in different centres. Most patients were taking medication, and treatment protocols differed across centres.Conclusion: Our results provide evidence for structural network–level alterations in patients with OCD involving 2 frontosubcortical circuits of relevance for the disorder and indicate that structural covariance contributes to fully characterizing brain alterations in patients with psychiatric disorders.

Choriocarcinoma is a highly malignant tumor of trophoblastic origin. Most cases occur in association with preceding gestational events. However, on very rare occasions, nongestational choriocarcinoma arises from germ cell or trophoblastic differentiation in different types of carcinoma. This article reports the case of a 58-year-old woman with primary nongestational choriocarcinoma of the uterus that developed 19 years after her final pregnancy and 4 years after menopause. A total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed. Histopathological examination showed choriocarcinoma of the uterus without components of other germ cell tumors. Karyotype analysis of the tumor cells demonstrated XX. We confirmed its nongestational origin by DNA polymorphism analysis at 15 short tandem repeat loci. After surgery, the patient was given four courses of combination chemotherapy. She is still alive and there has been no evidence of recurrence 3 years after surgery.

Dysfunctional beliefs may contribute to the development and maintenance of obsessive–compulsive disorder (OCD) according to some cognitive theories. As little has been investigated about the pathophysiology of dysfunctional beliefs in OCD, this study aimed to determine the anatomical regions that are related to OCD-related dysfunctional beliefs. We first examined 23 non-medicated patients with OCD by magnetic resonance imaging (MRI) and assessed their dysfunctional beliefs using the Obsessive Beliefs Questionnaire-44 (OBQ-44). OBQ-44 has three factors: (1) inflated personal responsibility and the tendency to overestimate threat (OBQ-RT), (2) perfectionism and intolerance of uncertainty (OBQ-PI), and (3) over-importance and over-control of thoughts (OBQ-IC). Voxelwise analysis was used to investigate the correlation between whole brain gray matter volume and each score of OBQ-44 covarying for age, gender, education, severity, and intracranial volume. We found a significant negative correlation between gray matter volume and OBQ-IC scores in the left amygdala; there was no significant correlation with other scores. Comparison of the amygdala volume between patients with OCD and 23 matched healthy controls indicated no volume difference between groups. Taken together, the left amygdala volume may play a role in the presence of certain dysfunctional beliefs in OCD patients.

DNA mismatch repair (MMR) greatly contributes to genome integrity via the correction of mismatched bases that are mainly generated by replication errors. Postreplicative MMR excises a relatively long tract of error-containing single-stranded DNA. MutL is a widely conserved nicking endonuclease that directs the excision reaction to the error-containing strand of the duplex by specifically nicking the daughter strand. Because MutL apparently exhibits nonspecific nicking endonuclease activity in vitro, the regulatory mechanism of MutL has been argued. Recent studies suggest ATP-dependent conformational and functional changes of MutL, indicating that the regulatory mechanism involves the ATP binding and hydrolysis cycle. In this study, we investigated the effect of ATP binding on the structure of MutL. First, a cross-linking experiment confirmed that the N-terminal ATPase domain physically interacts with the C-terminal endonuclease domain. Next, hydrogen/deuterium exchange mass spectrometry clarified that the binding of ATP to the N-terminal domain induces local structural changes at the catalytic sites of MutL C-terminal domain. Finally, on the basis of the results of the hydrogen/deuterium exchange experiment, we successfully identified novel regions essential for the endonuclease activity of MutL. The results clearly show that ATP modulates the nicking endonuclease activity of MutL via structural rearrangements of the catalytic site. In addition, several Lynch syndrome-related mutations in human MutL homolog are located in the position corresponding to the newly identified catalytic region. Our data contribute toward understanding the relationship between mutations in MutL homolog and human disease.

Areduced fever response and fewer signs and symptoms of infection can delay diagnosis and increase complications of infection in patients with anorexia nervosa (AN). Lung abscess and retropharyngeal abscess have been reported in patients with AN, but brain abscess as a consequence of exacerbation of infection has not been described. Here, we report the case of a patient with AN who had a limited clinical response to infection and developed a brain abscess due to sepsis after pneumonia. Written informed consent to the report of this case was obtained from the patient and her family.

There has been increasing evidence indicating gray matter abnormalities in patients with obsessive–compulsive disorder (OCD). Several voxel-based morphometry (VBM) studies have reported volume changes in the insular cortex. Although there are distinct differences in the connectivity and functions in the anterior and posterior insular cortices, these two regions have never been distinguished in previous VBM studies. In this study, we adopted a region of interest (ROI) method to measure insular volume separately. We investigated insular volume in 32 drug-free patients with OCD and in 34 healthy controls using magnetic resonance imaging (MRI). Repeated measures multivariate analysis of covariance (MANCOVA) was conducted to examine the difference between the patients and the controls. Compared with the healthy controls, the patients had a significantly larger gray matter volume in the anterior insular cortex bilaterally (post hoc test, p = 0.036; left, p = 0.047; right). This is the first volumetric MRI study to separately investigate the anterior and posterior insular cortex volumes in non-medicated patients with OCD. The results suggest that the anterior insular cortex may be related to the pathophysiology of OCD.

Although many cases of fatal hydrogen sulfide poisoning have been reported, in most of these cases, it resulted from the accidental inhalation of hydrogen sulfide gas. In recent years, we experienced 17 autopsy cases of fatal hydrogen sulfide poisoning due to the inhalation of intentionally generated hydrogen sulfide gas. In this study, the concentrations of sulfide and thiosulfate in blood, urine, cerebrospinal fluid and pleural effusion were examined using GC/MS. The sulfide concentrations were blood: 0.11-31.84, urine: 0.01-1.28, cerebrospinal fluid: 0.02-1.59 and pleural effusion: 2.00-8.59 (μg/ml), while the thiosulfate concentrations were blood: 0-0.648, urine: 0-2.669, cerebrospinal fluid: 0.004-0.314 and pleural effusion: 0.019-0.140 (μmol/ml). In previous reports, the blood concentration of thiosulfate was said to be higher than that of sulfide in hydrogen sulfide poisoning cases, although the latter was higher than the former in 8 of the 14 cases examined in this study. These results are believed to be strongly influenced by the atmospheric concentration of hydrogen sulfide the victims were exposed to and the time interval between exposure and death.

The aim of this study was to identify brain regions associated with performance on various measures of the clock drawing test (CDT) using magnetic resonance imaging (MRI).We recruited 48 participants (four healthy, eight with mild cognitive impairment and 36 with Alzheimer's disease). Multiple regression analyses identified relationships between each CDT scoring system (Shulman CDT, Rouleau CDT and CLOX1) and regional gray matter (GM) volume.CDT scores were positively correlated with regional GM volume in the right parietal lobe for all three CDT scoring systems. In addition, CDT scores were positively correlated with regional GM volume in the bilateral posterior temporal lobes for the Shulman CDT, in the right posterior inferior temporal lobe for the Rouleau CDT and in the right posterior superior temporal lobe for the CLOX1.Although the scoring systems share commonalities, each CDT scoring system may reflect different areas of brain damage.

Late-onset psychosis (LOP) has become increasingly prevalent in the clinical setting, especially in the highly aged society, due to the increasing numbers of older people and its disruptive impact on the lives of patients and caregivers. Although previous studies have identified some of the features of LOP (Webster and Grossberg, 1998; Mitford et al., 2010; Tan and Seng, 2012), some of the previous studies did not include patients with dementia and mood disorders. This study addresses the features of LOP in consecutive outpatients to provide information that supports the differential diagnosis.

The atmospheric carbon-14 ((14)C) concentration remained relatively stable until 1955, but then rapidly increased after 1955 by nuclear bomb tests, peaked in 1963, and decreased thereafter. Recently, Spalding et al. proposed epoch-making method for determining date of birth (DOB) using the tooth enamel (14)C incorporated during enamel formation. However, because the (14)C level analyzed in one tooth gives two possible age ranges (up-slope or down-slope of the bomb curve), a variety of teeth that formed in different periods are required for estimating DOB in this method. Enamel formation in a tooth moves from the incisal (occlusal) side to the cervical side. Taking advantage of this characteristic, we have first succeeded in specifying the age range from only single tooth by measuring (14)C in the incisal (occlusal) and cervical regions of the enamel separately. To date, no method of determining DOB or age estimation from single tooth enamel has been made. Furthermore, this method of dividing tooth into smaller parts could be useful for producing a more accurate DOB. Our new method is a powerful tool for identification when we can use only extremely few specimens in forensic casework.

Proinflammatory cytokines and growth factors have been thought to play crucial roles in the pathology of acute myelogenous leukemia (AML) by supporting the proliferation and survival of AML cells in an autocrine and paracrine manner, although further elucidation is required. JTE-607 was originally identified as a multiple cytokine inhibitor that suppresses production of proinflammatory cytokines from lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells. Herein, we report that JTE-607 exhibits inhibitory activity on the growth of AML cell lines accompanying reduction of the proinflammatory cytokine and growth factor production. In in vitro studies, JTE-607 suppressed expression and production of cytokines, which are spontaneously up-regulated in AML cell lines. JTE-607 also abrogated proliferation of AML cells in a concentration range in which colony formation of normal bone marrow cells was not affected. The growth inhibition by JTE-607 was characterized by induction of cell-cycle arrest at the S-phase and apoptosis, accompanied by a decrease in c-Myc and increase in p21(waf1/cip1). In a leukemia model engrafted with U-937 cells, JTE-607 significantly prolonged survival in mice and reduced human cytokine mRNA levels in the bone marrow. These results suggest the usefulness of JTE-607 in therapeutic applications for patients with hypercytokinemia and aggressive AML cell proliferation.

Background: The aim of this study was to identify the brain regions associated with the severity of delusions in individuals with Alzheimer’s disease (AD) using single-photon emission computed tomography. Methods: Thirty-five AD patients participated in this study. Multiple regression analysis was performed to identify a linear correlation between the delusion subscale score of the Neuropsychiatric Inventory (NPI) and regional cerebral blood flow (rCBF) in AD patients with delusions (n = 14). In addition, rCBF in patients with (n = 14) and without delusions (n = 21) was compared using a 2-sample t test. Results: The delusion subscale score of the NPI was negatively correlated with rCBF in the right anterior insula (uncorrected p < 0.01 at the voxel level and corrected p < 0.05 at the cluster level). Compared to patients without delusions, however, rCBF in the right anterior insula was not significantly decreased in patients with delusions. Conclusion: We suggest that right anterior insular dysfunction may exacerbate delusions, although it is not responsible for the onset of delusions.

The serotonin transporter (5-HTT) and other markers of the serotonergic system have been of interest in the pathophysiology of obsessive-compulsive disorder (OCD). Previous studies using single photon emission computed tomography (SPECT) with [(123)I]beta-CIT or positron emission tomography (PET) with [(11)C]McN5652 have not shown consistent findings about 5-HTT in OCD patients. The aim of the present study was to investigate 5-HTT binding using [(11)C]DASB, which has higher selectivity or specific binding-to-nonspecific binding ratios for 5-HTT compared to the aforementioned radioligands. Four drug-naive and 6 drug-free patients with OCD who were free of comorbid depression and 18 gender and age-matched healthy subjects underwent PET scans with [(11)C]DASB. The severity of OCD was assessed by Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) (mean+/-SD: 22+/-7.6, range: 7-32). The binding potential (BP(ND)) of [(11)C]DASB was calculated using a two-parameter multilinear reference tissue model (MRTM2). The parametric images of BP(ND) were analyzed using a statistical parametric mapping system. Significant reductions of BP(ND) were observed in the right posterior and left anterior insular cortices in patients with OCD compared to controls. Region-of-interest analysis has also confirmed significant reduction of BP(ND) in the insular cortex. Although significantly reduced BP(ND) in the orbitofrontal cortex was also observed in patients with OCD compared to controls, this finding should be considered with caution because of the very low 5-HTT binding in the region. On the other hand, no significant correlation was observed between the Y-BOCS score and BP(ND). The change in [(11)C]DASB binding in the insular cortex suggests that dysfunction of the serotonergic system in the limbic area might be involved in the pathophysiology of OCD.

Objective To determine the incidence of potential medical adverse events among patients undergoing forensic autopsy, and to present the characteristics of potential medical adverse events. Design Retrospective review of consecutive autopsy records. Setting Department of Forensic Medicine, the Jikei University School of Medicine, Tokyo, Japan. Participants A total of 3355 forensic autopsy cases between 1983 and 2006. Main outcome measures Incidence of potential medical adverse events identified in decedents undergoing forensic autopsy, classified by actual occurrence as ‘confirmed’, ‘equivocal’ and ‘negative’ cases; proportion of potential diagnostic, performance and system errors among potential medical adverse events. Results Of 291 autopsies (8.7%) with potential medical adverse events, 66 cases (22.7%) were confirmed, 42 cases (14.4%) were negative and 183 cases (62.9%) were equivocal. Confirmed cases consisted of potential diagnostic errors in 49 cases (74.2%) and performance errors in 17 cases (25.8%). Equivocal cases included 99 cases associated with potential diagnostic errors (54.1%) and 60 cases associated with potential system errors (32.8%). In 38 of the confirmed cases (57.5%), serious exacerbation of patient condition occurred outside the medical facility. Conclusions Potential medical adverse events are not uncommon in decedents undergoing forensic autopsy. They are particularly associated with potential diagnostic errors. Forensic autopsy may provide information that could be used to improve care and reduce deaths due to potential medical adverse events.

DNA recombination events need to be strictly regulated, because an increase in the recombinational frequency causes unfavorable alteration of genetic information. Recent studies revealed the existence of a novel anti-recombination enzyme, MutS2. However, the mechanism by which MutS2 inhibits homologous recombination has been unknown. Previously, we found that Thermus thermophilus MutS2 (ttMutS2) harbors an endonuclease activity and that this activity is confined to the C-terminal domain, whose amino acid sequence is widely conserved in a variety of proteins with unknown function from almost all organisms ranging from bacteria to man. In this study, we determined the crystal structure of the ttMutS2 endonuclease domain at 1.7-Å resolution, which resembles the structure of the DNase I-like catalytic domain of Escherichia coli RNase E, a sequence-nonspecific endonuclease. The N-terminal domain of ttMutS2, however, recognized branched DNA structures, including the Holliday junction and D-loop structure, a primary intermediate in homologous recombination. The full-length of ttMutS2 digested the branched DNA structures at the junction. These results indicate that ttMutS2 suppresses homologous recombination through a novel mechanism involving resolution of early intermediates.

The purpose of this study was to determine the brain regions associated with anosognosia in Alzheimer's disease (AD). Anosognosia for memory disturbance was assessed in 29 probable AD patients, based on the discrepancy between questionnaire scores of the patients and their caregivers. In I-123-IMP single photon emission computed tomography (SPECT), a significant association was found between anosognosia and decreased perfusion in the orbitofrontal cortex, using regression analysis. This result is consistent with the previous studies that have reported an association between frontal dysfunction and anosognosia, and further suggests that the orbitofrontal cortex specifically associates with anosognosia in AD within the frontal cortex.

A 30-year-old woman was admitted to the first institution with subacutely progressive aphasia and depression. Despite of lacking conclusive evidence on magnetic resonance imaging, cerebrospinal fluid examination, or electroencephalogram, we tentatively diagnosed her disease as limbic encephalopathy due to its acute progression. High-dose methylprednisolone was started on admission. However, symptoms did not improve. To make matters worse, psychiatric symptoms, such as hallucinations and emotional incontinence, appeared on the same day. Additional treatment with plasma exchange and intravenous immunoglobulin administration was also ineffective. Therefore, we could not manage the patient in a general ward due to severe psychiatric symptoms. The patient was transferred to a psychiatric ward in the second institution. She received both psychiatric treatment and steroid therapy, including a second course of intravenous high-dose methylprednisolone, followed by long-term oral prednisolone. Her symptoms gradually improved. A final diagnosis of Hashimoto's encephalopathy was made based on the patient's clinical course and positive results for both serum anti-thyroid antibody and anti-NAE antibody. In our case, long-term oral steroid therapy under psychiatric treatment was effective for good outcome.