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Purpose This study aimed to determine whether coronary artery calcium score (CACS) can be a prognostic indicator for the development of major adverse cardiac events (MACEs) and compare the value of CACS with that of the 123I-betamethyl-p-iodophenyl-pentadecanoic acid (123I-BMIPP) defect score (BDS) in patients with non-ischemic heart failure with preserved ejection fraction (NIHFpEF). Methods Among 643 consecutive patients hospitalized due to acute heart failure, 108 (74 ± 13y) were identified to have NIHFpEF on non-contrast regular chest computed tomography and 123I-BMIPP single-photon emission computed tomography (SPECT). We evaluated whether CACS and BDS were associated with MACEs using multivariate Cox models. Results Thirty-two MACEs developed at a mean follow-up period of 2.4 years. Higher CACS (hazard ratio [HR] 2.27, 95% confidence interval [CI] 1.10–4.67) and higher BDS (HR 22.14, 95% CI 7.95–61.60) were significantly associated with the development of MACEs. Patients showing higher CACS and BDS carried a significantly higher risk for developing MACE (HR 23.65, 95% CI 10.33–54.13, p

Background The aim of this study was to evaluate the effect of balloon pulmonary angioplasty (BPA) using lung perfusion single-photon emission computed tomography (SPECT) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Methods and Results 20 consecutive patients (64 ± 15 years) who were diagnosed with CTEPH and underwent BPA were included in this study. All patients underwent lung perfusion SPECT before and after BPA. The relationship between functional %volume of the lung calculated from the lung perfusion SPECT (FVL-LPSPECT), and other clinical parameters before and after BPA was assessed using the Wilcoxon signed-rank test. The correlation between each parameter and mean pulmonary artery pressure (mPAP) using the Spearman’s correlation was performed. To determine predictors of mPAP for evaluating treatment effectiveness, significant parameters were included in multiple regression analysis. After BPA, world health organization functional classification, six-minute walk distance (6MWD), mPAP, and FVL-LPSPECT significantly improved. FVL-LPSPECT (r = − 0.728, P r = − 0.571, P = 0.009) were significant correlation of mPAP. In the multiple regression analysis, FVL-LPSPECT was the most significant predictor of improvement in mPAP after BPA (P Conclusions This study demonstrated that the lung perfusion SPECT could be a potential measurement of the effectiveness of BPA in patients with CTEPH.

This study aimed to determine whether coronary artery calcium score (CACS) can be a prognostic indicator for the development of major adverse cardiac events (MACEs) and compare the value of CACS with that of the

Background Atrial fibrillation (AF) is the most common cardiac arrhythmia, and those afflicted have reduced quality of life, functional status, and cardiac performance. The patients with AF have a high risk of coronary heart disease and cardiovascular disease. Although the prevalence of AF is increasing, cognitive disorders are also on the rise in tandem with the aging of the population. The patients with dementia have also experienced lower the quality of life and have increased mortality. Technetium 99m ECD brain perfusion single photon emission computed tomography (99mTc-ECD brain perfusion SPECT) is a useful modality for diagnosing dementia and identifying high risk patients with mild cognitive impairment. However, there are few reports about the relationship between the value of Z score calculated by 99mTc-ECD brain perfusion SPECT and prognosis of patients with AF and dementia. Purpose The aim of this study was to evaluate the prognostic values of brain perfusion using 99mTc-ECD SPECT in patients with AF and dementia. Methods Among 405 consecutive patients who were diagnosed as AF in cardiac outpatients and subsequently diagnosed as dementia using Mini-Mental State Examination by neurologists or psychiatrists, we identified 170 patients (81 ± 10 years) who underwent 99mTc-ECD brain perfusion SPECT for the current study. Of those, 73, 73, and 24 were diagnosed as Alzheimer’s dementia (AD), vascular dementia (VD), and non-specified dementia respectively. Multivariate Cox model was used to assess if higher Z score by 99mTc-ECD brain perfusion SPECT and clinical parameters were associated with major adverse cardiovascular events (MACE) including cardiac death, myocardial infarction, hospitalization for heart failure, and stroke. Sub-analyses of multivariate Cox models by AD or VD were also assessed. The cut-off values of Z score were determined using area under the curve by a receiver operating characteristic analysis based on MACE occurrences. Results During a mean follow-up of 1258 ± 1044 days, 62 MACE occurred. There was not significant difference of MACE between AD and VD (33%, vs. 44%, p = 0.153). By multivariable Cox model, the higher Z score of temporal-occipital-pariental lobe was associated with increased MACE compared to the lower group (HR 2.521, 95% CI 1.465–4.337, p < 0.001). In a sub-analysis of patients with AD, Z score was the most significant prognostic factor for MACE (HR 3.969, 95% CI 1.374–11.468, p = 0.011). The similar trend was observed in those with VD (HR 2.247, 95% CI 1.028–4.913, p = 0.043). Conclusion: This study demonstrated that the Z score of temporal-occipital-pariental lobe by 99mTc-ECD brain perfusion SPECT could be a potential prognostic value among patients with AF and dementia, regardless of type of dementia.

Imaging of myocardial fatty acid metabolism using 123I-betamethyl-p-iodophenyl-pentadecanoic acid (123I-BMIPP) SPECT is useful for identifying high-risk patients with known ischemic heart disease. However, its utility for patients who have nonischemic heart failure with preserved ejection fraction is not well known. This study aimed to evaluate the prognostic value of the 123I-BMIPP defect score in such patients. Methods: Of 804 consecutive patients who were admitted to the hospital because of acute heart failure and underwent 123I-BMIPP SPECT, we identified 133 (mean age ± SD, 73 ± 13 y) who had normal coronary arteries by invasive coronary angiography and preserved left ventricular ejection fraction (≥50%) by echocardiography. 123I-BMIPP defects were quantitatively scored to obtain summed defect scores in 17 segments of 123I-BMIPP SPECT images. The patients were divided into 2 groups based on their score. The multivariate Cox model was used to assess a possible correlation between a higher score (≥4, n = 46) and major adverse cardiac events, including cardiac death, cardiovascular events, and hospitalization for heart failure, compared with a lower score (

Objectives To define the ranges of biochemical markers during hypoglycemia for the diagnosis of congenital hyperinsulinism (CHI), using high sensitivity insulin assays. Subjects A total of 298 patients with CHI and 58 control patients with non-hyperinsulinemic hypoglycemia, who were diagnosed after 2007. Methods The levels of biochemical markers (glucose, insulin, β-hydroxybutyrate [BHB], free fatty acids [FFA], lactate, ammonia) at the time of hypoglycemia were analyzed along with the maximal glucose infusion rate (GIR) to maintain euglycemia and clinical outcomes. Results Median levels of blood glucose in patients with CHI and in controls were 30 and 46 mg/dL, while insulin levels were 9.90 and undetectable ( 1.25 μU/mL, BHB < 2000 µmol/L, and FFA < 1248 µmol/L predicted CHI with sensitivities of 97.5, 96.2, and 95.2% and specificities of 84.2, 89.3, and 92.3%, respectively. Maximal GIR in the CHI groups tended to decrease with age. In addition, decreased gestational age, low birth weight, and elevated lactate at hypoglycemia were significantly more common in patients who were off treatment within 100 days without pancreatectomy. Conclusions After introduction of high-sensitive assays, the diagnostic value of insulin was improved, allowing for more efficient cutoffs to be set for diagnosis of CHI. Premature birth, low birth weight and elevated lactate might be helpful in predicting early remission of hypoglycemia.

In India, the new skill development policy has started and expectations from stakeholders including multi-national companies, non-governmental organizations, and people who suffer from unemployment are mixed towards the training policy ‘Skill India (SI)’.The government expects the country to have a drastic change to skilled nation. Corporate Social Responsibility (CSR) investments in the country tend to shift from philanthropy to create new social values, e.g. skill development and social business (SB) promotions with appropriate trainings for young people. The aim of this article is to find out what exactly the tendencies of Indian Corporate Social Responsibility investments regarding the new policy and issues are based on the interview data. And also it tries to find out some possibilities to make the policy work better. The author will explain and analyze the results of the survey conducted to companies and schools who are main actors to carry out the mission and discuss possible solutions based on suggestions made by CSR personnel, student trainees, school teachers, staffs including social workers.

Background Patients with atrial fibrillation (AF) and dementia experience reduced quality of life and increased mortality. Technetium 99m ECD brain perfusion single-photon emission computed tomography (99mTc-ECD brain perfusion SPECT) is a beneficial modality for diagnosing dementia and identifying high-risk patients with mild cognitive impairment. The aim of this study was to evaluate the prognostic value of brain perfusion using 99mTc-ECD SPECT in patients with AF and dementia. Methods Of a total of 405 consecutive patients diagnosed with AF as cardiac outpatients with dementia using the Mini-Mental State Examination by neurologists or psychiatrists, we identified 170 patients (81 ± 10 years) who underwent 99mTc-ECD brain perfusion SPECT. Of them, 73, 73, and 24 were diagnosed with Alzheimer’s dementia (AD), vascular dementia (VD), and non-specified dementia, respectively. A multivariable Cox model was used to assess if higher Z-score by 99mTc-ECD brain perfusion SPECT and clinical parameters were associated with major adverse cardiovascular events (MACE) including cardiac death, myocardial infarction, hospitalization for heart failure, and stroke. Results During a mean follow-up of 1258 ± 1044 days, 62 MACE occurred. There was no significant difference in MACE between AD and VD (33%, vs. 44%, p = 0.153). The multivariable Cox model confirmed that the higher Z-score of temporo-parieto-occipital lobe was associated with increased MACE compared to the lower group (HR 2.521, 95% CI 1.465–4.337, p < 0.001). Conclusion This study demonstrated that decreased cerebral blood flow in the temporo-parieto-occipital lobe could be a potential prognostic value in patients with both AF and dementia.

Background There are few reports pertaining to Asian patients with neonatal diabetes mellitus (NDM) caused by activating mutations in the ATP-sensitive potassium channel genes (KATP-NDM). Objectives To elucidate the characteristics of Japanese patients with KATP-NDM. Methods By the amplification and direct sequencing of all exons and exon-intron boundaries of the KCNJ11 and ABCC8 genes, 25 patients with KATP-NDM were identified from a total of 70 patients with NDM. Clinical data were collected from the medical charts. Results Sixteen patients had mutations in KCNJ11 and nine in ABCC8. Eight novel mutations were identified; two in KCNJ11 (V64M, R201G) and six in ABCC8 (R216C, G832C, F1176L, A1263V, I196N, T229N). Interestingly, V64M caused DEND (developmental delay, epilepsy, neonatal diabetes) syndrome in our patient, while mutation of the same residue (V64G) had been reported to cause congenital hyperinsulinism. Mutations in ABCC8 were associated with TNDM (4/9) or isolated PNDM (5/9), whereas those in KCNJ11 were associated with more severe phenotypes, including DEND (3/16), iDEND (intermediate DEND, 4/16), or isolated PNDM (6/16). Switching from insulin to glibenclamide monotherapy was successful in 87.5% of the patients. Neurological improvement was observed in two patients, one with DEND (T293N) and one with iDEND (R50P) syndrome. Three others with iDEND mutations (R201C, G53D, and V59M) remained neurologically normal at 5, 1, and 4 years of age, respectively, with early introduction of sulfonylurea. Conclusion Overall, clinical presentation of KATP-NDM in Japanese patients was similar to those of other populations. Early introduction of sulfonylurea appeared beneficial in ameliorating neurological symptoms.

Background Hypospadias has multifactorial causes and occurs at a high frequency among very low-birthweight infants. Placental insufficiency is hypothesized to be one cause of hypospadias; that is, decreased human chorionic gonadotropin (hCG) secretion caused by placental insufficiency is suspected to result in abnormal male external genitalia, but there is little direct evidence to support this. The aim of this study was therefore to identify the features of hypospadias and to clarify the male genital abnormalities caused by fetal growth restriction (FGR). Methods We reviewed the clinical data of boys who underwent hypospadias repair between 2005 and 2011 at Kyoto University Hospital. Results Twenty boys were included in this study. Fifteen (75%) of the subjects were preterm or low-birthweight infants. Thirteen (65%) had FGR, 60% of whom had severe hypospadias regardless of gestational age. In addition, 92% of the FGR infants also had other genital anomalies, such as cryptorchidism, bifid scrotum, or micropenis. In contrast, only 14% and 43% of the non-FGR infants had severe hypospadias or genital anomalies other than hypospadias, respectively. Placental histopathology was available in eight FGR infants, in seven of whom it was suggestive of blood flow deficiency such as infarction and single umbilical artery. Conclusions Infants with FGR have a high incidence of hypospadias. FGR caused by placental dysfunction, but not low birthweight, is a risk factor for severe hypospadias associated with multiple genital anomalies.

Present article focuses on social impact evaluation of waste management models such as social enterprises and municipal-oriented PP Partnership with participation of waste pickers’ cooperative and community in Pune, India. Data has been collected through interviewing waste pickers and social enterprise management personnel and focus group discussions. Our evaluation focuses on social aspects and system’s contribution to better quality of life. It also evaluates the working conditions of waste pickers. Our study further analyzes waste management’s aspects in relation to broader social and environmental issues such as urban public health. Research findings show that social enterprise practices are effective in increasing the income of waste pickers and efficient in collecting and segregating waste. It shows that the social enterprise model is working efficiently and encourages competition for better service quality. This article begins by explaining the social enterprises model and Public Private Partnership (PPP) model and their techniques in handling waste management issues in India. It evaluates their social impact, profitability, and innovativeness. The social enterprise model has been analyzed in terms of its concepts, opportunities, potentiality, organization, shared value creation and recent developments. Finally we explored further on the model and systems to find out the best possible model to solve environmental issues and bring better quality life for the community.

The aim of this study was to evaluate the prognostic values of sympathetic nerve system usingAmong 403 consecutive patients with stable HF who underwentThis study demonstrated that the nighttime VLFP adding to WR could be a potential prognostic value among patients with HFpEF.

To define the ranges of biochemical markers during hypoglycemia for the diagnosis of congenital hyperinsulinism (CHI), using high sensitivity insulin assays.A total of 298 patients with CHI and 58 control patients with non-hyperinsulinemic hypoglycemia, who were diagnosed after 2007.The levels of biochemical markers (glucose, insulin, β-hydroxybutyrate [BHB], free fatty acids [FFA], lactate, ammonia) at the time of hypoglycemia were analyzed along with the maximal glucose infusion rate (GIR) to maintain euglycemia and clinical outcomes.Median levels of blood glucose in patients with CHI and in controls were 30 and 46 mg/dL, while insulin levels were 9.90 and undetectable (.5) μU/mL, respectively. Similarly, median levels of BHB were 17.5 and 3745 µmol/L, and those of FFA were 270.5 and 2660 µmol/L, respectively. For patients after 5 months, cutoffs of insulin1.25 μU/mL, BHB2000 µmol/L, and FFA1248 µmol/L predicted CHI with sensitivities of 97.5, 96.2, and 95.2% and specificities of 84.2, 89.3, and 92.3%, respectively. Maximal GIR in the CHI groups tended to decrease with age. In addition, decreased gestational age, low birth weight, and elevated lactate at hypoglycemia were significantly more common in patients who were off treatment within 100 days without pancreatectomy.After introduction of high-sensitive assays, the diagnostic value of insulin was improved, allowing for more efficient cutoffs to be set for diagnosis of CHI. Premature birth, low birth weight and elevated lactate might be helpful in predicting early remission of hypoglycemia.

Being socially responsible is now a business obligation for by corporate entities. Today, about 90% of leading companies in India are involved in various CSR programmes such as working for education, health, empowerment of women and environment. Recently, CSR has evolved from philanthropy to a business related phenomenon because the new CSR concept with gaining some strategic advantage and sustainability has been widely recognized. This article examines whether corporates in India (including multinationals operating business in India) are practicing strategic CSR based on the survey conducted in Talegaon Maharashtra Industrial Development Council (MIDC) in Pune, India. Also, we try to measure the community impact socially and economically. The result shows that the most of the companies in Talegaon still practice a philanthropic approach but they have made improvement on community impact from 2011 to 2013. After the action research and intervention, some companies started a developmental and strategic approach for their community. It can be concluded that the quantity and area of CSR have been increased according to the community needs and community participation is very important to conduct CSR.

The HNF4A p.R76W mutation causes congenital hyperinsulinism with Fanconi syndrome. Here, we report two cases who also presented with increased urinary calcium excretion and one had a transient hepatic dysfunction with hepatomegaly. Clinical variations including transient liver dysfunction is a likely mutation-specific clinical characteristic.

We studied seven cases of Alzheimer's disease (AD). Six of the patients had presenilin 1 (PS1) mutations (PS1AD). Three novel PS1 mutations (T99A, H131R and L219R) and three other missense mutations (M233L, H163R and V272A) were found in the PS1AD group. We measured the levels of phosphorylated tau (ptau-181, ptau-199) and Aβ (Aβ1-42, Aβ1-40 and Aβ1-38) in the cerebrospinal fluid (CSF) of PS1AD patients, early-onset sporadic AD (EOSAD), late-onset sporadic AD (LOSAD) and non-demented subjects (ND). The CSF levels of Aβ1-42 in the three AD groups were significantly lower than those of the ND group (p < 0.0001). CSF levels of Aβ1-42 in the PS1AD group were significantly lower than those in the two sporadic AD groups. The Aβ1-40 and Aβ1-38 levels in the CSF of the PS1AD group were significantly lower than those of the three other groups (p < 0.0001, respectively). The levels of Aβ1-40, Aβ1-38 and Aβ1-42 in the CSF of the PS1AD group remained lower than those of the ND group for 4 years. Not only CSF Aβ1-42, but also Aβ1-40 and Aβ1-38 decreased in the advanced stages of PS1AD.

There are few reports pertaining to Asian patients with neonatal diabetes mellitus (NDM) caused by activating mutations in the ATP-sensitive potassium channel genes (KATP-NDM).To elucidate the characteristics of Japanese patients with KATP-NDM.By the amplification and direct sequencing of all exons and exon-intron boundaries of the KCNJ11 and ABCC8 genes, 25 patients with KATP-NDM were identified from a total of 70 patients with NDM. Clinical data were collected from the medical charts.Sixteen patients had mutations in KCNJ11 and nine in ABCC8. Eight novel mutations were identified; two in KCNJ11 (V64M, R201G) and six in ABCC8 (R216C, G832C, F1176L, A1263V, I196N, T229N). Interestingly, V64M caused DEND (developmental delay, epilepsy, neonatal diabetes) syndrome in our patient, while mutation of the same residue (V64G) had been reported to cause congenital hyperinsulinism. Mutations in ABCC8 were associated with TNDM (4/9) or isolated PNDM (5/9), whereas those in KCNJ11 were associated with more severe phenotypes, including DEND (3/16), iDEND (intermediate DEND, 4/16), or isolated PNDM (6/16). Switching from insulin to glibenclamide monotherapy was successful in 87.5% of the patients. Neurological improvement was observed in two patients, one with DEND (T293N) and one with iDEND (R50P) syndrome. Three others with iDEND mutations (R201C, G53D, and V59M) remained neurologically normal at 5, 1, and 4 years of age, respectively, with early introduction of sulfonylurea.Overall, clinical presentation of KATP-NDM in Japanese patients was similar to those of other populations. Early introduction of sulfonylurea appeared beneficial in ameliorating neurological symptoms.

The focal form of congenital hyperinsulinism (CHI) is characterized by a cluster of abnormal insulin-oversecreting β cells within a restricted area of the pancreas. Although identification of the focal lesion is very important in the management of CHI, it has been reported that imaging studies, including computed tomography (CT), magnetic resonance imaging (MRI) scans, or angiography, are not helpful in identifying the focal lesion. Currently, fluorine-18-L-dihydroxyphenylalanine positron emission tomography (18F-DOPA PET) is believed to be the only imaging modality that can identify the focal lesions. In this report, however, we present a case of a 7-month-old girl with the focal form of CHI, caused by a loss-of-function mutation in the ABCC8 gene, whose lesion was clearly visible as a hyperenhancing nodule on contrast-enhanced CT and dynamic MRI imaging.

Field instruction, a crucial component of social work education, is recognized as an educational process to facilitate integrative and experiential learning. The effectiveness of social workers in India lies in its fieldwork education system and field action project. This article starts with the objectives and the concepts of minimum and quality standards for social work education with reference to the criteria of assessment in National Assessment and Accreditation Council and University Grants Commission. The author will then examine the factors that contribute to the encouragement of students to learn social work skills to meet the standards. The analysis appears to indicate Field Action Project and supervision are the most effective factors (with correlation coefficient p value

Silica (SiO2)-coated ceria (CeO2) nanoparticles were prepared using water-in-oil microemulsion. Polyoxyethylene (15) cetylether and cyclohexane were used as a surfactant and organic solvent. SiO2-coated CeO2 nanoparticles were obtained by hydrolysis of metal alkoxide (tetraethylorthosilicate, TEOS) in the solution containing CeO2 precursor nanoparticles. The effects of CeO2 sources (Ce metal salt) and CeO2 particle-forming agents on the morphology of SiO2–CeO2 particles were investigated. Observation via transmission electron microscopy revealed that the type of particle-forming agent affected the nanoparticles' morphology and that CeO2 nanoparticles were spherically coated with SiO2 when using oxalic acid ((COOH)2) as a particle-forming agent of CeO2. Furthermore, the transmittance of the particles was high in the visible region (above 400 nm) and decreased in the ultraviolet region.

The POU transcription factor Pit-1 functions in the development of somatotrophs, lactotrophs, and thyrotrophs of the anterior pituitary gland. It also plays a role in cell-specific gene expression and regulation of the gene products from these cell types, GH, prolactin, and TSH, respectively. In the present report we studied a patient with severe growth failure. Provocative studies revealed undetectable GH, prolactin, and TSH levels, and her pituitary gland was hypoplastic on magnetic resonance imaging. She had a novel homozygous nonsense mutation in the 3′ end of the first α-helix of the POU-specific domain of the Pit-1 gene. This mutation results in a truncated protein with loss of most of the Pit-1 DNA-binding domains. Interestingly, her parents, who each have one mutant allele, have evidence of mild endocrine dysfunction. Thus, two normal copies of the Pit-1 gene appear necessary for full Pit-1 gene function.

Skin sulfhydryl oxidase (SOx) is an enzyme that catalyzes disulfide (S–S) cross-linking through the oxidation of sulfhydryl compounds in the skin. In this study, using the enzyme purified from rat seminal vesicle, we obtained peptide sequences for SOx by mass spectrometry. We then searched for SOx nucleotides corresponding highly to the rat peptide sequences by assembling murine-expressed sequence tags (ESTs) from the GeneBank database. The assembled mouse SOx cDNA has an open reading frame of 1704-bp nucleotides, translating into a size of 568 amino acids. The calculated molecular mass of the mouse SOx protein is 65 kDa. This mouse sequence can be amplified from total RNAs of various mouse tissue samples by reverse transcription polymerase chain reaction, especially highly amplified from those of the seminal vesicles and epidermis. The cDNA fragment was subsequently cloned into the mammalian expression vector (pTARGET-MSSOx), allowing us to express mouse recombinant SOx protein in cultured cells. When pTARGET-MSSOx was transfected, Western blot analysis using anti-SOx antiserum could detect a 65 kDa-band of recombinant SOx in both samples from the whole cell extract and the medium after the harvest of the HEK cells. In immunohistochemical analysis, the Pt-K2 cells, following the introduction of pTARGET-MSSOx, seemed to generate a SOx protein reactive to anti-SOx antiserum in the cells. Moreover, the indirect staining of the S–S bonds using N -(7-dimethylamino-4-methyl coumarinyl) maleimide (DACM), following the addition of N -ethylmaleimide and dithiothreitol, showed that the formation of S–S bridges almost matched the localization of SOx expression in the Pt-K2 cells after the transfection. In essence, we cloned skin SOx cDNA and characterized it as one of the S–S cross-linking enzymes. The SOx clone from mouse epidermis seems to be useful for investigating the potential function of the enzyme in the epidermis, especially for understanding the physiological role of SOx in the differentiation of keratinocytes.

Hypospadias has multifactorial causes and occurs at a high frequency among very low-birthweight infants. Placental insufficiency is hypothesized to be one cause of hypospadias; that is, decreased human chorionic gonadotropin (hCG) secretion caused by placental insufficiency is suspected to result in abnormal male external genitalia, but there is little direct evidence to support this. The aim of this study was therefore to identify the features of hypospadias and to clarify the male genital abnormalities caused by fetal growth restriction (FGR).We reviewed the clinical data of boys who underwent hypospadias repair between 2005 and 2011 at Kyoto University Hospital.Twenty boys were included in this study. Fifteen (75%) of the subjects were preterm or low-birthweight infants. Thirteen (65%) had FGR, 60% of whom had severe hypospadias regardless of gestational age. In addition, 92% of the FGR infants also had other genital anomalies, such as cryptorchidism, bifid scrotum, or micropenis. In contrast, only 14% and 43% of the non-FGR infants had severe hypospadias or genital anomalies other than hypospadias, respectively. Placental histopathology was available in eight FGR infants, in seven of whom it was suggestive of blood flow deficiency such as infarction and single umbilical artery.Infants with FGR have a high incidence of hypospadias. FGR caused by placental dysfunction, but not low birthweight, is a risk factor for severe hypospadias associated with multiple genital anomalies.

Peripheral myelin protein 22 (PMP22) resides in the plasma membrane and is required for myelin formation in the peripheral nervous system. Many PMP22 mutants accumulate in excess in the endoplasmic reticulum (ER) and lead to the inherited neuropathies of Charcot-Marie-Tooth (CMT) disease. However, the mechanism through which PMP22 mutants accumulate in the ER is unknown. Here, we studied the quality control mechanisms for the PMP22 mutants L16P and G150D, which were originally identified in mice and patients with CMT. We found that the ER-localised ubiquitin ligase Hrd1/SYVN1 mediates ER-associated degradation (ERAD) of PMP22(L16P) and PMP22(G150D), and another ubiquitin ligase, gp78/AMFR, mediates ERAD of PMP22(G150D) as well. We also found that PMP22(L16P), but not PMP22(G150D), is partly released from the ER by loss of Rer1, which is a Golgi-localised sorting receptor for ER retrieval. Rer1 interacts with the wild-type and mutant forms of PMP22. Interestingly, release of PMP22(L16P) from the ER was more prominent with simultaneous knockdown of Rer1 and the ER-localised chaperone calnexin than with the knockdown of each gene. These results suggest that CMT disease-related PMP22(L16P) is trapped in the ER by calnexin-dependent ER retention and Rer1-mediated early Golgi retrieval systems and partly degraded by the Hrd1-mediated ERAD system.

The most common form of transient neonatal diabetes mellitus (TNDM) is 6q24-related TNDM. Patients are treated with insulin during the neonatal period until spontaneous remission. However, diabetes often recurs in adolescence, and there is no standard therapy for patients with a relapse. A paternal duplication at the 6q24 critical region spanning the pleiomorphic adenoma gene-like 1 PLAGL1 gene was found in a Japanese patient with TNDM relapse. The patient was treated with a dipeptidyl peptidase-4 (DPP4) inhibitor, alogliptin, at a dose of 25 mg per day. Immediately after treatment initiation, his hemoglobin A1c (HbA1c) levels dropped from 7.0-7.5% (52-58 mmol/mol) to 6.0-6.5% (41-47 mmol/mol) and remained stable for over a year. We reported the successful treatment of relapsed 6q24-related TNDM with a DPP4 inhibitor. Although insulin has been the conventional treatment for such patients, treatments targeting the GLP1 pathway can be a useful alternative because these patients retain the β cell mass and responsiveness through G protein-coupled pathways.

A 100-year-old man visited our hospital with a complaint of penile tumor formation with bleeding and pain. The tumor was 5cm in long diameter with an irregular surface, and extended from the glans via the coronal sulcus to the dorsal surface of the preputium. The clinical diagnosis was stage I penile cancer, and partial penectomy was performed. The pathological diagnosis was well-differentiated squamous cell carcinoma (pT1bcN0M0). To our knowledge, including foreign references, this is the oldest penile cancer patient in the literature. On discussing the operative course in very elderly patients, appropriate preoperative examination for circulatory and respiratory risks and evaluation of cognitive ability are considered essential. Although it is not difficult to conclude that only this operative procedure reveals enough radicality, we believe that it was the appropriate selection for relief of the patient's pain with full consideration of the invasiveness and risks.

The molecular mechanisms of neuronal morphology and synaptic vesicle transport have been largely elusive, and only a few of the molecules involved in these processes have been identified. Here, we developed a novel morphology-based gene trap method, which is theoretically applicable to all cell lines, to easily and rapidly identify the responsible genes. Using this method, we selected several gene-trapped clones of rat pheochromocytoma PC12 cells, which displayed abnormal morphology and distribution of synaptic vesicle-like microvesicles (SLMVs). We identified several genes responsible for the phenotypes and analyzed three genes in more detail. The first gene was BTB/POZ domain-containing protein 9 (Btbd9), which is associated with restless legs syndrome. The second gene was cytokine receptor-like factor 3 (Crlf3), whose involvement in the nervous system remains unknown. The third gene was single-stranded DNA-binding protein 3 (Ssbp3), a gene known to regulate head morphogenesis. These results suggest that Btbd9, Crlf3, and Ssbp3 regulate neuronal morphology and the biogenesis/transport of synaptic vesicles. Because our novel morphology-based gene trap method is generally applicable, this method is promising for uncovering novel genes involved in the function of interest in any cell lines.—Hashimoto, Y., Muramatsu, K., Kunii, M., Yoshimura, S., Yamada, M., Sato, T., Ishida, Y., Harada, R., Harada, A. Uncovering genes required for neuronal morphology by morphology-based gene trap screening with a revertible retrovirus vector.

A 25-year-old Japanese woman presented with contracture of the fingers and toes, and difficulty in opening her mouth. Her grandparents are first cousins, but none of the other members of the family are affected. Bulla formation started at birth on areas of the skin that received pressure, and in infancy and early childhood the lesions were limited only to the acral areas. She also had bilateral, incomplete syndactylies involving all web spaces ( Fig. 1a). The formation of blisters ceased after the age of 15 years, but a generalized progressive poikiloderma then appeared with accompanying cutaneous atrophy of the skin of the neck, trunk, and extremities ( Fig. 1b). The patient experienced mild photosensitivity of the face and neck. At age 18 years, surgical removal of the webbing of all her fingers was performed. Oral examination showed atrophy of the buccal mucosa, and an inability to fully open the mouth. The patient also suffered from poor dentition and easily bleeding gums, but had no symptoms of esophageal dysfunction. Figure 1. Clinical manifestations of the patient with Kindler syndrome. (a) Dorsal surface of the patient's hands. Note the marked cutaneous atrophy with a severely wrinkled appearance on the dorsal surface of the hands, as well as the proximal fusion of the fingers. (b) Lower left leg of the patient. Atrophic thinning of the skin and poikiloderma with reticular pigmentation are evident Histology of separate biopsy specimens, taken from the poikilodermatous pretibial and trunk skin, showed classical features of poikiloderma, namely epidermal atrophy with flattening of the rete ridges, vacuolization of basal keratinocytes, pigmentary incontinence, and mild dermal perivascularization ( Fig. 2a). Interestingly, dyskeratotic cells ( Fig. 2b) and eosinophilic rounded bodies (colloid bodies) ( Fig. 2c) were frequently found at the basal keratinocyte layer and in the upper dermis, respectively. Pigment was also present in the upper epidermis. Figure 2. Hematoxylin and eosin staining of a biopsy specimen taken from pretibial skin. (a) Epidermal atrophy with flattening of the rete ridges. Note the dyskeratotic cells (arrowheads) and vacuolar degeneration of the basal layer in the epidermis. Bar = 50 μm. (b) Higher magnification of dyskeratotic cells (arrowheads). Bar = 10 μm. (c) Higher magnification of colloid bodies (arrowheads) in the superficial dermis. Bar = 10 μm To rule out the possibility of a congenital epidermolysis bullosa, ultrastructural and immunofluorescence studies were performed. Ultrastructural studies demonstrated the reduplication of the basal lamina with branching structures within the upper dermis and cleavage between the lamina densa and the cell membrane of the keratinocytes ( Fig. 3a). The numbers of associated anchoring fibrils did not seem to be reduced, and colloid bodies and dyskeratotic cells were detected. Immunofluorescence studies with the antibody against type VII collagen (LH 7 : 2) were subsequently carried out. The results showed extensive broad bands with intermittently discontinuous and reticular staining at the dermo-epidermal junction (DEJ) ( Fig. 3b), whereas a linear distribution is typically seen in healthy tissue (data not shown). Interestingly, direct immunofluorescence studies revealed intracellular accumulation of immunoglobulin G (IgG), IgM, IgA, and C3 in colloid bodies under the basement membrane ( Fig. 3c). Figure 3. Ultrastructural and immunohistochemical findings of the patient with Kindler syndrome. (a) Ultrastructural study of the dermo-epidermal junction. The branching structures of the lamina densa (arrowheads) were frequently seen. The asterisks show the cleavage in the lamina lucida. Bar = 1 μm. (b) Immunohistochemical studies with the antibody to type VII collagen (LH 7 : 2). An extensive broad band with reticular patterns is evident. Bar = 50 μm. E, epidermis; D, dermis. (c) Direct immunofluorescence study. Intracytoplasmic deposition of IgM in the basal keratinocytes is evident (arrowheads). Bar = 50 μm. E, epidermis; D, dermis

We report the case of a 73-year-old Japanese woman suffering from antiepiligrin (laminin 5) cicatricial pemphigoid (CP) with typical clinical and immunopathological features. Histologically, the lesional mucous membrane showed a subepidermal blister formation. When indirect immunofluorescence techniques with skin split by 1 M NaCl as the substrate were used, the patient’s serum reacted only to the dermal side. Immunoprecipitation studies demonstrated that the patient’s serum contained IgG autoantibodies directed against a set of polypeptides that corresponded to epiligrin (laminin 5). After corticosteroids and immunosuppressive agents had been administered systemically, the patient’s autoantibody titer decreased and the cutaneous and mucosal blister formations were suppressed. However, the ocular lesions persisted in spite of these therapeutic regimens. After combining these treatments with double-filtration plasmapheresis, the ocular lesions improved and showed almost no progression. Plasmapheresis may thus present a new option for the treatment of CP.

To investigate the neuronal function of genes in vivo, a neuron-specific and inducible gene targeting system is desirable. In this study, we generated a knockin mouse line that expresses a fusion protein consisting of the Cre recombinase and the progesterone receptor (CrePR) in neurons. The neuron-specific expression of CrePR was attained by inserting CrePR gene into the tau locus, because tau is expressed strongly in neurons but scarcely in glias and other tissues. By crossing this knockin mouse line (tau(CrePR)) with ROSA26 lacZ reporter mouse line (R26R), we observed that the antiprogesterone RU486 could induce recombinase activity of the CrePR specifically in neurons. Thus, tau (CrePR) knockin line is a useful tool for studying neuronal gene functions.