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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

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 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.

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.

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.

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.

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 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.

We present two Japanese cases of involutional lipoatrophy. The first case is that of a 30-year-old woman, who first appeared at our hospital complaining of a localized, well-demarcated depression, approximately 3 × 4 cm in size, normal to slightly erythematous in coloration, on the lateral side of the left upper arm (Fig. 1a). The condition was asymptomatic, and she had noticed this anomaly a month prior to consultation. She received intramuscular injections of corticosteroids of unknown dosage at the affected site for the treatment of allergic rhinitis 4 months prior to her present consultation. Figure 1. Clinical, histological and immunohistological findings in two cases of localized involutional lipoatrophy. Loss of subcutaneous tissue in the left upper arm is seen both in the first (a) and second (b) cases. Arrowheads indicate the depressed region. (c) The involved regions showed a decrease in the size of individual lipocytes in the first case (bar = 10 µm). (d) Immunoperoxidase staining for CD68 in the first case. Scattered macrophages (arrowheads) were identified within the affected adipose tissue and surrounding connective tissue (bar = 10 µm) Download figure to PowerPoint The second patient, a 23-year-old woman, appeared at our hospital complaining of a similar macule 4 × 4 cm in size, which she noticed several weeks prior to her most recent consultation. She had no history of injury or injection at the site before the development of the condition (Fig. 1b). She had been under treatment for atopic dermatitis since early childhood and was treated only with topical applications of white petrolatum containing 2% salicylic acid for the past several years. In order to rule out the possibility of acquired partial lipodystrophy associated with localized scleroderma, lupus profundus and the other connective tissue diseases, a histological examination was performed for both patients. Histopathological analysis of the region exhibited a well-defined fat lobule composed of numerous small adipocytes (Fig. 1c) embedded in hyaline connective tissue. Edema and dilated capillaries were noticeable in the subcutaneous tissue surrounding the area. Inflammatory cells were not prominent, although mononuclear cells were observed in both patients. No epidermal change was seen in either patient. Direct and indirect immunofluorescence studies revealed no deposits of immunoreactants in the skin of either patient. Immunohistochemical studies with the antibody against macrophage (anti-CD68 antigen; DAKO.) showed that positive cells were scattered around blood vessels and shrunken lipocytes in the subcutaneous tissues (Fig. 1d). Most of these cells in the fat lobules were also positive for mucin stains such as Alcian blue. No abnormal findings came to light in the ordinary hematological and blood chemistry examinations of both patients. The autoantibody screening tests using antinuclear, anti-DNA, anticentromere, and anti-Scl-70 antibodies were negative in both patients.

We report a case of ichthyosis linearis circumflexa (ILC) without the typical atopic manifestations and deformities of the hair shaft. The patient responded positively to treatment with topical tacrolimus, suggesting that abnormalities in the immunoregulatory mechanism may be involved in the pathogenesis of ILC.