Evaluation of balloon pulmonary angioplasty using lung perfusion SPECT in patients with chronic thromboembolic pulmonary hypertension.

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 < 0.001) and 6MWD (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 < 0.001). CONCLUSIONS: This study demonstrated that the lung perfusion SPECT could be a potential measurement of the effectiveness of BPA in patients with CTEPH.

Prognostic values of coronary artery calcium score and 123I-BMIPP SPECT in patients with non-ischemic heart failure with preserved ejection fraction.

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). 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. Thirty-two MACEs developed at a mean follow-up period of 2.4 years. CACS > 0 (hazard ratio [HR] 2.38, 95% confidence interval [CI] 1.02-5.54) and higher BDS (HR 16.00, 95% CI 5.88-43.49) were significantly associated with the development of MACEs. The proportion of patients who experienced MACEs was significantly higher in the CACS > 0 and high BDS group than in the CACS = 0 and low BDS group (3% vs. 75%, p < 0.001). CACS, as well as BDS, could serve as potential prognostic indicators in patients with NIHFpEF.

Prognostic value of 99mTc-ECD brain perfusion SPECT in patients with atrial fibrillation and dementia.

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.

Prognostic values of 123I-MIBG myocardial scintigraphy and heart rate variability in patients with heart failure with preserved ejection fraction.

BACKGROUND: The aim of this study was to evaluate the prognostic values of sympathetic nerve system using 123I-MIBG myocardial scintigraphy and using Holter electrocardiogram (ECG) in patients with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: Among 403 consecutive patients with stable HF who underwent 123I-MIBG myocardial scintigraphy and Holter ECG, we identified 133 patients (64 ± 16 years) who had preserved ejection fraction (≥ 50%) by echocardiography. Multivariate Cox model was used to assess if washout rate (WR) by 123I-MIBG scintigraphy and very low frequency power (VLFP) by Holter ECG was associated with major adverse cardiovascular events (MACE). During a mean follow-up of 5.4 ± 4.1 years, 39 MACE occurred. The lower nighttime VLFP (HR 3.29, 95% CI 1.56 to 6.92) and higher WR (HR 4.01, 95% CI 1.63 to 9.88) were the significant prognostic factors for MACE. As compared to high nighttime VLFP and low WR group, MACE risk was significantly the highest in the low nighttime VLFP and high WR group (HR 40.832; 95% CI 5.378 to 310.012, P < 0.001). CONCLUSION: This study demonstrated that the nighttime VLFP adding to WR could be a potential prognostic value among patients with HFpEF.

Prognostic Value of 123I-BMIPP SPECT in Patients with Nonischemic Heart Failure with Preserved Ejection Fraction.

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 (<4, n = 87). Results: During a mean follow-up of 2.5 y, 35 major adverse cardiac events occurred. The median scores in the high-score and low-score groups were 7.13 ± 4.21 and 1.29 ± 0.80, respectively. By multivariate Cox analysis, a higher score was associated with increased major adverse cardiac events, compared with a lower score (hazard ratio, 11.04; 95% confidence interval, 4.93-24.74; P < 0.001). Conclusion: This study demonstrated that the defect score by 123I-BMIPP SPECT may have potential prognostic value in patients who have nonischemic heart failure with preserved ejection fraction.

Diagnosis of congenital hyperinsulinism: Biochemical profiles during hypoglycemia.

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, ß-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 (<.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 insulin >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.

Molecular and clinical features of KATP -channel neonatal diabetes mellitus in Japan.

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.

Fetal growth restriction but not preterm birth is a risk factor for severe hypospadias.

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.

Focal form of congenital hyperinsulinism clearly detectable by contrast-enhanced computed tomography imaging.

The focal form of congenital hyperinsulinism (CHI) is characterized by a cluster of abnormal insulin-oversecreting ß 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 ((18)F-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.

Two patients with HNF4A-related congenital hyperinsulinism and renal tubular dysfunction: A clinical variation which includes transient hepatic dysfunction.

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.

Fluvoxamine by itself has potential to directly induce long QT syndrome at supra-therapeutic concentrations.

Fluvoxamine is one of the typical selective serotonin-reuptake inhibitors. While its combined use with QT-prolonging drugs has been contraindicated because of the increase in plasma concentrations of such drugs, information is still limited whether fluvoxamine by itself may directly prolong the QT interval. We examined electropharmacological effects of fluvoxamine together with its pharmacokinetic profile by using the halothane-anesthetized dogs (n = 4). Fluvoxamine was intravenously administered in three escalating doses of 0.1, 1 and 10 mg/kg over 10 min with a pause of 20 min between the doses. The low dose provided therapeutic plasma drug concentration, whereas the middle and high doses attained approximately 10 and 100 times of the therapeutic ones, respectively. Supra-therapeutic concentration of fluvoxamine exerted the negative chronotropic, inotropic and hypotensive effects; and suppressed the atrioventricular nodal and intraventricular conductions, indicating inhibitory actions on Ca2+ and Na+ channels, whereas it delayed the repolarization in a reverse use-dependent manner, reflecting characteristics of rapidly activating delayed rectifier K+ current channel-blocking property. Fluvoxamine prolonged the terminal repolarization phase at 100 times higher concentration than the therapeutic, indicating its proarrhythmic potential. Thus, fluvoxamine by itself has potential to directly induce long QT syndrome at supra-therapeutic concentrations.

Rer1 and calnexin regulate endoplasmic reticulum retention of a peripheral myelin protein 22 mutant that causes type 1A Charcot-Marie-Tooth disease.

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.

Relapsing 6q24-related transient neonatal diabetes mellitus successfully treated with a dipeptidyl peptidase-4 inhibitor: a case report.

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 ß cell mass and responsiveness through G protein-coupled pathways.

[Partial penectomy for penile cancer in a centenarian man].

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.

Cerebrospinal fluid levels of phosphorylated tau and Aß1-38/Aß1-40/Aß1-42 in Alzheimer's disease with PS1 mutations.

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 Aß (Aß1-42, Aß1-40 and Aß1-38) 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 Aß1-42 in the three AD groups were significantly lower than those of the ND group (p < 0.0001). CSF levels of Aß1-42 in the PS1AD group were significantly lower than those in the two sporadic AD groups. The Aß1-40 and Aß1-38 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 Aß1-40, Aß1-38 and Aß1-42 in the CSF of the PS1AD group remained lower than those of the ND group for 4 years. Not only CSF Aß1-42, but also Aß1-40 and Aß1-38 decreased in the advanced stages of PS1AD.

Uncovering genes required for neuronal morphology by morphology-based gene trap screening with a revertible retrovirus vector.

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.

Neuron-specific recombination by Cre recombinase inserted into the murine tau locus.

To determine the neuronal function of genes in vivo, the neuron-specific deletion of a target gene in animals is required. Tau, a microtubule-associated protein, is expressed abundantly in neurons but scarcely in glias and other tissues. Therefore, to generate mice that express Cre recombinase in neurons, we inserted Cre recombinase into the tau locus. By crossing these tau-Cre mice with ROSA26 lacZ reporter mice, we observed Cre recombinase activity in the neurons from most of the central nervous system, but not in glias nor in non-neuronal tissues. This neuronal-specific activity appeared during embryogenesis. We further crossed tau-Cre mice with rab8 'floxed' mice, and showed that the recombination was nearly complete in the brain, but incomplete or non-detectable in other tissues. Thus, tau-Cre knockin mouse is a useful tool for studying the neuronal function of a gene in vivo.

Neuron-specific and inducible recombination by Cre recombinase in the mouse.

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.